WO2022235779A1

WO2022235779A1 - Methods of administering terevalefim

Info

Publication number: WO2022235779A1
Application number: PCT/US2022/027646
Authority: WO
Inventors: Shakil ASLAM
Original assignee: Angion Biomedica Corp.
Priority date: 2021-05-05
Filing date: 2022-05-04
Publication date: 2022-11-10

Abstract

Provided herein are technologies for administering terevalefim to subjects in need thereof.

Description

METHODS OF ADMINISTERING TEREVALEFIM RELATED APPLICATIONS [0001] This application claims the benefit of and priority to U.S. Application No. 63/184,586, filed May 5, 2021, the entire contents of which are hereby incorporated by reference. BACKGROUND [0002] Scatter factor (SF; also known as hepatocyte growth factor (HGF), and hereinafter referred to and abbreviated as HGF/SF) is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis and angiogenesis. When an organ is injured, the body releases HGF into the blood. HGF then travels to the site of the injury and binds to the promoter region of the c-Met receptor gene on cells in that location. HGF is the only ligand known to bind to c-Met and cause its activation. The binding of HGF to c-Met triggers a series of downstream proteins responsible for preventing apoptosis (cell death), stimulating cell proliferation, promoting angiogenesis (formation of new blood vessels), improving cellular motility, and remodeling the extracellular matrix, all in order to restore normal structure and function to the injured organ. HGF/SF has a short half-life of 3-5 min (Chang, H.-K., et al., Mol Ther.2016 Sep; 24(9): 1644– 1654). SUMMARY [0003] The present disclosure provides certain technologies and/or improvements for administering terevalefim (i.e., Compound 1). In some embodiments, the present disclosure provides insight that certain modes of administering terevalefim may provide advantages, e.g., to certain patient populations. [0004] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects receiving maintenance hemodialysis. In some embodiments, the subject is experiencing or has been diagnosed with renal failure. In some embodiments, the subject is experiencing or has been diagnosed with end-stage renal disease. In some embodiments, the subject has been on maintenance hemodialysis for at least 3 months. In some embodiments, the subject is receiving hemodialysis at least three times per week. In some embodiments, the subject has been determined to have one or more laboratory parameters selected from serum albumin ≥ 3.0 gm/dL, blood hemoglobin ≥ 10.0 gm/dL, and liver transaminases (ALT, AST) < 2x the upper limit of normal. In some embodiments, the subject has been determined to have a single pool urea (Kt/V) ≥ 1.3 for two consecutive months prior to administration of Compound 1. In some embodiments, a dose of Compound 1 is administered on an on-dialysis day, an off- dialysis day, or without regard for whether or not the subject is receiving hemodialysis that day. [0005] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are or have been simultaneously exposed to a cytochrome P450 inhibitor. In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are receiving or have received a cytochrome P450 inhibitor. In some embodiments, the cytochrome P450 inhibitor is a CYP1A2 inhibitor. In some embodiments, the CYP1A2 inhibitor is selected from ciprofloxacin, enoxacin, and fluvoxamine. In some embodiments, the CYP1A2 inhibitor is ciprofloxacin. In some embodiments, ciprofloxacin is or was administered in a dose of about 500 mg BID. In some embodiments, the CYP1A2 inhibitor is fluvoxamine. [0006] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are not at risk for torsades de pointes and/or that do not display certain risk factors (e.g., certain cardiac risk factors, etc.) described herein. In some embodiments, a method further comprises monitoring a subject for risk factors over time, and optionally, if risk factors develop, discontinuing administration of Compound 1. In some embodiments, a method further comprises monitoring the subject for risk factors over time, and optionally, if risk factors develop, reducing the dose of Compound 1. [0007] In some embodiments, the present disclosure provides alternative dosing schedules for administration of Compound 1. In some embodiments, the present disclosure encompasses the recognition that increased dose and/or dosing frequency may provide increased therapeutic effect(s) without increasing safety risks. In some embodiments, Compound 1 is administered in a dose of 2 mg/kg, 4 mg/kg, or 6 mg/kg once or twice daily. [0008] In some embodiments, the present disclosure encompasses the recognition that administration of a flat dose of Compound 1 may provide certain advantages over weight-based dosing, e.g., ease and convenience of administration, etc. In some embodiments, the present disclosure provides methods of administering Compound 1 without using a weight-based dose. For example, in some embodiments, the present disclosure provides methods of administering Compound 1 in a dose of 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg once or twice daily. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG.1 shows the disposition of subjects in the human clinical trial of Example 6. [0010] FIG.2 shows Kaplan-Meier curves for time to production of ≥1200 cc urine over 24 h by study arm. [0011] FIG.3 shows mean total daily urine output (in cc) from post-transplant Day 1 to Day 14 by study arm. [0012] FIG.4 shows least squares mean change from baseline (Day 1) in total daily urine output (in cc) from post-transplant Day 2 to Day 14 by study arm. [0013] FIG.5 shows least squares mean serum creatinine (mg/dL) by study arm at screening, Day 3, Day 7, Day 14, Day 28, Month 6, and Month 12. [0014] FIG.6 shows mean 24-hour urine creatinine clearance (mL/min/1.73 m²) over time by study arm. [0015] FIG.7 shows serum c-reactive protein (CRP) (mg/dL) by study arm at Day 1 and Day 3 post-transplant. [0016] FIG.8 shows mean neutrophil gelatinase-associated lipocalin (NGAL) (ng/mL) by study arm at Day 1 and Day 3 post-transplant. [0017] FIG.9 shows the time to first dialysis session in the first 7 days post-transplant by study arm. [0018] FIG.10 shows the cumulative number of dialysis sessions through Day 28 by treatment group. [0019] FIG.11 shows the length of transplant hospitalization (in days) per subject by treatment arm. [0020] FIG.12 shows least squares mean estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²) by study arm at screening, Day 3, Day 7, Day 14, Day 28, Month 6 and Month 12. [0021] FIG.13 shows the duration of dialysis through Day 28 by treatment arm. [0022] FIG.14 shows incidence of graft failure over time by study arm. [0023] FIG.15 shows mean eGFR (mL/min/1.73 m²) by study arm at screening, Day 3, Day 7, Day 14, Day 28, Month 6 and Month 12, overlaid with the National Kidney Foundation’s predictive CKD stages. [0024] FIG.16 shows the lowest two quintiles (solid lines) of patients with worst urine output within 24 hours after a kidney transplantation have a significantly decreased chance of their new kidney surviving for five years compared to the highest quintile (dashed line) (Schnuelle, P. et al. Nephrol. Dial. Transplant (2007) 22:235-45). [0025] FIG.17 shows patients with the highest eGFR (small dotted line) at discharge after a kidney transplantation have better cumulative kidney transplant survival as compared with patients with lower eGFR at discharge (large dotted and solid lines) (based on data reported in Schnuelle, P. et al. Nephrol. Dial. Transplant (2007) 22:235-45). [0026] FIG.18 provides XRPD pattern of Compound 1 Form A calculated from single crystal X-ray diffraction data. [0027] FIG.19 provides XRPD pattern of Compound 1 Form A. [0028] FIG.20 provides TGA curve of Compound 1 Form A. [0029] FIG.21 provides DSC thermogram of Compound 1 Form A. [0030] FIG.22 provides XRPD pattern of Compound 1 Lot I. [0031] FIG.23 provides TGA curve of Compound 1 Lot I. [0032] FIG.24 provides DSC thermogram of Compound 1 Lot I. [0033] FIG.25 provides single crystal X-ray crystallography of Compound 1 Form A. N and S atoms are labeled; unlabeled non-hydrogen atoms are carbon. [0034] FIG.26 provides a comparison of XRPD patterns of Compound 1 Lot I and Compound 1 Single Crystal Form A. [0035] FIG.27 is a graph showing mean AUC of the percent increase in sCr above baseline from Day 2 to Day 6 (starting from 24 hours after the end of CPB). [0036] FIG.28 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (using last observation carried forward). [0037] FIG.29 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (using last observation carried forward). [0038] FIG.30 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (with missing values imputed as MAKE30 response). [0039] FIG.31 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (with missing values imputed as MAKE90 response). [0040] FIG.32 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (with no imputation). [0041] FIG.33 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (with no imputation). [0042] FIG.34 is a graph showing proportion of subjects developing MAKE30, and the proportion that experienced death or worsening of kidney function. [0043] FIG.35 is a graph showing proportion of subjects developing MAKE90, and the proportion that experienced worsening of kidney function. [0044] FIG.36 is a graph showing mean eGFR at Day 30 (using MMRM analysis). [0045] FIG.37 is a graph showing proportion of subjects diagnosed with AKI (per KDIGO criteria) through Day 5. [0046] FIG.38 is a graph showing mean length of hospitalization. [0047] FIG.39 is a graph showing maximum percent increase in sCr from baseline to Day 6. [0048] FIG.40 is a graph showing mean serum creatinine over time. [0049] FIG.41 is a graph showing proportion of subjects with AKI (per serum creatinine based KDIGO criteria) through Day 7. [0050] FIG.42 is a graph showing time to recovery from AKI (defined as return of serum creatinine to baseline or below) in subjects diagnosed before Day 5. [0051] FIG.43 is a graph showing time to recovery from AKI (defined as return of serum creatinine to baseline or below) in subjects diagnosed before Day 7. [0052] FIG.44 is a graph showing proportion of subjects with ≥ 20% reduction from baseline in eGFR over time. Data for Compound 1 (i.e., terevalefim) is shown on the left and data for placebo is shown on the right for each time point. [0053] FIG.45 is a graph showing proportion of subjects with ≥ 25% reduction from baseline in eGFR over time. Data for Compound 1 (i.e., terevalefim) is shown on the left and data for placebo is shown on the right for each time point. [0054] FIG.46 is a graph showing mean maximum percent change from baseline in eGFR and sCr through Day 90. DETAILED DESCRIPTION Definitions [0055] The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value. [0056] As used herein, the term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and/or a site of responsive processes, cells, tissues, etc.) As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. As described herein, in many embodiments, administration is parenteral, e.g., via intravenous (IV) administration, which in some embodiments may be or comprise IV perfusion); in some embodiments, one or more instances of perfusion may be performed. In some embodiments, amount perfused and/or rate of perfusion may be selected, for example, in light of a characteristic such as subject weight, age, presence and/or extent of one or more relevant symptom(s), timing relative to transplant procedure, etc. [0057] As used herein, the term “combination therapy” refers to a clinical intervention in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g. two or more therapeutic agents). In some embodiments, the two or more therapeutic regimens may be administered simultaneously. In some embodiments, the two or more therapeutic regimens may be administered sequentially (e.g., a first regimen administered prior to administration of any doses of a second regimen). In some embodiments, the two or more therapeutic regimens are administered in overlapping dosing regimens. In some embodiments, administration of combination therapy may involve administration of one or more therapeutic agents or modalities to a subject receiving the other agent(s) or modality. In some embodiments, combination therapy does not necessarily require that individual agents be administered together in a single composition (or even necessarily at the same time). In some embodiments, two or more therapeutic agents or modalities of a combination therapy are administered to a subject separately, e.g., in separate compositions, via separate administration routes (e.g., one agent orally and another agent intravenously), and/or at different time points. In some embodiments, two or more therapeutic agents may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity), via the same administration route, and/or at the same time. [0058] As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, circumstances, individuals, or populations, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, comparable agents, entities, situations, sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features. Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, circumstances, individuals, or populations, etc. to be considered comparable. For example, those of ordinary skill in the art will appreciate that sets of circumstances, agents, entities, situations, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different agents, entities, situations, sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied. [0059] As used herein, the term “pharmaceutical composition” refers to a composition comprising a pharmaceutical active (which may be, comprise, or otherwise become an active agent upon administration of the composition), formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, a pharmaceutical composition is or comprises a pharmaceutical active present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces. In some embodiments, as described herein, a pharmaceutical composition is formulated for parenteral administration (e.g., for IV administration such as by infusion). [0060] The term “pharmaceutically acceptable salt form,” as used herein, refers to a form of a relevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and/or lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). [0061] As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, individual, population, sample, sequence or value of interest is compared with a reference or control agent, individual, population, sample, sequence or value. In some embodiments, a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control. [0062] As will be understood from context, “risk” of a disease, disorder, and/or condition refers to a likelihood that a particular individual will develop the disease, disorder, and/or condition. In some embodiments, risk is expressed as a percentage. In some embodiments, risk is from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 up to 100%. In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples. In some embodiments, a reference sample or group of reference samples have a known risk of a disease, disorder, condition and/or event. In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual. In some embodiments, relative risk is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. [0063] As used herein, the term “subject” refers to an organism, typically a mammal (e.g., a human). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is at risk of (e.g., susceptible to), e.g., at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is an individual to whom diagnosis and/or therapy and/or prophylaxis is and/or has been administered. The terms “subject” and “patient” are used interchangeably herein. [0064] As used herein, the term “treat” (also “treatment” or “treating”) refers to any administration of a therapy that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. Hepatocyte Growth Factor Mimetics [0065] PCT Application No. PCT/US2003/040917, filed December 19, 2003 and published as WO 2004/058721 on July 15, 2004, the entirety of which is hereby incorporated by reference, describes certain compounds that act as HGF/SF mimetics. Such compounds include Compound 1:

or a pharmaceutically acceptable salt thereof (i.e., Compound 1 in a pharmaceutically acceptable salt form). Compound 1 has been demonstrated to be remarkably useful for treatment of a variety of conditions including, for example, fibrotic liver disease, ischemia-reperfusion injury, cerebral infarction, ischemic heart disease, renal disease, lung fibrosis, damaged and/or ischemic organs, transplants or grafts, stroke, cerebrovascular disease, and renal fibrosis, among others (see, for example, WO 2004/058721, WO 2010/005580, US 2011/0230407, US 7879898, and WO 2009/064422, each of which is hereby incorporated by reference in its entirety). Exemplary methods of using Compound 1 for, e.g., administering to patients with delayed graft function after kidney transplantation or with acute lung injury, are described in WO 2021/087392 and WO 2021/183774, each of which is hereby incorporated by reference. In particular, Compound 1 is or has been the subject of clinical trials for delayed graft function in recipients of a deceased donor kidney (Clinicaltrials.gov identifier: NCT02474667), as well as acute kidney injury after cardiac surgery involving cardiopulmonary bypass (Clinicaltrials.gov identifier: NCT02771509), and COVID-19 pneumonia (Clinicaltrials.gov identifier: NCT04459676). Compound 1 has also been demonstrated to mitigate post-ischemic kidney injury (see Narayan, P., et al. Am. J. Physiol. Renal Physiol.311:F352-F361, 2016). Without wishing to be bound by any particular theory, it is believed that the HGF mimetic capability of Compound 1 imparts a variety of beneficial attributes and activities. [0066] Compound 1 is also known by at least the following names: ● Terevalefim; ● 3-[(1E)-2-(thiophen-2-yl)ethen-1-yl]-1H-pyrazole; and ● (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole. [0067] A synthesis of Compound 1, (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole, is described in detail in Example 7 of WO 2004/058721, as well as in Example 11 herein. An alternative synthesis of Compound 1 is provided in Example 12 herein. [0068] Those skilled in the art will appreciate that Compound 1 has a structure that can exist in various tautomeric forms, including (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole and (E)-5-[2-(2- thienyl)vinyl]-1H-pyrazole, or any mixture thereof. Moreover, those skilled in the art, reading the present disclosure, will appreciate that, in many embodiments, teachings described herein are not limited to any particular tautomeric form. Accordingly, in some embodiments, Compound 1 may be referred to as (E)-3(5)-[2-(2-thienyl)vinyl]-1H-pyrazole. The present disclosure contemplates use of all tautomeric forms of Compound 1. [0069] In some embodiments, Compound 1 is provided and/or utilized (e.g., for inclusion in a composition and/or for delivery to a subject) in accordance with the present disclosure in a form such as a salt form. As already noted herein, pharmaceutically acceptable salts are well known in the art. [0070] In some embodiments, Compound 1 is provided and/or utilized (e.g., for inclusion in (e.g., during one or more steps of manufacturing of) a composition and/or for delivery to a subject) in accordance with the present disclosure in a form such as a solid form. Certain solid forms of Compound 1 are described in PCT Application No. PCT/US2020/027710, filed April 10, 2020 and published as WO 2020/210657 on October 15, 2020, the entirety of which is hereby incorporated by reference. In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure in an amorphous solid form, in a crystalline solid form, or in a mixture thereof. In some embodiments, a composition is substantially free of amorphous Compound 1. As used herein, the term “substantially free” means lacking a significant amount (e.g., less than about 10%, less than about 5%, less than about 3%, less than about 2%, or less than about 1%). In some embodiments, a composition comprises at least about 90% by weight of crystalline Compound 1. In some embodiments, a composition comprises at least about 95% by weight of crystalline Compound 1. In some embodiments, a composition comprises at least about 97%, about 98%, or about 99% by weight of crystalline Compound 1. In some embodiments, a crystalline solid form may be or comprise a solvate, hydrate, or an unsolvated form. The use of any and all such forms are contemplated by the present disclosure. [0071] In some embodiments, a crystalline solid form of Compound 1 is Form A. In some embodiments, Form A of Compound 1 is unsolvated (e.g., anhydrous). [0072] In some embodiments, Form A is characterized by one or more peaks in its XRPD pattern selected from those at about 8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees 2-theta. In some embodiments, Form A is characterized by two or more peaks in its XRPD pattern selected from those at about 8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees 2-theta. In some embodiments, Form A is characterized by three or more peaks in its XRPD pattern selected from those at about 8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees 2-theta. [0073] In some embodiments, Form A is characterized by peaks in its XRPD pattern at about 8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees 2-theta. In some embodiments, Form A is characterized by peaks in its XRPD pattern at about 8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees 2-theta, corresponding to d-spacing of about 10.22, about 8.01, about 5.11, about 3.55, and about 3.46 angstroms. [0074] In some embodiments, Form A is characterized by substantially all of the peaks (degrees 2-theta) in its XRPD pattern, optionally corresponding to d-spacing (angstroms), at about:

[0075] In some embodiments, Form A is characterized by one or more of the following: (i) an XRPD pattern substantially similar to that depicted in FIG.18 and/or FIG.19; (ii) a TGA pattern substantially similar to that depicted in FIG.20; (iii) a DSC pattern substantially similar to that depicted in FIG.21; and (iv) a melting point of about 116.42 °C. [0076] As used herein, the term “about” when used in reference to a degree 2-theta value refers to the stated value ± 0.2 degree 2-theta. In some embodiments, “about” refers to the stated value ± 0.1 degree 2-theta. [0077] Unless otherwise indicated, as used herein “Compound 1” refers to (E)-3-[2-(2- thienyl)vinyl]-1H-pyrazole in any available form, such as, e.g., a tautomer, salt form, and/or solid form thereof. [0078] Certain liquid (e.g., for intravenous or intraperitoneal administration) and solid (e.g., for oral administration) formulations of Compound 1 have been described. See, for example, PCT Application No. PCT/US2009/004014, filed July 9, 2009 and published as WO 2010/005580 on January 14, 2010, the entirety of which is hereby incorporated by reference. See also, PCT Application No. PCT/US21/54776, filed October 13, 2021 and published as WO 2022/081703 on April 21, 2022, the entirety of which is hereby incorporated by reference. [0079] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a liquid formulation. In some embodiments, a liquid formulation comprises Compound 1 in a concentration of from about 0.8 mg/mL to about 10 mg/mL. In some embodiments, a liquid formulation comprises from about 6 mg/mL to about 100 mg/mL, from about 6 mg/mL to about 80 mg/mL, from about 6 mg/mL to about 60 mg/mL, from about 6 mg/mL to about 40 mg/mL, from about 6 mg/mL to about 20 mg/mL, from about 10 mg/mL to about 100 mg/mL, from about 10 mg/mL to about 80 mg/mL, from about 10 mg/mL to about 60 mg/mL, from about 10 mg/mL to about 40 mg/mL, or from about 10 mg/mL to about 20 mg/mL Compound 1. In some embodiments, a liquid formulation comprises from about 6 mg/mL to about 10 mg/mL Compound 1. In some embodiments, a liquid formulation comprises about 6 mg/mL Compound 1. In some embodiments, a liquid formulation comprises about 10 mg/mL Compound 1. [0080] In some embodiments, a liquid formulation comprising Compound 1 further comprises polyethylene glycol (e.g., polyethylene glycol 300). In some embodiments, a liquid formulation comprises from about 10% (w/v) to about 90% (w/v), from about 10% (w/v) to about 65% (w/v), from about 20% (w/v) to about 80% (w/v), from about 20% (w/v) to about 60% (w/v), from about 30% (w/v) to about 70% (w/v), or from about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300). In some embodiments, a liquid formulation comprises about 10% (w/v), about 20% (w/v), about 30% (w/v), about 40% (w/v), about 50% (w/v), about 60% (w/v), about 70% (w/v), about 80% (w/v), or about 90% (w/v) polyethylene glycol (e.g., polyethylene glycol 300). In some embodiments, a liquid formulation comprises from about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300). In some embodiments, a liquid formulation comprises about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300). In some embodiments, a liquid formulation comprises about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300). [0081] In some embodiments, a liquid formulation comprising Compound 1 further comprises polysorbate (e.g., polysorbate 80). In some embodiments, a liquid formulation comprises from about 1% (w/v) to about 25% (w/v), from about 2% (w/v) to about 20% (w/v), or from about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80). In some embodiments, a liquid formulation comprises about 1% (w/v), about 2% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 10% (w/v), about 15% (w/v), about 20% (w/v), or about 25% (w/v) polysorbate (e.g., polysorbate 80). In some embodiments, a liquid formulation comprises from about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80). In some embodiments, a liquid formulation comprises about 10% (w/v) polysorbate (e.g., polysorbate 80). In some embodiments, a liquid formulation comprises about 6% (w/v) polysorbate (e.g., polysorbate 80). [0082] In some embodiments, a liquid formulation comprising Compound 1 is aqueous. In some embodiments, a liquid formulation comprises aqueous components, such as aqueous buffer, normal saline, or buffered saline (e.g., phosphate buffered saline). In some embodiments, a liquid formulation comprising Compound 1 further comprises saline solution, buffer, or buffered saline solution (e.g., phosphate-buffered saline). In some embodiments, aqueous buffer is any suitable aqueous buffer. In some embodiments, aqueous buffer is an aqueous phosphate buffer, i.e., an aqueous solution comprising one or more phosphate salts (e.g., monobasic potassium phosphate and/or dibasic sodium phosphate). In some embodiments, aqueous buffer comprises monobasic potassium phosphate and dibasic sodium phosphate in a weight ratio of 1.76:7.26. In some embodiments, aqueous buffer is an aqueous acetate buffer, i.e., an aqueous solution comprising one or more acetate salts. In some embodiments, aqueous buffer is an aqueous citrate buffer, i.e., an aqueous solution comprising one or more citrate salts. In some embodiments, phosphate-buffered saline is an aqueous solution comprising one or more phosphate salts (e.g., monobasic potassium phosphate and/or dibasic sodium phosphate) and one or more chloride salts (e.g., sodium chloride and/or potassium chloride). In some embodiments, phosphate-buffered saline comprises 0.2 mg/mL potassium chloride, 0.2 mg/mL monobasic potassium phosphate, 8.0 mg/mL sodium chloride, and 2.16 mg/mL sodium phosphate dibasic heptahydrate. In some embodiments, normal saline is an aqueous solution comprising one or more chloride salts (e.g., sodium chloride and/or potassium chloride). In some embodiments, normal saline comprises 0.9% sodium chloride by weight. [0083] In some embodiments, a liquid formulation comprises aqueous components in an amount suitable to balance other components (e.g., to bring the total volume to 100% of the desired volume). In some embodiments, a liquid formulation comprises from about 10% (w/v) to about 90% (w/v), from about 20% (w/v) to about 80% (w/v), from about 30% (w/v) to about 70% (w/v), or from about 40% (w/v) to about 60% (w/v) aqueous components. In some embodiments, a liquid formulation comprises about 10% (w/v), about 20% (w/v), about 30% (w/v), about 40% (w/v), about 50% (w/v), about 60% (w/v), about 70% (w/v), about 80% (w/v), or about 90% (w/v) aqueous components. In some embodiments, a liquid formulation comprises about 40% (w/v) aqueous components (e.g., phosphate buffered saline). In some embodiments, a liquid formulation comprises about 40% (w/v) aqueous components (e.g., aqueous buffer, e.g., aqueous phosphate buffer). In some embodiments, a liquid formulation comprises about 64% (w/v) aqueous components (e.g., normal saline and phosphate buffered saline). In some embodiments, a liquid formulation comprises about 64% (w/v) aqueous components (e.g., aqueous buffer, e.g., aqueous phosphate buffer). In some embodiments, a liquid formulation comprises about 24% (w/v) phosphate buffered saline and about 40% (w/v) normal saline. [0084] In some embodiments, a liquid formulation comprises Compound 1 and further comprises about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300) and about 10% (w/v) polysorbate (e.g., polysorbate 80). In some such embodiments, the liquid formulation is aqueous. In some such embodiments, the liquid formulation further comprises phosphate- buffered saline and/or normal saline. [0085] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL to about 10 mg/mL Compound 1; about 20% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0086] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL to about 10 mg/mL Compound 1; about 20% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0087] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL to about 10 mg/mL Compound 1; about 20% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0088] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0089] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0090] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0091] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0092] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0093] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0094] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and about 40% (w/v) phosphate buffered saline. [0095] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0096] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0097] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0098] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0099] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0100] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0101] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and about 64% (w/v) aqueous buffer. [0102] In some embodiments, Compound 1 is provided and/or utilized in accordance with the present disclosure as a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); about 24% (w/v) phosphate buffered saline; and about 40% (w/v) normal saline. [0103] In some embodiments, liquid formulations of Compound 1 provided herein are prepared by a process comprising a step of combining: crystalline Compound 1 (e.g., Form A); polyethylene glycol (e.g., polyethylene glycol 300); polysorbate (e.g., polysorbate 80); and one or more aqueous components to obtain the formulation. [0104] In some embodiments, liquid formulations of Compound 1 provided herein are prepared by a process comprising a step of combining: crystalline Compound 1 (e.g., Form A); polyethylene glycol (e.g., polyethylene glycol 300); polysorbate (e.g., polysorbate 80); water; and one or more inorganic salts (e.g., phosphate salts and/or chloride salts) to obtain the formulation. [0105] In some embodiments, liquid formulations of Compound 1 provided herein are prepared by a process comprising a step of combining: crystalline (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole (e.g., Form A); polyethylene glycol (e.g., polyethylene glycol 300); polysorbate (e.g., polysorbate 80); and one or more aqueous components (e.g., phosphate buffered saline and/or normal saline) to obtain the formulation. [0106] In some embodiments, a liquid formulation has a pH of about 5 to about 9. In some embodiments, a liquid formulation has a pH of about 6 to about 8. In some embodiments, a liquid formulation has a pH of about 7 (e.g., about 7.4). In some embodiments, a liquid formulation has a pH of about 6.4 to about 8.4 or about 7.4 to about 7.9. [0107] In some embodiments, a liquid formulation is suitable for intravenous administration. In some embodiments, a liquid formulation is suitable for intravenous administration over about 10 min, about 20 min, about 30 min, or about 40 min. In some embodiments, a liquid formulation is suitable for intravenous administration of about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg Compound 1. In some embodiments, a liquid formulation is suitable for intravenous administration of about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg Compound 1. Provided Methods [0108] The present disclosure provides certain technologies and/or improvements for administration of terevalefim (i.e., Compound 1), or a pharmaceutically acceptable salt thereof. Such technologies and/or improvements may be useful in methods of treating any indication for which Compound 1 is a suitable therapy. For example, provided technologies and/or improvements may be useful in methods of treating delayed graft function, acute kidney injury associated with cardiac surgery involving cardiopulmonary bypass (CSA-AKI), and/or acute lung injury (e.g., ALI associated with COVID-19 pneumonia). Subjects on Hemodialysis [0109] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects receiving maintenance hemodialysis. In some embodiments, the present disclosure encompasses the recognition that hemodialysis may or may not alter pharmacokinetic properties of Compound 1, and therefore, methods of administering Compound 1 to patients receiving chronic hemodiaylsis may or may not need to be adjusted accordingly. [0110] In some embodiments, the subject is receiving or has received hemodialysis prior to being administered Compound 1. In some embodiments, the subject is receiving or has received hemodialysis following administration of at least one dose of Compound 1. [0111] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects receiving maintenance hemodialysis on an on-dialysis day. An on- dialysis day is a day on which the subject undergoes dialysis. In some embodiments, Compound 1 is administered before dialysis (e.g., 5-30 minutes before dialysis). In some embodiments, pharmacokinetic properties of Compound 1 are not meaningfully altered by hemodialysis, and optionally, Compound 1 is administered on an on-dialysis day. In some embodiments, pharmacokinetic properties of Compound 1 are altered by hemodialysis, and optionally, a Compound 1 dosing regimen is adjusted accordingly (e.g., by increasing the dose and/or dosing frequency). [0112] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects receiving maintenance hemodialysis on an off-dialysis day. An off- dialysis day is a day on which the subject does not undergo dialysis (e.g., subject is not undergoing dialysis within a 24 hour period). In some embodiments, pharmacokinetic properties of Compound 1 are meaningfully altered by hemodialysis, and optionally, Compound 1 is administered on an off-dialysis day. In some embodiments, pharmacokinetic properties of Compound 1 are not meaningfully altered by hemodialysis, and optionally, Compound 1 is administered on an off-dialysis day. [0113] In some embodiments, the present disclsoure provides methods of administering Compound 1 to subjects receiving maintenance hemodialysis, regardless of whether it is an on- dialysis day or an off-dialysis day. In some embodiments, pharmacokinetic properties of Compound 1 are not meaningfully altered by hemodialysis, and optionally, Compound 1 is administered on an on-dialysis day and/or an off-dialysis day. [0114] In some embodiments, the subject is experiencing or has been diagnosed with renal failure. In some embodiments, the subject is experiencing or has been diagnosed with end-stage renal disease. [0115] In some embodiments, the subject has been on maintenance hemodialysis for at least 3 months. In some embodiments, the subject is receiving hemodialysis at least three times per week. [0116] In some embodiments, the subject has been determined to have one or more laboratory parameters selected from serum albumin ≥ 3.0 gm/dL, blood hemoglobin ≥ 10.0 gm/dL, and liver transaminases (ALT, AST) < 2x the upper limit of normal. In some embodiments, the subject has been determined to have a single pool urea (Kt/V) ≥ 1.3 for two consecutive months prior to administration of Compound 1. Subjects Taking CYP450 Inhibitors [0117] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are or have been simultaneously exposed to a cytochrome P450 inhibitor. In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are receiving or have received a cytochrome P450 inhibitor. [0118] In some embodiments, the present disclosure encompasses the recognition that, because in vitro assays indicated that Compound 1 was a substrate for CYP1A2, there may or may not be a drug-drug interaction in subjects receiving both Compound 1 and a cytochrome P450 inhibitor (e.g., a CYP1A2 inhibitor). In some embodiments, if pharmacokinetic properties of Compound 1 are meaningfully altered by co-administration with a cytochrome P450 inhibitor (e.g., a CYP1A2 inhibitor), then administration of Compound 1 may be discontinued and/or adjusted accordingly (e.g., by increasing or decreasing dose and/or dosing frequency of Compound 1). In some embodiments, if pharmacokinetic properties of Compound 1 are not meaningfully altered by co- adminstration with a cytochrome P450 inhibitor (e.g., a CYP1A2 inhibitor), then Compound 1 is administered to subjects regardless of whether or not they are receiving or have received a cytochrome P450 inhibitor (e.g., a CYP1A2 inhibitor). [0119] In some embodiments, provided methods comprise administering Compound 1 to a subject who is receiving or has received a CYP1A2 inhibitor. In some embodiments, the CYP1A2 inhibitor is selected from ciprofloxacin, enoxacin, and fluvoxamine. In some embodiments, the CYP1A2 inhibitor is ciprofloxacin. In some embodiments, ciprofloxacin is or was administered in a dose of about 500 mg BID. In some embodiments, the CYP1A2 inhibitor is fluvoxamine. Subjects with Cardiac Risk Factors [0120] In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects that are not at risk for torsades de pointes and/or that do not display certain risk factors (e.g., certain cardiac risk factors, etc.) described herein. In some embodiments, the present disclosure provides methods of administering Compound 1 to subjects regardless of their risk level for torsades de pointes and/or regardless of whether or not they display certain risk factors (e.g., certain cardiac risk factors, etc.) described herein. [0121] Without wishing to be bound by theory, drugs that delay cardiac repolarization (e.g., as evidenced by QT/QTc prolongation) may pose certain risks, particularly to patients with one or more risk factors. In some embodiments, the present disclosure encompasses the recognition that if Compound 1 does not induce QT/QTc prolongation, then Compound 1 is administered to subjects regardless of their risk factors. In some embodiments, the present disclosure encompasses the recognition that if Compound does induce QT/QTc prolongation, then Compound 1 is not administered to subjects with certain risk factors and/or Compound 1 administration is discontinued in subjects with certain risk factors and/or a Compound 1 dosing regimen is adjusted in subjects with certain risk factors. In some embodiments, QT/QTc prolongation is assessed from a change in baseline in corrected QT interval by Fridericia’s formula (ΔQTcF) in subjects administered Compound 1 compared to subjects administered placebo. [0122] In some embodiments, provided methods comprise administering Compound 1 to subjects who are not at risk for torsades de pointes. In some embodiments, provided methods comprise administering Compound 1 to subjects who do not display one or more of the following risk factors: family history of sudden cardiac death; history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome); uncontrolled hypertension (e.g., supine systolic blood pressure > 140 mmHg and/or supine diastolic blood pressure >100 mmHg); history or evidence of myocardial infarction, cardiac surgery revascularization (e.g., coronary artery bypass grafting or percutaneous translumincal coronary angioplasty), unstable angina, cerebrovascular accident or stroke or transient ischemic attack, pacemaker, atrial fibrillation, flutter, or non-sustained or sustained ventricular tachycardia, congestive heart failure (Grade III and IV according to New York Heart Association [NYHA] classification), hypokalemia, or unexplained syncope or syncope related to a cardiac arrhythmia; 12-lead ECG with clinically significant abnormalities of rate, rhythm, intervals, or conduction after resting supine for >10 minutes (e.g., flat T waves, evidence of previous myocardial infarction, left ventricular hypertrophy, nonspecific ST-T wave changes, QTcF > 450 msec, PR > 200 msec, QRS > 110 msec, heart rate below 50 or above 90 bpm, second- or third-degree atrioventricular block, complete right bundle branch block, or complete left bundle branch bock); or aspartate aminotransferase, ALT or bilirubin above the upper limit of normal. [0123] In some embodiments, provided methods further comprise monitoring a subject for one or more risk factors described herein over time, and optionally, if one or more risk factors develop, discontinuing administration of Compound 1. In some embodiments, provided methods further comprise monitoring a subject for one or more risk factors described herein over time, and optionally, if one or more risk factors develop, reducing the dose and/or dosing frequency of Compound 1. Increased Dose and/or Dosing Frequency [0124] In some embodiments, the present disclosure provides alternative dosing schedules for administration of Compound 1. In some embodiments, the present disclosure encompasses the recognition that increased dose and/or dosing frequency may provide increased therapeutic effect(s) without increasing safety risks. [0125] In some embodiments, Compound 1 is administered in a dose of 2 mg/kg, 4 mg/kg, or 6 mg/kg once or twice daily. In some embodiments, Compound 1 is administered in a dose of 2 mg/kg once daily. In some embodiments, Compound 1 is administered in a dose of 2 mg/kg twice daily. In some embodiments, Compound 1 is administered in a dose of 4 mg/kg once daily. In some embodiments, Compound 1 is administered in a dose of 4 mg/kg twice daily. In some embodiments, Compound 1 is administered in a dose of 6 mg/kg once daily. In some embodiments, Compound 1 is administered in a dose of 6 mg/kg twice daily. [0126] In some embodiments, the present disclosure encompasses the recognition that a dose of 4 mg/kg and/or 6 mg/kg once daily may provide increased therapeutic effect(s) without increasing safety risks, as compared to a dose of 2 mg/kg once daily. In some embodiments, the present disclosure encompasses the recognition that a dose of 2 mg/kg, 4 mg/kg, and/or 6 mg/kg twice daily may provide increased therapeutic effect(s) without increasing safety risks, as compared to a dose of 2 mg/kg once daily. [0127] In some embodiments, the present disclosure provides methods of administering Compound 1, according to a regimen established to achieve one or more PK characteristics described herein (e.g., in Example 1). In some embodiments, the present disclosure provides methods of administering Compound 1, according to a regimen established to achieve one or more of the following in a population of healthy subjects administered a single dose of Compound 1: ● median T_max of from about 0.50 h to about 0.58 h or from about 0.50 h to about 0.60 h (e.g., about 0.50 h, about 0.58 h, or about 0.60 h); ● mean C_max of from about 1190 ng/mL to about 1300 ng/mL or from about 500 ng/mL to about 1300 ng/mL (e.g., about 506 ng/mL, about 750 ng/mL, about 1000 ng/mL, about 1190 ng/mL or about 1300 ng/mL); ● mean C_max/D of from about 2.65 ng/mL/mg to about 4.45 ng/mL/mg (e.g., about 2.67 ng/mL/mg, about 3.0 ng/mL/mg, about 3.40 ng/mL/mg, about 4.0 ng/mL/mg, or about 4.41 ng/mL/mg); ● mean AUC(0-last) of from about 1430 ng.h/mL to about 1800 ng.h/mL or from about 685 ng.h/mL to about 1800 ng.h/mL (e.g., about 685 ng.h/mL, about 800 ng.h/mL, about 1000 ng.h/mL, about 1200 ng.h/mL, about 1430 ng.h/mL, about 1600 ng.h/mL, or about 1800 ng.h/mL); ● mean AUC(0-last)/D of from about 4.02 ng.h/mL/mg to about 4.84 ng.h/mL/mg (e.g., about 4.02 ng.h/mL/mg, about 4.2 ng.h/mL/mg, about 4.4 ng.h/mL/mg, about 4.6 ng.h/mL/mg, or about 4.84 ng.h/mL/mg); ● mean AUC(0-inf) of from about 1290 ng.h/mL to about 2000 ng.h/mL or from about 748 ng.h/mL to about 2000 ng.h/mL (e.g., about 748 ng.h/mL, about 1000 ng.h/mL, about 1290 ng.h/mL, about 1500 ng.h/mL, about 1750 ng.h/mL, or about 2000 ng.h/mL); ● mean AUC(0-inf)/D of from about 4.06 ng.h/mL/mg to about 5.35 ng.h/mL/mg (e.g., about 4.06 ng.h/mL/mg, about 4.2 ng.h/mL/mg, about 4.53 ng.h/mL/mg, about 4.8 ng.h/mL/mg, about 5.0 ng.h/mL/mg, or about 5.35 ng.h/mL/mg); ● mean AUCextrap of from about 2.5% to about 4.95% or from about 2.5% to about 7.27% (e.g., about 2.51%, about 3%, about 4%, about 4.95%, about 6%, or about 7.27%); ● mean T1/2 of from about 2.07 h to about 2.4 h or from about 2.07 h to about 2.84 h (e.g., about 2.07 h, about 2.2 h, about 2.4 h, about 2.6 h, or about 2.84 h); ● mean CL of from about 3680 mL/min to about 4455 mL/min or from about 3170 mL/min to about 4455 mL/min (e.g., about 3170 mL/min, about 3300 mL/min, about 3500 mL/min, about 3680 mL/min, about 3900 mL/min, about 4100 mL/min or about 4455 mL/min); and ● mean Vz of from about 660 L to about 855 L (e.g., about 660 L, about 700 L, about 747 L, about 800 L, or about 855 L). [0128] In some embodiments, the present disclosure provides methods of administering Compound 1, according to a regimen established to achieve one or more of the following in a population of healthy subjects administered multiple doses of Compound 1: ● median T_max of from about 0.50 h to about 0.58 h (e.g., about 0.50 h or about 0.58 h); ● mean C_max of from about 682 ng/mL to about 987 ng/mL or from about 414 ng/mL to about 987 ng/mL (e.g., about 414 ng/mL, about 444 ng/mL, about 493 ng/mL, about 513 ng/mL, about 682 ng/mL, about 758 ng/mL, about 832 ng/mL, or about 987 ng/mL); ● mean C_max/D of from about 2.21 ng/mL/mg to about 3.20 ng/mL/mg (e.g., about 2.21 ng/mL/mg, about 2.39 ng/mL/mg, about 2.45 ng/mL/mg, about 2.56 ng/mL/mg, about 2.62 ng/mL/mg, about 2.85 ng/mL/mg, about 2.96 ng/mL/mg, or about 3.20 ng/mL/mg); ● mean AUC(0-tau) of from about 962 ng.h/mL to about 1210 ng.h/mL or from about 564 ng.h/mL to about 1210 ng.h/mL (e.g., about 564 ng.h/mL, about 630 ng.h/mL, about 709 ng.h/mL, about 962 ng.h/mL, about 1140 ng.h/mL, about 1180 ng.h/mL, or about 1210 ng.h/mL); ● mean AUC(0-tau)/D of from about 3.12 ng.h/mL/mg to about 4.09 ng.h/mL/mg (e.g., about 3.12 ng.h/mL/mg, about 3.26 ng.h/mL/mg, about 3.6 ng.h/mL/mg, about 3.65 ng.h/mL/mg, about 3.84 ng.h/mL/mg, about 3.91 ng.h/mL/mg, or about 4.09 ng.h/mL/mg); ● mean T1/2 of from about 2.28 h to about 2.37 h or from about 2.28 h to about 3.23 h (e.g., about 2.28 h, about 2.37 h, about 2.7 h, about 3.04 h, or about 3.23 h); ● mean CLtau of from about 4070 mL/min to about 5350 mL/min (e.g., about 4070 mL/min, about 4260 mL/min, about 4340 mL/min, about 4560 mL/min, about 4620 mL/min, about 4650 mL/min, about 4800 mL/min, about 5120 mL/min, or about 5350 mL/min); ● mean CLr of from about 0.596 mL/min to about 0.637 mL/min or from about 0.215 mL/min to about 0.637 mL/min (e.g., about 0.215 mL/min, about 0.228 mL/min, about 0.434 mL/min, about 0.587 mL/min, about 0.596 mL/min, about 0.600 mL/min, about 0.637 mL/min, or about 0.648 mL/min); ● mean Vztau of from about 555 L to about 1130 L (e.g., about 555 L, about 698 L, about 776 L, about 779 L, about 812 L, about 932 L, about 1100 L, or about 1130 L); and ● mean CumAe of from about 40788 ng to about 51791 ng or from about 15324 ng to about 51791 ng (e.g., about 15324 ng, about 16022 ng, about 20806 ng, about 20969 ng, about 30000 ng, about 40788 ng, about 43344 ng, about 46496 ng, or about 51791 ng). Flat Doses [0129] In some embodiments, the present disclosure encompasses the recognition that administration of a flat dose of Compound 1 may provide certain advantages over weight-based dosing, e.g., ease and convenience of administration, etc. Additionally, in some embodiments, the present disclosure encompasses the recognition that administration of a flat dose is achievable, because slight variations in the weight-based dose do not meaningfully affect the safety profile (e.g., see Example 1 which demonstrates safely administering between 2 mg/kg and 6 mg/kg of Compound 1 to healthy volunteers). [0130] In some embodiments, the present disclosure provides methods of administering Compound 1 without using a weight-based dose. For example, in some embodiments, the present disclosure provides methods of administering Compound 1 in a dose of 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg once or twice daily. In some embodiments, provided methods comprise administering Compound 1 in a dose of from about 100 mg to about 500 mg, from about 150 mg to about 250 mg, or from about 180 mg to about 280 mg once or twice daily. Delayed Graft Function [0131] Provided methods of administering Compound 1 (e.g., administering Compound 1 to subjects receiving chronic hemodialysis and/or administering Compound 1 to subjects receiving a cytochrome P450 inhibitor and/or administering Compound 1 to subjects without cardiac risk factors and/or administering Compound 1 in an increased dose and/or dosing frequency and/or administering Compound 1 in a flat dose) may be useful for treating delayed graft function (DGF). [0132] Delayed graft function (DGF) after kidney transplantation is associated with lower graft survival, higher mortality and greater healthcare costs. Patients displaying DGF lack acceptable autonomous kidney function and require renal replacement therapy in the first week after transplant. Most transplant centers report a DGF rate of 20 to 50% (Boom H, Mallat MJ, de Fijter JW, Zwinderman AH, Paul LC. Delayed graft function influences renal function but not survival. Transplant Proc.2001;33(1-2):1291). Kidneys that manifest DGF have a higher frequency of adverse outcomes, including decreased graft function, decreased graft survival, and result in increased patient mortality. Additionally, the duration of DGF is an important prognostic factor for graft survival, and studies have reported that prolonged DGF (>6 days) has a deleterious effect on graft survival and that DGF is the single most important determinant of 1 year graft survival (Giral-Classe M, Hourmant M, Cantarovich D, et al. Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys. Kidney Int. 1998;54(3):972–978). Though there are currently no approved therapies for treating DGF, current strategies for managing DGF include supporting patients with dialysis and monitoring for rejection with serial biopsies, typically while patients continue to be administered drugs such as calcineurin inhibitors (CNI), corticosteroids, and mycophenolate mofetil (MMF; an inosine monophosphate dehydrogenase inhibitor). As a result, DGF increases transplant-associated costs because of longer hospital stays, more frequent out-patient clinic visits, increased imaging, increased invasive procedures including inpatient and outpatient dialysis, and pharmacologic therapies. Moreover, if a patient experiences graft failure (e.g., related to DGF), the patient must begin dialysis again, restarting the adverse health and economic cycles. [0133] In some embodiments, the present disclosure provides methods of treating (e.g., lessening the severity of, such as by delaying onset and/or reducing degree and/or frequency of one or more features of) DGF, which methods may comprise, for example administering a small molecule mimetic of hepatocyte growth factor (HGF, also known as scatter factor (SF)). HGF/SF is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis, and angiogenesis. Certain small molecule mimetics of HGF/SF have been shown to be useful for treating or lessening severity of a variety of diseases, disorders, and conditions. [0134] The present disclosure provides methods of improving renal function in a subject or a population of subjects who have undergone renal transplantation and/or are at risk of DGF. The present disclosure encompasses the recognition that particular modes of administering an HGF/SF mimetic achieve certain desirable outcomes across a population of subjects at risk of DGF. For example, the present disclosure demonstrates that administration of an HGF/SF mimic to a relevant population according to particular regimen(s) can achieve certain treatment effects across that population. In some embodiments, such population may be or comprise subjects who have undergone renal transplantation with a cadaveric kidney (e.g., a kidney from a donor after cardiac death or a kidney from a donor after brain death). [0135] In particular, among other things, the present disclosure provides an insight that provided methods can achieve greater long-term success for kidney transplants (e.g., after 6 months or 12 months) in subjects receiving an HGF/SF mimetic. Thus, the present disclosure encompasses the recognition that administration of HGF/SF mimetics shortly after renal transplantation (e.g., within about 36 hours or within about 30 hours) can provide significant long-term benefits for the health and quality of life for subjects receiving provided therapies. [0136] The present disclosure also provides the insight that provided methods demonstrate durability of particular effects (e.g., of better renal function after transplantation) in subjects receiving an HGF/SF mimetic. For example, in some embodiments, increased renal function, as measured by, e.g., increased estimated glomerular filtration rate and/or decreased serum creatinine concentration, is maintained for at least 28 days, at least 6 months, or at least 12 months after renal transplantation. Without wishing to be bound by any particular theory, subjects with an estimated glomerular filtration rate after at least 28 days, at least 6 months, or at least 12 months that achieves a lower chronic kidney disease (CKD) stage on the National Kidney Foundation’s predictive CKD scale are expected to have increased life expectancies, compared to those with a higher CKD stage. [0137] The present disclosure also provides insight that, in some embodiments, Compound 1 may be administered to a subject or population of subjects in need thereof, regardless of the subject’s malignancy status (e.g., current malignancy status and/or history of malignancy). [0138] Provided herein are methods of treating DGF in a subject or in a population of subjects, comprising administering Compound 1 (e.g., by administering a composition that comprises and/or delivers Compound 1 as described herein) to the subject in need thereof. DGF is a severe form of acute kidney injury (AKI) resulting from ischemia-reperfusion injury (caused by oxygen deprivation and reintroduction) following kidney transplantation and defined as the need for dialysis within seven days following transplantation. It is distinct from transplant rejection and is most commonly seen in recipients of deceased-donor kidneys, in part due to the longer periods of warm ischemia (ischemia occurring at body temperature) and cold ischemia (ischemia occurring during kidney preservation and transport) typical for deceased-donor kidney transplants. DGF is most commonly defined as the need for dialysis (i.e., the extracorporeal removal of waste products from the blood when the kidneys are in a state of failure) within seven days following transplantation. In the United States, 70% of the 23,000 kidney transplant procedures performed annually use deceased-donor kidneys, and nearly one-third of these transplant recipients, or more than 5,000 patients per year, are diagnosed with DGF. DGF has a very high clinical and economic burden, and there are no approved therapies. [0139] One of the challenges with DGF stems from the timing of the injury to the kidney, which can occur before the transplantation surgery. For example, in donors who die suddenly (e.g., cardiac death) or who have brain death, the kidney injury occurs when blood flow to the kidney is reduced or stopped, which occurs at or before the time of organ recovery. From that point, the lack of oxygen and nutrients continues to damage the donor kidney until the point at which it is successfully implanted into a recipient, which often takes place between 12 and 24 hours later. After the kidney is transplanted, it undergoes further damage as a result of reperfusion injury caused by the formation of free radicals as oxygen flow returns to the oxygen- starved organ. This combination of damage and its timing makes it difficult for interventions that only block damage pathways, for instance by targeting inflammatory pathways, to work effectively to improve kidney function and reduce the severity of DGF. [0140] Certain key metrics, including urine output and estimated glomerular filtration rate (eGFR), can be indicative of how a transplanted kidney is performing. Adverse readings in these key metrics can be indicative of kidney damage and more severe forms of DGF, and can be predictive of longer-term negative outcomes, such as reduced survival of the transplanted kidney and increased patient morbidity and mortality (Schnuelle, P. et al. Nephrol. Dial. Transplant (2007) 22:235-45). For example, FIG.16 shows that the lowest two quintiles of patients (solid lines) with the worst urine output within 24 hours after a kidney transplantation have a significantly decreased chance of their new kidney surviving for five years compared to the highest quintile (dashed line). See Schnuelle, P. et al.2007. FIG.17 shows that patients with the highest eGFR at discharge (small dotted line) have better cumulative kidney transplant survival than patients with lower eGFR at discharge (large dotted and solid lines) (based on data reported in Schnuelle, P. et al.2007). Regardless of the specific measurement used, the occurrence of more severe DGF is associated with an approximate 50% reduction in median graft survival time, from approximately ten years for patients with less severe DGF to approximately five years for patients who experienced more severe DGF. See Schnuelle, P. et al.2007. Thus, there is a need for therapies for treating (e.g., reducing severity of) DGF. [0141] In some embodiments, the present disclosure provides methods of administering to a subject or population of subjects who have undergone renal transplantation and are at risk of DGF a composition providing Compound 1, according to a regimen established to achieve one or more desirable outcomes. In some embodiments, the regimen is or has been established to achieve one or more desirable outcomes, relative to that observed for a comparable reference population that has not received Compound 1 (e.g., that has received a reference composition which does not deliver Compound 1). [0142] In some embodiments, certain parameters may be evaluated to determine if a desirable outcome is achieved. For example, in some embodiments, certain measures of kidney function, such as serum creatinine (SCr) and/or estimated glomerular filtration rate (eGFR) can be obtained from a subject’s blood sample; in some embodiments, such measures can be used to assess if renal function is improving after kidney transplantation. eGFR can be calculated from SCr using, e.g., the MDRD or MDRD4 formula, or the CKD-EPI formula. In some embodiments, eGFR is calculated from SCr using the MDRD or MDRD4 formula. In some embodiments, eGFR is calculated from SCr using the CKD-EPI formula. See Chen, Y.-W., et al. World J. Gastroenterol.2011 Oct 28;17(40):4532-4538. Additionally or alternatively, other indications of kidney function may be evaluated, including urine output, number of dialysis sessions, duration of dialysis, length of hospitalization, and/or incidence of graft failure. Any one or more of parameters such as these may, in some embodiments, be useful for determining short-term and/or long-term efficacy of Compound 1 after renal transplantation. [0143] In some embodiments, the present disclosure provides a method comprising: administering to a subject or population of subjects who have undergone renal transplantation and are at risk of delayed graft function a composition providing Compound 1 according to a regimen established to achieve one or more of: (i) a greater mean estimated glomerular filtration rate at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation; (ii) a greater mean increase in estimated glomerular filtration rate from baseline at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation; (iii) a lesser mean serum creatinine concentration at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation; (iv) a greater mean decrease in serum creatinine concentration from baseline at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation; (v) a greater incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation; (vi) a shorter median time to achieve 1200 cc urine output over a 24 hour period within 28 days after renal transplantation; (vii) a lesser mean number of dialysis sessions per subject within 28 days after renal transplantation; (viii) a shorter mean duration of dialysis within 28 days after renal transplantation; (ix) a shorter mean length of hospitalization after renal transplantation; and (x) a lower incidence of graft failure within about 12 months after renal transplantation, relative to a comparable reference population. [0144] In some embodiments, the present disclosure provides a method comprising: administering to a subject or population of subjects who have undergone renal transplantation and are at risk of delayed graft function a composition providing Compound 1 according to a regimen established to achieve one or more of: (i) a greater mean estimated glomerular filtration rate at about 6 months or about 12 months after renal transplantation; (ii) a greater mean increase in estimated glomerular filtration rate from baseline at about 6 months or about 12 months after renal transplantation; (iii) a lesser mean serum creatinine concentration at about 6 months or about 12 months after renal transplantation; and (iv) a greater mean decrease in serum creatinine concentration from baseline at about 6 months or about 12 months after renal transplantation, relative to a comparable reference population. [0145] In some embodiments, the present disclosure provides a method comprising: administering to a subject or population of subjects who have undergone renal transplantation and are at risk of delayed graft function a composition providing Compound 1, according to a regimen established to achieve one or more of: (i) a greater mean estimated glomerular filtration rate at about 12 months after renal transplantation; (ii) a greater proportion of patients with an estimated glomerular filtration rate greater than about 30 mL/min/1.73 m² at about 30 days, about 90 days, about 6 months or about 12 months after renal transplantation; (iii) a lesser proportion of patients with (1) PNF (defined as a continuous requirement for dialysis for at least 60 days after renal transplantation); (2) DGF (assessed by proportion of patients requiring dialysis within 7 days after renal transplantation); or (3) SGF (defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required); (iv) a shorter mean length of hospitalization after renal transplantation; and (v) a lesser number of days a patient remains dialysis dependent within the first 30 days after renal transplantation, relative to a comparable reference population. [0146] In some embodiments, in methods provided herein, a reference population has not received a composition providing Compound 1. In some embodiments, in methods provided herein, a reference population has received an otherwise comparable reference composition that does not provide Compound 1 (e.g., a placebo, such as normal saline). In some embodiments, in methods provided herein, a reference composition may be or comprise normal saline. In some embodiments, in methods provided herein, a reference composition may be or may have been administered at the same intervals and/or volumes as a composition providing Compound 1. [0147] As used herein, “mean” may refer to an average and/or a least squares mean (LS mean). In some embodiments, “mean” may refer to a LS mean (e.g., a MMRM LS mean). For example, in some embodiments, a regimen has been established to achieve one or both of (i) a greater mean (e.g., a LS mean) estimated glomerular filtration rate at about 6 months or about 12 months after renal transplantation; and (ii) a lesser mean (e.g., a LS mean) serum creatinine concentration at about 6 months or about 12 months after renal transplantation, relative to a comparable reference population. [0148] In some embodiments, a composition providing Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point (e.g., about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation). In some embodiments, a composition providing Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0149] In some embodiments, a particular effect may be or comprise a particular mean estimated glomerular filtration rate (eGFR) at a particular time point. In some embodiments, a particular effect may be or comprise a greater mean estimated glomerular filtration rate (eGFR) at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation. In some embodiments, a particular effect may be or comprise a greater mean estimated glomerular filtration rate (eGFR) at about 6 months after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, a particular effect may be or comprise a greater mean estimated glomerular filtration rate (eGFR) at about 12 months after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, a particular effect may be or comprise a greater mean estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI equation based on serum creatinine, at about 12 months after renal transplantation, relative to an appropriate reference as described herein. [0150] In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of greater than about 12 mL/min/1.73 m², greater than about 13 mL/min/1.73 m², or greater than about 15 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of greater than about 20 mL/min/1.73 m², greater than about 25 mL/min/1.73 m², or greater than about 30 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of greater than about 30 mL/min/1.73 m², greater than about 32 mL/min/1.73 m², or greater than about 35 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of greater than about 40 mL/min/1.73 m², greater than about 45 mL/min/1.73 m², or greater than about 48 mL/min/1.73 m² at about 6 months or about 12 months after renal transplantation. [0151] In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of from about 12 mL/min/1.73 m² to about 18 mL/min/1.73 m², from about 13 mL/min/1.73 m² to about 17 mL/min/1.73 m², or from about 14 mL/min/1.73 m² to about 16 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of from about 22 mL/min/1.73 m² to about 36 mL/min/1.73 m², from about 24 mL/min/1.73 m² to about 34 mL/min/1.73 m², or from about 28 mL/min/1.73 m² to about 34 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of from about 32 mL/min/1.73 m² to about 44 mL/min/1.73 m², from about 34 mL/min/1.73 m² to about 42 mL/min/1.73 m², or from about 36 mL/min/1.73 m² to about 40 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of from about 40 mL/min/1.73 m² to about 55 mL/min/1.73 m², from about 40 mL/min/1.73 m² to about 50 mL/min/1.73 m², from about 45 mL/min/1.73 m² to about 55 mL/min/1.73 m², from about 45 mL/min/1.73 m² to about 50 mL/min/1.73 m², from about 48 mL/min/1.73 m² to about 55 mL/min/1.73 m², or about 48 mL/min/1.73 m² to about 50 mL/min/1.73 m² at about 6 months or about 12 months after renal transplantation. [0152] In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 15.1 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 32.1 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 39.0 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 50.0 mL/min/1.73 m² at about 6 months or about 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 50.0 mL/min/1.73 m² at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR of about 50.1 mL/min/1.73 m² at about 12 months after renal transplantation. [0153] In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is from about 5 mL/min/1.73 m² to about 15 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 15 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 12 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 13 mL/min/1.73 m², or from about 10 mL/min/1.73 m² to about 15 mL/min/1.73 m² greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation). [0154] In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is about 5 mL/min/1.73 m², about 8 mL/min/1.73 m², about 10 mL/min/1.73 m², about 12 mL/min/1.73 m², or about 15 mL/min/1.73 m² greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation). In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is about 11.5 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is about 8.4 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is about 10.5 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean eGFR that is about 12.3 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 12 months after renal transplantation. [0155] In some embodiments, a particular effect may be or comprise achieving a particular CKD stage on the National Kidney Foundation’s predictive scale at a particular time point (See, e.g., Example 7). In some embodiments, a particular effect may be or comprise achieving a lower CKD stage on the National Kidney Foundation’s predictive scale, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation. [0156] In some embodiments, the particular effect may be or comprise, for example, a CKD stage on the National Kidney Foundation’s predictive scale of 3B or lower, 3A or lower, 2 or lower, or 1 or lower at about 28 days, about 6 months, or about 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a CKD stage on the National Kidney Foundation’s predictive scale of 3A or lower, 2 or lower, or 1 or lower at about 6 months or about 12 months after renal transplantation. [0157] In some embodiments, a particular effect may be or comprise, for example, a particular mean (e.g., LS mean) increase in eGFR from baseline at a particular time point. In some embodiments, a particular effect may be or comprise a greater mean increase in eGFR from baseline at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation. In some embodiments, a particular effect may be or comprise a greater mean increase in eGFR from baseline at about 6 months after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, a particular effect may be or comprise a greater mean increase in eGFR from baseline at about 12 months after renal transplantation, relative to an appropriate reference as described herein. [0158] In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of greater than about 3 mL/min/1.73 m², greater than about 5 mL/min/1.73 m², or greater than about 8 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of greater than about 10 mL/min/1.73 m², greater than about 18 mL/min/1.73 m², or greater than about 22 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of greater than about 20 mL/min/1.73 m², greater than about 25 mL/min/1.73 m², or greater than about 30 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of greater than about 32 mL/min/1.73 m², greater than about 36 mL/min/1.73 m², or greater than about 40 mL/min/1.73 m² at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of greater than about 27 mL/min/1.73 m², greater than about 36 mL/min/1.73 m², or greater than about 40 mL/min/1.73 m² at about 12 months after renal transplantation. [0159] In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of from about 3 mL/min/1.73 m² to about 10 mL/min/1.73 m², from about 5 mL/min/1.73 m² to about 10 mL/min/1.73 m², or from about 7 mL/min/1.73 m² to about 9 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of from about 12 mL/min/1.73 m² to about 30 mL/min/1.73 m², from about 15 mL/min/1.73 m² to about 25 mL/min/1.73 m², or from about 20 mL/min/1.73 m² to about 25 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of from about 20 mL/min/1.73 m² to about 35 mL/min/1.73 m², from about 25 mL/min/1.73 m² to about 35 mL/min/1.73 m², or from about 28 mL/min/1.73 m² to about 32 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of from about 32 mL/min/1.73 m² to about 45 mL/min/1.73 m², from about 36 mL/min/1.73 m² to about 45 mL/min/1.73 m², or from about 38 mL/min/1.73 m² to about 42 mL/min/1.73 m² at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline of from about 30 mL/min/1.73 m² to about 45 mL/min/1.73 m², from about 36 mL/min/1.73 m² to about 45 mL/min/1.73 m², or from about 39 mL/min/1.73 m² to about 43 mL/min/1.73 m² at about 12 months after renal transplantation. [0160] In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline of about 8.25 mL/min/1.73 m² at about 7 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline of about 23.36 mL/min/1.73 m² at about 14 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline of about 30.26 mL/min/1.73 m² at about 28 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline of about 40.47 mL/min/1.73 m² at about 6 months after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline of about 41.23 mL/min/1.73 m² at about 12 months after renal transplantation. [0161] In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is from about 5 mL/min/1.73 m² to about 15 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 15 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 12 mL/min/1.73 m², from about 8 mL/min/1.73 m² to about 13 mL/min/1.73 m², or from about 10 mL/min/1.73 m² to about 15 mL/min/1.73 m² greater than that than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation). [0162] In some embodiments, a particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 6 mL/min/1.73 m², about 10 mL/min/1.73 m², about 11 mL/min/1.73 m², about 12 mL/min/1.73 m², or about 13 mL/min/1.73 m² greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 14 days, about 28 days, about 6 months or about 12 months after renal transplantation). In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 5.79 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 13.12 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 10.65 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 10.08 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean increase in eGFR from baseline that is about 12.57 mL/min/1.73 m² greater than that of an appropriate reference as described herein at about 12 months after renal transplantation. [0163] In some embodiments, a particular effect may be or comprise, for example, a particular proportion of patients with an eGFR greater than a particular value (e.g., greater than about 30 mL/min/1.73 m²) at a particular time point. In some embodiments, the particular effect may be or comprise, for example, a greater proportion of patients with an eGFR greater than a particular value (e.g., greater than about 30 mL/min/1.73 m²) at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 30 days, about 90 days, about 6 months and/or about 12 months after renal transplantation. [0164] In some embodiments, a particular effect may be or comprise, for example, a particular mean serum creatinine concentration (SCr) at a particular time point. In some embodiments, the particular effect may be or comprise, for example, a lesser mean SCr at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a lesser mean SCr at about 6 months after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, a lesser mean SCr at about 12 months after renal transplantation, relative to an appropriate reference as described herein. [0165] In some embodiments, the particular effect may be or comprise, for example, a mean SCr of less than about 6.25 mg/dL, about 6.0 mg/dL, or about 5.90 mg/dL at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of less than about 4.0 mg/dL, about 3.50 mg/dL, or about 3.30 mg/dL at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of less than about 2.90 mg/dL, about 2.50 mg/dL, or about 2.40 mg/dL at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of less than about 1.90 mg/dL, about 1.85 mg/dL, about 1.80 mg/dL, about 1.75 mg/dL, about 1.70 mg/dL, about 1.65 mg/dL, or about 1.60 mg/dL at about 6 months or about 12 months after renal transplantation. [0166] In some embodiments, the particular effect may be or comprise, for example, a mean SCr of from about 5.40 mg/dL to about 6.40 mg/dL, from about 5.50 mg/dL to about 6.0 mg/dL, or from about 5.70 mg/dL to about 5.90 mg/dL at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of from about 3.0 mg/dL to about 4.0 mg/dL, from about 3.10 mg/dL to about 3.50 mg/dL, or from about 3.20 mg/dL to about 3.30 mg/dL at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of from about 2.0 mg/dL to about 2.95 mg/dL, from about 2.10 mg/dL to about 2.50 mg/dL, or from about 2.20 mg/dL to about 2.35 mg/dL at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of from about 1.40 mg/dL to about 1.90 mg/dL, from about 1.55 mg/dL to about 1.85 mg/dL, from about 1.50 mg/dL to about 1.80 mg/dL, from about 1.45 mg/dL to about 1.75 mg/dL, from about 1.40 mg/dL to about 1.65 mg/dL, from about 1.45 mg/dL to about 1.55 mg/dL, or from about 1.55 mg/dL to about 1.65 mg/dL at about 6 months or about 12 months after renal transplantation. [0167] In some embodiments, the particular effect may be or comprise, for example, a mean SCr of about 5.82 mg/dL at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of about 3.24 mg/dL at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of about 2.29 mg/dL at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of about 1.60 mg/dL at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr of about 1.48 mg/dL at about 12 months after renal transplantation. [0168] In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is from about 0.50 mg/dL to about 1.0 mg/dL, from about 0.60 mg/dL to about 0.90 mg/dL, or from about 0.65 mg/dL to about 0.85 mg/dL less than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, or about 28 days after renal transplantation). In some embodiments the particular effect may be or comprise, for example, a mean SCr that is from about 0.20 mg/dL to about 0.50 mg/dL, from about 0.25 mg/dL to about 0.45 mg/dL, from about 0.25 mg/dL to about 0.35 mg/dL, from about 0.35 mg/dL to about 0.45 mg/dL, from about 0.28 mg/dL to about 0.32 mg/dL, or from about 0.40 mg/dL to about 0.45 mg/dL less than that of an appropriate reference as described herein at a particular time point (e.g., at about 6 months or about 12 months after renal transplantation). [0169] In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.90 mg/dL, about 0.85 mg/dL, about 0.80 mg/dL, about 0.75 mg/dL, about 0.70 mg/dL, or about 0.65 mg/dL less than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, or about 28 days after renal transplantation). In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.20 mg/dL, about 0.25 mg/dL, about 0.30 mg/dL, about 0.35 mg/dL, about 0.40 mg/dL, about 0.45 mg/dL, or about 0.50 mg/dL less than that of an appropriate reference as described herein at a particular time point (e.g., at about 6 months or about 12 months after renal transplantation). [0170] In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.67 mg/dL less than that of an appropriate reference as described herein at about 7 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.79 mg/dL less than that of an appropriate reference as described herein at about 14 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.70 mg/dL less than that of an appropriate reference as described herein at about 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.29 mg/dL less than that of an appropriate reference as described herein at about 6 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean SCr that is about 0.43 mg/dL less than that of an appropriate reference as described herein at about 12 months after renal transplantation. [0171] In some embodiments, a particular effect may be or comprise, for example, a particular mean decrease in SCr from baseline at a particular time point. In some embodiments, the particular effect may be or comprise, for example, a greater mean decrease in SCr from baseline at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration); in some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a greater mean decrease in SCr from baseline at about 6 months after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, a greater mean decrease in SCr from baseline at about 12 months after renal transplantation, relative to an appropriate reference as described herein. [0172] In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of greater than about 1.5 mg/dL, greater than about 1.8 mg/dL, or greater than about 2.0 mg/dL at about 7 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of greater than about 3.9 mg/dL, greater than about 4.2 mg/dL, or greater than about 4.5 mg/dL at about 14 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of greater than about 5.0 mg/dL, greater than about 5.3 mg/dL, or greater than about 5.5 mg/dL at about 28 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of greater than about 6.0 mg/dL, greater than about 6.1 mg/dL, or greater than about 6.2 mg/dL at about 6 months after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of greater than about 6.0 mg/dL, greater than about 6.2 mg/dL, or greater than about 6.4 mg/dL at about 12 months after renal transplantation. [0173] In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of from about 1.4 mg/dL to about 2.5 mg/dL, from about 1.6 mg/dL to about 2.2 mg/dL, or from about 1.9 mg/dL to about 2.1 mg/dL at about 7 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of from about 3.9 mg/dL to about 5.0 mg/dL, from about 4.4 mg/dL to about 4.9 mg/dL, or from about 4.5 mg/dL to about 4.7 mg/dL at about 14 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of from about 4.9 mg/dL to about 6.0 mg/dL, from about 5.4 mg/dL to about 5.8 mg/dL, or from about 5.5 mg/dL to about 5.7 mg/dL at about 28 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of from about 6.0 mg/dL to about 6.8 mg/dL, from about 6.1 mg/dL to about 6.5 mg/dL, or from about 6.2 mg/dL to about 6.4 mg/dL at about 6 months after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline of from about 6.0 mg/dL to about 6.8 mg/dL, from about 6.2 mg/dL to about 6.6 mg/dL, or from about 6.3 mg/dL to about 6.5 mg/dL at about 12 months after renal transplantation. [0174] In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 2.05 mg/dL at about 7 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 4.63 mg/dL at about 14 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 5.59 mg/dL at about 28 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 6.27 mg/dL at about 6 months after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 6.40 mg/dL at about 12 months after renal transplantation. [0175] In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is from about 0.50 mg/dL to about 1.0 mg/dL, from about 0.60 mg/dL to about 0.90 mg/dL, or from about 0.65 mg/dL to about 0.85 mg/dL greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, or about 28 days after renal transplantation). In some embodiments the particular effect may be or comprise, for example, a mean SCr that is from about 0.10 mg/dL to about 0.60 mg/dL, from about 0.20 mg/dL to about 0.50 mg/dL, or from about 0.25 mg/dL to about 0.45 mg/dL greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 6 months or about 12 months after renal transplantation). [0176] In some embodiments, a particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 0.85 mg/dL, about 0.80 mg/dL, about 0.75 mg/dL, about 0.70 mg/dL, or about 0.65 mg/dL greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 7 days, about 14 days, or about 28 days after renal transplantation). In some embodiments, the particular effect may be or comprise, for example, a mean decrease in SCr from baseline that is about 0.20 mg/dL, about 0.25 mg/dL, about 0.30 mg/dL, about 0.35 mg/dL, about 0.40 mg/dL, about 0.45 mg/dL, or about 0.50 mg/dL greater than that of an appropriate reference as described herein at a particular time point (e.g., at about 6 months or about 12 months after renal transplantation). [0177] In some embodiments, a particular effect may be or comprise, for example, a particular incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a greater incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, at least about 50%, at least about 60%, at least about 70%, or at least about 75% of subjects achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, from about 45% to about 90%, from about 50% to about 85%, from about 60% to about 80% or from about 70% to about 80% of subjects achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a percentage of subjects achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation that is about 25, about 30, about 35, about 40, or about 45 percentage points greater than that of an appropriate reference as described herein. [0178] In some embodiments, a particular effect may be or comprise, for example, a particular median time for the subjects to achieve 1200 cc urine output over a 24 hour period. In some embodiments, the particular effect may be or comprise, for example, a shorter median time for the subjects to achieve 1200 cc urine output over a 24 hour period, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, a median time for the subjects to achieve 1200 cc urine output over a 24 hour period from about 2 days to about 12 days, from about 3 days to about 10 days, or from about 4 days to about 8 days. In some embodiments, the median time for the subjects to achieve 1200 cc urine output over a 24 hour period is about 2 days, about 4 days, about 5 days, about 6 days, or about 8 days. In some embodiments, the particular effect may be or comprise, for example, a median time for the subjects to achieve 1200 cc urine output over a 24 hour period is about 12 days, about 10 days, about 9 days, about 8 days, or about 6 days shorter than that of an appropriate reference as described herein. In some embodiments, the median time for the subjects to achieve 1200 cc urine output over a 24 hour period is about 9 days shorter than that of an appropriate reference as described herein. [0179] In some embodiments, the particular effect may be or comprise, for example, a particular mean number of dialysis sessions per subject within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a lesser mean number of dialysis sessions per subject within 28 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, a number of dialysis sessions of less than about 3.8, less than about 3.5, or less than about 3.0 per subject within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a number of dialysis sessions of from about 2.0 to about 3.8, from about 2.5 to about 3.5, or from about 2.7 to about 3.0 per subject within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a number of dialysis sessions of at least about 0.5, at least about 0.75 or at least about 1.0 fewer per subject within 28 days after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, a number of dialysis sessions of from about 0.25 to about 1.5, from about 0.5 to about 1.25, or from about 0.75 to about 1.25 fewer per subject within 28 days after renal transplantation, relative to an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, the mean number of dialysis sessions per subject within 28 days after renal transplantation of about 1.0. [0180] In some embodiments, a particular effect may be or comprise, for example, a particular mean duration of dialysis within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a shorter mean duration of dialysis within 28 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis of less than about 10 days, less than about 9 days, or less than about 8 days within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis of from about 6 days to about 10 days, from about 6.5 days to about 9.5 days, or from about 7 days to about 8 days within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis of about 7.6 days within 28 days after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis that is about 2.8, about 2.6, about 2.4, about 2.2, or about 2.0 days shorter than that of an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis that is about 2.4 days shorter than that of an appropriate reference as described herein. In some embodiments, the particular effect may be or comprise, for example, a mean duration of dialysis that is from about 3.0 days to about 2.0 days, from about 2.8 days to about 2.2 days, or from about 2.6 days to about 2.2 days shorter than that of an appropriate reference as described herein. [0181] In some embodiments, a particular effect may be or comprise, for example, a particular mean number of days a patient remains dialysis dependent within the first 30 days after renal transplantation. In some embodiments, a number of days a patient remains dialysis dependent is measured from the first day of treatment (i.e., within about 30 hours of renal transplantation) until either (i) the day of last dialysis session, wherein a last dialysis session is a dialysis session which is followed by 7 consecutive dialysis-free days, or (ii) Day 30. In some embodiments, the particular effect may be or comprise, for example, a fewer number of days a patient remains dialysis dependent within the first 30 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0182] In some embodiments, a particular effect may be or comprise, for example, a particular mean length of hospitalization after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a shorter mean length of hospitalization after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, a mean length of hospitalization after renal transplantation of less than about 11 days, about 10 days, about 9 days, or about 8 days. In some embodiments, the particular effect may be or comprise, for example, a mean length of hospitalization after renal transplantation of from about 6 days to about 11 days, from about 7 days to about 10 days, or from about 7 days to about 8 days. In some embodiments, the particular effect may be or comprise, for example, a mean length of hospitalization after renal transplantation of about 7.6 days. In some embodiments, the particular effect may be or comprise, for example, a mean length of hospitalization after renal transplantation of about 4.4 days, about 4.2 days, about 4.0 days, about 3.8 days, about 3.6 days, or about 3.4 days shorter than that of an appropriate reference, as described herein. [0183] In some embodiments, a particular effect may be or comprise, for example, a particular incidence of graft failure within 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a lower incidence of graft failure within 12 months after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). In some embodiments, the particular effect may be or comprise, for example, less than about 20%, about 15%, about 10%, or about 5% of subjects experiencing graft failure within 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, from about 30% to about 0%, from about from about 20% to about 0%, from about 10% to about 0% or from about 5% to about 0% of subjects experiencing graft failure within 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, about 0% of subject experiencing graft failure within 12 months after renal transplantation. In some embodiments, the particular effect may be or comprise, for example, a percentage of subjects experiencing graft failure that is about 20, about 25, about 30, or about 35 percentage points less than that of an appropriate reference as described herein. [0184] In some embodiments, a particular effect may be or comprise, for example, a particular incidence of DGF, as assessed by proportion of patients requiring dialysis within 7 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a lower incidence of DGF, as assessed by proportion of patients requiring dialysis within 7 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0185] In some embodiments, a particular effect may be or comprise, for example, a particular proportion of patients with primary non-function (PNF), defined as a continuous requirement for dialysis for at least 60 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a lesser proportion of patients with primary non-function (PNF), defined as a continuous requirement for dialysis for at least 60 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0186] In some embodiments, a particular effect may be or comprise, for example, a particular proportion of patients with slow graft function (SGF), defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required. In some embodiments, a particular effect may be or comprise, for example, a lesser proportion of patients with slow graft function (SGF), defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0187] In some embodiments, a particular effect may be or comprise, for example, a particular proportion of patients with (1) PNF (defined as a continuous requirement for dialysis for at least 60 days after renal transplantation); (2) DGF (assessed by proportion of patients requiring dialysis within 7 days after renal transplantation); (3) SGF (defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required); or (4) none of (1)-(3). In some embodiments, a particular effect may be or comprise, for example, a lesser proportion of patients with (1) PNF (defined as a continuous requirement for dialysis for at least 60 days after renal transplantation); (2) DGF (assessed by proportion of patients requiring dialysis within 7 days after renal transplantation); and/or (3) SGF (defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required), relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0188] In some embodiments, a particular effect may be or comprise, for example, a particular proportion of patients with acute rejection, e.g., at a particular time point, e.g., after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a lesser proportion patients with acute rejection, e.g., at a particular time point, e.g., after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0189] In some embodiments, a particular effect may be or comprise, for example, a particular level of C-reactive protein (CRP), e.g., at a particular time point, e.g., within about 1 day or about 3 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a particular decrease from baseline of CRP levels, e.g., at a particular time point, e.g., within about 3 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a greater decrease from baseline of CRP levels, e.g., at a particular time point, e.g., within about 3 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0190] In some embodiments, a particular effect may be or comprise, for example, a particular level of neutrophil gelatinase-associated lipocalin (NGAL), e.g., at a particular time point, e.g., within about 1 day or about 3 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a particular decrease from baseline of NGAL levels, e.g., at a particular time point, e.g., within about 3 days after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a greater decrease from baseline of NGAL levels, e.g., at a particular time point, e.g., within about 3 days after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0191] In some embodiments, a particular effect may be or comprise, for example, a particular level of kidney injury molecule-1 (KIM-1), e.g., at a particular time point, e.g., after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a particular difference from baseline of KIM-1 levels, e.g., at a particular time point, e.g., after renal transplantation. In some embodiments, a particular effect may be or comprise, for example, a greater difference from baseline of KIM-1 levels, e.g., at a particular time point, e.g., after renal transplantation, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition providing Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0192] In some embodiments, the present disclosure encompasses the recognition that administration of a composition providing Compound 1 to particular patient populations may achieve certain desirable results. In some embodiments, a composition providing Compound 1 is administered to a particular patient population according to a regimen established to achieve a particular effect (e.g., at a particular time point). [0193] In some embodiments, a particular effect in a population of subjects who have received a kidney from a donor after brain death (DBD) may be or comprise, for example, a particular incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation. In some embodiments, the particular effect in a population of subjects who have received a kidney from a DBD may be or comprise, for example, a greater incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation, relative to an appropriate reference (e.g., as is observed in a comparable population of subjects who have not received a kidney from a DBD). [0194] The present disclosure also provides methods of administering Compound 1 (e.g., by administering a composition that comprises and/or delivers Compound 1 as described herein) to a subject or population of subjects in need thereof, regardless of the subject’s malignancy status. Among other things, HGF/SF is known to stimulate c-MET (e.g., in injured organ tissues), which leads to activation of various cellular pathways, including, e.g., those involved in tissue repair. In addition, it is suspected that uncontrolled activation of c-MET can initiate tumorigenesis and/or stimulate tumor growth. As described above, Compound 1 is a HGF/SF mimetic, and as such, without wishing to be bound by theory, administration of Compound 1 under certain conditions might be expected to promote initiation or growth of cancer and/or other malignancies. Yet, experiments have demonstrated that, surprisingly, this may not be the case when Compound 1 is administered according to methods provided herein. Accordingly, the present disclosure encompasses the recognition that Compound 1 can be administered to a subject or population of subjects in need thereof, regardless of the subject’s malignancy status. It will be appreciated that such insight may be applicable not only to methods of treating indications described herein (e.g., treating DGF, improving renal function after kidney transplantation, etc.), but also to methods of treating any indication for which Compound 1 therapy is suitable. [0195] In some embodiments, the present disclosure provides methods comprising administering a composition providing Compound 1 (e.g., as provided herein) to a subject or population of subjects in need thereof, wherein the subject is suffering from an active malignancy or has suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of the composition). In some such embodiments, the subject has not suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. In some embodiments, the subject is suffering from or has suffered from glioma, colon cancer, or pancreatic cancer. [0196] In some embodiments, the present disclosure provides methods comprising administering a composition providing Compound 1 (e.g., as provided herein) to a subject or population of subjects in need thereof, wherein the subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy. In some embodiments, a subject has not be assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy if prior to administration of Compound 1 (e.g., within about 1 year, about 6 months, about 3 months, about 2 months, about 1 month, about 2 weeks, or about 1 week), the subject has not been questioned about and/or screened for an active malignancy or a history of a solid, metastatic or hematologic malignancy. In some embodiments, a subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy if a decision to administer Compound 1 therapy (e.g., by a physician) did not depend upon questioning of and/or screening of the subject for an active malignancy or a history of a solid, metastatic or hematologic malignancy. [0197] In some embodiments, one or more subjects or populations selected to receive Compound 1 as described herein are characterized by one or more factors such as, for example, one or more of: presence of one or more risk factors for DGF, characteristic(s) of donor source, etc. [0198] In some embodiments, a subject or population thereof has undergone renal transplantation. In some embodiments, a subject or population thereof has end-stage renal disease; alternatively or additionally, in some embodiments, a subject or population thereof has received and/or is receiving dialysis (e.g., maintenance dialysis). In some embodiments, a subject or population thereof has not undergone a preemptive renal transplantation. In some embodiments, a subject or population thereof did not exhibit normal urine output, e.g., prior to renal transplantation; alternatively or additionally, in some embodiments, a subject or population thereof did not receive dialysis prior to renal transplantation. In some embodiments, a subject or population thereof has or had renal failure requiring hemodialysis or peritoneal dialysis initiated at least 3 months prior to renal transplantation. [0199] In some embodiments, a subject or population thereof has undergone renal transplantation about 36 hours prior to administration of Compound 1 (e.g., within about 12 hours, about 18 hours, about 24 hours, about 30 hours, or about 36 hours of administration of Compound 1). In some embodiments, a subject or population thereof has undergone renal transplantation about 30 hours prior to administration of Compound 1 (e.g., within about 12 hours, about 18 hours, about 24 hours, or about 30 hours of administration of Compound 1). In some embodiments, blood flow was restored to an engrafted kidney during a subject or population’s renal transplantation about 30 hours prior to administration of Compound 1 (e.g., within about 12 hours, about 18 hours, about 24 hours, or about 30 hours of administration of Compound 1). [0200] In some embodiments, a subject or population thereof has undergone renal transplantation and is at risk of DGF. In some embodiments, a subject or population thereof who is at risk of DGF exhibits no urine output or an average urine output of less than 50 cc/h over at least 8 consecutive hours or exhibits normal urine output following transplantation that diminished to an average of less than 50 cc/h over at least 8 consecutive hours. In some embodiments, a subject or population thereof who is at risk of DGF exhibits a creatinine reduction ratio of less than 30% from pre-transplantation to 24 h after transplantation. [0201] In some embodiments, a subject or population thereof has received a kidney from a healthy donor. In some embodiments, a subject or population thereof has received a kidney from a donor with a history of diabetes mellitus (e.g., Type I diabetes or Type II diabetes) or hypertension. In some embodiments, a subject or population thereof has received a kidney from a donor without a history of diabetes mellitus (e.g., Type I diabetes or Type II diabetes) or hypertension. [0202] In some embodiments, a subject or population thereof has not previously undergone a renal transplantation. In some embodiments, a subject or population thereof has undergone only one renal transplantation. [0203] In some embodiments, a subject or population thereof has received a kidney from a live donor. In some embodiments, a subject or population thereof has received a kidney from a deceased donor (i.e., a cadaveric donor). In some embodiments, a subject or population thereof has received a kidney from a donor after brain death (DBD). In some embodiments, a subject or population thereof has received a kidney from a donor after cardiac death (DCD). [0204] In some embodiments, a subject or population thereof has received a kidney from a donor with a terminal serum creatinine concentration (SCr) of less than or equal to about 2.2 mg/dL. [0205] In some embodiments, a subject or population thereof has received a kidney with a cold ischemia time of less than or equal to about 40 h. In some embodiments, a subject or population thereof has received a kidney with a cold ischemia time of less than or equal to about 30 h. [0206] In some embodiments, a subject or population thereof has undergone a renal transplantation which utilized pulsatile machine perfusion (PMP). In some such embodiments, a subject or population thereof has received a kidney with a cold ischemia time of less than or equal to about 40 h. [0207] In some embodiments, a subject or population thereof is not and will not be the recipient of multiple organ transplantation. In some embodiments, a subject or population thereof is not the recipient of a pediatric en-bloc kidney transplantation. In some embodiments, a subject or population thereof is not the recipient of an ABO-incompatible kidney. In some embodiments, a subject or population thereof is not the recipient of a kidney preserved by normothermic machine perfusion. [0208] In some embodiments, a subject or population thereof did not have a measurable donor-specific antibody or positive cross-match requiring deviation from standard immunosuppressive therapy prior to renal transplantation. [0209] In some embodiments, a subject or population thereof is not receiving and has not received a cytochrome P4501A2 (CYP1A2) inhibitor, ciprofloxacin, or fluvoxamine. In some embodiments, a subject or population thereof is not receiving and has not received a cytochrome P4501A2 (CYP1A2) inhibitor. In some embodiments, a subject or population thereof is not receiving and has not received ciprofloxacin or fluvoxamine. [0210] In some embodiments, a subject or population thereof is female. In some such embodiments, a subject or population thereof had a negative pregnancy test prior to transplantation. In some such embodiments, a subject or population thereof is not breastfeeding. In some embodiments, a subject or population thereof is male. [0211] In some embodiments, a subject or population thereof is at least 18 years of age. [0212] In some embodiments, a subject or population thereof is not suffering from sepsis or an active bacterial infection. In some embodiments, a subject or population thereof does not have a history of a positive HIV test. [0213] In some embodiments, a subject or population thereof has a dry weight of less than or equal to 120 kg. In some embodiments, a subject or population thereof has a BMI of less than 35. In some embodiments, a subject or population thereof has a BMI of less than 40. [0214] In some embodiments, a subject or population is not suffering from or susceptible to a malignancy (e.g., an active malignancy). In some embodiments, a subject or population is not receiving treatment for a malignancy (e.g., an active malignancy). In some embodiments, a subject or population does not have a history of solid or hematological malignancies (e.g., within the past 5 years). In some embodiments, a subject or population is not suffering from or susceptible to a malignancy (e.g., an active malignancy) other than a basal or squamous cell carcinoma-in-situ of the skin that was diagnosed more than 2 years prior. In some embodiments, a subject or population thereof is not suffering from an active malignancy or has not suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of Compound 1 therapy). In some embodiments, a subject or population thereof has suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. [0215] In some embodiments, a subject or population is suffering from or susceptible to a malignancy (e.g., an active malignancy). In some embodiments, a subject or population is receiving treatment for a malignancy (e.g., an active malignancy). In some embodiments, a subject or population has a history of solid or hematological malignancies (e.g., within the past 5 years). In some embodiments, a subject or population is suffering from or susceptible to a malignancy (e.g., an active malignancy) other than a basal or squamous cell carcinoma-in-situ of the skin that was diagnosed more than 2 years prior. In some embodiments, a subject or population thereof is suffering from an active malignancy or has suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of Compound 1 therapy). In some embodiments, a subject or population thereof has not suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. In some embodiments, a subject or population thereof is suffering from or has suffered from glioma, colon cancer, or pancreatic cancer. [0216] In some embodiments, a subject or population thereof has not been assessed for an active malignancy or a history of solid or hematological malignancies. In some embodiments, a subject or population thereof has not been assessed for an active malignancy or a history of a solid, metastatic, or hematologic malignancy. In some embodiments, a subject or population thereof has an unknown malignancy status (i.e., an unknown medical history with respect to malignancies). Acute Kidney Injury Associated with Cardiac Surgery Involving Cardiopulmonary Bypass [0217] Provided methods of administering Compound 1 (e.g., administering Compound 1 to subjects receiving chronic hemodialysis and/or administering Compound 1 to subjects receiving a cytochrome P450 inhibitor and/or administering Compound 1 to subjects without cardiac risk factors and/or administering Compound 1 in an increased dose and/or dosing frequency and/or administering Compound 1 in a flat dose) may be useful for treating acute kidney injury associated with cardiac surgery involving cardiopulmonary bypass (CSA-AKI). [0218] Acute kidney injury (AKI) occurs in about one-third of patients who undergo cardiac surgery involving cardiopulmonary bypass. Patients who experience cardiac surgery-associated acute kidney injury (CSA-AKI) have longer hospital stays and are at higher risk of death, progression to chronic kidney disease, and/or need for renal replacement therapy. See Ayad, S., et al. Kidney Int Rep (2020) 5, 2325-2332. Currently, there is no specific treatment or preventative therapy for AKI following cardiac surgery. [0219] In some embodiments, the present disclosure provides certain technologies for preventing and/or treating (e.g., lessening the severity of, such as by delaying onset and/or reducing degree and/or frequency of one or more features of) acute kidney injury associated with cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. In some embodiments, provided technologies comprise administration of a hepatocyte growth factor mimetic (e.g., Compound 1). [0220] In some embodiments, the present disclosure encompasses the recognition that provided technologies may be particularly effective for improving long-term outcomes (e.g., kidney function) in patients, e.g., patients at risk of acute kidney injury after cardiac surgery involving cardiopulmonary bypass. For example, in some embodiments, the present disclosure provides methods demonstrated to reduce the incidence or likelihood of a major adverse kidney event within 90 days after cardiac surgery. In some embodiments, the present disclosure provides methods demonstrated to reduce incidence or likelihood of worsening kidney function (e.g., ≥ 25% decrease in eGFR from baseline) within 90 days after cardiac surgery. It will be appreciated that such long-term effects may not be apparent in populations or subjects within shorter time periods (e.g., benefits may not be apparent 1, 2, 3, 5, 7, 14, or 30 days after cardiac surgery but are apparent, e.g., 90 days, after cardiac surgery). [0221] In some embodiments, the present disclosure also encompasses the recognition that timing of administration of a hepatocyte growth factor mimetic (e.g., Compound 1) may be particularly important for achieving certain desirable outcomes (e.g., lower likelihood for major adverse kidney event(s), improved kidney function, etc.). Without wishing to be bound by theory, it is believed that administration of a hepatocyte growth factor mimetic (e.g., Compound 1) as soon as possible after injury may maximize its effect. For example, in some embodiments, a hepatocyte growth factor mimetic (e.g., Compound 1) is administered within 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, or 36 hours of injury. In some embodiments, a hepatocyte growth factor mimetic (e.g., Compound 1) is administered within 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours after completion of cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. [0222] In some embodiments, the present disclosure encompasses the recognition that when a hepatocyte growth factor mimetic (e.g., Compound 1) is administered as soon as possible after injury (e.g., as soon as possible after cardiac surgery involving cardiopulmonary bypass), then beneficial long-term outcomes are more likely, e.g., those described herein. [0223] In some embodiments, the present disclosure provides methods comprising administering a hepatocyte growth factor mimetic (e.g., Compound 1) to a subject or population of subjects who have undergone cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. [0224] In some embodiments, the present disclosure provides methods comprising administering a hepatocyte growth factor mimetic (e.g., Compound 1) to a subject or population of subjects at risk of acute kidney injury following cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. [0225] In some embodiments, the present disclosure provides methods of treating or preventing acute kidney injury (e.g., cardiac surgery-associated acute kidney injury) comprising administering a hepatocyte growth factor mimetic (e.g., Compound 1) to a subject or population of subjects in need thereof. [0226] In some embodiments, the present disclosure provides methods of reducing, in a subject or population of subjects, the incidence or likelihood of a major adverse kidney event comprising administering a hepatocyte growth factor mimetic (e.g., Compound 1) to a subject or population of subjects in need thereof. [0227] In some embodiments, the present disclosure provides methods of improving renal function and/or minimizing loss of renal function, comprising administering a hepatocyte growth factor mimetic (e.g., Compound 1) to a subject or population of subjects who have undergone cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. [0228] In some embodiments, the present disclosure provides methods of preventing and/or treating acute kidney injury, e.g., cardiac surgery-associated acute kidney injury (CSA-AKI), in a subject or population thereof, comprising administering Compound 1 to the subject in need thereof. In some embodiments, such administering is achieved by administering a composition that is or comprises Compound 1 or a composition that otherwise delivers Compound 1. [0229] In some embodiments, the present disclosure provides methods comprising administering Compound 1 to a subject or population of subjects who have undergone cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. In some embodiments, the cardiac surgery is or comprises coronary artery bypass graft; aortic valve replacement with or without aortic root repair; mitral, tricuspid, or pulmonic valve replacement or repair; combined replacement of several cardiac valves; coronary artery bypass graft with aortic, mitral, tricuspid, or pulmonic valve replacement or repair; or coronary artery bypass graft with combined cardiac valve replacement or repair. [0230] In some embodiments, a subject or population thereof is selected to receive Compound 1 as described herein based on one or more factors, such as, for example, the presence of one or more risk factors for CSA-AKI, etc. [0231] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who has undergone a cardiac surgical procedure involving cardiopulmonary bypass. In some embodiments, the cardiac surgical procedure involving cardiopulmonary bypass is coronary artery bypass graft; aortic valve replacement or repair with or without aortic root repair; mitral, tricuspid, or pulmonic valve replacement or repair; combined replacement of several cardiac valves; coronary artery bypass graft with aortic, mitral, tricuspid, or pulmonic valve replacement or repair; or coronary artery bypass graft with combined cardiac valve replacement or repair. [0232] In some embodiments, a subject or population thereof has undergone cardiac surgery (e.g., a non-emergent cardiac surgery). In some embodiments, a subject or population thereof has undergone cardiac surgery involving cardiopulmonary bypass. In some embodiments, a subject or population thereof has undergone coronary artery bypass graft. In some embodiments, a subject or population thereof has undergone aortic valve replacement or repair with or without aortic root repair. In some embodiments, a subject or population thereof has undergone mitral, tricuspid, or pulmonic valve replacement or repair. In some embodiments, a subject or population thereof has undergone combined replacement of several cardiac valves. In some embodiments, a subject or population thereof has undergone coronary artery bypass graft with aortic, mitral, tricuspid, or pulmonic valve replacement or repair. In some embodiments, a subject or population thereof has undergone coronary artery bypass graft with combined cardiac valve replacement or repair. [0233] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who has one or more of the following AKI risk factors (e.g., prior to cardiac surgery involving cardiopulmonary bypass): ● estimated glomerular filtration rate (eGFR) of ≥ 20 and < 30 mL/min/1.73m²; ● eGFR ≥ 30 and < 60 mL/min/1.73m² and one of the Additional Risk Factors (other than age ≥ 75 years); or ● eGFR ≥ 60 mL/min/1.73m² and two of the Additional Risk Factors, wherein the Additional Risk Factors are selected from: ● undergoing a combined valve and coronary surgery; ● previous cardiac surgery with sternotomy; ● left ventricular ejection fraction (LVEF) ≤ 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days prior to surgery; ● diabetes mellitus requiring insulin treatment; ● non-insulin-requiring diabetes with documented presence of at least moderate (+2 or > 100 mg/dL) proteinuria on urine analysis (via medical history or dipstick); ● documented New York Heart Association (NYHA) Class III or IV within 1 year prior to index surgery; and ● age ≥ 75 years only if eGFR ≥ 60 mL/min/1.73m². [0234] In some embodiments, a subject or population thereof has an eGFR of ≥ 20 and < 30 mL/min/1.73m², e.g., prior to cardiac surgery. In some embodiments, a subject or population thereof has an eGFR of ≥ 30 and < 60 mL/min/1.73m², e.g., prior to cardiac surgery. In some embodiments, a subject or population thereof has an eGFR of ≥ 60 mL/min/1.73m², e.g., prior to cardiac surgery. [0235] In some embodiments, prior to surgery, a subject or population thereof has an eGFR of ≥ 20 and < 30 mL/min/1.73m² and at least one AKI risk factor selected from the group consisting of: (a) undergoing a combined valve and coronary surgery; (c) left ventricular ejection fraction (LVEF) of ≤ 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days before the cardiac surgery; (d) diabetes mellitus requiring insulin treatment; (e) non-insulin-requiring diabetes with documented presence of at least moderate proteinuria (+2 or ≥ 100 mg/dL) on urine analysis via medical history or dipstick; and (f) documented New York Heart Association (NYHA) Class III or IV within 1 year before the cardiac surgery. [0236] In some embodiments, prior to surgery, a subject or population thereof has an eGFR of ≥ 30 and < 60 mL/min/1.73m² and at least one AKI risk factor selected from the group consisting of: (a) undergoing a combined valve and coronary surgery; (b) previous cardiac surgery with sternotomy; (c) left ventricular ejection fraction (LVEF) of ≤ 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days before the cardiac surgery; (d) diabetes mellitus requiring insulin treatment; (e) non-insulin-requiring diabetes with documented presence of at least moderate proteinuria (+2 or ≥ 100 mg/dL) on urine analysis via medical history or dipstick; and (f) documented New York Heart Association (NYHA) Class III or IV within 1 year before the cardiac surgery. [0237] In some embodiments, prior to surgery, a subject or population thereof has an eGFR of ≥ 60 mL/min/1.73m² and at least two AKI risk factors selected from the group consisting of: (a) undergoing a combined valve and coronary surgery; (b) previous cardiac surgery with sternotomy; (c) left ventricular ejection fraction (LVEF) of ≤ 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days before the cardiac surgery; (d) diabetes mellitus requiring insulin treatment; (e) non-insulin-requiring diabetes with documented presence of at least moderate proteinuria (+2 or ≥ 100 mg/dL) on urine analysis via medical history or dipstick; (f) documented New York Heart Association (NYHA) Class III or IV within 1 year before the cardiac surgery; and (g) age ≥ 75 years if eGFR is ≥ 60 mL/min/1.73m². [0238] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who does not have prior evidence of active renal injury (e.g., no acute rise in serum creatinine > 0.3 mg/dL). [0239] In some embodiments, provided methods further comprise administering Compound 1 to a subject who has eGFR ≥ 20 mL/min/1.73m² within 48 hours pre-surgery. [0240] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who (i) does not have ongoing sepsis or partially treated infection; (ii) does not have currently active infection requiring antibiotic treatment; (iii) does not have active malignancy or history of solid, metastatic or hematologic malignancy within 5 years prior to administration, with the exception of basal or squamous cell carcinoma of the skin that has been removed; (iv) has not been administered iodinated contrast material within 24 hours prior to surgery; and/or (v) is not diagnosed with AKI as defined by KDIGO criteria within 48 hours prior to surgery. [0241] In some embodiments, a subject or population thereof has not (i) experienced cardiogenic shock or hemodynamic instability within 24 hours prior to surgery; and/or (ii) required cardiopulmonary resuscitation within 7 days prior to cardiac surgery. [0242] In some embodiments, a subject or population thereof has no need for a defibrillator or permanent pacemaker, mechanical ventilation, IABP, LVAD, or other form of mechanical circulatory support within 7 days prior to surgery. [0243] In some embodiments, a subject or population thereof has not experienced an intra- operative complication during a cardiac surgery, e.g., involving cardiopulmonary bypass. For example, intra-operative complications may include implantation of an IABP or LVAD, acute myocardial infarction, cardiac arrest, and procedure-associated decrease in ejection fraction. [0244] In some embodiments, the present disclosure provides methods of treating or preventing acute kidney injury (e.g., cardiac surgery-associated acute kidney injury) comprising administering Compound 1 to a subject or population of subjects in need thereof. It will be appreciated that a regimen that treats or prevents acute kidney function may encompass a regimen that has been established, in a population of subjects, to preserve kidney function (i.e., no further loss of kidney function relative to before and/or after surgery) and/or to restore kidney function (i.e., kidney function is increased relative to before and/or after surgery). [0245] In some embodiments, the present disclosure provides methods of reducing, in a subject or population of subjects, the incidence or likelihood of a major adverse kidney event comprising administering Compound 1 to a subject or population of subjects in need thereof. As used herein, a major adverse kidney event (MAKE) is (i) death; (ii) need for renal replacement therapy; or (iii) worsening of kidney function, defined as a ≥ 25% reduction in eGFR. See Billings, F.T. and Shaw A.D., Nephron. Clin. Pract.2014; 127(0): 89-93. [0246] In some embodiments, the present disclosure provides methods of improving renal function, comprising administering Compound 1 to a subject or population of subjects who have undergone cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. Improved renal function can be evaluated by any suitable means. In some embodiments, improved renal function is indicated by a reduced KDIGO stage of AKI severity (e.g., a reduction of one or more units). In some embodiments, improved renal function is indicated by increased eGFR and/or decreased serum creatinine. In some embodiments, improved renal function is indicated by reduced proteinuria. [0247] In some embodiments, the present disclosure provides methods of minimizing loss of renal function, comprising administering Compound 1 to a subject or population of subjects who have undergone cardiac surgery, e.g., cardiac surgery involving cardiopulmonary bypass. Minimization of loss of renal function can be evaluated by any suitable means. In some embodiments, a regimen that minimizes loss of renal function has been established, in a population of subjects, to achieve a lesser decrease in kidney function (e.g., lesser decrease in eGFR and/or lesser increase in serum creatinine), relative to a comparable reference population. [0248] In some embodiments, provided methods comprise administering Compound 1 within a particular time after completion of cardiac surgery (e.g., cardiac surgery involving cardiopulmonary bypass). In some embodiments, a first dose of Compound 1 is administered within 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 26 hours, 28 hours, 30 hours, 32 hours, 34 hours, or 36 hours of completion of cardiac surgery. In some embodiments, Compound 1 is administered within 10 hours of completion of cardiac surgery. In some embodiments, Compound 1 is administered within 6 hours of completion of cardiac surgery. In some embodiments, Compound 1 is administered within 4 hours of completion of cardiac surgery. In some embodiments, Compound 1 is administered within 2 hours of completion of cardiac surgery. In some embodiments, Compound 1 is administered within 1 hour of completion of cardiac surgery. [0249] In some embodiments, provided methods comprise administering Compound 1 to a subject or population thereof according to a regimen established to achieve one or more particular effects. In some embodiments, a regimen has been established to achieve one or more particular effects relative to that observed for a comparable reference population that has not received Compound 1 (e.g., that has received a reference composition which does not deliver Compound 1). In some embodiments, provided methods comprise administering Compound 1 to a subject or population thereof according to a regimen established to achieve a particular effect at a particular time point. In some embodiments, provided methods comprise administering Compound 1 to a subject or population thereof according to a regimen established to achieve a particular effect at a particular time point, relative to an appropriate reference as described herein. [0250] In some embodiments, a particular effect is or comprises incidence of major adverse kidney events, e.g., within 30 days or 90 days after cardiac surgery. [0251] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a major adverse kidney event within 90 days (MAKE90) after cardiac surgery, relative to a comparable reference population. [0252] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a major adverse kidney event within 30 days (MAKE30) after cardiac surgery, relative to a comparable reference population. [0253] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a decline in eGFR of ≥ 25% from baseline within, e.g., 2 days, 3 days, 4 days, 7 days, 14 days, 30 days, or 90 days, after cardiac surgery, relative to a comparable reference population. [0254] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a decline in eGFR of ≥ 25% within 90 days after cardiac surgery, relative to a comparable reference population. [0255] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a decline in eGFR of ≥ 25% within 30 days after cardiac surgery, relative to a comparable reference population. [0256] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects who experienced a decline in eGFR of ≥ 20% from baseline within, e.g., 2 days, 3 days, 4 days, 7 days, 14 days, 30 days, or 90 days, after cardiac surgery, relative to a comparable reference population. [0257] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects diagnosed with AKI (e.g., according to KDIGO criteria) within 5 days after cardiac surgery, relative to a comparable reference population. [0258] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in the number of subjects diagnosed with AKI (e.g., according to KDIGO criteria) within 7 days after cardiac surgery, relative to a comparable reference population. [0259] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a reduction in length of hospitalization (e.g., as measured from 24 hours after the end of cardiac surgery), relative to a comparable reference population. [0260] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a lesser mean maximum percent increase in serum creatinine from baseline within 6 days after cardiac surgery, relative to a comparable reference population. [0261] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a lesser mean AUC of the percent increase in serum creatinine above baseline within 6 days after cardiac surgery, relative to a comparable reference population. [0262] In some embodiments, provided methods comprise administering to a subject or population thereof a composition comprising Compound 1 according to a regimen established to achieve a lesser time to recovery from AKI (e.g., in subjects diagnosed before Day 5 or Day 7), relative to a comparable reference population. In some such embodiments, recovery from AKI is defined as a return of serum creatinine levels to baseline or below. [0263] In some embodiments, provided methods comprise administering a composition comprising Compound 1 according to a regimen established to achieve one or more of the following: ● lesser mean AUC of the percent increase in serum creatinine (sCr) above baseline over time, starting from 24 hours after the end of CPB through Day 6; ● greater or lesser change in eGFR from baseline to Day 30 (e.g., greater increase in eGFR from baseline to Day 30 and/or lesser decrease in eGFR from baseline to Day 30); ● lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 5; ● shorter length of hospitalization starting from 24 hours after the end of CPB; ● lesser maximum percent increase in sCr level from baseline that occurs between 24 hours after the end of CPB and/or Day 6; ● lesser mean AUC of the percent increase in sCr above baseline over time, starting from the end of CPB through Day 5, through Day 7, through Day 14, and/or through Day 30; ● lesser mean percent increase of sCr above Baseline, at 24 hours after the end of CPB, and/or at Day 3, Day 4, Day 5, and/or Day 7; ● lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 7; ● lesser proportion of patients with severe renal injury using KDIGO AKI staging, at 24 hours after the end of CPB, at Day 3, at Day 4, Day 5, Day 7, Day 14, and/or Day 30; ● lesser proportion of patients with AKI at 24 hours after the end of CPB, Day 3, Day 4, Day 5, and/or Day 7; ● shorter time in days from the occurrence of AKI diagnosed postoperatively through Day 5 to recovery from AKI and/or through Day 7 to recovery from AKI; ● shorter time in days to improvement (e.g., reduction in KDIGO’s stage of AKI severity by one or more unit) in renal function from the day of occurrence of AKI diagnosed postoperatively through Day 5 and/or through Day 7; ● among patients with AKI diagnosed postoperatively through Day 5, greater proportion of patients with renal function recovery, progression, or stabilization at Day 30; ● greater slope of decline of the creatinine curve from the day of peak sCr through Day 5, Day 7, Day 14 and/or Day 30; ● lesser proportion of patients requiring initiation of any form of renal replacement therapy (RRT) during the index hospitalization and within Days 1-30; ● lesser proportion of patients developing a composite endpoint comprising the following events: death, worsening of kidney function defined as ≥ 25% decrease in eGFR from baseline, or receiving renal replacement therapy (RRT) during the 30-day and/or 90-day postoperative periods; and ● lesser proportion of patients having a ≥ 20 % reduction from baseline in eGFR at Days 2, 3, 4, 7, 14, 30, and/or 90, relative to a comparable reference population. [0264] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who has undergone cardiac surgery involving cardiopulmonary bypass (CPB) and is at risk of AKI, according to a regimen established to achieve greater mean AUC of the percent increase in serum creatinine above baseline, starting from 24 hr after the end of CPB through Day 6, relative to a comparable reference population. [0265] In some embodiments, provided methods further comprise administering Compound 1 to a subject or population of subjects who has undergone cardiac surgery involving cardiopulmonary bypass (CPB) and is at risk of AKI, according to a regimen established to achieve one or more of the following: ● greater mean AUC of the percent increase in serum creatinine above baseline, starting from 24 hr after the end of CPB through Day 6; ● greater maximum percent increase in sCr level from baseline Day 5; ● greater mean percent increase in serum creatinine above baseline over time starting from the end of CPB through Day 5, through Day 7, through Day 14, and through Day 30; ● greater mean percent increase of sCr above baseline at 24 hr after the end of CPB, and at Day 3, Day 4, Day 5, and Day 7; ● lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 5; ● lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 7; ● greater proportion of subjects with less severe renal injury using KDIGO AKI staging at 24 hr after the end of CPB, at Day 3, at Day 4, Day 5, Day 7, Day 14, and Day 30; ● lesser proportion of subjects with AKI at 24 hr after the end of CPB, Day 3, Day 4, Day 5, Day 7; ● lesser time in days from the occurrence of AKI diagnosed postoperatively through Day 5 to recovery from AKI and through Day 7 to recovery from AKI; ● lesser time in days to improvement in renal function from the day of occurrence of AKI diagnosed postoperatively through Day 5 and through Day 7; ● greater proportion of subjects with renal function recovery, progression, or stabilization among subjects with AKI diagnosed postoperatively at Day 30; ● greater proportion of subjects with renal function recovery, progression, or stabilization through Day 5, among subjects with AKI diagnosed postoperatively; ● greater slope of decline of the creatinine curve from the day of peak sCr through Day 5, Day 7, Day 14 and Day 30; ● lesser proportion of subjects requiring initiation of any form of renal replacement therapy up to Day 30; ● shorter length of index hospital stay through Day 90; ● lesser proportion of subjects developing a composite endpoint comprising the following events: death, worsening of kidney function during the 30-day post-operative period, and worsening of kidney function during 90-day post-operative period; ● greater change from baseline in eGFR at Days 4, 7, 14, 30 and 90; ● lesser proportion of subjects having a ≥ 20 % reduction from baseline in eGFR at Days 2, 3, 4, 7, 14, and 30 and 90; ● greater maximal change from baseline in eGFR and sCr through Day 90; and ● greater urine volume over 12-hour periods for the first 72 hours post-CPB, relative to a comparable reference population. [0266] In some embodiments, provided methods comprise administering Compound 1 once daily for 4 days. In some embodiments, provided methods comprise administering Compound 1 as a daily intravenous infusion for 4 days. In some embodiments, provided methods comprise administering the first dose of Compound 1 within 4 hours of completing CPB. [0267] In some embodiments, a composition providing Compound 1 is administered intravenously. In some embodiments, a composition providing Compound 1 is administered over about 10 min, about 20 min, about 30 min, or about 40 min. In some embodiments, a composition providing Compound 1 is administered intravenously in an amount suitable to provide about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg Compound 1. In some embodiments, a composition providing Compound 1 is administered intravenously at an infusion rate suitable to provide about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, or about 10 mg/kg Compound 1 over about 10 min, about 20 min, about 30 min, or about 40 min. In some embodiments, compositions comprising Compound 1 are administered as an infusion over about 30 min in an amount suitable to provide about 2 mg/kg Compound 1. Acute Lung Injury [0268] Provided methods of administering Compound 1 (e.g., administering Compound 1 to subjects receiving chronic hemodialysis and/or administering Compound 1 to subjects receiving a cytochrome P450 inhibitor and/or administering Compound 1 to subjects without cardiac risk factors and/or administering Compound 1 in an increased dose and/or dosing frequency and/or administering Compound 1 in a flat dose) may be useful for treating acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). [0269] Provided herein are methods of treating a subject or a population of subjects comprising administering Compound 1 (e.g., by administering a composition that comprises and/or delivers Compound 1 as described herein) to the subject(s) in need thereof. In some embodiments, such administering is achieved by administering a composition that delivers Compound 1 (e.g., in some embodiments, a composition that is or comprises Compound 1, or a composition that otherwise delivers Compound 1 – e.g., that is or comprises a prodrug of Compound 1, a complex or other entity that releases Compound 1 upon administration, etc.). [0270] In some embodiments, the present disclosure provides methods of treating a respiratory disease, disorder or condition comprising administering to a subject or a population susceptible to or suffering from a respiratory disease, disorder or condition a composition that provides Compound 1. In some embodiments, the present disclosure provides methods of treating acute lung injury or acute respiratory distress syndrome in a subject or population in need thereof comprising administering to the subject a composition that provides Compound 1. In some embodiments, the present disclosure provides methods of treating acute lung injury in a subject or population in need thereof comprising administering to the subject a composition that provides Compound 1. In some embodiments, the present disclosure provides methods of treating acute respiratory distress syndrome in a subject or population in need thereof comprising administering to the subject a composition that provides Compound 1. [0271] Acute lung injury and the more severe acute respiratory distress syndrome (ARDS) represent a spectrum of lung disease characterized by the sudden onset of pulmonary edema, inflammatory cell infiltration and impaired oxygenation. Current treatment strategies for severe ARDS include mechanical ventilation which, while potentially life-saving, can exacerbate lung injury, and antibiotics, which are the standard of care under certain treatment guidelines. Antibiotics are generally given prophylactically to prevent secondary infection related to ARDS as opposed to treating the ARDS itself. There are no approved pharmacologic options for ARDS. Common causes of ALI and ARDS include aspiration pneumonia, viral or bacterial pneumonia, sepsis, inhalational injury (e.g., from smoke or chemicals), trauma, and blood transfusions. [0272] ARDS is generally defined by the 2012 ARDS Task Force “Berlin” definition. Key components of the Berlin definition are acute hypoxemia in ventilated patients receiving certain levels of positive end expiratory pressure and demonstration of non-cardiogenic bilateral opacities on imaging studies, with severity graded into mild, moderate, and severe ARDS, based on the PaO₂/FiO ratio. [0273] In some embodiments, the present disclosure provides methods comprising administering to a subject or population who is suffering from or susceptible to a respiratory disorder a composition that provides Compound 1. In some embodiments, a subject or population is suffering from or susceptible to acute lung injury. In some embodiments, a subject or population is suffering from or susceptible to acute respiratory distress syndrome. [0274] In some embodiments, the present disclosure provides methods of administering Compound 1 to a population of subjects who are suffering from or susceptible to a respiratory disease, disorder or condition as described herein, for example by administering a composition that provides Compound 1, e.g., according to a dosing regimen described herein. In some embodiments, a population is a population of subjects who are suffering from or susceptible to acute lung injury. In some embodiments, a population is a population of subjects who are suffering from or susceptible to acute respiratory distress syndrome. [0275] In some embodiments, the present disclosure provides methods of administering Compound 1 to a population of subjects who are suffering from or susceptible to a respiratory disease, disorder or condition as described herein, for example by administering a composition that provides Compound 1, e.g., according to a regimen established to achieve one or more desirable outcomes. In some embodiments, a population is a population of subjects who are suffering from or susceptible to acute lung injury. In some embodiments, a population is a population of subjects who are suffering from or susceptible to acute respiratory distress syndrome. In some embodiments, a regimen is or has been established to achieve one or more desirable outcomes in a population to which Compound 1 has been administered, relative to a comparable reference population that has not received Compound 1 (e.g., that has received a reference composition which does not deliver Compound 1). [0276] In some embodiments, in methods provided herein, a reference population has not received a composition that provides Compound 1. In some embodiments, in methods provided herein, a reference population has received an otherwise comparable reference composition that does not provide Compound 1 (e.g., a placebo, such as normal saline). In some embodiments, in methods provided herein, a reference composition may be or comprise normal saline. In some embodiments, in methods provided herein, a reference composition may be or may have been administered at the same intervals and/or volumes as a composition that provides Compound 1. [0277] In some embodiments, certain parameters may be evaluated to determine if a desirable outcome is achieved. Any one or more of parameters such as these may, in some embodiments, be useful for determining short-term and/or long-term efficacy of Compound 1 administered to the patient population. Alternatively or additionally, any one or more of such parameters may be assessed to monitor patient response to Compound 1 therapy. [0278] In some embodiments, the present disclosure provides a method comprising: administering to a subject, or to a population of subjects, suffering from or susceptible to a respiratory disease, disorder or condition as described herein a composition that provides Compound 1 according to a regimen established to achieve one or more of: decreased lung injury score, reduced mortality, reduced lung histopathology, better cytokine evaluation, better lung MPO measurement, improved pulmonary function, reduced lung obstruction in bronchus and bronchioles, and better cardiopulmonary variables, relative to a comparable reference population. [0279] In some embodiments, the present disclosure provides methods of improving outcomes for patients suffering from or susceptible to a disease, disorder or condition that is (i.e., is statistically and/or is in fact for the particular patient) associated with one or more undesirable respiratory features such as for example inflammation in the lungs, fluid in the lungs, fibroids in the lungs, etc., by administration of Compound 1 (e.g., alone and/or in combination with other therapy, for example directed at the underlying disease, disorder or condition, or otherwise being used in treatment of the patient(s)). [0280] In some embodiments, the disease, disorder or condition being treated in methods provided herein is characterized by pulmonary edema, pulmonary epithelial cell apoptosis, inflammatory cell infiltration, impaired oxygenation, hypoxemia and/or lung fibrosis. [0281] In some embodiments, a composition that provides Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point (e.g., about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after injury and/or randomization and/or first administration of Compound 1). In some embodiments, a composition that provides Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0282] In some embodiments, a particular effect may be or comprise: decreased lung injury score, reduced mortality, reduced lung histopathology, better cytokine evaluation, better lung MPO measurement, improved pulmonary function, reduce lung obstruction in bronchus and bronchioles, and/or better cardiopulmonary variables. [0283] In some embodiments, a particular effect may be or comprise decreased mortality rate relative to a comparable reference population. [0284] In some embodiments, a particular effect may be or comprise increased lung function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: increased pulmonary output, increased arterial oxygen (PaO₂), decreased arterial carbon dioxide (PaCO₂), increased ratio of PaO₂/FiO₂, decreased lung injury score, decreased lung hydroxyproline concentration, decreased lung collagen level, decreased lung TGFβ1 concentration, and increased blood pH, relative to a comparable reference population. [0285] In some embodiments, a particular effect may be or comprise increased kidney function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of kidney function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: decreased serum creatinine concentration, increased estimated glomerular filtration rate (eGFR), decreased blood urea nitrogen concentration, increased urine output, decreased kidney TGFβ1 concentration, and lesser incidence of dialysis, relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: decreased serum creatinine concentration, reduced change in serum creatinine concentration (e.g., over a particular period of time), increased estimated glomerular filtration rate (eGFR), reduced change in eGFR (e.g., over a particular period of time), increased measured glomerular filtration rate, reduced change in measured glomerular filtration rate (e.g., over a particular period of time), decreased blood urea nitrogen concentration, reduced change in blood urea nitrogen concentration (e.g., over a particular period of time), increased urine output, decreased kidney TGFβ1 concentration, and lesser incidence of dialysis, relative to a comparable reference population. Kidney function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, kidney function is evaluated based on one or more of blood urea nitrogen concentration, serum creatinine concentration, eGFR, measured glomerular filtration rate, serum albumin concentration, urinalysis, renal clearance, renal imaging, renal histology, etc. [0286] In some embodiments, a particular effect may be or comprise improved heart function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of heart function relative to a comparable reference population. Heart function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, heart function is evaluated based on one or more of troponin I levels, 12-lead electrocardiogram, echocardiogram, radiographic or nuclear medicine imaging, cardiac histology, etc. [0287] In some embodiments, a particular effect may be or comprise improved liver function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of liver function relative to a comparable reference population. Liver function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, liver function is evaluated based on one or more of serum albumin concentration; total, direct, and/or indirect bilirubin levels; aspartate aminotransferase levels; alanine aminotransferase levels; alkaline phosphatase levels; gamma-glutamyl transpeptidase levels; imaging; histology, etc. [0288] In some embodiments, the particular effect may be or comprise, for example, one or more effects as described in the Examples herein. [0289] In some embodiments, Compound 1 is useful in treating a disorder or condition selected from acute lung injury, acute respiratory distress syndrome, pneumonia (e.g., influenza- associated pneumonia or COVID-19-associated pneumonia), pulmonary edema, TGFβ1-induced lung injury, emphysema, chemically-induced (e.g., chlorine gas) lung injury, thermally-induced (e.g., smoke or burn) lung injury, shock-induced lung injury (e.g., lipopolysaccharide-induced shock), ischemic reperfusion lung injury, hemorrhagic shock lung injury, radiation-induced lung injury, blunt trauma to lung, and lung transplantation injury (see, for example, Huang C, e al. The Lancet.2020 Jan 24.; Chen N, et al. The Lancet.2020 Jan 30; Hess, D.R. Semin. Respir. Crit. Care Med.2014 Aug;35(4):418-30; Hess, D.R. Respir Care.2011 Oct;56(10):1555-72; Brower, R.G., Fessler, H.E. Clin. Chest Med.2000 Sep;21(3):491-510; Haas, C.F. Crit. Care Clin.2011 Jul;27(3):469-86; Siobal, M.S., Hess, D.R. Respir. Care 2010 Feb;55(2):144-57, discussion 157- 61; Izumida, H., Fujishima, S. Masui 2013 May;62(5)541-6; Wang D et al. JAMA Published online February 7, 2020; Zhu, et al. Zhonghua Liu Xing Bing Xue Za Zhi.2020;41(2):145–151; Xu, Z., et al. Lancet Respir. Med.2020 Feb 18; and Brauer, R. et al. Amer. J. Respir. Crit. Care Med.2016 Aug 1;194(3), the entirety of each of which is incorporated herein by reference). In some embodiments, Compound 1 is useful in treating a disorder or condition selected from acute lung injury, acute respiratory distress syndrome, pneumonia (e.g., influenza-associated pneumonia or COVID-19-associated pneumonia or aspiration pneumonia), pulmonary edema, chemically-induced (e.g., chlorine gas) lung injury, thermally-induced (e.g., smoke or burn) lung injury, shock-induced lung injury (e.g., septic shock or lipopolysaccharide-induced shock or cardiogenic shock), ischemic reperfusion lung injury, hemorrhagic shock lung injury, radiation- induced lung injury, blunt trauma to lung, and lung transplantation injury. [0290] It will be appreciated that acute organ injury is the rapid deterioration of organ function and viability. Acute organ injury triggers immediate activation of repair pathways, which help to restore function and facilitate recovery of the injured organ. Without wishing to be bound by theory, it is believed that the HGF/c-Met pathway is the most important repair pathway triggered in response to an acute organ injury. [0291] In some embodiments, provided methods are useful for treating an acute organ injury (e.g., an acute injury of the lung). In some embodiments, provided methods comprise administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population who has experienced or is experiencing acute organ injury (e.g., an acute injury of the lung). In some embodiments, acute organ injury is caused by ischemia/hypoxia (i.e., oxygen deprivation of the organ). In some embodiments, acute organ injury is caused by reperfusion injury, which can lead to hemodynamic shear. In some embodiments, acute organ injury is caused by viral infection, such as by H1N1, a coronavirus (e.g., SAR-CoV-2, MERS-CoV, or SARS-CoV), influenza, etc. In some embodiments, acute organ injury is caused by traumatic injury such as by blunt trauma, thermal burns, chemical burns or injury, etc. [0292] In some embodiments, the present disclosure provides a method of protecting an organ (e.g., the lung) from injury, the method comprising administering to a subject or population an HGF/SF mimetic (e.g., Compound 1). In some embodiments, the present disclosure provides a method of promoting alveolar regeneration, the method comprising administering to a subject or population an HGF/SF mimetic (e.g., Compound 1). [0293] In some embodiments, the present disclosure provides a method of administering a HGF/SF mimetic (e.g., Compound 1) according to a regimen established to achieve one or more of: reduction of ongoing apoptosis and injury, thus maintaining the alveolar barrier integrity; mitigation of a rise in alveolar wall permeability and fluid extravasation in the alveolar space; improvement in gas exchange due to preservation of alveolar wall and reducing the alveolar wall and space edema; reduction in the inflammatory cell infiltration of the lungs; and induction of proliferation and regeneration of the alveolar epithelial cells, relative to a comparable reference population. [0294] In some embodiments, the present disclosure provides a method of stimulating human endothelia and/or bronchial cell proliferation without creating fibroblasts, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some such embodiments, the present disclosure provides a method of increasing the levels of endothelial and/or bronchial cell proliferation, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0295] In some embodiments, provided methods are useful for treating pulmonary edema. In some embodiments, provided methods are useful for treating a disease, disorder, or condition characterized by pulmonary edema. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to pulmonary edema. In some embodiments, the present disclosure provides a method of decreasing or attenuating pulmonary edema, relative to a comparable reference population, in a subject or population suffering from acute lung injury, the method comprising administering to the subject or population a HGF/SF mimetic (e.g., Compound 1). In some embodiments, the present disclosure provides a method of preventing, attenuating, or reducing red cell and/or neutrophil infiltration in alveolar spaces, relative to a comparable reference population, in a subject or population suffering from acute lung injury, the method comprising administering to the subject or population a HGF/SF mimetic (e.g., Compound 1). In some such embodiments, the HGF/SF mimetic (e.g., Compound 1) is administered 12 or 24 hours, or more, following lung injury. [0296] A variety of pulmonary insults stimulates production and release of TGFβ1 into the pulmonary parenchyma, leading to acute cell death. Transforming growth factor beta (TGFβ1) is a protein that controls proliferation, cellular differentiation, and other functions in most cells and is known to be a critical mediator in acute lung injury. Accordingly, provided methods are useful in treating TGFβ1-induced acute lung injury. In some embodiments, the present disclosure provides a method of preventing, delaying the onset of, or reducing the severity of TGFβ1- induced acute lung injury, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of decreasing pulmonary cell death, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of improving pulmonary epithelial regeneration, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of preserving or maintaining pulmonary architecture and/or reducing alveolar flooding, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0297] In some embodiments, provided methods are useful for treating shock-associated acute lung injury. Shock-associated acute lung injury can have a variety of underlying causes, including septic shock, LPS-induced shock, hemorrhagic shock, or cardiogenic shock. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to shock-associated acute lung injury (e.g., acute lung injury associated with septic shock, LPS-induced shock, hemorrhagic shock, or cardiogenic shock). In some embodiments, the present disclosure provides a method of attenuating shock-associated acute lung injury, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of preventing, attenuating, mitigating, or reducing histopathological lung injury score, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of preventing, attenuating, mitigating, or reducing apoptotic cell death, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0298] In some embodiments, provided methods are useful for treating a chemically induced acute lung injury. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to a chemically induced acute lung injury. In some embodiments, a subject or population has been exposed to chlorine gas, phosgene gas, or other inhaled toxin. In some embodiments, the present disclosure provides a method of preventing, delaying the onset of, or reducing the severity of chemically induced acute lung injury, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of preventing, delaying the onset of, or reducing the severity of pulmonary infiltration, relative to a comparable reference population, in a subject or population suffering from chemically induced acute lung injury, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0299] In some embodiments, the present disclosure provides a method of maintaining, enhancing, or increasing pulmonary output and/or arterial oxygen levels, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of maintaining, enhancing, or increasing arterial oxygen levels, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0300] In some embodiments, provided methods are useful for treating acute lung injury associated with hemorrhagic shock (e.g., hemorrhagic shock from trauma). In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to acute lung injury associated with hemorrhagic shock (e.g., hemorrhagic shock from trauma). In some embodiments, the present disclosure provides a method of attenuating and/or decreasing lung injury associated with hemorrhagic shock, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0301] In some embodiments, provided methods are useful for treating ischemia-reperfusion lung injury. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to ischemia-reperfusion lung injury (e.g., a subject or population of subjects who have undergone lung transplantation). In some embodiments, the present disclosure provides a method of attenuating ischemia-reperfusion lung injury, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of attenuating alveolar thickening, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some such embodiments, the HGF/SF mimetic (e.g., Compound 1) protects or preserves pulmonary architecture following ischemic reperfusion. In some embodiments, the present disclosure provides a method of preventing, attenuating, delaying the onset of, or mitigating IL-1 and/or IL-6 bronchoalveolar lavage fluid (BALF) accumulation, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0302] In some embodiments, provided methods are useful for treating emphysema. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to emphysema. In some embodiments, the present disclosure provides a method of preventing, delaying the onset of, or reducing the severity of emphysema, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of increasing arterial levels of PaO₂, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of decreasing arterial levels of PaCO₂, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0303] In some embodiments, provided methods are useful for treating a thermally induced acute lung injury (e.g., an acute lung injury associated with smoke inhalation and/or thermal burn). In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to a thermally induced acute lung injury (e.g., an acute lung injury associated with smoke inhalation and/or thermal burn). In some embodiments, the present disclosure provides a method of attenuating lung injury associated with or resulting from a thermal injury (i.e., smoke or burn), relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of increasing or improving lung gas exchange, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0304] In some embodiments, provided methods are useful for treating radiation-induced acute lung injury. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to a radiation-induced acute lung injury. In some embodiments, a subject or population has been exposed to ionizing radiation. In some embodiments, the present disclosure provides a method of attenuating or decreasing radiation-induced pulmonary apoptosis and/or inflammation, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0305] In some embodiments, provided methods are useful for treating acute lung injury associated with lung transplantation. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects who have undergone a lung transplantation and/or who are susceptible to an associated acute lung injury. In some embodiments, the present disclosure provides a method of attenuating lung injury associated with transplantation, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of increasing blood pH and/or oxygen levels, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of increasing or improving alveolar air space, relative to a comparable reference population, the method comprising administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0306] In some embodiments, provided methods are useful for treating acute lung injury associated with blunt trauma to the lung. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects who have experienced a blunt trauma to the lung. [0307] In some embodiments, provided methods are useful for treating acute lung injury and/or ARDS associated with pneumonia. In some embodiments, pneumonia is viral pneumonia (e.g., influenza-associated pneumonia or COVID-19-associated pneumonia. In some embodiments, pneumonia is bacterial pneumonia. In some embodiments, pneumonia is aspiration pneumonia. In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects who are suffering from or susceptible to pneumonia (e.g., viral pneumonia, bacterial pneumonia, or aspiration pneumonia). [0308] In some embodiments, the present disclosure provides methods comprising administering to a subject who is receiving or has received therapy with extracorporeal membrane oxygenation (ECMO) a composition that provides Compound 1. [0309] In some embodiments, provided methods comprise administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population who is receiving therapy with ECMO and is at risk for acute lung injury. In some embodiments, the present disclosure provides a method of preserving or maintaining kidney function in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of mitigating, ameliorating, minimizing, or reducing damage to the kidneys in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of improving lung function in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0310] The present disclosure also provides methods of administering Compound 1 (e.g., by administering a composition that comprises and/or delivers Compound 1 as described herein) to a subject or population of subjects in need thereof, regardless of the subject’s malignancy status. Among other things, HGF/SF is known to stimulate c-MET (e.g., in injured organ tissues), which leads to activation of various cellular pathways, including, e.g., those involved in tissue repair. In addition, it is suspected that uncontrolled activation of c-MET can initiate tumorigenesis and/or stimulate and/or promote tumor growth. As described above, Compound 1 is a HGF/SF mimetic, and as such, without wishing to be bound by theory, administration of Compound 1 under certain conditions might be expected to promote initiation or growth of cancer and/or other malignancies. Yet, experiments have demonstrated that, surprisingly, this may not be the case when Compound 1 is administered according to methods provided herein. Accordingly, the present disclosure encompasses the recognition that Compound 1 can be administered to a subject or population of subjects in need thereof, regardless of the subject’s malignancy status. It will be appreciated that such insight may be applicable not only to methods of treating indications described herein (e.g., treating acute lung injury, acute respiratory distress syndrome, COVID-19 pneumonia, etc.), but also to methods of treating any indication for which Compound 1 therapy is suitable. [0311] In some embodiments, the present disclosure provides methods comprising administering a composition that provides Compound 1 (e.g., as provided herein) to a subject or population of subjects in need thereof, wherein the subject is suffering from an active malignancy or has suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of the composition). In some such embodiments, the subject has not suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. In some embodiments, the subject is suffering from or has suffered from glioma, colon cancer, or pancreatic cancer. [0312] In some embodiments, the present disclosure provides methods comprising administering a composition that provides Compound 1 (e.g., as provided herein) to a subject or population of subjects in need thereof, wherein the subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy. In some embodiments, a subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy if prior to administration of Compound 1 (e.g., within about 1 year, about 6 months, about 3 months, about 2 months, about 1 month, about 2 weeks, or about 1 week), the subject has not been questioned about and/or screened for an active malignancy or a history of a solid, metastatic or hematologic malignancy. In some embodiments, a subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy if a decision to administer Compound 1 therapy (e.g., by a physician) did not depend upon questioning of and/or screening of the subject for an active malignancy or a history of a solid, metastatic or hematologic malignancy. COVID-19 Pneumonia and Other Viral Pneumonias [0313] Over the past 15 years, three respiratory viruses have attracted significant attention because of the high proportion of affected patients who develop critical illness and ARDS: influenza, (particularly influenza A H1N12009); Middle Eastern respiratory syndrome coronavirus (MERS-CoV); and SARS coronavirus (SARS-CoV). Recently, a fourth virus emerged, the SARS coronavirus 2 (SARS-CoV-2), the proximate cause of COVID-19. COVID- 19 is a respiratory tract infection caused by SARS-CoV-2 (2019-nCoV). According to WHO Interim Guidance, the most common diagnosis in severe COVID-19 patients is severe pneumonia. It is estimated that approximately 14% of people with COVID-19 develop severe disease requiring hospitalization and oxygen support and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by ARDS, sepsis and septic shock, and multiorgan failure, including AKI, neurological injuries, and cardiac injury. [0314] Clinical presentation among reported cases of COVID-19 varies in severity from asymptomatic infection to mild illness to severe or fatal illness. Acute respiratory distress syndrome (ARDS) developed in 17-29% of hospitalized patients, and secondary infection developed in 10% of patients (Huang C, e al. The Lancet.2020 Jan 24.; Chen N, et al. The Lancet.2020 Jan 30, each of which is hereby incorporated by reference in its entirety). In one report, the median time from symptom onset to ARDS was 8 days (Wang D et al. JAMA Published online February 7, 2020, which is hereby incorporated by reference in its entirety). Most patients with ARDS develop respiratory failure severe enough to require mechanical ventilator support in an intensive care unit (ICU). Mechanical ventilation can exacerbate lung injury (Hess DR. Semin Respir Crit Care Med.2014 Aug;35(4):418-30; Hess DR. Respir Care. 2011 Oct;56(10):1555-72; Brower RG, Fessler HE. Clin Chest Med 2000 Sep;21(3):491-510, each of which is hereby incorporated by reference in its entirety). Approximately 20-30% of hospitalized patients with COVID-19 and pneumonia have required intensive care for respiratory support (Huang C, e al. The Lancet.2020 Jan 24.; Wang D et al. JAMA Published online February 7, 2020). Among critically ill patients admitted to an intensive care unit, 11-64% received high-flow oxygen therapy and 47-71% received mechanical ventilation; some hospitalized patients have required advanced organ support with endotracheal intubation and mechanical ventilation (4-42%) (Chen N, et al. Lancet.2020 Jan 30; Wang D et al. JAMA Published online February 7, 2020; Zhu, et al. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145–151, which are hereby incorporated by reference in their entirety). A small proportion of patients have also been supported with extracorporeal membrane oxygenation (ECMO) (3-12%) (Chen N, et al. The Lancet.2020 Jan 30; Wang D et al. JAMA Published online February 7, 2020; Zhu, et al. Zhonghua Liu Xing Bing Xue Za Zhi.2020;41(2):145–151). Other reported complications include cardiac injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ failure. Post-mortem examinations in one patient who died of ARDS reported pulmonary findings of diffuse alveolar damage. [0315] Accordingly, in some embodiments, provided methods comprise administering a HGF/SF mimetic (e.g., Compound 1) to a subject or population who is characterized by one or more of the following: admitted to an intensive care unit; receiving endotracheal intubation; receiving mechanical ventilation; receiving extracorporeal membrane oxygenation (ECMO); suspected of having, or has been diagnosed with, viral-induced lung injury; suspected of having, or has been diagnosed with, COVID-19-associated pneumonia; suspected of having, or has been diagnosed with, viral influenza-associated pneumonia; suspected of having, or has been diagnosed with, co-morbidities COVID-19 and pneumonia; suspected of having, or has been diagnosed with, co-morbidities viral influenza and pneumonia; and suspected of having, or has been diagnosed with, one or more additional complications selected from diffuse alveolar damage (DAD), cardiac injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ failure. [0316] The FDA has only approved one drug for treating COVID-19, the antiviral agent remdesivir. Remdesivir is recommended only for hospitalized patients who require supplemental oxygen; however, it is not typically recommended for patients on mechanical ventilation due to limited benefits at an advanced stage of disease. Clinical management includes prompt implementation of recommended infection prevention and control measures and supportive management of complications, including advanced organ support. Existing drugs for other indications, including lopinavir-ritonavir (HIV protease inhibitors), chloroquine/hydroxychloroquine (an immunosuppressive drug and anti-parasite), are being used in the clinics for the treatment of COVID-19, but their efficacy remains to be established in clinical trials (Al-Tawfiq, Al-Homoud, and Memish 2020; Cao et al.2020; Cortegiani et al. 2020; Gordon et al.2020; Ko et al.2020; Wang, Cao, et al.2020). In a recently published clinical trial, in adult patients with severe COVID-19, no benefit was observed with lopinavir- ritonavir treatment beyond standard care in hospitalized adult patients with severe COVID-19 (Cao et al.2020). Vaccines against SARS-CoV-2 are beginning to become available to certain populations of subjects; however, widespread vaccine availability remains to be realized. Therefore, there is an urgent unmet medical need to develop new drugs for COVID-19 infection and associated lung injury. [0317] While there is a critical need to develop anti-viral drugs to treat COVID-19, it is also crucial to develop therapies that reduce organ injury induced by SARS-CoV-2 and further amplified by a dysregulated immune and inflammatory response. China’s National Health Commission treatment guidelines recommend treatment with IL-6

inhibitor, tocilizumab, for patients with severe COVID-19 and elevated IL-6 levels. This agent and another IL-6 inhibitor, sarilumab are currently being evaluated in clinical trials in the US. Cytokine induced organ injury and inflammation, “cytokine storm”, increase vascular permeability and exacerbate impaired pulmonary gas exchange. [0318] The present disclosure encompasses the recognition that Compound 1, through activation of c-Met, a crucial pathway that limits organ injury and promotes organ repair, has a great therapeutic potential in COVID-19. Many patients with COVID-19 have evidence of injury to the heart and kidneys, in addition to the lungs, presumably mediated by viral binding to ACE2, which is heavily expressed in all of these organs. In particular, recent multi-site studies from the United States show that 22% to 36% of patients hospitalized with COVID-19 had acute kidney injury and 3% to 14% required dialytic intervention. Compound 1 is effective in reducing injury to these organs in various animal models while preserving tissue architecture, function, and improving animal survival. Thus, Compound 1 provides a unique opportunity to improve clinical outcomes by exerting beneficial effects on multiple organs affected by COVID- 19. [0319] In some embodiments, the present disclosure provides methods of treating (e.g., reducing severity and/or progression of) pulmonary dysfunction in patients (e.g., adult patients) hospitalized with COVID-19 pneumonia. In some embodiments, the present disclosure provides methods of treating (e.g., reducing severity and/or progression of) pulmonary and/or renal dysfunction in patients (e.g., adult patients) hospitalized with COVID-19 pneumonia. In some embodiments, such methods comprise administering intravenously 2 mg/kg Compound 1 twice daily for 5 days. In some embodiments, such methods comprise administering intravenously 2 mg/kg Compound 1 once daily for 4 days. In some embodiments, such methods comprise administering intravenously 2 mg/kg Compound 1 once daily for 3 days. [0320] In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population suffering from or susceptible to pulmonary and/or renal dysfunction (e.g., a subject or population hospitalized with COVID-19 pneumonia). In some embodiments, provided methods comprise administering a composition that provides Compound 1 to a subject or population who is hospitalized with COVID-19 pneumonia. [0321] In some embodiments, the present disclosure provides methods of administering Compound 1 to a subject or a population suffering from or susceptible to pulmonary and/or renal dysfunction (e.g., a subject or population hospitalized with COVID-19 pneumonia), e.g., according to a dosing regimen described herein. In some embodiments, the present disclosure provides methods of administering Compound 1 to a subject or a population who is hospitalized with COVID-19 pneumonia, e.g., according to a dosing regimen described herein. [0322] In some embodiments, the present disclosure provides methods of administering Compound 1 to a subject or population who is suffering from or susceptible to pulmonary and/or renal dysfunction (e.g., a subject or population hospitalized with COVID-19 pneumonia), for example by administering a composition that provides Compound 1, e.g., according to a regimen established to achieve one or more desirable outcomes. In some embodiments, the present disclosure provides methods of administering Compound 1 to a subject or a population who is hospitalized with COVID-19 pneumonia, for example by administering a composition that provides Compound 1, e.g., according to a regimen established to achieve one or more desirable outcomes. In some embodiments, the regimen is or has been established to achieve one or more desirable outcomes in a population to which Compound 1 has been administered, relative to a comparable reference population that has not received Compound 1 (e.g., that has received a reference composition which does not deliver Compound 1). [0323] In some embodiments, certain parameters may be evaluated to determine if a desirable outcome is achieved. Any one or more of parameters such as these may, in some embodiments, be useful for determining short-term and/or long-term efficacy of Compound 1 administered to the patient population. Alternatively or additionally, any one or more of such parameters may be assessed to monitor patient response to Compound 1 therapy. [0324] In some embodiments, the present disclosure provides a method comprising: administering to a subject, or to a population of subjects, suffering from viral pneumonia (e.g., hospitalized with COVID-19 pneumonia) a composition that provides Compound 1 according to a regimen established to achieve one or more of: decreased lung injury score, reduced mortality, reduced lung histopathology, better cytokine evaluation, better lung MPO measurement, improved pulmonary function, reduce lung obstruction in bronchus and bronchioles, andbetter cardiopulmonary variables, relative to a comparable reference population. [0325] In some embodiments, the present disclosure provides methods of improving outcomes for patients suffering from or susceptible to a disease, disorder or condition that is (i.e., is statistically and/or is in fact for the particular patient) associated with one or more undesirable respiratory features such as for example inflammation in the lungs, fluid in the lungs, fibroids in the lungs, etc., by administration of Compound 1 (e.g., alone and/or in combination with other therapy, for example directed at the underlying disease, disorder or condition, or otherwise being used in treatment of the patient(s)). [0326] In some embodiments, in methods provided herein, a reference population has not received a composition that provides Compound 1. In some embodiments, in methods provided herein, a reference population has received an otherwise comparable reference composition that does not provide Compound 1 (e.g., a placebo, such as normal saline). In some embodiments, in methods provided herein, a reference composition may be or comprise normal saline. In some embodiments, in methods provided herein, a reference composition may be or may have been administered at the same intervals and/or volumes as a composition that provides Compound 1. [0327] As used herein, “mean” may refer to an average and/or a least squares mean (LS mean). In some embodiments, “mean” may refer to a LS mean (e.g., a MMRM LS mean). [0328] In some embodiments, a composition that provides Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point (e.g., about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after injury and/or randomization and/or first administration of Compound 1). In some embodiments, a composition that provides Compound 1 is administered according to a regimen established to achieve a particular effect, e.g., at a particular time point, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1, which comparable population may, in some embodiments, have received a reference composition that is otherwise comparable but does not provide Compound 1 upon administration). [0329] In some embodiments, a particular effect may be achieved within a particular time frame or by a particular time point. In some embodiments, such time point may be, for example, about 7 days, about 14 days, about 28 days, about 6 months and/or about 12 months after initiation of Compound 1 therapy as described herein. In some embodiments, a particular effect may be achieved at about 28 days after initiation of Compound 1 therapy as described herein. [0330] In some embodiments, a particular effect may be or comprise a particular proportion of patients alive, without the need for mechanical ventilation and free of the need for renal replacement therapy (on an ongoing basis), e.g., at Day 28. In some embodiments, a particular effect may be or comprise an increased proportion of patients alive, without the need for mechanical ventilation and free of the need for renal replacement therapy (on an ongoing basis), e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0331] In some embodiments, a particular effect may be or comprise a particular proportion of patients alive, without the need for mechanical ventilation and free of the need for renal replacement therapy, e.g., at Day 28. In some embodiments, a particular effect may be or comprise an increased proportion of patients alive, without the need for mechanical ventilation and free of the need for renal replacement therapy, e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0332] In some embodiments, a particular effect may be or comprise a particular all-cause mortality. In some embodiments, a particular effect may be or comprise a reduced all-cause mortality, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0333] In some embodiments, a particular effect may be or comprise a particular proportion of patients not requiring mechanical ventilation, e.g., at Day 28. In some embodiments, a particular effect may be or comprise an increased proportion of patients not requiring mechanical ventilation, e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0334] In some embodiments, a particular effect may be or comprise a particular proportion of patients not requiring renal replacement therapy on an on-going basis, e.g., at Day 28. In some embodiments, a particular effect may be or comprise an increased proportion of patients not requiring renal replacement therapy on an on-going basis, e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0335] In some embodiments, a particular effect may be or comprise a particular number of ventilator-free days, e.g., through Day 28. In some embodiments, a particular effect may be or comprise an increased number of ventilator-free days, e.g., through Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0336] In some embodiments, a particular effect may be or comprise a particular proportion of patients requiring initiation of mechanical ventilation and/or ECMO, e.g., through Day 28. In some embodiments, a particular effect may be or comprise a reduced proportion of patients requiring initiation of mechanical ventilation and/or ECMO, e.g., through Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0337] In some embodiments, a particular effect may be or comprise a particular proportion of patients requiring initiation of renal replacement therapy (RRT), e.g., through Day 28. In some embodiments, a particular effect may be or comprise a reduced proportion of patients requiring initiation of renal replacement therapy, e.g., through Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0338] In some embodiments, a particular effect may be or comprise a particular number of days to renal recovery (defined as freedom from further RRT on an ongoing basis) in subjects who were on RRT at time of randomization. In some embodiments, a particular effect may be or comprise a reduced number of days to renal recovery (defined as freedom from further RRT on an ongoing basis) in subjects who were on RRT at time of randomization, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0339] In some embodiments, a particular effect may be or comprise a particular number of ICU days, e.g., through Day 28. In some embodiments, a particular effect may be or comprise a reduced number of ICU days, e.g., through Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0340] In some embodiments, a particular effect may be or comprise a particular score on an ordinal scale (e.g., the ordinal scale of Example 9), e.g., at Day 28. In some embodiments, a particular effect may be or comprise a reduced score on an ordinal scale (e.g., the ordinal scale of Example 9), e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0341] In some embodiments, a particular effect may be or comprise a particular change (e.g., a reduction) in score on an ordinal scale (e.g., the ordinal scale of Example 9), e.g., at Day 28. In some embodiments, a particular effect may be or comprise a greater change (e.g., a greater reduction) in score on an ordinal scale (e.g., the ordinal scale of Example 9), e.g., at Day 28, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0342] In some embodiments, a particular effect may be or comprise a particular number of days to hospital discharge from an initiating event (e.g., randomization in a clinical trial, admission to a hospital, admission to an ICU, etc.). In some embodiments, a particular effect may be or comprise a particular number of days to hospital discharge from randomization. In some embodiments, a particular effect may be or comprise a reduced number of days to hospital discharge from randomization, relative to an appropriate reference as described herein (e.g., as is observed in a comparable population who has not received a composition that provides Compound 1). [0343] In some embodiments, a particular effect may be or comprise, decreased lung injury score, reduced mortality, reduced lung histopathology, better cytokine evaluation, better lung MPO measurement, improved pulmonary function, reduce lung obstruction in bronchus and bronchioles, or better cardiopulmonary variables. [0344] In some embodiments, a particular effect may be or comprise a better cytokine evaluation (e.g., as evidenced by reduced or resolved systemic or localized inflammation). [0345] In some embodiments, a particular effect may be or comprise decreased mortality rate relative to a comparable reference population. [0346] In some embodiments, a particular effect may be or comprise reduced time to improvement in oxygenation for at least 48 hours (e.g., reduced time to achieve an increase in SpO₂/FiO₂ of 50 or greater compared to the nadir SpO₂/FiO₂), reduced mean change from baseline on an 8-point Ordinal Scale (e.g., the ordinal scale described in Example 9), reduced time to improvement from admission in one category on an 8-point Ordinal Scale (e.g., the ordinal scale described in Example 9), reduced number of days with hypoxemia, reduced time to improvement in oxygenation for at least 48 hours by clinical severity (e.g., reduced time to achieve an increase in SpO₂/FiO₂ of 50 or greater compared to the nadir SpO₂/FiO₂), increased number of ventilator free days in the first 30 days, reduced number of patients requiring initiation of mechanical ventilation and/or ECMO, reduced number of patients admitted into an intensive care unit, reduced number of days of hospitalization (e.g., among survivors), and/or reduced number of patients with secondary bacterial and/or fungal infection. [0347] In some embodiments, a particular effect may be or comprise increased lung function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: increased pulmonary output, increased arterial oxygen (PaO₂), decreased arterial carbon dioxide (PaCO₂), increased ratio of PaO₂/FiO₂, decreased lung injury score, decreased lung hydroxyproline concentration, decreased lung collagen level, decreased lung TGFβ1 concentration, and increased blood pH, relative to a comparable reference population. [0348] In some embodiments, a particular effect may be or comprise increased kidney function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of kidney function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: decreased serum creatinine concentration, increased estimated glomerular filtration rate (eGFR), decreased blood urea nitrogen concentration, increased urine output, decreased kidney TGFβ1 concentration, and lesser incidence of dialysis, relative to a comparable reference population. In some embodiments, a particular effect may be or comprise one or more of: decreased serum creatinine concentration, reduced change in serum creatinine concentration (e.g., over a particular period of time), increased estimated glomerular filtration rate (eGFR), reduced change in eGFR (e.g., over a particular period of time), increased measured glomerular filtration rate, reduced change in measured glomerular filtration rate (e.g., over a particular period of time), decreased blood urea nitrogen concentration, reduced change in blood urea nitrogen concentration (e.g., over a particular period of time), increased urine output, decreased kidney TGFβ1 concentration, and lesser incidence of dialysis, relative to a comparable reference population. Kidney function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, kidney function is evaluated based on one or more of blood urea nitrogen concentration, serum creatinine concentration, eGFR, measured glomerular filtration rate, serum albumin concentration, urinalysis, renal clearance, renal imaging, renal histology, etc. [0349] In some embodiments, a particular effect may be or comprise improved heart function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of heart function relative to a comparable reference population. Heart function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, heart function is evaluated based on one or more of troponin I levels, 12-lead electrocardiogram, echocardiogram, radiographic or nuclear medicine imaging, cardiac histology, etc. [0350] In some embodiments, a particular effect may be or comprise improved liver function relative to a comparable reference population. In some embodiments, a particular effect may be or comprise less deterioration of liver function relative to a comparable reference population. Liver function can be evaluated using any method known in the art, such as one or more Study Assessments described in Example 9 herein. In some embodiments, liver function is evaluated based on one or more of serum albumin concentration; total, direct, and/or indirect bilirubin levels; aspartate aminotransferase levels; alanine aminotransferase levels; alkaline phosphatase levels; gamma-glutamyl transpeptidase levels; imaging; histology, etc. [0351] In some embodiments, the disease, disorder or condition being treated in methods provided herein is characterized by pulmonary edema, pulmonary epithelial cell apoptosis, inflammatory cell infiltration, impaired oxygenation, hypoxemia and/or lung fibrosis. [0352] In some embodiments, the present disclosure provides methods of administering Compound 1 to a subject or a population of subjects who are suffering from or susceptible to a respiratory disease, disorder or condition such as, e.g., COVID-19 lung injury. [0353] In some embodiments, the present disclosure provides methods comprising administering to a subject who is receiving or has received therapy with extracorporeal membrane oxygenation (ECMO) a composition that provides Compound 1. [0354] In some embodiments, provided methods comprise administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population who is receiving therapy with ECMO and is at risk for acute lung injury. In some embodiments, the present disclosure provides a method of preserving or maintaining kidney function in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of mitigating, ameliorating, minimizing, or reducing damage to the kidneys in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. In some embodiments, the present disclosure provides a method of improving lung function in a subject or population receiving ECMO relative to a comparable reference population, the method comprising administering an HGF/SF mimetic (e.g., Compound 1) to a subject or population in need thereof. [0355] In some embodiments, provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and one or more anti-viral agents. In some embodiments, such anti-viral agents are selected from oseltamivir, lopinavir, ritonavir, chloroquine, hydroxychloroquine, and remdesivir, and combinations thereof. In some embodiments, provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and anti-viral therapy. In some such embodiments, anti-viral therapy comprises hydroxychoroquine and azithromycin. [0356] In some embodiments, provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and one or more IL-6 inhibitors. Non- limiting examples of IL-6 inhibitors include tocilizumab and sarilumab. [0357] In some embodiments, one or more subjects or populations selected to receive Compound 1 (e.g., according to provided methods) are characterized by one or more factors described herein. It will be appreciated that, in some embodiments, a subject or population is characterized by multiple (i.e., more than one) factors described herein. [0358] In some embodiments, one or more subjects or populations selected to receive Compound 1 as described herein are characterized by one or more factors such as, for example, one or more of: presence of one or more risk factors or characteristics of a respiratory disease, disorder, or condition. In some embodiments, such subject(s) or population(s) may display, for example, one or more features of lung inflammation, fluid in the lungs, fibroids in the lungs, difficulty breathing, etc. Alternatively or additionally, in some embodiments, such subject(s) or population(s) may be suffering from an underlying condition (e.g., infection, trauma, etc.) that is associated with (e.g., established to be correlated with) a respiratory disease, disorder or condition. [0359] In some embodiments, a respiratory disease, disorder or condition may involve one or more of airway (i.e., may affect tubes that carry gases such as oxygen into and out of the lungs), lung tissue (i.e., may involve inflammation and/or scarring of lung tissue), and/or circulation (i.e., may involve clotting, inflammation, and/or scarring of blood vessels in the lungs). [0360] In some embodiments, a subject or population is suffering from or susceptible to acute respiratory distress (e.g., ARDS as defined by the Berlin criteria). In some embodiments, a subject or population is suffering from or susceptible to mild ARDS (e.g., as defined by the Berlin criteria). In some embodiments, a subject or population is suffering from or susceptible to moderate ARDS (e.g., as defined by the Berlin criteria). In some embodiments, a subject or population is suffering from or susceptible to severe ARDS (e.g., as defined by the Berlin criteria). In some embodiments, a subject or population is suffering from or susceptible to ARDS, e.g., mild ARDS or moderate ARDS (as defined in the Berlin criteria using PaO₂/FiO₂). [0361] In some embodiments, a subject or population is suffering from acute lung injury. [0362] In some embodiments, a subject or population is suffering from or susceptible to ALI or ARDS secondary to, induced by, or otherwise associated with one or more of ischemia, drugs and/or toxins, neonatal status, radiation, etc. [0363] In some embodiments, a subject or population is suffering from or susceptible to a chronic respiratory disease, disorder or condition. [0364] In some embodiments, a subject or population is suffering from or susceptible to pulmonary edema. [0365] In some embodiments, a subject or population is suffering from or susceptible to shock-associated acute lung injury (e.g., acute lung injury associated with septic shock, LPS- induced shock, hemorrhagic shock, or cardiogenic shock). In some embodiments, a subject or population is in shock (e.g., septic shock, LPS-induced shock, hemorrhagic shock, or cardiogenic shock). [0366] In some embodiments, a subject or population is suffering from or susceptible to a chemically induced acute lung injury. In some embodiments, a subject or population is suffering from or susceptible to a radiation-induced acute lung injury. In some embodiments, a subject or population may be or have been exposed to one or more drugs and/or toxins (e.g., chlorine gas or phosgene gas) or radiation. In some embodiments, a subject or population has been exposed to chlorine gas, phosgene gas, or other inhaled toxin. In some embodiments, a subject or population has been exposed to ionizing radiation. [0367] In some embodiments, a subject or population is suffering from or susceptible to acute lung injury associated with hemorrhagic shock (e.g, hemorrhagic shock from trauma). In some embodiments, a subject or population has experienced a traumatic injury (e.g., to the lung). [0368] In some embodiments, a subject or population is suffering from or susceptible to acute lung injury associated with blunt trauma to the lung. In some embodiments, a subject or population has experienced a blunt trauma injury of the lung. [0369] In some embodiments, a subject or population is suffering from or susceptible to ischemia-reperfusion lung injury. In some embodiments, a subject or population is suffering from or susceptible to acute lung injury associated with lung transplantation. In some embodiments, a subject or population has undergone a lung transplantation. [0370] In some embodiments, a subject or population is suffering from or susceptible to emphysema. [0371] In some embodiments, a subject or population is suffering from or susceptible to a thermally induced acute lung injury (e.g., an acute lung injury associated with smoke inhalation and/or thermal burn). In some embodiments, a subject or population is suffering from or has suffered from smoke inhalation and/or burn. [0372] In some particular embodiments, a subject or population is suffering from or susceptible to a pneumonia (e.g., a viral pneumonia, bacterial pneumonia, or aspiration pneumonia). In some embodiments, a subject or population is suffering from pneumonia (e.g., as confirmed by, e.g., chest imaging). In some embodiments, a subject or population is suffering from COVID-19 pneumonia (e.g., as confirmed by chest imaging). In some embodiments, a subject or population is suffering from or susceptible to COVID-19 pneumonia (e.g., as confirmed by chest imaging). [0373] Alternatively or additionally, in some particular embodiments, a subject or population may be suffering from or susceptible to infection, for example viral infection, e.g., with a respiratory virus such as respiratory syncytial virus (RSV), influenza, and/or a coronavirus (e.g., COVID-19). [0374] Still further alternatively or additionally, in some particular embodiments, a subject or population may be suffering from or susceptible to one or more of a common cold, pneumonia, lung cancer, pulmonary embolism allergy, asthma, bronchiostasis or bronchitis, chronic obstructive pulmonary disease (COPD), a cold, obstructive sleep apnea syndrome, pulmonary hypertension, tuberculosis, or a viral infection (e.g., with a coronavirus (e.g., COVID-19), an influenza virus, an RSV, etc.). [0375] In some embodiments, a subject or population is or has been a smoker. In some embodiments, a subject or population is not and has never been a smoker. [0376] In some embodiments, a subject or population is in respiratory failure. [0377] In some embodiments, a subject or population may be in the presence of or have been exposed to one or more risk factors such as, for example, allergens, air pollution (indoor and/or outdoor), smoking, infection (e.g., with a bacterial, viral, or fungal pathogen whose infection is associated with respiratory symptom(s)), or gas agents (e.g., chlorine gas or phosgene gas). [0378] In some embodiments, a subject or population may display one or more symptoms or characteristics selected from the group consisting of chills, cough, difficulty breathing, fever, headache, etc. In some particular embodiments, a subject or population may display cough (e.g., dry cough) and fever. In some embodiments, a subject or population may display one or more of symptoms or features selected from labored breathing, rapid breathing, muscle fatigue, general weakness, low blood pressure, shortness of breath, and confusion, and combinations thereof. [0379] In some embodiments, a subject or population may be or have been diagnosed with an infectious disease (e.g., infection with a microbe or virus), for example through detection of a nucleic acid and/or antigen characteristic of a particular infectious agent in a sample(s) (e.g., that is or comprises blood, feces, saliva, serum, sputum, sweat, tears, urine, etc.) from the subject(s). [0380] In some embodiments, a subject or population has been admitted to an intensive care unit. [0381] In some embodiments, a subject or population is or was on a ventilator and/or is or was receiving supplemental oxygen. [0382] In some embodiments, a subject or population is resistant to oxygen therapy. [0383] In some embodiments, a subject or population is receiving or has received endotracheal intubation. [0384] In some embodiments, a subject or population may be having, have had, or be at risk of having a myocardial infarction. [0385] Without wishing to be bound by any particular theory, subjects receiving therapy with an HGF/SF mimetic (e.g., Compound 1) may benefit from therapy with one or more additional agents. See, for example, Narasaraju, T., et al. Curr. Mol. Med.2014;(14)690-702. In some embodiments, a subject or population is receiving or has received one or more additional therapies. In some embodiments, a subject or population is receiving or has received one or more antibiotics, antivirals, corticosteroids, and painkillers, and combinations thereof. In some embodiments, a subject or population is receiving or has received one or more antivirals. In some such embodiments, a subject or population is diagnosed with or suspected of having COVID-19 and is receiving or has received one or more antivirals. In some embodiments, a subject or population is receiving or has received antiviral therapy selection from oseltamivir, lopinavir, ritonavir, chloroquine, hydroxychloroquine, and remdesivir, and combinations thereof. In some embodiments, a subject or population is receiving or has received antiviral therapy comprising hydroxychloroquine and azithromycin. In some embodiments, a subject or population is receiving or has received one or more IL-6 inhibitors. In some embodiments, a subject or population is receiving or has received one or more IL-6 inhibitors selected from tocilizumab and sarilumab. [0386] Those skilled in the art, reading the present disclosure will appreciate that, in some embodiments, appropriate subjects or populations to receive Compound 1 therapy as described herein may be those described in one or more of Combes, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome, N Engl. J. Med.378;21, May 24, 2018, 1965; JAMA.2009;302(17):1888-1895; or Peek et al., Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet, September 16, 2009, DOI:10.1016/S0140-6736(09)61069-2 (the entirety of each of which is incorporated herein by reference). [0387] In some embodiments, the present disclosure provides the recognition that subjects or populations that receive therapy with extracorporeal membrane oxygenation (ECMO) benefit from treatment with an HGF/SF mimetic (e.g., Compound 1). ECMO stands for extracorporeal membrane oxygenation. In some embodiments, subjects or populations who need ECMO have a severe and life-threatening illness that stops their heart or lungs from working properly. In some embodiments, ECMO is used during life-threatening conditions such as severe lung damage from, e.g., infection, or shock after a massive heart attack. [0388] In some embodiments, a subject or population is receiving or has received therapy with ECMO. In some embodiments, subjects or populations are supported by an ECMO machine for only a few hours. In some embodiments, subjects or populations are supported by an ECMO machine for one or more days. In some embodiments, subjects or populations are supported by an ECMO machine for one or more weeks. In some embodiments, a subject is a child, or a population consisting of children, of less than 18 years. In some embodiments, a subject is an adult or an adult population. In some embodiments, a subject is an adult, or a population consisting of adults, of 55 years or older. In some embodiments, a subject or population receives treatment, or is eligible for treatment, with ECMO wherein the subject’s or population’s lungs cannot provide enough oxygen to the body even when given extra oxygen. In some embodiments, a subject or population receives treatment, or is eligible for treatment, with ECMO wherein the subject’s or population’s lungs cannot expel carbon dioxide even with help from a mechanical ventilator. [0389] Without wishing to be bound by any particular theory, patients on ECMO are particularly susceptible to acute kidney injury. Accordingly, in some embodiments, a subject or population who is receiving ECMO, or is eligible for ECMO, is at risk for acute kidney injury. [0390] In some embodiments, a subject or population is further characterized by impaired kidney function. In some embodiments, a subject is suffering from acute kidney injury (e.g., secondary to ECMO therapy). In some embodiments, a subject or population is suffering from a renal ischemia/reperfusion injury, renal failure, renal fibrosis, or a renal trauma. In some embodiments, a subject or population is receiving or has received dialysis (e.g., 1, 2, 3, 4, or 5 or more sessions in the last 1 week, 2 weeks, 3 weeks or more). In some embodiments, a subject or population has undergone renal transplantation (e.g., in the last 1 day, 2 days, 3 days, 1 week, 2 weeks, or more). [0391] In some embodiments, a subject or population is experiencing respiratory complications, e.g., associated with COVID-19, influenza, chemical or thermal injury, chemical or thermal burns, etc. In some embodiments, a subject or population is suspected of suffering from a coronavirus. In some such embodiments, a subject or population is suspected of suffering from COVID-19. In some embodiments, a subject or population is or has been diagnosed with a coronavirus. In some such embodiments, a subject or population is or has been diagnosed with COVID-19. [0392] Without wishing to be bound by any particular theory, subjects suffering from COVID-19 may be particularly susceptible to heart and/or kidney injuries, in addition to lung injury, presumably due to viral binding to ACE2, which is heavily expressed in all of these organs. Accordingly, in some embodiments, a subject or population is suffering from or susceptible to heart dysfunction, e.g., in addition to pulmonary dysfunction. In some embodiments, a subject or population suffering from or susceptible to heart dysfunction is characterized using one or more Study Assessments described in Example 9 herein or any other method known in the art (e.g., troponin I levels, 12-lead electrocardiogram, echocardiogram, radiographic or nuclear medicine imaging, cardiac histology, etc.). In some embodiments, a subject or population is suffering from or susceptible to renal dysfunction, e.g., in addition to pulmonary dysfunction. In some embodiments, a subject or population suffering from or susceptible to renal dysfunction is characterized using one or more Study Assessments described in Example 9 herein or any other method known in the art (e.g., blood urea nitrogen concentration, serum creatinine concentration, eGFR, measured glomerular filtration rate, serum albumin concentration, urinalysis, renal clearance, renal imaging, renal histology, etc.). [0393] Further, without wishing to be bound by any particular theory, subjects suffering from COVID-19 may be particularly susceptible to liver injuries, in addition to lung and/or heart and/or kidney injuries. Accordingly, in some embodiments, a subject or population is suffering from or susceptible to liver dysfunction, e.g., in addition to pulmonary dysfunction. In some embodiments, a subject or population suffering from or susceptible to liver dysfunction is characterized using one or more Study Assessments described in Example 9 herein or any other method known in the art (e.g., serum albumin concentration; total, direct, and/or indirect bilirubin levels; aspartate aminotransferase levels; alanine aminotransferase levels; alkaline phosphatase levels; gamma-glutamyl transpeptidase levels; imaging; histology, etc.). [0394] In some embodiments, a subject or population is hospitalized (e.g., hospitalized with COVID-19 pneumonia). [0395] In some embodiments, a subject or population has provided a sample (e.g., a respiratory tract sample) that tests positive using a reverse-transcriptase-polymerase-chain- reaction (RT-PCR) assay for SARS-CoV-2. In some such embodiments, the sample has tested positive during the same hospitalization in which the subject or population is receiving or has received therapy with Compound 1. [0396] In some embodiments, a subject or population has an ordinal score of 4 or 5, e.g., on the ordinal scale described in Example 9. In some embodiments, a subject or population has an ordinal score of 1, 2, or 3, e.g., on the ordinal scale described in Example 9. In some embodiments, a subject or population has an ordinal score of 6 or 7, e.g., on the ordinal scale described in Example 9. In some embodiments, a subject or population has an ordinal score of 5, e.g., on the ordinal scale described in Example 9. In some embodiments, a subject or population has an ordinal score of 4, e.g., on the ordinal scale described in Example 9. In some embodiments, a subject or population has an ordinal score of 5, e.g., on the ordinal scale described in Example 9. [0397] In some embodiments, a subject or population is receiving or has received non- invasive ventilation and/or high-flow oxygen. In some embodiments, a subject or population is receiving or has received non-invasive ventilation and/or high-flow oxygen and has an ordinal score of 5, e.g., on the ordinal scale described in Example 9. [0398] In some embodiments, a subject or population has a fraction of inspired oxygen (FiO₂) of greater than about 40%. Fraction of inspired oxygen can be measured by any method known in the art. In some embodiments, a FiO₂ of greater than about 40% corresponds to greater than about 5 L/min with a nasal cannula and/or greater than about 10 L/min with a venturi mask and/or greater than about 8 L/min with a conventional mask and/or using a mask with oxygen reservoir. In some embodiments, a subject or population has a FiO₂ of greater than about 40% and an ordinal score of 4, e.g., on the ordinal scale described in Example 9. [0399] In some embodiments, a subject or population has a fraction of inspired oxygen (FiO₂) of less than about 40%. Fraction of inspired oxygen can be measured by any method known in the art. In some embodiments, a FiO₂ of less than about 40% corresponds to less than about 5 L/min with a nasal cannula and/or less than about 10 L/min with a venturi mask and/or less than about 8 L/min with a conventional mask and/or using a mask with oxygen reservoir. In some embodiments, a subject or population has a FiO₂ of less than about 40% and an ordinal score of 4, e.g., on the ordinal scale described in Example 9. [0400] In some embodiments, a subject or population has an oxygen saturation (SaO₂) of about 94% or less (e.g., about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, or about 85%, or less), e.g., while breathing ambient air. [0401] In some embodiments, a subject or population has a ratio of partial pressure of oxygen (PaO₂) to fraction of inspired oxygen (FiO₂) that is about 300 mmHg or less (e.g., less than about 300 mmHg, less than about 200 mmHg, or less than about 100 mmHg). [0402] In some embodiments, a subject or population is not suffering from or susceptible to a malignancy (e.g., an active malignancy). In some embodiments, a subject or population is not receiving treatment for a malignancy (e.g., an active malignancy). In some embodiments, a subject or population does not have a history of solid or hematological malignancies (e.g., within the past 5 years). In some embodiments, a subject or population is not suffering from or susceptible to a malignancy (e.g., an active malignancy) other than a basal or squamous cell carcinoma-in-situ of the skin that was diagnosed more than 2 years prior. In some embodiments, a subject or population thereof is not suffering from an active malignancy or has not suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of Compound 1 therapy). In some embodiments, a subject or population thereof has suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. [0403] In some embodiments, a subject or population is suffering from or susceptible to a malignancy (e.g., an active malignancy). In some embodiments, a subject or population is receiving treatment for a malignancy (e.g., an active malignancy). In some embodiments, a subject or population has a history of solid or hematological malignancies (e.g., within the past 5 years). In some embodiments, a subject or population is suffering from or susceptible to a malignancy (e.g., an active malignancy) other than a basal or squamous cell carcinoma-in-situ of the skin that was diagnosed more than 2 years prior. In some embodiments, a subject or population thereof is suffering from an active malignancy or has suffered from a solid, metastatic or hematologic malignancy (e.g., within 5 years prior to administration of Compound 1 therapy). In some embodiments, a subject or population thereof has not suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed. In some embodiments, a subject or population thereof is suffering from or has suffered from glioma, colon cancer, or pancreatic cancer. [0404] In some embodiments, a subject or population thereof has not been assessed for an active malignancy or a history of solid or hematological malignancies. In some embodiments, a subject or population thereof has not been assessed for an active malignancy or a history of a solid, metastatic, or hematologic malignancy. In some embodiments, a subject or population thereof has an unknown malignancy status (i.e., an unknown medical history with respect to malignancies). [0405] In some embodiments, a subject or population does not have an alanine aminotransferase (ALT) level greater than three times upper limit of normal (ULN) at baseline. [0406] In some embodiments, a subject or population does not have an aspartate transaminase (AST) level greater than three times ULN at baseline. [0407] In some embodiments, a subject or population does not have a total bilirubin level greater than two times ULN at baseline. [0408] In some embodiments, a subject or population does not require treatment with CYP1A2 inhibitors. In some embodiments, a subject or population does not require treatment with ciprofloxacin and/or fluvoxamine. In some embodiments, a subject or population is not receiving a CYP1A2 inhibitor. In some embodiments, a subject or population is not receiving ciprofloxacin or fluvoxamine. In some embodiments, a subject or population has not received ciprofloxacin or fluvoxamine (e.g., on the day(s) Compound 1 is administered and/or for 24 hours after last infusion of Compound 1). In some embodiments, a subject or population has not consumed a caffeinated beverage (e.g., on the day(s) Compound 1 is administered and/or for 24 hours after last infusion of Compound 1). [0409] Non-limiting examples of CYP1A2 inhibitors include alosetron, caffeine, ciprofloxacin, duloxetine, fluvoxamine, melatonin, ramelteon, selegiline, tacrine, tasimelteon, tizanidine, and theophylline. [0410] In some embodiments, a subject or population is not receiving or has not received any other investigational drug product or procedure. [0411] In some embodiments, a subject or population is not a recipient of a solid organ and/or hematopoietic cell transplantation. [0412] In some embodiments, a subject or population is not suffering from end stage renal disease. In some embodiments, a subject or population is not being treated with maintenance hemodialysis or peritoneal dialysis, e.g., prior to the same hospitalization in which the subject or population is receiving Compound 1 therapy. In some embodiments, renal replacement therapy (RRT) is initiated during the same hospitalization in which the subject or population is receiving Compound 1 therapy. [0413] In some embodiments, a subject or population is male and/or nonpregnant females. In some embodiments, a subject or population is not pregnant or breastfeeding. [0414] In some embodiments, a subject or population is adult (e.g., 18 years of age or older). [0415] In some embodiments, Compound 1 is administered according to a dosing regimen over a period of time, for example during some or all of which the patient(s) is/are ventilated. In some embodiments, such period of time may be 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more; in some embodiments, such period of time may be about 10 days or fewer (e.g., about 8, 7, 6, 5, or 4 days). [0416] In some embodiments, one or more of the following is monitored before, during, and/or after Compound 1 therapy: arterial blood gasses (ABGs) or draws from an arterial line to calculate the A-a gradient, A-a ratio, or the P/F ratio (PaO₂/FiO₂), in some embodiments at a plurality of time points (e.g., over the first 24-38 hours), frequently for the first 48 hours; in some embodiments such assessment(s) may establish impact on (e.g., improvement of) gas exchange ventilator (in hours), days in ICU, days in hospital, % of patients discharged alive, or % of patients who progress to multi-organ failure. [0417] In some embodiments, one or more of the following is monitored before, during, and/or after Compound 1 therapy: score on an 8-point ordinal scale (e.g., as described in Example 9), SpO₂/FiO₂, high-sensitivity C-reaction protein (HS-CRP), absolute lymphocyte count, serum ferritin, serum interleukin-6 (IL-6), serum myoglobin, D-dimer, creatine phosphokinase (CPK), CPK-MB, troponin (e.g., troponin I), and LDH. In some embodiments, such assessment(s) may establish impact on (e.g., improvement of) oxygenation, days with hypoxemia, ventilator-free days, percentage of patients discharged alive, percentage of patients requiring mechanical ventilation and/or ECMO, percentage of patients in ICU, days in ICU, days in hospital (e.g., among survivors), and/or percentage of patients with secondary bacterial and/or fungal infections. [0418] In some embodiments, Compound 1 therapy as described herein is not administered to patients who have multi-organ failure. Administration [0419] In some embodiments, a composition providing Compound 1, as described herein, can be administered in accordance with methods (e.g., according to a regimen) provided herein. [0420] In some embodiments, a composition providing Compound 1 is administered intravenously. In some embodiments, a composition providing Compound 1 is administered over about 10 min, about 20 min, about 30 min, or about 40 min. In some embodiments, a composition providing Compound 1 is administered intravenously in an amount suitable to provide about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg Compound 1. In some embodiments, a composition providing Compound 1 is administered intravenously at an infusion rate suitable to provide about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg Compound 1 over about 10 min, about 20 min, about 30 min, or about 40 min. In some embodiments, provided formulations are administered as an infusion over about 30 min in an amount suitable to provide about 2 mg/kg Compound 1. [0421] In some embodiments, methods provided herein comprise periodic administration of Compound 1 (e.g., three or four infusions of Compound 1 separated by 24 (± 2) hours). In some embodiments, methods provided herein comprise administration of one, two, three, four or five infusions of Compound 1 separated by a regular interval. In some embodiments, methods provided herein comprise administration of six, seven, eight, nine, or ten infusions of Compound 1 separated by a regular interval. In some such embodiments, a regular interval can be about 24 hours, about 30 hours, or about 36 hours. In some such embodiments, a regular interval can be about 12 hours (e.g., 12 hours ± 2 hours). [0422] In some embodiments, methods provided herein comprise periodic administration of Compound 1 throughout a course of treatment (e.g., a course of treatment of about 1, about 2, about 3, about 4, or about 5 days). In some embodiments, Compound 1 is administered once daily throughout a course of treatment (e.g., a course of treatment of about 1, about 2, about 3, about 4, or about 5 days). In some embodiments, a course of treatment is about 3 days. In some embodiments, a course of treatment is about 4 days. [0423] In some embodiments, a composition providing Compound 1 is administered once daily for three days. In some embodiments, a composition providing Compound 1 is administered at 2 mg/kg once daily for three days. In some embodiments, a composition providing Compound 1 is administered once daily for four days. In some embodiments, a composition providing Compound 1 is administered at 2 mg/kg once daily for four days. [0424] In some embodiments, a composition providing Compound 1 is first administered within about 12 hours, about 18 hours, about 24 hours, about 30 hours, about 36 hours, or about 42 hours of an initiating event (e.g., randomization, acute injury, or surgery). In some embodiments, a composition providing Compound 1 is administered for a second time within about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours from the time of first administration. In some embodiments, a composition providing Compound 1 is administered for a third time within about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours from the time of second administration. In some embodiments, a composition providing Compound 1 is administered for a fourth time within about 20 hours, about 22 hours, about 24 hours, about 26 hours, or about 28 hours from the time of third administration. [0425] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0426] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0427] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0428] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0429] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and aqueous buffer. [0430] In some embodiments, the present disclosure provides a method comprising intravenously administering to a subject or population a formulation comprising: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0431] In some embodiments, the present disclosure provides a method comprising steps of: (i) providing a first formulation of Compound 1; (ii) diluting the first formulation with normal saline to give a second formulation of Compound 1; and (iii) administering the second formulation to a subject or population in need thereof (e.g., as described herein). In some such embodiments, a first formulation of Compound 1 is more concentrated (e.g., 10 mg/mL) than a second formulation of Compound 1 (e.g., 6 mg/mL). In some embodiments, provided methods further comprise diluting the first formulation under aseptic conditions. In some embodiments, provided methods further comprise diluting the first formulation within 1 day, 2 days, or 3 days prior to administering the second formulation. [0432] In some embodiments, a first formulation of Compound 1 comprises: about 10 mg/mL Compound 1; about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components; and a second formulation of Compound 1 comprises: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0433] In some embodiments, a first formulation of Compound 1 comprises: about 10 mg/mL Compound 1; about 40% (w/v) to about 60% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline; and a second formulation of Compound 1 comprises: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 5% (w/v) to about 15% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0434] In some embodiments, a first formulation of Compound 1 comprises: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components; and a second formulation of Compound 1 comprises: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components. [0435] In some embodiments, a first formulation of Compound 1 comprises: about 10 mg/mL Compound 1; about 50% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 10% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline; and a second formulation of Compound 1 comprises: about 6 mg/mL Compound 1; about 30% (w/v) polyethylene glycol (e.g., polyethylene glycol 300); about 6% (w/v) polysorbate (e.g., polysorbate 80); and one or more aqueous components selected from phosphate buffered saline and normal saline. [0436] Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only. EXAMPLES Example 1. A Phase 1, 2-Part, Double-Blind, Single-Center Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Intravenous Doses of Compound 1 in Healthy Male and Female Subjects Study Objectives and Endpoints [0437] In Part 1 of the study, the primary objective was to assess the safety and tolerability of single ascending doses of Compound 1 administered as an intravenous (IV) infusion, and the endpoints were incidence of adverse events (AE) and assessment of physical examinations, safety laboratory tests, vital signs and electrocardiograms (ECGs). The secondary objective was to characterize the pharmacokinetics (PK) of single ascending doses of Compound 1 administered as an IV infusion, and the endpoints were calculation of the following parameters where possible and appropriate: Tmax, Cmax, AUC(0-last), AUC(0-inf) and T1/2. [0438] In Part 2 of the study, the primary objective was to assess the safety and tolerability of multiple ascending doses of Compound 1 administered as an IV infusion once daily (QD) and twice daily (BID) for 7 days, and the endpoints were incidence of AEs and assessment of physical examinations, safety laboratory tests, vital signs and ECGs. The secondary objective was to characterize the IV PK of multiple ascending doses of Compound 1 administered as an IV infusion, and the endpoints were calculation of the following parameters where possible and appropriate: Tmax, Cmax, AUC(0-tau) and T1/2. Methodology [0439] This was a 2-part, single center, double-blind, randomized, study of single ascending doses (SAD; Part 1) and multiple ascending doses (MAD; Part 2) of Compound 1 in healthy male subjects and healthy female subjects of non-childbearing potential. [0440] Subjects who took part in Part 1 were not permitted to take part in Part 2. Subjects were screened for inclusion in the study up to 28 days prior to dosing and were admitted to the clinical unit in the morning of the day before dosing (Day -1). [0441] Part 1 (SAD): Part 1 was a double-blind, SAD study. It was planned to enroll 3 cohorts of 6 subjects each to ensure a minimum of 5 evaluable subjects per cohort, randomized in a 4:2 ratio to receive Compound 1 or placebo. Subjects received the following treatments:

[0442] Compound 110 mg/mL sterile solution (containing 50% weight/volume PEG 300 NF, 10% weight/volume polysorbate 80 NF and phosphate buffered saline, provided in glass vials) was diluted with sterile saline to the final concentration of 6 mg/mL and administered via a peripheral vein over 30 min using a study-dedicated, calibrated infusion pump and the same administration set. The calibrated infusion pump was used to reduce variability in dosage administration in order to assess the impact of dosage administration in a controlled setting. [0443] Dose escalation was to occur following interim review of the safety data (up to 24 h post-dose) after each cohort. [0444] Each cohort followed the same study design. Subjects were dosed in a randomized, double-blind manner on the morning of Day 1 following an overnight fast (minimum 8 h). Administration of Compound 1 or placebo was performed with an appropriate interval (approximately 10 min) between subjects based on logistical requirements. Subjects remained resident in the clinical unit until 24 h post-dose (up to Day 2). [0445] Following each of Regimens A and B, there was an interim data review of safety data up to 24 h post-dose from the previous cohort(s) to determine the decision to escalate to the next planned dose level. [0446] A follow-up phone call took place 3 to 7 days post-dose (Days 4 to 8) to ensure the ongoing wellbeing of the subjects. [0447] Part 2 (MAD): Part 2 was a 2 period, double-blind, MAD study, initiated after completion of Part 1 (SAD) and review of safety data. It was planned to enroll 2 cohorts of 8 subjects each to ensure a minimum of 6 evaluable subjects per cohort, randomized in a 6:2 ratio to receive Compound 1 or placebo. Each cohort participated in 2 periods, with QD dosing in the first period and BID dosing in the second period. Subjects were only randomized once (on the morning of Day 1 before dosing in Period 1), and received either Compound 1 or placebo in both study periods. There was a minimum 24 h washout between the final dose of Compound 1 or placebo during Period 1 and the first dose of Compound 1 or placebo in Period 2 for each cohort. Subjects received the following treatments:

^a On Day 7, only the morning dose is given. [0448] Compound 110 mg/mL sterile solution (containing 50% weight/volume PEG 300 NF, 10% weight/volume polysorbate 80 NF and phosphate buffered saline, provided in glass vials) was diluted with sterile saline to the final concentration of 6 mg/mL and administered via a peripheral vein over 30 min using a study-dedicated, calibrated infusion pump and the same administration set. The calibrated infusion pump was used to reduce variability in dosage administration in order to assess the impact of dosage administration in a controlled setting. [0449] Dose escalation from QD to BID dosing occurred following interim review of the safety data (up to 24 h post-dose on Day 1 and Day 7) after Period 1 (Regimens D and E). [0450] Dosing in Part 2 could occur in parallel to the conduct of Part 1 of the study; however, the dose to be administered in Regimen D was selected based on emerging safety data from preceding cohorts in Part 1 (i.e., after safety has been confirmed in Cohort 2). The total dose level did not exceed 8 mg/kg/day. [0451] Each cohort followed the same study design for QD and BID dosing. Subjects were dosed in a randomized, double-blind manner. For QD dosing, subjects were dosed on the morning of Days 1 to 7 following an overnight fast (minimum 8 h). For BID dosing, subjects were dosed on the mornings following an overnight fast (minimum 8 h) and evenings (approximately 12 h after the morning dose) fasted from 2 h before dosing until 1 h post-end of infusion, on Days 1 to 6, and on the morning of Day 7. Subjects were only randomized once, and received either Compound 1 or placebo in both study periods. Administration of Compound 1 or placebo was performed with an appropriate interval (approximately 10 min) between subjects based on logistical requirements. Subjects remained resident in the clinical unit until 24 h post-final dose (up to Day 8 of Period 2). [0452] There was an interim decision based on safety data up to 24 h post-dose in Cohort 2 of Part 1 to determine the dose to be administered in the first cohort of Part 2 (Period 1). Following Period 1 (Cohorts D and E), there was an interim data review based on collated safety data up to 24 h post-dose on Day 1 and up to 24 h post-final dose on Day 7 to confirm progression to BID dosing in Period 2. There was a washout period of least 24 h and no more than 10 days between Period 1 and Period 2. [0453] A follow-up phone call took place 3 to 7 days post-last dose of Period 2 (Days 10 to 14) to ensure the ongoing wellbeing of the subjects. If a subject was to report any AEs which represented a cause for concern, they were to be required to attend the clinical unit for a follow-up assessment. This was to be an unscheduled visit. Number of Subjects (Planned and Analyzed): [0454] Part 1 (SAD): Planned: 3 cohorts of 6 subjects each, Enrolled: 18 (12 subjects randomized to active treatment, 6 subjects randomized to placebo), Completed: 18, Discontinued: 0. Safety population: 18, Safety analysis set: 18. PK population: 12, PK analysis set: 12. [0455] Part 2 (MAD): Planned: 2 cohorts of 8 subjects each, Enrolled: 17 (13 subjects randomized to active treatment, 4 subjects randomized to placebo), Completed: 15, Discontinued: 2 (both randomized to 4 mg/kg QD). Safety population: 17, Safety analysis set Period 1: 17, Safety analysis set Period 1: 15. PK population: 12, PK analysis set Period 1: 12, PK analysis set Period 2: 11. Diagnosis and Main Criteria for Inclusion [0456] Healthy males, or healthy females of non-childbearing potential that had a negative urine pregnancy test at screening and negative serum pregnancy test at admission, between 18 and 55 years of age with a body mass index between 18.0 and 30.0 kg/m² or, if outside the range, considered not clinically significant by the investigator, and weight ≥50 kg and ≤100 kg. Exclusion Criteria [0457] Subjects were excluded from the study if one or more of the following statements was applicable: ● Received any IMP in a clinical research study within 5 half-lives or within 30 days prior to first dose. However, in no event, was the time between last receipt of IMP and first dose less than 30 days. ● Study site employees, or immediate family members of a study site or sponsor employee● Previously been enrolled in this study. Subjects who had taken part in Part 1 were not permitted to take part in Part 2. ● History of any drug or alcohol abuse in the past 2 years or regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit is equivalent to 1 ounce of hard liquor or 4 ounces of wine or 12 ounces of beer) ● A confirmed positive alcohol urine test at screening or admission ● Current smokers and those who had smoked within the last 12 months or current users of e-cigarettes and nicotine replacement products and those who had used these products within the last 12 months ● A confirmed positive urine cotinine test at screening or admission ● Females of childbearing potential ● Subjects with pregnant or lactating partners ● Poor venous access that limited phlebotomy ● Clinically significant abnormal clinical chemistry, hematology or urinalysis as judged by the investigator ● Positive drugs of abuse test result ● Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results ● Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation ● History of cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator. ● Alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase or bilirubin above the upper limit of normal at screening ● Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients ● Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever was allowed unless it was active ● Significant serious skin disease, including rash, food allergy, eczema, psoriasis, or urticaria ● Active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed ● Clinical suspicion of active malignancy by history and physical examination ● Unwilling or unable to comply with the protocol or reside in the clinical unit during the study period or to fully cooperate with the investigator or the site personnel ● Significant organ abnormality or disease ● Considering or scheduled to have any surgical procedure during the study ● Received any known hepatic or renal clearance altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazines) for a period of 3 months prior to the first IMP administration ● Received ciprofloxacin and/or fluvoxamine within 30 days prior to first IMP administration ● Subjects who drank liquids or ate food containing caffeine from 7 days prior to first IMP administration until 24 h after the last IMP administration ● Subjects who drank liquids or ate food containing cruciferous vegetables (e.g., cabbage, cauliflower, broccoli) from 7 days prior to first IMP administration until 24 h after the last IMP administration ● Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study medication ● Subjects who donated blood from clinical unit admission, throughout the study duration, and for at least 30 days following last dose of study medication ● Subjects who were taking, or had taken, any prescribed or over-the-counter drug or herbal remedies (other than 4 g per day acetaminophen or HRT) in the 14 days before IMP administration. Exceptions could apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator ● Failure to satisfy the investigator of fitness to participate for any other reason Test Product, Dose and Mode of Administration [0458] Subjects received the following test investigation medicinal products (IMPs) in the fasted state:

Duration of Treatment [0459] Part 1 (SAD): A single IV dose of Compound 1 or placebo was administered on a single dosing occasion. A follow-up phone call took place 3 to 7 days post-dose (Days 4 to 8). [0460] Part 2 (MAD): Multiple doses of Compound 1 or placebo were administered on 7 consecutive days for each regimen (QD or BID). A follow-up phone call took place 3 to 7 days post-last dose of Period 2 (Days 10 to 14). Criteria for Evaluation [0461] Pharmacokinetics (PK): The following PK parameters for Compound 1 in plasma were estimated where possible and appropriate for each subject by non-compartmental analysis methods using Phoenix^® WinNonlin^® software (v8.0, Certara USA, Inc., USA). Plasma Pharmacokinetic Parameters: Part 1 (SAD):

Plasma Pharmacokinetic Parameters: Part 2 (MAD) Days 1 and 7:

Urine Pharmacokinetic Parameters: Part 2 (MAD) Days 1 and 7 for each period

[0462] Safety: The evaluation of safety parameters comprised analysis of AEs, laboratory variables (hematology, clinical chemistry and urinalysis), vital signs (blood pressure, heart rate, respiratory rate and oral temperature), ECGs and physical examination findings. Statistical Methods [0463] No formal statistical analysis was performed for the safety data. Descriptive statistics were considered adequate for a study of this type. [0464] For each study part separately, summary statistics (i.e., number of subjects with an observation (n), mean, standard deviation [SD], coefficient of variation [CV%], median, minimum, maximum, geometric mean, geometric SD and geometric CV%) of concentration data were to be calculated for each time point and dose level for Compound 1 in plasma. Summary statistics of plasma PK parameters were also to be calculated for Compound 1 for each dose level, and day for Part 2, by study part. [0465] Part 1: Dose Proportionality: Formal statistical analysis was to be performed on the PK parameters Cmax, AUC(0-last) and AUC(0-inf) to assess dose proportionality in Part 1. In addition, the power model was to be used to estimate the increase in the PK parameter resulting from a doubling in the dose (i.e., 2^β). The 90% confidence interval (CI) associated with this estimate was also to be provided. [0466] Part 2: Dose Proportionality: On Day 7, dose-proportionality was to be assessed for QD and BID dosing separately, on a pairwise basis using PROC MIXED for the natural log transformed dose adjusted PK parameters Cmax/D and AUC(0-tau)/D. The method specified was to be the restricted maximum likelihood. The PK parameters were to be dose-adjusted prior to analysis. The model was to include a term for the dose fitted as a fixed effect. [0467] A point estimate and 90% CI for the difference of test compared with reference was to be constructed using the error variance obtained from the analysis of variance (ANOVA). The null hypothesis was to be that there is no difference between test and reference treatment means. [0468] The adjusted test and reference means including their differences and 90% CIs of the difference obtained from the model, for each PK parameter of interest, were to be back transformed on the log scale to obtain adjusted geometric mean ratios (GMRs) and 90% CIs for the ratios. A 90% CI containing the value 1 was to be an indication of dose proportionality. [0469] Part 2: Dose Accumulation: Accumulation ratios were to be calculated using AUC values from serial sampling after the first and last dose of each cohort for the QD and BID administrations separately. [0470] Accumulation for each Compound 1 QD and BID dose was to be evaluated by comparing the natural log transformed PK parameters Cmax and AUC(0-tau) on Day 7 with Day 1. A natural log transformation was to be applied to the PK parameters. A mixed-effects model with day fitted as a fixed effect and subject fitted as a random effect was to be used to estimate the difference between Day 7 and Day 1 on the natural log scale for each PK parameter. [0471] Point estimates and their associated 90% CIs for the difference (Day 7 minus Day 1) for Cmax and AUC(0-tau) were to be constructed using the error variance obtained from the mixed effects model. The point and interval estimates were to be back transformed to obtain GMRs (Day 7/Day 1) and 90% CIs for the ratios. Results [0472] PK Results, Part 1 (SAD): Geometric mean (geometric CV%) plasma PK parameters for Compound 1 following single IV infusion doses of Compound 1 in the fasted state are presented below:

^a median (range); ^b min, max [0473] Following a single IV infusion of Compound 1 over 30 min to healthy male and female subjects at dose levels of 2 mg/kg, 4 mg/kg and 6 mg/kg in the fasted state, concentrations of Compound 1 were evident from the first sampling time point of 0.25 h post-dose (15 min post-start of infusion) in all subjects over the entire dose range. Maximum plasma concentrations of Compound 1 occurred between 0.50 and 1.00 h post-start of infusion with median Tmax values of 0.60, 0.50 and 0.58 h post-start of infusion or the 2 mg/kg, 4 mg/kg and 6 mg/kg doses, respectively. Maximum concentrations were reached at the end of infusion (0.5 h) for the majority of subjects (8 of 12 subjects across Part 1). For 2 of 4 subjects at the 2 mg/kg dose level ([1.00 h] and [0.70 h]) and for 2 of 4 subjects ([0.67 h] and [0.67 h]) at the 6 mg/kg dose level, Tmax occurred after the end of infusion. Concentrations then declined in a generally biphasic manner and remained quantifiable until between 4.50 and 8.50 h post-start of infusion for the 2 mg/kg dose, and until between 6.50 and 8.50 h post-start of infusion for the 4 mg/kg and 6 mg/kg doses. One subject (2 mg/kg) exhibited a lower maximum exposure (Cmax 354 ng/mL) to Compound 1, which was followed by a comparable overall exposure (based on an AUC(0-last) of 666 ng.h/mL). However, that subject’s profile shape was not in line with other subjects, with a slower distribution phase indicated. This subject received the entire 30 min infusion without interruption or AEs; however, based on the profile shape, the potential for extravasation of the dose should be considered. A reliable T1/2 was not calculated for that subject. [0474] Terminal slopes were reliably determined for 2, 2, and 3 out of the 4 dosed subjects in the 2 mg/kg, 4 mg/kg and 6 mg/kg dose groups, respectively. The start time of the terminal elimination phase ranged from 40 min to 5.5 h post-start of infusion across the dosing range, with similar resultant terminal elimination half-lives (individual estimates ranging from 1.21 to 4.00 h) and geometric mean (geometric CV%) values of 2.693 h (48.9%), 2.309 h (41.7%) and 2.073 h (66.9%) for the 2 mg/kg, 4 mg/kg and 6 mg/kg single infusion doses, respectively.Where terminal slopes could not be reliably determined, this was a result of an unacceptable coefficient of determination (i.e., R² adjusted <0.9). [0475] Following administration of 2 mg/kg, 4 mg/kg and 6 mg/kg Compound 1 in the fasted state, the geometric mean (geometric CV%) Cmax values were 506 ng/mL (28.3%), 1300 ng/mL (20.9%) and 1190 ng/mL (21.1%), respectively. The geometric mean (geometric CV%) AUC(0- last) values were 685 ng.h/mL (14.0%), 1430 ng.h/mL (31.2%) and 1800 ng.h/mL (25.1%), respectively. The AUC(0-inf) values ranged from 617 to 878 ng.h/mL for the 2 mg/kg dose (n = 2), 950 to 1630 ng.h/mL for the 4 mg/kg dose (n = 2) and had a geometric mean (geometric CV%) value of 2000 ng.h/mL (26.5%) for the 6 mg/kg dose (n = 3). Where AUC(0-inf) values were not considered reliable, this was due to an unacceptable coefficient of determination (i.e., R² adjusted <0.9). [0476] Total body clearance (CL) following single infusions ranged from 2770 to 3570 mL/min for the 2 mg/kg dose (n = 2), from 3220 to 5690 mL/min for the 4 mg/kg dose (n = 2) and had a geometric mean (geometric CV%) value of 3680 mL/min (25.4%) for the 6 mg/kg dose (n = 3). [0477] Volume of distribution (Vz) ranged from 599 to 895 L for the 2 mg/kg dose (n = 2), from 854 to 856 L for the 4 mg/kg dose (n = 2) and had a geometric mean (geometric CV%) value of 660 L (51.3%) for the 6 mg/kg dose level (n = 3). Vss ranged from 327 to 388 L for the 2 mg/kg dose (n = 2), 421 to 440 L for the 4 mg/kg dose (n = 2) and had a geometric mean (geometric CV%) of 395 L (28.1%) for the 6 mg/kg dose. [0478] PK Results, Part 2 (MAD): Geometric mean (geometric CV%) plasma PK parameters for Compound 1 following single and multiple IV infusion doses of Compound 1 for 7 Days in the fasted state are presented below for Day 1 and 7:

Day 1

Day 7

^a median (range); ^b min, max [0479] Mean (SD) cumulative amount of Compound 1 excreted in urine following single and multiple IV infusion doses of Compound 1 for 7 days in the fasted state are presented below for Day 1 and 7:

* Relative to the dosing interval, i.e., over 0 to 24 h for the QD dosing regimens (D and E) and over 0 to 12 h for the BID dosing regimens (F and G). [0480] QD Dosing (Period 1): Following a single IV infusion of Compound 1 over 30 min on Day 1 to healthy male and female subjects at dose levels of 2 mg/kg and 4 mg/kg QD (n = 6), plasma concentrations of Compound 1 were quantifiable from 0.25 h post-dose (i.e., 15 min post-start of infusion) in all subjects. Maximum plasma concentrations of Compound 1 were observed between 0.50 and 0.67 h post-start of infusion in all subjects, with a median Tmax of 0.58 h post-start of infusion for both dose levels. [0481] Following a single 2 mg/kg and 4 mg/kg IV infusion of Compound 1 on Day 1, geometric mean (geometric CV%) Cmax values were 513 ng/mL (11.3%) and 832 ng/mL (35.1%), respectively. The geometric mean AUC(0-tau) values on Day 1 were 709 ng.h/mL (14.1%) and 1140 ng.h/mL (26.4%), respectively. [0482] Geometric mean (geometric CV%) total body clearance based on AUC(0-tau) (CLtau) values were 4070 mL/min (23.0%) and 4650 mL/min (25.9%) on Day 1 for 2 mg/kg and 4 mg/kg QD dosing, respectively. The volume of distribution ranged from 387 to 722 L for the 2 mg/kg dose level (n = 2) and had a geometric mean (geometric CV%) value of 776 L (40.2%) for the 4 mg/kg dose level (n = 3). [0483] Following multiple IV infusion doses of Compound 1 at dose levels of 2 mg/kg and 4 mg/kg QD in the fasted state for 7 days, maximum plasma concentrations of Compound 1 were observed between 0.50 and 0.70 h post-start of infusion on Day 7, with a median Tmax of 0.50 h post-dose (i.e., end of infusion) for both dose levels. Plasma Compound 1 concentrations then declined in a biphasic manner with concentrations quantifiable until between 5.50 and 11.92 h for both dose levels. [0484] Terminal slopes were reliably determined for 2 of 6 subjects in the 2 mg/kg QD dose group and for 5 subjects in the 4 mg/kg QD dose group on Day 7, following 7 days QD dosing. The start of the terminal elimination phase ranged between 40 min and 6.5 h post-start of infusion. For the 2 mg/kg QD dose group, the terminal elimination half-lives ranged from 1.40 to 5.06 h. The geometric mean (geometric CV%) half-life for the 4 mg/kg dose level was 2.374 h (51.2%). Where terminal slopes could not be reliably determined, this was a result of an unacceptable coefficient of determination (i.e., R² adjusted <0.9). [0485] Following multiple 2 mg/kg and 4 mg/kg QD doses in the fasted state the geometric mean (geometric CV%) Cmax values on Day 7 were 444 ng/mL (15.6%) and 758 ng/mL (16.0%), respectively. The geometric mean (geometric CV%) AUC(0-tau) values were 633 ng.h/mL (16.8%) and 962 ng.h/mL (9.3%), respectively. [0486] Geometric mean (geometric CV%) total body clearance based on AUC(0-tau) values on Day 7 were 4560 mL/min (25.3%) and 5350 mL/min (19.0%) for 2 mg/kg and 4 mg/kg QD dosing, respectively. The volume of distribution ranged from 443 to 1420 L for the 2 mg/kg dose level (n = 2) and had a geometric mean (geometric CV%) value of 1100 L (52.5%) for the 4 mg/kg dose level (n = 5). Vss on Day 7 ranged from 348 to 685 L for the 2 mg/kg QD dose (n = 2) and had a geometric mean (geometric CV%) of 595 (42.9%) for the 4 mg/kg QD dose (n = 5). [0487] The mean (SD) amount of Compound 1 recovered in urine (cumulative Ae) following the 2 mg/kg and 4 mg/kg QD doses over the 0 to 24 h period on Day 1 was 15324.40 ng (11306.70 ng) and 46495.95 ng (24239.02 ng), respectively. On Day 7, mean (SD) cumulative Ae was 16022.59 ng (11331.46 ng) and 40788.24 ng (18726.55 ng), respectively. Geometric mean (geometric CV%) renal clearance (CLr) for the 2 mg/kg and 4 mg/kg QD doses were, respectively 0.215 mL/min (248.4%) and 0.600 mL/min (53.4%) on Day 1, and 0.228 mL/min (389.4%) and 0.648 mL/min (58.1%) on Day 7. [0488] BID Dosing (Period 2): Following a single IV infusion of Compound 1 over 30 min on Day 1 to healthy male and female subjects at dose levels of 2 mg/kg and 4 mg/kg BID, plasma concentrations of Compound 1 were quantifiable from 0.25 h post-dose (i.e., 15 min post-start of infusion) in all subjects. Maximum plasma concentrations of Compound 1 were observed between 0.50 and 0.67 h post-start of infusion in all subjects, apart from one subject who had a Tmax of 2.50 h post-start of infusion. Median Tmax was 0.50 h post-start of infusion for both dose levels on Day 1. [0489] Following a single 2 mg/kg and 4 mg/kg IV infusion dose of Compound 1 on Day 1, geometric mean (geometric CV%) Cmax values were 493 ng/mL (15.2%) and 682 ng/mL (61.4%), respectively. The geometric mean AUC(0-tau) values on Day 1 were 626 ng.h/mL (14.8%) and 1210 ng.h/mL (22.4%), respectively. [0490] On Day 1, geometric mean (geometric CV%) CLtau was 4620 mL/min (22.9%) and 4260 mL/min (17.7%) for 2 mg/kg and 4 mg/kg QD dosing, respectively. The geometric mean (geometric CV%) volume of distribution was 698 L (35.2%) for the 2 mg/kg dose (n = 3) and 779 L (27.6%) for the 4 mg/kg dose level (n = 4). [0491] Following multiple IV doses of Compound 1 at dose levels of 2 mg/kg and 4 mg/kg BID in the fasted state for 7 days, maximum plasma concentrations of Compound 1 were observed between 0.50 and 0.58 h post-start of infusion on Day 7, with a median Tmax of 0.50 h post-start of infusion for both dose levels. Plasma Compound 1 concentrations then declined in a biphasic manner with concentrations quantifiable until between 5.50 and 11.92 h for the 2 mg/kg BID dose and until between 8.50 and 11.92 h for the 4 mg/kg BID dose level. [0492] Terminal slopes were reliably determined for 2 of 6 subjects in the 2 mg/kg BID dose group and for 3 of 5 subjects in the 4 mg/kg BID dose group on Day 7, following 7 days BID dosing. The terminal elimination phases began between 40 min and 4.5 h post-start of infusion for both BID dose levels. For the 2 mg/kg BID dose group, the terminal elimination half-lives ranged from 2.12 to 3.95 h. The geometric mean (geometric CV%) half-life for the 4 mg/kg dose level was 2.280 h (46.3%). Where terminal slopes could not be reliably determined, this was a result of an unacceptable coefficient of determination (i.e., R² adjusted <0.9). [0493] Following multiple 2 mg/kg and 4 mg/kg BID IV infusion doses in the fasted state, on Day 7, the geometric mean (geometric CV%) Cmax values were 414 (14.8%) and 987 (14.9%), respectively. The geometric mean (geometric CV%) AUC(0-tau) values were 564 ng.h/mL (25.5%) and 1180 ng.h/mL (31.1%), respectively. [0494] On Day 7, geometric mean (geometric CV%) CLtau values were 5120 mL/min (35.8%) and 4340 mL/min (31.9%). The volume of distribution (Vztau) ranged from 1070 to 1190 L for the 2 mg/kg dose level (n = 2) and had a geometric mean (geometric CV%) of 812 L (67.2%) for the 4 mg/kg dose level (n = 3). Vzz on Day 7 ranged from 523 to 600 L for the 2 mg/kg BID dose (n = 2) and had a geometric mean (geometric CV%) of 474 (34.6%) for the 4 mg/kg BID dose (n = 5). [0495] The mean (SD) amount of Compound 1 recovered in urine following the 2 mg/kg and 4 mg/kg BID doses over the 0 to 12 h period on Day 1 was 20805.93 ng (9591.98 ng) and 51791.40 ng (26629.47 ng), respectively. On Day 7, mean (SD) cumulative Ae was 20968.63 ng (7308.78 ng) and 43344.00 ng (10292.96 ng), respectively. Geometric mean (geometric CV%) renal clearance (CLr) for the 2 mg/kg and 4 mg/kg BID doses were, respectively, 0.434 mL/min (148.6%) and 0.637 mL/min (66.0%) on Day 1, and 0.587 mL/min (48.1%) and 0.596 mL/min (50.7%) on Day 7. [0496] Dose Proportionality – Part 1 (SAD): Peak exposure increased between the 2 mg/kg and 4 mg/kg doses; however, there was no increase between the 4 mg/kg and 6 mg/kg doses. For Cmax, the β estimate was less than 1 (0.84), and the associated lower bound limit of the 90% CI (0.50) was not contained within the critical region (0.68 and 1.33). Similarly, estimates of 2^β were less than 2, indicating a less than proportional increase in peak exposure with respect to dose. For AUC(0-last) the β (90% CI) estimate was 0.90 (0.63, 1.17) and 2^β was 1.87. Although the 90% CI for β is not entirely contained within the critical region (0.68 and 1.33), and the 2^β is less than 2, dose proportionality of overall exposure cannot be discounted. Small sample size may be relevant to interpretation of these results. [0497] Dose Proportionality – QD Dosing Part 2 (MAD): Dose adjusted peak and overall Compound 1 exposure levels for the 4 mg/kg dose level were on average 96% and 85% of those for the 2 mg/kg dose, indicating a marginally below proportional response. However, the ratios of the adjusted geometric means and their associated 90% CIs do indicate possible dose proportionality between the 2 mg/kg and 4 mg/kg dose levels (i.e., ratios close to and 90% CIs containing the value 100%). [0498] Dose Proportionality – BID Dosing Part 2 (MAD): Dose adjusted peak and overall Compound 1 exposure levels for the 4 mg/kg dose level were on average 34% and 18% higher than those for the 2 mg/kg dose. The lower limit of the 90% CI of the GMRs for Cmax/D is 108%, indicating that peak exposure is significantly higher for the 4 mg/kg dose. The higher exposure associated with the 4 mg/kg dose for Cmax/D is not as evident for AUC(0-tau)/D. Small sample size and variability within the data (which produces wide confidence intervals) may be relevant to interpretation of these results. [0499] Dose Proportionality Day 1 – Part 1 (SAD) and Part 2 (MAD) Combined: Dose adjusted peak Compound 1 exposure levels (i.e., Cmax/D and AUC(0-last)/D) for the 4 mg/kg dose level were on average similar to the 2 mg/kg dose. A dose-proportional increase in peak exposure (Cmax/D) was seen with the doubling in dose, the geometric mean ratio (90% CI) was 103.09% (80.55, 131.94). The geometric mean ratio (90% CI) for AUC(0-last)/D was 94.35% (75.91, 117.27). The associated 90% CIs for both peak and overall exposure encompassed 100%, representing the null hypothesis of no difference between the 2 dose levels with respect to average peak and overall exposure. When the assessment of dose-proportionality was performed removing the subjects who had exhibited anomalously low exposure (one subject (2 mg/kg, Part 1) and one subject (4 mg/kg, Part 2) who had an anomalously low exposure for their BID dose) the exposure based on Cmax and AUC(0-last) increased in a similar manner (n = 9). There was a dose proportional increase in Cmax and AUC(0-last) following the doubling in dose, with geometric mean ratio (90% CI) of 99.86% (76.44%,130.45) for Cmax and a geometric mean ratio (90% CI) of 94.21% (73.75, 120.33) for AUC(0-last). [0500] Dose Accumulation – QD Dosing Part 2 (MAD): The results indicated that dose accumulation for the 2 mg/kg dose was approximately 13% less for Cmax, and around 11% less for AUC(0-tau) on Day 7 compared to Day 1 (n = 6). The 90% CI for Cmax contained 100% and the upper bound of the 90% CI for AUC(0-tau) approached 100%, indicating a degree of similarity with respect to exposure between Days 1 and 7. For the 4 mg/kg dose, Cmax on Day 7 was approximately 9% less than on Day 1, and AUC(0-tau) was also approximately 14% less (n = 5). The Day 7/Day 1 ratios all being below 100% indicate no dose accumulation following 7 days dosing with Compound 1. [0501] Dose Accumulation – BID Dosing Part 2 (MAD): The results indicated that dose accumulation for the 2 mg/kg dose was on average 16% less for Cmax and 10% less for AUC(0- tau) on Day 7 compared to Day 1 (n = 6). The associated 90% CI for Cmax did not encompass 100%, and the upper bound of the 90% CI for AUC(0-tau) was just over 100% (101.56%), indicating a possible difference between Days 7 and 1 with respect to average exposure, but no evidence of dose accumulation. [0502] For the 4 mg/kg dose, Cmax was on average 45% greater on Day 7 compared to Day 1, indicating dose accumulation (n = 5). However, the associated 90% CI range was very wide owing to one subject having a very low Cmax on Day 1; therefore, the results should be interpreted with caution. The AUC(0-tau) results show no evidence of dose accumulation, with similar estimates observed on Day 7 and Day 1. The associated 90% CI contained 100% thus confirming there was no difference between days. However, there were only 5 subjects included in the analysis of the 4 mg/kg dose; therefore, the small sample size may be relevant to the interpretation of the results. [0503] Safety Results: Single ascending doses of IV Compound 1 at 2, 4 and 6 mg/kg were well tolerated in healthy subjects, with no subjects reporting an adverse drug reaction (ADR). Multiple ascending doses of IV Compound 1 at 2 mg/kg and 4 mg/kg QD and BID over 7 days were well tolerated in healthy subjects, with 1 subject in the 2 mg/kg QD dose group and 1 subject in the 4 mg/kg QD dose group reporting ADRs of headache and infusion site extravasation, respectively. One subject withdrew from the study after experiencing the mild treatment-emergent AE (TEAE) of infusion site extravasation following administration of 4 mg/kg Compound 1 QD; however, this was assessed as not related to the IMP. There were no significant safety laboratory, vital signs or ECG results throughout the study. Example 2. A Single Part, Non-Randomized, Open-Label Study Designed to Evaluate the Effect of a CYP1A2 Inhibitor (e.g., Ciprofloxacin and/or Fluvoxamine) on the Pharmacokinetics of Compound 1, in Healthy Male Subjects and Healthy Female Subjects of Non-Childbearing Potential Study Objectives and Endpoints [0504] The primary objective of this study is to determine the effect of multiple doses of a CYP1A2 inhibitor (e.g., ciprofloxacin and/or fluvoxamine) on the pharmacokinetics (PK) of Compound 1, and the endpoints are results of the formal statistical analysis of the following PK parameters for Compound 1 following intravenous (IV) administrations of Compound 1 when co-administered with multiple oral administrations of a CYP1A2 inhibitor (e.g., ciprofloxacin and/or fluvoxamine), compared to when administered alone: Cmax, AUC(0-last) and AUC(0-inf) where appropriate. [0505] The secondary objectives of this study are to further characterize the IV PK of Compound 1 when administered alone and when co-administered with multiple oral administrations of a CYP1A2 inhibitor (e.g., ciprofloxacin and/or fluvoxamine) and to assess safety of Compound 1. The endpoints are measurement of the appropriate PK parameters of Compound 1 in plasma where possible, including but not limited to: Tmax, Lambda-z, T1/2, CL, Vz, and incidence of adverse events (AEs) and assessment of vital signs, 12-lead electrocardiograms (ECGs), physical examinations and laboratory safety tests. [0506] It will be appreciated that, while the below protocol describes use of ciprofloxacin, a similar protocol may be used with fluvoxamine. Study Rationale [0507] Preclinical data indicate that Compound 1 is a potential substrate for CYP1A2. In vitro studies were conducted with recombinant human cytochrome (CYP) P450 isozymes to characterize the individual CYP P450 isozymes that could metabolize Compound 1. Compound 1 was a particularly good substrate for CYP1A2. In vitro studies investigating the effects of Compound 1 on human CYP P450 isozymes showed no evidence that clinically relevant inhibition of these enzymes is likely to occur, except for transient inhibition of CYP1A2- mediated metabolism (IC50 = 1.9 μM). Compound 1 did not induce CYP1A2 or CYP3A in in vitro studies with human hepatocytes. Drug-drug interaction potential of Compound 1 is investigated in this study to determine whether co-administration of Compound 1 with an inhibitor of CYP1A2 results in altered exposure of Compound 1. [0508] Guidance provided by the FDA (Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available online: https://www.fda.gov/drugs/drug- interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and- inducers#table3-2v (accessed 05 March 2021)), as well as the prescribing information for ciprofloxacin (Bayer HealthCare Pharmaceuticals Inc. Cipro Highlights of Prescribing Information. May 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2020/019537s091,020780s048lbl.pdf#page=39 (accessed 05 March 2021)), indicates that ciprofloxacin (a broad spectrum fluoroquinolone antibacterial agent) is a strong inhibitor of CYP1A2. Therefore, during this study, single doses of Compound 1 are administered both without ciprofloxacin (on Day 1) and following twice daily (BID) ciprofloxacin dosing (on Days 3 to 6, with Compound 1 administered on Day 6 only), and plasma samples will be collected for the characterization of the PK of Compound 1 following both IMP doses. [0509] Ciprofloxacin may be administered with or without food, though when given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of ciprofloxacin is not substantially affected by food. Dosing guidance recommends that concomitant administration of ciprofloxacin with dairy products (like milk or yogurt) or calcium- fortified juices alone should be avoided, since decreased absorption is possible. The study drugs are administered in the fasted state during this study. Methodology [0510] This is a single center, non-randomized, open-label, single regimen, drug-drug interaction study in healthy male subjects and healthy female subjects of non-childbearing potential. It is planned to enroll approximately 23 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 18 subjects). An evaluable subject is defined as a subject who has received all doses of Compound 1 and ciprofloxacin and has evaluable pharmacokinetic (PK) data until 24 hours post-final investigational medicinal product (IMP) dose (relative to the end of infusion). [0511] Each subject receives the following study drugs:

^a Compound 1 is administered intravenously as 30 (± 5) minute infusions; ^b Ciprofloxacin is administered as an oral tablet with a total of approximately 240 mL of water. Fasted dosing of ciprofloxacin is required on morning of Day 6 only; meal restrictions are not required for ciprofloxacin dosing on Days 3-5 nor evening of Day 6. The final dose of ciprofloxacin is administered on evening of Day 6. Study Design [0512] Subjects undergo preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects are admitted to the clinical unit in the morning of the day before the first dose of study drug (Day -1) and remain in clinical unit until Day 7. [0513] Subjects are dosed with the IMP (Compound 1 solution) by a 30 (± 5) minute IV infusion on the morning of Day 1 in the fasted state (e.g., following an 8-hour overnight fast). On Days 3 to 6, subjects are administered the non-investigational medicinal product (NIMP; e.g., ciprofloxacin) twice daily (BID; every 12 hours [Q12h]). A dose of ciprofloxacin and a second dose of the IMP (Compound 1) is administered on the morning of Day 6 in the fasted state; ciprofloxacin dosing takes place approximately 90 (± 15) minutes prior to the start of the IMP infusion. The final dose of ciprofloxacin is administered on the evening of Day 6. Meal restrictions are not required for ciprofloxacin dosing on Days 3-5 nor on the evening of Day 6. [0514] Pharmacokinetic and safety (12-lead electrocardiograms [ECGs], vital signs, physical examinations and laboratory safety tests) assessments are performed at pre-defined time points from admission/pre-dose until discharge from the clinical unit. [0515] Subjects remain on site until approximately 24 hours post-final IMP dose (relative to the end of infusion; i.e., Day 7). A follow-up phone call takes place on 3 to 7 days post-final IMP dose (Days 9 to 13) to ensure the ongoing wellbeing of the subjects. If a subject reports any adverse events (AEs) which represent a cause for concern, additional visits are arranged per investigator’s judgment. Number of Subjects Planned [0516] It is planned to enroll approximately 23 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 18 subjects). Subjects withdrawn due to an IMP-related AE will not be replaced. Subjects who are withdrawn for other reasons may be replaced as required by agreement between the investigator and the sponsor to ensure a minimum of 18 evaluable subjects. Duration of Study [0517] Subjects receive a single administration of IMP (Compound 1 solution) on 2 separate occasions (mornings of Days 1 and 6) and BID (Q12h) administrations of NIMP (ciprofloxacin) on 4 consecutive days (mornings and evenings of Days 3 to 6). The estimated time from screening until the follow-up phone call is approximately 6 weeks. Main Inclusion Criteria [0518] Healthy males and healthy females of non-childbearing potential aged 18 to 55 years inclusive at time of signing informed consent. Body mass index (BMI) 18.0 to 32.0 kg/m² as measured at screening, and weight ≥50 kg and ≤100 kg at screening and admission. Exclusion Criteria [0519] Subjects are excluded from the study if one or more of the following statements is applicable: ● Subjects who have received any IMP in a clinical research study within 5 half-lives or within 30 days prior to first dose. However, in no event, shall the time between last receipt of IMP and first dose be less than 30 days. ● Subjects who are study site or sponsor employees, or are immediate family members of, a study site or sponsor employee ● Evidence of current SARS-CoV-2 infection ● History of any drug or alcohol abuse in the past 2 years ● Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = 12 oz 1 bottle/can of beer, 1 oz 40% spirit, or 5 oz glass of wine) ● A confirmed positive urine alcohol test ● Current smokers and those who have smoked within the last 12 months or current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months ● A confirmed positive urine cotinine test. ● Females of childbearing potential who are pregnant or lactating (all female participants must have a negative highly sensitive urine and serum pregnancy test). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum FSH concentration ≥40 IU/L)]Male subjects with pregnant or lactating partners ● Have poor venous access that limits phlebotomy ● Clinically significant abnormal clinical chemistry, hematology or urinalysis as judged by the investigator at screening or admission and clinically significant abnormal coagulation as judged by the investigator at screeningAspartate aminotransferase, ALT or bilirubin above the upper limit of normal ● Presence of clinically significant abnormality following review of vital signs, full physical examination and ECG. ● Positive drugs of abuse test result ● Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results ● Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation at screening onlyHistory of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease (except cholecystectomy), neurological or psychiatric disorder, as judged by the investigator ● A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). ● Subject has a history or presence of any condition known to interfere with the absorption, distribution, metabolism or excretion of drugs ● Subject has a history of allergy to fluoroquinolones. ● Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients ● Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active ● Significant serious skin disease, including rash, food allergy, eczema, psoriasis, or urticaria ● Subjects with an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed ● Clinical suspicion of active malignancy by history and physical examination ● Subject is unwilling or unable to comply with the protocol or reside in the clinical unit during the study period or to fully cooperate with the investigator or the site personnel● Subject has a significant organ abnormality or disease ● Subject is considering or scheduled to have any surgical procedure during the study● Subject has received any known hepatic or renal clearance altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazines) for a period of 3 months prior to the first study drug administration ● Subject has received ciprofloxacin and/or fluvoxamine within 30 days prior to first study drug administration ● Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study medication ● Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 2 g per day acetaminophen or HRT) in the 14 days before first study drug administration. (COVID-19 vaccines are accepted concomitant medications. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator ● Failure to satisfy the investigator of fitness to participate for any other reason Investigational Medicinal Product, Dose and Mode of Administration [0520] The following IMP and NIMP are used in this clinical study:

Pharmacokinetic Assessments: [0521] Blood samples are collected for the analysis of Compound 1 in plasma. Additionally, blood samples are collected for the analysis of ciprofloxacin exposure. Pharmacokinetic- concentration time data are analyzed for Compound 1 in plasma, using Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA) using appropriate non-compartmental techniques to obtain estimates of the PK parameters presented below, where possible and appropriate.

Safety Assessments [0522] The safety assessments to be conducted are: adverse event (AE) monitoring, clinical laboratory tests (clinical chemistry, hematology and urinalysis, coagulation assessments), physical examinations, 12-lead ECGs, and vital signs. Statistical Methodology [0523] Log transformed AUC(0-last), AUC(0-inf) and Cmax values for Compound 1 will be analyzed using a mixed effects model with terms for treatment (i.e., Compound 1 and Compound 1 with ciprofloxacin) as fixed effect and subject as a random effect. Adjusted geometric mean ratios (GMRs) and 90% confidence interval (CI) for the comparison between Compound 1 with ciprofloxacin and Compound 1 dosed alone will be provided, where the ratios are defined as test/reference. If the 90% CI for each parameter lies within the acceptance interval of 80.00% to 125.00% then the ciprofloxacin doses will be considered to not have a clinically relevant effect of the exposure of Compound 1. [0524] No formal statistical analysis will be performed for the safety data. Descriptive summaries of treatment emergent adverse events (TEAEs), clinical chemistry and hematology, vital signs and ECGs including changes from baseline will be presented by treatment (where treatment is Compound 1, ciprofloxacin and Compound 1 + ciprofloxacin) and time point (as appropriate). Sample Size and Power [0525] It is planned to enroll approximately 23 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 18 subjects). An evaluable subject is defined as a subject who has received all doses of Compound 1 and ciprofloxacin and has evaluable PK data until 24 hours post-final IMP dose (relative to the end of infusion). [0526] Power calculations based on AUC(0-inf) for Compound 1 show that a sample size of 18 subjects is required to demonstrate equivalence of the PK of Compound 1 with ciprofloxacin (Day 6) and without ciprofloxacin (Day 1). [0527] The following assumptions were used in these power calculations: 80% power, 5% alpha, equivalence bounds of 80.00% to 125.00% (i.e., based on two one-sided tests), a ratio of means of 1.05, and an intra-subject coefficient of variation (CV%) of 19%. Assuming a maximum dropout rate of 20%, a total of 23 subjects will therefore be needed to obtain 18 evaluable subjects. AUC(0-inf) was used as the intra subject CV% was greater than that for Cmax. Note that the intra subject CV% for AUC(0-inf) was similar to that for AUC(0-last). Example 3. A Pharmacokinetic Study of Compound 1 Injected Intravenously in Stable Adult Maintenance Hemodialysis Subjects Study Objectives and Endpoints [0528] The primary objective of this study is to measure the pharmacokinetic parameters of two doses of Compound 1 administered intravenously, one dose off-dialysis and one dose on- dialysis in subjects on maintenance hemodialysis. [0529] The secondary objectives of this study are to assess the safety of Compound 1 in subjects with renal failure on maintenance hemodialysis and to assess the amount of Compound 1 recovered in the dialysate over a standard 3- to 4-hour hemodialysis treatment. Study Design [0530] This study is a single center, open label study designed to evaluate the pharmacokinetics and safety of two infusions of Compound 1 (at 2.0 mg/kg, administered as IV infusion over 30 minutes) in subjects on maintenance hemodialysis. A washout period of at least 5 days is required between the two doses. Subjects in this study must be receiving hemodialysis thrice weekly with documentation of adequate delivered dose of dialysis. [0531] One infusion of Compound 1 is administered on an off-dialysis day (‘off-dialysis’ dose) and the other dose will be administered prior to a scheduled dialysis (‘on-dialysis’ dose). Venous blood samples will be obtained from a peripheral vein to determine pharmacokinetic parameters off- and on-dialysis. The off-dialysis infusion of Compound 1 is administered intravenously before the scheduled hemodialysis (e.g., 24-40 hours before scheduled hemodialysis) and infusion of the on-dialysis dose of Compound 1 begins 30 minutes prior to the start of hemodialysis treatment. Hemodialysis starts at the end of the drug infusion period within, e.g., 5-30 minutes. The hemodialysis schedule of the subjects is not altered for the purpose of this study. All drug administrations are performed using a calibrated infusion pump dedicated exclusively to the study. All infusion kits, tubing, catheters, syringes used are identical over the course of the study. Preparation, mixing, and infusion procedures for drug administration are identical. [0532] Samples of venous blood for the determination of pharmacokinetic parameters are obtained within one hour prior to dosing (pre-dose) and at the following specified time points: 15 ± 1 min after the start of infusion, at time 0 (defined as the end of study drug infusion), and at 10 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, and 24 h (all ± 3 min) after completion of the infusion. [0533] Additional arterial blood samples are drawn from the blood inlet and outlet ports of the dialyzer simultaneously at 5 minutes after the start of hemodialysis and at 1, 2, 3 and 4 hours post completion of the infusion, assuming initiation of hemodialysis within 5-30 minutes after completion of infusion. [0534] The duration of subject participation is approximately 14 days. Subjects remain at the study site for 3 days during each dosing period with follow-up assessments between dosing periods. A final follow-up assessment occurs on Day 14. Number of Subjects [0535] A total of 16 subjects are planned for participation in this study. Inclusion Criteria [0536] Subjects who meet the following inclusion criteria are eligible to participate in this study: ● Adult male or female subjects, 18 to 75 years of age who have been on maintenance hemodialysis for at least 3 months. ● Receive hemodialysis three (3) times a week. ● Target post-dialysis dry body weight < 125 kg. ● Have laboratory parameters at screening as follows: o Serum albumin ≥ 3.0 gm/dL o Blood hemoglobin ≥ 9.0 gm/dL o Serum liver transaminases (ALT, AST) < 2x the upper limit of normal;● Have adequate single pool urea Kt/V ≥ 1.2) for the two consecutive readings in the month preceding the screening visit. Exclusion Criteria [0537] Subjects are excluded from the study if one or more of the following statements is applicable: ● Subjects treated with cytochrome 4501A2 (CYP1A2) inhibitors ciprofloxacin (Cipro®) or fluvoxamine (Luvox®) within 14 days prior to anticipated first dose of study medication. ● Ongoing bacterial infection requiring the use of antibiotics or history of antibiotics use within 2 weeks prior to screening. ● History of or positive results of HIV test. ● History of previous organ transplant, hepatitis or known liver disease. Patients with a history of hepatitis (HBV, HCV, EBV or CMV) and ALT/AST above normal limits at screening are excluded from participation in the study. ● Have ongoing drug abuse/dependence (including alcohol); or recent history (within the past 5 years) of, or treatment for, alcohol or drug abuse. Subjects abstain from alcohol during the 48 hours prior to screening and the 48 hours prior to admission until discharge from the clinical unit. Subjects who consume alcohol within 48 hours prior to screening are excluded from participation in the study. ● Subject is currently participating in or has participated in an investigational drug or medical device study within 30 days or five half-lives (half-lives as applied to subjects with almost no renal function), whichever is longer, prior to consent to participate in this study. ● Subject is unwilling or unable to comply with the protocol or to cooperate fully with the Investigator or the site personnel. ● Subject is deemed not medically stable for the study in the opinion of the Investigator or the subject’s primary nephrologist. ● Subject is unable to understand or provide written informed consent. ● Pregnant or lactating females at time of screening. Study Drug [0538] Compound 1 is administered intravenously as a unit dose based on dry body weight (e.g., 2 mg/kg). Compound 1 is provided as a 10 mg/mL stock solution. A pharmacist prepares the final dosing solution based on pharmacy compounding instructions. The stock solution will be prepared for same day use. One dose is administered 24 hours preceding the scheduled dialysis and the second dose is administered just prior to the start of the scheduled dialysis. Duration of Treatment [0539] Eligible subjects receive two infusions (the first off-dialysis and the second on- dialysis) of 2 mg/kg Compound 1 administered intravenously over 30 minutes. Pharmacokinetic and Safety Assessments [0540] PK parameters including, but not limited to, C_max, AUC, T_1/2, CL and Vd are calculated using standard non-compartmental techniques using validated software program such as WinNONLIN or a suitable alternative. Summary statistics (e.g., mean, standard deviation, range) are calculated for each parameter. [0541] Safety is assessed by the following parameters: ● Adverse events (AEs) ● Treatment-emergent AEs ● Physical examination ● Vital signs ● Laboratory tests (e.g., blood chemistry, hepatic, coagulation, hematology) ● Electrocardiogram ● Pregnancy test ● Concomitant medications Statistical Methods [0542] With a total sample of 16 (8 in each treatment sequence; the first off-dialysis and the second on-dialysis), the study has approximately 88% power at the 5% level to reject the null hypotheses that the geometric mean ratio of Cmax (or AUC) after the infusion on-dialysis vs. off-dialysis is below 0.6 or above 1.4; i.e., the two geometric means are not equivalent, and in favor of the alternative hypothesis that the geometric means of the two groups are equivalent, assuming that the expected ratio of geometric means is 0.85, the between-subject coefficient of variation is 0.4, and the intra-subject coefficient of variation is 0.25 based on historical data of Compound 1. Example 4. A Single Part, Four-Way Crossover, Randomized, Partially-Blinded Study to Evaluate the Effect of Intravenous Compound 1 on Baseline-Adjusted QT/QTc Interval in the Fasted State in Healthy Male Subjects and Healthy Female Subjects of Non- Childbearing Potential Study Objectives and Endpoints [0543] The primary objective of this study was to evaluate the effect of Compound 1 on placebo-corrected change from baseline (ΔΔ) QT/corrected QT (QTc) interval, following single intravenous (IV) doses in healthy adults, and the endpoint was change from baseline in corrected QT interval by Fridericia’s formula (ΔQTcF) (electrocardiograms [ECGs] obtained digitally) for Compound 1 at therapeutic and supra-therapeutic dose levels compared to placebo. Due to early termination of this study, sufficient data to meet the primary objective of the study were not obtained. [0544] The secondary objectives and endpoints of this study were: ● ● ● ● ●

Methodology [0545] This was a single center, randomized, partially-blinded, single dose four-way crossover thorough QT/corrected QT (TQT) study in healthy male subjects and healthy female subjects of non-childbearing potential. It was planned to enroll 48 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 40 subjects). An evaluable subject was defined as a subject who has evaluable Holter extraction and pharmacokinetic (PK) data for all 4 regimens, and has completed the study. It was planned that an equal number of male subjects and female subjects of non-childbearing potential would be enrolled (i.e., 24 of each). [0546] Each subject was to receive the following treatments in an order according to the randomization schedule:

^a Compound 1 and the matching placebo are administered intravenously as 30 minute infusion; ^b Moxifloxacin is administered as an oral tablet with a total of 240 mL of water. Study Design [0547] Subjects underwent preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects were admitted to the clinical unit in the morning of the day before the first dose of study drug (Day -1). [0548] Subjects were randomized before administration of the first dose of study drug to one of the following treatment sequences:

[0549] Subjects were to be dosed on the morning of Day 1 of each treatment period (i.e., Days 1, 5, 9 and 13 of clinical residency) according to the randomization schedule following an 8 hour overnight fast. Regimens A, B and D were to be administered in a double-blind fashion whereas Regimen C was to be administered open-label. There was to be a minimum washout of 3 days between each study drug administration. [0550] Holter electrocardiogram (ECG), additional safety (12-lead ECGs, vital signs, physical examinations and laboratory safety tests) and PK assessments were to be performed at pre-defined time points from pre-dose until discharge from the clinical unit. [0551] Subjects were to remain on site until approximately 25 hours post-final dose (Day 14 of clinical residency) following completion of discharge procedures. Follow-up phone calls were to take place on 3 to 7 days post-final dose (Days 16 to 20) and on 30 days post-final dose (Day 43) to ensure the ongoing wellbeing of the subjects. If a subject reported any adverse events (AEs) which represented a cause for concern, they were to be required to attend the clinical unit for a follow-up assessment. This would have been an unscheduled visit. Number of Subjects Planned [0552] It was planned to enroll 48 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 40 subjects). It was planned that an equal number of male subjects and female subjects of non-childbearing potential will be enrolled (i.e., 24 of each). [0553] Subjects withdrawn due to a study drug-related AE were not be replaced. Subjects who were withdrawn for other reasons could have been replaced as required by agreement between the investigator and the sponsor to ensure sufficient evaluable subjects. Up to 8 replacement subjects could have been enrolled into the study. It was planned that the replacement subject was the same gender as the subject they have replaced. The maximum number of subjects that may be dosed was planned to be 56. Duration of Study [0554] Subjects were to receive a single drug product administration on 4 separate occasions (a single dose administration of Compound 1 on two occasions, and single doses of moxifloxacin and placebo on separate occasions), with a minimum washout of 3 days between each product administration. The estimated time from screening until the final follow-up phone call was planned to be approximately up to 11 weeks. Main Inclusion Criteria [0555] Healthy males and healthy females of non-childbearing potential aged 18 to 55 years inclusive at time of signing informed consent. Body mass index (BMI) 19.0 to 32.0 kg/m² as measured at screening and weight between ≥50 kg and ≤100 kg. Exclusion Criteria [0556] Subjects were excluded from the study if one or more of the following statements was applicable: ● Subjects who have received any IMP in a clinical research study within 5 half-lives or within 30 days prior to first dose. However, in no event, shall the time between last receipt of IMP and first dose be less than 30 days. ● Subjects who are study site or sponsor employees, or are immediate family members of a study site or sponsor employee ● Evidence of current SARS-CoV-2 infection ● History of any drug or alcohol abuse in the past 2 years ● Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = 12 oz 1 bottle/can of beer, 1 oz 40% spirit, or 5 oz glass of wine) ● A confirmed positive alcohol urine test at screening or admission ● Current smokers and those who have smoked within the last 12 months or current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months ● A confirmed positive urine cotinine test at screening or admission. ● Females of childbearing potential. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum FSH concentration ≥40 IU/L) ● Male subjects with pregnant or lactating partners ● Have poor venous access that limits phlebotomy ● Clinically significant abnormal clinical chemistry, hematology or urinalysis as judged by the investigator ● Presence of clinically significant abnormality following review of vital signs, full physical examination and ECG. ● Positive drugs of abuse test result ● Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results ● Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance (CLcr) of <80 mL/min using the Cockcroft-Gault equation ● History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease (except cholecystectomy), neurological or psychiatric disorder, as judged by the investigator ● Family history of sudden cardiac death. ● A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). ● Uncontrolled hypertension: supine systolic BP >140 mmHg and/or supine diastolic BP >100 mmHg at screening (may be repeated after 15 minutes and exclusion will be based on the last measurement). ● History or evidence of any of the following: o myocardial infarction o cardiac surgery revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) o unstable angina o cerebrovascular accident or stroke or transient ischemic attack, pacemaker, atrial fibrillation, flutter, or non-sustained or sustained ventricular tachycardia, congestive heart failure (Grade III and IV according to New York Heart Association [NYHA] classification); hypokalemia, unexplained syncope or syncope related to a cardiac arrhythmia. ● 12-lead ECG with any clinically significant abnormalities of rate, rhythm, intervals, or conduction after resting supine for >10 minutes, as determined by the Investigator including: o Any characteristics which would make QT assessment unreliable, including flat T waves. Evidence of a previous myocardial infarction, left ventricular hypertrophy, or more than minor nonspecific ST-T wave changes o QTcF > 450 msec o PR >200 msec o QRS > 110 msec o HR below 50 or above 90 beats/min o Second- or third-degree atrioventricular block o Complete right bundle branch block o Complete left bundle branch block. ● Aspartate aminotransferase, ALT or bilirubin above the upper limit of normal at screening ● Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients ● Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active ● Significant serious skin disease, including rash, food allergy, eczema, psoriasis, or urticaria ● Subjects with an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed ● No clinical suspicion of active malignancy by history and physical examination ● Subject is unwilling or unable to comply with the protocol or reside in the clinical unit during the study period or to fully cooperate with the investigator or the site personnel ● Subject has a significant organ abnormality or disease ● Subject is considering or scheduled to have any surgical procedure during the study ● Subject has received any known hepatic or renal clearance altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazines) for a period of 3 months prior to the first study drug administration ● Subject has received ciprofloxacin and/or fluvoxamine within 30 days prior to first study drug administration ● Donation of blood within 2 months or donation of plasma within 7 days prior to first dose of study drug ● Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 2 g per day acetaminophen or HRT) in the 14 days before study drug administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the investigator ● Failure to satisfy the investigator of fitness to participate for any other reason Investigational and Non-Investigational Medicinal Products, Dose and Mode of Administration [0557] The following investigational medicinal products (IMPs) and non-investigational medicinal product (NIMP) were administered in the fasted state in this clinical study:

Pharmacokinetic Assessments [0558] Blood samples were collected for the analysis of Compound 1 and moxifloxacin in plasma. The plasma concentration data for Compound 1 and moxifloxacin were analyzed using Phoenix WinNonlin v8.0 or a more recent version (Certara USA, Inc., USA) using appropriate non-compartmental techniques to obtain estimates of the PK parameters presented below, where possible and appropriate.

Pharmacodynamic Assessments (Holter Electrocardiograms): [0559] Subjects underwent continuous Holter ECG monitoring from 1 hour prior to the start of dosing until up to 25 hours post-completion of dosing for each regimen (i.e., on Days 1 and 2, Days 5 and 6, Days 9 and 10, and Days 13 and 14 of clinical residency). PK time-matched extractions were taken in triplicate at pre-defined time points. Safety Assessments [0560] The safety assessments to be conducted were adverse event (AE) monitoring, 12-lead ECGs, vital signs, clinical laboratory tests (clinical chemistry, hematology and urinalysis), and physical examinations. Statistical Methodology [0561] Hotler Electrocardiogram Data: The following analysis of ECG data was planned: For all continuous ECG parameters from each period, baseline is the average of the derived ECG intervals from the 3 ECG time points prior to treatment administration on Day 1 for the respective period. [0562] By-Time Point Analysis: The by-time point analysis for corrected QT interval by Fridericia’s formula (QTcF) is based on a linear mixed-effects model with change from baseline in QTcF (ΔQTcF) as the dependent variable, time (i.e., post-dose time point: categorical), period, sequence, treatment, and time-by-treatment interaction as fixed effects, and baseline QTcF as a covariate. An unstructured covariance matrix is specified for the repeated measures at post-dose time points for subject within treatment period. The model also includes a subject specific random effect. If the model with unstructured covariance matrix fails to converge, other covariance matrices are considered. From this analysis, the adjusted mean and 2-sided 90% confidence interval (CI) is calculated for the contrast “Compound 1 vs placebo” for each dose of Compound 1 at each post-dose time point, separately. If the upper bound of the 90% CI for both doses of Compound 1 at all post-dose time points is less than 10 msec then it is concluded that Compound 1 does not prolong the QTc interval to a clinically significant degree. The following time points are included in the statistical model: time 0 hours (defined as the end of infusion) and 10 minutes, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12 and 24 hours post-completion of the infusion. [0563] For heart rate (HR), PR and QRS, the supportive analysis is based on the change from baseline post-dose (ΔHR, ΔPR and ΔQRS). The same (by-time point analysis) model is used as described for QTcF. The adjusted mean, standard error and 2-sided 90% CI from the statistical modeling for both change from baseline and placebo-corrected change from baseline values are listed in the tables and graphically displayed. [0564] The analysis to show assay sensitivity is based on ΔQTcF post-dosing with moxifloxacin. The same model is used as described for the primary analysis. For the 3 pre- defined time points (1, 2 and 3 hours post-dose), the contrast in treatment placebo-corrected change from baseline in corrected QT interval by Fridericia’s formula (ΔΔQTcF) = “moxifloxacin vs placebo” will be tested against the 1-sided null hypothesis ΔΔQTcF ≤ 5 msec on the 5% level. Multiplicity is controlled by using a Hochberg procedure. If after this procedure the adjusted mean of ΔΔQTcF is significantly larger than 5 msec for at least 1 time point of these 3 time points, assay sensitivity is considered to have been demonstrated. In addition, 2-sided 90% CIs are obtained for the contrast at all time points. [0565] Concentration-QTc Analysis: The relationship between Compound 1 plasma concentrations and ΔQTcF is quantified using a linear mixed-effects modeling approach. The model has ΔQTcF as the dependent variable, Compound 1 plasma concentration as the exploratory variate (0 for placebo and below the limit of quantification samples), centered baseline QTcF (i.e., baseline QTcF for individual subject minus the population mean baseline QTcF for all subjects in the same period) as an additional covariate, treatment (active = 1 or placebo = 0) and time (i.e., post-dose time point: categorical) as fixed effects, and random intercept and slope per subject. An unstructured covariance matrix is specified for the random effects. From the model, the slope (i.e., the regression parameter for concentration) and the treatment-effect-specific intercept (defined as the difference between active and placebo) are estimated together with the 2-sided 90% CI. [0566] The predicted effect and its 2-sided 90% CI for placebo-adjusted ΔQTcF (ΔΔQTcF) at this geometric mean Cmax of each of the two dose levels of Compound 1 is obtained. The upper bound of the two-sided 90% CI for the highest clinically relevant exposure should be <10 msec to conclude the absence of a clinically significant effect on QTcF. [0567] Additional exploratory analyses (via graphical displays and/or model fitting) include accounting for a delayed effect (hysteresis) and the justification for the choice of pharmacodynamic (PD) model (linear vs non-linear). Pharmacodynamic Data [0568] No formal statistical analysis is performed for the PK data. Descriptive statistics (e.g., mean, median, standard deviation [SD], minimum, maximum and number of subjects with an observation [n], coefficient of variation [CV%], geometric mean and geometric CV%) were considered adequate for a study of this type. Safety Data [0569] No formal statistical analysis was to be performed for the safety data. Descriptive summaries of treatment-emergent adverse events (TEAEs), clinical chemistry and hematology, vital signs and ECGs including changes from baseline were to be presented by treatment and time point (as appropriate). Sample Size and Power [0570] It was planned to enroll 48 subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 40 subjects). An evaluable subject was defined as a subject who had evaluable Holter extraction and PK data for all 4 regimens, and had completed the study. Dose Rationale [0571] Single IV doses of Compound 1 up to 6.0 mg/kg as well as daily and twice per day doses of up to 4 mg/kg administered for 7 days have previously been shown to be safe and well tolerated in healthy volunteers. The proposed therapeutic dose of Compound 1 for this study was a single IV dose of 2 mg/kg, which is a dose that is well tolerated. [0572] The proposed supra-therapeutic dose of Compound 1 for this study was a single IV dose of 6 mg/kg. The supra-therapeutic dose of Compound 1 was selected based on possible worst-case scenarios for high Compound 1 exposure due to intrinsic and extrinsic factors as described below and was based on predictions from on currently available in vitro, preclinical and clinical data. [0573] Based on in vitro data, Compound 1 might be considered a substrate and an inhibitor of CYP1A2. The risk of clinically relevant CYP-mediated drug-drug interactions with Compound 1 is low for the following reasons: short duration of therapy (3 or 4 days); short half- life of elimination from plasma (2-5 hours); absence of drug accumulation in plasma; absence of induction of major CYP enzymes; and lack of DDI liability predicted by SimCYP PBPK modeling. Compound 1 is an inhibitor of CYP1A2 (IC50 =1.9 μM), but is not a time-dependent inhibitor of this isoform. Given the rapid clearance of Compound 1 observed in vivo, the likelihood of potential inhibition of CYP1A2-mediated metabolism of other drugs by Compound 1 is low. Simulated clinical trials predicted changes in plasma exposure of CYP1A2 sensitive substrates that are not clinically significant (<1.25-fold) when co-administered with 2 mg/kg IV Compound 1 QD for 4 days. PBPK model also indicated that the predicted changes in plasma exposure of Compound 1 during co-administration with strong inhibitors of CYP1A2 to subjects are either of no clinical significance (AUCR<1.25) or a weak interaction (AUCR = 1.40). [0574] The supra-therapeutic dose in this study was planned to achieve overall Compound 1 concentrations that are 3-fold higher than the anticipated AUC(0-last) of 807 ng.h/mL corresponding to administration of 2.0 mg/kg (i.e., the maximum observed AUC(0-last) at that dose level in a healthy volunteer study). Therefore, Compound 1 AUC(0-last) for the supra- therapeutic dose level in this study was targeted to be 2,400 ng.h/mL (i.e., the maximum observed AUC(0-last) following administration of 6.0 mg/kg in a healthy volunteer study). Therefore, a single IV dose of 6.0 mg/kg of Compound 1 had been selected as the supra therapeutic level for the study. Results [0575] Following single IV administrations of Compound 1 at 2 mg/kg (therapeutic), and 6 mg/kg (supra-therapeutic) doses to the 4 subjects included in the PK evaluable set, maximum plasma concentrations of Compound 1 were generally observed in the first PK sample following the end of the 30 minutes infusion; an exception to this was seen in one subject following the 6 mg/kg dose, where a slightly later Tmax at 0.67 hours post-start of infusion indicated there may be evidence of extravascular administration. The median Tmax occurred at 0.517 hours post-start of infusion for both dose levels. Peak and overall exposure to Compound 1 (as measured by geometric mean Cmax, AUC(0-24) and AUC(0-last)) increased approximately 3.2- fold, 2.3-fold and 2.4-fold, respectively, with the 3.0-fold increase in dose (from 2 mg/kg at the therapeutic dose level to 6 mg/kg at the supra-therapeutic dose level). [0576] Inter-subject variability associated with plasma Compound 1 exposure ranged between 13.1% and 108.9%. The wide range of variability noted with the 2 mg/kg dose is mainly due to one subject who showed substantially increased concentrations of Compound 1 at the 6.5 and 8.5 hours post-start of infusion time points, resulting in an increase in peak and overall exposure and a substantial delay in Tmax to 6.5 hours post-start of infusion compared to the other evaluable subjects at the 2 mg/kg therapeutic dose level. That subject’s maximum plasma concentration of Compound 1 at the 2 mg/kg dose level was 2.6-fold greater than the group geometric mean for Cmax. Overall exposure for that subject, based on AUC(0-last), was 3.7-fold greater than the group geometric mean. Consideration of the demographics associated with this individual showed no differences when compared to the rest of the group. Investigation into any root cause for these unexpected results was unsuccessful; therefore, the results remained as observed. [0577] The volume of distribution for plasma Compound 1 appeared to increase slightly with the increase in dose from 2 mg/kg (therapeutic dose) to 6 mg/kg (supra-therapeutic dose); however, for both dose levels, the volume of distribution was higher than plasma volume, indicating distribution outside the vascular space, into the tissues. [0578] Total clearance of Compound 1 appeared similar across both the therapeutic (2 mg/kg) and supra-therapeutic (6 mg/kg) doses, with the range of total clearance being higher than typical hepatic plasma flow rates. [0579] The plasma half-life of Compound 1 appeared slightly increased with the increase in dose, which was likely due to better definition of the terminal portion of the curve at the higher supra-therapeutic dose level. Overall, the individual subject half-life values for plasma Compound 1 reported in this study ranged between 1.75 and 5.05 hours, which is similar to values previously observed. [0580] Following a single oral administration of 400 mg Moxifloxacin Hydrochloride Tablet, moxifloxacin was absorbed with median Tmax at 2.5 hours post-dose. Geometric mean peak and overall exposure to moxifloxacin (as measured by Cmax and AUC(0-last)) was 1680 ng/mL and 20400 ng.h/mL, respectively, with the inter-subject variability associated with exposure remaining low, ranging between 8.6% and 21.1%. [0581] Following IV administration of either 2 mg/kg Compound 1 (therapeutic dose) or 6 mg/kg Compound 1 (supra-therapeutic dose), 5 subjects reported AEs that led to IMP withdrawal; one of the subjects reported 2 severe AEs (an SAE of shock and an AE of depressed level of consciousness) following 6 mg/kg Compound 1 administration. There were no deaths during this study. The SAE of shock was determined to be unexpected and related to study drug. The study was paused as a result of the suspected unexpected serious adverse reaction. No evidence of non-compliance was determined. AEs of this nature had not been observed to any extent in previous studies across the same dose range (i.e., up to 6 mg/kg) in healthy subjects and only to a much lesser extent in patients. Moreover, there did not appear to be a relationship between Compound 1 dose level and the incidence of AEs that led to IMP withdrawal, which was greater for the 2 mg/kg dose level than for the 6 mg/kg dose level (although the 2 severe AEs occurred at the 6 mg/kg dose level). [0582] The AEs that led to IMP withdrawal were associated with the system organ classes (SOCs) of vascular disorders, cardiac disorders, nervous system disorders, respiratory, thoracic and mediastinal disorders, general disorders and administration site conditions, skin and subcutaneous tissue disorders, and gastrointestinal disorders. All AEs that led to IMP withdrawal were considered to be related or possibly related to the administration of Compound 1 by the investigator, and the majority occurred shortly after the start of the Compound 1 infusion. Most of the AEs resolved spontaneously after the infusion was stopped; IV fluid administration was required to treat the SAE of shock, which subsequently resolved without sequalae. [0583] All other AEs reported following Compound 1 administration were non-serious and were mild or moderate in severity; all AEs reported following administration of Placebo or 400 mg Moxifloxacin Hydrochloride Tablet were mild in severity. The incidence of TEAEs and ADRs was higher following administration of Compound 1 compared to Placebo. [0584] The SOC of nervous system disorders (in particular headache, dizziness and paresthesia) comprised the most frequently reported AEs/ADRs during the study. AEs/ADRs within the SOC of general disorders and administration site conditions were also commonly reported, including feeling hot, chest discomfort and asthenia. Other commonly reported AEs were flushing, nausea, dyspnea and back pain. No other AE (within any SOC) was reported by more than 1 subject for any regimen. [0585] All TEAEs had resolved prior to the end of the study, and the majority resolved without medication. [0586] There were no clinically significant safety laboratory or physical examination results during the study. There were no clinically relevant differences between the 2 mg/kg and 6 mg/kg dose levels of Compound 1 or between Compound 1 and Placebo or 400 mg Moxifloxacin Hydrochloride Tablet for any vital signs or 12-lead ECG parameter, and there were no clinically relevant trends in vital signs or 12-lead ECG results following administration of Compound 1. Overall Conclusions [0587] The study was terminated early, and therefore, there were not enough evaluable subjects to determine the effect of Compound 1 on change from baseline QT/QTc interval. [0588] Following IV administration of either 2 mg/kg Compound 1 (therapeutic dose) or 6 mg/kg Compound 1 (supra-therapeutic dose), 5 subjects reported AEs that led to IMP withdrawal; one subject reported 2 severe AEs following 6 mg/kg Compound 1 administration, one of which (shock) was an SAE. The AEs that led to IMP withdrawal were associated with numerous different SOCs, including vascular, cardiac and nervous system disorders. There were no deaths during this study. [0589] All other AEs reported during the study were non-serious and were mild or moderate in severity. Most of the AEs resolved spontaneously after study drug administration was stopped and all TEAEs resolved prior to the end of the study. [0590] There were no clinically significant safety laboratory or physical examination results throughout the study, and no clinically relevant trends in vital signs or 12-lead ECG results following administration of Compound 1. [0591] Following single IV administrations of Compound 1 (30 minutes infusion duration) at 2 mg/kg (therapeutic), and 6 mg/kg (supra-therapeutic) dose levels, maximum plasma concentrations of Compound 1 occurred with a median Tmax at 0.517 hours post-start of infusion (which reflects the timing of the end-of-infusion PK blood samples) for both treatments. [0592] Peak and overall exposure to Compound 1 (as measured by geometric mean Cmax, AUC(0-24) and AUC(0-last)) increased by approximately 3.2-fold, 2.3-fold and 2.4-fold, respectively, with the 3.0-fold increase in dose (from 2 mg/kg at the therapeutic dose level to 6 mg/kg at the supra-therapeutic dose level). [0593] The individual subject plasma half-life of Compound 1 ranged between 1.75 and 5.05 hours for both dose levels, with a slight increase in half-life at the supra-therapeutic (6 mg/kg) dose (where n = 4; geometric mean = 3.552 hours) compared to the therapeutic (2 mg/kg) dose (where n = 2), likely due to better definition of the terminal portion of the curve. [0594] The systemic clearance from plasma was high, was approximately 10-fold higher than the hepatic blood flow. and similar for the 2 and 6 mg/kg doses. The volume of distribution was large, higher than the total body water indicating good distribution of Compound 1to the tissues. [0595] The geometric mean volume of distribution ranged from 480 to 820 L for the 2 mg/kg dose (n = 2), from 671 to 1530 L for the 6 mg/kg dose (n = 4) and had a geometric mean (geometric CV%) value of 1100 L (40.7%) for the 6 mg/kg dose level (n = 4), which is higher than total body water, indicating distribution outside the vascular space and extensive distribution into tissue. [0596] The PK of Compound 1in this study was comparable to the PK observed previously in a healthy volunteer study and to the PK observed in a pilot study in patients on hemodialysis. The PK of Moxifloxacin following an oral dose of 400 mg in the fasted state were expected based on reported data on the drug label. [0597] Example 5. An Open Label, Single-Dose Study to Assess the Mass Balance Recovery, Absorption, Metabolism and Excretion of [¹⁴C]-Compound 1 in Healthy Male Subjects Study Objectives and Endpoints [0598] The primary objectives and endpoints of this study were:

[0599] The secondary objectives and endpoints of this study were:

Methodology [0600] This was a Phase 1 open-label, single center, non-randomized study to assess the mass balance recovery, metabolism and excretion of a single intravenous (IV) infusion of [¹⁴C]- Compound 1 in healthy male subjects. It was planned to enroll 6 healthy male subjects to ensure data in an appropriate number of evaluable subjects (a minimum of 4 subjects). A subject was considered to be an evaluable subject if they have provided mass balance and PK samples for up to at least 4 days after drug administration or have demonstrated >90% mass balance recovery, or had <1% of the administered dose eliminated in excreta for two consecutive days, whichever was sooner. [0601] Each subject received a single intravenous administration of a solution containing 240 mg [¹⁴C]-Compound 1 and 5.2 MBq [¹⁴C] as a 30 min (± 5 min) infusion. Study Design [0602] Subjects underwent preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects were admitted in the evening on the day before dosing (Day -1). [0603] Subjects were dosed on the morning of Day 1 following an 8 h overnight fast and remained resident in the clinical unit until up to 168 h after dosing (up to Day 8). It was planned that subjects were to be released as a group when all subjects have achieved a mass balance cumulative recovery of >90% or if <1% of the dose administered had been collected in urine and feces within two separate, consecutive 24 h periods. This could have resulted in the subjects being discharged as a group prior to completion of the planned residency period. If the mass balance criteria were achieved during the planned residency period, collection of all samples (blood, urine and feces) was to be stopped once the current 24 h collection period is complete and subjects underwent discharge assessments. If mass balance criteria had not been met by all subjects on Day 8, the residency period for the subjects not achieving the mass balance criteria could have been extended up to a maximum of an additional 96 h to 264 h post-dose (up to Day 12). Only urine and/or fecal samples were to be collected during the extended residency period. If the mass balance criteria were still not met by Day 12, or if additional residency was not considered appropriate or necessary, then home collections of urine and/or feces could have been requested at the discretion of the investigator for individual subjects and these subjects are asked to bring these specimens to the clinic every 2-3 days until the discharge criteria are met. [0604] Two subjects were discharged on Day 8. One subject was discharged on Day 9, and one subject was discharged on Day 11. All subjects therefore met the mass balance discharge criteria without requirement for home collections. Number of Subjects Planned [0605] It was planned to enroll 6 healthy male subjects to ensure data in a minimum of 4 evaluable subjects. If a subject did not complete the study for a non-drug related reason, he would have been considered a non-completer and could have been replaced. Six subjects were enrolled in the study, and six subjects completed the study. All subjects were included in the safety, PK, and mass balance populations and analysis sets. Duration of Study [0606] Subjects received a single administration on one occasion. The estimated time from screening until end of study was approximately up to 5 weeks. Main Inclusion Criteria [0607] Healthy males aged 30 to 65 years inclusive at the time of signing informed consent. Body mass index (BMI) between 18.0 and 32.0 kg/m² and weight of ≥ 50 kg and ≤ 120 kg as measured at screening. Exclusion Criteria [0608] Subjects were excluded from the study if one or more of the following statements was applicable: ● Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1 ● Subjects who are, or are immediate family members of, a study site or sponsor employee ● Evidence of current SARS-CoV-2 infection. ● History of any drug or alcohol abuse (including recreational drugs like cannabis products) in the past 2 years ● Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type). ● A confirmed positive alcohol breath test at screening or admission ● Smoking or use of nicotine-containing products within the last 12 months prior to the first dose administration. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission ● Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months ● Subjects with history of food or medication allergies ● Subjects with partners who are pregnant or lactating or planning to become pregnant during the study or within 90 days after study drug administration ● Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionizing Radiation Regulations 2017, shall participate in the study ● Subjects who do not have suitable veins for multiple venipunctures/cannulation as assessed by the investigator or delegate at screeningClinically significant abnormal clinical chemistry, liver function tests, hematology or urinalysis as judged by the investigator. Subjects with Gilbert’s Syndrome are allowed. ● Confirmed positive drugs of abuse test result ● Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody results ● Evidence of renal impairment at screening, as indicated by an estimated CLcr of <80 mL/min using the Cockcroft-Gault equation ● History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator ● Subjects with a history of cholecystectomy ● History of serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients ● Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active ● Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood or donation or loss of more than 1.5 liters of blood in the 10 months preceding the first administration of study drug ● Subjects who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 2 g of paracetamol per day) in the 14 days before IMP administration. Exceptions may apply on a case-by-case basis, if considered not to interfere with the objectives of the study, as determined by the investigator. ● Vaccination with live vaccines within 30 days prior to dosing or intention to receive live vaccines until the safety follow-up visit ● Acute diarrhea or constipation in the 7 days before the predicted Day 1. If screening occurs >7 days before the Day 1, this criterion will be determined on Day 1. Diarrhea will be defined as the passage of liquid feces and/or a stool frequency of greater than 3 times per day. Constipation will be defined as a failure to open the bowels more frequently than every other day. ● Failure to satisfy the investigator of fitness to participate for any other reason Investigational Medicinal Product, Dose, and Mode of Administration [0609] Subjects received the following investigational medicinal products (IMPs) in this clinical study in the fasted state:

Mass Balance Assessments [0610] The following mass balance parameters for total radioactivity (TR) in urine, feces, and total excreta (total; urine and feces combined) were calculated:

Metabolite Profiling and Identification Assessment [0611] Metabolite profiling of plasma, urine and feces was performed using, e.g., liquid chromatography-radio-detection with subsequent mass spectrometry where appropriate. Identification of the chemical structure of each metabolite accounting for greater than 10% of circulating radioactivity in plasma (“AUC pool”) and accounting for greater than 10% of the dose in the urine and feces (from urine pools and feces homogenate pools) is performed. Pharmacokinetic Assessments [0612] Pharmacokinetic-concentration time data were analyzed for Compound 1 and total radioactivity in plasma using Phoenix® WinNonlin® v8.0 or a more recent version (Certara USA, Inc., USA) using appropriate non-compartmental techniques to obtain estimates of the PK parameters presented below, where appropriate and possible. Whole blood:plasma concentration ratios were calculated for total radioactivity.

Safety Assessments [0613] The safety assessments conducted were adverse event (AE) monitoring, 12-lead electrocardiogram (ECGs), vital signs, clinical laboratory tests (clinical chemistry, hematology, and urinalysis), and physical examinations. Statistical Methodology [0614] No formal statistical analysis was performed for the mass balance, PK, or safety data. Descriptive statistics (e.g., number of subjects with an observation [n], mean, standard deviation [SD], coefficient of variation (CV%) median, minimum, and maximum) were considered adequate for a study of this type. Additional statistics were provided for PK-related data, including coefficient of variation (CV%), geometric mean and geometric CV%. Sample Size and Power [0615] The study was exploratory and no formal sample size calculation was made. Based on experience from previous studies of a similar design, a total of 6 subjects were to be enrolled and a minimum 4 evaluable subjects was considered sufficient to meet the objectives of the study. Dose Rationale [0616] A clinical dose of Compound 1 is 2 mg/kg given by intravenous infusion daily for 3 days. Single IV doses of Compound 1 up to 6.0 mg/kg as well as daily and twice per day doses of up to 4 mg/kg administered for 7 days have also previously been shown to be safe and well tolerated in healthy volunteers. In a previous clinical study, actual doses of Compound 1 administered to healthy volunteers ranged from 132 to 468 mg. The proposed Compound 1 dose for this study was a single IV dose of 240 mg, which is a dose well tolerated, and represents a clinical dose of 2 mg/kg in patients weighting up to 120 kg. Subjects with body weight below 40 kg were not included in this study. Results [0617] Following administration of a single IV dose of 240 mg [¹⁴C]-Compound 1 Solution for Infusion, an average of 92.3% of the radioactivity administered was recovered in excreta over a 240-hour sampling period, with the majority (71%) being excreted within 24 hours post-dose. Mean total reactivity (TR) recovery >90% was achieved in total excreta by 96 hours post-dose. Excretion of TR in urine was largely complete by 48 hours post-dose, with small (≤0.6%) mean increases in the 24-hour periods after this time point. Excretion of TR in feces was largely complete by 120 hours post-dose, with <0.3% mean increases in the 24-hour periods after this time point. [0618] The majority of TR (73.5%) was recovered by urinary excretion, suggesting renal clearance was the main route of elimination of [¹⁴C]-Compound 1-derived radioactivity. The fecal recovery was low (10.8%) within the first 48 hours post-dose, which may indicate the drug was well absorbed, as it was not immediately excreted in the feces, but likely eliminated in the bile. [0619] Following administration of a single IV dose of 240 mg [¹⁴C]-Compound 1 Solution for Infusion, maximum Compound 1 concentrations were noted at the end of infusion in all subjects, with a median T_max of 0.500 hours post-start of infusion. The estimated geometric mean plasma half-life was 2.91 hours. The inter-subject variability (geometric CV) associated with exposure was low at 12.9% to 24.6%. [0620] Renal clearance of Compound 1 was low, with a geometric mean of 0.459 mL/min, suggesting renal function has minimal impact on elimination of Compound 1 in its parent form. Less than 0.04% of the Compound 1 dose was excreted unchanged in both the urine and feces. The geometric mean volume of distribution was 545 L, which was appreciably higher than total body water (42 L), indicating extensive distribution into the tissues/metabolism of Compound 1. The geometric mean total clearance was 2160 mL/min, which was higher than typical hepatic (1450 mL/min) and adrenal (1240 mL/min) blood flow rates in man. [0621] Exposure to Compound 1 accounted for approximately 3.5% of circulating plasma TR based on AUC(0-last), suggesting there are additional circulating components in plasma following administration of [¹⁴C]-Compound 1. [0622] The apparent plasma terminal half-lives for TR (13.5 and 76.7 hours) were longer than that observed for Compound 1 (2.91 hours). This may suggest the presence of uncharacterized metabolites with longer terminal elimination. However, due to the difference in analytical techniques used between the two analytes, as well as individual subjects’ sensitivity to the analytes, some variability in results is expected and should be taken into consideration. [0623] The geometric mean whole blood to plasma TR concentration ratios generally indicated non-preferential distribution of TR to the cellular components of whole blood, with ratios tending to be less than 1 (range: 0.562 to 1.09). The geometric mean whole blood to plasma TR concentration ratios tended to decrease with time until 2.5 hours post-start of infusion, with the ratio returning back to 0.906 by 12 hours post-start of infusion. [0624] Overall, Compound 1 was well tolerated by healthy male subjects when administered as a single dose of 240 mg [¹⁴C]-Compound 1 as a 30 min IV infusion in the fasted state, with no subjects reporting an ADR. There were no deaths, SAEs, severe AEs or AEs leading to IMP withdrawal. There were no infusion site reactions reported. [0625] One AE (back pain) was reported by one subject during the study; the AE was mild, considered unrelated to [¹⁴C]-Compound 1 and resolved before the end of the study. The subject received paracetamol and ibuprofen as required for the treatment of the AE. There were no other AEs reported during the study. [0626] There were no significant safety laboratory, vital signs, ECG or physical examination findings reported throughout the study. Overall Conclusions [0627] Following a single IV infusion of 240 mg [¹⁴C]-Compound 1, an average of 92.3% of the radioactivity administered was recovered in excreta over a 240-hour sampling period, with the majority of TR (73.5%) recovered in the urine, which indicated renal excretion was the main route of elimination of [¹⁴C]-Compound 1-derived radioactivity following IV dosing. [0628] The mean TR recovery >70% was achieved by 24 hours and >90% was achieved in total excreta by 96 hours post-dose. The recovery of TR in urine was largely complete by 72 hours post-dose. Excretion of TR in feces was largely complete by 120 hours post-dose. [0629] Over the 240-hour sampling period, less than 0.04% of the administered dose was excreted unchanged as Compound 1 in both the urine and feces. [0630] Exposure to Compound 1 accounted for 3.5% of circulating plasma TR based on AUC(0-last), suggesting that there are additional circulating components in plasma following administration of [¹⁴C]-Compound 1. [0631] The geometric mean whole blood to plasma TR concentration ratios generally indicated non-preferential distribution of TR to the cellular components of whole blood (range: 0.562 to 1.09). [0632] Maximum plasma Compound 1 concentrations were seen at the end of the infusion in all subjects as expected (0.50 hours post-start of the infusion), except in one subject where T_max occurred slightly later (by 1 minute), owing to the timing of the end-of-infusion PK blood sample. Maximum plasma TR concentrations were observed between 0.67 hours and 1 hour post-start of infusion. [0633] The apparent plasma T_1/2 values for plasma TR (13.5 and 76.7 hours) were longer than that observed for Compound 1 (2.911 hours), suggesting the presence of uncharacterized metabolites with longer terminal elimination phases. [0634] Compound 1 was well tolerated when administered to healthy male subjects as a single dose of 240 mg [¹⁴C]-Compound 1 for IV infusion in the fasted state, with only 1 subject reporting an AE (mild back pain) that was unrelated to Compound 1 and no subjects reporting an ADR, including no infusion site reactions. [0635] There were no significant safety laboratory, vital signs, ECG, or physical examination results throughout the study. Example 6. A Hepatocyte Growth Factor Mimetic Improves Outcomes in Patients at Risk of DGF: A Randomized Double-Blind Placebo-Controlled Phase 2 Human Clinical Trial Overall Study Design and Plan [0636] The study was a multi-center, randomized, double-blind, placebo-controlled, Phase 2 study. [0637] Subjects undergoing kidney transplant were eligible for enrollment if they met at least one of the following conditions: 1) inadequate urine output (oliguria), defined as <50 cc/h urine output for eight consecutive hours over the first 24 h post-transplant; or 2) low creatinine clearance, defined as a creatinine reduction ratio of <30% from pre-transplantation to 24 h post- transplant. In addition, the kidney donor had to have a terminal creatinine ≤2.2 mg/dL. [0638] Eligible subjects were randomized 2:1 to receive 2 mg/kg Compound 1 or placebo via 30 min intravenous (IV) infusion. Initial infusion occurred within 36 h of renal transplant (Day 1), with two subsequent infusions at 24 (± 2) h intervals. An initial cohort of subjects was infused over 10 to 12 minutes. Based upon site feedback, the protocol was amended and the remaining subjects were infused over 30 min. [0639] Subjects were monitored during initial hospitalization, with subsequent clinical visits on Days 7, 14, and 28. Subjects were contacted by phone on Days 5, 6, and 8 to 13. Following completion of the study on Day 28, long-term data on graft survival and renal function were collected approximately 6 and 12 months after renal transplantation. [0640] During a subject’s stay in the hospital (Days 1 to 3 and, if applicable, Day 4), blood samples were collected for determination of immunosuppressant levels and for pharmacokinetic (PK) analyses of Compound 1 and its metabolites. The subject’s renal output over 24 h was assessed daily for 14 days after first study drug infusion and again on Day 28. Other assessments included standard safety measures, blood and urine biomarkers of renal function, and 24 h urine creatinine clearance. Selection of Study Population [0641] Subjects were assessed for eligibility according to the following criteria: 1. Males and females ≥18 years of age 2. Had renal transplantation due to end-stage renal disease (ESRD) requiring chronic dialysis 3. Study drug could be administered within 36 h after transplantation 4. Received kidney from a healthy donor, or a donor with history of diabetes mellitus or hypertension 5. Donor terminal serum creatinine (SCr) ≤2.2 mg/dL 6. No urine output, or average urine output of <50 cc/h over eight or more consecutive hours, or normal urine output following transplantation that diminished to an average of <50 cc/h over eight or more consecutive hours; or creatinine reduction ratio <30% from pre-transplantation to 24 h after transplant 7. Reason for low urine output was unlikely due to structural changes. If clinically indicated, an ultrasound was performed. 8. Dry weight ≤120 kg, body mass index (BMI) <35 9. Women of child bearing potential had a negative serum pregnancy test prior to transplantation 10. Women of child bearing potential (including perimenopausal women who had a menstrual period within one year) agreed to use two forms of an effective birth control regimen, including at least one-barrier method, during the 28-day study period. Men agreed to use condoms during the 28-day study period. 11. In the opinion of the investigator, the subject was capable of understanding and complying with the protocol 12. Subjects signed the informed consent document prior to performance of any study-related procedure including screening procedure [0642] Subjects who met any of the following criteria were excluded from study participation: 1. Subject with normal urine output and not requiring dialysis prior to renal transplantation (i.e., had pre-emptive renal transplantation) 2. Signs and symptoms of volume depletion 3. Recipient of multiple organ transplantation or scheduled for multiple organ transplantation 4. Recipient of pediatric en-bloc kidney transplantation 5 Recipient of kidney with cold ischemia time >40 h 6. Had measurable donor-specific antibody or positive cross-match requiring deviation from standard immunosuppressive therapy 7. Was participating in or had participated in an investigational drug or medical device study within 30 days or five half-lives, whichever was longer, prior to enrollment into this study 8. Concurrent sepsis or active bacterial infection 9. Had an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that had been removed 10. Women of child bearing potential who were breast feeding 11. History of positive human immunodeficiency virus (HIV) test 12. History of rheumatoid arthritis 13. Subjects who required the cytochrome P4501A2 (CYP1A2) inhibitors, ciprofloxacin, and/or fluvoxamine (Luvox^®) 14. Subject was unwilling or unable to comply with the protocol or to cooperate fully with the investigator or the site personnel 15. Subject was not deemed medically stable for the study in the opinion of the investigator or the subject’s primary nephrologist [0643] Infusions of study drug were pre-specified to be discontinued if a subject: x Withdrew consent; or x Developed a serious adverse event (SAE) attributable to study drug following administration of study drug; or x Had a >3-fold increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) from pre-infusion to post- infusion of study drug. If AST or ALT was >3-fold higher than the pre-infusion value, the laboratory test could be repeated the same day to verify an increase. If AST or ALT still was >3-fold greater than the value prior to infusion, study drug was not to be administered. In addition, the investigator or medical monitor could decide at any time that infusion of study drug be canceled or delayed if a repeat administration placed the subject at risk for an adverse event (AE). Treatment [0644] The active treatment was 2 mg/kg Compound 1 administered in a 30 min IV infusion. The first infusion was administered within 36 h after transplant, with two subsequent infusions at 24 ± 2 h intervals. An initial cohort of subjects was infused over 10 to 12 min. Based upon site feedback, the protocol was amended and the remaining subjects were infused over 30 min. The volume of infusion was controlled by the infusion pump, based upon the subject’s baseline weight (0.33 mL/kg) with a maximum infusion of 40 mL. Placebo was normal saline (United States Pharmacopeia [USP]) administered at the same intervals and volumes (0.33 mL/kg). [0645] Eligible subjects were randomized 2:1 to receive either 2 mg/kg Compound 1 or placebo. Sites were provided a set of ordered envelopes with treatment assignment and the pharmacist prepared either active treatment or placebo based upon the ordered card. Subject enrollment was initially stratified by source of donor kidney: 1) without history of diabetes mellitus or hypertension, and 2) with history of diabetes mellitus and/or hypertension. This stratification was subsequently removed. [0646] The dose regimen used in this study (2 mg/kg Compound 1) was selected based on data from nonclinical efficacy studies, as well as clinical studies assessing PK and safety in healthy volunteers and renal failure patients on hemodialysis. Preclinical studies determined that c-Met receptor upregulation occurs within 6 to 48 h following renal injury, and that Compound 1 administration within 24 h following renal ischemia injury improves renal outcome and attenuates mortality at doses up to 2 mg/kg. A dose escalation study in healthy volunteers, and a PK and safety study in patients on and off dialysis, confirmed 2 mg/kg as the optimal dose. Animal studies showed that repeat administration of Compound 1 was associated with improved renal outcomes. In a Phase 1 study of healthy subjects and a clinical study in subjects with renal failure on and off hemodialysis, IV infusions of Compound 1 were well tolerated at doses up to 6 mg/kg, the maximal practical dose. Other Medications [0647] All concomitant medications, including dose, were recorded at study entry. Use of new concomitant medications or changes in dose of concomitant medications were recorded until the final study visit. The dose and dosing regimen of all prescriptions and non-prescription therapies and medications were documented. [0648] Subjects could receive concomitant immunosuppressive regimens used as part of standard-of-care by the clinical center. Based upon the known metabolism, serum levels of cyclosporine, tacrolimus, and sirolimus were not expected to be affected by co-administration of study drug. Serum concentrations of immunosuppressants other than MPA were assayed on Days 1 to 4, prior to the morning or evening dose of immunosuppressant and prior to daily dosing of Compound 1. Both Compound 1 and MPA (the active metabolite of MMF) are metabolized by glucuronidation and the potential for drug-drug interaction has not been determined. For the trough concentration assay, blood samples were drawn within 1 h prior to the morning or evening dose of MMF/other immunosuppressant on Day 1, and 1 h prior to the morning dose of MMF/other immunosuppressant on Days 2 to 4. [0649] Based on in vitro data, Compound 1 was considered both a substrate and an inhibitor of CYP1A2. Drugs utilizing the CYP1A2 enzyme were avoided, if possible, on days that study drug was administered and for the 24 h period after the last infusion. Caffeine intake (e.g., tea, coffee, and caffeine-containing drinks) was prohibited within 3 h before and up to 3 h after infusion. In addition, potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine were prohibited during treatment and up to 24 h following the last infusion of study drug. Efficacy Variables [0650] The primary efficacy variable was time (in days) until production of ≥1200 cc of urine over a 24 h period. The following secondary outcomes were also measured: ● Mean total daily urine output through Day 14 ● Change from baseline in urine production at Days 2 to 14 ● Mean serum creatinine (SCr) at Days 3, 7, 10, 14, and 28 and Months 6 and 12 ● Mean measured 24-h creatinine clearance at Days 3, 7, 14, and 28 ● Mean serum levels of the biomarkers C-reactive protein (CRP) and neutrophil gelatinase- associated lipocalin (NGAL) at Days 1 and 3 ● Incidence of DGF, defined as the initiation of dialysis, through Day 7 after transplantation ● Number of dialysis sessions through Days 7, 14, and 28 ● Length of hospitalization following transplantation ● Acute rejection episodes ● Graft survival at 6 and 12 months post-transplant [0651] In addition, three post hoc analyses were performed: ● Mean estimated glomerular filtration rate (eGFR) at screening, Day 3, Day 7, Day 14, Day 28, Month 6 and Month 12 by study arm ● Descriptive analysis of duration of dialysis during first 28 days post-transplant by study arm ● Log rank test of time to graft failure over the first 12 months after transplant by study arm [0652] Certain efficacy variables were measured as described in the following paragraphs: [0653] Total Daily Urine Output: During hospitalization, daily total urine output for each 24 h period was recorded. Following discharge, subjects recorded their total urine output in a diary each day through Day 14, and again on Day 28. The total urine output was recorded daily and obtained from the subject either by phone or through a scheduled study visit. [0654] 24-hour Urine Collection for Creatinine Clearance: Four 24-h urine samples were collected to measure creatinine clearance on Days 3, 7, 14, and 28. The subjects were provided handouts on 24 h urine collections and instructed to collect their urine for a 24 h period before the scheduled visits on Days 3, 7, 14, and 28. The 24-h urine samples were tested for sodium, potassium, chloride, and creatinine. Day 3 was selected as the first time point following transplantation to collect urine for creatinine clearance, since subjects in the study were likely to have unstable SCr at earlier time points due to acute renal injury post-transplantation. If the SCr levels remained unstable at the time of urine collection, clearance was estimated by averaging the SCr at the start and at the end of the collection. [0655] Urine Analysis: A urine sample was collected on Days 14 and 28 to assess for signs of persistent inflammation in the urinary tract. Subjects with recent transplantation may have active sediments and variable findings on microscopic analysis. Subjects with inflammatory findings on urine analysis such as the presence of leukocyte esterase, ≥2-5 white blood cells (WBCs) per high power field, or leukocyte casts were evaluated for causes, such as infection. In subjects with new or increased findings of inflammation on Day 28, a follow-up urine analysis was performed within seven to ten days after the Day 28 evaluation. [0656] Biomarkers: Inflammatory (C-reactive protein; CRP) and renal function (neutrophil gelatinase-associated lipocalin; NGAL) serum assays were performs. One 5 mL sample of blood was collected using heparin as an anticoagulant on Days 1 (pre-dose), 2 (pre-dose), 3 (pre-dose), 4 (if subject remained in hospital), 7, 14, and 28. Urine samples (10 mL each) were collected in the morning on the same days. The total volume and time of collection were recorded for each sample. [0657] Rejection Episodes: On each study day, the investigator recorded any episodes of acute rejection, including how they were identified, documented, and treated. [0658] Dialysis: On Days 1, 2, 3, 4, 5, 6, 7, 10, 14 and 28, the investigator recorded whether a patient received dialysis. Data were retrospectively collected on all dialysis sessions that occurred during the first 28 days. [0659] Graft Survival and Renal Function: Approximately 6 and 12 months after the kidney transplant, the clinical site assessed subjects for graft survival and renal function. eGFR was derived from SCr for all timepoints using the MDRD4 formula. (See Levey, A. S., et al. Ann. Intern. Med.2006; 145:247-54.) [0660] Adverse Events: An AE was any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome, or disease which either occurred during the study (if absent at baseline), or appeared to worsen (if present at baseline). The investigator monitored subjects for the occurrence of AEs throughout their participation in the study. All AEs, regardless of seriousness or relationship to study drug, including those occurring during the screening period (where applicable), were recorded. Whenever possible, symptoms were grouped as a single syndrome or diagnosis. The investigator was to specify the date of onset, maximal intensity, corrective therapy given, outcome, and their opinion regarding if there was a reasonable possibility that the AE was caused by the study drug. The causal relationship of an AE to the study drug was the best estimate of the investigator at the time of reporting. AEs were graded as mild, moderate, or severe based on the intensity of symptoms and the degree of limitation of usual daily activities. [0661] Clinical Laboratory Assessments: Samples of venous blood were collected for the measurement of hematology and chemistry parameters at Screening and Days 2, 3, 4, 7, 14, and 28. Hematology parameters included hematocrit, hemoglobin, total leukocyte count, differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelet count. Chemistry parameters included glucose, sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, albumin, AST, ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, creatine kinase, lactate dehydrogenase (LDH), and total and direct bilirubin. Venous blood was drawn at Screening from female subjects of childbearing potential for pregnancy testing if results prior to transplantation were not available. Laboratory results were also evaluated by the investigator to determine if any abnormal results were clinically significant for an individual and were considered an AE. [0662] MPA and Immunosuppressant Drug Levels: Samples of venous blood were collected daily on Days 1 to 4 for the analysis of levels of MPA (in subjects receiving the immunosuppressant MMF) and other immunosuppressants (cyclosporine, tacrolimus, or sirolimus; unless the subject had been discharged from the hospital before Day 4). The blood samples were drawn within 1 h prior to the morning or evening dose of MMF/other immunosuppressant on Day 1, and 1 h prior to the morning dose of MMF/other immunosuppressant on Days 2 to 4. The time of blood sampling, the time of administration of the previous MMF or immunosuppressant dose, and the previous MMF or immunosuppressant dose level were recorded in source documents and in the case report form (CRF). Disposition of Subjects [0663] FIG.1 shows the disposition of subjects. Twenty-nine subjects were screened and consented to participate in the study. One subject was judged by their physician to be too medically fragile to participate and was withdrawn from participation before randomization. The remaining 28 subjects were randomized: 19 to Compound 1 and 9 to placebo. Of the 28 subjects randomized, one subject in the placebo arm withdrew consent after the second infusion and did not complete the study. Withdrawal occurred after a moderate left bundle branch block, assessed as unrelated to the study product. All other subjects completed the study. The mean ± SD duration of the study across subjects was 29.0 ± 7.79 days (range: 4 to 50 days). [0664] Seven subjects were retrospectively identified as not meeting all eligibility criteria, but received study drug and subsequently completed the study. Three subjects in the Compound 1 arm received their initial infusions more than 28 h after transplantation: at 29 h 14 min; 29 h 14 min; 30 h 20 min. One subject in the placebo arm received the first infusion within the prescribed 36 h window (35 h 35 min), but there was a note in the subject record stating that the initial infusion time was extended from 36 h to 38 h. [0665] One subject in the Compound 1 arm was identified as having low urine output that a physician determined may have been due to structural issues associated with subsequent, non- kidney-related surgery. One subject in each study arm was discovered to have a history of prostate cancer, 3 years (Compound 1 arm) and 18 years (placebo arm) before enrollment. One subject in the placebo arm received a donor kidney with terminal creatinine ≤2.2 mg/dL. [0666] There were 12 deviations from the planned dosing regimen. In the Compound 1 arm, there were six dosing deviations in four subjects. One subject failed to receive an infusion on Day 2 due to issues with dialysis that resulted in arm pain. One subject had Day 3 infusion delayed outside the 24-hour window. One subject had Day 3 infusion stopped and restarted. One subject had reduced infusion time on Day 3, while one subject had increased infusion times on Days 1 and 3. In the placebo arm, there were five dosing deviations in three subjects. One subject had infusions stopped and restarted on Days 1, 2, and 3. One subject had Day 3 infusion delayed to Day 5. One subject did not have their line flushed after infusion on Day 1. Demographic Baseline Characteristics [0667] The demographic characteristics of the subjects in the clinical trial are shown in Table 1. Compared to the placebo arm, subjects in the Compound 1 arm were younger (mean ± SD = 54.7 ± 13.65 vs 65.7 ± 12.84 years), more likely to be female (21.1% vs 11.1%), and more likely to be black or African American (42.1% vs 22.2%). Table 1: Demographics

Table 1: Demographics

[0668] The baseline clinical characteristics and medical history of the subjects are shown in Table 2 and Table 3, respectively. Compared to subjects in the placebo arm, subjects in the Compound 1 arm were higher in body weight (Compound 1 = 90.92 kg; placebo = 79.78 kg) and dry weight (Compound 1 = 86.85 kg; placebo = 80.85 kg), as well as BMI (Compound 1 = 30.1; Placebo = 28.0). The percentage of subjects who reported currently consuming alcohol was similar between study arms (Compound 1 = 26%; placebo = 33%), though subjects in the Compound 1 arm who drank reported an average of 4.0 ± 4.24 drinks per week, vs 1.7 ± 1.15 in the placebo arm. Three subjects (15.8%) in the Compound 1 arm were current smokers vs none in the placebo arm. Table 2: Baseline Clinical Characteristics

Table 2: Baseline Clinical Characteristics

[0669] Medical history was generally similar between study arms (Table 3). Hypertension was nearly universal across both groups (Compound 1 = 94.7%; placebo = 100.0%). Diabetes/hyperglycemia was highly prevalent in both arms (Compound 1 = 68.4%; placebo = 66.7%). Prevalence of gastrointestinal disease, musculoskeletal, urogenital, eye, and other surgeries were similar between groups. [0670] In a few areas, there was a higher prevalence of disease in the placebo vs Compound 1 arm. Though highly prevalent in both groups, cardiovascular disease was higher in the placebo arm (100.0%) vs Compound 1 (78.9%). This was driven by higher prevalence of atherosclerotic disease/procedures, arrhythmia, heart failure, valve disease/disorder, and myocardial infarct in the placebo arm. The incidence of neuropsychiatric disorders and respiratory disorders were higher in the placebo arm (55.6% vs 26.3%; 33.3% vs 21.1% respectively), but not driven by any specific diagnoses. Table 3: Medical History

Table 3: Medical History

[0671] As per protocol, all 28 randomized subjects received a renal transplant. The characteristics of donors and donor kidneys are presented in Table 4. The majority of kidneys in both groups were from donors after brain death (DBD) (Compound 1 = 68.4%; placebo = 77.8%). However, there were slightly more donors after cardiac death (DCD) in the Compound 1 arm (Compound 1 = 21.1%; placebo = 11.1%). Donors in the Compound 1 arm were younger (43.0 ± 21.2 years) than donors in the placebo arm (56.3 ± 10.8 years) and had a lower prevalence of diabetes/hypertension (Compound 1 = 63.2%; placebo = 77.8%). The mean time from organ procurement to transplant was nearly identical between study arms (Compound 1 = 23.3 h; placebo = 23.7 h), as was total transplant time (Compound 1 = 3.2 h; placebo = 3.0 h). Table 4: Donor/Kidney and Renal Transplantation Characteristics

Results [0672] Time to Production of ≥1200 cc Urine over 24 Hours: Kaplan-Meier curves for time to production of ≥1200 cc urine over 24 h by study arm are presented in FIG.2. At Day 28, 78.9% of subjects in the Compound 1 arm achieved ≥1200 cc urine output over 24 h vs 44.4% of subjects in the placebo arm (Table 5). The time from transplantation to production of ≥1200 cc of urine over 24 h was longer in the placebo arm than the Compound 1 arm (Log Rank test: χ²=2.799, p = 0.094; Hazard ratio = 2.49, 95% CI=0.82, 7.55). [0673] The median number of days from transplantation to production of ≥1200 cc of urine over 24 h was 5 days for the Compound 1 arm (95% CI: 2.4, 12.0) and 14 days for the placebo arm (95% CI: 2.44, -; Table 5Table ). The upper limit of the median could not be computed for the placebo arm, as <50% of subjects achieved the endpoint. Two subjects were excluded from the Survival Analysis as they reached 1200 cc urine over 24 h prior to the start of first infusion of investigational medicinal product. Table 5: Time to Production of ≥1200 cc of Urine Over 24 Hours

[0674] Mean Total Daily Urine Output: FIG.3 shows MMRM LS mean and SE for total daily urine output (in cc) from post-transplant Day 1 to Day 14 by study arm. Day 1 urine output was higher (+ 90 cc) in the Compound 1 arm vs placebo arm. On 8 of the next 13 days, urine output was higher in the Compound 1 arm vs placebo: Day 2 = +313 cc; Day 3 = +127 cc; Day 4 = +703 cc; Day 5 = +782 cc; Day 8 = +70 cc; Day 10 = +471 cc; Day 12 = +459 cc; Day 13 = +529 cc. On days 9, 11 and 13, urine output differed by <50 cc between study arms. On Days 6 and 7, urine output was lower in the Compound 1 arm: Day 6 = -353 cc; Day 7 = -162 cc. [0675] On Day 28, urine output was lower in the Compound 1 arm: Compound 1 = 972 cc; placebo = 1652 cc; difference = -680 cc. However, this difference may have been largely driven by one placebo patient with urine output of 3500 cc. The removal of this subject reduced the difference between groups to 116 cc higher in the placebo arm. [0676] Change from Day 1 Urine Production through Day 14: FIG.4 shows MMRM LS mean and SE for change from baseline (Day 1) in total daily urine output (in cc) from post- transplant Day 2 to Day 14 by study arm. On Days 2 to 5, the Compound 1 arm showed increases from baseline urine production (+408; +178; +531; +606, respectively), while the placebo arm showed small increases or decreases from baseline (+95; +51; -171; -176, respectively). On Days 8, 10, 12 and 13, the change from baseline total daily urine production was greater in the Compound 1 arm vs Placebo (+869 vs +799; +1056 vs +585; +860 vs +400; +729 vs +200, respectively). The differences between study arms was <50 cc on Days 9, 11 and 14. On Days 6 and 7, the Compound 1 arm showed less increase from baseline than placebo (+82 vs +436; +417 vs +479, respectively). [0677] Serum Creatinine: FIG.5 shows MMRM LS mean and SE for serum creatinine (mg/dL) over time by study arm. Compared to placebo, subjects in the Compound 1 arm had higher SCr at screening (Compound 1 mean = 8.32; placebo mean = 7.01; difference = +1.31 mg/dL) and Day 3 (Compound 1 mean = 7.23, SE = 0.50; placebo mean = 6.90, SE = 0.73; difference = +0.33 mg/dL). On Days 7, 14, 28, Months 6 and 12, subjects in the Compound 1 arm had lower SCr than subjects in the Placebo arm (difference = -0.67; -0.79; -0.70; -0.29; -0.43 mg/dL, respectively). Table 6 summarizes MMRM LS means and SE for SCr. Table 6

[0678] Table 7 summarizes results of mean SCr change from baseline over time for the Compound 1 arm and placebo arm. Table 7

[0679] Mean 24-Hour Creatinine Clearance: FIG.6 shows mean and SD of the mean for 24- hour urine creatinine clearance (mL/min/1.73 m²) over time by study arm. As shown, creatinine clearance was equivalent across study arms at Day 3 (Compound 1 = 4.7; placebo = 4.2); higher in the placebo arm at Day 7 (Compound 1 = 10.1; placebo = 16.3); and higher in the Compound 1 arm on Day 14 (Compound 1 = 23.0; placebo = 14.5) and Day 28 (Compound 1 = 22.1; placebo = 19.4). [0680] C-Reactive Protein (CRP): FIG.7 shows serum CRP (mg/dL) by study arm at Day 1 and Day 3 post-transplant. On Day 1, CRP was higher in the Compound 1 arm (mean = 7.5, SE = 0.9) vs placebo (mean = 5.7, SE = 1.8). On Day 3, CRP was lower in the Compound 1 arm (mean = 2.2, SE = 0.4) vs placebo (mean = 2.9, SE = 0.7). There was a greater decrease in CRP in the Compound 1 arm (-68.6% from baseline) than in the placebo arm (-17.5% from baseline). [0681] Neutrophil Gelatinase-Associated Lipocalin (NGAL): FIG.8 shows NGAL (ng/mL) by study arm at Day 1 and Day 3 post-transplant. On Day 1, NGAL was higher in the Compound 1 arm (mean = 1152, SE = 121) vs placebo (mean = 646, SE = 102). On Day 3, NGAL was nearly equivalent between the Compound 1 arm (mean = 614, SE = 85) vs placebo (mean = 571, SE = 101). There was a greater decrease in NGAL in the Compound 1 arm (-43.5% from baseline) vs the placebo arm (-12.5% from baseline). [0682] Incidence of DGF: DGF was defined by the initiation of dialysis during the first seven days after transplantation. As shown in FIG.9, the percentage of subjects receiving dialysis in the first 7 days was slightly higher in the Compound 1 group (73.6%) vs placebo (66.6%). It should be noted that 10 of the 14 (71%) subjects in the Compound 1 arm who progressed to DGF had their first dialysis session before study drug was administered, versus 2 of 6 (33%) subjects in the placebo arm. All patients who received dialysis had their first session within the first 7 days after transplantation. The reason listed for dialysis for most subjects was “transplant DGF” or “DGF”. Other reasons included uremia, anuria, metabolic acidosis, hyperkalemia, fluid overload, and end stage renal disease. An AE was associated with the dialysis session due to DGF for three subjects. [0683] Number of Dialysis Sessions through Day 28: The cumulative number of dialysis sessions through Day 28 by treatment group are shown in FIG.10. As shown, on average there were 1.0 more dialysis sessions during the first 28 days after transplant in the placebo arm (mean = 3.8, SE = 1.4) versus the Compound 1 arm (mean = 2.8, SE = 0.6). [0684] Length of Hospitalization Following Transplantation: FIG.11 shows the mean length of transplant hospitalization (in days) by treatment arm. The mean length of hospitalization was 7.6 days (SE = 0.5) for the Compound 1 arm and 11.4 days (SE = 3.4) for the placebo arm, a difference of 3.8 days less for the Compound 1 arm. It should be noted that there was an outlier in the placebo arm with a hospitalization length of 35 days. Removing this patient from the analysis reduced the incremental hospital days for placebo to 0.5 days. [0685] Number of Acute Rejection Episodes: There was no incidence of acute rejection in either study arm. [0686] Mean Estimated Glomerular Filtration Rate (eGFR): FIG.12 shows mean and SE from a mixed effects repeated measures model with an autoregressive covariance matrix for eGFR (mL/min/1.73 m²) by study arm at screening, Day 3, Day 7, Day 14, Day 28, Month 6 and Month 12. Two subjects in the placebo arm experienced graft failure and resumed maintenance dialysis. Their 6-month and 12-month eGFR values were set to zero. One subject in the placebo arm had 12-month eGFR collected at Month 15; this value was included in the 12-month analysis. [0687] As shown, eGFR was higher in the Compound 1 arm vs placebo arm on Day 14 (Compound 1 mean = 32.1, SE = 3.4; placebo = 20.6, SE = 5.1); Day 28 (Compound 1 mean = 39.0, SE = 3.5; placebo = 30.6, SE = 5.1); Month 6 (Compound 1 mean = 50.0, SE = 3.5; placebo = 39.5, SE = 5.0); and Month 12 (Compound 1 mean = 50.1, SE = 3.5; placebo = 37.8, SE = 5.0). At Month 12, eGFR was 25% higher in the Compound 1 vs placebo. The difference between groups in difference of LS means from baseline at Day 14, Day 28, Month 6, and Month 12 were 13.1 (95% CI = 0.96, 25.28), 10.7 (95% CI = -1.47, 22.76), 10.1 (95% CI = -1.85, 22.01), and 12.6 (95% CI = 0.60, 24.54) mL/min/1.73 m² respectively. The p-values from the MMRM at Days 14, 28, Month 6, and Month 12 were p = 0.035; p = 0.085; p =0.097 and p = 0.040, respectively. [0688] Results are summarized in Table 8. Table 8

[0689] Duration of Dialysis: The duration of dialysis through Day 28 by treatment arm is shown in FIG.13. As shown, on average duration of dialysis was 2.4 days shorter for the Compound 1 arm (mean = 7.6, SE = 2.0) vs placebo (mean = 10.0, SE = 3.9). [0690] Graft Failure at 6 and 12 Months: FIG.14 shows incidence of graft failure over time by study arm. Two subjects (22%) in the placebo arm experienced graft failure within the first 12 months after transplant vs no subjects in the Compound 1 arm (χ² = 4.66, P = 0.03). Because there were no events in the Compound 1 arm, a hazard ratio could not be calculated. There was a discrepancy in the date of graft failure for one subject. At the 6-month visit, the subject reported that graft failure had already occurred and eGFR was not reported for this subject at 6 months. However, the investigator noted graft failure as an AE at 8 months, when the subject was hospitalized. For the purpose of this analysis, the more conservative 8-month hospitalization date reported by the investigator was used. [0691] Adverse Events (AE): There were no deaths nor discontinuations of study drug due to adverse events. While the percent of subjects experiencing an AE was nearly equivalent across study arms, the number of AEs per subject was twice as high in the placebo arm than in the Compound 1 arm. In the Compound 1 arm, there was a total of 99 AEs reported in 17 (89.5%) subjects, an average of 5.8 events per subject. In the placebo arm, there was a total of 89 AEs reported in 8 (88.9%) subjects, an average of 11.1 events per subject. [0692] Treatment-emergent adverse events (TEAEs) followed a similar pattern: while a slightly lower percent of subjects in the Compound 1 group experienced a TEAE, the number of events per subject was twice as high in the placebo group. In the Compound 1 arm, 83 TEAEs were reported in 15 (78.9%) subjects, an average of 5.5 TEAEs per subject (Table 9). Six of these TEAEs were assessed by the investigator as related to study drug. In the placebo arm, 78 TEAEs were reported in 8 (88.9%) subjects, an average of 9.8 TEAEs per subject (Table 9). None of the TEAEs in the placebo arm were assessed by the investigator as related to study drug. The majority of TEAEs were rated as mild: 72.3% in the Compound 1 arm, 78.2% in the placebo arm. However, there were 11 TEAEs in the Compound 1 arm rated as severe, vs 1 in the placebo arm. In 7 of the 12 system organ classes (SOCs) with TEAEs in >5% of subjects, the event rate in the placebo arm exceeded that in the Compound 1 arm by >10%. This was largely driven by higher dyspnoea and oedema in the placebo arm. In the one SOC in which the event rate in the Compound 1 arm exceeded the placebo arm (renal and urinary disorders), the difference was due to higher nocturia in the Compound 1 arm. [0693] Serious adverse events (SAEs) followed a similar pattern (note: all SAEs were treatment emergent; Table 9). In the Compound 1 arm, 8 (42.1%) subjects reported a total of 16 TESAEs, an average of 2.0 TESAEs per subject. In the placebo arm, 4 (44.4%) subjects reported 17 TESAEs, an average of 4.3 TESAEs per subject. None of the TESAEs in either study arm were assessed by the investigator as related to study drug. The most common SOC for TESAEs was renal and urinary disorders, which included 2 incidents of acute renal failure in the placebo group. There was a pronounced difference in when TESAEs occurred. In the Compound 1 arm, 75% of TESAEs occurred <28 days after treatment. In the placebo arm, 76% of TESAEs occurred >28 days after treatment. [0694] An overview of all AEs is shown in Table 9: Table 9: Adverse Events – Overview

Efficacy Conclusions [0695] The totality of the efficacy data indicated that Compound 1 improves short-term and long-term renal function in patients who have undergone kidney transplantation and shown signs and symptoms of significant renal injury immediately post-transplantation. In the short-term, initial oliguria (<50 cc urine per hour for 8 consecutive hours post-transplant) was more likely to resolve in the Compound 1 arm in the 28 days post-transplant (Compound 1 = 78.9%; Placebo = 44.4%), and resolved more quickly (Compound 1 = 5 days; placebo=14 days). Consistent with this result, over the first 14 days after transplant, daily urine output was higher, and increased more over baseline, in the Compound 1 arm. [0696] Serologic results also showed a short-term efficacy signal in favor of Compound 1. While SCr was higher in the Compound 1 arm at baseline and Day 3, it was lower than placebo from on Days 7, 14 and 28. Adjusting SCr by gender, race and age to derive estimated glomerular filtration rate, the Compound 1 arm showed better eGFR at Days 14 and 28. CRP, a measure of inflammation, decreased in both study arms, but was higher in the Compound 1 arm at baseline and lower in the Compound 1 arm at Day 3 (68.6% reduction for Compound 1; 17.5% reduction for placebo). NGAL, a measure of kidney tissue damage, was higher in the Compound 1 arm at baseline, then decreased to a level similar to placebo at Day 3 (43.5% reduction). There was little change in the placebo arm (-12.5%). [0697] There were also differences in clinical treatment indicating in favor of Compound 1. While the percentage of patients requiring dialysis in the first week, and number of dialysis sessions in the first 28 days did not differ between groups, duration of dialysis was 2.2 days shorter in the Compound 1 arm. Hospitalization for transplant was 3.8 days shorter in the Compound 1 arm. [0698] There was a signal in favor of Compound 1 on both long-term outcome measures. eGFR was 11 to 13 mL/min/1.73 m² higher in the Compound 1 arm at 6 and 12 months. At one year, there were more graft failures in the placebo arm (n = 2; 22%) than the Compound 1 arm (n = 0; 0%). [0699] Overall, urologic, serologic and clinical treatment measures manifested a pattern in which patients in the Compound 1 arm showed improved kidney function when compared to placebo. Example 7. Mean eGFR Results Suggest Increased Life Expectancy in Subjects Receiving Compound 1 [0700] The National Kidney Foundation has set guidelines for classification of chronic kidney disease (CKD) based in part on a subject’s eGFR and summarized in Table 10 below (Levey, A.S., et al. National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Ann. Intern. Med.2003;139:137-147; UK and Scottish Renal Associations. Consensus statement on management of early CKD, February 2007. Edinburgh: Royal College of Physicians of Edinburgh; 2007). Table 10.

[0701] FIG.15 shows mean eGFR (mL/min/1.73 m²) by study arm at screening, Day 3, Day 7, Day 14, Day 28, Month 6 and Month 12, overlaid with the National Kidney Foundation’s predictive chronic kidney disease staging criteria for eGFR. As shown in FIG.15, subjects who received Compound 1 reached one stage lower than those receiving a placebo after 6 months and after 12 months, indicating better outcomes for these subjects. [0702] Evidence suggests that subjects at lower stages on the CKD scale have significant long-term mortality benefits versus patients at higher stages. For example, an average 7.7 year increase in life expectancy, on average, is projected for a 50-year-old male moving from CKD Stage 3B disease down to CKD Stage 3A disease. Similarly, a 9.1 year increase in life expectancy, on average, is projected for a 50-year-old female moving from CKD Stage 3B disease to CKD Stage 3A disease. (Turin, T.C., et al. Chronic kidney disease and life expectancy. Nephrol. Dial. Transplant.2012;27:3182-3186.) Thus, administration of Compound 1 to subjects at risk of DGF, as provided herein, is expected to increase life expectancies of those subjects. Example 8. A Multicenter, Prospective, Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study of Compound 1 to Improve Graft Function and Reduce the Severity of Kidney Dysfunction or Delayed Graft Function in Recipients of a Deceased Donor Kidney Objectives [0703] Primary: To improve graft function and reduce the severity of kidney dysfunction or delayed graft function following kidney transplantation in recipients of a deceased donor kidney. [0704] Secondary: ● To demonstrate the safety and efficacy of Compound 1 in recipients of a deceased donor renal allograft with high risk of DGF. ● To demonstrate the efficacy of Compound 1 in reducing the intensive requirement for healthcare resource utilization in recipients of a deceased donor renal allograft with DGF. Criteria for Evaluation Efficacy: [0705] Primary Endpoint: The primary endpoint was renal function assessed by eGFR (using the CKD-EPI equation based on serum creatinine), with a primary analysis time point consisting of eGFR at month 12. [0706] Secondary Endpoint: ● The proportion of patients with eGFR > 30 at Day 30, Day 90, Day 180, and Day 360 (at each time point). ● The proportion of subjects categorized as experiencing (1) Primary Non Function (PNF); (2) DGF (dialysis within the first 7 days); (3) slow graft function (SGF; defined as sCr > 3 mg/dL within the first 7 days, without dialysis required); or (4) none of the above. ● Length of hospitalization following transplantation. ● The severity of DGF assessed by its duration of dialysis as measured by the number of days a patient remains dialysis dependent from the first day of treatment (Day 1) until the day of the last dialysis session, which is followed by 7 consecutive dialysis-free days, or until Day 30, whichever comes first. [0707] For the severity of dialysis secondary endpoint (fourth endpoint above), the last dialysis session was defined as the day when a patient received his/her last dialysis before achieving 7 consecutive dialysis-free days, or by Day 30, whichever came first. Patients who stopped dialysis in the period from Day 24 to Day 29 were followed for 7 days, even though that required following the patient beyond Day 30, to be sure they had met the requirement for 7 consecutive dialysis-free days. For example, patients whose last dialysis session was on Day 29, must remain dialysis-free to Day 36 in order for Day 29 to be considered the last day of dialysis dependency. The maximal day of the assessment for the duration of dialysis endpoint was 36 days. If dialysis was reinstituted after a dialysis-free period of at least 7 days, but still within the first 30 days post-transplant, it was recorded, but was considered to be a new episode of renal insufficiency and was not considered to be DGF. If a patient or graft was lost within the first 30 days, it was imputed that the patient required dialysis until Day 30 (i.e., the worst result with respect to the duration of dialysis endpoint). Primary non-function (PNF) was defined as continuous dialysis dependency for at least 60 days post-transplant. Such patients were also counted as having required dialysis out to 30 days, but the incidence of PNF was also recorded. [0708] Exploratory Endpoints: ● Incidence of DGF assessed by proportion of patients requiring dialysis within the first 7 days post-transplant. ● The proportion of patients with PNF, defined as a continuous requirement for dialysis for at least 60 days post-treatment. ● Proportion of patients with acute rejection. ● Plasma and urine biomarkers such as: C-reactive protein (CRP), neutrophil gelatinase- associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). [0709] Safety: [0710] Safety was assessed by the following parameters: ● Adverse events (AEs) ● Treatment-emergent AEs ● Serious AEs (SAEs) ● Physical examination ● Vital signs ● Laboratory tests (clinical blood chemistry, coagulation, hematology, urinalysis) ● Electrocardiogram ● Pregnancy test ● Concomitant medications/treatments Methodology [0711] The study was a randomized, placebo-controlled, multicenter, double-blind, Phase 3, two-arm parallel study. The Sponsor and all site personnel, including site monitors, patients, the Medical Monitor, and the Investigators were blinded to individual treatment assignments for the duration of the study. [0712] Patients in this study were at enhanced risk for ischemia-reperfusion injury leading to early poor function or the need for dialysis in the first week following transplantation of a kidney from a deceased donor. Patients who fulfilled all other eligibility criteria were randomized in a 1:1 fashion to receive 2 mg/kg Compound 1 or placebo (normal saline). Study drug was administered daily over a 30-minute period (± 5 minutes) for a total of 3 intravenous (IV) infusions. [0713] Recipients of a kidney from either a donation after brain death (DBD) donor or donation after cardiac death (DCD) donor were considered eligible and were stratified at randomization. Recipients of DCD kidneys were capped at 20% of enrollment. Kidneys may have been preserved by static cold storage or cold pulsatile machine perfusion (PMP), but PMP kidneys were capped at 40% of enrollment. Recipients of normothermic pulsatile machine perfused kidneys, which is still an emerging technology, were not enrolled in this study. These randomization stratification factors were included in the primary efficacy analysis. [0714] The primary efficacy outcome was the assessment of renal function by eGFR (as estimated using the CKD-EPI sCr based equation). [0715] All patients enrolled were followed for the assessment of the primary efficacy variable and out to Day 360 for the specified safety and renal function assessments. All adverse events were collected until Day 90. Thereafter, serious adverse events and events including rejection episodes including BPACR [biopsy proven acute cellular rejection] and tACR [treated biopsy proven or clinically suspected acute cellular rejection] and antibody-mediated rejection [AMR], as well as malignancies and clinically significant infections were continued to be collected out to Day 360. Visits past Day 180 collected information either via phone or medical chart/record review. Renal function (SCr, eGFR) and patient and graft survival were also collected out to Day 360. In addition, the calcineurin (CNI) dose and the associated trough level (also collected as standard of care) were collected through Day 360. Study Population [0716] The study was conducted in recipients of a deceased donor renal allograft who were at high risk for ischemia-reperfusion injury leading to early poor function or the need for dialysis in the first week following transplantation, as delineated below. [0717] Inclusion Criteria: Subjects were assessed for eligibility according to the following criteria: ● All patients must provide written informed consent using an Institutional Review Board/Independent Ethics Committee approved consent form and must understand and be willing and able to comply with the requirements of the study, including screening procedures and all required study visits. ● Males and females greater than or equal to 18 years of age. ● Renal failure requiring hemodialysis or peritoneal dialysis initiated at least 3 months prior to transplantation. ● Patient is to be the recipient of a first kidney transplant from a deceased donor. ● Study drug can be administered starting within 30 hours after restoration of blood flow to the engrafted kidney. ● Body mass index < 40 based on patient’s body weight. Body weight and height parameters obtained within 7 days prior to study entry may be used. ● Estimated donor organ cold ischemia time < 30 hours (for PMP kidneys < 40 hours). ● Females of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year): o Must have a negative serum pregnancy test prior to transplantation. o Must agree to use 2 forms of effective birth control regimen (at least one-barrier method) during the initial 30-day study period or agree to maintain total abstinence throughout the initial 30-day study period. ● Male patients must agree to use condoms or other suitable means of pregnancy prevention such as abstinence during the initial 30-day study period. ● Patient has poor renal function in the first 24 hours post-transplantation based on an average urine output (UO) of <50 mL/hour over any 8 consecutive hours, to maximize the likelihood that the patient requires dialysis within the first 7 days post-transplant, irrespective of pre-transplant donor and recipient risk factors. ● Reason for low UO is not due to structure or vascular abnormalities which, when indicated should be confirmed with a renal ultrasound with Doppler study and/or vascular or urinary tract contrast studies. [0718] Exclusion Criteria: Subjects who met any of the following criteria were excluded from study participation: ● Scheduled for multiple organ transplantation or prior recipient of a transplanted organ. ● Recipient of an ABO-incompatible kidney. ● Recipient of pediatric en bloc kidney transplantation or adult or pediatric planned transplant of dual kidneys (from the same donor) not transplanted en bloc. ● Recipient of a kidney preserved by normothermic PMP. ● Has measurable donor-specific antibody or positive cross-match requiring desensitization prior to transplantation or deviation from standard immunosuppressive therapy. ● Either the donor or the recipient is currently participating in or has participated in an investigational drug or medical device study within 30 days or five drug half-lives, whichever is longer, prior to enrollment into this study. Patients cannot be given another investigational agent during the course of this study (through Day 360). Patients (recipient and donor kidneys) may participate in another concurrent study only if that study is a non-interventional, observational investigation. ● Concurrent sepsis or active bacterial infection. ● Has an active malignancy or history within 5 years prior to enrollment in the study of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma in situ of the skin that has been adequately treated. ● Female who is breastfeeding. ● History of positive human immunodeficiency virus test. ● Requires treatment with the cytochrome P450 (CYP) 1A2 inhibitors, ciprofloxacin and/or fluvoxamine (Luvox®). ● Unwilling or unable to comply with the protocol or to cooperate fully with the Investigator or the site personnel. ● Not deemed medically appropriate for the study in the opinion of the Investigator. Investigational Product, Dosage and Mode of Administration [0719] A Compound 1 stock solution (10 mg/mL) was diluted at the clinical site. Normal saline was used as placebo. Eligible patients received placebo or 2 mg/kg of Compound 1, via IV infusion over 30 minutes, once daily for 3 days, with the first dose administered within 30 hours after transplantation in patients who met inclusion criteria for treatment of DGF. The subsequent two doses were administered 24 ± 2 hours after the previous dose. [0720] Patients were randomized to Compound 1 or placebo in a 1:1 ratio using a central randomization process. Allocation to treatment was stratified on type of donor: DBD or DCD, and on method of preservation (cold static storage or cold machine perfusion). No more than 20% of the enrolled patients had kidneys from DCD donors and no more than 40% of the transplanted kidneys had been preserved by cold PMP. Duration of Treatment [0721] 2 mg/kg of Compound 1 or placebo by IV infusion once daily for 3 days. Duration of Study [0722] The planned duration of this study was 360 days. Reference Therapy, Dosage and Mode of Administration [0723] Placebo (normal saline) IV infusion. Concomitant Medications [0724] Induction and maintenance immunosuppression and concomitant medications were administered to all patients according to standard institutional protocol. If approved generic substitutions were available for an agent, they could be used, but the same generic alternative was used for a patient throughout the study until at least Day 90. [0725] All concomitant medications were recorded from the time of study enrollment to Day 90. Thereafter, immunosuppressants, antimicrobials, angiotensin converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARBs) usage was recorded through Day 360. Medications specific to the administration of anesthesia for surgery were not recorded. [0726] All patients receive antibody induction therapy, preferably with rabbit polyclonal anti-thymocyte globulin but anti-CD25 monoclonal antibodies were also allowed (anti-IL2R, basiliximab). Thymoglobulin was administered at a dose of 1.5 mg/kg administered over 4 to 6 days as tolerated, preferably with the first dose administered in the operating room. Adjustments in the dose and/or frequency of delivery was permitted to allow for institutional standard of care dosing, however the reasons should have been clearly stated in the medical record and appropriate case report form. Alternatively, basiliximab was administered in compliance with the product labeling. [0727] Initial maintenance immunosuppression was tacrolimus in combination with either mycophenolate mofetil (MMF) or mycophenolate sodium (MPS). Tacrolimus was started within 48 hours of transplantation; if a delay was needed for cause, the Medical Monitor should have been consulted. Cyclosporine could be used in place of tacrolimus if approved by the medical monitor. Switching from tacrolimus to cyclosporine was allowed for clinical cause. [0728] MMF was administered at 750-1000 mg twice a day. Corresponding doses of MPS as recommended in the package insert were used. In all cases, the dose could be adjusted for clinical cause. Azathioprine could be substituted for mycophenolic acid-based therapy if necessary after consultation with the Medical Monitor. Initial use of belatacept, sirolimus or everolimus was not allowed but if switching of immunosuppression was needed for cause, the medical monitor should have been consulted and the reason for the switch should have been recorded. [0729] All subjects received concomitant corticosteroids with a rapid taper from high dose to a maintenance dose of at least 5 mg per day to be maintained until at least Day 30. Full steroid withdrawal was permitted only after 30 days post-transplant. Complete steroid avoidance or immediate minimization was not allowed. Daily dose levels of corticosteroids were recorded. Adjustments in the dose were permitted to allow institutional standard of care dosing, however the reasons should have been clearly stated in the medical record and appropriate case report form. [0730] Anti-viral, anti-fungal and anti-microbial prophylaxis was required but was to be based on local standard of care, including regimens for cytomegalovirus and Pneumocystis jiroveci and other antiviral, antifungal, and antimicrobial prophylaxis. Statistical Methods [0731] All statistical tests were two-sided and at the 5% level of significance. Efficacy Analysis [0732] The primary analysis of the primary and secondary efficacy endpoints were based on the Full Analysis Set (FAS), where all subjects who were randomized (and treated) and who received a deceased donor renal allograft were analyzed. The primary efficacy endpoint was eGFR assessed by the (sCr based) CKD-EPI equation, with a primary time point of eGFR at 12 months estimated using a Mixed Model Repeated Measures (MMRM) approach, adjusting for stratification factors. Analyses for continuous secondary and exploratory endpoints were assessed similarly, except where endpoints did not represent repeated assessments (e.g. duration of dialysis and length of hospitalization) which were assessed in an ANOVA framework. [0733] Analysis of the proportion of subjects with eGFR > 30 (over time) was conducted using a Generalized Linear Model (GLM), adjusting for stratification factors. [0734] The difference between treatments with respect to categorical endpoints such as the incidence of Delayed Graft Function (DGF) and Primary Non Function (PNF) and separately for the ordinal categories (the percentage of subjects experiencing 1) PNF, 2) DGF (dialysis within the first 7 days) or 3) SGF (defined as sCr > 3 mg/dL within the first 7 days, without dialysis required) or 4) none of the above) were analyzed using Cochran-Mantel-Haenszel (CMH) test stratified by the randomization stratification variables. For the ordinal categories of PNF, DGF, SGF or none, the test of interest was the test of differences in row mean scores. Safety Analysis [0735] All subjects receiving any part of at least one infusion of study treatment were evaluated for safety. The safety analyses included evaluation of the incidence of treatment- emergent AEs, Grade 3 or greater AEs, SAEs, and AEs leading to discontinuation of study treatment. Laboratory and vital signs assessments were evaluated over time on study using descriptive statistics. Shift analyses of relevant clinical laboratory parameters were produced showing shifts across low, normal, and high categories. [0736] Incidence rates (e.g., BPACR, tACR, AMR, malignancies) were compared between treatment groups, as well as Graft and subject survival. Example 9. A Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Phase 2 Study to Assess Safety and Efficacy of Compound 1 in Patients Hospitalized with Confirmed COVID-19 Pneumonia. Primary Objective: [0737] To assess clinical efficacy of Compound 1 plus standard of care relative to placebo plus standard of care in reducing the severity and progression of pulmonary and renal dysfunction and mortality in adult patients hospitalized with COVID-19 pneumonia. Secondary Objectives: [0738] To assess safety of Compound 1 in patients hospitalized with COVID-19 pneumonia. [0739] To assess efficacy to prevent progression to requiring mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) and/or renal replacement therapy. [0740] To assess efficacy to reduce number of days on mechanical ventilation and/or ECMO. [0741] To assess efficacy of Compound 1 to reduce ICU length of stay in patients with COVID-19 pneumonia. Study Design: [0742] This was a randomized, prospective, double-blind, placebo-controlled, parallel-arm, multicenter study which assessed the efficacy and safety of Compound 1 plus the standard of care (SOC) vs. placebo plus SOC in patients with COVID-19 pneumonia. Patients hospitalized with confirmed pneumonia with COVID-19 who met the inclusion criteria but none of the exclusion criteria were eligible to participate in this study. The eligible patients were randomized in 1:1 ratio to Compound 1 + SOC or placebo + SOC. Subjects were stratified at randomization by disease severity (moderate [Score 4] vs. severe [Score 5]) based on the WHO’s disease severity scale assessment 8-point Ordinal Scale. [0743] Compound 1 was administered by once daily intravenous (IV) infusions of 2 mg/kg for a total of 4 doses. The first dose was started within 6 hours of randomization. Subsequent doses were administered 24 ± 4 hours after the previous dose. [0744] Patients were followed for safety and efficacy up to Day 28 ± 2 days, with Day 1 being the day of randomization. Patients were assessed daily until their discharge from the hospital or Day 28 after randomization. [0745] Safety was monitored by an independent Safety Review Committee on an ongoing basis. The following 8-point Ordinal Scale as recommended by the World Health Organization (WHO’s) task force on COVID-19 efficacy endpoints was used for inclusion/exclusion and some of the secondary efficacy endpoints:

[0746] There were approx. up to 50 patients per treatment group (i.e., a total of approx. up to 100 patients). Eligibility Criteria: [0747] To be eligible for the study, participants were required to meet all of the following inclusion criteria: ● Patient is a male or nonpregnant female patients 18 years of age or older. ● Patient has a positive reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for SARS-CoV-2 in a respiratory tract sample during the current hospital admission. ● Patient has pneumonia confirmed by chest imaging. ● Patient has moderate to severe disease based on WHO’s disease severity scale assessment 8-point Ordinal Scale at time of randomization defined as: o Score 4, only those with FiO₂ >40% (FiO₂ >40% defined as nasal cannula > 5 L/min, venturi mask > 10 L/min, conventional mask > 8 L/min, or mask with oxygen reservoir). o Score 5 (Non-invasive ventilation or high-flow oxygen). ● Patient has ability to provide informed consent signed by study patient or legally acceptable representative. ● Patient has willingness and ability to comply with study-related procedures/assessments. [0748] A participant who met any of the following exclusion criteria was excluded from the study: ● Has an active malignancy or history of solid or hematological malignancies within 5 years prior to enrollment in the study. Patients who had basal or squamous cell carcinoma-in-situ of the skin that was diagnosed > 2 years prior to the study enrollment and not currently being treated are eligible for study enrollment. ● Patient is pregnant or breast-feeding. ● Patient, in the opinion of the investigator, is unlikely to survive for ≥ 48 hours from the time of screening. ● Patient has any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study. ● Patient with alanine aminotransferase (ALT) or aspartate transaminase (AST) > 3x upper limit of normal (ULN) and/or total bilirubin > 2x ULN at baseline. ● Requires treatment with the cytochrome P4501A2 (CYP1A2) inhibitors, ciprofloxacin and/or fluvoxamine. ● Patients participating in any other clinical trial with an investigational drug product or procedure. ● Recipients of solid organ and/or hematopoietic cell transplantation. ● Patient is known to have End Stage Renal Disease (ESRD) and was being treated with maintenance hemodialysis or peritoneal dialysis prior to the current hospitalization. (Patients who initiated renal replacement therapy due to Acute Kidney Injury during their current hospitalization are eligible for the study.) Drug Product, Dosage, and Mode of Administration: [0749] Compound 1 for intravenous (IV) administration is a sterile solution with a concentration of 10 mg/mL. The solution also contains 50% weight per volume (w/v) PEG 300 national formulary, 10% w/v polysorbate 80 NF, and phosphate buffered saline. [0750] Patients received 2 mg/kg Compound 1 or placebo (equivalent volume of normal saline), via IV infusion over 30 minutes, once-daily for 4 days. The first dose was started within 6 hours of randomization. The subsequent doses were administered 24 ± 4 hours after the previous dose for a total of 4 doses. A regular schedule for administering subsequent doses every 24 hours was established. [0751] If a patient misses a scheduled dose of Compound 1, the missed dose may be administered as long as there are at least 12 hours between the end of the infusion of the “make- up” dose and the next scheduled dose of Compound 1. [0752] The 10 mg/mL stock solution was diluted with normal saline to a concentration of 6 mg/mL before being administered. Volume was administered according to the patient’s weight. An equivalent volume of normal saline was used as placebo. Duration of Treatment: [0753] Once-daily for 4 days. Reference Therapy, Dosage, and Mode of Administration: [0754] Patients received SOC as adopted by the participating institution plus placebo. Normal saline was used as placebo. Patients received a volume of normal saline equivalent to that containing active drug on a mL/kg basis. Criteria for Evaluation: [0755] Primary Endpoint: ● Proportion of patients alive, without need for mechanical ventilation and free of the need for renal replacement therapy (RRT) (on an ongoing basis) at Day 28. [0756] Secondary Endpoints: ● All-cause mortality. ● Proportion of patients not requiring mechanical ventilation at Day 28. ● Proportion of patients not requiring RRT on an on-going basis at Day 28. ● Number of ventilator free days in the first 28 days. ● Proportion of patients requiring initiation of mechanical ventilation and/or ECMO through Day 28. ● Proportion of patients requiring initiation of renal replacement therapy through Day 28. ● Number of days to renal recovery (defined as freedom from further RRT on an ongoing basis) in subjects who were on RRT at the time of randomization. ● Number of ICU days from randomization to Day 28. ● Change in WHO 8-point ordinal scale from randomization to Day 28. ● Number of days to hospital discharge from randomization. [0757] Exploratory Endpoints: ● Mean change from baseline in biomarkers: high-sensitivity C-reactive protein (HS-CRP), D-dimer, absolute lymphocyte count, ferritin, myoglobin, troponin, lactate dehydrogenase (LDH) [0758] Safety: ● Collection of Adverse Events (AEs) emerging during treatment, Grade 3 or greater, serious adverse events (SAEs), and AEs leading to discontinuation of study treatment. ● Laboratory parameters (hematology, chemistry, troponin, hepatic, coagulation, urinalysis) ● Vital signs ● Electrocardiogram Statistical Methods: [0759] Efficacy Analysis: [0760] Sample size: Approximately 100 patients were enrolled in this study. [0761] Methods: Continuous variables were summarized with descriptive statistics (number of non-missing values [n], mean, median, standard deviation [SD], minimum, and maximum). All categorical variables were summarized with frequency counts and percentages, as applicable. Time to event variables were analyzed using Kaplan-Meier (K-M) survival estimates. The K-M survival curves were compared between treatment groups using Log-rank test. K-M estimates including 25^th, 50^th, and 75^th percentiles, 95% confidence intervals (CIs), and number and percent censored were presented. A Mixed Model Repeated Measures (MMRM) analysis or Analysis of Covariance (ANCOVA) was carried out for continuous variables, depending on the number of assessments post-baseline. For binary endpoints, difference in proportions between treatment groups were analyzed using a Mantel-Haenszel Test, stratifying on baseline severity. Analyses were carried out on the Full Analysis Set. [0762] Interim Analysis: Formal interim analysis was not planned, however safety data were reviewed on an ongoing basis by an independent Safety Review Committee. [0763] Safety Analysis: All patients randomized and who received SOC plus placebo or received SOC and any part of at least one infusion of study treatment (Compound 1) were evaluated for safety. The safety analyses include evaluation of the incidence of treatment- emergent AEs, Grade 3 or greater AEs, SAEs, and AEs leading to discontinuation of study treatment. Laboratory and vital signs assessments were evaluated over time on study using descriptive statistics. Shift analyses of relevant clinical laboratory parameters were produced showing shifts across low, normal, and high categories. Study Assessments [0764] Demographics and Disease Characteristics: The patient’s date of birth, sex, race and ethnicity were recorded at the Screening visit. Disease characteristics were recorded including date of first contact with the virus (i.e., exposure), date of symptom onset, date SARS-CoV-2 virus test (RT-PCR)/NAT positive. [0765] Medical History: A detailed medical history for each patient was obtained at Screening. All relevant past and present conditions, as well as prior malignancies and/or surgical procedures, were recorded for the main body systems. Key clinical features and symptoms of COVID-19 collected at screening were not considered adverse events until the definition of an AE was met. [0766] Physical Examination: A complete physical examination was performed at Screening which included the following: an examination of the skin, general appearance, neck (including thyroid), eyes, ears, nose, throat, lymph nodes, chest (lungs), heart, abdomen, musculoskeletal system, neurological system and any additional assessments needed to establish baseline status or evaluate symptoms or adverse events. Symptom-directed physical examinations were performed as needed for safety evaluations on other study visits. [0767] Smoking History: Smoking history was collected at Screening. [0768] Height and Weight: Height and weight were collected on Day 1. Weight was required within prior 72 hours prior to randomization and was used for dosing calculations. [0769] Vital Signs: Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate, and temperature) were collected at all study visits. On days when Compound 1 is administered, vital signs were collected just prior to the infusion of Compound 1, at the completion of infusion, and then at 4 hours post completion of each infusion. At all other study visits, vital signs were collected once. [0770] 12-Lead Electrocardiogram: A 12-lead ECG was performed as part of Screening. Standard of care results can be used for screening if taken during the current hospitalization. A 12-lead ECG was performed at Days 2, 4, 14, and 28. [0771] Laboratory Assessments: Laboratory assessment was measured at Screening through Day 14 while the patient is hospitalized, and during follow-up visit on Day 28±2. Hematology included hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC) with differential (including bands, if available), and platelet count. Blood chemistry included glucose, phosphorus, total protein, blood urea nitrogen (BUN), creatinine, albumin, and electrolytes (sodium, potassium, calcium, bicarbonate, chloride). Hepatic profile included total, direct and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma- glutamyl transpeptidase (GGTP). Coagulation profile included International Normalized Ratio (INR) and activated partial thromboplastin time (APTT). Troponin I was collected on Days 2, 4, 6, 9, 11, 14. Urinalysis measured urine pH, specific gravity, protein, glucose, ketones, bilirubin, blood, microscopic. Women of childbearing potential must have had a negative serum/urine pregnancy screen at the Screening visit. A serum/urine pregnancy screen was also collected at Day 28. Additional Laboratory assessments including HS-CRP, D-dimer, ferritin, LDH, and myoglobin were collected at Baseline, Days 6, 9, and 14. [0772] CT Scan (as clinically indicated): Computed tomography (CT) scan was conducted at Screening/Baseline and at Day 28±2. [0773] Chest X-ray: Chest x-ray was conducted at Screening/Baseline and as indicated per SOC. [0774] WHO Ordinal Disease Severity Assessment: Disease severity was assessed by the WHO COVID-19 Task Force 8-point Ordinal Scale for Clinical Improvement. Disease severity was assessed at Screening/Baseline, daily through Day 14 while the patient was hospitalized, Day 15-28 if patient was hospitalized and during follow-up visits Day 14 and Day 28±2. [0775] Oxygen Administration and Assessment of Oxygenation: Use of supplemental oxygen administration including the type, percent, flow start date/time, and flow end date/time and patient’s oxygen saturation (SaO2) was recorded at Screening/Baseline, daily through Day 14 while the patient was hospitalized, Day 15-28 if patient was hospitalized and during follow- up visits Day 14 and Day 28±2. Patient SaO2, PaO2, and FiO2 was measured as available. [0776] Mechanical Ventilation: Use of any ventilatory support type was recorded at Screening/Baseline, daily through Day 14 while the patient was hospitalized, Day 15-28 if patient was hospitalized and during follow-up visits Day 14 and Day 28±2. [0777] Record Hospital Admission and Discharge Dates: Hospital admission and discharge dates on or before Day-28/Final Visit were recorded. [0778] Intensive Care Unit Admission and Discharge Dates: Intensive care unit admission and discharge dates on or before Day-28/Final Visit were recorded. [0779] SARS-CoV-2 Viral Load: Test for confirmation of positive or negative for COVID19 SARS-CoV-2 virus by NAT or PCR (RT-PCR) was collected at baseline and then as indicated as SOC through Day 28±/ End of Study visit. Example 10. A Multicenter, Prospective, Parallel-Group, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study of Compound 1 to Assess the Safety and Efficacy of Compound 1 in Patients Developing Acute Kidney Injury After Cardiac Surgery Summary [0780] This was a randomized, prospective, parallel-group, double-blind, placebo-controlled, multicenter study. Patients who would be undergoing a surgical procedure involving CPB and were at elevated risk pre-surgery for AKI were eligible to participate in the study. Patients were randomized 1:1 to receive either Compound 1 or placebo (normal saline) immediately after surgery. Study drug was administered for a total of 4 daily intravenous (IV) infusions. The first post-operative dose MUST have been started within 4 hours of completing CPB. The second dose was administered 24 ± 2 hours after completing CPB, and the third and fourth doses were administered 24 ± 2 hours after each previous dose. [0781] Patients were followed for safety, PK (in a subset of patients), and efficacy up to Day 90, with Day 1 being the day of the first infusion of study drug. Patients were assessed daily through Day 7 and then on Days 14, 30 and 90. [0782] Efficacy endpoints included assessment of post-CPB renal injury, expressed as percent increase in sCr above Baseline over time and the maximum percent increase in sCr following CPB, from 24 hours after end of CPB through Day 5; the proportion of patients reaching each KDIGO stage or having no AKI at specified time points through Day 30; and analyses among patients who develop AKI assessing time to recovery or reduction in KDIGO stage. [0783] Approximately 100 patients were randomized; 50 patients were randomized to Compound 1 and 50 patients to placebo. Arms and Intervention

Outcome Measures [0784] The primary outcome measure was the mean AUC of the percent increase in serum creatinine above baseline, starting from 24 hr after the end of CPB through Day 6. [0785] Other outcome measures included: ● The maximum percent increase in sCr level from baseline Day 5 ● The mean percent increase in serum creatinine above baseline over time starting from the end of CPB through Day 5, through Day 7, through Day 14, and through Day 30 ● The mean percent increase of sCr above baseline at 24 hr after the end of CPB, and at Day 3, Day 4, Day 5, and Day 7 ● The proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 5 ● The proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 7 ● Proportion of patients by severity of renal injury using KDIGO AKI staging at 24 hr after the end of CPB, at Day 3, at Day 4, Day 5, Day 7, Day 14, and Day 30 ● The proportion of patients with AKI at 24 hr after the end of CPB, Day 3, Day 4, Day 5, Day 7 ● Time in days from end of CPB to occurrence of AKI within Days 1-5 and within Days 1- 7 ● Time in days from the occurrence of AKI diagnosed postoperatively through Day 5 to recovery from AKI and through Day 7 to recovery from AKI through Day 5 to recovery from AKI and through Day 7 to recovery from AKI ● Time in days to improvement in renal function from the day of occurrence of AKI diagnosed postoperatively through Day 5 and through Day 7 ● The proportion of patients with renal function recovery, progression, or stabilization among patients with AKI diagnosed postoperatively at Day 30 ● Among patients with AKI diagnosed postoperatively, the proportion of patients with renal function recovery, progression, or stabilization through day 5 ● The slope of decline of the creatinine curve from the day of peak sCr through Day 5, Day 7, Day 14 and Day 30 ● Proportion of patients requiring initiation of any form of renal replacement therapy up to Day 30 ● Length of index hospital stay through Day90 ● Proportion of patients developing a composite endpoint comprising the following events: death, worsening of kidney function during the 30-day and 90-day post-operative periods ● Changes from baseline in eGFR at Days 4, 7, 14, 30 and 90 ● Proportion of patients having a ≥ 20 % reduction from baseline in eGFR at Days 2, 3, 4, 7, 14, and 30 and 90 ● Maximal change from baseline in eGFR and sCr through Day 90 ● Changes in circulating or urinary biomarkers of renal injury through Day 90 ● Urine volume over 12-hour periods for the first 72 hours post-CPB ● Cmax pre-dose, immediately after completing the 4th infusion, and at 2 hours and at 6 hours from the start of the 4th infusion ● AUC pre-dose, immediately after completing the 4th infusion, and at 2 hours and at 6 hours from the start of the 4th infusion ● Relationship of post-first infusion Compound 1 blood levels with the primary and secondary endpoints set forth above. Inclusion Criteria [0786] Subjects eligible for this study met the following inclusion criteria: ● Patient is either male or female ≥ 18 years. ● Patient has provided written informed consent, and is willing and able to comply with the requirements of the study protocol, including screening procedures. ● Patient must be scheduled for and undergo a non-emergent cardiac surgical procedure involving CPB. Eligible procedures include: o Coronary artery bypass graft (CABG) alone o Aortic valve replacement or repair alone, with or without aortic root repair o Mitral, tricuspid, or pulmonic valve replacement or repair alone o Combined replacement of several cardiac valves o CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair o CABG with combined cardiac valve replacement or repair. ● Patient must have the following risk factor(s) for AKI prior to surgery: o Estimated glomerular filtration rate (eGFR) of ≥ 20 and < 30 ml/min/1.73m2, or o eGFR ≥ 30 and < 60 mL/min/1.73m2 and ONE of the following Additional Risk Factors (other than age ≥ 75 years), or o eGFR ≥ 60 ml/min/1.73m2 (eGFR will be calculated using the abbreviated MDRD equation (MDRD-4, often referred to as the Levey equation): eGFR = 186.3 x sCr-1.154 x Age-0.203 x [0.742 if Female] x [1.212 if Black]); and TWO of the following Additional Risk Factors o Additional Risk Factors are: ● Combined valve and coronary surgery ● Previous cardiac surgery with sternotomy ● Left ventricular ejection fraction (LVEF) < 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days prior to surgery ● Diabetes mellitus requiring insulin treatment ● Non-insulin-requiring diabetes with documented presence of at least moderate (+2 or > 100 mg/dL) proteinuria on urine analysis (medical history or dipstick) ● Documented NYHA Class III or IV within 1 year prior to index surgery ● Age ≥ 75 years can be considered an Additional Risk Factor only for patients with eGFR ≥ 60 ml/min/1.73m2. ● Patient must have presented for surgery without prior evidence of active renal injury defined as no acute rise in sCr > 0.3 mg/dL or no 50% increase in sCr between the time of Screening and pre-surgery. ● Patient's body mass index (BMI) < 40 at Screening. Exclusion Criteria [0787] Subjects were excluded from the study if one or more of the following statements was applicable: ● Patient has eGFR < 20 mL/min/1.73 m2 within 48 hours pre-surgery as measured by MDRD 4. ● Patient has ongoing sepsis or partially treated infection. Sepsis is defined as the presence of a confirmed pathogen, along with fever or hypoperfusion (i.e., acidosis and new onset elevation of liver function tests) or hypotension requiring pressor use prior to surgery. ● Currently active infection requiring antibiotic treatment. ● Patient who has an active (requiring treatment) malignancy or history within 5 years prior to enrollment in the study, of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed. ● Administration of iodinated contrast material within 24 hours prior to cardiac surgery. ● Patients diagnosed with AKI as defined by KDIGO criteria within 48 hours prior to surgery. Example 11. Synthesis of Compound 1 [0788] As described in Example 7 of WO 2004/058721, Compound 1 was synthesized according to Scheme 1.

Scheme 1 [0789] To a solution of diethoxyphosphorylacetaldehyde tosylhydrazone (3, 75 g) in 400 mL of THF was added 11.6 g of 60% NaH in portions, and the solution was stirred for 15 min. The solution was cooled to 0 °C, and then a solution of 3-(2-thienyl)acrylaldehyde (2) in 100 mL THF was added dropwise. The reaction was then stirred at room temperature for 1 hour, then at reflux for 1 hour. The reaction mixture was partitioned between 5% NaH2PO4 and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the crude product as a brown oil. Purification via silica gel column chromatography afforded 8.3 g of a yellow powder. Trituration with dichlormethane/hexane afforded 4.4 g of yellow powder having >98% purity: ¹H NMR (CDCl₃) δ 6.47 (d, 1 H, J = 1.5 Hz), 6.93 (d, 1 H, J = 9.9 Hz), 6.99 (dd, 1 H, J = 3.9, 2.1 Hz), 7.06 (d, 1 H, J = 2.1 Hz), 7.20 (d, 1 H, J = 3.9 Hz), 7.22 (d, 1 H, J = 9.9 Hz), 7.57 (d, 1 H, J = 1.5 Hz). [0790] The conversion of 3-arylacrylaldehydes into substituted pyrazoles via treatment with diethoxyphosphorylacetaldehyde tosylhydrazone (3) is described in the literature (Almirante, N.; Cerri, A.; Fedrizzi, G.; Marazzi, G.; Santagostino, M. Tetrahedron Lett.1998, 39, 3287). 3-(2- thienyl)acrylaldehyde (2) was prepared from 2-thienaldehyde and acetaldehyde as described in Heskin, H., Miller, R. E., Nord, F. F. J. Org. Chem.1951, 16, 199. Example 12. Alternative Synthesis of Compound 1

Step 1. Synthesis of (E)-4-(thiophen-2-yl)but-3-en-2-one (2.1) [0791] To a solution of thiophene-2-carboxaldehyde (1.1, 40 kg) in 70 L of acetone was added 80 kg of 0.4 M aqueous NaOH slowly at 5 °C. The solution was warmed to room temperature and stirred for 2-3 hours. Dichloromethane (approx.4.5 volumes) was then added to the reaction mixture, the layers were allowed to separate, and the organic layer was removed. The aqueous layer was extracted with dichloromethane (approx.0.7 volumes), the layers were allowed to separate, and the organic layer was combined with the first organic layer. Water (approx.0.8 volumes) was added, the layers were allowed to separate, and the organic layer was combined with the first and second organic layers. The combined organic layers were then concentrated and diluted with toluene, which was then distilled with a Dean Stark apparatus to remove water. The mixture was then polish filtered and further concentrated to 3-4 volumes to provide a solution of (E)-4-(thiophen-2-yl)but-3-en-2-one (2.1) in toluene, which was carried forward into the next step without further purification. Step 2. Synthesis of (1E,4E)-1-(dimethylamino)-5-(thiophen-2-yl)penta-1,4-dien-3-one (2.3) [0792] To a solution of 2.1 in toluene from the previous step, N,N-dimethylformamide dimethylacetal (2.2a, 97 kg), was added and the reaction mixture heated at reflux for 36 hours. The reaction mixture was then concentrated to 2.5-3.5 volumes. The resulting slurry was cooled to room temperature and ethyl acetate was added. The resulting solids were filtered, washed with ethyl acetate, and dried under vacuum to afford (1E,4E)-1-(dimethylamino)-5-(thiophen-2- yl)penta-1,4-dien-3-one (2.3) in 55% yield from thiophene-2-carboxaldehyde (2.1). [0793] In some instances, a slurry of seed material of 2.3 in ethyl acetate was added after concentration of the reaction mixture. Seed material of 2.3 can be prepared using the process described above. Step 3. Synthesis of Compound 1 [0794] 2.3 (40 kg) was dissolved in 130 kg of isopropyl alcohol under nitrogen, and the mixture was cooled to 10 °C. Acetic acid (13 kg) was then added at 5-25 °C. The solution was then cooled to 5-15 °C, followed by slow addition of hydrazine hydrate (11.5 kg) while maintaining a temperature of 10-25 °C. The reaction mixture was then stirred at 20 °C. Once the reaction was judged to be complete (e.g., using HPLC or thin layer chromatography), water was added, and the resulting solids were filtered, washed with a mixture of isopropyl alcohol and water (1:4), and dried to afford crude Compound 1 in 90% yield. [0795] Crude Compound 1 (26 kg) was dissolved in 42 kg acetonitrile at 65-75 °C and then slowly cooled to 15-25 °C to induce crystallization. The resulting solids were filtered and washed with a mixture of acetonitrile and water, and then dried under vacuum. The solids were then dissolved in ethyl acetate at 55-65 °C and polish filtered. n-Heptane (200 kg) was then added to the mixture at 50-60 °C. The mixture was cooled to 15-25 °C, the resulting solids were isolated by filtration, washed with n-heptane, and dried under vacuum to afford crystalline Compound 1 in 67% yield. Example 13. Preparation and Characterization of Compound 1 Solid Form A General Methods: X-Ray Powder Diffraction (XRPD) [0796] XRPD patterns of samples from scaled-up preparations were recorded at ambient temperature on a Bruker D8 Advance X-ray diffractometer (Karlsruhe, Germany) using Cu KĮ radiation (λ = 1.54 Å) at 40 kV, 40 mA passing through a Vario monochromator (Karlsruhe, Germany). The sample was loaded on a zero-background holder and gently pressed by a clean glass slide to ensure co-planarity of the powder surface with the surface of the holder. Data were collected in a continuous scan mode with a step size of 0.05° and dwell time of 1 s over an angular range of 3° to 40° 2^. Obtained diffractograms were analyzed with DIFFRAC.EVA diffraction software (Bruker, Wisconsin, USA). [0797] In some cases, the X-ray intensity data were measured on a Bruker D8 Eco diffractometer system equipped with a graphite monochromator and a Cu KĮ Sealed tube (λ = 1.54 Å). The sample was loaded in a polyimide capillary and collected data in transmission mode. Bruker’s APEX3 software suite (Bruker, Wisconsin, USA) was used to collect and extract the intensity data. Obtained diffractograms were analyzed with TOPAS software (Bruker, Wisconsin, USA).Mercury 4.2.0 software (Build 257471, Cambridge Crystallographic Data Centre, UK) was used to calculate the XRPD patterns from single crystal data. Thermogravimetric Analysis (TGA) [0798] TGA was performed using a Discovery TGA 5500 (TA® Instruments, New Castle, Delaware, USA) instrument operating with TRIOS software (Version 5.0). The sample was placed in an aluminum pan. The sample cell was purged with dry nitrogen at a flow rate of 15 mL/min. A heating rate of 10 °C/min from 25 °C to desired temperature was used in all the experiments. Differential Scanning Calorimetry (DSC) [0799] Conventional DSC experiments were performed using a Discovery DSC 250 (TA® Instruments, New Castle, Delaware, USA) instrument equipped with a refrigerated cooling system (RCS90) and operating with TRIOS software (Version 5.0). The sample cell was purged with dry nitrogen at a flow rate of 50 mL/min. Accurately weighed samples (2í5 mg) placed in TZero pans with a pin hole were scanned at a heating rate of 10 °C/min over a temperature range of 25 °C to desired temperature was used in all the experiments. Compound 1 Lot I [0800] Compound 1 was provided (e.g., via the method of Example 12) in a form with an XRPD as shown in FIG.22, a TGA as shown in FIG.23, and a DSC as shown in FIG.24. Herein, this material is referred to as “Compound 1 Lot I.” Form A [0801] Compound 1 Form A was synthesized by recrystallizing Compound 1 Lot I from methanol. In a typical reaction, ~450 mg of Compound 1 Lot I was dissolved in 2 mL of methanol while heating at 50 °C. Resultant solution was kept at room temperature and allowed for slow evaporation of the solvent. Crystals suitable for single crystal X-ray diffraction were obtained within one day. [0802] Compound 1 Form A bulk powder was prepared as follows: ~ 5 g of Compound 1 Lot I was suspended in 5 mL of methanol and slurried at room temperature for two days. The resulting solid was filtered using 0.45 μm PTFE syringe filter. [0803] Single crystal X-ray diffraction of Compound 1 Form A was obtained (FIG.25). Crystal data and structure refinement parameters are summarized below:

[0804] The XRPD pattern of Compound 1 Form A calculated from single crystal X-ray diffraction data is shown in FIG.18 and is summarized below:

[0805] The XRPD pattern of Compound 1 Form A bulk powder is shown in FIG.19. Comparison of observed XRPD pattern of Compound 1 Form A bulk powder corresponds well with the calculated XRPD pattern (FIG.18). [0806] TGA of Compound 1 Form A is shown in FIG.20. A weight loss of 0.6% was observed up to 150 °C. [0807] DSC of Compound 1 Form A is shown in FIG.21. One endotherm was observed at 116.42 °C. [0808] A comparison of Compound 1 Lot I is shown in FIG.26 and verifies that Compound 1 Lot I matches Form A. Example 14. Preparation of a Compound 1 Formulation [0809] Polyethylene glycol 300 (175 kg) and polysorbate 80 (35 kg) were combined in a 440 L vessel. Compound 1 (3.5 kg, adjusted for purity, water content, and residual solvent) was added and stirred for 60 minutes. Phosphate buffered saline was filtered and added to the solution until the total mass of the compounding mixture was 381.5 kg. 1.0 N HCl and/or 1.0 N NaOH was added to bring pH to 7.5-7.9. The resulting solution was filtered through 0.45 μm and 0.22 μm polish filters in succession, then filled into 20 mL Type 1 glass vials with a target fill weight of 25.12 g per vial and nitrogen over-fill. Vials were capped with B2-40 West stoppers and sealed. Example 15. Alternative Preparation of a Terevalefim Formulation [0810] Polyethylene glycol 300 (0.6 kg) and polysorbate 80 (0.12 kg) were combined in a vessel. Compound 1 (0.012 kg, adjusted for purity, water content, and residual solvent) was added and stirred until dissolved. A portion of water (e.g., water for injection) was added to the mixture, equal to approximately half the expected quantity. Then, monobasic potassium phosphate (0.00176 kg) was added, followed by dibasic sodium phosphate (0.00726 kg). The pH was then adjusted as needed using 1.0 N HCl (aq) and 1.0 N NaOH (aq) to achieve a pH of 7.7 ± 0.2. Water (e.g., water for injection) was added to bring the Compound 1 concentration to 6 mg/mL. This Example provided a formulation comprising: about 6 mg/mL terevalefim, about 30% (w/v) polyethylene glycol 300, about 6% (w/v) polysorbate 80, about 0.07% (w/v) monobasic potassium phosphate, about 0.4% (w/v) dibasic sodium phosphate, and about 63% (w/v) water. Example 16. A Multicenter, Prospective, Parallel-Group, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study of Compound 1 to Assess the Safety and Efficacy of Compound 1 in Patients Developing Acute Kidney Injury After Cardiac Surgery Objectives [0811] Primary: To assess the safety and efficacy of Compound 1 compared to placebo when administered to patients at risk for developing acute kidney injury (AKI) following cardiac surgical procedures involving cardiopulmonary bypass (CPB). [0812] Secondary: To assess the pharmacokinetics (PK) of Compound 1 in a subset of patients following surgical procedures involving CPB. Study Design [0813] This was a randomized, prospective, parallel-group, double-blind, placebo-controlled, multicenter study. Patients who were undergoing a surgical procedure involving CPB and were at elevated risk pre-surgery for AKI were eligible to participate in the study. Patients were randomized 1:1 to receive either Compound 1 or placebo (normal saline) immediately after surgery. [0814] Compound 1 was administered for a total of 4 daily intravenous (IV) infusions. The first postoperative dose was started within 4 hours of completing CPB. The second dose was administered 24 ± 2 hours after completing CPB, and the third and fourth doses were administered 24 ± 2 hours after each previous dose. [0815] Patients were followed for safety, post-first infusion Compound 1 levels, Compound 1 PK (in a subset of patients), and efficacy up to Day 90, with Day 1 being the day of the first infusion of study drug. Patients were assessed daily through Day 7 and then on Days 14, 30 and 90. [0816] Efficacy endpoints included assessment of post-CPB renal injury, expressed as area under the curve (AUC) of percent increase in serum creatinine (sCr) above baseline over time and the maximum percent increase in sCr following CPB, from 24 hours after end of CPB through Day 6; the proportion of patients reaching each KDIGO stage or having no AKI at specified time points through Day 30; and analyses among patients who develop AKI assessing time to recovery or reduction in KDIGO stage. Baseline was defined as sCr value obtained pre- surgery. KDIGO stages are defined as follows:

[0817] The study was designed to enroll 240 patients (120 patients per treatment group). The study randomized 275 patients and dosed 259 patients. Eligibility Criteria [0818] Subjects eligible for this study met the following inclusion criteria: ● Patient was either male or female ≥ 18 years. ● Patient has provided written informed consent, and is willing and able to comply with the requirements of the study protocol, including screening procedures. ● Patient was scheduled for and underwent a non-emergent cardiac surgical procedure involving CPB. Eligible procedures include: o Coronary artery bypass graft (CABG) alone o Aortic valve replacement or repair alone, with or without aortic root repair o Mitral, tricuspid, or pulmonic valve replacement or repair alone o Combined replacement of several cardiac valves o CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair o CABG with combined cardiac valve replacement or repair. ● Patient had the following risk factor(s) for AKI prior to surgery: o Estimated glomerular filtration rate (eGFR) of ≥ 20 and < 30 mL/min/1.73m²; or o eGFR ≥ 30 and < 60 mL/min/1.73m² and ONE of the following Additional Risk Factors (other than age ≥ 75 years); or o eGFR ≥ 60 mL/min/1.73m² and TWO of the following Additional Risk Factors, o eGFR was calculated using the abbreviated MDRD equation (MDRD-4, often referred to as the Levey equation): eGFR = 186.3 x sCr-1.154 x Age-0.203 x [0.742 if Female] x [1.212 if Black]). o Additional Risk Factors were: ● Combined valve and coronary surgery ● Previous cardiac surgery with sternotomy ● Left ventricular ejection fraction (LVEF) ≤ 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days prior to surgery● Diabetes mellitus requiring insulin treatment ● Non-insulin-requiring diabetes with documented presence of at least moderate (+2 or ≥ 100 mg/dL) proteinuria on urine analysis (medical history or dipstick) ● Documented NYHA Class III or IV within 1 year prior to index surgery● Age ≥ 75 years was considered an Additional Risk Factor only for patients with eGFR ≥ 60 mL/min/1.73m². ● Patient presented for surgery without prior evidence of active renal injury, defined as no acute rise in sCr > 0.3 mg/dL or no 50% increase in sCr between the time of Screening and pre-surgery. ● Patient's body mass index (BMI) < 40 at Screening. ● Female patients of childbearing potential (including perimenopausal women who have had a menstrual period within 1 year): o Must have had a negative serum pregnancy test prior to surgery. o Must have agreed (1) to use two forms of effective birth control regimen (at least one barrier method) during the 90-day study period or (2) to maintain total abstinence throughout the 90-day study period. ● Male patients must have agreed to use condoms or other suitable means of pregnancy prevention, such as abstinence, during the 90-day study period. [0819] Subjects were excluded from this study if one or more of the following statements applied: ● Patient had eGFR < 20 mL/min/1.73 m² within 48 hours pre-surgery as measured by MDRD-4. ● Patient had ongoing sepsis or partially treated infection. Sepsis was defined as the presence of a confirmed pathogen, along with fever or hypoperfusion (i.e., acidosis and new onset elevation of liver function tests) or hypotension requiring pressor use prior to surgery. ● Patient had currently active infection requiring antibiotic treatment. ● Patient had an active (requiring treatment) malignancy or history of solid, metastatic or hematologic malignancy within 5 years prior to screening visit for study, with the exception of basal or squamous cell carcinoma of the skin that had been removed. ● Patient was administered iodinated contrast material within 24 hours prior to cardiac surgery. ● Patient was diagnosed with AKI as defined by KDIGO criteria within 48 hours prior to surgery. ● Patient had cardiogenic shock or hemodynamic instability within 24 hours prior to randomization, defined as SBP < 80 mmHg and pulse > 120 beats/min and requirement for inotropes or vasopressors or other mechanical devices, such as intra-aortic balloon pump (IABP). ● Patient needed any of the following within 7 days prior to surgery: defibrillator or permanent pacemaker, mechanical ventilation, IABP, left ventricular assist device (LVAD), or other form of mechanical circulatory support. ● Patient required cardiopulmonary resuscitation within 7 days prior to cardiac surgery. ● Female patient was lactating or breast feeding. ● Patient had history of positive human immunodeficiency virus (HIV) test. ● Patient required treatment with the cytochrome P4501A2 (CYP1A2) inhibitors, ciprofloxacin (Cipro®) and/or fluvoxamine (Luvox®). ● Patient was unwilling or unable to comply with the protocol or cooperate fully with the Investigator or site personnel. ● Patient was not deemed medically stable for the study in the opinion of the Investigator or the subject’s primary nephrologist. ● Patient had a clinical or laboratory diagnosis of shock liver. ● Patient had a procedure during surgery or experienced an intra-operative complication which, in the opinion of the Investigator, precluded dosing of the patient with study drug; examples include implantation of an IABP or LVAD, acute myocardial infarction, cardiac arrest during surgery, and procedure-associated decrease in ejection fraction. ● Patient received an investigational agent within 30 days or 5 half-lives of the agent, whichever is longer, prior to randomization. Study Drug, Dosage, and Mode of Administration [0820] Compound 1 for IV administration was a solution with a concentration of 10 mg/mL. The solution also contained 50% (w/v) PEG 300 NF, 10% (w/v) polysorbate 80 NF, and phosphate buffered saline. The 10 mg/mL stock solution was diluted with normal saline before being administered. The pharmacy at the clinical site prepared 6 mg/mL Compound 1 in an infusion bag on the day the study drug was administered. Volume was administered according to the patient’s weight. [0821] Patients received 2 mg/kg of Compound 1, via IV infusion over 30 minutes, once daily for 4 days. Dosing was based on patient weight collected on Day of Surgery, Pre-surgery. The first post-operative dose was started within 4 hours of completing CPB. The second dose was administered 24 ± 2 hours after completing CPB, and the third and fourth doses were administered 24 ± 2 hours after the respective previous dose. [0822] Reference therapy was a placebo (normal saline) IV infusion. Patients received a volume of normal saline equivalent to that containing the active drug on a mL/kg basis. Duration [0823] Duration of treatment was once daily for 4 days. Patients were followed for up to 90 days after surgery. Criteria for Evaluation [0824] Primary Endpoint: ● Mean AUC of the percent increase in serum creatinine (sCr) above baseline over time, starting from 24 hours after the end of CPB through Day 6. [0825] Secondary Endpoints: ● Change in eGFR from baseline to Day 30. ● Proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 5. ● Length of hospitalization starting from 24 hours after the end of CPB. [0826] Exploratory Endpoints: ● Maximum percent increase in sCr level from baseline that occurs between 24 hours after the end of CPB and Day 6. ● Mean AUC of the percent increase in sCr above baseline over time, starting from the end of CPB through Day 5, through Day 7, through Day 14, and through Day 30. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7, Day 14 and Day 30 analysis. ● Mean percent increase of sCr above Baseline, at 24 hours after the end of CPB, and at Day 3, Day 4, Day 5, and Day 7. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7 analysis. ● Proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 7. ● Proportion of patients by severity of renal injury using KDIGO AKI staging, at 24 hours after the end of CPB, at Day 3, at Day 4, Day 5, Day 7, Day 14, and Day 30. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7, Day 14 and Day 30 analysis. ● Proportion of patients with AKI at 24 hours after the end of CPB, Day 3, Day 4, Day 5, Day 7. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7 analysis. ● Time in days from end of CPB to occurrence of AKI within Days 1-5 and within Days 1- 7. ● Time in days from the occurrence of AKI diagnosed postoperatively through Day 5 to recovery from AKI and through Day 7 to recovery from AKI. Recovery was defined as a post-operative sCr level that returns to or is below pre-operative baseline level within Days 1-30. Baseline was defined as the last sCr level measured during the 24 hours prior to surgery. The occurrence of AKI was the study day on which a KDIGO criterion is first met. ● Time in days to improvement in renal function from the day of occurrence of AKI diagnosed postoperatively through Day 5 and through Day 7. Improvement was defined as a reduction in KDIGO’s stage of AKI severity by 1 or more unit. ● Among patients with AKI diagnosed postoperatively through Day 5, the proportion of patients with renal function recovery, progression, or stabilization at Day 30. The three response variables were defined as: 1) Recovery – Decrease in sCr below pre-operative baseline level; 2) Stabilization - sCr at 30 days that is no higher than its initial rise; and 3) Progression – Increase in sCr at Day 30 that is higher than its initial rise. The same endpoint was analyzed among patients with AKI diagnosed postoperatively through Day 7. ● Slope of decline of the creatinine curve from the day of peak sCr through Day 5, Day 7, Day 14 and Day 30. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7, Day 14 and Day 30 analysis. ● Proportion of patients requiring initiation of any form of renal replacement therapy (RRT) during the index hospitalization and within Days 1-30. ● Proportion of patients developing a composite endpoint comprising the following events: death, worsening of kidney function defined as ≥ 25% decrease in eGFR from baseline, or receiving renal replacement therapy (RRT) during the 30-day and 90-day postoperative periods. ● Changes from baseline in eGFR at Days 4, 7, 14, 30 and 90. Any patient with a new or first occurrence of AKI beyond Day 5 post-surgery was excluded from the Day 7, Day 14, Day 30, and Day 90 analysis. ● Proportion of patients having a ≥ 20 % reduction from baseline in eGFR at Days 2, 3, 4, 7, 14, and 30 and 90. ● Maximal change from baseline in eGFR and sCr through Day 90. ● Changes in circulating or urinary biomarkers of renal injury (e.g., C-reactive protein [CRP], neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule-1 [KIM-1], S-cystatin C). ● Urine output over 12-hour periods for the first 72 hours post-CPB. ● Relationship of post-first infusion Compound 1 blood levels with the primary and secondary endpoints set forth above. [0827] Pharmacokinetic Endpoints: A single blood sample for plasma Compound 1 analysis was collected from all patients immediately (within 2 minutes) at the end of the first Study Drug infusion (Study Day 1). Blood samples for PK analysis were collected relative to the time of the 4th (last) infusion of study drug at the following four time points: pre-dose, immediately after completing the 4th infusion, and at 2 hours and at 6 hours from the start of the 4th infusion. Pharmacokinetic parameters (if sufficient Compound 1 plasma concentration data were available) were obtained from the first 5 evaluable patients enrolled in the study receiving Compound 1 at the 2 mg/kg dose level. If a dose reduction was required, pharmacokinetic parameters from an additional 5 evaluable patients receiving the lower dose of Compound 1 were evaluated, after which no further collections of PK samples were performed. PK endpoints included: ● AUC: area under the concentration-time curve; ● t1/2: half-life ● V_d: volume of distribution ● CL: clearance ● C_{end of infusion}: Compound 1 plasma concentration at the end of the infusion [0828] Safety Parameters: ● Adverse events (AEs) ● Laboratory parameters (hematology, chemistry, hepatic, coagulation, urinalysis) ● Electrocardiograms ● Vital signs ● Physical examinations Concomitant Medications [0829] Without wishing to be bound by theory, the liver may play an important role in the clearance of Compound 1, and CYP1A2 is the main CYP enzyme responsible for the metabolism of Compound 1. In vitro studies investigating the effects of Compound 1 on human CYP P450 isozymes showed no evidence that clinically relevant inhibition of these enzymes is likely to occur, except for a transient inhibition of CYP1A2-mediated metabolism. Based on the results of in vitro studies, Compound 1 is not expected to be an inducer of the most common CYP enzymes at in vivo relevant concentrations. Severe renal injury did not affect the plasma pharmacokinetic profile of Compound 1 in rats, and the vast majority of intact Compound 1 is not eliminated by the kidney. [0830] Patients must not have received an investigational product within 30 days or 5 half- lives, whichever is longer, prior to enrollment. Patients could not participate in another interventional investigational study during the course of this study (until after Day 90). Patients could not use cytochrome P4501A2 (CYP1A2) inhibitors, ciprofloxacin (Cipro®) and/or fluvoxamine (Luvox®) through Day 14. Statistical Methods [0831] All statistical tests were two-sided and were at the 5% level of significance. The recommended sample size was based on feasibility and not on statistical criteria per se; but should be of sufficient size to produce reliable estimates of the potential benefit of Compound 1 versus placebo. Efficacy Analysis [0832] The analyses of the primary and secondary efficacy endpoints were based on the Full Analysis Set (FAS), which included all patients who are randomized and receive any doses of study drug (Compound 1 or placebo). Subset populations included patients who received 1, 2 or 3 doses of study drug. Analyses of the primary endpoint and some secondary endpoints were also conducted in the per-protocol (PP) population defined as patients who received all 4 daily infusions of study drug and experienced no post-operative event that is known to diminish renal function, e.g., sepsis, acute worsening of cardiac function. [0833] The primary efficacy endpoint was the severity of post-CPB renal injury, measured by area-under-the-curve (AUC) of the percent increase of sCr above baseline, starting from 24 hours after the end of CPB through Day 6. For each individual subject, the percent change from baseline at each assessment time point was calculated and the AUC derived using the trapezoidal rule. Mean difference in AUC between Compound 1 and placebo were provided along with 95% confidence interval. Mean difference in AUC was compared between treatments groups using ANOVA model (SAS PROC MIXED procedure) with treatment group included as an independent variable. Safety Analysis [0834] All patients randomized and receiving any part of at least one infusion of study treatment (Compound 1 or placebo) were evaluated for safety. The safety analyses included evaluation of the incidence of treatment-emergent AEs, Grade 3 or greater AEs, serious adverse events (SAEs), and AEs leading to discontinuation of study treatment. Laboratory and vital signs assessments were evaluated over time on study using descriptive statistics. Shift analyses of relevant clinical laboratory parameters were produced showing shifts across low, normal, and high categories. Results [0835] Baseline demographics for the study are described in Table 11: Table 11.

[0836] Baseline clinical characteristics for the study are described in Table 12: Table 12.

[0837] Baseline AKI Risk Factors in subjects with eGFR ≥ 20 and < 30 mL/min/1.73 m² are provided in Table 13: Table 13.

[0838] Baseline AKI Risk Factors in subjects with eGFR ≥ 30 and < 60 mL/min/1.73 m² and one Additional Risk Factor, not age ≥ 75, are provide in Table 14: Table 14.

[0839] Baseline AKI Risk Factors in subjects with eGFR ≥ 60 mL/min/1.73 m² and two Additional Risk Factors are provide in Table 15: Table 15.

[0840] FIG.27 is a graph showing mean AUC of the percent increase in sCr above baseline from Day 2 to Day 6 (starting from 24 hours after the end of CPB). [0841] FIG.28 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (using last observation carried forward). [0842] FIG.29 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (using last observation carried forward). Notably, the study demonstrated a 40% (p=0.155) reduction in the number of patients who experienced a MAKE90 (19 (14.7%) subjects in the Compound 1 arm vs.28 (21.5%) subjects in the placebo arm; adjusted odds ratio 0.60 (95% CI, 0.3-1.21), p = 0.155). [0843] FIG.30 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (with missing values imputed as MAKE30 response). [0844] FIG.31 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (with missing values imputed as MAKE90 response). [0845] FIG.32 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 30 days after surgery (with no imputation). [0846] FIG.33 is a graph showing proportion of subjects developing a major adverse kidney event (MAKE) within 90 days after surgery (with no imputation). [0847] FIG.34 is a graph showing proportion of subjects developing MAKE30, and the proportion that experienced death or worsening of kidney function. [0848] FIG.35 is a graph showing proportion of subjects developing MAKE90, and the proportion that experienced worsening of kidney function. Notably, fewer subjects treated with Compound 1 experienced a decline in eGFR of ≥ 25% at day 90 (6 (5.6%) subjects in the Compound 1 arm vs.18 (16.2%) subjects in the placebo arm, p = 0.012). [0849] FIG.36 is a graph showing mean eGFR at Day 30 (using MMRM analysis). [0850] FIG.37 is a graph showing proportion of subjects diagnosed with AKI (per KDIGO criteria) through Day 5. [0851] FIG.38 is a graph showing mean length of hospitalization. [0852] FIG.39 is a graph showing maximum percent increase in sCr from baseline to Day 6. [0853] FIG.40 is a graph showing mean serum creatinine over time. [0854] FIG.41 is a graph showing proportion of subjects with AKI (per serum creatinine based KDIGO criteria) through Day 7. [0855] FIG.42 is a graph showing time to recovery from AKI (defined as return of serum creatinine to baseline or below) in subjects diagnosed before Day 5. [0856] FIG.43 is a graph showing time to recovery from AKI (defined as return of serum creatinine to baseline or below) in subjects diagnosed before Day 7. [0857] FIG.44 is a graph showing proportion of subjects with ≥ 20% reduction from baseline in eGFR over time. Data for Compound 1 (i.e., terevalefim) is shown on the left and data for placebo is shown on the right for each time point. [0858] FIG.45 is a graph showing proportion of subjects with ≥ 25% reduction from baseline in eGFR over time. Data for Compound 1 (i.e., terevalefim) is shown on the left and data for placebo is shown on the right for each time point. [0859] FIG.46 is a graph showing mean maximum percent change from baseline in eGFR and sCr through Day 90. [0860] Incidence of TEAE (100% Compound 1 vs.97.7% placebo) and grade 3 or higher TEAE (31.8% Compound 1 vs.31.5% placebo) were similar between treatment arms. Incidence of related TEAE (17.8% Compound 1 vs.10.8% placebo) and SAE (41.9% Compound 1 vs. 36.2% placebo) were slightly higher in the Compound 1-treated arm. Incidence of TEAE leading to study drug discontinuation was high in the terevalefim-treated arm (12.4% vs.2.3% placebo). The most frequent TEAE leading to study drug discontinuation in the General Disorders System Organ Class was infusion site pain, asthenia, feeling cold, infusion site irritation, and malaise. Incidence of death was similar between treatment arms (7.8% Compound 1 vs.7.7% placebo). Incidence of serious hepatic events was also similar between arms (1.6% Compound 1 vs.1.5% placebo). Example 17. An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of Compound 1 Injected Intravenously in Stable Adult Maintenance Hemodialysis Subjects [0861] This study was a single center, single-dose, open-label study designed to evaluate the pharmacokinetics (PK) and safety of one infusion of Compound 1 (at 2 mg/kg, administered as an IV infusion over 30 minutes [± 5 minutes]) to subjects on maintenance hemodialysis (HD). This study was performed as described in Example 3, except that only the “off-dialysis” dose of Compound 1, as described therein, was administered. Results [0862] This single center, single-dose, open-label study was designed to evaluate the PK and safety of one infusion of Compound 1 (2 mg/kg, administered as IV infusion over 30 minutes [± 5 minutes]) to subjects with renal failure who were receiving maintenance HD (i.e., HD 3 times weekly). The study was conducted to assess the impact of HD on the PK disposition of Compound 1, as well as characterizing its behavior in subjects with severe renal dysfunction requiring renal replacement therapy. Subjects received Compound 1 > 24 hours preceding the next scheduled HD session. [0863] The primary objective of the study was to measure the PK parameters of a single dose of Compound 1 administered intravenously > 24 hours before the next scheduled HD session in subjects on maintenance HD. The PK results of the study showed the following: x Careful selection of the IV infusion pumps, calibration, and measuring the dispensing accuracy prior to dosing, along with enhanced precautionary measures related to dose calculation and PK sampling, resulted in a low between-subject variability (geometric CV% range was 14.0% to 21.1% across the whole study for C_max and AUC). Even with this additional attention to dose administration, there was still 1 instance of a possible IV infusion distal to the PK sampling site, as judged by the highly anomalous end-of - infusion and mid-infusion concentrations observed in 1 subject. The rest of the plasma concentrations for this subject were comparable to the concentrations of the other subjects in the study. When the concentrations of the suspected contaminated samples were excluded from the estimation of the PK parameters, it was observed that this subject had similar AUC values to the other subjects. Venous stenosis, which is common in ESRD patients undergoing hemodialysis, may be another potential reason to help explain the anomalous Ceoi observed in this subject. ● Following a single IV infusion of Compound 1 over 30 minutes at a dose of 2 mg/kg, maximum plasma Compound 1 concentrations were observed at 0.25 hour post start of infusion in the majority of subjects, instead of at the expected 0.5 hour (end of infusion time). ● There was also one instance of an extravascular drug administration, as determined by the potentially lower Cmax and Tmax values longer than the actual infusion time (0.7 hour) observed for this subject. However, this subject received the complete dose of Compound 1 and had similar AUC values to the other subjects. ● The plasma elimination half-lives of Compound 1 were very short, ranging from 0.6 to 4.4 hours (geometric means [CV%] of 1.87 [66.1%] hours). ● The total CL observed was high (geometric mean [CV%] 5037 [18.3%] mL/min, which is approximately 3.5-fold higher than the hepatic blood flow. ● V_z values were large and had a geometric mean (geometric CV%) of 722 L (55.5%) which is higher than the total body water, indicating distribution of Compound 1 outside the vascular space and extensive distribution into tissues. ● The PK of Compound 1 in patients with end-stage renal disease (ESRD) on stable HD (n=8) observed in this study was comparable to the PK observed previously in healthy volunteers following administration of a single 2 mg/kg dose. The geometric mean C_max values were 452.36 (21.1%) vs.506 ng/mL (28.3%), and the AUC0-last values were 514.26 (14%) vs.685 ngāh/mL (14.0%), in this study versus in previous studies. The differences in AUC values between the studies may be due to the small number of subjects included. [0864] Evaluation of safety was a secondary objective in this study. The safety results of the study showed the following: ● Compound 1 was well tolerated in subjects in this study, who had renal failure and were receiving maintenance HD 3 times weekly. The 5 subjects who experienced TEAEs had only 1 event each; the TEAEs were treatment-related for 3 of the 5 subjects. There were no severe or serious TEAEs and no TEAEs leading to death or study discontinuation. ● There were no clinically relevant changes from baseline and no notable shifts from baseline in any clinical laboratory test results, vital signs measurements, or 12-lead ECG findings. Overall Conclusions [0865] Following a single IV infusion of Compound 1 at a dose of 2 mg/kg, plasma concentrations declined in a biphasic manner with short elimination half-lives (geometric mean of 1.87 hours (66.1%). Compound 1 was rapidly and highly cleared from the circulation. Its large V_z suggests extensive distribution into tissues. [0866] The PK of Compound 1 in ESRD patients in this study was comparable to the PK observed previously in healthy volunteers following administration of a single 2 mg/kg dose, which implies that renal function did not alter the PK of Compound 1. A human ADME study in healthy volunteers confirmed that renal clearance of Compound 1 had minimal impact on its elimination (as parent compound). [0867] Taken together, the results of data from these studies suggest that patients with renal impairment may be administered clinical doses of Compound 1 (2 mg/kg) without dose adjustment based on their renal function. [0868] Compound 1 was well tolerated in subjects with renal failure who were receiving maintenance HD 3 times weekly. The overall safety profile of Compound 1 in this study was consistent with other clinical studies.

Claims

CLAIMS 1. A method comprising a step of administering to a subject or population of subjects in need thereof terevalefim, or a pharmaceutically acceptable salt thereof, wherein the subject is receiving maintenance hemodialysis.

2. The method of claim 1, wherein the subject is experiencing or has been diagnosed with renal failure.

3. The method of claim 1 or 2, wherein the subject is experiencing or has been diagnosed with end-stage renal disease.

4. The method of any one of claims 1-3, wherein the subject has been on maintenance hemodialysis for at least 3 months.

5. The method of any one of claims 1-4, wherein the subject is receiving hemodialysis at least three times per week.

6. The method of any one of claims 1-5, wherein the subject has been determined to have one or more laboratory parameters selected from: serum albumin ≥ 3.0 gm/dL; blood hemoglobin ≥ 10.0 gm/dL; and liver transaminases (ALT, AST) < 2x the upper limit of normal.

7. The method of any one of claims 1-6, wherein the subject has been determined to have a single pool urea (Kt/V) ≥ 1.3 for two consecutive months prior to administration of terevalefim.

8. The method of any one of claims 1-7, wherein a dose of terevalefim is administered on an off-dialysis day.

9. The method of any one of claims 1-8, wherein a dose of terevalefim is administered on an on-dialysis day.

10. The method of any one of claims 1-9, wherein terevalefim is administered regardless of whether or not the subject is receiving hemodialysis on the same day.

11. A method comprising a step of administering to a subject or a population of subjects in need thereof terevalefim, or a pharmaceutically acceptable salt thereof, wherein the subject is or has been simultaneously exposed to a cytochrome P450 inhibitor.

12. A method comprising a step of administering to a subject or a population of subjects in need thereof terevalefim, or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or has received a cytochrome P450 inhibitor.

13. The method of claim 11 or 12, wherein the cytochrome P450 inhibitor is a CYP1A2 inhibitor.

14. The method of claim 13, wherein the CYP1A2 inhibitor is selected from ciprofloxacin, enoxacin, and fluvoxamine.

15. The method of claim 14, wherein the CYP1A2 inhibitor is ciprofloxacin.

16. The method of claim 15, wherein ciprofloxacin is or was administered in a dose of about 500 mg twice daily.

17. The method of claim 14, wherein the CYP1A2 inhibitor is fluvoxamine.

18. A method comprising a step of administering to a subject or a population of subjects in need thereof terevalefim, or a pharmaceutically acceptable salt thereof, wherein the subject is not at risk for Torsades de Pointes.

19. A method comprising a step of administering to a subject or a population of subjects in need thereof terevalefim, or a pharmaceutically acceptable salt thereof, wherein the subject does not have any one or more of the following risk factors: family history of sudden cardiac death; history of risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome); uncontrolled hypertension (e.g., supine systolic blood pressure > 140 mmHg and/or supine diastolic blood pressure >100 mmHg); history or evidence of myocardial infarction, cardiac surgery revascularization (e.g., coronary artery bypass grafting or percutaneous translumincal coronary angioplasty), unstable angina, cerebrovascular accident or stroke or transient ischemic attack, pacemaker, atrial fibrillation, flutter, or non-sustained or sustained ventricular tachycardia, congestive heart failure (Grade III and IV according to New York Heart Association [NYHA] classification), hypokalemia, or unexplained syncope or syncope related to a cardiac arrhythmia; 12-lead ECG with clinically significant abnormalities of rate, rhythm, intervals, or conduction after resting supine for >10 minutes (e.g., flat T waves, evidence of previous myocardial infarction, left ventricular hypertrophy, nonspecific ST-T wave changes, QTcF > 450 msec, PR > 200 msec, QRS > 110 msec, heart rate below 50 or above 90 bpm, second- or third-degree atrioventricular block, complete right bundle branch block, or complete left bundle branch bock); or aspartate aminotransferase, ALT or bilirubin above the upper limit of normal.

20. The method of claim 18 or 19, further comprising monitoring the subject for risk factors over time, and optionally, if risk factors develop, discontinuing administration of terevalefim.

21. The method of claim 18 or 19, further comprising monitoring the subject for risk factors over time, and optionally, if risk factors develop, reducing the dose of terevalefim.

22. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 2 mg/kg once daily.

23. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 4 mg/kg once daily.

24. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 6 mg/kg once daily.

25. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 2 mg/kg twice daily.

26. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 4 mg/kg twice daily.

27. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 6 mg/kg twice daily.

28. The method of any one of claims 1-21, wherein terevalefim is administered in a dose of 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg once or twice daily.

29. The method of any one of the preceding claims, wherein terevalefim is administered intravenously.

30. The method of any one of the preceding claims, wherein terevalefim is administered as a composition comprising: about 6 mg/mL terevalefim; about 20% (w/v) to about 40% (w/v) polyethylene glycol 300; about 5% (w/v) to about 15% (w/v) polysorbate 80; and one or more aqueous components.

31. The method of any one of the preceding claims, wherein terevalefim is administered as a composition comprising: about 6 mg/mL terevalefim; about 20% (w/v) to about 40% (w/v) polyethylene glycol 300; about 5% (w/v) to about 15% (w/v) polysorbate 80; and one or more aqueous components selected from phosphate buffered saline and normal saline.

32. The method of any one of the preceding claims, wherein the subject has undergone renal transplantation.

33. The method of any one of the preceding claims, wherein the subject is in need of improved kidney graft function.

34. The method of any one of the preceding claims, wherein the subject is suffering from or susceptible to delayed graft function.

35. The method of any one of the preceding claims, wherein terevalefim is administered within 30 h after renal transplantation.

36. The method of any one of the preceding claims, wherein the subject is at risk of delayed graft function.

37. The method of any one of the preceding claims, wherein the subject has an average urine output of less than about 50 mL/hour over any consecutive 8 hours in the first 24 hours after transplantation.

38. The method of any one of the preceding claims, wherein the subject has received a kidney from a deceased donor.

39. The method of any one of the preceding claims, wherein the composition is administered according to a regimen established to achieve one or more of: (i) a greater mean estimated glomerular filtration rate at about 6 months or about 12 months after renal transplantation; (ii) a greater mean increase in estimated glomerular filtration rate from baseline at about 6 months or about 12 months after renal transplantation; (iii) a lesser mean serum creatinine concentration at about 6 months or about 12 months after renal transplantation; and (iv) a greater mean decrease in serum creatinine concentration from baseline at about 6 months or about 12 months after renal transplantation, relative to a comparable reference population.

40. The method of claim 39, wherein the reference population has received an otherwise comparable reference composition that does not provide terevalefim.

41. The method of claim 39 or 40, wherein the regimen has been established to achieve a greater mean estimated glomerular filtration rate at about 12 months after renal transplantation, relative to a comparable reference population.

42. The method of any one of claims 39-41, wherein the estimated glomerular filtration rate was calculated using the CKD-EPI equation.

43. The method of any one of claims 39-42, wherein the regimen has been established to achieve a mean estimated glomerular filtration rate of from about 45 mL/min/1.73 m² to about 55 mL/min/1.73 m² at about 12 months after renal transplantation.

44. The method of any one of claims 39-43, wherein the regimen has been established to achieve a greater mean increase in estimated glomerular filtration rate from baseline at about 12 months after renal transplantation.

45. The method of any one of claims 39-44, wherein the regimen has been established to achieve a mean increase in estimated glomerular filtration rate from baseline of from about from about 36 mL/min/1.73 m² to about 45 mL/min/1.73 m² at about 12 months after renal transplantation.

46. The method of any one of claims 39-45, wherein the regimen has been established to achieve a lesser mean serum creatinine concentration at about 12 months after renal transplantation, relative to a comparable reference population.

47. The method of any one of claims 39-46, wherein the regimen has been established to achieve a mean serum creatinine concentration of from about 1.45 mg/dL to about 1.75 mg/dL at about 12 months after renal transplantation.

48. The method of any one of claims 39-47, wherein the regimen has been established to achieve a greater mean decrease in serum creatinine concentration from baseline at about 12 months after renal transplantation.

49. The method of any one of claims 39-48, wherein the regimen has been established to achieve a mean decrease in serum creatinine concentration from baseline of from about from about 6.1 mg/dL to about 6.5 mg/dL at about 12 months after renal transplantation.

50. The method of any one of claims 39-49, wherein the regimen has further been established to achieve one or more of: (v) a greater incidence of achieving 1200 cc urine output over a 24 hour period within 28 days after renal transplantation; (vi) a shorter median time to achieve 1200 cc urine output over a 24 hour period within 28 days after renal transplantation; (vii) a lesser mean number of dialysis sessions per subject within 28 days after renal transplantation; (viii) a shorter mean duration of dialysis within 28 days after renal transplantation; (ix) a shorter mean length of hospitalization after renal transplantation; (x) a lower incidence of graft failure within 12 months after renal transplantation; (xi) a lesser mean serum creatinine concentration at about 7, 14, or 28 days after renal transplantation; (xii) a greater mean decrease in serum creatinine concentration from baseline at about 7 days, about 14 days, or about 28 days after renal transplantation; (xiii) a greater mean estimated glomerular filtration rate at about 7, 14, or 28 days after renal transplantation; and (xiv) a greater mean increase in estimated glomerular filtration rate from baseline at about 7 days, about 14 days, or about 28 days after renal transplantation, relative to a comparable reference population.

51. The method of any one of claims 39-50, wherein the regimen has further been established to achieve one or more of: (xv) a greater proportion of patients with an estimated glomerular filtration rate greater than about 30 mL/min/1.73 m² at about 30 days, about 90 days, about 6 months or about 12 months after renal transplantation; (xvi) a lesser proportion of patients with (1) PNF (defined as a continuous requirement for dialysis for at least 60 days after renal transplantation); (2) DGF (assessed by proportion of patients requiring dialysis within 7 days after renal transplantation); or (3) SGF (defined as having a SCr < 3 mg/dL within the first 7 days after renal transplantation without dialysis required); (xvii) a shorter mean length of hospitalization after renal transplantation; and (xviii) a lesser number of days a patient remains dialysis dependent within the first 30 days after renal transplantation, relative to a comparable reference population.

52. The method of any one of the preceding claims, wherein the subject is suffering from an active malignancy or has suffered from a solid, metastatic or hematologic malignancy.

53. The method of any one of the preceding claims, wherein the subject has not been assessed for an active malignancy or a history of a solid, metastatic or hematologic malignancy.

54. The method of any one of the preceding claims, wherein the subject has undergone a cardiac surgical procedure involving cardiopulmonary bypass.

55. The method of any one of the preceding claims, wherein the cardiac surgical procedure involving cardiopulmonary bypass is coronary artery bypass graft; aortic valve replacement or repair with or without aortic root repair; mitral, tricuspid, or pulmonic valve replacement or repair; combined replacement of several cardiac valves; coronary artery bypass graft with aortic, mitral, tricuspid, or pulmonic valve replacement or repair; or coronary artery bypass graft with combined cardiac valve replacement or repair.

56. The method of any one of the preceding claims, wherein the subject is at risk of acute kidney injury following cardiac surgery involving cardiopulmonary bypass.

57. The method of any one of the preceding claims, wherein the subject has one or more of the following risk factors: (i) estimated glomerular filtration rate (eGFR) of ≥ 20 and < 30 mL/min/1.73m²; (ii) eGFR ≥ 30 and < 60 mL/min/1.73m2 and one of the Additional Risk Factors (other than age ≥ 75 years); or (iii) eGFR ≥ 60 mL/min/1.73m² and two of the Additional Risk Factors, wherein the Additional Risk Factors are selected from: combined valve and coronary surgery; previous cardiac surgery with sternotomy; left ventricular ejection fraction (LVEF) < 35% by invasive or noninvasive diagnostic cardiac imaging within 90 days prior to surgery; diabetes mellitus requiring insulin treatment; non-insulin-requiring diabetes with documented presence of at least moderate (+2 or > 100 mg/dL) proteinuria on urine analysis (via medical history or dipstick); documented New York Heart Association (NYHA) Class III or IV within 1 year prior to index surgery; and age ≥ 75 years only if eGFR ≥ 60 mL/min/1.73m².

58. The method of any one of the preceding claims, wherein, prior to the cardiac surgery, the subject had an eGFR of ≥ 20 to < 30 mL/min/1.73m² and at least one AKI risk factor selected from combined valve and coronary artery bypass graft (CABG) surgery; left ventricular ejection fraction of ≤ 35%; diabetes mellitus requiring insulin treatment; non-insulin requiring diabetes with moderate (+2) proteinuria; and NYHA class III or IV within 1 year prior to surgery.

59. The method of any one of the preceding claims, wherein, prior to the cardiac surgery, the subject had an eGFR of ≥ 30 to < 60 mL/min/1.73m² and at least one AKI risk factor selected from combined valve and CABG surgery; previous cardiac surgery with sternotomy; left ventricular ejection fraction of ≤ 35%; diabetes mellitus requiring insulin treatment; non-insulin requiring diabetes with moderate (+2) proteinuria; and NYHA class III or IV within 1 year prior to surgery.

60. The method of any one of the preceding claims, wherein, prior to the cardiac surgery, the subject had an eGFR of ≥ 60 mL/min/1.73m² and at least two AKI risk factors selected from combined valve and CABG surgery; previous cardiac surgery with sternotomy; left ventricular ejection fraction of ≤ 35%; diabetes mellitus requiring insulin treatment; non-insulin requiring diabetes with moderate (+2) proteinuria; NYHA class III or IV within 1 year prior to surgery; and age ≥ 75 years.

61. The method of any one of the preceding claims, wherein the subject does not have prior evidence of active renal injury (e.g., no acute rise in serum creatinine > 0.3 mg/dL).

62. The method of any one of the preceding claims, wherein the subject has eGFR ≥ 20 mL/min/1.73m² within 48 hours pre-surgery.

63. The method of any one of the preceding claims, wherein the subject: does not have ongoing sepsis or partially treated infection; does not have currently active infection requiring antibiotic treatment; does not have active malignancy or history of solid, metastatic or hematologic malignancy within 5 years prior to administration, with the exception of basal or squamous cell carcinoma of the skin that has been removed; has not been administered iodinated contrast material within 24 hours prior to surgery; and/or is not diagnosed with AKI as defined by KDIGO criteria within 48 hours prior to surgery.

64. The method of any one of the preceding claims, wherein terevalefim is administered according to a regimen established to achieve a reduction in the number of subjects who experienced a major adverse kidney event within 90 days after the cardiac surgery (MAKE90), relative to a comparable reference population.

65. The method of any one of the preceding claims, wherein terevalefim is administered according to a regimen established to achieve a reduction in the number of subjects who experienced a reduction in eGFR of ≥ 25% at 90 days after the cardiac surgery.

66. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve a reduction in the number of subjects who experienced a major adverse kidney event within 30 days after the cardiac surgery (MAKE30), relative to a comparable reference population.

67. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve a reduction in serum creatinine within 5 days after the cardiac surgery, relative to a comparable reference population.

68. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve an increase in eGFR, as measured from baseline to about day 30 after the cardiac surgery, relative to a comparable reference population.

69. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve an increase in eGFR, as measured from baseline to about day 60 after the cardiac surgery, relative to a comparable reference population.

70. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve an increase in eGFR, as measured from baseline to about day 90 after the cardiac surgery, relative to a comparable reference population.

71. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve a reduction in proportion of subjects diagnosed with acute kidney injury (AKI) according to the KDIGO criteria as assessed or determined within about 5 days after cardiac surgery, relative to a comparable reference population.

72. The method of any one of the preceding claims, wherein the terevalefim is administered according to a regimen established to achieve a reduction in length of hospitalization, as measured from 24 hours after the end of the cardiopulmonary bypass, relative to a comparable reference population.

73. The method of any one of the preceding claims, wherein terevalefim is administered according to a regimen established to achieve greater mean AUC of the percent increase in serum creatinine above baseline, starting from 24 hr after the end of CPB through Day 6, relative to a comparable reference population.

74. The method of claim 73, wherein the reference population has received an otherwise comparable reference composition that does not provide terevalefim.

75. The method of any one of the preceding claims, wherein terevalefim is administered according to a regimen established to achieve one or more of the following: greater mean AUC of the percent increase in serum creatinine above baseline, starting from 24 hr after the end of CPB through Day 6; greater maximum percent increase in sCr level from baseline Day 5; greater mean percent increase in serum creatinine above baseline over time starting from the end of CPB through Day 5, through Day 7, through Day 14, and through Day 30; greater mean percent increase of sCr above baseline at 24 hr after the end of CPB, and at Day 3, Day 4, Day 5, and Day 7; lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 5; lesser proportion of subjects who are diagnosed with AKI per KDIGO criteria through Day 7; greater proportion of patients with less severe renal injury using KDIGO AKI staging at 24 hr after the end of CPB, at Day 3, at Day 4, Day 5, Day 7, Day 14, and Day 30; lesser proportion of patients with AKI at 24 hr after the end of CPB, Day 3, Day 4, Day 5, Day 7; lesser time in days from the occurrence of AKI diagnosed postoperatively through Day 5 to recovery from AKI and through Day 7 to recovery from AKI; lesser time in days to improvement in renal function from the day of occurrence of AKI diagnosed postoperatively through Day 5 and through Day 7; greater proportion of patients with renal function recovery, progression, or stabilization among patients with AKI diagnosed postoperatively at Day 30; greater proportion of patients with renal function recovery, progression, or stabilization through Day 5, among patients with AKI diagnosed postoperatively; greater slope of decline of the creatinine curve from the day of peak sCr through Day 5, Day 7, Day 14 and Day 30; lesser proportion of patients requiring initiation of any form of renal replacement therapy up to Day 30; shorter length of index hospital stay through Day 90; lesser proportion of patients developing a composite endpoint comprising the following events: death, worsening of kidney function during the 30-day post-operative period, and worsening of kidney function during 90-day post-operative period; greater change from baseline in eGFR at Days 4, 7, 14, 30 and 90; lesser proportion of patients having a ≥ 20 % reduction from baseline in eGFR at Days 2, 3, 4, 7, 14, and 30 and 90; greater maximal change from baseline in eGFR and sCr through Day 90; and greater urine volume over 12-hour periods for the first 72 hours post-CPB, relative to a comparable reference population.

76. The method of any one of the preceding claims, wherein the first dose of terevalefim is administered within four hours of cardiac surgery involving CPB.

77. The method of any one of the preceding claims, wherein terevalefim is administered within three hours of the cardiac surgery.

78. The method of any one of the preceding claims, wherein terevalefim is administered within two hours of the cardiac surgery.

79. The method of any one of the preceding claims, wherein terevalefim is administered within one hour of the cardiac surgery.

80. The method of any one of the preceding claims, wherein terevalefim is administered within 30-45 minutes of the cardiac surgery.

81. The method of any one of the preceding claims, wherein the subject is suffering from or susceptible to acute lung injury or acute respiratory distress syndrome.

82. The method of any one of the preceding claims, wherein the subject is suffering from or susceptible to pneumonia.

83. The method of any one of the preceding claims, wherein the subject is suffering from pneumonia confirmed by chest imaging.

84. The method of any one of the preceding claims, wherein the subject is suspected of having or has been diagnosed with a viral infection.

85. The method of any one of the preceding claims, wherein the subject is suspected of having or has been diagnosed with a respiratory viral infection.

86. The method of any one of the preceding claims, wherein the subject is suspected of having or has been diagnosed with COVID-19.

87. The method of any one of the preceding claims, wherein the subject is hospitalized with COVID-19 pneumonia.

88. The method of any one of the preceding claims, wherein the subject has a score of 4 or 5 on the WHO’s disease severity scale assessment 8-point Ordinal Scale (e.g., as described in Example 9).

89. The method of any one of the preceding claims, wherein the subject has a fraction of inspired oxygen (FiO₂) of greater than 40%.

90. The method of any one of the preceding claims, wherein the subject is receiving or has received mechanical ventilation.

91. The method of any one of the preceding claims, wherein the subject is receiving or has received extracorporeal membrane oxygenation (ECMO).

92. The method of any one of the preceding claims, wherein the subject has impaired kidney function.

93. The method of any one of the preceding claims, wherein the subject is receiving or has received renal replacement therapy.

94. The method of any one of the preceding claims, wherein the subject is not suffering from an active malignancy and has not suffered from a solid or hematologic malignancy.

95. The method of any one of the preceding claims, wherein the subject is suffering from an active malignancy or has suffered from a solid or hematologic malignancy.

96. The method of any one of the preceding claims, wherein the subject has not been assessed for an active malignancy or a history of a solid or hematologic malignancy.

97. The method of any one of the preceding claims, wherein the subject is suffering from or susceptible to pulmonary edema, shock-associated acute lung injury, chemically induced acute lung injury, radiation-induced acute lung injury, acute lung injury associated with hemorrhagic shock, blunt trauma injury to the lung, ischemia-reperfusion lung injury, or thermally induced acute lung injury.

98. The method of any one of the preceding claims, wherein the composition is administered according to a regimen established to achieve, when administered to a relevant population, increased lung function relative to a comparable reference population.

99. The method of any one of the preceding claims, wherein the composition is administered according to a regimen established to achieve, when administered to a relevant population, one or more of: (i) increased proportion of patients alive without need for mechanical ventilation and free of need for renal replacement therapy on an ongoing basis at Day 28; (ii) reduced all-cause mortality; (iii) increased proportion of patients not requiring mechanical ventilation at Day 28; (iv) increased proportion of patients not requiring renal replacement therapy on an ongoing basis at Day 28; (v) increased number of ventilator-free days through Day 28; (vi) reduced proportion of patients requiring initiation of mechanical ventilation and/or ECMO through Day 28; (vii) reduced proportion of patients requiring initiation of renal replacement therapy through Day 28; (viii) reduced number of days to renal recovery in subjects who were on RRT at time of randomization; (ix) reduced number of ICU days through Day 28; (x) reduced score on an ordinal scale at Day 28; and (xi) reduced number of days to hospital discharge from randomization, relative to a comparable reference population.

100. The method of any one of the preceding claims, wherein the composition is administered according to a regimen established to achieve, when administered to a relevant population, increased kidney function relative to a comparable reference population.