WO2021183774A1 - Traitement de la détresse respiratoire aiguë - Google Patents

Traitement de la détresse respiratoire aiguë Download PDF

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Publication number
WO2021183774A1
WO2021183774A1 PCT/US2021/021926 US2021021926W WO2021183774A1 WO 2021183774 A1 WO2021183774 A1 WO 2021183774A1 US 2021021926 W US2021021926 W US 2021021926W WO 2021183774 A1 WO2021183774 A1 WO 2021183774A1
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WIPO (PCT)
Prior art keywords
compound
subject
population
lung
injury
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PCT/US2021/021926
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English (en)
Inventor
Swarnalatha PAKA
Itzhak D. Goldberg
Jay R. VENKATESAN
III John Francis NEYLAN
Shakil ASLAM
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Angion Biomedica Corp.
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Publication of WO2021183774A1 publication Critical patent/WO2021183774A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • ARDS Acute lung injury
  • ARDS the more severe acute respiratory distress syndrome
  • ALI Acute lung injury
  • ARDS the more severe acute respiratory distress syndrome
  • ARDS can be associated with various events and/or conditions, including infections, and can be associated with significant mortality. Incidence of ARDS is between 150,000 and 200,000 cases per year in the United States, resulting in between 40,000 and 80,000 deaths per year. Additionally, more than 200 million people worldwide are affected by asthma, and more than 60 million suffer from COPD.
  • ARDS acute respiratory distress syndrome
  • Current supportive measures for patients in acute respiratory distress are often associated with adverse side effects; there thus remains a need for new therapies.
  • 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) a respiratory disease, disorder or condition (e.g., ARDS), which methods may comprise, for example administering a small molecule mimetic of hepatocyte growth factor (HGF, also known as scatter factor (SF)).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • the present disclosure provides methods of treating COVID-19 pneumonia, such methods comprising administering a small molecule mimetic of HGF/SF.
  • HGF/SF is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis, and angiogenesis
  • Gazdhar A. et al. Hum. Gene Ther. 2013 Jan;24(l): 105-16; Watanabe, M. et al. MolTher. 2005 July; 12(1)58-67; Kato, N. et al. Centr. Nerv. Syst. Agents Med. Chem.2009 Dec;9(4):300-6; Romero-Vasquez, F. et al. Biochim. Biophys. Acta 2012 Oct;1822(10):1590-9; Sala, V. et al. CellMol. Life Sci. 2011 May;58(10: 1703-17; Aharinejad, S. et al. Lancet 2004 May 8;363(9420): 1503-8; Vivekananda,
  • Compound 1 can enhance oxygenation, gas exchange, and recovery in subjects suffering from or susceptible to respiratory disease(s), disorder(s) and/or condition(s) (e.g., as may be associated with and/or result from damage, injury, infection, etc.), specifically including ARDS.
  • subjects are receiving therapy with, or experience lung function that would benefit from, extracorporeal membrane oxygenation (ECMO).
  • ECMO extracorporeal membrane oxygenation
  • HGF may mitigate both the decline in surfactant proteins and the inhibition of AT2 cell proliferation caused by hyperoxia (Zhong, L.L., et al. J. Cent. S. Univ. Med. Sci. 2007 Nov 30; 32(6): 1051-57)
  • HGF may mitigate both the decline in surfactant proteins and the inhibition of AT2 cell proliferation caused by hyperoxia
  • certain studies have indicated a potential role for HGF in lung repair and recovery from ALLARDS (Panganiban, R.A.M., et al., ActaPharm. Sinica 2011; 32:12-20; Yanagita, K., et al. J. Biol. Chem. 1993 Oct 5; 268(28)21212-7, Ware, L.B., et al. Am. J.
  • Compound 1 is an HGF mimic. HGF has been established to activate the c-Met receptor, and to stimulate various regenerative downstream processes; it is not thought to activate FGF receptors.
  • the present disclosure demonstrates, in a variety of respiratory (e.g., ARDS) models, that pathway activation (e.g., by Compound 1) achieves improved outcomes.
  • the present disclosure demonstrates certain beneficial effects of Compound 1 relevant to respiratory diseases, disorders and conditions, and provides technologies for treating such diseases, disorders and conditions with Compound 1 therapy as described herein.
  • FIG. 1A is a graph of proliferation of endothelial cells treated with HGF vs. Compound 1.
  • FIG. IB is a graph of proliferation of bronchial cells treated with HGF vs. Compound 1.
  • FIG. 1C is a graph of proliferation of fibroblasts treated with HGF vs. Compound 1
  • FIG. 2A is a graph showing concomitant Compound 1 therapy reduces lung weight wet/dry ratio in a bleomycin mouse model.
  • FIG. 2B depicts exemplary H&E stained lung tissue samples from a bleomycin mouse model.
  • FIG. 2C is a graph showing delayed Compound 1 therapy reduces lung weight wet/dry ratio in a bleomycin mouse model.
  • FIG. 3A is a graph showing survival of mice in which TGFpi expression was induced.
  • FIG. 3B is a graph showing that Compound 1 treatment decreased pulmonary cell death in a mouse model of induced TGFpi expression.
  • FIG. 3C is a graph showing that Compound 1 treatment improved pulmonary epithelial regeneration (by PCNA) in a mouse model of induced TGF i expression.
  • FIG. 4A is a graph of mean lung injury score from lung tissue samples from a LPS- induced shock associated ALI mouse model.
  • FIG. 4B depicts exemplary H&E stained lung tissue samples from a LPS-induced shock associated ALI mouse model.
  • FIG. 4C is a graph showing that Compound 1 treatment decreased apoptotic cell death in a LPS-induced shock associated ALI mouse model.
  • FIG. 5A is a graph of survival in Compound 1 vs. vehicle cohorts in mice with Ch- induced lung injury.
  • FIG. 5B is a graph of BALF protein concentration in Compound 1 vs. vehicle cohorts in mice with Ch-induced lung injury.
  • FIG. 6A is a graph showing increased pulmonary output in Compound 1 vs. vehicle cohorts in a PPE-induced emphysema rat model.
  • FIG. 6B is a graph showing increased arterial oxygen concentration in Compound 1 vs. vehicle cohorts in a PPE-induced emphysema rat model.
  • FIG. 7A is a graph of mean lung injury score from lung tissue samples in a hemorrhagic shock-induced lung injury rat model.
  • FIG. 7B depicts exemplary H&E stained lung tissue samples from a hemorrhagic shock-induced lung injury rat model.
  • FIG. 8A is a graph of end expiration volume in a pulmonary ischemia-reperfusion rat model.
  • FIG. 8B is a graph of blood pH in a pulmonary ischemia-reperfusion rat model.
  • FIG. 8C and FIG. 8D are graphs of blood oxygen levels in a pulmonary ischemia-reperfusion rat model.
  • FIG. 8E is a graph of pulmonary epithelial regeneration (PNCA) in a pulmonary ischemia-reperfusion rat model.
  • PNCA pulmonary epithelial regeneration
  • FIG. 9A is a graph of lung weight wet/dry ratio after Compound 1 vs vehicle treatment in canines with warm lung ischemia-reperfusion injury.
  • FIG. 9B is a graph of lung function after Compound 1 vs vehicle treatment in canines with warm lung ischemia-reperfusion injury.
  • FIG. 9C is a graph of IL-1 levels after Compound 1 vs vehicle treatment in canines with warm lung ischemia-reperfusion injury.
  • FIG. 9D is a graph of IL-6 levels after Compound 1 vs vehicle treatment in canines with warm lung ischemia-reperfusion injury.
  • FIG. 9E depicts exemplary H&E stained lung sections from canines with warm lung ischemia-reperfusion injury.
  • FIG. 10 is a graph showing lung weight wet/dry ratio after delayed Compound 1 treatment vs. vehicle in a bleomycin mouse model.
  • FIG. 11A is a graph showing survival in mice treated with Compound 1 vs. vehicle in a murine model of pulmonary TGFp l induction.
  • FIG. 1 IB is a graph showing that Compound 1 decreased pulmonary cell death in murine model of pulmonary TGF l induction.
  • FIG. 11C is a graph showing that Compound 1 increased pulmonary epithelial regeneration (PCNA) in murine model of pulmonary TGFp l induction.
  • FIG. 11D depicts exemplary micro CT images of inflated and formalin fixed lungs, which suggest that treatment with Compound 1 preserves pulmonary microarchitecture murine model of pulmonary TGF l induction.
  • PCNA pulmonary epithelial regeneration
  • FIG. 12A is a graph showing Compound 1 attenuated mortality in sheep subjected to smoke inhalation and burn injury.
  • FIG. 12B is a graph showing Compound 1 improved pulmonary gas exchange in sheep subjected to smoke inhalation and bum injury.
  • FIG. 13A is a graph showing lung hydroxyproline levels in Compound 1 vs. vehicle cohorts for a genetic (TSK1/+) mouse model of systemic sclerosis including pulmonary fibrosis.
  • FIG. 13B is a graph showing extent of Sirius red staining in lung tissue samples from a genetic (TSK1/+) mouse model of systemic sclerosis including pulmonary fibrosis.
  • FIG.13C depicts exemplary Sirius red stained lung tissue samples from a genetic (TSK1/+) mouse model of systemic sclerosis including pulmonary fibrosis.
  • FIG. 14 is a graph showing lung hydroxyproline levels in a TGFpi -induced lung fibrosis in mouse model.
  • FIG. 15A is a graph showing pulmonary apoptosis (determined by TUNEL) in mice exposed to ionizing radiation.
  • FIG. 15B is a graph showing caspase 3 levels in mice exposed to ionizing radiation.
  • FIG. 15C is a graph showing lung inflammation as judged by staining for F4/80 in mice exposed to ionizing radiation.
  • FIG. 16A is a graph showing lung mass in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 16B is a graph showing lung collagen-1 levels in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 16C is a graph showing extent of Sirius red staining in lung tissue samples from mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 16D is a graph showing lung TGFpi levels in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 17A is a graph showing kidney TGFfFl levels in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 17B is a graph showing liver TGFpi levels in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 17C is a graph showing liver aSMA levels in mice exposed to radiation that received Compound 1 vs vehicle.
  • FIG. 18A is a graph showing arterial Pa02 for rats treated with Compound 1 vs vehicle in a (PPE)-induced emphysema rat model.
  • FIG. 18B is a graph showing arterial PaC02 for rats treated with Compound 1 vs vehicle in a (PPE)-induced emphysema rat model.
  • FIG. 19A is a graph showing pulmonary apoptosis (caspase 3 staining) at 24 hr reperfusion in rats with ischemia-reperfusion injury.
  • FIG. 19B depicts exemplary H&E stained lung tissue samples from rats with ischemia-reperfusion injury.
  • FIG. 20A is a graph showing end-expiration air volume following pulmonary 90 min ischemia-reperfusion in rats treated with Compound 1 vs vehicle.
  • FIG. 20B is a graph showing blood pH prior to sacrifice in rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 20C is a graph showing blood oxygen tension (p02) prior to sacrifice in rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 20D is a graph showing blood oxygen saturation (s02) prior to sacrifice in rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 20E is a graph showing pulmonary epithelial regeneration (PCNA immunoreactivity) in rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 20F is a graph showing pulmonary cell death in rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 20G depicts exemplary lung tissue samples from rats with ischemia-reperfusion injury treated with Compound 1 vs vehicle.
  • FIG. 21A depicts exemplary scans of rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 21B is a graph showing blood pH in rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 21C is a graph showing pC02 in rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 21D is a graph showing p02 in rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 21E is a graph showing s02 in rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 21F depicts exemplary H&E stained lung tissue samples from rats with syngeneic lung transplantation injury that received Compound 1 vs vehicle.
  • FIG. 22A is a graph showing survival in sheep subjected to smoke inhalation and 40% body surface burn injury treated with Compound 1 vs vehicle.
  • FIG. 22B is a graph showing pulmonary gas exchange in sheep subjected to smoke inhalation and 40% body surface burn injury treated with Compound 1 vs vehicle.
  • FIG. 22C is a graph showing cumulative fluid balance in sheep subjected to smoke inhalation and 40% body surface burn injury treated with Compound 1 vs vehicle.
  • FIG. 22D depicts exemplary H&E stained lung tissue samples from sheep subjected to smoke inhalation and 40% body surface bum injury treated with Compound 1 vs vehicle.
  • FIG. 23A is a graph showing lung weight wet/dry ratio in mice treated with Compound 1 vs vehicle in a bleomycin model.
  • FIG. 23B depicts exemplary H&E stained lung tissue samples from mice treated with Compound 1 vs. vehicle in a bleomycin mouse model.
  • FIG. 24 is a graph showing lung weight wet/dry ratio in mice treated with Compound 1 vs vehicle 24 hours after administration of bleomycin in a bleomycin model.
  • FIG. 25A is a graph showing pulmonary hydroxyproline levels in mice treated with Compound 1 vs vehicle in a mouse model of pulmonary fibrosis.
  • FIG. 25B is a graph showing extent of pulmonary Sirius red staining in mice treated with Compound 1 vs vehicle in a mouse model of pulmonary fibrosis.
  • FIG. 26A is a graph showing endothelial (HUVEC) cell proliferation stimulated by HGF/SF or Compound 1.
  • FIG. 26B is a graph showing MRC-5 proliferation in the presence of HGF/SF or Compound 1.
  • FIG. 27 is graph showing human bronchial epithelial cell (HBEC) proliferation stimulated by HGF/SF or Compound 1.
  • FIG. 28B is a graph showing proliferation of knockdown bPAECs treated with Compound 1.
  • FIG. 28C is a graph showing proliferation of knockdown bPAECs treated with HGF/SF.
  • FIG. 29 is a graph showing bPAEC migration when treated with Compound 1 or HGF/SF.
  • FIG. 30 depicts exemplary human bronchial epithelial cells stained with FITC- labeled Annexin-V, treated with either Compound 1 or vehicle.
  • FIG. 31A is a graph showing expiration volume of rats treated with Compound 1 (15 mg/kg or 45 mg/kg) vs vehicle in a rodent model of elastase-induced emphysema.
  • FIG. 31B is a graph showing arterial oxygen concentration of rats treated with Compound 1 (15 mg/kg or 45 mg/kg) vs vehicle in a rodent model of elastase-induced emphysema.
  • FIG. 31C is a graph showing mean linear intercept of rats treated with Compound 1 (15 mg/kg or 45 mg/kg) vs vehicle in a rodent model of elastase-induced emphysema.
  • FIG. 31D exemplary lung tissue samples stained with H&E obtained from rats treated with Compound 1 (15 mg/kg or 45 mg/kg) vs vehicle in a rodent model of elastase-induced emphysema.
  • FIG. 32A is a graph showing serum creatinine levels in dogs subjected to renal ischemia-reperfusion and treated with immediate or delayed Compound 1.
  • FIG. 32B is a graph showing BUN levels in dogs subjected to renal ischemia-reperfusion and treated with immediate or delayed Compound 1.
  • FIG. 33A is a graph showing percentage of FhC -exposed Annexin-V positive cells treated with Compound 1 vs vehicle.
  • FIG. 33B is a graph showing percentage of Annexin-V and Propidium Iodide negative (healthy live) cells treated with Compound 1 vs vehicle.
  • FIG. 34 is a graph showing Annexin-V and propidium iodide staining of 4MBr-5 cells challenged with H2O2 and treated with Compound 1 or HGF.
  • FIG. 35 is a graph showing mouse NIH/3T3 cell proliferation when exposed to Compound 1 or HGF.
  • FIG. 36A shows survival of mice exposed to radiation that were treated with Compound 1 vs vehicle.
  • FIG. 36B is a graph showing BALF turbidity in radiation-exposed mice that were treated with Compound 1 vs vehicle.
  • FIG. 38 is a Kaplan-Meier survival graph from a TGFpi -induced acute lung injury mouse model.
  • FIG. 39A shows percent survival of Compound 1 vs vehicle treatment in a first study of an orthotopic glioma model.
  • FIG. 39B shows percent survival of Compound 1 vs vehicle treatment in a second study of an orthotopic glioma model.
  • FIG. 40A shows colon tumor size of Compound 1 vs vehicle treatment in a human colon tumor xenograft model.
  • FIG. 41A shows pancreatic tumor volume of Compound 1 vs vehicle treatment in a human pancreatic tumor xenograft model.
  • FIG. 41B shows pancreatic tumor weight of Compound 1 vs vehicle treatment in a human pancreatic tumor xenograft model.
  • FIG. 42 provides XRPD pattern of Compound 1 Lot I.
  • FIG. 43 provides TGA curve of Compound 1 Lot I.
  • FIG. 44 provides DSC thermogram of Compound 1 Lot I.
  • FIG. 45 provides single crystal X-ray crystallography of Compound 1 Form A. N and S atoms are labeled; unlabeled non-hydrogen atoms are carbon.
  • FIG. 46 provides XRPD pattern of Compound 1 Form A calculated from single crystal X-ray diffraction data.
  • FIG. 47 provides XRPD pattern of Compound 1 Form A.
  • FIG. 48 provides TGA curve of Compound 1 Form A.
  • FIG. 49 provides DSC thermogram of Compound 1 Form A.
  • FIG. 50 provides a comparison of XRPD patterns of Compound 1 Lot I and Compound 1 Single Crystal Form A.
  • administering 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.)
  • 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.
  • 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.
  • 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.
  • one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure.
  • administration may be parenter
  • 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.
  • administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • 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.
  • IV intravenous
  • 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.
  • 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.
  • 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.
  • a 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.
  • 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.
  • 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.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspension
  • salt form 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).
  • 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.
  • 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.
  • the term “subject” refers 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.
  • 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.
  • a subject displays one or more symptoms or characteristics of a disease, disorder or condition.
  • a subject does not display any symptom or characteristic of a disease, disorder, or condition.
  • a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition.
  • 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.
  • Compound 1 has a CAS Registry No. of 1070881-42-3 and is also known by at least the following names:
  • Compound 1 has a structure that can exist in various tautomeric forms, including (E)-3-[2-(2-thienyl)vinyl]-lH-pyrazole and (E)-5-[2-(2- thienyl)vinyl]-lH-pyrazole, or any mixture thereof.
  • 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]-lH-pyrazole.
  • the present disclosure contemplates use of all tautomeric forms of Compound 1.
  • 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, WO 2009/064422, the entirety of each of which is hereby incorporated by reference).
  • 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).
  • Compound 1 s HGF mimic capability imparts a variety of beneficial attributes and activities.
  • certain subjects may receive additional benefit (e.g., improved kidney function) from therapy as described herein.
  • 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.
  • a form such as a salt form.
  • pharmaceutically acceptable salts are well known in the art.
  • 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.
  • a composition is substantially free of amorphous Compound 1.
  • 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%).
  • a composition comprises at least about 90% by weight of crystalline Compound 1.
  • a composition comprises at least about 95% by weight of crystalline Compound 1.
  • a composition comprises at least about 97%, about 98%, or about 99% by weight of crystalline Compound 1.
  • 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.
  • a crystalline solid form of Compound 1 is Form A.
  • Form A of Compound 1 is unsolvated (e.g., anhydrous).
  • a Form A of Compound 1 is prepared according to the procedure described in Example 48.
  • 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.
  • 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. [0077] 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:
  • Form A is characterized by one or more of the following:
  • 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.
  • Compound 1 refers to (E)-3-[2-(2- thienyl)vinyl]-lH-pyrazole in any available form, such as, e.g., a tautomer, salt form, and/or solid form thereof.
  • 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 W02010/005580 on January 14, 2010, the entirety of which is hereby incorporated by reference.
  • Compound 1 is provided and/or utilized in accordance with the present disclosure as a liquid formulation.
  • a liquid formulation comprises Compound 1 in a concentration of from about 0.8 mg/mL to about 10 mg/mL.
  • a liquid formulation comprising Compound 1 further comprises 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).
  • a liquid formulation comprising Compound 1 further comprises 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).
  • a liquid formulation comprising Compound 1 is aqueous. In some embodiments, a liquid formulation comprising Compound 1 further comprises saline solution, buffer, or buffered saline solution (e.g., phosphate-buffered saline).
  • 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).
  • the liquid formulation is aqueous.
  • the liquid formulation further comprises phosphate- buffered saline and/or normal saline.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components selected from phosphate buffered saline and normal saline.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components selected from phosphate buffered saline and normal saline.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components selected from phosphate buffered saline and normal saline.
  • 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.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components selected from phosphate buffered saline and normal saline.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components selected from phosphate buffered saline and normal saline.
  • 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.
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • phosphate buffered saline e.g., polysorbate 80
  • 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 (e.g., phosphate buffered saline and/or normal saline) to obtain the formulation.
  • crystalline Compound 1 e.g., Form A
  • polyethylene glycol e.g., polyethylene glycol 300
  • polysorbate e.g., polysorbate 80
  • aqueous components e.g., phosphate buffered saline and/or normal saline
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Acute lung injury and the more severe acute respiratory distress syndrome 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.
  • 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.
  • 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 PaCk/FiO ratio.
  • 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.
  • a subject or population is suffering from or susceptible to acute lung injury.
  • a subject or population is suffering from or susceptible to acute respiratory distress syndrome.
  • 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.
  • a population is a population of subjects who are suffering from or susceptible to acute lung injury.
  • a population is a population of subjects who are suffering from or susceptible to acute respiratory distress syndrome.
  • 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.
  • a population is a population of subjects who are suffering from or susceptible to acute lung injury.
  • a population is a population of subjects who are suffering from or susceptible to acute respiratory distress syndrome.
  • 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).
  • a reference population has not received a composition that provides Compound 1.
  • a reference population has received an otherwise comparable reference composition that does not provide Compound 1 (e.g., a placebo, such as normal saline).
  • a reference composition may be or comprise normal saline.
  • a reference composition may be or may have been administered at the same intervals and/or volumes as a composition that provides Compound 1.
  • 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.
  • 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.
  • 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)).
  • 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.
  • the disease, disorder or condition being treated in methods provided herein is characterized by pulmonary edema, pulmonary epithelial cell apoptosis, inflammatory cell infdtration, impaired oxygenation, hypoxemia and/or lung fibrosis.
  • 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).
  • 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.
  • 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).
  • 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.
  • a particular effect may be or comprise decreased mortality rate relative to a comparable reference population.
  • a particular effect may be or comprise increased lung function relative to a comparable reference population.
  • a particular effect may be or comprise one or more of: increased pulmonary output, increased arterial oxygen (PaC ), decreased arterial carbon dioxide (PaCCh), increased ratio of PaCh/FiCh, decreased lung injury score, decreased lung hydroxyproline concentration, decreased lung collagen level, decreased lung TGFp l concentration, and increased blood pH, relative to a comparable reference population.
  • 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 fdtration rate (eGFR), decreased blood urea nitrogen concentration, increased urine output, decreased kidney TGFp l concentration, and lesser incidence of dialysis, relative to a comparable reference population.
  • eGFR estimated glomerular fdtration rate
  • 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 TGF i 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 46 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.
  • 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 46 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.
  • 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 46 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.
  • the particular effect may be or comprise, for example, one or more effects as described in the Examples herein.
  • 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, TGFp i -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.
  • pneumonia e.g., influenza- associated pneumonia or COVID-19-associated pneumonia
  • pulmonary edema e.g., TGFp i -induced lung injury
  • emphysema emphysema
  • chemically-induced lung injury e.g.
  • 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 bum) 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.
  • 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 bum) lung injury, shock-induced lung injury (e.g.,
  • provided methods are useful for treating an acute organ injury (e.g., an acute injury of the lung).
  • 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).
  • acute organ injury is caused by ischemia/hypoxia (i.e., oxygen deprivation of the organ).
  • acute organ injury is caused by reperfusion injury, which can lead to hemodynamic shear.
  • 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.
  • acute organ injury is caused by traumatic injury such as by blunt trauma, thermal burns, chemical burns or injury, etc.
  • 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).
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • provided methods are useful for treating pulmonary edema.
  • provided methods are useful for treating a disease, disorder, or condition characterized by pulmonary edema.
  • provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to pulmonary edema.
  • 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).
  • the present disclosure provides a method of preventing, attenuating, or reducing red cell and/or neutrophil infdtration 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).
  • a HGF/SF mimetic e.g., Compound 1
  • the HGF/SF mimetic e.g., Compound 1
  • TGFpl Transforming growth factor beta
  • HGF/SF mimetic e.g., Compound 1
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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).
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • provided methods are useful for treating a chemically induced acute lung injury.
  • 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.
  • a subject or population has been exposed to chlorine gas, phosgene gas, or other inhaled toxin.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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
  • provided methods are useful for treating acute lung injury associated with hemorrhagic shock (e.g., hemorrhagic shock from trauma).
  • 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).
  • 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.
  • HGF/SF mimetic e.g., Compound 1
  • provided methods are useful for treating ischemia-reperfusion lung injury.
  • 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).
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • the HGF/SF mimetic protects or preserves pulmonary architecture following ischemic reperfusion.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • provided methods are useful for treating emphysema.
  • provided methods comprise administering a composition that provides Compound 1 to a subject or population of subjects suffering from or susceptible to emphysema.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • the present disclosure provides a method of increasing arterial levels of PaC , 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.
  • a HGF/SF mimetic e.g., Compound 1
  • the present disclosure provides a method of decreasing arterial levels of PaCCh, 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • provided methods are useful for treating radiation-induced acute lung injury.
  • 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.
  • a subject or population has been exposed to ionizing radiation.
  • 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.
  • HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • 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.
  • 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.
  • a HGF/SF mimetic e.g., Compound 1
  • provided methods are useful for treating acute lung injury associated with blunt trauma to the lung.
  • 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.
  • provided methods are useful for treating acute lung injury and/or ARDS associated with pneumonia.
  • pneumonia is viral pneumonia (e.g., influenza-associated pneumonia or COVID-19-associated pneumonia.
  • pneumonia is bacterial pneumonia.
  • pneumonia is aspiration pneumonia.
  • 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).
  • 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.
  • ECMO extracorporeal membrane oxygenation
  • 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.
  • an HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • an HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • 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.
  • 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 described herein (e.g., Example 45) demonstrate 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.
  • treating indications described herein e.g., treating acute lung injury, acute respiratory distress syndrome, COVID-19 pneumonia, etc.
  • 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).
  • the subject has not suffered from a basal or squamous cell carcinoma of the skin that has been treated and/or removed.
  • the subject is suffering from or has suffered from glioma, colon cancer, or pancreatic cancer.
  • 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.
  • a composition that provides Compound 1 e.g., as provided herein
  • 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.
  • 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 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.
  • 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.
  • DAD diffuse alveolar damage
  • 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.
  • 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.
  • Compound 1 provides a unique opportunity to improve clinical outcomes by exerting beneficial effects on multiple organs affected by COVID- 19.
  • 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.
  • 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.
  • such methods comprise administering intravenously 2 mg/kg Compound 1 twice daily for 5 days.
  • such methods comprise administering intravenously 2 mg/kg Compound 1 once daily for 4 days.
  • such methods comprise administering intravenously 2 mg/kg Compound 1 once daily for 3 days.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • viral pneumonia e.g., hospitalized with COVID-19 pneumonia
  • 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)).
  • 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.
  • a reference population has not received a composition that provides Compound 1.
  • a reference population has received an otherwise comparable reference composition that does not provide Compound 1 (e.g., a placebo, such as normal saline).
  • a reference composition may be or comprise normal saline.
  • a reference composition may be or may have been administered at the same intervals and/or volumes as a composition that provides Compound 1.
  • “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).
  • 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).
  • 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.
  • 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).
  • 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. [0158] 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.
  • 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).
  • 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.
  • 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).
  • a particular effect may be or comprise a particular all-cause mortality.
  • 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).
  • 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). [0162] 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.
  • 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).
  • 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).
  • 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).
  • a particular effect may be or comprise a particular proportion of patients requiring initiation of renal replacement therapy (RRT), e.g., through Day 28.
  • RRT renal replacement therapy
  • 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).
  • 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.
  • 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).
  • a particular effect may be or comprise a particular number of ICU days, e.g., through Day 28.
  • 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).
  • a particular effect may be or comprise a particular score on an ordinal scale (e.g., the ordinal scale of Example 38), e.g., at Day 28.
  • a particular effect may be or comprise a reduced score on an ordinal scale (e.g., the ordinal scale of Example 38), 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).
  • 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 38), e.g., at Day 28.
  • 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 38), 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).
  • 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).
  • 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.
  • a particular effect may be or comprise a better cytokine evaluation (e.g., as evidenced by reduced or resolved systemic or localized inflammation).
  • a particular effect may be or comprise decreased mortality rate relative to a comparable reference population.
  • 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 Sp02/Fi02 of 50 or greater compared to the nadir Sp02/Fi02), reduced mean change from baseline on an 8-point Ordinal Scale (e.g., the ordinal scale described in Example 38), reduced time to improvement from admission in one category on an 8-point Ordinal Scale (e.g., the ordinal scale described in Example 38), 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 Sp02/Fi02 of 50 or greater compared to the nadir Sp02/Fi02), 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
  • a particular effect may be or comprise increased lung function relative to a comparable reference population.
  • a particular effect may be or comprise one or more of: increased pulmonary output, increased arterial oxygen (PaCh), decreased arterial carbon dioxide (PaCCh), increased ratio of PaCh/FiCh, decreased lung injury score, decreased lung hydroxyproline concentration, decreased lung collagen level, decreased lung TGFp l concentration, and increased blood pH, relative to a comparable reference population.
  • 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 TGFp l concentration, and lesser incidence of dialysis, relative to a comparable reference population.
  • eGFR estimated glomerular filtration rate
  • 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 fdtration 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 TGF i 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 46 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.
  • 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 46 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.
  • 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 46 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.
  • 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.
  • 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. [0181] 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.
  • ECMO extracorporeal membrane oxygenation
  • 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.
  • an HGF/SF mimetic e.g., Compound 1
  • 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.
  • 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.
  • an HGF/SF mimetic e.g., Compound 1
  • 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.
  • provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and one or more anti-viral agents.
  • anti-viral agents are selected from oseltamivir, lopinavir, ritonavir, chloroquine, hydroxychloroquine, and remdesivir, and combinations thereof.
  • provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and anti-viral therapy.
  • anti-viral therapy comprises hydroxychoroquine and azithromycin.
  • provided methods comprise administering to a subject or population an HGF/SF mimetic (e.g., Compound 1) and one or more IL-6 inhibitors.
  • HGF/SF mimetic e.g., Compound 1
  • IL-6 inhibitors include tocilizumab and sarilumab.
  • one or more subjects or populations selected to receive Compound 1 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.
  • 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.
  • 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.
  • 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.
  • an underlying condition e.g., infection, trauma, etc.
  • 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).
  • 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
  • circulation i.e., may involve clotting, inflammation, and/or scarring of blood vessels in the lungs.
  • a subject or population is suffering from or susceptible to acute respiratory distress (e.g., ARDS as defined by the Berlin criteria).
  • a subject or population is suffering from or susceptible to mild ARDS (e.g., as defined by the Berlin criteria).
  • a subject or population is suffering from or susceptible to moderate ARDS (e.g., as defined by the Berlin criteria).
  • a subject or population is suffering from or susceptible to severe ARDS (e.g., as defined by the Berlin criteria).
  • 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 Pa02/Fi02).
  • a subject or population is suffering from acute lung injury.
  • 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.
  • a subject or population is suffering from or susceptible to a chronic respiratory disease, disorder or condition.
  • a subject or population is suffering from or susceptible to pulmonary edema.
  • 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).
  • a subject or population is in shock (e.g., septic shock, LPS-induced shock, hemorrhagic shock, or cardiogenic shock).
  • 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.
  • drugs and/or toxins e.g., chlorine gas or phosgene gas
  • 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). [0196] 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.
  • hemorrhagic shock e.g, hemorrhagic shock from trauma.
  • a subject or population has experienced a traumatic injury (e.g., to the lung).
  • 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.
  • 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.
  • a subject or population is suffering from or susceptible to emphysema.
  • 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).
  • a subject or population is suffering from or has suffered from smoke inhalation and/or bum.
  • a subject or population is suffering from or susceptible to a pneumonia (e.g., a viral pneumonia, bacterial pneumonia, or aspiration pneumonia).
  • a subject or population is suffering from pneumonia (e.g., as confirmed by, e.g., chest imaging).
  • a subject or population is suffering from COVID-19 pneumonia (e.g., as confirmed by chest imaging).
  • a subject or population is suffering from or susceptible to COVID-19 pneumonia (e.g., as confirmed by chest imaging).
  • 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).
  • a respiratory virus such as respiratory syncytial virus (RSV), influenza, and/or a coronavirus (e.g., COVID-19).
  • 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.).
  • COPD chronic obstructive pulmonary disease
  • 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.
  • a subject or population is in respiratory failure.
  • 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).
  • 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).
  • 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.
  • a subject or population may display cough (e.g., dry cough) and fever.
  • 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.
  • 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).
  • an infectious disease e.g., infection with a microbe or virus
  • a sample(s) e.g., that is or comprises blood, feces, saliva, serum, sputum, sweat, tears, urine, etc.
  • a subject or population has been admitted to an intensive care unit.
  • a subject or population is or was on a ventilator and/or is or was receiving supplemental oxygen.
  • a subject or population is resistant to oxygen therapy.
  • a subject or population is receiving or has received endotracheal intubation.
  • a subject or population may be having, have had, or be at risk of having a myocardial infarction.
  • subjects receiving therapy with an HGF/SF mimetic may benefit from therapy with one or more additional agents.
  • an HGF/SF mimetic e.g., Compound 1
  • a subject or population is receiving or has received one or more additional therapies.
  • a subject or population is receiving or has received one or more antibiotics, antivirals, corticosteroids, and painkillers, and combinations thereof.
  • a subject or population is receiving or has received one or more antivirals.
  • a subject or population is diagnosed with or suspected of having COVID-19 and is receiving or has received one or more antivirals.
  • a subject or population is receiving or has received antiviral therapy selection from oseltamivir, lopinavir, ritonavir, chloroquine, hydroxychloroquine, and remdesivir, and combinations thereof.
  • a subject or population is receiving or has received antiviral therapy comprising hydroxychloroquine and azithromycin.
  • a subject or population is receiving or has received one or more IL-6 inhibitors.
  • a subject or population is receiving or has received one or more IL-6 inhibitors selected from tocilizumab and sarilumab.
  • 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).
  • CESAR severe adult respiratory failure
  • 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.
  • subjects or populations who need ECMO have a severe and life-threatening illness that stops their heart or lungs from working properly.
  • ECMO is used during life-threatening conditions such as severe lung damage from, e.g., infection, or shock after a massive heart attack.
  • a subject or population is receiving or has received therapy with ECMO.
  • subjects or populations are supported by an ECMO machine for only a few hours.
  • subjects or populations are supported by an ECMO machine for one or more days.
  • subjects or populations are supported by an ECMO machine for one or more weeks.
  • a subject is a child, or a population consisting of children, of less than 18 years.
  • a subject is an adult or an adult population.
  • a subject is an adult, or a population consisting of adults, of 55 years or older.
  • 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.
  • 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.
  • 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. [0218] 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.
  • acute kidney injury e.g., secondary to ECMO therapy
  • a subject or population is suffering from a renal ischemia/reperfusion injury, renal failure, renal fibrosis, or a renal trauma.
  • 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).
  • 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).
  • a subject or population is experiencing respiratory complications, e.g., associated with COVID-19, influenza, chemical or thermal injury, chemical or thermal burns, etc.
  • a subject or population is suspected of suffering from a coronavirus.
  • a subject or population is suspected of suffering from COVID-19.
  • a subject or population is or has been diagnosed with a coronavirus.
  • a subject or population is or has been diagnosed with COVID-19.
  • 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.
  • a subject or population is suffering from or susceptible to heart dysfunction, e.g., in addition to pulmonary dysfunction.
  • a subject or population suffering from or susceptible to heart dysfunction is characterized using one or more Study Assessments described in Example 46 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.).
  • a subject or population is suffering from or susceptible to renal dysfunction, e.g., in addition to pulmonary dysfunction.
  • a subject or population suffering from or susceptible to renal dysfunction is characterized using one or more Study Assessments described in Example 46 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.).
  • 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.
  • a subject or population suffering from or susceptible to liver dysfunction is characterized using one or more Study Assessments described in Example 46 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.).
  • Study Assessments described in Example 46 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.
  • a subject or population is hospitalized (e.g., hospitalized with COVID-19 pneumonia).
  • 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.
  • a sample e.g., a respiratory tract sample
  • RT-PCR reverse-transcriptase-polymerase-chain- reaction
  • the sample has tested positive during the same hospitalization in which the subject or population is receiving or has received therapy with Compound 1.
  • a subject or population has an ordinal score of 4 or 5, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an ordinal score of 1, 2, or 3, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an ordinal score of 6 or 7, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an ordinal score of 5, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an ordinal score of 4, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an ordinal score of 5, e.g., on the ordinal scale described in Example 38.
  • 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 38.
  • a subject or population has a fraction of inspired oxygen (FiCh) of greater than about 40%. Fraction of inspired oxygen can be measured by any method known in the art.
  • a FiCh 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.
  • a subject or population has a FiCh of greater than about 40% and an ordinal score of 4, e.g., on the ordinal scale described in Example 38.
  • a subject or population has a fraction of inspired oxygen (FiCk) of less than about 40%. Fraction of inspired oxygen can be measured by any method known in the art.
  • a FiCk 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.
  • a subject or population has a FiCk of less than about 40% and an ordinal score of 4, e.g., on the ordinal scale described in Example 38.
  • a subject or population has an oxygen saturation (Sa02) 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.
  • Sa02 oxygen saturation
  • a subject or population has a ratio of partial pressure of oxygen (Pa02) to fraction of inspired oxygen (Fi02) 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).
  • 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.
  • a malignancy e.g., an active malignancy
  • 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.
  • a subject or population is suffering from or susceptible to a malignancy (e.g., an active malignancy).
  • a subject or population is receiving treatment for a malignancy (e.g., an active malignancy).
  • a subject or population has a history of solid or hematological malignancies (e.g., within the past 5 years).
  • 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.
  • 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.
  • 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).
  • a subject or population does not have an alanine aminotransferase (ALT) level greater than three times upper limit of normal (ULN) at baseline.
  • a subject or population does not have an aspartate transaminase (AST) level greater than three times ULN at baseline.
  • a subject or population does not have a total bilirubin level greater than two times ULN at baseline.
  • 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).
  • Non-limiting examples of CYP1A2 inhibitors include alosetron, caffeine, ciprofloxacin, duloxetine, fluvoxamine, melatonin, ramelteon, selegiline, tacrine, tasimelteon, tizanidine, and theophylline.
  • a subject or population is not receiving or has not received any other investigational drug product or procedure.
  • a subject or population is not a recipient of a solid organ and/or hematopoietic cell transplantation.
  • a subject or population is not suffering from end stage renal disease.
  • 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.
  • renal replacement therapy RRT is initiated during the same hospitalization in which the subject or population is receiving Compound 1 therapy.
  • a subject or population is male and/or nonpregnant females.
  • a subject or population is not pregnant or breastfeeding.
  • a subject or population is adult (e.g., 18 years of age or older).
  • a composition that provides Compound 1, as described herein can be administered in accordance with methods (e.g., according to a regimen) provided herein.
  • a composition that provides Compound 1 is administered intravenously.
  • a composition that provides Compound 1 is administered (e.g., intravenously) over about 10 min, about 20 min, about 30 min, or about 40 min.
  • a composition that provides 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.
  • a composition that provides 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.
  • provided formulations are administered as an infusion over about 30 min in an amount suitable to provide about 2 mg/kg Compound 1.
  • 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).
  • 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).
  • 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).
  • a course of treatment is about 3 days.
  • a course of treatment is about 4 days.
  • methods provided herein comprise administration (e.g., intravenous administration) of Compound 1 (e.g., 2 mg/kg) twice a day for 5 days.
  • a composition that provides Compound 1 is first administered within about 6 hours of an initiating event (e.g., randomization or acute injury).
  • a composition that provides Compound 1 is administered for a second time within about 12 hours (e.g., within 10 hours, within 12 hours, or within 14 hours) from the time of first administration.
  • a composition that provides Compound 1 is administered for a third, fourth, fifth, sixth, seventh, eighth, ninth, and/or tenth time within about 12 hours (e.g., within 10 hours, within 12 hours, or within 14 hours) from the time of a prior administration.
  • methods provided herein comprise administration (e.g., intravenous administration) of Compound 1 (e.g., 2 mg/kg) once a day for 4 days.
  • a composition that provides Compound 1 is first administered within about 6 hours, 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 or acute injury).
  • a composition that provides 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.
  • a composition that provides 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 that provides 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.
  • methods provided herein comprise administration (e.g., intravenous administration) of Compound 1 (e.g., 2 mg/kg) once a day for 3 days.
  • Compound 1 e.g., 2 mg/kg
  • a composition that provides 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 or acute injury).
  • a composition that provides 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.
  • a composition that provides 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • provided methods further comprise diluting the first formulation under aseptic conditions.
  • provided methods further comprise diluting the first formulation within 1 day, 2 days, or 3 days prior to administering the second formulation.
  • 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.
  • a second formulation of Compound 1 comprises: about 6 mg/mL Compound 1; about 20% (w/v) to about 40% (w/
  • 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.
  • Compound 1 therapy as described herein is initiated within 24, 20, 28, 26, 24, 12, 10, 8, 6, 4, 2, or 1 hours of initiation of mechanical ventilation; in some embodiments, Compound 1 therapy is initiated within 10, 8, 6, 4, or 2 hours of such ventilation initiation; in some embodiments within 4 hours.
  • Compound 1 is administered by IV infusion and/or at a dose of about 2 mg/kg over a period of time (e.g., about 30 min).
  • Compound 1 is administered in a plurality of doses, e.g., of fixed doses.
  • 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.
  • a 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).
  • 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 (Pa02/Fi02), 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.
  • ABSs arterial blood gasses
  • P/F ratio P/F ratio
  • 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 38), Sp02/Fi02, high-sensitivity C-reaction protein (HS-CRP), absolute lymphocyte count, serum ferritin, serum interleukin-6 (H-6), serum myoglobin, D-dimer, creatine phosphokinase (CPK), CPK-MB, troponin (e.g., troponin I), and LDH.
  • H-6 high-sensitivity C-reaction protein
  • CPK creatine phosphokinase
  • CPK-MB troponin (e.g., troponin I), and LDH.
  • 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.
  • Compound 1 therapy as described herein is not administered to patients who have multi-organ failure.
  • a method of treating a respiratory disease, disorder or condition comprising: administering to a subject susceptible to or suffering from a respiratory disease, disorder or condition a composition that provides (E)-3-[2-(2-thienyl)vinyl]-lH-pyrazole.
  • a method of treating acute lung injury or acute respiratory distress syndrome in a subject in need thereof comprising administering to the subject a composition that provides (E)-3-[2-(2-thienyl)vinyl]-lH-pyrazole.
  • a method comprising: administering to a subject who is suffering from or susceptible to a respiratory disorder a composition that provides (E)-3-[2-(2-thienyl)vinyl]-lH-pyrazole.
  • a method comprising: administering to a subject who is receiving or has received therapy with extracorporeal membrane oxygenation a composition that provides (E)-3-[2-(2-thienyl)vinyl]-lH-pyrazole.
  • antiviral therapy is selected from lopinavir, ritonavir, chloroquine, hydroxychloroquine, azithromycin, and redesivir, and combinations thereof.
  • composition is administered according to a regimen established to achieve, when administered to a relevant population, a decreased mortality rate relative to a comparable reference population.
  • 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.
  • composition is administered according to a regimen established to achieve, when administered to a relevant population, one or more of:
  • compositions are administered according to a regimen established to achieve, when administered to a relevant population, one or more of:
  • composition is administered according to a regimen established to achieve, when administered to a relevant population, one or more of:
  • 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.
  • composition is administered according to a regimen established to achieve, when administered to a relevant population, one or more of:
  • composition is administered intravenously.
  • composition is administered in a dose of about 2 mg/kg.
  • composition is administered twice daily.
  • composition is administered once daily.
  • composition is administered for 4 consecutive days.
  • composition comprises:
  • Example 2 Compound 1 Stimulated Endothelial Cell and Bronchial Cell Proliferation but not Fibroblast Cell Proliferation
  • HGF endothelial and epithelial cell proliferation but not that of fibroblasts.
  • Endothelial cells (HUVECs), bronchial epithelial cells (HBECs) and lung fibroblasts (MRC-5) were grown to semi confluence in serum medium for 24 hours. Cells were then serum starved for 2 hours, followed by the addition of vehicle, HGF (50 ng/ml) or Compound 1 (36 mM) for 24 hours. The cells were washed with PBS and [3H]-thymidine incorporation determined as a measure of proliferation. Compound 1 produced a similar increase in endothelial (FIG. 1A) and bronchial (FIG. IB) cells proliferation as HGF, but not fibroblasts (FIG. 1C).
  • Example 4 Compound 1 protects against TGFpi-induced acute lung injury.
  • TGFp l Transforming growth factor beta
  • TGFp l Transforming growth factor beta
  • a small colony of mice with a lung-specific TGFpi transgene that is regulated by a doxycycline-(dox) induced promoter was obtained.
  • Compound 1 significantly improved the survival of mice in a 10 day treatment period (FIG. 3 A). Some mice were sacrificed 3 days after TGFpi induction, and the Compound 1 treated cohort was shown to have decreased pulmonary cell death (FIG. 3B) and improved pulmonary epithelial regeneration (by PCNA) vs vehicle cohort (FIG. 3C).
  • Example 5 Attenuates lipopolysaccharide (LPS) induced shock associated ALI in a mouse model.
  • LPS lipopolysaccharide
  • LPS Bacterial endotoxin
  • E.coli E.coli
  • Sigma Bacterial endotoxin
  • lungs were evaluated for histopathological injury score by two independent observers (FIG. 4B) and TUNEL for apoptosis.
  • Compound 1 treatment significantly attenuated LPS/shock associated lung injury score (FIG. 4A) and decreased apoptotic cell death (FIG. 4C) compared to the vehicle cohort.
  • Example 6 Compound 1 protects against chlorine (CL) toxicity
  • the acute effects of Ch inhalation can range from mild respiratory mucus membrane irritation to marked denudation of the mucosa, pulmonary infiltration, pulmonary edema and death.
  • Recovery from Ck-induced lung injury requires repair and/or regeneration of the epithelial layer.
  • Compound 1 can aid in the prevention or recovery from Ch- induced pulmonary damage, C57BL/6 mice were exposed to Ch. Mortality of 27% was observed after 5 days and a significant increase in pulmonary infiltration was determined by an increase in the protein concentration in the bronchial alveolar lavage (BAL) fluid.
  • Treatment with Compound 1 (2 mg/kg, IP, QD, initiated 3 hours after Ch exposure) resulted in a marked increase in animal survival (FIG. 5A) and a significant reduction in pulmonary infiltration (FIG. 5B).
  • Example 7 Compound 1 enhances pulmonary output and arterial oxygen levels in established emphysema model
  • Example 8 Compound 1 reduces hemorrhagic shock (HS) induced lung injury in a rat model.
  • Rats were exposed to 90 min left pulmonary global normothermic ischemia and 72 hr reperfusion.
  • Example 10 Compound 1 attenuates canine warm lung ischemia-reperfusion (I-R) injury
  • I-R warm lung ischemia-reperfusion
  • This example simulates a “marginal lung” from a cardiac arrest donor.
  • Adult male dogs were exposed to 90 min of left lung normothermic ischemia by pulmonary artery occlusion and 180 min reperfusion.
  • Seven subjects were treated with Compound 1 (10 mg/kg, iv) and six were treated with vehicle at reperfusion. Since preclinical pharmacokinetic (PK) data indicate that the plasma Compound 1 level (Cmax and AUC) in rats is ⁇ 5X higher than in dogs, due to more avid clearance in dogs, a Compound 1 dose, of 10 mg/kg (5X higher than in rats) was used.
  • PK pharmacokinetic
  • Treatment with Compound 1 decreased pulmonary edema (FIG. 9A) and improved arterial oxygenation levels (FIG. 9B). Additionally, there was a marked attenuation of alveolar thickening in dogs treated with Compound 1 as represented in H&E lung sections, indicating protection of the pulmonary architecture at 180 minutes post-reperfusion (FIG. 9E). Compound 1 treatment also decreased inflammatory cytokines IL-1 (FIG. 9C) and IL-6 (FIG. 9D), known promoters of lung graft injury, in BAL significantly.
  • Example 11 Determination the dose response and therapeutic time window of Compound 1 in a two-hit HS+LPS model of ALI/ARDS
  • HS Hemorrhagic shock
  • MAP mean arterial pressure
  • RL Ringer’s lactate
  • a tracheotomy is performed with intratracheal (IT) instillation of either LPS or saline (sham), followed by mechanically ventilated breaths using a rodent ventilator.
  • I intratracheal
  • sham saline
  • a rodent ventilator a small group of sham, HS+LPS challenged rats are sacrificed after 6 hr to evaluate the extent of acute lung injury and histopathological score. After confirmation of injury score, series- 1 study is conducted.
  • IL- 1 />, IL- 6, IL-10 and TNF-a proinflammatory cytokines in the serum and lung tissue lysates
  • IL- 6 />, IL- 6, IL-10 and TNF-a proinflammatory cytokines in the serum and lung tissue lysates
  • Therapeutic window study In a pilot study, a small group of sham, HS+LPS challenged rats are sacrificed after 24 hrs to evaluate the extent of established acute lung injury and histopathological score. After confirmation of established lung injury, series-2 study is conducted. HS+LPS challenged rats after 24 hrs, are randomized to vehicle or Compound 1 groups. The optimal dose of Compound ldetermined from series-1 study is administered via the IV route daily for 7 days and 14 days.
  • MAP and pulmonary function tests are performed using the Flexivent system to obtain ventilator mechanics: peak airway pressure, pause airway pressure, lung static and dynamic pressure.
  • blood is collected for gas analysis, arterial and venous oxygenation (p02), arterial and venous saturation (PC02), pH, base excess electrolytes (sodium, calcium and potassium), hematocrit, hemoglobin, complete blood count with differential. Animals are then sacrificed and the efficacy measures as in series-1 study are conducted.
  • Rats are anesthetized, tracheostomized, and placed on the FlexiVent system for forced oscillatory measurements.
  • the use of the Flexivent system includes onsite demonstration and training using sentinel animals to assure proficiency in conducting lung function measurements. Rats are ventilated with a tidal volume of 10 mL/kg at a frequency of 150 breaths/min and a PEEP of 3 cm H2O to prevent alveolar collapse.
  • Total lung capacity (TLC), Snapshot, Quickprime-3, and pressure- volume (PV) loops with constant increasing pressure (PVr-P) are consecutively performed using the Flexivent system according to the manufacturer’s protocols.
  • a Snapshot perturbation maneuver uses a three-cycle sinusoidal wave of inspiration and expiration to measure total respiratory system resistance (R), dynamic compliance (C), and elastance (E).
  • a Quickprime-3 perturbation which produces a broadband frequency (0.5 to 19.75 Hz) over 3 seconds, measures Newtonian resistance which is a measure of central airway resistance (Rn), inertance (I), tissue damping (G), tissue elastance (H) and hysteresivity (eta).
  • PV loops are generated between 30 cm H2O to -30 cm H2O pressure to obtain vital capacity (A), the upper portion of the deflation PV curve (K), quasi-static compliance (Cst) and elastance (Est), and the area of PV loop (Area). All perturbations are performed until three acceptable measurements with coefficient of determination (COD) > 0.9 recorded in each individual rat.
  • forced vital capacity (FVC) and peak expiratory flow (PEF) are measured using the Flexivent system.
  • the primary endpoints for the evaluation of efficacy are evidence of decrease in pathological lung injury score, normalized MAP and improvement in pulmonary function in the Compound 1 treated groups compared to the vehicle cohort. Observed efficacy is expected to be due to decreases in apoptotic cell death, cellular infiltrates, proinflammatory cytokines in the BAL and tissue lysates compared to the vehicle cohort. Efficacy and optimal therapeutic time window for Compound 1 in a disease-relevant model of HS+LPS induced ARDS is expected to be defined using the study described above.
  • Example 12 Evaluating efficacy of Compound 1 in a smoke inhalation and burn induced ALI/ARDS sheep model
  • Cardiopulmonary hemodynamics MAP, pulmonary artery pressure, central venous pressure, left atrium pressure, heart rate, cardiac output, blood gas analysis, arterial and venous oxygenation (P02), arterial and venous saturation (PC02), pH, electrolytes (sodium, calcium and potassium), hematocrit, hemoglobin, CBC with differential, ventilatory mechanics: peak airway pressure, pause airway pressure, and lung static and dynamic pressure are measured at 48 hr and 5 day time points. Then sheep are sacrificed. Lung tissues are frozen and formalin fixed for lung histology.
  • the arterial carboxyhemoglobin (COHb) level is determined immediately after the smoke inhalation.
  • COHb carboxyhemoglobin
  • All surviving sheep are placed on a ventilator with positive end expiratory pressure set to 5 cm H2O and tidal volume maintained at 15 ml/kg.
  • the sheep are ventilated (Servo Ventilator 300, Siemens-El ema AB, Sweden) with 100% oxygen for the first 3 hrs after injury for rapid clearance of CO in order to reduce COHb.
  • the fraction of inspired oxygen (Fi02) is adjusted according to blood gas analysis to maintain Pa02 above 80 mm Hg.
  • Respiratory rate is initially set at 20 breaths/minute and there after adjusted to keep PaC02 between 25-35 mm Hg.
  • Example 13 Compound 1 delayed treatment decreases pulmonary edema.
  • Example 14 Compound 1 attenuates TGFpi-induced mortality and acute lung injury.
  • a variety of pulmonary insults stimulate production and release of TGFpi into the pulmonary parenchyma which leads to acute cell death.
  • FIG. 11C Micro CT images of inflated and formalin fixed lungs suggest that treatment with Compound 1 preserves pulmonary microarchitecture in this model (FIG. 11D).
  • Example 15 Compound 1 attenuates acute lung injury in a sheep model of smoke inhalation and burn injury.
  • Example 16 Compound 1 prevents progression to pulmonary fibrosis.
  • Compound 1 The effect of Compound 1 on pulmonary collagen accumulation was evaluated in a genetic (TSK1/+) mouse model of systemic sclerosis including pulmonary fibrosis.
  • Example 17 Compound 1 is orally efficacious in a TGFpi-induced lung fibrosis in mouse model.
  • Example 18 Compound 1 treatment mitigates ionizing radiation induced pulmonary cell apoptosis and inflammation.
  • Example 19 Compound 1 treatment mitigates radiation induced lung fibrosis.
  • mice were exposed to 6 Gy and treated with Compound 1 (2 mg/kg, IP, QD) for 4.5 months.
  • Compound 1 treatment mitigated the pulmonary fibrosis, as judged by reduced lung mass (FIG. 16 A), collagen- 1 levels (FIG. 16B), Sirius red staining (FIG. 16C), and TGF b ⁇ levels (FIG. 16D).
  • Example 20 Compound 1 treatment decreases radiation induced kidney and liver injury.
  • Compound 1 treatment also decreased kidney and liver fibrotic markers including TGFpi (FIG. 17A and FIG. 17B) and aSMA (FIG. 17C) significantly.
  • Example 21 Evaluation of the radiation dose and time course of c-Met upregulation in lung tissues after thoracic irradiation of mice.
  • C57L/J mice closely resemble humans with respect to sensitivity to radiation and susceptibility to pneumonitis as well as pulmonary fibrosis.
  • C57L/J mice are exposed to 10, 12.5 and 17.5 Gy of thoracic irradiation (whole thoracic lesion irradiation, or WTLI) using 137 Cs source @ 1 Gy/min. These three doses have been shown to generate three representative pathological courses with increased severity following radiation. The mice are sacrificed after 1, 3, 7, 14, 30 and 60 days.
  • a time course of HGF and its receptor, c-Met upregulation in lungs at both transcriptional level (by RTPCR) and translational level (by Western blots), and the pathological sequelae of pneumonitis after irradiation (mortality, BAL and pulmonary edema, tissue injury, apoptosis, and inflammation) are evaluated.
  • a non-exposed remote organ, i.e., kidneys, are collected and frozen as a negative control.
  • Example 22 Efficacy of Compound 1 in two studies using the porcine pancreatic elastase (PPE)-induced emphysema rat model.
  • PPE pancreatic elastase
  • PPE was prepared in PBS at 250 U/kg body weight and 250 pL instilled IT. A PBS- instilled group was included. The day after PPE-instillation, the rats were randomly divided into two groups, Vehicle and Compound 1 (2 mg/kg, IP) QD for 6 weeks and arterial blood was drawn from an abdominal artery of each rat with an arterial blood sampler (Quick ABG, Vital Signs Colorado, Inc.), and quickly applied to aNPT7 analyzer (Radiometer/Copenhagen). Compound 1 significantly increased Pa02 (p ⁇ 0.05) (FIG. 18A) and decreased PaC02 (p ⁇ 0.05) (FIG. 18B) as compared to the vehicle treated group.
  • Example 23 Compound 1 Attenuates Pulmonary 30 min Ischemia-24 hr Reperfusion Injury.
  • Compound 1 Mitigates Pulmonary Ischemia-reperfusion Injury: Treatment with Compound 1 immediately following 30 min pulmonary ischemia in the rat attenuated pulmonary apoptosis (caspase 3 staining) at 24 hr reperfusion (FIG. 19A, ⁇ Compound 1 ⁇ 0.05 vs vehicle). Representative sections from normal (sham), postischemic vehicle and postichemic Compound 1 -treated lungs showing necroinflammatory response in vehicle that is absent in Compound 1 -treated group (FIG. 19B).
  • Example 24 Compound 1 Attenuates Pulmonary 90 min Ischemia-72 hr Reperfusion Injury.
  • End-expiration air volume was calculated by the equations shown below: [0304] Single lung function immediately prior to sacrifice was also evaluated by obtaining blood gas levels from the left pulmonary vein using an Abbot I-STAT blood gas analyzer. Lungs were evaluated histopathologically for pulmonary epithelial regeneration (PCNA immunoreactivity) and microarchitecture. Treatment with Compound 1 was associated with significant improvement in postischemic end-expiration air volume, blood pH, and blood oxygen levels, enhanced pulmonary epithelial regeneration, reduced pulmonary cell death, and preservation of lung microarchitecture.
  • PCNA immunoreactivity pulmonary epithelial regeneration
  • Compound 1 Mitigates Pidmonary Ischemia-reperfusion Injury: Compound 1 improves end-expiration air volume following pulmonary 90 min ischemia-reperfusion (FIG. 20A). Prior to sacrifice, Compound 1 -treated cohort exhibited improved blood pH (FIG. 20B), blood oxygen tension (p02) (FIG. 20C) and blood oxygen saturation (s02) (FIG. 20D). Compound 1 treatment was also associated with improved pulmonary epithelial regeneration following reduced pulmonary parenchymal inflammation and neutrophil invasion. 8, p ⁇ 0.05 vs vehicle (FIG. 20E and FIG. 20G). Compound 1 treatment additionally reduced pulmonary cell death (FIG. 20F).
  • Example 25 Compound 1 Attenuates Syngeneic Rat Lung Transplantation Injury.
  • FIG. 21E preserved alveolar air space (FIG. 21F, H&E stained lung tissue samples) and attenuated the parenchymal collapse and neutrophil invasion observed in the vehicle cohort.
  • Example 26 Compound 1 Attenuates Acute Lung Injury in a Sheep Model of Smoke Inhalation + Burn Injury.
  • Compound 1 Attenuates Ovine Acute Lung Injury: In sheep subjected to smoke inhalation and 40% body surface burn injury, treatment with Compound 1 attenuated mortality (FIG. 22A), improved pulmonary gas exchange (FIG. 22B) and preserved fluid balance (FIG. 22C). Examination of H&E-stained lung section indicated that Compound 1 treatment (B1 and B2) is associated with decreased alveolar flooding and decreased inflammation compared to vehicle cohort (VI and V2) (FIG. 22D).
  • Example 27 Compound 1 Decreases Pulmonary Edema.
  • Example 28 24-hr Delayed Compound 1 Treatment Attenuates Pulmonary Edema.
  • Example 29 Compound 1 Reverses Pulmonary Fibrosis.
  • Example 30 Compound 1 is Non-Mitogenic for Fibroblasts.
  • SF/HGF As a growth factor, an important aspect of SF/HGF activity is to induce endothelial cell proliferation. By contrast, SF/HGF is non-mitogenic for fibroblasts.
  • HUVECs human umbilical vein endothelial cell
  • MRC-5 fibroblasts 3H-thymidine incorporation, which is a measure of the rate of DNA synthesis, was used as a marker of cell proliferation.
  • SF/HGF activity Another important pulmotrophic aspect of SF/HGF activity is to induce epithelial cell proliferation.
  • Compound 1 was tested to determine if, like SF/HGF, it exhibits this activity.
  • Human bronchial epithelial cells (HBECs) were grown to 30-50% confluence in medium containing complete serum for 16-24 hours. Cells were then serum starved for 1-2 hours, followed by the addition of vehicle, Compound 1 or SF/HGF (positive control) for 16-24 hours.
  • [3H]-thymidine was added to the medium and incubation continued for another 4-5 hours. The cells were washed three times with PBS and [3H]-thymidine incorporation determined as a measure of proliferation (increased DNA synthesis).
  • Compound 1 Stimulates Bronchial Epithelial Cell Proliferation. Subconfluent HBECs in 48 well plates were treated with vehicle, Compound 1 (36 mM) or SF/HGF (25 ng/mL) for 24 hours in serum free medium. 3H-thymidine incorporation into newly synthesized DNA was assessed and compared to the vehicle controls (FIG. 27).
  • Proliferation of pulmonary endothelial cells is an important pulmotrophic activity of SF/HGF.
  • Compound 1 like SF/HGF, exhibits proliferative activity and whether the activity is mediated through the SF/HGF receptor c-Met
  • bPAEC bovine pulmonary endothelial cells
  • c-Met siRNAs and a lipo-transfecting reagents were used to knock down the c-Met mRNA level in bPAEC cells, and real time RT-PCR was performed to measure this effect.
  • the results show that Compound 1, similar to SF/HGF, promotes proliferation of bPAEC cells through the SF/HGF receptor c-Met.
  • FIG. 28B and FIG. 28C show the effects of knocking down c-Met mRNA on Compound 1 and SF/HGF-driven pulmonary endothelial cell proliferation.
  • Example 33 Compound 1 Stimulates Migration of Pulmonary Endothelial Cells.
  • SF/HGF Another important pulmotrophic activity of SF/HGF is to stimulate migration of pulmonary endothelial cells.
  • bPAEC cells were used to test if Compound 1, like SF/HGF, can stimulate migration of the cells.
  • the CytoSelect 24-well cell migration assay (Cell Biolabs, Inc.) was used to measure the migration of bPAEC cells according to the kit manual. The results indicate that Compound 1 stimulates bPAEC cells migration, similar to SF/HGF.
  • Pulmonary ischemia-reperfusion injury is frequently associated with apoptosis of pulmonary epithelial cells.
  • SF/HGF treatment in this setting is associated with reduced pulmonary epithelial death.
  • Compound 1 protects epithelial cells against apoptosis.
  • Human bronchial epithelial cells were grown to 80% confluence and then treated with bleomycin (to induce apoptosis) + vehicle or Compound 1 or SF/HGF for 24 to 48 hrs. Cells were then washed with serum free media and stained with FITC-labeled Annexin-V. Both Compound 1 and SF/HGF protected epithelial cells from apoptosis (FIG. 30)
  • Example 35 Oral Compound 1 Reverses Emphysema.
  • Results are expressed as mean ⁇ standard error of the mean (SEM) for each group. Two-way ANOVA was used to compare the BUN and creatinine time course in the dog ischemia-reperfusion study. Results are considered significant when p ⁇ 0.05.
  • Example 37 Compound 1 Protects Bronchial Epithelial Cells from IhC -Induced Apoptosis
  • Bronchial epithelial cells (4MBr-5) were grown to sub-confluence and then treated with vehicle or Compound 1 (10 mM) for 24 hours. Cells were then challenged with H2O2 (200 mM) for 1 hour, washed with serum-free media and stained with FITC-labeled Annexin-V and Propidium Iodide. Cells were analyzed by FACS and the percentage of Annexin-V positive cells in vehicle controls was found to be 34.8% of the total number of cells.
  • Example 38 A Multicenter, Randomized, Open-Label Phase 2 Study to Assess Safety and Efficacy of Compound 1 in Patients Hospitalized with COVID-19 Pneumonia.
  • Compound 1 will be administered by 2 daily intravenous (IV) infusions of 2 mg/kg for a total of 10 doses. The first dose will be started within 6 hours of randomization. The subsequent doses will be administered 12 ⁇ 2 hours after the previous dose. [0334] Patients will be followed for safety and efficacy up to Day 30, with Day 1 being the day of the first infusion of study drug. Patients will be assessed daily through Day 14 and then on Days 21 and 30.
  • IV intravenous
  • Efficacy endpoints include assessment of the clinical severity on an 8-point Ordinal Scale as recommended by the World Health Organization’s task force on COVID-19 efficacy endpoints:
  • RT-PCR reverse-transcriptase-polymerase-chain-reaction
  • Compound 1 for IV administration is a solution with a concentration of 10 mg/mL.
  • the solution also contains 50% (w/v) polyethylene glycol 300 NF, 10% (w/v) polysorbate 80 NF, and phosphate buffered saline.
  • Patients will receive 2 mg/kg of Compound 1 via IV infusion over 30 minutes twice daily for 5 days.
  • the first dose will be started within 6 hours of randomization.
  • the subsequent doses will be administered 12 ⁇ 2 hours after the previous dose for a total of 10 doses.
  • ICU intensive care unit
  • H-CRP high-sensitivity C-reaction protein
  • IL-6 semm interleukin-6
  • IL-6 semm myoglobin
  • D-dimer D-dimer
  • CPK creatine phosphokinase
  • CPK-MB troponin
  • LDH low-sensitivity C-reaction protein
  • Continuous variables will be summarized with descriptive statistics (the number of non-missing values [n], mean, median, standard deviation [SD], minimum, and maximum). All categorical variables will be summarized with frequency counts and percentages, as applicable.
  • Time to event variables will be analyzed using Kaplan-Meier (K-M) survival estimates.
  • K-M survival curves will be compared between treatment groups using Log-rank test.
  • K-M estimates including 25th, 50th, and 75th percentiles, 95% confidence intervals (CIs), and number and percent censored will be presented.
  • Student’s t test will be carried out for normally distributed variables.
  • Wilcoxon rank-sum test will be used for non-normally distributed variables, Difference in proportions between treatment groups will be analyzed using Fisher’s exact test.
  • Compound 1 is administered by once daily intravenous (IV) infusions of 2 mg/kg for a total of 4 doses. The first dose is started within 6 hours of randomization. Subsequent doses are administered 24 ⁇ 4 hours after the previous dose.
  • IV intravenous
  • Patient is a male or nonpregnant female patients 18 years of age or older.
  • RT-PCR reverse-transcriptase-polymerase-chain-reaction
  • ALT alanine aminotransferase
  • AST aspartate transaminase
  • 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.
  • the first dose is started within 6 hours of randomization.
  • the subsequent doses are administered 24 ⁇ 4 hours after the previous dose for a total of 4 doses.
  • a regular schedule for administering subsequent doses every 24 hours is established.
  • 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.
  • Patients receive SOC as adopted by the participating institution plus placebo. Normal saline is used as placebo. Patients receive a volume of normal saline equivalent to that containing active drug on a mL/kg basis.
  • H-CRP high-sensitivity C-reactive protein
  • D-dimer D-dimer
  • absolute lymphocyte count ferritin
  • myoglobin myoglobin
  • troponin lactate dehydrogenase
  • Sample size Approximately 100 patients are enrolled in this study.
  • K-M survival estimates Time to event variables are analyzed using Kaplan-Meier (K-M) survival estimates.
  • K-M survival curves will be 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 are presented.
  • a Mixed Model Repeated Measures (MMRM) analysis or Analysis of Covariance (ANCOVA) are carried out for continuous variables, depending on the number of assessments post-baseline.
  • MMRM Mixed Model Repeated Measures
  • ANCOVA Analysis of Covariance
  • 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) are 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 are evaluated over time on study using descriptive statistics. Shift analyses of relevant clinical laboratory parameters are produced showing shifts across low, normal, and high categories.
  • Example 40 Effect of Compound 1 on EhC -Induced Apoptosis in Bronchial Epithelial Cells
  • Bronchial epithelial cells (4MBr-5) were grown to sub-confluence and treated with vehicle or Compound 1 (10 mM) or HGF (50 ng/mL) for 24 hours. Cells were then challenged with H2O2 (200 mM) for 1 hour, washed with serum-free media and stained with FITC-labeled Annexin-V and propidium iodide (PI). Cells were analyzed for Annexin-V and PI stained fractions with a fluorescence-activated cell sorter and cells were divided in four staining categories based on Annexin and PI staining intensity.
  • Annexin-V staining precedes the loss of membrane integrity which accompanies the latest stages of cell death resulting from either apoptotic or necrotic processes. Therefore, staining with Annexin-V is used in conjunction with a vital dye such as propidium iodide to identify early apoptotic cells (PI negative, Annexin-V positive). Viable cells with intact membranes exclude PI, whereas the membranes of dead and damaged cells are permeable to PI. Cells that are considered viable are Annexin-V and PI negative; cells that are in early apoptosis are Annexin-V positive and PI negative; and cells that are in late apoptosis or already dead are both Annexin-V and PI positive. As shown in FIG. 34, both treatment with Compound 1 and with HGF changed the overall distribution of cells amongst different staining categories.
  • a vital dye such as propidium iodide
  • NIH/3T3 cells a mouse fibroblast cell line
  • DMEM fetal bovine serum
  • FBS 10% FBS
  • Cells were grown in culture flasks (T75 and T150) and incubated at 37 °C in an incubator conditioned with 5% CC .
  • growth medium was removed and the cell monolayer was rinsed with PBS and treated with 0.25% trypsin until the cell monolayer was detached, which was monitored under a microscope. Cells were dispersed by gentle pipetting and split into new flasks.
  • NIH/3T3 cells were seeded at 1000 to 1500 cells per well in 48-well plates in complete medium containing 10% serum, and grown to 30 to 40% confluency for 24 hours. Cells were then serum-starved for 1 to 2 hours in RPMI medium containing 1% BSA, followed by treatment with HGF (25 ng/mL), Compound 1 (17 mM), or DMSO for 16 to 24 hours.
  • HGF 25 ng/mL
  • Compound 1 17 mM
  • DMSO DMSO
  • [ 3 H]-Thymidine was added at 10 pCi/mL to the medium and incubation continued for another 4 to 5 hours. Cells were washed 3 times with PBS and lysed with 0.5 mL of alkaline lysis buffer containing 0.5 N NaOH and 1 % SDS.
  • NIH/3T3 fibroblasts were incubated with Compound 1 (5 mM) or HGF (25 ng/mL), and [ 3 H]-thymidine incorporation was used as a measure of cell proliferation.
  • Compound 1 5 mM
  • HGF 25 ng/mL
  • [ 3 H]-thymidine incorporation was used as a measure of cell proliferation.
  • NIH/3T3 fibroblasts which do not express the c-Met receptor, neither HGF nor Compound 1 stimulated cell proliferation.
  • serum which contains many growth stimulating factors, was evaluated in parallel and was found to stimulate NIH/3T3 cell proliferation.
  • Example 42 Compound 1 Protects Against Radiation-Induced Injury
  • Eight- to ten-week old male C57BL/6 mice were anesthetized with a mixture of ketamine (100 mg/kg) + xylazine (10 mg/kg)) via intraperitoneal injection. Mice were aligned on a prone position and exposed to total body irradiation (TBI) at 1 Gy /min for 7 min (7 Gy) using an MDS Nordion Gamma Cell-40 Exactor/Research Irradiator (Cs-137 source, Cold Spring Harbor Laboratories, NY) with a beam of collimator. Sham-irradiated mice were treated in the same way, except that the radiation source was not turned on. After irradiation, when the mice were fully awake and mobile, they were transported to the animal facility (15-minute drive).
  • BALF Bronchoalveolar lavage fluid
  • % transmission is an indicator of BAL turbidity, which is a readout of the number of all infiltrating white cells. Results are expressed as % transmittance readings and as D transmittance (the difference in % transmittance between experimental samples and background), which is directly proportional to BAL turbidity.
  • BALF Bronchoalveolar lavage fluid
  • a transmittance The difference in transmittance between experimental samples and background was calculated (A transmittance).
  • the A transmittance is proportional to BALF turbidity and an indicator of infiltration.
  • BALF turbidity was markedly increased in radiation-exposed vehicle-treated animals, indicating significant pulmonary infiltration as a result of radiation exposure.
  • turbidity was significantly reduced compared to the vehicle-treated cohort (FIG. 36B). This indicates that Compound 1 significantly reduced pulmonary infiltration resulting from radiation exposure.
  • Example 43 Compound 1 Protects Against TGFpi-Induced Acute Lung Injury (3-day study)
  • TGFpl -transgenic male and female mice were administered doxy cy dine (dox) in the drinking water (0.5 mg/mL dox and 20 g/L sucrose) to induce high level lung-specific expression of TGFpi.
  • dox doxy cy dine
  • dox feeding 0.5 mg/mL dox and 20 g/L sucrose in drinking water
  • lung tissue sections were immunohistologically stained with an antibody against proliferating cell nuclear antigen (PCNA), a marker of cell proliferation, and an antibody against Caspase-3, a marker of cell apoptosis.
  • PCNA proliferating cell nuclear antigen
  • Compound 1 -treated doxy cy cline-exposed animals showed a significant increase in PCNA staining compared to vehicle-treated animals (FIG. 37A). This indicates that Compound 1 stimulates lung cell proliferation after TGF 1 -induced pulmonary damage. It should be noted that no difference in PCNA staining between lungs from Control animals and TGF i Vehicle animals was expected, and that lung regeneration was only enhanced in the TGF i Compound 1 group.
  • Compound 1 -treated animals showed a significant decrease in Caspase-3 staining compared to vehicle-treated animals (FIG. 37B). This indicates that Compound 1 protects lung cells from TGF l -induced apoptosis.
  • Example 44 Compound 1 Protects Against TGFpi-Induced Acute Lung Injury (10-day study)
  • mice Eight-to-10 week old TGFpi -transgenic male and female mice (approximately 25 g body weight) were administered doxycycline (dox) in the drinking water (0.5 mg/mL dox and 20 g/L sucrose) to induce high level lung-specific expression of TGFpi.
  • dox doxycycline
  • Example 45 Effect of Compound 1 on Growth of c-Met-expressing Human Tumor Cells in Immunocompromised Mice
  • the culture medium used was Eagle's minimum essential medium (EMEM) modified with Eagle's balanced salt solution and 2 mM L-glutamine, 1 mM sodium pyruvate, 0.1 mM nonessential amino acids, and 1.5 g/L sodium bicarbonate, supplemented with 10% fetal bovine serum (FBS).
  • EMEM Eagle's minimum essential medium
  • FBS fetal bovine serum
  • PBS phosphate buffered saline
  • EDTA trypsin-ethylenediaminetetraacetic acid
  • FIG. 39A shows percent survival of Compound 1 vs vehicle treatment in a first study of an orthotopic glioma model.
  • FIG. 39B shows percent survival of Compound 1 vs vehicle treatment in a second study of an orthotopic glioma model.
  • HT29 Human colon cancer cells HT29 (obtained from ATCC), which express c-Met (Wielenga, V. J., et al. Am. J. Pathol. 2000 Nov; 157(5): 1563-73), were used in the colon tumor xenograft model.
  • HT-29 cells were maintained and cultured using protocols provided by ATCC and summarized as follows. Cells were grown in culture flasks (T75 and T150) and incubated at 37 °C in an incubator conditioned with 5% CCh. The culture medium used was McCoy's 5A medium modified to contain 1.5 mM L-glutamine and 2200 mg/L sodium bicarbonate, supplemented with 10% FBS.
  • Cells were separated from each other by gentle pipetting. Cells in culture were split twice a week at a ratio of approximately 1:5. Harvested cells were suspended in growth medium containing no serum for animal injection. Cells (1 x 106 cells in 100 pL) were injected SC in the right hind flank of BALB/c nude mice. Tumors were allowed to grow for 7 days, then animals were treated daily until Day 27 with 2 mg/kg Compound 1 or vehicle administered via 50 pL IP injection. Tumor size was measured with dial calipers on Days 7, 12, 15, 19, 22, 27 and survival was recorded. Animals were sacrificed on Day 27 and tumor size and weight was recorded.
  • FIG. 40A shows colon tumor size of Compound 1 vs vehicle treatment in a human colon tumor xenograft model.
  • Human pancreatic ductal carcinoma cells SUIT-2 obtained from the Japanese Collection of Research Bioresources [JCRB] Cell Bank), which express c-Met (Maehara, N., et al. ChBr J. Cancer 2001 Mar 23;84(6):864-73), were used in the pancreatic tumor xenograft model.
  • SUIT-2 cells were maintained and cultured using protocols provided by the JCRB Cell Bank and summarized as follows. Cells were grown in culture flasks (T75 and T150) and incubated at 37 °C in an incubator conditioned with 5% CO2. The culture medium used was Roswell Park Memorial Institute (RPMI) with 10% FBS.
  • RPMI Roswell Park Memorial Institute
  • FIG. 41A shows pancreatic tumor volume of Compound 1 vs vehicle treatment in a human pancreatic tumor xenograft model.
  • FIG. 41B shows pancreatic tumor weight of Compound 1 vs vehicle treatment in a human pancreatic tumor xenograft model.
  • Compound 1 treatment did not increase the size (FIG. 41 A) or weight (FIG. 41B) of the pancreatic tumor.
  • Example 46 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.
  • 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.
  • IV intravenous
  • Patient is a male or nonpregnant female patients 18 years of age or older.
  • RT-PCR reverse-transcriptase-polymerase-chain-reaction
  • ALT alanine aminotransferase
  • AST aspartate transaminase
  • UPN upper limit of normal
  • TCB total bilirubin
  • CYP1A2 cytochrome P450 1A2
  • 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.
  • 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.
  • Normal saline was used as placebo. Patients received a volume of normal saline equivalent to that containing active drug on a mL/kg basis.
  • H-CRP high-sensitivity C-reactive protein
  • D-dimer D-dimer
  • absolute lymphocyte count ferritin
  • myoglobin myoglobin
  • troponin lactate dehydrogenase
  • Sample size Approximately 100 patients were enrolled in this study.
  • Methods Continuous variables were summarized with descriptive statistics (number of non-missing values [n], mean, median, standard deviation [SD], minimum, and maximum).
  • K-M Kaplan-Meier
  • CIs 95% confidence intervals
  • ANCOVA Analysis of Covariance
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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. [0435] CT Scan (as clinically indicated): Computed tomography (CT) scan was conducted at Screening/Baseline and at Day 28 ⁇ 2.
  • Chest X-rav Chest x-ray was conducted at Screening/Baseline and as indicated per soc.
  • 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 (Sa02) 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 Sa02, Pa02, and Fi02 was measured as available.
  • Intensive Care Unit Admission and Discharge Dates Intensive care unit admission and discharge dates on or before Day-28/Final Visit were recorded.
  • 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.
  • 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 (lE,4E)-l-(dimethylamino)-5-(thiophen-2-yl)penta-l,4-dien-3-one (2.3) [0444] 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.
  • 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.
  • Compound 1 was provided (e.g., via the method of Example 47) in a form with an XRPD as shown in FIG. 42, a TGA as shown in FIG. 43, and a DSC as shown in FIG. 44.
  • this material is referred to as “Compound 1 Lot I.”
  • 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. [0454] 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 pm PTFE syringe filter.
  • TGA of Compound 1 Form A is shown in FIG. 48. A weight loss of 0.6% was observed up to 150 °C.
  • Ill and 0.22 mih 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.

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Abstract

L'invention concerne des technologies pour traiter une ou plusieurs maladies, troubles ou états respiratoires par l'administration de (E)-3-[2-(2-thiényl)vinyl]-1H-pyrazole.
PCT/US2021/021926 2020-03-12 2021-03-11 Traitement de la détresse respiratoire aiguë WO2021183774A1 (fr)

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CN114716417A (zh) * 2022-06-09 2022-07-08 北京远大九和药业有限公司 化合物与富马酸的结晶形式的原料药及其药物组合物和用途
US11655240B1 (en) 2022-05-10 2023-05-23 Beijing Grand Johamu Pharmaceutical Company, Ltd. Crystal form of compound and fumaric acid, pharmaceutical composition and method for treating coronavirus-induced diseases
WO2023163971A1 (fr) * 2022-02-23 2023-08-31 Athira Pharma, Inc. Méthodes de traitement de troubles liés à la covid
WO2023225628A3 (fr) * 2022-05-20 2023-12-21 Janssen Pharmceutica Nv Procédés pour atténuer une lésion pulmonaire conjointement avec une exposition à un rayonnement et/ou à des traitements par rayonnement ou radiomimétiques

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Publication number Priority date Publication date Assignee Title
WO2023163971A1 (fr) * 2022-02-23 2023-08-31 Athira Pharma, Inc. Méthodes de traitement de troubles liés à la covid
US11655240B1 (en) 2022-05-10 2023-05-23 Beijing Grand Johamu Pharmaceutical Company, Ltd. Crystal form of compound and fumaric acid, pharmaceutical composition and method for treating coronavirus-induced diseases
WO2023225628A3 (fr) * 2022-05-20 2023-12-21 Janssen Pharmceutica Nv Procédés pour atténuer une lésion pulmonaire conjointement avec une exposition à un rayonnement et/ou à des traitements par rayonnement ou radiomimétiques
CN114716417A (zh) * 2022-06-09 2022-07-08 北京远大九和药业有限公司 化合物与富马酸的结晶形式的原料药及其药物组合物和用途
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