WO2023062595A1 - Traitement de sujets atteints d'hypertension artérielle pulmonaire à l'aide de rodatristat éthyle - Google Patents

Traitement de sujets atteints d'hypertension artérielle pulmonaire à l'aide de rodatristat éthyle Download PDF

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WO2023062595A1
WO2023062595A1 PCT/IB2022/059864 IB2022059864W WO2023062595A1 WO 2023062595 A1 WO2023062595 A1 WO 2023062595A1 IB 2022059864 W IB2022059864 W IB 2022059864W WO 2023062595 A1 WO2023062595 A1 WO 2023062595A1
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bid
rodatristat
ethyl
subject
administered
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PCT/IB2022/059864
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Howard LAZARUS
Jill DENNING
Stephen Wring
William Symonds
Michelle PALACIOS
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Altavant Sciences Gmbh
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present disclosure relates to methods for treating a subject diagnosed with pulmonary arterial hypertension (PAH) by administering a therapeutic amount of rodatristat ethyl to the subject.
  • PAH pulmonary arterial hypertension
  • Pulmonary arterial hypertension is a severe, incurable disease characterized by remodeling of the pulmonary arterial bed, leading to elevations in resting mean pulmonary artery pressures, subsequent right ventricular hypertrophy, and eventually, right heart failure and death.
  • Current standard-of care therapies for PAH target three different pathways - namely, the endothelin-1 pathway, the nitric oxide pathway, and the prostacyclin pathway. Humbert M. Ghofrani H-A. Thorax 2016: 71;73-83. doi: 10. 1136/thoraxjnl-2015-207170.
  • Serotonin-targeted approaches for the treatment of PAH have been evaluated. These include receptor antagonists (e.g., ketanserin and terguride), or transporter reuptake inhibitors (e.g., fluoxetine). Unfortunately, the results have been disappointing and limited by several factors including choice of receptor target, inadequate drug exposure, and importantly, blockade of only one pathway or receptor that allows for an increase in serotonin availability for other pathway s/receptors. Serotonin’s broad activity across these multiple pathways may explain why neither serotonin transporter inhibition nor subtype -specific serotonin receptor antagonists alone have been able to fully reverse the negative effects caused by excess local serotonin in PAH. No clinical studies have evaluated reduction in the overall peripheral and lung serotonin pool via TPH1 inhibition.
  • receptor antagonists e.g., ketanserin and terguride
  • transporter reuptake inhibitors e.g., fluoxetine
  • Rodatristat ethyl (RVT-1201) is a pro-drug for the active tryptophan hydroxylase (TPH1) inhibitor rodatristat (KAR5417) and is in development for treatment of PAH. Following oral administration, rodatristat ethyl is rapidly absorbed and hydrolyzed to rodatristat, KAR5417.
  • TPH1 active tryptophan hydroxylase
  • a method of reducing or eliminating one or more symptoms of PAH in an unhealthy subject comprising administering a therapeutic amount of rodatristat ethyl to the subject.
  • a method of improving exercise capacity in an unhealthy subject comprising administering a therapeutic amount of rodatristat ethyl to the subject.
  • the exercise capacity of the subject may increase by more than about 10% over a baseline for the subject.
  • a method of lowering pulmonary vascular resistance (PVR) in an unhealthy subject comprising administering a therapeutic amount of rodatristat ethyl to the subject is disclosed.
  • the pulmonary vascular resistance (PVR) may be reduced by more than about 5%, from a baseline for the subject.
  • a method of reducing an occurrence of hospitalizations for PAH in an unhealthy subject over a treatment period comprising administering a therapeutic amount of rodatristat ethyl to the subject.
  • the occurrence of hospitalizations may be reduced by about more than about 5% over a baseline of the subject and/or over an average rate of occurrence of hospitalization for untreated unhealthy subjects.
  • a method for slowing disease progression of PAH in an unhealthy subject over a period of about 24 weeks, about one year, about two years, or more, comprising administering rodatristat ethyl to the subject is disclosed.
  • a method for reducing a concentration of N-terminal pro-brain natriuretic peptide in an unhealthy subject over a treatment period comprising administering a therapeutic amount of rodatristat ethyl to the subject.
  • the treatment period may be about 24 weeks to about two years.
  • the concentration of N-terminal pro-brain natriuretic peptide may be reduced by about more than about 5%, over a baseline for the subject.
  • a method of improving right ventricular function or reducing right atrial size in an unhealthy subject comprising administering a therapeutic amount of rodatristat ethyl to the subject.
  • the rodatristat ethyl may be rodatristat ethyl, Form 3.
  • the therapeutic amount may be about 200 mg to about 2400 mg of rodatristat ethyl administered to the subject once daily.
  • the therapeutic amount may be about 100 mg to about 1200 mg of rodatristat ethyl administered to the subject twice per day (BID), or about 100 mg BID, 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl.
  • the therapeutic amount may be administered to the subject for a period of about 24 weeks.
  • Figure 1 is a plot of an XRPD of a crystalline compound of (S)-ethyl 8-(2-amino-6- ((R)- 1 -(5-chloro-[ 1 , 1 '-biphenyl] -2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8- diazaspiro[4.5]decane-3-carboxylate according to the present disclosure (crystalline Form 3).
  • Figure 2 is a table showing different dosing regimens administered during a study of rodatristat ethyl, including a treatment period and an open label extension period.
  • Figure 3 is a graph showing results of a study of dose-dependent reductions in the development of occluded vessels following rodatristat ethyl treatment to rats.
  • Rodatristat is metabolically stable and has low potential for drug interactions with PAH medications. There is low potential for metabolic drug-drug interactions (DDIs) between rodatristat ethyl and approved medications for pulmonary arterial hypertension (PAH).
  • DCIs metabolic drug-drug interactions
  • Rodatristat ethyl is in Phase 2 clinical development (ELEVATE 2 Study) for PAH.
  • RE is an orally bioavailable pro-drug for the tryptophan hydroxylase (TPH) inhibitor, rodatristat (R).
  • TPH1 is the rate-limiting enzyme for peripheral biosynthesis of serotonin (5-HT) and is up-regulated in PAH. Excess 5-HT has been implicated in the pathology of PAH. See MacLean, M.R. 2018. The serotonin hypothesis in pulmonary hypertension revisited: targets for novel therapies. Pulm Circ. 8 (2). 1-9.
  • Rodatristat ethyl is regarded as safe and well tolerated following once or twice daily dosing, with no deaths, serious adverse events nor dose-limiting toxicities identified.
  • Over 150 healthy subjects have received either single or multiple dose (up to 14 days of 800 mg BID) rodatristat ethyl regimens. Healthy subjects may receive multiple doses of rodatristat ethyl over the range 100 to 800 mg BID or 500 to 800 mg once daily for 14 days.
  • Pharmacodynamic assessments for reduction in serotonin biosynthesis have demonstrated robust, dose-dependent reductions of 5-hydroxyindoleacetic acid (5-HIAA), the major biomarker metabolite of serotonin, in plasma and urine. Reductions in serotonin biosynthesis may exceed those associated with efficacy in rat monocrotaline and SUGEN hypoxia models of PAH.
  • 5-hydroxyindoleacetic acid 5-HIAA
  • (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2- trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is referred to herein rodatristat ethyl (RE) and in the literature also as KAR5585 and RVT-1201.
  • Rodatristat ethyl has the following structure:
  • Form 3 exhibits the following x-ray powder diffraction pattern (XRPD):
  • the x-ray powder diffraction pattern is carried out with a Cu K ⁇ radiation source according to the following method: PANalvtical X'Pert PRO MPD Diffractometer - Reflection Geometry
  • Selected XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu K ⁇ radiation produced using a long, fine-focus source and a nickel filter.
  • the diffractometer was configured using the symmetric Bragg- Brentano geometry.
  • a silicon specimen NIST SRM 640e was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position.
  • a specimen of the sample was prepared as a thin, circular layer centered on a silicon zero-background substrate.
  • Antiscatter slits (SS) were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) and the incident- beam SS.
  • X'Celerator scanning position-sensitive detector located 240 mm from the sample and Data Collector software v. 2.2b.
  • the data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) and the incident- beam SS.
  • Figure 1 was generated using validated software PattemMatch v 2.3.6.
  • rodatristat ethyl is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1- biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid, which has the following structure:
  • rodatristat (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1-biphenyl]-2-yl)-2,2,2-trifluoroeth- oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid is referred to herein as rodatristat.
  • Rodatristat is also referred to in the literature as KAR5417. When rodatristat ethyl enters the bloodstream, it substantially converts to rodatristat.
  • the amorphous form of KAR5417 can be prepared by the method set forth in Example 34c of U.S. Patent No. 9,199,994, which again is incorporated herein in its entirety.
  • Rodatristat ethyl doses selected for use in the treatment of unhealthy subjects described herein may achieve a clinically meaningful reduction in serotonin in the majority (e.g., more than about 50%, more than about 60%, more than about 65%, more than about 70%, more than about 75%, more than about 80%, or more than about 85%) of patients with PAH.
  • An unhealthy subject as referred to herein, means a human diagnosed with PAH or otherwise having PAH.
  • PAH treatable includes (1) idiopathic (IPAH), (2) heritable (HPAH), and (3) associated (APAH), which is the most common type of PAH.
  • PAH associated with other medical conditions including, , (a) collagen vascular disease (or connective tissue disease; PAH-CTD) which include autoimmune diseases such as scleroderma or lupus; (b) congenital heart and lung disease; PAH-CHD (c) portal hypertension (e.g., resulting from liver disease); PoPH; (d) HIV infection; and (4) drugs or toxins (e.g., appetite suppressants, cocaine, and amphetamines).
  • Symptoms of PAH include the following: fatigue, lethargy, exertional dyspnea, presyncope/syncope, cough, hoarseness, hypotension, fluid retention, lower extremity edema, chest pain, and cyanosis.
  • the amount of rodatristat ethyl to be administered will vary depending on factors such as the following: the compound selected, method of administration, release profde, and composition formulation.
  • a typical dosage will be a therapeutic amount of about 1 mg/kg/day to about 50 mg/kg/day and more typically from about 5 mg/kg/day to about 30 mg/kg/day, based on the weight of the patient.
  • a most preferred compound is rodatristat ethyl in crystalline Form 3.
  • Individual oral dosage forms typically have therapeutic amounts from about 50 mg to about 3000 mg of rodatristat ethyl and additional amounts of one or more pharmaceutically acceptable excipients.
  • Other useful individual oral dosage forms can, by way of example, have rodatristat ethyl or rodatristat in amounts of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, 450 mg, 500 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, and about 1200 mg, particularly 600 mg and 1200 mg, or 300 mg and 600 mg.
  • Other amounts between 50 mg to 3000 mg are possible, for example, from about 325 mg to about 475 mg, from about 350 mg to about 500 mg, from about 375 mg to about 525 mg, from about 400 mg to about 550 mg, from about 425 mg to about 575 mg, from about 450 mg to about 600 mg, from about 475 mg to about 625 mg, from about 500 mg to about 650 mg, from about 525 mg to about 675 mg, from about 550 mg to about 700 mg, from about 575 mg to about 725 mg, from about 600 mg to about 750 mg, from about 625 mg to about 775 mg, from about 650 mg to about 800 mg, from about 675 mg to about 825 mg, from about 700 mg to about 850 mg, from about 725 mg to about 875 mg, from about 750 mg to about 900 mg, from about 775 mg to about 925 mg, from about 800 mg to about 950 mg, from about 825 to about 975, from about 850 mg to about 1000 mg, from about 900 mg to about 1150 mg
  • a oral dosage form has up to 600 mg of rodatristat ethyl, optionally Form 3, taken twice per day (BID), for a total of up to 1200 mg per day.
  • Another oral dosage form has up to 300 mg of rodatristat ethyl, optionally Form 3, taken twice per day, for a total of up to 600 mg per day. It is also possible to take these preferred dosage forms on a once-per-day (SID) basis or three times per daily basis (TID).
  • the unit doses of rodatristat ethyl may be taken about 12 hours apart. In a regimen of twice daily dosing, the unit doses of rodatristat ethyl may be taken about 12 hours apart with food.
  • the therapeutic amount may be about 100 mg to about 1200 mg of rodatristat ethyl administered to the subject twice per day (BID), or about 100 mg BID, 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl.
  • the therapeutic amount may be about 200 mg to about 2400 mg of rodatristat ethyl administered to the subject once daily, or about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300, or about 2400 mg of rodatristat ethyl administered once daily.
  • the duration of treatment may vary depending on factors such as the following: the compound selected, method of administration, health of the subject, and composition formulation.
  • rodatristat ethyl in an oral dosage form to treat a disease particularly PH/PAH/APAH/IPAH/HPAH
  • rodatristat ethyl may be administered for one week to about 52 weeks, or more, and any amount of time therebetween, e.g., 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, and so forth.
  • the method disclosed herein may include a period of administration of rodatristat ethyl, followed by a rest period, during which time rodatristat ethyl is not administered to the patient.
  • the rest period may be less than one week, one week, or more than one week, e.g., 10 days, two weeks, three weeks, or more.
  • a method may include administering a therapeutically effective amount, about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • a method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • a method may include administering a therapeutically effective amount, about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • Methods of this disclosure with doses of about 300 mg to about 600 mg BID have a high probability, that is over about 60%, of achieving a targeted about 40% reduction in serotonin biosynthesis in an unhealthy subject.
  • dosing regimens of about 300 mg to about 600 mg BID may have a high probability, that is over about 60%, of lowering serotonin biosynthesis to an extent that has the potential to lower pulmonary vascular resistance (PVR) and improve exercise capacity over an about 24-week treatment period.
  • PVR as used herein, is measured by right heart catheterization (RHC) in subjects with PAH. The parameters measured during the RHC are listed below: o Heart rate - Heart rate is determined at the time of the cardiac output (CO) measured by thermodilution.
  • CO is measured until two consecutive values do not differ by >10%; the last value is recorded in the electronic case report form (eCRF).
  • eCRF electronic case report form
  • o Cardiac Output by the Thermodilution Method - Thermodilution is the protocol-required method for the estimation of CO. At least three determinations that are within 10% variability of one another must be measured. Measurements must be repeated until this reliability is met.
  • the mean CO is defined as the average of these three measurements and used for the calculation of PVR.
  • the mean value is recorded in the eCRF. Investigators must ensure that the individual values and the calculation of the mean are recorded in the source documents.
  • Pulmonary capillary wedge pressure or left ventricular end diastolic pressure The pulmonary capillary wedge pressure or left ventricular end diastolic pressure should be recorded as the mean of three separate measurements taken at end- expiration, involving balloon deflation and re wedging of the balloon for these separate measurements. It is strongly preferred that the same assessment (pulmonary capillary wedge pressure or left ventricular end diastolic pressure) be performed for RHC assessments. In situations where this is not possible, the investigator should provide an explanation in the eCRF. All values should be available in the source documents. o Mixed venous oxygen saturation - Blood gas by pulmonary artery mixed venous blood sample should be measured and recorded in the eCRF. All values should be available in the source documents. o Five parameters will be calculated.
  • Pulmonary artery compliance ratio of stroke volume to pulmonary artery pulse pressure
  • Body surface area (m 2 ) 0.007184 x (weight in kilograms) 0425 x (height in centimeters) 0725
  • Exercise capacity as used herein may be determined by the standard six- minute walk test, which is a simple, commonly used, standardized measure of functional exercise capacity and endurance. It is performed in accordance with the American Thoracic Society Guidelines. American Thoracic Society. ATS statement: guidelines for the six- minute walk test. Am J Respir Crit Care Med 2002; 166(1): 111-7 [Erratum: ATS statement guidelines for the six-minute walk test. Am J Respir Crit Care Med 2016 193(10): 1185] . An increase from baseline in the six-minute walk distance (6MWD) following intervention indicates symptomatic improvement over that period. Improvement in 6MWD has been correlated with improvements in quality of life.
  • a method of improving exercise capacity in an unhealthy subject comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • exercise capacity qualified herein as the 6MWD
  • a method of lowering pulmonary vascular resistance (PVR) in an unhealthy subject comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • Lowering pulmonary vascular resistance (PVR) may mean a percent change of more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 30%, more than about 40%, or more than about 50% from baseline to 24 weeks of pulmonary vascular resistance in an unhealthy subject.
  • Lowering pulmonary vascular resistance may mean a percent change of about 5% to about 90%, about 10% to about 80%, about 15% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 80% from baseline to 24 weeks of PVR in an unhealthy subject.
  • Baseline as used in this method is the PVR of the subject prior to the beginning of treatment.
  • a method of reducing the incidence of mortality in an unhealthy subject over a period of about 24 weeks, about one year, about two years, or more, comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • the incidence of mortality may be reduced compared to unhealthy subjects not receiving treatment by about more than about 5%, more than about 10%, more than about 15%, more than about 20%, or more than about 50%.
  • a method of reducing an occurrence of hospitalizations for PAH e.g., any hospitalization for worsening PAH, lung, or heart and lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy
  • PAH e.g., any hospitalization for worsening PAH, lung, or heart and lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • a method for slowing disease progression of PAH in an unhealthy subject over a period of about 24 weeks, about one year, about two years, or more, comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • Disease progression is defined herein as a decrease of >15% from baseline in the six-minute walk distance (6MWD) combined with World Health Organization (WHO) Functional Class II or III (WHO FC III or IV) symptoms at two consecutive visits separated by at least 14 days (adjudicated). Disease progression may be reduced compared to unhealthy subjects not receiving treatment by about more than about 5%, more than about 10%, more than about 15%, more than about 20%, or more than about 50%.
  • 6MWD six-minute walk distance
  • WHO FC III or IV World Health Organization
  • Disease progression may be reduced compared to unhealthy subjects not receiving treatment by about more than about 5%, more than about 10%, more than about 15%, more than about 20%, or more than about 50%.
  • a method for improving hemodynamics in an unhealthy subject over a treatment period, e.g., of about 24 weeks, about one year, about two years, or more, comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein is disclosed.
  • Hemodynamics include one or more of the following: cardiac output, cardiac index, mPAP, right atrial pressure, pulmonary vascular resistance (PVR), pulmonary arterial wedge pressure, mixed venous oxygen saturation, and pulmonary artery compliance.
  • the method for improving hemodynamics may include lowering PVR in the subject by more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 30%, more than about 40%, or more than about 50% from baseline in the subject.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • a method for reducing a concentration of N-terminal pro-brain natriuretic peptide in an unhealthy subject over a period of about 24 weeks, about one year, about two years, or more, comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein comprising administering rodatristat ethyl to the subject according to any of the dosing regimens set forth herein is disclosed.
  • N-terminal pro-brain natriuretic peptide concentration is a strong predictor of disease progression and mortality in patients with PAH, and its concentrations are a good marker of response to treatment.
  • the concentration of N- terminal pro-brain natriuretic peptide may be reduced compared to a baseline for the unhealthy subject by about more than about 5%, more than about 10%, more than about 15%, more than about 20%, or more than about 50%.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • a method of improving right ventricular function in an unhealthy subject comprising administering rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • PAH can cause a reduction in right ventricular function by 10% to greater than 50%.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • Improving right ventricular function may be detected by comparing serial echocardiography from baseline to after treatment of an unhealthy subject.
  • Baseline right ventricular function is the right ventricular function of the subject prior to the beginning of treatment.
  • Resting cardiac echocardiographic endpoints include right atrial size and measures of right ventricular function (tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and right ventricular fractional area change).
  • a core imaging laboratory for centralized blinded adjudication of the echocardiogram endpoints is used.
  • right ventricular function measured as mean change in systolic excursion of the tricuspid annular plane measured by serial echocardiography, may improve by more than about 5%, more than about 10%, more than about 20%, more than about 30%, or more than about 50%, over baseline right ventricular function.
  • a method of reducing right atrial size in an unhealthy subject comprising administering rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • Right atrial enlargement is an abnormally large upper chamber of your heart. This may occur when there is too much blood or the pressure is high in the right atrium.
  • One cause of right atrium enlargement is PAH.
  • right atrial size may be reduced by about more than about 5%, more than about 10%, more than about 15%, more than about 20%, or more than about 50% from baseline for the subject.
  • Baseline right atrial size is the right atrial size of the subject prior to the beginning of treatment.
  • An echocardiogram may be used to measure right atrial size and right ventricular function.
  • a method of reducing or eliminating one or more symptoms of PAH in an unhealthy subject comprising administering rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period. Symptoms may be reduced from baseline in the subject, i.e., pretreatment.
  • a method for the treatment of an unhealthy subject comprising administering rodatristat ethyl according to any of the dosing regimens set forth herein, wherein, compared to baseline, the unhealthy subject experiences one or more of the following: lowering in PVR; change in cardiac index, mPAP, mean right atrial pressure, mixed venous oxygen saturation, and/or pulmonary artery compliance; prolonged time to clinical worsening; change in WHO FC III or IV symptoms; improved 6MWD; reduced concentration in N-terminal pro-brain natriuretic peptide; reduced right arterial size; and change in right ventricle function: tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and/or right ventricle fractional area change from baseline.
  • the foregoing changes may be an increase or decrease of the condition/symptom in a manner that is an improvement over the baseline of that condition/symptom measured in the unhealthy subject.
  • Reduction of the occurrence of adverse side effects may mean that at least one of the five safety endpoints is reduced by over about 50%.
  • Reduction of the occurrence of adverse side effects may mean that at least one of the five safety endpoints is reduced by over about 50%, and at least one additional safety endpoint is reduced by over about 10%.
  • a method of achieving a reduction in urinary 5-HIAA in an unhealthy subject within 14 days after administration comprising administering to the subject an effective amount of rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • the reduction in urinary 5-HIAA in the subject may be greater than about 20%, greater than about 30%, or greater than about 40%.
  • a method for reducing the level of serotonin biosynthesis in an unhealthy subject within 14 days after administration comprising administering to the subject an effective amount of rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • the method may include administering about 100 mg to about 2400 mg of rodatristat ethyl once daily to an unhealthy subject.
  • the method may include administering about 100 mg to about 1200 mg, or about 200 mg to about 1000 mg of rodatristat ethyl twice per day (BID) to an unhealthy subject.
  • the method may include administering about 200 mg BID, about 300 mg BID, about 400 mg BID, about 500 mg BID, about 600 mg BID, about 700 mg BID, about 800 mg BID, about 900 mg BID, about 1000 mg BID, about 1100 mg BID, or about 1200 mg BID of rodatristat ethyl to an unhealthy subject for a period of about 24 weeks to about 2 years, about 24 weeks, or other treatment period.
  • the reduction in the level of serotonin biosynthesis may be at least about 20%, at least about 30%, or at least about 40% in an unhealthy subject within 14 days after administration comprising administering to the subject an effective amount of rodatristat ethyl according to any of the dosing regimens set forth herein is disclosed.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, individual or human that is being sought by a researcher, medical doctor or other clinician.
  • the therapeutically effective amount of the compound may range from about 10 mg/kg/day to about 1000 mg/kg/day.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • a compound or composition of this disclosure can be administered orally, subcutaneously, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Parenteral administration can involve subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
  • compositions can be prepared as solid dosage forms for oral administration (e.g., capsules, tablets, pills, powders, granules and the like).
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can include one or more binders, lubricants, glidants, inert diluents, preservatives, disintegrants, or dispersing agents.
  • Tablets and other solid dosage forms, such as capsules, pills and granules can include coatings, such as enteric coatings.
  • ELEVATE 2 is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial comparing the efficacy, safety, and tolerability of two rodatristat ethyl oral regimens in patients with PAH over a 24-week treatment period. Participants are randomized 1 : 1 : 1 to placebo, 300 mg BID or 600 mg BID of rodatristat ethyl ( Figure 2).
  • the Main Study consists of clinic visits (Screening, Day 1, Week 4, Week 12, and Week 24), the option of a clinic or home visit (Week 18 and Week 28 [Follow-up Visit], and telemedicine/phone calls (Week 2 and Week 8).
  • the first 24 weeks of the OLE will mirror that of the Main Study with clinic visits (Day 1 [Week 24 of the Main Study], Week 4, Week 12, and Week 24), the option of a clinic or home visit (Week 18 and Early Termination [if applicable]), and telemedicine/phone calls (Week 2 and Week 8).
  • the OLE will consist of phone calls and clinic visits every four and 24 weeks, respectively with a follow-up visit four weeks after the last dose of rodatristat ethyl should a patient discontinue treatment.
  • Total trial duration for patients that either terminate early or do not enroll in the OLE will be ⁇ 32 weeks.
  • Criteria for temporary or permanent discontinuation of IP include changes associated with liver chemistry, severe gastrointestinal abnormalities, electrocardiogram, and psychiatric evaluations. An interim analysis for safety will be performed at Week 12.
  • An external, multidisciplinary Independent Data Monitoring Committee will review the progress of the trial and perform interim reviews of unblinded safety and efficacy data at regular intervals and provide safety recommendations.
  • An external, separate, Independent Adjudication Committee will standardize the review of the clinical worsening endpoint and reduce the bias and variability from investigators involved in the study.
  • Rodatristat ethyl is provided as a 300-mg oral tablet manufactured by Patheon Pharmaceuticals (Ontario, Canada). All participants receive two tablets BID based on their randomization (either 2 x matched placebo (placebo), 1 x 300 mg and 1 x placebo, or 2 x 300 mg). The rodatristat ethyl doses selected are based on prior pharmacodynamic observations in nonclinical models of PAH and pharmacokinetic, pharmacodynamic, safety, and tolerability data in healthy subjects receiving rodatristat ethyl for up to 14 days.
  • Temporary dosage reductions may be made to manage an adverse event including gastrointestinal (e.g., diarrhea, nausea, or vomiting) or liver enzyme increase occurring during the 24 weeks of the study. Judicious use of antidiarrheal and/or anti-emetic medications are permitted. One level of dose reduction is allowed. If an adverse event(s) continues, the patient may stop taking the IP completely for up to seven days before restarting. All determinations of IP dose reduction are to be discussed with the medical monitor prior to implementing unless time does not allow for safety.
  • the Sponsor, investigators, study-site personnel, patients, and statisticians are blinded. The IP is taken approximately 12 hours apart with food. Participants receive at least four bottles of IP for four weeks of dosing at each clinic visit or by mail. Participant compliance as assessed at each visit by the study-site personnel consists of direct questioning and counts of IP supplies. Patients are reminded of the importance of taking their IP as directed.
  • the primary objective is to evaluate the effect of rodatristat ethyl on the percent change from baseline of PVR, as measured by right heart catheterization (RHC) in patients with PAH.
  • RHC right heart catheterization
  • Hemodynamics cardiac index, mPAP, mean right atrial pressure, mixed venous oxygen saturation, and pulmonary artery compliance
  • Time to clinical worsening defined as the first occurrence of a composite endpoint of 1) death from any cause; 2) hospitalization for worsening PAH (any hospitalization for worsening PAH, lung, or heart and lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy); and 3) disease progression defined as a decrease of >15% from baseline in the six-minute walk distance (6MWD) combined with WHO FC III or IV symptoms at two consecutive visits separated by at least 14 days (adjudicated).
  • 6MWD six-minute walk distance
  • Echocardiographic measures of right atrial size and right ventricular function (tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and right ventricular fractional area change)
  • PAH-SYMPACT® Pulmonary Arterial Hypertension- Symptoms and Impact
  • the purpose of the OLE is to provide continuous, uninterrupted access to rodatristat ethyl for patients who participated in the Main Study if the patient appears to benefit from the therapy as determined by the investigator and patient.
  • the OLE also provides patients receiving placebo during the Main Study the opportunity to receive treatment with rodatristat ethyl (300 or 600 mg BID).
  • the objective of the OLE is to evaluate the long-term safety, tolerability, and efficacy of rodatristat ethyl in patients with PAH. There are five safety endpoints:
  • the efficacy endpoints include:
  • IP investigational product
  • PAH pulmonary arterial hypertension
  • Stable therapy is defined as receiving the same medication(s) for >12 weeks prior to the screening RHC and at a stable dose level for each for >8 weeks prior to the screening RHC. Any instances where doses of a medication have been missed prior to RHC must be discussed with the Medical Monitor prior to performing the RHC
  • WHO pulmonary hypertension (PH) Group 1 PAH associated with portal hypertension or schistomomiasis, PH due to left heart disease (WHO PH Group 2), lung diseases and/or hypoxia (WHO PH Group 3), chronic thromboembolic PH (WHO PH Group 4), or PH with unclear multifactorial mechanisms (WHO PH Group 5)
  • PAH associated with significant venous or capillary involvement pulmonary capillary wedge pressure >15 mmHg
  • pulmonary capillary hemangiomatosis pulmonary capillary hemangiomatosis
  • portal hypertension or unrepaired congenital heart defects
  • Atrial fibrillation e. Atrial fibrillation f. Left atrial volume index >41 mL/m 2 [or left atrial diameter (LA) > 4 cm if LAVi unavailable]
  • the patient has a history of, or currently has, a constrictive cardiomyopathy
  • valvular heart disease as determined by the Investigator, including a. Greater than mild aortic and/or mitral stenosis and/or b. Severe mitral and/or aortic regurgitation (> Grade 3).
  • End stage renal disease defined as receiving peritoneal dialysis hemodialysis, or status after renal transplantation, or severe liver disease defined as Child-Pugh Class C, with or without cirrhosis
  • Depression that is currently rated as severe defined as a score of >16 on the Quick Inventory of Depressive Symptomatology [Clinician Rated] and/or Hospital Anxiety and Depression Scale depression and/or anxiety score >15), recent suicidal behavior (either preparatory acts/behavior, aborted attempt, interrupted attempt, or actual attempt in the past three months per the screening Columbia-Suicide Severity Rating Scale), or active suicidal ideation with intent to act (defined as Columbia-Suicide Severity Rating Scale category score of 4 or 5 in the past month)
  • Male patients are eligible to participate if they do not have a female partner who is pregnant or who intends to become pregnant during the Open-Label Extension. Male patients and female partners must agree to use protocol-approved contraception starting four weeks prior to the first dose of IP, during the treatment period, and for at least 100 days after the last dose of IP. Male patients must refrain from donating sperm during this period.
  • the planned sample size is 90 patients with 30 patients randomized to each of 3 treatment cohorts in a 1: 1: 1: randomization. Thirty patients per cohort will provide at least 80% power at a significance level of 0.05 (2-sided hypothesis) to detect a treatment difference of 0.75 times of standard deviation in the percentage change for PVR from baseline between an active cohort and the placebo cohort.
  • PAH pulmonary arterial hypertension
  • IRT interactive response technology
  • IP investigational product
  • QIDS-C Quick Inventory of Depressive Symptomatology (Clinician Rated); WHO FC: World Health Organization Functional Class; NT -pro BNP: N-terminal pro-brain natriuretic peptide level; PAH SYMPACT: Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire; 5-HIAA: 5- hydroxyindoleacetic acid
  • IRT interactive response technology
  • Selexipag and its active metabolite, ACT-333679 are prostacyclin receptor agonists approved for the treatment of PAH, and they are substrates of cytochrome P4502C8.
  • a potential for a weak interaction with substrates of the drug metabolizing enzyme cytochrome P450 2C8 was identified in vitro experiments and in silico modeling for rodatristat ethyl. Since selexipag and ACT-333679 are substrates of cytochrome P450 2C8, a selexipag-rodatristat clinical interaction study in healthy subjects was performed.
  • Blood samples for pharmacokinetic analysis of plasma rodatristat ethyl, rodatristat, selexipag, and ACT-333679 are collected and plasma concentrations will be determined using validated liquid chromatography with tandem mass spectrometry methods.
  • blood samples for evaluation of plasma rodatristat ethyl and rodatristat are collected predose on Day 1 and Week 4, Week 12 (a postdose blood sample collected between 1 and 8 hours after the morning dose), and Week 24 (if the patient enrolls in the OLE, this blood sample will be collected prior to the morning rodatristat ethyl dose).
  • Blood samples for evaluation of selexipag and ACT-333679 are collected during the Main Study (predose on Day 1 and Week 4) and during the first 24 weeks of the OLE (OLE baseline visit and Week 4). Patients will take their selexipag in the clinic at these visits allowing the pharmacokinetic samples to be collected approximately 12 hours after the prior dose. Blood samples for the pharmacokinetic analysis of selexipag and ACT-333679 are only collected in patients whose standard-of-care therapy includes selexipag.
  • 5-HIAA is a stable metabolite of serotonin and a target-specific biomarker of its biosynthesis. Blood samples and urine samples are being collected for determination of plasma and urine 5-HIAA and creatinine-corrected 5-HIAA concentrations at predose on Day 1 and at Weeks 4, 12, and 24. Plasma and urine concentrations of 5-HIAA will be determined using validated liquid chromatography with tandem mass spectrometry methods. Urine creatinine will be measured by means of a Roche Cobas (Roche Diagnostics, Indianapolis, IN, USA) using the Roche Jaffe creatinine method as part of the clinical chemistry panel.
  • the change from baseline to Week 24 will be analyzed using an analysis of covariance model with treatment as a fixed effect, randomization stratum and baseline assessment as covariates. The estimated between-treatments differences, 95% confidence intervals, and p-values will be determined.
  • Safety analyses will be performed using the safety population. Safety and tolerability will be evaluated by assessment of adverse event incidence and changes in clinical laboratory tests, physical examinations, vital signs measurements, electrocardiogram readings, and suicidal ideation and behavior ratings at various time points during the trial.
  • a vaccine will be donated to a child in a developing part of the world, and the participant will receive a certificate commemorating their participation in ELEVATE 2 and the vaccine donation.
  • Patient engagement that takes patient needs and experiences into consideration and guides interactions may ignite the PAH-patient community interest in clinical research and speed up development of new medicines.
  • the exploratory endpoints for actigraphy and time to clinical improvement are included to provide clinically meaningful data.
  • the Best 6-Minute EffortTM for actigraphy allows assessment of real-world evidence on patients’ exercise capacities. Also, because patients’ activity data are uploaded every 24 hours, actigraphy compliance can be monitored daily. The time to clinical improvement is a medically relevant composite endpoint. Since treatment regimens may include 2, 3, or 4 medications, there is anticipation for improvement or a lack of deterioration in patients’ PAH.
  • the ELEVATE 2 trial design incorporates endpoints to generate the essential clinical efficacy, safety, pharmacokinetic, and pharmacodynamic data needed to evaluate the ability of rodatristat ethyl to ameliorate PAH by halting or reversing pulmonary vascular remodeling through its unique mechanism of TPH1 inhibition.
  • the rat SUGEN/hypoxia PAH(SuHx) model was used to assess reductions in vascular occlusions (>70%) following rodatristat ethyl monotherapy. Occlusions were measured following induction of PAH (subcutaneous injection of SUGEN SU5416 and hypoxia for 21 days) and after 28 days QD oral monotherapy with 50, 100 or 200mg/kg oral rodatristat ethyl. Vehicle was a diseased control group that received excipient without drug. Formalin fixed lung tissue was processed and sectioned for histological analysis. The outer and inner perimeters of the vessel walls were delineated using Image Pro software and relative vessel wall thickness was determined using the calculation:

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Abstract

L'invention concerne des méthodes de traitement d'un sujet chez lequel on a diagnostiqué une hypertension artérielle pulmonaire (HTAP). L'invention concerne également des méthodes d'abaissement de la résistance vasculaire pulmonaire, d'amélioration de la capacité d'exercice, et/ou de ralentissement de la progression d'une maladie par l'administration d'une dose thérapeutique de rodatristat éthyle au sujet. L'invention concerne en outre des procédés de réduction de l'incidence de la mortalité, du nombre d'hospitalisations, de l'hémodynamique et/ou de la taille auriculaire droite par l'administration d'une dose thérapeutique de rodatristat éthyle au sujet.
PCT/IB2022/059864 2021-10-14 2022-10-14 Traitement de sujets atteints d'hypertension artérielle pulmonaire à l'aide de rodatristat éthyle WO2023062595A1 (fr)

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