WO2023079486A1

WO2023079486A1 - Treatment of pulmonary arterial hypertension with rodatristat and ambrisentan

Info

Publication number: WO2023079486A1
Application number: PCT/IB2022/060605
Authority: WO
Inventors: Michelle PALACIOS; Stephen Wring; Howard LAZARUS; Robert J. AIELLO
Original assignee: Altavant Sciences Gmbh
Priority date: 2021-11-03
Filing date: 2022-11-03
Publication date: 2023-05-11

Abstract

There is a method for treating pulmonary arterial hypertension with a combination therapy of rodatristat ethyl and ambrisentan. The method has the step of administering to a human subject in need thereof both (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan sufficient to reduce the incidence of vascular occlusions, reduce the mean pulmonary arterial pressure, and/or decrease right ventricular hypertrophy in the subject. There are also provided other methods for treating pulmonary arterial hypertension.

Description

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION WITH RODATRISTAT AND AMBRISENTAN

FIELD OF THE DISCLOSURE

[0001] The present disclosure relates to methods for treating pulmonary arterial hypertension with rodatristat ethyl and ambrisentan.

BACKGROUND OF THE DISCLOSURE

[0002] Pulmonary arterial hypertension (PAH) 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. Am Heart J. 2011 Aug; 162(2): 201-13, doi: 10.1016/j.ahj. 2011.05.012. Epub 2011 Jul 13. 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: 7I;73-83. doi: 10. 1136/thoraxjnl-2015-207170.

[0003] Rodatristat ethyl (RVT-1201) is a pro-drug for the active tryptophan hydroxylase (TPH) inhibitor rodatristat (KAR5417) and is in development for treatment of PAH. Following oral administration, rodatristat ethyl is rapidly absorbed and hydrolyzed to rodatristat, KAR5417.

[0004] It would be desirable to have a method for treating PAH in which the incidence of vascular occlusions, PVR, and/or the mean pulmonary arterial pressure is substantially reduced.

SUMMARY OF THE DISCLOSURE

[0005] A method for treating pulmonary arterial hypertension is disclosed. The method has the step of administering to a human subject in need thereof both (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan sufficient to decrease right ventricular hypertrophy. The method has the step of administering to a human subject in need thereof both (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan sufficient to reduce mean pulmonary arterial pressure and/or the incidence of vascular occlusion, and/or lower pulmonary vascular resistance (PVR) in the human subject compared to before treatment. The rodatristat ethyl may be rodatristat ethyl, Form 3. The therapeutically effective amount of rodatristat ethyl may be up to about 2400 mg, or about 800 mg to about 1200 mg, and the therapeutically effective amount of ambrisentan may be up to about 10 mg per day, or about 5 mg to about 10 mg per day.

[0006] A method of decreasing right ventricular hypertrophy in a subject with pulmonary arterial hypertension, with each method including a step of administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan. The rodatristat ethyl may be rodatristat ethyl, Form 3. The therapeutically effective amount of rodatristat ethyl is up to about 2400 mg, or about 800 mg to about 1200 mg, and the therapeutically effective amount of ambrisentan is up to about 10 mg per day, or about 5 mg to about 10 mg per day.

[0007] A method of lowering pulmonary vascular resistance (PVR) in a subject with pulmonary arterial hypertension is disclosed, comprising administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan. The rodatristat ethyl may be rodatristat ethyl, Form 3. The therapeutically effective amount of rodatristat ethyl may be up to about 2400 mg, or about 800 mg to about 1200 mg, and the therapeutically effective amount of ambrisentan may be up to about 10 mg per day, or about 5 mg to about 10 mg per day.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Embodiments of the present disclosure are described herein with reference to the following figures.

[0009] Figure 1 is a graph of the results of a study showing the reduction of >70% occluded vessels after monotherapy treatment compared to treatment with rodatristat ethyl and ambrisentan.

[00010] Figure 2 is a graph of the results of a study showing lowering of mPAP after monotherapy treatment compared to treatment with rodatristat ethyl and ambrisentan.

[00011] Figure 3 is a graph of the results of a study showing treatment with rodatristat ethyl and ambrisentan reduced right ventricular hypertrophy in the SUGEN-hypoxia model.

DETAILED DESCRIPTION OF THE DISCLOSURE

[00012] 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).

[00013] Rodatristat ethyl (RE) 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.

PAH Pharmaceutical Actives

[00014] (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,l'-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:

[00015] The amorphous form of (S)-ethyl 8-(2-amino-6-((R)-l-(5-chloro-[l,T- biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylate can be prepared by the method set forth in Example 63i of U.S. Patent No.

9,199,994, which is incorporated herein by reference in its entirety. The amorphous form can then be converted to crystalline form by methods described in U.S. Patent Publication 2020/0148681 Al, published May 14, 2020, which is incorporated herein by reference in its entirety. Forms 1 and 3 can be prepared by the methods set forth in U.S. Patent Publication 2020/0148681 Al.

[00016] Form 3 exhibits the following x-ray powder diffraction pattern (XRPD):

[00017] The x-ray powder diffraction pattern is carried out with a Cu Ka radiation source according to the following method:

PANalytical X'Pert PRO MPD Diffractometer - Reflection Geometry [00018] Selected XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation produced using a long, fine-focus source and a nickel filter. The diffractometer was configured using the symmetric Bragg- Brentano geometry. Prior to the analysis, 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. Seller 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 (D S) and the incident-beam SS.

[00019] The metabolite of rodatristat ethyl is (S)-8-(2-amino-6-((R)-l-(5-chloro-[l,T- biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3- carboxylic acid, which is of the formula

[00020] (S)-8-(2-amino-6-((R)-I-(5-chloro-[l,T-biphenyl]-2-yl)-2,2,2-trifluoroeth- ^oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxyhc acid is referred to herein as rodatristat. Rodatristat is also referred to in the literature as KAR5417. When rodatristat ethyl is absorbed, 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.

FDA-Approved PAH Pharmaceutical Active [00021] Ambrisentan is an endothelin receptor antagonist selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6- dimethylpyrimidin-2-yl)oxy] -3 -methoxy-3, 3 -diphenylpropanoic acid. It contains a single chiral center determined to be the (S) configuration and has the following structural formula:

[00022] As used herein, 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.

[00023] As used herein the term "treating" or "treatment" 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).

[00024] A subject, as referred to herein, may mean an animal, a mammal or a human. An unhealthy subject is an animal or a human diagnosed with PAH or otherwise having PAH. The human subject, as referred to herein, means a human diagnosed with PAH or otherwise having PAH. The human subject may be experiencing some or all of the symptoms of PAH.

[00025] The types of PAH treatable according to the methods disclosed herein include (1) idiopathic (IP AH), (2) heritable (HP AH), and (3) associated (APAH), which is the most common type of PAH. The latter is 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). [00026] Symptoms of PAH include the following: fatigue, lethargy, exertional dyspnea, presyncope/syncope, cough, hoarseness, hypotension, fluid retention, lower extremity edema, chest pain, and cyanosis.

[00027] Side effects of PAH include the following: the aforementioned symptoms, side effects of multi-drug treatment regimens and diminished quality of life for the subject and family caregivers

[00028] 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.

[00029] In some embodiments, pharmaceutical 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.

[00030] Dosages/compositions according to the disclosure include the combinations of rodatristat ethyl and/or rodatristat with ambrisentan, an FDA-approved PAH pharmaceutical active disclosed above. A combination therapy may include rodatristat ethyl and ambrisentan. Rodatristat ethyl and ambrisentan may be administered separately or together. A combination of rodatristat ethyl and ambrisentan may be an oral dosage form. A combination of rodatristat and ambrisentan may be a non-oral form of administration, e.g., parenteral, are preferred.

[00031] 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. Typically, for rodatristat ethyl or rodatristat in an oral dosage form to treat or prevent a disease, particularly PH/PAH/APAH/IPAH/HPAH, a typical dosage will be a therapeutic amount of about 1 mg/kg/day to about 50 mg/kg/day, or from about 5 mg/kg/day to about 30 mg/kg/day, based on the weight of the subject. The compound may be 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, 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 about 300 mg, about 600 mg, about 800 mg, about 1000 mg, and about 1200 mg. Other amounts between about 50 mg to about 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 300 mg to about 600 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 600 mg to about 1200 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, from about 1000 mg to about 1200 mg, from about 1100 mg to about 1250 mg, and from about 1200 mg to about 1350 mg.

[00032] 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).

[00033] In a regimen of twice daily dosing, 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. [00034] 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.

[00035] 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. For 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. [00036] 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 subject. 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.

[00037] A method may include administering a therapeutically effective amount, about 100 mg to about 1000 mg, or about 200 mg to about 800 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, or about 800 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.

[00038] 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.

[00039] Rodatristat ethyl and ambrisentan may be administered in an amount of up to 2400 mg of rodatristat ethyl and up to about 10 mg of ambrisentan per day. Rodatristat ethyl may be administered in an amount of about 200 mg to about 2400 mg of rodatristat ethyl per day and about 5 mg to about 10 mg of ambrisentan per day. Rodatristat ethyl and ambrisentan may be administered once daily, twice daily or three times daily. About 100 mg to about 1200 mg, or about 200 mg to about 800 mg, of rodatristat ethyl, and about 2.5 mg to about 5 mg of ambrisentan may be administered twice per day. About 300 mg to about 600 mg of rodatristat ethyl and about 2.5 mg to about 5 mg of ambrisentan may be administered twice per day. Rodatristat ethyl and ambrisentan may be administered in an oral dosage regimen. The rodatristat ethyl and ambrisentan may be administered in the same dosage form or in separate dosage forms.

[00040] When administered in the same dosage form, a pharmaceutical composition may comprise about 2.5 mg to about 5 mg ambrisentan, and about 200 mg to about 600 mg rodatristat ethyl. The pharmaceutical composition may be in the form of a pill or tablet formulated for oral administration.

[00041] The duration of administration may vary depending on factors such as the following: the compound selected, method of administration, health of the subject, and composition formulation. For the combination therapy in an oral dosage form to treat a disease, particularly PH/PAH/APAH/IPAH/HPAH, rodatristat ethyl and ambrisentan may be administered for one week to multiple years, or for the remainder of the subject’s life, and any amount of time (e.g. weeks, months or years) therebetween.

[00042] Combinations of rodatristat ethyl with ambrisentan may be formulated such that one or more of the following are accomplished: (A) the risk of DDI interactions is low,

(B) synergistic or additive reduction in symptoms of PAH compared to the rodatristat/rodatristat ethyl and the FDA-approved PAH pharmaceutical active(s) alone, and

(C) synergistic or additive reduction in side effects of PAH compared to the rodatristat/rodatristat ethyl and ambrisentan alone.

[00043] A method of decreasing right ventricular hypertrophy in a subject having pulmonary arterial hypertension is disclosed. That method comprises administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan. The method may include administering about 100 mg to about 2400 mg of rodatristat ethyl per day, and up to about 10 mg of ambrisentan per day to a human subject in need thereof. 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), and about 2.5 mg to about 5 mg of ambrisentan BID to the human subject in need thereof. The rodatristat ethyl may be administered in 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. The right ventricular hypertrophy in the subject may decrease over about 10%, about 15%, over about 20%, or over about 25% compared to baseline pretreatment. The right ventricular hypertrophy in the subject may decrease about 15% to about 40%, about 20% to about 35%, or about 25% to about 30% compared to pretreatment.

[00044] In the method of administering rodatristat ethyl and ambrisentan, right ventricular hypertrophy in the subject may decrease more than the decrease observed by administration of rodatristat ethyl monotherapy, or ambrisentan monotherapy administered in the same regimen as the combination therapy. The same regimen means the same daily dosing amounts and for the same duration. In the method of administering rodatristat ethyl and ambrisentan, right ventricular hypertrophy in the subject may decrease more than about 5%, more than about 50%, or more than double the decrease observed by administration of rodatristat ethyl monotherapy in the same regimen. In the method of administering rodatristat ethyl and ambrisentan, right ventricular hypertrophy in the subject may decrease more than about 5%, more than about 20%, or more than about 50% than the decrease observed by administration of ambrisentan monotherapy in the same regimen.

[00045] A method of reducing the percentage of vessels occluded at > 70% in a subject with pulmonary arterial hypertension is disclosed. The method comprises administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan. The method may include administering about 100 mg to about 2400 mg of rodatristat ethyl per day, and up to about 10 mg of ambrisentan per day to a human subject in need thereof. 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), and about 2.5 mg to about 5 mg of ambrisentan BID to the human subject in need thereof. The rodatristat ethyl may be administered in 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. With this method, the percentage of vessels occluded at > 70% in the subject may be reduced over about 20%, over about 30%, over about 40%, over about 50%, over about 60%, over about 70%, over about 80%, over about 90% compared to baseline pretreatment. The percentage of vessels occluded at > 70% in the subject may be reduced about 50% to about 98%, about 60% to about 98%, about 70% to about 98%, about 80% to about 98%, or about 90% to about 98% compared to baseline pretreatment. The method disclosed herein may reduce the percentage of vessels occluded at > 70% to near baseline normoxic levels, i.e., to the level of an average healthy subject without PAH. [00046] In the method of administering rodatristat ethyl and ambrisentan, the percentage of vessels occluded at > 70% in the subject may be reduced more than the reduction observed by administration of rodatristat ethyl monotherapy, or ambrisentan monotherapy administered in the same regimen as the combination therapy. In the method of administering rodatristat ethyl and ambrisentan, the percentage of vessels occluded at > 70% in the subject may be reduced more than about 5%, more than about 50%, or more than double the reduction observed by administration of rodatristat ethyl monotherapy in the same regimen. In the method of administering rodatristat ethyl and ambrisentan, the percentage of vessels occluded at > 70% in the subject may be reduced more than about 5%, more than about 20%, or more than about 50% than the reduction observed by administration of ambrisentan monotherapy in the same regimen.

[00047] A method of reducing the incidence of vascular occlusions in a subject with pulmonary arterial hypertension is disclosed. The method comprises administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan. The method may include administering about 100 mg to about 2400 mg of rodatristat ethyl per day, and up to about 10 mg of ambrisentan per day to a human subject in need thereof. 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), and about 2.5 mg to about 5 mg of ambrisentan BID to the human subject in need thereof. The rodatristat ethyl may be administered in 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. With this method, the incidence of vascular occlusions in the subject may be reduced over about 20%, over about 30%, over about 40%, over about 50%, over about 60%, over about 70%, over about 80%, over about 90% compared to baseline pretreatment. The incidence of vascular occlusions in the subject may be reduced about 50% to about 98%, about 60% to about 98%, about 70% to about 98%, about 80% to about 98%, or about 90% to about 98% compared to baseline pretreatment. The method disclosed herein may reduce the incidence of vascular occlusions to near baseline normoxic levels, i.e., to the level of an average healthy subject without PAH.

[00048] In the method of administering rodatristat ethyl and ambrisentan, the incidence of vascular occlusions in the subject may be reduced more than the reduction observed by administration of rodatristat ethyl monotherapy, or ambrisentan monotherapy administered in the same regimen as the combination therapy. In the method of administering rodatristat ethyl and ambrisentan, the incidence of vascular occlusions in the subject may be reduced more than about 5%, more than about 50%, or more than double the reduction observed by administration of rodatristat ethyl monotherapy in the same regimen. In the method of administering rodatristat ethyl and ambrisentan, the incidence of vascular occlusions in the subject may be reduced more than about 5%, more than about 20%, or more than about 50% than the reduction observed by administration of ambrisentan monotherapy in the same regimen.

[00049] A method for treating pulmonary arterial hypertension, comprising administering to a human subject in need thereof both (A) an amount of rodatristat ethyl and (B) an amount of ambrisentan sufficient to reduce the mean pulmonary arterial pressure in the human subject by at least about 5% compared to before treatment. Also disclosed is a method of reducing the mean pulmonary arterial pressure in a human subject in need thereof (e.g., diagnosed with PAH) comprising administering rodatristat ethyl and ambrisentan 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 per day, and up to about 10 mg of ambrisentan per day to a human subject in need thereof. 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), and about 2.5 mg to about 5 mg of ambrisentan BID to the human subject in need thereof. The rodatristat ethyl may be administered in 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. The mean pulmonary arterial pressure (mPAP) in the human subject may be reduced by at least about 5%, at least about 10%, at least about 15%, or at least about 20%, compared to the mPAP in the subject before treatment. The mean pulmonary arterial pressure (mPAP) in the human subject may be reduced by about 5% to about 70%, about 5% to about 60%, about 5% to about 50%, or about 10% to about 50%, compared to the mPAP in the subject before treatment. The mPAP in the human subject may be reduced by at least about 12 mmHg, or at least about 15 mmHg compared to the mPAP in the subject before treatment.

[00050] A method of lowering pulmonary vascular resistance (PVR) in a human subject in need thereof (e.g., diagnosed with PAH) comprising administering rodatristat ethyl and ambrisentan 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 per day, and up to about 10 mg of ambrisentan per day to a human subject in need thereof. 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), and about 2.5 mg to about 5 mg of ambrisentan BID to the human subject in need thereof. The rodatristat ethyl may be administered in 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. 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 the human subject. Lowering pulmonary vascular resistance (PVR) 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 the human subject. Baseline as used in this method is the PVR of the subject prior to the beginning of treatment.

[00051] 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). 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. If the mean cardiac output is autogenerated, investigators must ensure that the measurements used to calculate the mean are within the 10% variability and are available to be recorded in the source documents and in the eCRF. The last value is recorded in the eCRF. o Systemic arterial pressures (systolic, diastolic, and mean) - Systemic arterial pressures are taken just prior to entry of the catheter and should be measured until two consecutive mean values do not differ by >10%. The last value is recorded in the eCRF. All values should be available in the source documents. o Pulmonary arterial pressures (systolic, diastolic, and mean) - Pulmonary arterial pressures should be measured at end expiration and should be measured until two consecutive mean values do not differ by >10%. The last value is recorded in the eCRF. All values should be available in the source documents. Mean pulmonary arterial pressure (mPAP) as determined by the site’s medical instrument (automatically generated) is entered into the electronic data capture system. If the site’s medical instrument does not automatically generate the mPAP, it should then be calculated manually using the equation: mPAP = ([diastolic pulmonary arterial pressure x 2] + systolic pulmonary arterial pressure) 3 o Mean right atrial pressure - Mean right arterial pressure should be measured until two consecutive values do not differ by >10%. If mean right atrial pressure values are <10 mmHg, the two consecutive values must not differ by >1 mmHg. The last value is recorded in the eCRF. All values should be available in the source documents. o 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 endexpiration, 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.

PVR (dyne*sec/cm⁵) = ([mPAP - pulmonary capillary wedge pressure] mean CO) x 80 or ([mPAP - left ventricular end diastolic pressure] mean CO) x 80

Cardiac index = CO body surface area

Stroke volume = CO heart rate Pulmonary artery compliance = ratio of stroke volume to pulmonary artery pulse pressure

Body surface area (m²) = 0.007184 x (weight in kilograms)⁰⁴²⁵ x (height in centimeters)⁰⁷²⁵

[00052] A method for treating pulmonary arterial hypertension is disclosed, comprising administering to a human subject in need thereof both (A) an amount of rodatristat ethyl and (B) an amount of ambrisentan sufficient to reduce the incidence of vascular occlusions and reduce the mean pulmonary arterial pressure, and, optionally, decrease right ventricular hypertrophy in the subject compared to before treatment. A method for treating pulmonary arterial hypertension is disclosed, comprising administering to a human subject in need thereof both (A) an amount of rodatristat ethyl and (B) an amount of ambrisentan sufficient to reduce the incidence of vascular occlusions and decrease right ventricular hypertrophy, and, optionally, reduce the mean pulmonary arterial pressure, in the subject compared to before treatment. A method for treating pulmonary arterial hypertension is disclosed, comprising administering to a human subject in need thereof both (A) an amount of rodatristat ethyl and (B) an amount of ambrisentan sufficient to reduce the mean pulmonary arterial pressure, and decrease right ventricular hypertrophy in the subject compared to before treatment. Each of the foregoing methods for treating pulmonary arterial hypertension may optionally also include lowering pulmonary vascular resistance (PVR) in the subject compared to before treatment. Each of the terms in these embodiments has the same meaning and definition as set forth with respect to the embodiments in preceding paragraphs.

[00053] The disclosure is further illustrated herein by the following non-limiting examples.

EXAMPLES

[00054] EXAMPLE 1

[00055] Rodatristat Ethyl Monotherapy and Combination with Ambrisentan Reverses Incidence of Vascular Occlusions to Baseline Normoxic Levels in the Rat SUGEN-Hypoxia Model of Pulmonary Arterial Hypertension

[00056] A rat SUGEN/hypoxia PAH (SuHx) model assessed reductions in vascular occlusions (>70%) following rodatristat ethyl (RODA) monotherapy, ambrisentan monotherapy, and combination of RODA with ambrisentan. 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 RODA, lOmg/kg ambrisentan, or combinations of lOmg/kg tadalafil and lOmg/kg ambrisentan, or lOOmg/kg RODA and lOmg/kg ambrisentan (ri>l 1 /active treatment).

[00057] Induction of PAH after SuHx resulted in 6.5±2.5% pulmonary vessels occluded >70% versus healthy control (no SuHx) animals (0%). Subsequent sham treatment for 28 days led to a further 6.6% increase in occlusions to 13.1±2.7%. Low dose (50mg/kg) RODA monotherapy largely prevented (p<0.001) the post-SuHx development of occlusions retaining them at 7.2±4.1%. Higher RODA doses reversed (p<0.0001) the post-hypoxic incidence from 6.5±2.5% to 2.9±2.1% (lOOmg/kg) and 2.2±2.3% (200mg/kg).

[00058] Combination therapy of RODA ( 1 OOmg/kg) and ambrisentan ( 1 Omg/kg) reduced (P0.0001) post hypoxia occlusions further to 0.2±0.6%, comparable with normoxic controls. Combination therapy with ambristentan (1 Omg/kg) and tadalafil (1 Omg/kg) reduced (p<0.0001) post-hypoxia occlusions to 3.1±2.3%. While this combination achieved a clear treatment benefit, the combination of RODA and ambrisentan was superior in reducing the incidence of vascular occlusions. Figure 1 shows that administration of the combined treatment of RODA and ambrisentan reduced the percentage occluded vessels significantly lower below the baseline pretreatment than ambrisentan monotherapy or RODA monotherapy, and also reduced the percentage occluded vessels to near baseline normotoxic level (shown as 0 on the y-axis).

[00059] Reductions in vascular occlusions following RODA or ambristentan monotherapy, or ambrisentan/tadalafil combination, did not significantly lower mPAP, consistent with the multifaceted causes of vascular resistance. However, the combination of RODA and ambrisentan did lower mPAP by 17.6mmHg (p<0.001) supporting the value of targeting complementary mechanisms. A graphic depiction of the results is shown in Figure 2.

[00060] In conclusion, monotherapy with RODA reduced pulmonary vascular occlusions in the rat SuHx PAH model. Combination with ambrisentan suggested synergistic benefit reducing occlusions to near normal control levels with reduction in mPAP, together supportive of clinical benefit for RODA in treatment of PAH. [00061] EXAMPLE 2

[00062] The rat SUGEN/hypoxia PAH (SuHx) model was used to assess decrease in right ventricular hypertrophy following SUGEN-hypoxia induction. PAH was induced in the rats (subcutaneous injection of SUGEN SU5416 and hypoxia for 21 days) (SUGEN treatment, switch to hypoxia). After 21 days, the rats were removed from hypoxia and divided into 5 groups for the comparison of treatment alternatives. The treatment groups were as follows: 1) 100 mg/kg/day rodatristat ethyl, 2) 10 mg/kg/day ambrisentan, 3) 10 mg/kg/day ambrisentan+10 mg/kg/day tadalafil, 4) 100 mg/kg/day rodatristat ethyl+10 mg/kg/day ambrisentan, or 5) vehicle (diseased control group received excipient without drug). Normoxia group is a healthy control comparison; no exposure to hypoxic environment. Drug treatment was administered for 28 days. At day 49 from the beginning of the study, the rats were analyzed for right ventricular (RV) hypertrophy. The treatment groups were as follows: 100 mg/kg/day rodatristat ethyl, 10 mg/kg/day ambrisentan, 10 mg/kg/day ambrisentan+10 mg/kg/day tadalafil, 100 mg/kg/day rodatristat ethyl+10 mg/kg/day ambrisentan, or vehicle, with each administered once daily for 28 days. Compared to the vehicle: the group receiving 100 mg/kg/day rodatristat ethyl showed a decrease of 6% in RV hypertrophy; the group receiving 10 mg/kg/day ambrisentan showed a decrease of 21% in RV hypertrophy; the group receiving 10 mg/kg/day ambrisentan+10 mg/kg/day tadalafil showed a decrease of 24% in RV hypertrophy; and the group receiving 100 mg/kg/day rodatristat ethyl+10 mg/kg/day ambrisentan showed a decrease of 30% in RV hypertrophy. A graphic depiction of the results is shown in Figure 3. The results demonstrate that the combination treatment of rodatristat ethyl and ambrisentan significantly decreased RV hypertrophy following SUGEN-hypoxia induction compared to rodatristat ethyl or ambrisentan alone, as well as the combination of ambrisentan and tadalafil.

[00063] It should be understood that the foregoing description is only illustrative of the present disclosure. Various alternatives and modifications can be devised by those skilled in the art without departing from the present disclosure. Accordingly, the present disclosure is intended to embrace all such alternatives, modifications and variances which fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS

1. A method for treating pulmonary arterial hypertension, comprising administering to a human subject in need thereof both (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan sufficient to reduce the mean pulmonary arterial pressure in the human subject by at least about 5% compared to before treatment.

2. The method of claim 1, wherein the rodatristat ethyl is rodatristat ethyl, Form 3.

3. The method of claim 1 or 2, wherein the mean pulmonary arterial pressure in the human subject is reduced at least 12 mmHg compared to before treatment.

4. The method of any one of claims 1-3, wherein the therapeutically effective amount of rodatristat ethyl is up to about 2400 mg per day and the therapeutically effective amount of ambrisentan is up to about 10 mg per day.

5. The method of any one of claims 1-4, wherein the therapeutically effective amount of rodatristat ethyl is about 800 mg to about 1200 mg per day, and the therapeutically effective amount of ambrisentan is about 5 mg to about 10 mg per day.

6. The method of any one of claims 1-4, wherein the therapeutically effective amount of rodatristat ethyl is about 200 mg to about 600 mg administered twice daily.

7. The method of any one of claims 1-4, wherein the therapeutically effective amount of ambrisentan is about 2.5 mg to about 5 mg administered twice daily.

8. The method of any one of claims 1-7, wherein rodatristat ethyl and ambrisentan are administered in an oral dosage regimen.

9. The method of any one of claims 1-8, wherein rodatristat ethyl and ambrisentan are administered in the same dosage form.

10. The method of any one of claims 1-8, wherein rodatristat ethyl and ambrisentan are administered in separate dosage forms.

11. A method of decreasing right ventricular hypertrophy in a subject with pulmonary arterial hypertension comprising administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan, wherein right ventricular hypertrophy in the subject decreases over about 10% compared to before treatment.

12. The method of claim 11, wherein the rodatristat ethyl is rodatristat ethyl, Form 3.

13. The method of claim 11 or 12, wherein the right ventricular hypertrophy decreases over about 15% in the subject compared to before treatment.

14. The method of any one of claims 11-13, wherein the right ventricular hypertrophy in the subject decreases over about 20% compared to before treatment.

15. The method of any one of claims 11-14, wherein the therapeutically effective amount of rodatristat ethyl is up to about 2400 mg and the therapeutically effective amount of ambrisentan is up to about 10 mg per day.

16. The method of any one of claims 11-14, wherein the therapeutically effective amount of rodatristat ethyl is about 800 mg to about 1200 mg, and about 5 mg to about 10 mg of ambrisentan per day.

17. The method of any one of claims 11-14, wherein the therapeutically effective amount of rodatristat ethyl is about 200 mg to about 600 mg administered twice daily.

18. The method of any one of claims 11-15, wherein the therapeutically effective amount of ambrisentan is about 2.5 mg to about 5 mg administered twice daily.

19. The method of any one of claims 11-18, wherein rodatristat ethyl and ambrisentan are administered in an oral dosage regimen.

20. The method of any one of claims 11-19, wherein rodatristat ethyl and ambrisentan are administered in the same dosage form.

21. The method of any one of claims 11-19, wherein rodatristat ethyl and ambrisentan are administered in separate dosage forms.

22. A method of reducing the incidence of vascular occlusions in a subject with pulmonary arterial hypertension comprising administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan, wherein the percentage of vascular occlusions is reduced in the subject compared to before treatment.

23. The method of claim 22, wherein the rodatristat ethyl is rodatristat ethyl, Form 3.

24. The method of claim 22 or 23, wherein percentage of vascular occlusions is reduced over about 20% in the subject compared to before treatment.

25. The method of any one of claims 22-24, wherein percentage of vascular occlusions is reduced over about 30% in the subject compared to before treatment.

26. The method of any one of claims 22-25, wherein the therapeutically effective amount of rodatristat ethyl is up to about 2400 mg and the therapeutically effective amount of ambrisentan is up to about 10 mg per day.

27. The method of any one of claims 22-26, wherein the therapeutically effective amount of rodatristat ethyl is about 800 mg to about 1200 mg, and about 5 mg to about 10 mg of ambrisentan per day.

28. The method of any one of claims 22-27, wherein the therapeutically effective amount of rodatristat ethyl is about 200 mg to about 600 mg administered twice daily.

29. The method of any one of claims 22-28, wherein the therapeutically effective amount of ambrisentan is about 2.5 mg to about 5 mg administered twice daily.

30. The method of any one of claims 22-29, wherein rodatristat ethyl and ambrisentan are administered in an oral dosage regimen.

31. The method of any one of claims 22-30, wherein rodatristat ethyl and ambrisentan are administered in the same dosage form.

32. The method of any one of claims 22-30, wherein rodatristat ethyl and ambrisentan are administered in separate dosage forms.

33. A method of lowering pulmonary vascular resistance (PVR) in a subject with pulmonary arterial hypertension comprising administering to the subject (A) a therapeutically effective amount of rodatristat ethyl and (B) a therapeutically effective amount of ambrisentan.

34. The method of claim 33, wherein the pulmonary vascular resistance (PVR) is reduced by more than about 5% in the subject compared to before treatment.

35. The method of claim 33 or 34, wherein the rodatristat ethyl is rodatristat ethyl, Form 3.

36. The method of any one of claims 33-35, wherein the therapeutically effective amount of rodatristat ethyl is up to about 2400 mg per day, and the therapeutically effective amount of ambrisentan is up to about 10 mg per day.

37. The method of any one of claims 33-36, wherein the therapeutically effective amount of rodatristat ethyl is about 800 mg to about 1200 mg, and about 5 mg to about 10 mg of ambrisentan per day.

38. The method of any one of claims 33-36, wherein the therapeutically effective amount of rodatristat ethyl is about 200 mg to about 600 mg administered twice daily.

39. The method of any one of claims 33-36, wherein the therapeutically effective amount of ambrisentan is about 2.5 mg to about 5 mg administered twice daily.

40. The method of any one of claims 33-39, wherein rodatristat ethyl and ambrisentan are administered in an oral dosage regimen.

41. The method of any one of claims 33-39, wherein rodatristat ethyl and ambrisentan are administered in the same dosage form.

42. The method of any one of claims 33-39, wherein rodatristat ethyl and ambrisentan are administered in separate dosage forms.

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