LPA1 antagonists for treatment of interstitial lung disease

Abstract

The present disclosure relates to methods of treating interstitial lung disease by administering (1S, 3S)-3-((2-methyl-6-(1-methyl-5-(((methyl (propyl) carbamoyl) oxy) methyl)-1H-1, 2, 3-triazol-4-yl) pyridin-3-yl) oxy) cyclohexane-1-carboxylic acid (LPA1 antagonist).

Description

Cross - Reference to Related Applications

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63 / 476,992, filed on December 23, 2022, and U.S. Provisional Application No. 63 / 519,692, filed on August 15, 2023, and each of these provisional applications is hereby incorporated by reference in its entirety. Technical Field

[0002] This disclosure relates to methods of treating interstitial lung diseases by administering (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl) - oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (an LPA1 antagonist). Background Art

[0003] Interstitial lung diseases (ILDs) are a heterogeneous group of lung disorders classified together by imaging or histopathology based on shared clinical features, parenchymal lung scarring (fibrosis), and / or inflammation with different patterns of lung injury. ILDs can be caused by identifiable etiologies such as underlying systemic autoimmune diseases (e.g., systemic sclerosis or rheumatoid arthritis), environmental exposures (e.g., asbestos or silica), or drug toxicity, but are often idiopathic in nature. Idiopathic pulmonary fibrosis (IPF), one of the more common and most devastating types of ILD, is a chronic, progressive, and typically fatal lung disease of unknown etiology, characterized by worsening dyspnea due to scarring in the lungs, cough, loss of lung function, and necessarily having a pathologic and radiographic pattern called usual interstitial pneumonia (UIP) (Meltzer et al., Orphanet J. Rare Dis. 2008, 3:8). In addition to IPF, some patients with other forms of ILD develop a progressive fibrotic phenotype, characterized by worsening respiratory symptoms, worsening lung function, radiographic fibrosis progression, and early death.

[0004] To date, two approved therapies (pirfenidone and nintedanib) have significantly reduced lung function decline in patients with IPF, and both appear to have a modest impact on progression-free survival (Noble et al., Lancet 2011, 377(9779), 1760-1769; King et al., N. Engl. J. Med. 2014, 370(22), 2083-2092; Richeldi et al., New Engl J Med 2014, 370(22), 2071-2082). However, many patients still progress despite treatment. Another treatment option is lung transplantation, which has been shown to improve survival in carefully selected patients but is associated with complications (Kistler et al., BMC Pulmonary Med. 2014;14:139). Despite these advances, there remains a large unmet need for safe, well-tolerated, and effective therapies for IPF that improve lung function, delay disease progression, and reduce mortality.

[0005] Due to clinical and pathophysiological similarities between IPF and other forms of progressive pulmonary fibrosis (PPF), it has been shown that such disorders, regardless of etiology, share common pathological mechanisms leading to progressive pulmonary fibrosis and may thus have a similar response to treatment as IPF (Raghu et al., Am. J. Respir. Crit. Care Med. 2022, 205, e18–e47; du Bois et al., Am. J. Respir. Crit. Care Med. 2012, 186, 712–715; Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727). Indeed, in the recently published INBUILD trial, patients with PPF of diverse etiologies were treated with nintedanib or placebo. Compared with patients receiving placebo, patients treated with nintedanib had slower progression of pulmonary fibrosis, as demonstrated by a lower annual rate of decline in forced vital capacity (FVC) over the 52-week study period (Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727). The absolute treatment effect in the PPF study was similar in magnitude to the absolute treatment effect observed in the pivotal INPULSIS trial that led to the approval of nintedanib for the treatment of IPF. In addition, the IMPULSIS and INBUILD trials demonstrated that IPF and PPF patients were similar with respect to the rate of decline in FVC. Based on data from the INBUILD trial, health authorities have also approved nintedanib for patients with PPF. Nevertheless, since many patients are intolerant to nintedanib due to gastrointestinal side effects and because some patients may still progress despite treatment with nintedanib, there remains an unmet need for well-tolerated, effective therapies for PPF (Flaherty et al., N. Engl. J. Med. 2019, 381(18), 1718–1727).

[0006] Overall, patients with IPF and non-IPF (PPF) who exhibit disease progression have a high unmet need for effective and tolerable treatment. Fibrotic diseases such as these can be mediated by LPA, which signals via six LPA receptors (LPA 1-6 ). Signaling via LPA1 appears to be fundamental in the pathogenesis of fibrotic diseases.

[0007] U.S. Patent Application Publication No. 2017 / 0360759 (PCT Application Publication No. WO 2017 / 223016) discloses certain antagonists of lysophosphatidic acid (LPA) receptors for treating LPA-dependent or LPA-mediated disorders or diseases such as fibrosis of various organs including the lung.

[0008] The compound (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (hereinafter referred to as "Compound A") is described in U.S. Patent Application Publication No. 2017 / 0360759.

[0009] Compound A is a potent LPA1 antagonist in vitro (LPA1 Ki = 6.9 nM in CHO cells overexpressing human LPA1 and LPA1 Ki = 5.9 nM in normal human lung fibroblasts). Compound A is currently in clinical development as a therapy for IPF and PF-ILD. b =6.9nM, and LPA1 Ki b =5.9 nM in normal human lung fibroblasts). Compound A is currently in clinical development as a therapy for IPF and PF-ILD.

[0010] This disclosure provides a method of treating interstitial lung disease using Compound A. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 Shows the powder X-ray diffraction (PXRD) pattern of Form A.

[0012] Figure 2 Shows the differential scanning calorimetry (DSC) thermogram of Form A.

[0013] Figure 3 Shows the thermogravimetric analysis (TGA) thermogram of Form A.

[0014] Figure 4 Shows the water sorption isotherm of Form A.

[0015] Figure 5 Shows an overview of the Phase 2 trial.

[0016] Figure 6 Shows the rate of change of ppFVC in patients treated with placebo or Compound A.

[0017] Figure 7 Shows the change in FVC (mL) in patients treated with placebo or Compound A.

[0018] Figure 8Shows the absolute change in FVC (mL) relative to baseline in patients treated with placebo or Compound A.

[0019] Figure 9 Shows the rate of change of ppFVC according to background anti-fibrotic drug use in patients treated with placebo or Compound A.

[0020] Figure 10 Shows the change in percentage of ppFVC relative to baseline (primary endpoint) in PPF subjects treated with placebo or Compound A.

[0021] Figure 11 Shows the change in FVC (mL) relative to baseline (primary endpoint) in PPF subjects treated with placebo or Compound A.

[0022] Figure 12 Shows the change in percentage of ppFVC relative to baseline (primary endpoint) in PPF subjects with UIP treated with placebo or Compound A.

[0023] Figure 13 Shows the change in FVC (mL) relative to baseline (primary endpoint) in PPF subjects without UIP treated with placebo or Compound A.

[0024] Figure 14 Shows the rate of change of ppFVC in PPF subjects with and without UIP treated with placebo or Compound A.

[0025] Figure 15 Shows the change in percentage of ppFVC relative to baseline (primary endpoint) in PPF subjects taking anti-fibrotic drugs and treated with placebo and Compound A.

[0026] Figure 16 Shows the change in FVC (mL) relative to baseline (primary endpoint) in PPF subjects not taking anti-fibrotic drugs and treated with placebo or Compound A. SUMMARY OF THE INVENTION

[0027] In some aspects, the present disclosure provides a method for treating interstitial lung disease, the method comprising administering to a subject in need thereof Compound A at about 120 mg / day: or an equivalent amount of a pharmaceutically acceptable salt thereof. In some aspects, Compound A or its pharmaceutically acceptable salt is administered once daily.

[0028] In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered twice daily. In some aspects, about 60 mg of compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

[0029] In some aspects, the subject being treated is simultaneously being treated with one or more therapies for interstitial lung disease. In some aspects, the one or more therapies are pirfenidone. In some aspects, the one or more therapies are nintedanib.

[0030] In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to the subject with food. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to the subject without food.

[0031] In some aspects, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some aspects, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0032] In some aspects, compound A comprises a crystalline form characterized by at least one of the following: a) a single crystal structure having unit cell parameters substantially equal to the following: wherein the measurement of the single crystal structure is carried out at room temperature; b) a powder x-ray diffraction pattern substantially the same as that shown in Figure 1 ; c) a powder x-ray diffraction pattern comprising two or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2, and 26.8 ± 0.2 (obtained at room temperature and CuKα ); d) a powder x-ray diffraction pattern comprising three or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 14.5 ± 0.2, 14.7 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.1 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2, and 27.8 ± 0.2 (at room temperature and obtained below; e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2 ; f) a differential scanning calorimetry thermogram having an endotherm starting at about 152°C; and / or g) a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 .

[0033] In some aspects, compared to untreated subjects, the subject experiences a smaller decline in forced vital capacity (FVC) after the treatment period. In some aspects, compared to untreated subjects, the subject experiences a longer time to the first disease progression event after the treatment period, where the first disease progression event is selected from: Absolute predicted forced vital capacity percentage (ppFVC) relative to baseline ≥ 10%; Acute exacerbation of pulmonary fibrosis; Respiratory hospitalization; Lung transplantation; and All-cause death.

[0034] In some aspects, compared to untreated subjects, the subject experiences a longer time to the first disease progression event after the treatment period, where the first disease progression event is selected from: Absolute predicted forced vital capacity (ppFVC) decline relative to baseline ≥ 10%; Acute exacerbation of pulmonary fibrosis; Hospitalization related to pulmonary fibrosis; and All-cause death.

[0035] In some aspects, compared to untreated subjects, the subject experiences a smaller increase in the cough domain score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire during the treatment period. In some aspects, compared to untreated subjects, the subject experiences a smaller increase in the dyspnea score as measured by the Living with Pulmonary Fibrosis (L-PF) questionnaire during the treatment period.

[0036] In some aspects, the present disclosure provides about 120 mg / day of Compound A: or an equivalent amount of a pharmaceutically acceptable salt thereof for the treatment of interstitial lung disease.

[0037] In some aspects, the present disclosure provides about 120 mg / day of Compound A: Use of compound A or a pharmaceutically acceptable salt thereof in an equivalent amount in the manufacture of a medicament for treating interstitial lung disease. In some aspects, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some aspects, the interstitial lung disease is progressive pulmonary fibrosis (PPF). Detailed Description

[0038] The present disclosure provides a method for treating interstitial lung disease, the method comprising administering to a subject in need thereof about 120 mg / day of compound A: or a pharmaceutically acceptable salt thereof in an equivalent amount.

[0039] To facilitate a better understanding of the present specification, certain terms are first defined. Additional definitions are set forth throughout the detailed description. I. Definitions

[0040] Unless otherwise indicated, the following terms used in this application (including the specification and claims) have the definitions given below. It must be noted that as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are employed unless otherwise indicated. Additionally, the use of the term "including" and other forms such as "include", "includes", and "included" is non-restrictive. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0041] All measurements are subject to experimental error and are within the spirit of the present invention.

[0042] As used throughout the specification and claims in connection with a numerical value, the term "about" means an interval of accuracy familiar and acceptable to those skilled in the art. Such interval of accuracy is ±10%.

[0043] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no continuing adverse effect on the overall health of the subject being treated.

[0044] The terms "administration of" and / or "administering" a compound or composition should be understood to mean providing the compound or composition described herein to one or more subjects.

[0045] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit a distinct X-ray diffraction pattern.

[0046] As used herein, the term "antagonist" refers to a molecule, such as a compound, that reduces, inhibits, or blocks the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists.

[0047] As used herein, the term "BP" refers to blood pressure, the term "SBP" refers to systolic blood pressure, and the term "DBP" refers to diastolic blood pressure.

[0048] As used herein, terms such as "co-administer" are intended to cover the administration of a selected therapeutic agent to a single subject and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0049] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis.

[0050] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound that will, to some extent, alleviate one or more symptoms of the disease or disorder being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease. Techniques such as dose escalation studies can be used to determine the appropriate "effective" amount in any individual case.

[0051] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0052] As used herein, "polymorph" refers to a crystalline form of molecules and / or ions that have the same chemical structure but different spatial arrangements of the crystals formed.

[0053] The term "room temperature" generally means about 22 °C, but can vary up or down by 7 °C.

[0054] The terms "subject" and "participant" are used interchangeably and cover mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, etc. In one aspect, the mammal is a human.

[0055] As used herein, when used in reference to a crystalline form, "substantially pure" means a compound having the following purity: greater than 90% by weight, including greater than 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, and 99% by weight, and also including a crystalline form of Compound A equal to about 100% by weight. The remaining material includes one or more other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound A can be considered substantially pure because it has a purity greater than 90% by weight, as measured by means known and generally accepted in the art at the time, where the remaining less than 10% by weight of the material includes one or more other forms of Compound A and / or reaction impurities and / or processing impurities.

[0056] When the term "substantially identical" is used in reference to a PXRD or XRPD pattern, it should be understood that the measured peak positions for a given crystalline form of the same compound will vary within the error bounds. It should also be understood that the intensity of the peaks can vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of different peaks are not intended to limit the comparison of different PXRD scans.

[0057] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or disorder, preventing additional symptoms, inhibiting a disease or disorder (e.g., preventing the development of a disease or disorder), relieving a disease or disorder, causing regression of a disease or disorder, alleviating the condition caused by a disease or disorder, or prophylactically and / or therapeutically halting the symptoms of a disease or disorder. II. Compound A

[0058] Compound A is described in U.S. Patent Application Publication No. 2017 / 0360759.

[0059] In some aspects, Compound A includes the crystalline form "Form A". When dissolved, the crystalline form of Compound A loses its crystalline structure and is thus referred to as a solution of Compound A. However, all forms of the present invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. In addition, crystalline Form A of Compound A can be incorporated into solid formulations.

[0060] As used herein, a PXRD (powder x-ray diffraction) or XRPD (x-ray powder diffraction) pattern "comprising" or having a plurality of peaks selected from a specified set of peaks is intended to include a PXRD pattern having additional peaks not included in the specified set of peaks. For example, a PXRD pattern comprising four or more (preferably five or more) peaks at 2θ values selected from A, B, C, D, E, F, G, and H is intended to include a PXRD pattern having: (a) four or more (preferably five or more) peaks at 2θ values selected from A, B, C, D, E, F, G, and H; and (b) zero or more peaks that are not one of the A, B, C, D, E, F, G, and H peaks.

[0061] In some aspects, Form A is characterized by a single crystal structure having unit cell parameters that are substantially equal to the following: wherein the measurement of the single crystal structure is carried out at room temperature.

[0062] In some aspects, Form A has a powder x-ray diffraction pattern that is substantially the same as that shown in Figure 1 In some aspects, Form A has a powder x-ray diffraction pattern comprising two or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2, and 26.8 ± 0.2 (obtained at room temperature and CuKα

[0063] In some aspects, Form A has a powder x-ray diffraction pattern comprising three or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2, and 26.8 ± 0.2 (obtained at room temperature and CuKα In some aspects, Form A has a powder x-ray diffraction pattern comprising four or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2, and 26.8 ± 0.2 (obtained at room temperature and CuKα In some aspects, Form A has a powder x-ray diffraction pattern comprising four or more peaks at 2θ values selected from the following: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2, and 26.8 ± 0.2 (obtained at room temperature and CuKα obtained).

[0064] In some aspects, Form A has a powder X-ray diffraction pattern having 3 or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 14.5 ± 0.2, 14.7 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.1 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2, and 27.8 ± 0.2 (obtained at room temperature and CuKα In some aspects, Form A has a powder X-ray diffraction pattern having 4 or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 14.5 ± 0.2, 14.7 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.1 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2, and 27.8 ± 0.2 (obtained at room temperature and CuKα In some aspects, Form A has a powder X-ray diffraction pattern having 5 or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 14.5 ± 0.2, 14.7 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.1 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2, and 27.8 ± 0.2 (obtained at room temperature and CuKα obtained).

[0065] In some aspects, Form A has a powder X-ray diffraction pattern having 2 or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (obtained at room temperature and CuKα obtained below). In some aspects, Form A has a powder X-ray diffraction pattern having three or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (at room temperature and CuKα obtained below). In some aspects, Form A has a powder X-ray diffraction pattern having four or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, and 21.6 ± 0.2 (at room temperature and CuKα obtained below).

[0066] In some aspects, Form A has a differential scanning calorimetry thermogram that is substantially similar to that shown in Figure 2 In some aspects, Form A has a differential scanning calorimetry thermogram having an endotherm beginning at about 152 °C.

[0067] In some aspects, Form A has a thermogravimetric analysis thermogram that is substantially similar to that shown in

[0068] In some aspects, Form A has a differential scanning calorimetry thermogram that is substantially similar to that shown in Figure 3 III. Compositions In some aspects, the present disclosure provides compositions comprising Compound A. In some aspects, the present disclosure provides compositions comprising a crystalline form of Compound A. In some aspects, the present disclosure provides compositions comprising Form A of Compound A. As used herein, the term “composition” is intended to cover a product comprising the specified amounts of the specified ingredients, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients. Such term with respect to pharmaceutical compositions is intended to cover a product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product directly or indirectly resulting from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or negligible ingredients. Accordingly, the pharmaceutical compositions of the present invention cover any composition prepared by mixing the compounds of the present invention with a pharmaceutically acceptable carrier. With respect to “pharmaceutically acceptable carrier”, it means a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and harmless to its recipient.

[0069]

[0070] ​In some aspects, the compositions of the present disclosure are suitable for oral administration. These compositions can include solid, semi-solid, gel matrix or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gums, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some aspects, the compositions of the present disclosure suitable for oral administration are in the form of tablets or capsules. In some aspects, the compounds of the present disclosure can be in the form of capsules. In some aspects, the capsules can be immediate-release capsules.

[0071] The compositions of the present disclosure can be in the form of compressed tablets, triturated tablets, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets, or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can impart the same general characteristics as sugar coatings. Multi-compressed tablets are compressed tablets prepared by more than one compression cycle, including multi-layer tablets and compressed-coated tablets or dry-coated tablets.

[0072] In some aspects, the compounds of the present disclosure can be in the form of tablets. In some aspects, the compounds of the present disclosure can be in the form of compressed tablets. In some aspects, the compounds of the present disclosure can be in the form of film-coated compressed tablets. In some aspects, the compositions of the present disclosure can be in the form of film-coated compressed tablets.

[0073] In some aspects, the compositions of the present disclosure can be prepared by fluid bed granulation of the compounds of the present disclosure with one or more pharmaceutically acceptable carriers, vehicles, and / or excipients. In some aspects, the compositions of the present disclosure can be prepared by a fluid bed granulation method and can provide tablet formulations having good flowability, good compressibility, rapid dissolution, good stability, and / or minimal to no capping. In some aspects, the fluid bed granulation method can allow for the preparation of formulations having a high drug loading (such as more than 70% or more than 75% of the compounds of the present disclosure).

[0074] In some aspects, the compositions of the present disclosure can be in the form of soft or hard gelatin capsules, which can be made of gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules (also known as dry-filled capsules (DFC)) can consist of two parts that slide over one another to completely enclose the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells (such as gelatin shells) that are plasticized by the addition of glycerol, sorbitol, or similar polyols. In some aspects, the soft gelatin shell can contain preservatives to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, the preservatives described herein, including methylparaben and propylparaben, sorbic acid, and combinations thereof. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils, triglycerides, and combinations thereof. As is known to those skilled in the art, the capsule can also be coated to alter or maintain the dissolution of the active ingredient.

[0075] In some aspects, the compositions of the present disclosure can be in liquid or semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. In some aspects, an emulsion can be a two-phase system in which one liquid is dispersed throughout the other liquid in the form of small spheres, which can be water-in-oil or oil-in-water. The emulsion can contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. A suspension can contain a pharmaceutically acceptable suspending agent and a preservative. An aqueous alcoholic solution can contain a pharmaceutically acceptable acetal, such as a di-(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having from 1 to 6 carbon atoms), for example, acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. An elixir can be a clear solution, a sweetened solution, and an aqueous alcoholic solution. A syrup can be a concentrated aqueous solution of sugar (e.g., sucrose) and can contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement for administration.

[0076] In some aspects, the compositions of the present disclosure for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems.

[0077] In some aspects, the compositions of the present disclosure may be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include, but are not limited to, diluents, sweeteners, wetting agents and mixtures thereof. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include, but are not limited to, organic acids, carbon dioxide sources and mixtures thereof.

[0078] Colorants and flavorants may be used in all of the above dosage forms. In addition, flavorants and sweeteners may be used particularly in the formation of chewable tablets and lozenges.

[0079] In certain aspects, the compositions of the present disclosure may be formulated as immediate-release or modified-release dosage forms, including delayed-release, extended-release, pulsatile-release, controlled-release, targeted-release and programmed-release forms.

[0080] The compositions of the present disclosure may comprise another active ingredient that does not impair the therapeutic or prophylactic efficacy of the composition and / or may comprise a substance that enhances or supplements the efficacy of the composition.

[0081] In certain aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof may be administered orally. In some aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof may be administered in capsules. In some aspects, Compound A or a pharmaceutically acceptable salt and / or solvate thereof may be administered in tablets.

[0082] Typically, Compound A or a pharmaceutically acceptable salt thereof is administered as a mixture with a suitable pharmaceutical diluent, excipient or carrier (collectively referred to herein as pharmaceutical carriers), which are appropriately selected relative to the intended dosage form (i.e., oral tablets, capsules, elixirs, syrups, etc.) and are consistent with conventional pharmaceutical practice.

[0083] For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with an orally non-toxic pharmaceutically acceptable inert carrier (such as lactose, sucrose, dextrose, dextrates, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, etc.); for oral administration in liquid form, the oral pharmaceutical ingredient can be combined with any orally non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). In addition, when desired or necessary, suitable binders, lubricants, disintegrants, glidants, flavoring agents, and coloring agents can also be incorporated into the mixture.

[0084] In still other aspects, using standard coating procedures, such as those described in Remingon's Pharmaceutical Sciences, 20th Edition (2000), a film coating can be provided around the formulation of Compound A.

[0085] Dosage forms (pharmaceutical compositions) suitable for administration can contain from about 1 milligram to about 300 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.5% - 95% by weight based on the total weight of the composition. In some aspects, dosage forms suitable for administration can contain from about 10 to about 240 milligrams of active ingredient per dosage unit. In some aspects, dosage forms suitable for administration can contain about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, or about 240 mg of active ingredient per dosage unit.

[0086] In some aspects, the present disclosure provides pharmaceutical compositions that comprise Compound A or a pharmaceutically acceptable salt thereof as described herein and at least one pharmaceutically acceptable carrier.

[0087] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) about 5 wt% to 40 wt% of Compound A; (b) about 30 wt% to about 90 wt% of a diluent or mixture of diluents; (c) about 0 wt% to about 2 wt% of a glidant; (d) about 2 wt% to about 10 wt% of a disintegrant; and (e) about 0.25 wt% to about 4 wt% of a lubricant.

[0088] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0089] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) about 10 wt% to 30 wt% of Compound A; (b) about 40 wt% to about 85 wt% of a diluent or diluent mixture; (c) about 0 wt% to about 2 wt% of a glidant; (d) about 2 wt% to about 10 wt% of a disintegrant; and (e) about 0.25 wt% to about 4 wt% of a lubricant.

[0090] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0091] In some aspects, the diluents described herein are selected from lactose, sucrose, dextrose, glucose binder, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof. In some aspects, the diluent or diluent mixture is selected from microcrystalline cellulose and anhydrous lactose.

[0092] As used herein, the term "glidant" refers to a substance that improves the flowability of a powder (such as by reducing interparticle friction) when added to the powder. In some aspects, the glidants described herein are selected from silica, silicon dioxide, CAB-0-SILM-SP, AEROSIL, talc, starch, magnesium aluminum silicate, and combinations thereof. In some aspects, the glidant is silicon dioxide.

[0093] In some aspects, the disintegrants described herein are selected from natural starch, pregelatinized starch, sodium starch glycolate, methylcellulose crystalline, methylcellulose, cross-linked carboxymethylcellulose, sodium cross-linked carboxymethylcellulose, sodium cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked cross-linked carboxymethyl cellulose, cross-linked starch (such as sodium starch glycolate), cross-linked polymers (such as crospovidone, cross-linked polyvinylpyrrolidone), sodium alginate, clay, gum, and combinations thereof. In some aspects, the disintegrant is sodium cross-linked carboxymethylcellulose.

[0094] In some aspects, the surfactants described herein are selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, and combinations thereof. In some aspects, the surfactant is sodium lauryl sulfate.

[0095] In some aspects, the lubricants described herein are selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, waxes, and combinations thereof. In some aspects, the lubricant is magnesium stearate.

[0096] In some aspects, provided herein is a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) from about 5 wt% to 40 wt% of Compound A; (b) from about 15 wt% to about 70 wt% of microcrystalline cellulose and from about 15 wt% to about 70 wt% of anhydrous lactose; (c) from about 0 wt% to about 2 wt% of silicon dioxide; (d) from about 2 wt% to about 6 wt% of croscarmellose sodium; and (e) from about 0.25 wt% to about 1.5 wt% of magnesium stearate.

[0097] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet.

[0098] In some aspects, provided herein is a pharmaceutical formulation for oral administration, the pharmaceutical formulation comprising: (a) from about 10 wt% to 30 wt% of Compound A; (b) from about 25 wt% to about 70 wt% of microcrystalline cellulose and from about 25 wt% to about 70 wt% of anhydrous lactose; (c) from about 0 wt% to about 2 wt% of silicon dioxide; (d) from about 2 wt% to about 6 wt% of croscarmellose sodium; and (e) from about 0.25 wt% to about 1.5 wt% of magnesium stearate.

[0099] In some aspects, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some aspects, the pharmaceutical formulation for oral administration is a tablet. In some aspects, the tablet can be prepared with the components provided in Table 1 and / or Table 2. Table 1 Table 2

[0100] In some aspects, the pharmaceutical composition for oral administration can be prepared by direct compression or granulation (dry granulation, wet granulation, or melt granulation). IV. Treatment Methods

[0101] The present disclosure provides a method for treating interstitial lung disease by administering Compound A (an LPA1 antagonist). Lysophospholipids are membrane-derived bioactive lipid mediators. Lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC). Lysophospholipids affect basic cellular functions, which include cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect many biological processes, which include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0102] LPA acts in an autocrine and paracrine manner through several groups of specific G protein-coupled receptors (GPCRs). Binding of LPA to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) activates intracellular signaling pathways to produce a variety of biological responses.

[0103] Lysophospholipids (such as LPA) are minor lipid species in terms of quantity compared to their major phospholipid counterparts (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA has a role as a bioactive molecule and has a variety of physiological effects (such as, but not limited to, effects on blood pressure, platelet activation, and smooth muscle contraction) and a variety of cellular effects (which include cell growth, cell rounding, neurite retraction, and actin stress fiber formation, as well as cell migration). The effects of LPA are mainly receptor-mediated.

[0104] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates a series of downstream signaling cascades. These include, but are not limited to, mitogen-activated protein kinase (MAPK) activation, adenylate cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca 2+Mobilization, arachidonic acid release, Akt / PKB activation, and activation of small GTPases, Rho, ROCK, Rac, and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine-protein kinase Raf (c-RAF), proto-oncogene tyrosine-protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factor (GEF), glycogen synthase kinase 3 beta (GSK3b), c-jun N-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kappa B (NF-kB), N-methyl-D-aspartic acid (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RAC1). The actual pathways and the endpoints achieved depend on a series of variables, which include receptor usage, cell type, expression levels of receptors or signaling proteins, and LPA concentration. Almost all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, suggesting that LPA receptors signal in a collaborative manner. LPA1, LPA2, and LPA3 have high amino acid sequence similarity.

[0105] LPA is produced by activated platelets, activated adipocytes, neuronal cells, and other cell types. Serum LPA is generated through multiple enzymatic pathways involving monoacylglycerol kinase, phospholipase A1, secreted phospholipase A2, and lysophospholipase D (lysoPLD) (including autotaxin). The following several enzymes are involved in LPA degradation: lysophospholipase, lipid phosphate phosphatase, and LPA acyltransferase, such as endophilin. The concentration of LPA in human serum is estimated to be 1 - 5 μM. Serum LPA binds to albumin, low-density lipoprotein, or other proteins, which may protect LPA from rapid degradation. LPA molecular species with different acyl chain lengths and saturations are naturally occurring, including 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonoyl (20:4) LPA. The less abundant alkyl LPA has similar biological activity to acyl LPA, and different LPA species activate LPA receptor subtypes with different potencies.

[0106] LPA1 (previously known as VZG-1 / EDG-2 / mrec1.3) couples to the following three types of G proteins: G i / o 、G q and G 12 / 13. By activating these G proteins, LPA induces a series of cellular responses including but not limited to the following through LPA1: cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca 2+ mobilization, Akt activation, and Rho activation.

[0107] Widespread expression of LPA1 has been observed in adult mice, specifically present in the testis, brain, heart, lung, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1; it is present in the brain, heart, lung, placenta, colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

[0108] As used herein, the term "LPA-dependent" refers to a disorder or condition that does not occur or does not occur to the same extent in the absence of LPA.

[0109] As used herein, the term "LPA-mediated" refers to a disorder or condition that may occur in the absence of LPA but should occur in the presence of LPA.

[0110] As used herein, the terms "fibrosis" and "fibrotic disease" refer to conditions associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, and include but are not limited to fibrosis of a single organ or tissue (such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract), such as idiopathic pulmonary fibrosis, scleroderma, and chronic kidney disease.

[0111] Exemplary diseases, disorders or conditions involving fibrosis include, but are not limited to: lung diseases associated with fibrosis, such as idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory diseases (such as rheumatoid arthritis, scleroderma, lupus), cryptogenic fibrosing alveolitis, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (including those induced by bacterial pneumonia, trauma, viral pneumonia, ventilator, non-pulmonary sepsis and aspiration); chronic kidney diseases (renal fibrosis) associated with injury / fibrosis, such as glomerulonephritis secondary to systemic inflammatory diseases (such as lupus and scleroderma), diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft and hereditary nephritis (Alport); intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection or virus-induced liver fibrosis (e.g., chronic HCV infection) and autoimmune hepatitis; head and neck fibrosis, such as radiation-induced; corneal scarring, such as LASIK (laser in-situ keratomileusis), corneal transplantation and trabeculectomy; hypertrophic scars and keloids, such as burn-induced or surgical; and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease and Peyronie's disease.

[0112] Other diseases, disorders or conditions in which the LPA1 receptor may be involved include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal tract fibrosis, sinusitis, neutrophil-mediated inflammation, and fibroblast-mediated fibrosis, skin disorders (including skin proliferative or inflammatory disorders, such as atopic dermatitis, bullous disorders, collagen diseases, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, rosacea, wound healing, scars, hypertrophic scars, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome ( - Larsson Syndrome) and urticaria), respiratory diseases (including asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, etc. isocapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (including chronic bronchitis or emphysema), pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation and cystic fibrosis and hypoxia), and inflammatory / immune disorders (including psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, eczema, allograft or xenograft (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory diseases, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's thyroiditis and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic recurrent hepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopic dermatitis).

[0113] There are currently two approved treatments for interstitial lung disease: nintedanib and pirfenidone, but several compounds are currently under development. In certain aspects of the present disclosure, a subject administered compound A or a pharmaceutically acceptable salt thereof is receiving concomitant treatment with one or more therapies for interstitial lung disease. In some aspects, one or more therapies are selected from nintedanib and pirfenidone.

[0114] In certain aspects, about 100 mg to about 150 mg of compound A or an equivalent amount of its pharmaceutically acceptable salt is administered to the subject daily. In some aspects, about 110 mg to about 130 mg of compound A or an equivalent amount of its pharmaceutically acceptable salt is administered to the subject daily. In some aspects, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145 or about 150 mg of compound A or an equivalent amount of its pharmaceutically acceptable salt is administered to the subject daily. In some aspects, about 120 mg of compound A or an equivalent amount of its pharmaceutically acceptable salt is administered to the subject daily.

[0115] In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject once daily. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject twice daily. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject three times daily. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject four times daily. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject five times daily.

[0116] In some aspects, 120 mg of compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to a subject once daily. In some aspects, a 60 mg dose of compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to a subject twice daily. In some aspects, a 40 mg dose of compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to a subject three times daily. In some aspects, a 30 mg dose of compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to a subject four times daily. In some aspects, a 24 mg dose or an equivalent amount of a pharmaceutically acceptable salt thereof is administered to a subject five times daily.

[0117] In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject with food. In some aspects, compound A or a pharmaceutically acceptable salt thereof is administered to a subject without food.

[0118] In some aspects, compared to untreated subjects, subjects administered compound A or a pharmaceutically acceptable salt thereof experience slower disease progression. In some aspects, disease progression is measured by a decrease in the forced vital capacity (FVC) of the subject. In some aspects, compared to untreated subjects, subjects treated with compound A or a pharmaceutically acceptable salt thereof experience a smaller decrease in forced vital capacity (FVC) after the treatment period. FVC is the amount of air that a subject can forcefully exhale from his / her lungs after breathing in as deeply as possible. Typically, a spirometry test is used to measure FVC, which involves placing a special mask on the subject's face and having the subject inhale and exhale as forcefully as possible while collecting the measurements.

[0119] In some aspects, disease progression can be measured by the time it takes for a subject to experience a disease progression event. In some aspects, subjects administered Compound A or a pharmaceutically acceptable salt thereof experience a longer time to the first disease progression event after the treatment period compared to untreated subjects. In some aspects, the first disease progression event is an absolute predicted forced vital capacity percentage (ppFVC) of ≥ 10% relative to baseline. An absolute or relative decrease in predicted FVC% of ≥ 10% is associated with death. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to an absolute predicted forced vital capacity percentage (ppFVC) of ≥ 10% relative to baseline compared to untreated subjects.

[0120] In some aspects, the first disease progression event is an acute exacerbation (e.g., sudden worsening) of his / her pulmonary fibrosis. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to an acute exacerbation of pulmonary fibrosis compared to untreated subjects.

[0121] In some aspects, the first disease progression event is a respiratory hospitalization. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to a respiratory hospitalization compared to untreated subjects.

[0122] In some aspects, the first disease progression event is a hospitalization related to pulmonary fibrosis. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to a hospitalization related to pulmonary fibrosis compared to untreated subjects.

[0123] In some aspects, the first disease progression event is a lung transplant. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to a lung transplant compared to untreated subjects.

[0124] In some aspects, the first disease progression event is death. In some aspects, subjects treated with Compound A or a pharmaceutically acceptable salt thereof experience a longer time to all-cause death compared to untreated subjects.

[0125] In some aspects, subjects experience a longer time to the first disease progression event after the treatment period compared to untreated subjects, wherein the first disease progression event is selected from: An absolute predicted forced vital capacity percentage (ppFVC) of ≥ 10% relative to baseline; An acute exacerbation of pulmonary fibrosis; A respiratory hospitalization; A lung transplant; and All-cause death.

[0126] In some aspects, compared to untreated subjects, subjects experienced a longer time to the first disease progression event after the treatment period, where the first disease progression event is selected from: An absolute predicted forced vital capacity (ppFVC) decline of ≥10% relative to baseline; An acute exacerbation of pulmonary fibrosis; Hospitalization related to pulmonary fibrosis; and All-cause death.

[0127] In some aspects, disease progression is measured by a change in the score of the Lung-PF (Lung Fibrosis Quality of Life) questionnaire. The Lung-PF questionnaire assesses the symptoms and quality of life of patients with fibrotic interstitial lung disease (ILD). The scores in its dyspnea and cough domains (the responses to the items are based on 24-hour recall) range from 0 to 100, with higher scores indicating greater symptom severity (see, for example, Swigris JJ et al. BMJ Open Resp Res [BMJ Open Access Journal of Respiratory Diseases] 2022; 9: e001167. doi: 10.1136 / bmjresp-2021-001167). In some aspects, compared to untreated subjects, subjects administered Compound A or a pharmaceutically acceptable salt thereof experienced a smaller increase in the cough domain score as measured by the Lung-PF questionnaire during the treatment period. In some aspects, compared to untreated subjects, subjects experienced a smaller increase in the dyspnea score as measured by the Lung-PF questionnaire during the treatment period. Examples Example 1: Preparation of Crystalline Form A of Compound A

[0128] Crystalline forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from the melt, solid-state transformation from another phase, crystallization from supercritical fluids, and spray spraying. Techniques for crystallizing or recrystallizing a eutectic form from a solvent mixture include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, seeding the crystal into a supersaturated solvent mixture of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (anti-solvent) to the solvent mixture.

[0129] For crystallization techniques using solvents, the choice of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used. For example, a compound can be dissolved in a first solvent to provide a solution, and then an anti-solvent is added to reduce the solubility of the compound in the solution and obtain crystal formation. An anti-solvent is a solvent in which the compound has low solubility.

[0130] In one method of preparing crystals, a compound is suspended and / or stirred in a suitable solvent to obtain a slurry, which can be heated to facilitate dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain additional amounts of the compound to obtain a heterogeneous mixture of the compound and the solvent at a given temperature.

[0131] Seeds can be added to any crystallization mixture to promote crystallization. Seeds can be used to control the growth of a specific polymorph or to control the particle size distribution of the crystallization product. Thus, the calculation of the required amount of seeds depends on the size of the available seeds and the desired size of the average product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369 - 377. Generally, small-sized seeds are required to effectively control the growth of crystals in a batch. Small-sized seeds can be produced by sieving, grinding, or micronizing large crystals, or by microcrystallization of a solution. It should be noted that grinding or micronizing of the crystals does not result in any change in crystallinity relative to the desired crystal form (i.e., becoming amorphous or becoming another polymorph).

[0132] The cooled crystallization mixture can be filtered under vacuum, and the separated solid can be washed with a suitable solvent (such as cold recrystallization solvent) and dried under a nitrogen purge to obtain the desired crystalline form. The separated solid can be analyzed by suitable spectroscopic or analytical techniques (such as solid-state nuclear magnetic resonance, differential scanning calorimetry, X-ray powder diffraction, etc.) to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of greater than about 70% by weight, preferably greater than 90% by weight, of the separation yield based on the weight of the compound initially employed in the crystallization procedure. If desired, the product can be co-ground or passed through a sieve to deagglomerate the product.

[0133] The presence of more than one polymorph in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or by techniques such as Raman or infrared spectroscopy, solid state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern can indicate the presence of more than one polymorph in the sample. The simulated PXRD can be calculated from single crystal X-ray data. See Smith, D.K., “A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0134] The crystalline forms of Compound A according to the present invention can be characterized using a variety of techniques, the operation of which is well known to those of ordinary skill in the art. These forms can be characterized and distinguished using single crystal X-ray diffraction, which is based on the measurement of the unit cell of a single crystal of the form at a fixed analysis temperature. A detailed description of the unit cell is provided in Stout and Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the unique arrangement of atoms in the spatial relationships within the lattice can be characterized based on the observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder X-ray diffraction analysis (wherein the diffraction spectrum is compared with a simulated spectrum representative of the pure powder material, both run at the same analysis temperature) and measurement of the subject form (characterized as a series of 2θ values (usually four or more)).

[0135] Other means of characterizing the forms can be used, such as solid state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermogravimetric analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the subject forms. In addition to the techniques specifically described herein, the presence of a particular crystalline form can also be determined by other suitable analytical methods. Example 1A

[0136] At 20 °C, 150 mg of Compound A was dissolved in 1.5 mL of tetrahydrofuran (THF). 0.5 mL of this solution was subjected to rapid evaporation using a centrifugal evaporator to produce a solid of Form A. At 20 °C, 0.5 mL of the same solution was subjected to slow evaporation to produce a solid of Form A. Example 1B

[0137] At 20 °C, 200 mg of Compound A was dissolved in 1 mL of dichloromethane (DCM). 0.5 mL of this solution was subjected to rapid evaporation using a centrifugal evaporator to yield a solid of Form A. At 20 °C, 0.5 mL of the same solution was subjected to slow evaporation to yield a solid of Form A. Example 1C

[0138] At 50 °C, 100 mg of Compound A was dissolved in 0.5 mL of THF and kept stirring at 20 °C. 0.5 mL of water was added to the clear solution, which yielded a solid of Form A. Example 1D

[0139] At 50 °C, 100 mg of Compound A was dissolved in 1 mL of 2-methyl THF and kept stirring at 20 °C. 1 mL of n-heptane was added to the clear solution, which yielded a solid of Form A. Example 1E

[0140] A solution of Compound A in tert-amyl alcohol (t-AmOH) was concentrated in vacuo to 4 L / kg, then 15 L / kg of DCM and 10 L / kg of water were added. The layers were separated, and the DCM layer was concentrated in vacuo to 4 L / kg. 8 - 10 L / kg of ethyl acetate (EtOAc) was added to the DCM layer, then it was concentrated in vacuo to 4 L / kg. Another 8 - 10 L / kg of EtOAc was added, then it was concentrated in vacuo to 4 L / kg. 6 - 8 L / kg of EtOAc was added and warmed to 70 °C - 83 °C until completely dissolved. The resulting slurry was cooled to 0 °C - 10 °C over at least 2 hours, followed by aging for at least 12 hours. The slurry was filtered. The wet filter cake was washed with 3 - 5 L / kg of EtOAc and dried in vacuo at 55 °C - 60 °C to yield a solid of Form A. Example 1F

[0141] A solution of Compound A in t-AmOH was concentrated to 4 L / kg at 55 °C under vacuum, then 5 L / kg of 2-propanol (IPA) was added, and the mixture was concentrated to 4 L / kg at 55 °C under vacuum. This process was repeated two more times with 2 x 5 L / kg of IPA. The batch was cooled to 30 °C, then 1.3 L / kg of water was added and the mixture was heated to 45 °C - 55 °C. The resulting warm solution was filtered finely and cooled to 30 °C. 1 wt% of seed form A was added, followed by 2 L / kg of water. After at least 6 hours, an additional 8.7 L / kg of water was added. The resulting slurry was cooled to 20 °C over at least 30 minutes, and the slurry was aged for at least 3 hours. The solid was filtered, and the wet cake was washed successively with 3 L / kg of a water:IPA:t-AmOH mixture (11:3:1 by volume) and 3 L / kg of water, and dried under vacuum at 50 °C - 60 °C to obtain the solid of form A. Example 1G

[0142] To a solution of (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid isopropyl ester (500 mg, 1.025 mmol) in 1:1 THF / MeOH (10 mL) was added aqueous LiOH (1.538 mL of a 2 M solution, 3.08 mmol). The reaction mixture was stirred at 50 °C for 1 h, then cooled to room temperature, and the organic volatiles were removed in vacuo. The concentrated solution was washed with EtOAc, then acidified to pH ~6 - 7 (1 N aqueous HCl). The aqueous layer was extracted with EtOAc several times. The combined organic extracts were washed with water, dried (MgSO4), and the MgSO4 was filtered off. The EtOAc solution was concentrated in vacuo to yield the solid of form A.

[0143] The analytical data of the crystalline Compound A described herein were obtained using the following procedure. Single crystal

[0144] Single crystal X-ray data were collected on a Bruker X8 Kappa diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator with monochromated Cu Kα radiation. During data collection, the single crystal was at room temperature.

[0145] Indexing and processing of intensity data measured with the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711, USA). The final cell parameters were determined using the full data set. The structure was solved by the direct method and refined by full-matrix least-squares using the SHELXTL software package (G. M. Sheldrick, SHELXTL v6.14, Bruker, Madison, WI, USA). Structure refinement involves minimizing the function defined by ∑w(|F o |-|F c |) 2 where w is an appropriate weighting factor based on the error of the observed intensity, F o is the structure factor based on the measured reflections, and F c is the structure factor based on the calculated reflections. The agreement between the refined crystal structure model and the experimental X-ray diffraction data was evaluated by using the residual factors R = ∑||F o |-|F c || / ∑|F o | and wR = [∑w(|F o |-|F c |) 2 / ∑w|F o |] 1 / 2 . The difference Fourier maps were checked at all refinement stages. All non-hydrogen atoms were refined with anisotropic thermal displacement parameters. Hydrogen atoms were introduced using idealized geometry with isotropic temperature factors and included in the structure factor calculations with fixed parameters. Powder X-ray diffraction (PXRD)

[0146] PXRD patterns were acquired in the 2θ range of 2 - 40° on a Bruker D8 Advance system using Cu Kα (40 kV / 40 mA) radiation, a step size of 0.03° 2θ, and a LynxEye detector. Configuration on the incident beam side: Mirror, mirror exit slit (0.2 mm), 2.5-degree Soller slit, beam knife. Configuration on the diffracted beam side: anti-scatter slit (8 mm) and 2.5° Soller slit. The sample was flat-fixed on a zero-background silicon wafer. Differential scanning calorimetry (DSC)

[0147] DSC was performed on a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under a 40 mL / min N2 purge (for Q2000). DSC thermograms were obtained in crimped aluminum pans at 15 °C / min. Thermogravimetric analysis (TGA)

[0148] TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer under 40 mL / min N2 purge (for the balance) and 60 mL / min (for the sample in the aluminum pan). TGA thermograms were obtained at 15 °C / min. Water sorption isotherm

[0149] Water sorption isotherms were collected using approximately 270 mg of sample in a 250 μL ceramic pan in a TA Instruments VTI-SA+ vapor sorption analyzer. The sample was dried at 30 °C until a loss rate of 0.005 wt% / min was obtained for 10 minutes. The sample was tested at 25 °C and 4%, 5%, 15%, 25%, 35%, 45%, 50%, 65%, 75%, 85%, and 95% RH. Equilibrium was reached at each RH when a rate of 0.01 wt% / min was obtained for 35 minutes or when a maximum of 600 minutes had elapsed. Example 2. A double-blind, placebo-controlled, randomized, single- and multiple-ascending-dose study of the safety, pharmacokinetics, and exploratory pharmacodynamics of orally administered Compound A in healthy participants

[0150] The study was conducted in three parts in 112 healthy male and female participants (including 24 Japanese participants). Female participants were not of childbearing potential. The study aimed to evaluate the safety and tolerability, PK, and exploratory PD of an oral suspension of Compound A. Parts A and B (only cohort B1) enrolled healthy participants and were conducted at centers in the Netherlands, and Part B (cohorts B2 to B5) enrolled healthy non-Japanese participants and was conducted at centers in the United Kingdom (UK). Part C enrolled healthy Japanese participants and was conducted at the same centers in the UK.

[0151] Part A was a SAD study conducted in 6 consecutive dose-escalating cohorts (3, 10, 30, 100, 150, or 250 mg) of the planned number under fasting conditions, with 8 healthy participants in each cohort (6 receiving the active agent + 2 receiving placebo). Eligible participants in Part A (excluding participants in cohort A7 [Food Effect (FE) / pH cohort]) received a single administration of the study drug (Compound A or placebo) under fasting conditions. In cohorts A1 to A6, sentinel dosing was used (1 receiving the active agent + 1 receiving placebo, followed 48 hours later by the remaining participants of the cohort [5 receiving the active agent + 1 receiving placebo]). However, in cohort A6 (250 mg), due to dose-limiting events observed in the sentinel participants, only 2 sentinel participants were dosed, and further enrollment was then stopped. In addition to the 6 escalating dose cohorts, a cohort of 6 healthy participants (cohort A7; 6 receiving the active agent, i.e., 100 mg of Compound A) was included to evaluate the effects of food and pH on the bioavailability of Compound A in a Phase 3, open-label, fixed-sequence, crossover design (FE / pH cohort).

[0152] Part B was a MAD study conducted in 6 consecutive dose-escalating cohorts (10 mg QD, 30 mg QD, 30 mg BID, 60 mg BID, 125 mg BID, and ≤250 mg BID) of the planned number under fasting conditions, with 8 healthy participants in each cohort (6 receiving the active agent + 2 receiving placebo). However, cohort B6 (≤250 mg BID) was cancelled because sufficient safety and PK data had been obtained at doses up to 125 mg BID. Eligible participants received oral administration of the study drug (Compound A or placebo) for 14 days.

[0153] Part C was a MAD study conducted in 3 consecutive dose-escalating cohorts (30 mg BID, 60 mg BID, and 90 mg BID), with 8 healthy Japanese participants in each cohort (6 receiving the active agent + 2 receiving placebo). Eligible participants in cohorts C1 to C3 received oral administration of the study drug (Compound A or placebo) for 14 days.

[0154] Physical examinations, vital signs measurements (including orthostasis testing at selected time points in cohorts A6, B3 to B5, and C1 to C3), 12-lead electrocardiogram (ECG), and clinical laboratory evaluations were performed at selected times throughout the study. In addition, Holter monitoring was performed within the first 24 hours after dosing on Day 1 in Part A (not in the FE / pH cohort), and also within the first 24 hours after dosing on Day 1 and Day 14 in Parts B and C. Adverse events (AEs) were closely monitored in the participants. Blood samples were collected for PK analysis up to 14 days (follow-up visit) after the (last) administration of the study drug. In addition, blood and urine were collected for exploratory biomarker evaluation and biobanking of samples for potential analysis. Urine was collected for potential PK analysis up to 96 hours after administration of a single dose of Compound A or placebo in the SAD part, and on Day 1 up to 24 hours after the first (morning) dose of the study drug and on Day 14 up to 24 hours after the last (morning) dose of the study drug in the MAD part.

[0155] After oral administration of a single dose and multiple doses to healthy participants, Compound A was generally safe and well tolerated. Compound A was observed to be associated with a reversible decrease in BP, which generally reached its maximum 4 to 8 hours after dosing and was not associated with a significant change in heart rate. The BP decrease was mostly asymptomatic.

[0156] In the SAD cohort, Compound A dose-dependently, reversibly, and mostly asymptomatically decreased SBP and DBP with minimal effect on heart rate. The changes in blood pressure are shown in Tables 3 and 4 below. Table 3: Maximum mean (±SD) decrease in systolic and diastolic blood pressure relative to baseline and corresponding time within 12 hours after dosing in SAD DBP = diastolic blood pressure; SAD = single ascending dose; SBP = systolic blood pressure; SD = standard deviation a Maximum decrease identical to previous measurement Note: Baseline was defined as the last observation recorded before the first administration of the study drug in each period. Time (h) is the time since the last morning administration of the study drug. Table 4: Mean (±SD) systolic and diastolic blood pressure in SAD within 24 hours after dosing DBP = diastolic blood pressure; SAD = single ascending dose; SBP = systolic blood pressure; SD = standard deviation Note: The baseline was defined as the last observation recorded before the first administration of the study drug in each time period. Time (h) is the time since the last morning administration of the study drug.

[0157] In the MAD cohort, a reversible decrease in mean SBP and DBP occurred in all groups except the placebo QD group, which showed no change in BP. In the QD groups, the decrease occurred generally in a compound A dose-dependent manner. In the BID groups, both placebo and compound A treatments led to a decrease in BP, and there was no significant difference between the placebo and compound A groups. During the 14-day treatment period, there was no significant change in the magnitude of the BP decrease upon repeated dosing. In the Japanese MAD cohort, a reversible decrease in mean BP occurred in all groups (including placebo). There was no significant compound A dose-dependent BP decrease trend. Changes in blood pressure are shown in Tables 5 - 7 below. Table 5: Maximum mean (±SD) decrease in systolic and diastolic blood pressures relative to baseline and corresponding time - Part B (MAD cohort) BID = twice daily; DBP = diastolic blood pressure; MAD = multiple ascending doses; QD = once daily; SBP = systolic blood pressure; SD = standard deviation Note: The baseline was defined as the last observation recorded before the first administration of the study drug in each time period. Time (h) is the time since the last morning administration of the study drug. Table 6: Mean (±SD) systolic and diastolic blood pressures in MAD at 24 hours after the first and last doses BID = twice daily; DBP = diastolic blood pressure; MAD = multiple doses; QD = once daily; SBP = systolic blood pressure; SD = standard deviation Note: The baseline was defined as the last observation recorded before the first administration of the study drug in each time period. Time (h) is the time since the last morning administration of the study drug. Table 7: Maximum mean (±SD) decrease in systolic and diastolic blood pressures relative to baseline and corresponding time - Part C (Japanese MAD cohort) BID = twice daily; DBP = diastolic blood pressure; MAD = multiple ascending dose; SBP = systolic blood pressure. Note: Baseline was defined as the last observation recorded before the first administration of the study drug in each period. Time (h) is the time since the last morning administration of the study drug. Example 3. A double-blind, placebo-controlled, randomized, single- and multiple-ascending dose study of the safety, tolerability, and pharmacokinetics of compound A following oral administration in healthy Chinese participants.

[0158] A single dose of 60 mg and a multiple dose of 60 mg BID were selected for this Chinese PK bridging study to permit investigation of the PK, safety, and tolerability at clinically relevant doses. It will investigate the effect of genetic variation in genes related to drug absorption, distribution, metabolism, excretion, and transport on the PK of compound A in healthy Chinese participants. Single dose

[0159] On Day 1, eligible subjects will be randomly assigned in a 3:1 ratio to a single oral dose of compound A or a matching placebo. Participants will fast for at least 10 hours before dosing and will remain fasting until at least 4 hours after administration. Multiple dose

[0160] From Day 5 to Day 10, subjects will receive compound A BID or a matching placebo. On Day 11, subjects will receive the morning dose (last dose) of compound A or a matching placebo.

[0161] On Day 5 and Day 11, participants will fast for at least 10 hours before dosing and will remain fasting until at least 4 hours after administration of the morning dose.

[0162] On the mornings of Days 6 - 10, participants will also receive the dose in a fasting state; however, approximately 2 hours after dosing on these days, they will receive breakfast.

[0163] On the evenings of Days 5 - 10, participants will receive a second oral dose of compound A or placebo 12 hours after the morning dose. The evening dose will be administered approximately 2 hours after the start of dinner.

[0164] The study treatment will be administered with 240 mL of water. Example 4: A multicenter, randomized, double-blind, placebo-controlled, Phase 2 study of the efficacy, safety, and tolerability of compound A in participants with pulmonary fibrosis

[0165] Key safety and efficacy data from the final analysis of the IPF cohort in the Phase 2 study support the continued development of compound A in both IPF and PPF. A schematic diagram showing an overview of the two cohorts of the trial is shown in Figure 5 in. Example 4A: IPF Cohort

[0166] As of the data cut-off for the final analysis (August 4, 2022), a total of 278 participants with IPF were randomly assigned and 276 participants received treatment. The following male and female participants met the eligibility criteria for entry into the study: age ≥ 40 years, had IPF, and had a predicted percent forced vital capacity (ppFVC) ≥ 40% and a predicted percent DLCO (ppDLCO) ≥ 25%; diagnosed within 7 years of screening; centrally interpreted chest HRCT obtained at screening was consistent with UIP or probable UIP, or lung biopsy was consistent with UIP. The mean baseline ppFVC for all subjects was 76.5%. In the primary IPF cohort, participants were randomly assigned (1:1:1) to receive 30 mg or 60 mg of Compound A or placebo (PBO) twice daily for 26 weeks. At randomization, participants were stratified by standard of care (SoC) IPF therapy (pirfenidone vs. nintedanib vs. none) and region (Japan vs. the rest of the world).

[0167] The primary objective of the study was to determine the rate of change in ppFVC from baseline to Week 26. The primary objective was evaluated using a dual-imputation framework to address the intercurrent event of dose reduction to 10 mg BID or matching PBO when meeting a pre-specified low BP criterion. The primary imputation was used to estimate the treatment effect when dose reduction was implemented. A supplementary imputation was used to estimate the treatment effect without dose reduction.

[0168] Among the 276 treated participants who contributed to these analyses, 90% (n = 248) completed the 26-week treatment period and 10% (n = 28) discontinued treatment. Treatment discontinuation due to TEAE was balanced across treatment groups (PBO: 9.8%; 30 mg: 9.9%; 60 mg: 6.5%).

[0169] Table 8 shows the baseline demographics and clinical characteristics of the subject population in the IPF cohort. Table 8: Baseline Demographics and Clinical Characteristics *Values before and after the ± sign represent mean ± SD. Patients with PPF were allowed to continue background anti-fibrotic medications ± ILD-targeted immunosuppressants (see Supplementary Table S1). 6MWT, 6-minute walk test; BMI, body mass index; DL CO, DLCO, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; PPF, progressive pulmonary fibrosis; SD, standard deviation.

[0170] Summary results are described in Tables 9 - 12; and additional results from the final analysis of the IPF cohort are described below. Primary estimand:

[0171] Analysis strategy: The primary estimand was to evaluate the efficacy of Compound A at 30 mg or 60 mg twice daily compared to PBO in IPF participants meeting the inclusion criteria with or without SoC. The difference between each dose and PBO was used to compare the rate of decline of ppFVC (%) from baseline to Week 26 at the population level summary, regardless of whether the dose was reduced or treatment was stopped for any reason (treatment policy strategy). Efficacy results based on the primary estimand:

[0172] In the overall population, in both the primary and supplementary estimand frameworks, compared to PBO, the 60 mg dose group showed a favorable treatment response at Week 26, measured as the rate of decline of ppFVC and the rate of decline of FVC (mL) (Table 8). The 30 mg dose group did not show efficacy (data not shown).

[0173] In the overall population, in terms of the rate of decline of ppFVC, the 60 mg dose showed a treatment difference of 1.45 ± 0.81 (mean ± standard error of the mean [SEM]) [95% CI - 0.133, 3.028]. This corresponded to an overall relative reduction of 54% compared to the PBO decline slope (-2.67 ± 0.57).

[0174] When analyzing the rate of decline of FVC in mL (adjusted for age, sex, and height, as measured by the slope difference in the 60 mg group [-54.3 ± 20.76] and by the slope difference in the PBO group [-101.2 ± 20.45]), the 60 mg dose corresponded to a relative treatment difference of 46.9 mL compared to PBO (46.9 ± 29.14 (mean ± SEM) [95% CI - 10.3, 104.1]).

[0175] Subgroup analysis of background SoC (SoC vs. none) demonstrated a favorable response at the primary endpoint in the 60 mg group compared to the PBO group.

[0176] Among participants using background SoC (68% of the overall population), the 60 mg dose showed a treatment difference compared to PBO of 1.22 ± 0.87 (mean ± SEM) [95% CI -0.486, 2.929], which corresponds to a 39% relative treatment benefit compared to PBO.

[0177] Among participants not using background SoC (32% of the overall population), the 60 mg dose showed a treatment difference compared to PBO of 2.01 ± 1.7 (mean ± SEM) [95% CI -1.327, 5.355], which corresponds to a 113% relative treatment benefit compared to PBO. Supplementary estimands:

[0178] Analysis strategy: The supplementary estimand for the primary objective was to evaluate the efficacy of compound A at 30 mg or 60 mg twice daily compared to PBO without dose reduction in IPF subjects meeting the inclusion criteria with or without SoC. The rate of decline in ppFVC (%) from baseline to week 26 was compared as a group-level summary using the difference between each dose and PBO, regardless of whether treatment was stopped for any reason (treatment policy strategy). In the case of dose reduction, data collected after the dose reduction were considered irrelevant to the treatment effect of interest and were therefore treated as missing (while-on-treatment strategy).

[0179] Due to the protocol-defined low BP criterion, dose reduction to compound A 10 mg BID with matching PBO was implemented in 18 (6.5%) participants and was approximately evenly distributed between groups (PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%)).

[0180] In the overall population, the 60 mg dose showed a treatment difference in the rate of decline of ppFVC of 1.77 ± 0.82 (mean ± SEM) [95% CI 0.162, 3.370]. This corresponds to a 62% overall relative reduction compared to the PBO decline slope (-2.84 ± 0.57).

[0181] When analyzing FVC in mL (adjusted for age, sex, and height as measured by the slope difference in the 60 mg group [-47.2 ± 20.92] compared to the PBO group [-108.7 ± 20.58]), the 60 mg dose corresponded to a relative treatment difference of 61.4 mL compared to PBO.

[0182] Subgroup analysis of background SoC (SoC vs none) demonstrated a favorable response in the 60 mg group compared to the PBO group for the primary endpoint.

[0183] Among participants using background SoC (68% of the overall population), for the primary endpoint (rate of change in ppFVC), the 60 mg dose showed a treatment difference compared to PBO of 1.41 ± 0.89 (mean ± SEM) [95% CI -0.341, 3.151], which corresponds to a 44% relative treatment benefit compared to PBO.

[0184] Among participants not using background SoC (32% of the overall population), for the primary endpoint (rate of change in ppFVC), the 60 mg dose showed a treatment difference compared to PBO of 2.55 ± 1.73 (mean ± SEM) [95% CI -0.84, 5.948], which corresponds to a 123% relative treatment benefit compared to PBO.

[0185] Subgroup analysis of enrolled participants using stable background SoC (defined as nintedanib or pirfenidone; 68% of the overall population) and enrolled participants not using SoC (SoC-naïve; 32% of the overall population) showed favorable efficacy at 60 mg compared to PBO (Table 8).

[0186] Gender-based subgroup analysis revealed different rates of decline. Data not shown. Table 9: Estimated difference in rate of decline from baseline to Week 26 CI = confidence interval; FVC = forced vital capacity; PBO = placebo; ppFVC = percent predicted forced vital capacity; SE = standard error; SoC = standard of care. aFor the primary estimator, all observations were included in the analysis regardless of dose reduction to 10 mg BID or matching PBO to meet the low BP criteria. aFor the secondary estimator, all observations were included in the analysis until dose reduction to 10 mg BID or matching PBO to meet the low BP criteria. Table 10: Estimated rate of decline in ppFVC from baseline to Week 26

[0187] Additional data for the IPF cohort are shown in Figures 6 - 9 as Figure 6As shown, in the treatment policy strategy, the change rate of ppFVC in patients with IPF over 26 weeks was -2.7% for placebo, compared with -2.8% and -1.2% for the 30 mg and 60 mg compound A groups, respectively. The treatment difference between the 60 mg group and placebo was 1.4% (95% CI, -0.1 to 3.0), a relative reduction of 54%( Figure 6 A). Using the on-treatment strategy, the change rate of ppFVC was -2.8% for placebo, compared with -3.2% and -1.1% for the 30 mg and 60 mg compound A groups, respectively. The treatment difference between the 60 mg compound A group and placebo was 1.8% (95% CI, 0.2 to 3.4), a relative reduction of 62%( Figure 6 B). In the Bayesian analysis, under both estimators' strategies, the posterior probability of a positive treatment difference for 60 mg compound A compared with placebo was >95%.

[0188] The change rate of FVC (mL) in the IPF cohort is shown in Figure 7 while Figure 8 shows the absolute change in FVC. At week 26, the adjusted mean treatment difference in the absolute change in FVC (mL) between the 60 mg compound A and placebo groups was 45.5 mL( Figure 8 A).

[0189] Figure 9 shows the change rate of ppFVC in subjects with and without background anti-fibrotic treatment in the IPF cohort. The treatment difference in the change rate of ppFVC between the two groups was consistent( Figure 9 A and Figure 9 B). Summary of efficacy results: - In the overall population with and without SoC, compared with PBO, the 30 mg dose group did not show efficacy (data not shown). - In the overall population with and without SoC, as well as in the subgroup of participants using background SoC and in those not using SoC, the 60 mg dose group showed a favorable treatment response compared with PBO. - These results indicate that compound A has a favorable effect on FVC compared with PBO when used alone or in background therapy with nintedanib or pirfenidone.

[0190] Overall, overall adverse events were more frequently observed in subjects with at least one TEAE in the PBO group (Table 11). Discontinuation due to TEAE was balanced between treatment groups (PBO: 9.8%; 30 mg: 9.9%; 60 mg: 6.5%). Table 11: Summary of selected safety data AESI = Adverse Events of Special Interest; PBO = Placebo; TEAE = Treatment Emergent Adverse Event; TESAE = Treatment Emergent Serious Adverse Event. The total amount of the active agent includes two groups of 30 mg and 60 mg Safety assessment: - Generally speaking, overall safety events are more common in the PBO group. - Treatment Emergent Adverse Events (TEAE): · PBO: 74 (80.4%); 30 mg: 69 (75.8%); 60 mg: 69 (74.2%) - Adverse Events of Special Interest (AESI): · PBO: 19 (20.7%); 30 mg: 18 (19.8%); 60 mg: 9 (9.7%) - Treatment Emergent Serious Adverse Events (TESAE): · PBO: 16 (17.4%); 30 mg: 10 (11.0%); 60 mg: 10 (10.8%) - Discontinued due to TEAE: · PBO: 9 (9.8%); 30 mg: 9 (9.9%); 60 mg: 6 (6.5%) - TEAE related to the study treatment: · PBO: 20 (21.7%); 30 mg: 23 (25.3%); 60 mg: 25 (26.9%) - No major system organ class or preferred term was reported for treatment discontinuation - The total number of deaths was 13: · PBO: 4 (4.4%); 30 mg: 4 (4.4%); 60 mg: 5 (5.4%). · Causes of death: 9 due to disease progression; 3 due to pneumonia; 1 due to congestive heart failure. · Deaths related to TEAE: 9 (3.3%) participants, and the deaths occurred during the study period or within 28 days of the last dose of treatment. · PBO: 2 (2.2%); 30 mg: 3 (3.3%); 60 mg: 4 (4.3%). · Another 4 participants died outside the 28-day TEAE window.

[0191] Blood pressure monitoring: Among the participants using 60 mg, based on the pre-specified low BP safety monitoring and criteria in the protocol, the lowest frequencies of orthostatic intolerance, orthostatic hypotension, or pre-specified symptomatic or asymptomatic low BP criteria were observed.

[0192] In the overall population, the following orthostatic intolerance, orthostatic hypotension, or symptomatic or asymptomatic low BP events were observed: - Orthostatic intolerance was observed in 19 (6.9%) participants. · PBO: 7 (7.6%); 30 mg: 10 (11.0%); 60 mg: 2 (2.2%) - Orthostatic hypotension with asymptomatic low BP was observed in 54 (19.6%) participants. Note that orthostatic hypotension was defined as a decrease in SBP ≥ 20 mmHg or a decrease in DBP ≥ 10 mmHg upon assuming an upright posture from a supine or sitting position to a standing position. · PBO: 19 (20.7%); 30 mg: 21 (23.1%); 60 mg: 14 (15.1%) - Orthostatic hypotension with symptomatic low BP was observed in 21 (7.5%) participants. · PBO: 7 (7.6%); 30 mg: 9 (9.9%); 60 mg: 5 (5.4%) - Asymptomatic hypotension was observed in 59 (21.4%) participants. · PBO: 20 (21.7%); 30 mg: 22 (24.2%); 60 mg: 17 (18.3%) - Symptomatic hypotension was observed in 27 (9.8%) participants. · PBO: 10 (10.9%); 30 mg: 11 (12.1%); 60 mg: 6 (6.5%) - Due to the protocol-defined low BP criteria (as shown below), dose reduction to 10 mg of compound A BID with a matching PBO was implemented in 18 (6.5%) participants, and was approximately evenly distributed among the groups: PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%) Asymptomatic blood pressure reduction criteria

[0193] Patients experiencing any of the following were confirmed by retesting within 15 minutes: · Sitting systolic blood pressure < 85 mmHg · Sitting diastolic blood pressure < 55 mmHg · Orthostatic hypotension Symptomatic blood pressure reduction criteria

[0194] The patient experiences symptoms that the investigator believes may be related to a decrease in blood pressure and also experiences at least one of the following, confirmed by retesting within 15 minutes: · Seated systolic blood pressure < 100 mmHg or seated diastolic blood pressure < 60 mmHg · Seated systolic blood pressure decreased by ≥ 20 mmHg from the last visit or seated diastolic blood pressure decreased by ≥ 10 mmHg from the last visit · Orthostatic hypotension · Orthostatic tachycardia

[0195] Based on the BP monitoring and low BP criteria pre-specified in the protocol, these data demonstrate that, compared with PBO, the dose of Compound A 60 mg twice daily (BID) is not associated with any increased risk of orthostatic intolerance, orthostatic hypotension, orthostatic tachycardia, or symptomatic or asymptomatic low BP (Table 12). However, on Day 1 of dosing, a post-dose decrease in SBP was observed at 30 mg and 60 mg. The lowest post-dose mean decrease in seated SBP relative to baseline was observed 2 hours after dosing (PBO: -2.1 mmHg; Compound A 30 mg: -10.5 mmHg; Compound A 60 mg: -14.1 mmHg). These decreases were not associated with any clinical sequelae and were essentially self-limiting. Table 12: Summary of Hypotension Data Category, n(%) PBO (N = 92) 30 mg (N = 91) 60 mg (N = 93) Total Orthostatic intolerance 7(7.6) 10(11.0) 2(2.2) 19(6.9) Asymptomatic hypotension 20(21.7) 22(24.2) 17(18.3) 59(21.4) Orthostatic hypotension* 19(20.7) 21(23.1) 14(15.1) 54(19.6) Symptomatic hypotension 10(10.9) 11(12.1) 6(6.5) 27(9.8) Orthostatic hypotension* 7(7.6) 9(9.9) 5(5.4) 21(7.6) PBO = placebo *Orthostatic hypotension is defined as a decrease in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg upon assuming an upright posture from supine or seated to standing position.

[0196] The number of dose reductions (and percentage of total subjects in the group) in the IPF cohort: 5 (5.4) for placebo; 7 (7.7) for 30 mg Compound A; and 6 (6.5) for 60 mg Compound A.

[0197] The number of dose reductions (and percentage of total subjects in the group) in the IPF cohort: 5 (5.4) for placebo; 7 (7.7) for 30 mg Compound A; and 6 (6.5) for 60 mg Compound A. Example 4B: PPF Cohort

[0198] A total of 123 participants with PPF were randomly assigned. Participants (aged ≥ 21 years) were randomly assigned (1:1:1) to receive 30 mg or 60 mg Compound A or PBO twice daily for 26 weeks. The following subjects were enrolled: centrally interpreted HRCT obtained at screening demonstrated evidence of > 10% parenchymal fibrosis throughout the lungs and: (a) There is evidence of ILD progression within 24 months prior to screening. ILD progression is defined as: a relative decline in ppFVC of ≥10%, or a relative decline in ppFVC of ≥5% to <10% and an increase in the degree of fibrosis on chest computed tomography prior to screening compared with previous imaging, or symptoms associated with ILD progression and an increase in the degree of fibrosis on chest computed tomography prior to screening compared with previous imaging; (b) Have interstitial lung disease of different etiologies, excluding connective tissue disease-related interstitial lung disease (except rheumatoid arthritis-related interstitial lung disease) and sarcoidosis. Immunosuppressive drugs (mycophenolate mofetil, mycophenolic acid, azathioprine, and / or tacrolimus) are only permitted if the medication has been stable for ≥6 months prior to screening. If the patient is receiving the antifibrotic agent pirfenidone or nintedanib, the patient must have received a stable dose for ≥3 months prior to screening and during the screening period; if not receiving pirfenidone or nintedanib, the patient must never have used either drug or have received neither drug for 4 weeks prior to Day 1. A total of 47 (38.2%) subjects were receiving antifibrotic therapy (with or without immunosuppressive therapy). Among these subjects, 34 were receiving nintedanib treatment and 13 were receiving pirfenidone treatment. Participants were stratified by the presence (versus absence) of the usual interstitial pneumonia (UIP) pattern and background therapy (antifibrotic drug + / - ILD-targeted immunosuppression versus ILD-targeted immunosuppression alone versus none). 52% of the subjects had the UIP pattern, and unclassifiable ILD was the most common disease classification.

[0199] The statistical power of the study was insufficient to detect statistical significance (no formal test was performed). The target effect size was not defined in the study design. There were two estimators used for the analysis: Treatment policy: treatment effect in the case of dose reduction as part of the treatment regimen. On-treatment strategy: treatment effect without dose reduction.

[0200] Among the 123 treated participants who contributed to these analyses, 90.2% (n = 111) completed the 26-week treatment period, and 9.8% (n = 12) discontinued treatment (6 (4.9%) discontinued due to adverse events). Treatment discontinuation between treatment groups (PBO: 17.1%; 30 mg: 7.5%; 60 mg: 4.8%). A total of 91 (74%) subjects continued into the 26-week optional treatment extension (OTE) period.

[0201] A linear mixed-effects model using all FVC time points was used to estimate the primary efficacy endpoint in the PPF cohort, namely the rate of decline in FVC from baseline to week 26 (expressed as % of predicted value). It was analyzed under the primary estimand (using all data, treatment policy strategy) and under the supplementary estimand (using all data up to the dose reduction time point, on-treatment strategy). Analyses were performed in the overall population and in subgroups according to 1) whether background anti-fibrotic treatment was used and 2) the UIP radiographic pattern (presence or absence). The mean baseline ppFVC in the PPF cohort was 66.7%.

[0202] Table 13 shows the baseline demographics and clinical characteristics of the subjects in the PPF cohort, while Table 14 shows their baseline disease characteristics. Table 13: Baseline demographics and clinical characteristics *Values before and after the ± sign represent mean ± SD. Patients with PPF were allowed to continue background anti-fibrotic drugs ± ILD-targeted immunosuppressants (see Supplementary Table S1). 6MWT, 6-minute walk test; BMI, body mass index; DL CO , diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; PPF, progressive pulmonary fibrosis; SD, standard deviation. Table 14. Baseline disease characteristics of the PPF cohort ILD, interstitial lung disease; NSIP, non-specific interstitial pneumonia; PPF, progressive pulmonary fibrosis; UIP, usual interstitial pneumonia.

[0203] Pooled results are described in Tables 15 - 26; and additional results from the final analysis of the PPF cohort are described below. Table 15: Estimated differences in the rate of decline in ppFVC from baseline to week 26 in different subgroups · Efficacy of Compound A (60 mg) was shown in the population where 37% of patients used background anti-fibrotic drugs. · The relative reduction in the PPF cohort at 60 mg (69%) was similar to that in the IPF cohort (62%) · There was a clear dose response · Efficacy was consistent across all subgroups, i.e., independent of background anti-fibrotic drugs or UIP pattern. Table 16: Primary analysis of FVC (% predicted): Rate of decline in overall population - primary estimator - treatment policy strategy (relative reduction = 74%) Table 17: Primary analysis of FVC (% predicted): Rate of decline in overall population - supplementary estimator - on-treatment strategy (relative reduction = 69.3%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 41) -4.24(0.94) 30 mg (n = 39) -2.45(0.96) 30 mg - Placebo 1.78(1.34) [-0.86，4.43] 60 mg (n = 42) -1.3(0.92) 60 mg - Placebo 2.94(1.32) [0.35，5.53]

[0204] Additional data for the PPF cohort are shown in Figures 6 - 16 as follows. As Figure 6 shown, according to the treatment policy strategy, the rate of change in ppFVC over 26 weeks for patients with PPF was -4.3% for placebo, compared with -2.7% and -1.1% for the 30 mg and 60 mg compound A groups, respectively. The treatment difference for 60 mg compound A compared with placebo was 3.2% (95% CI, 0.7 to 5.6), a relative reduction of 74%( Figure 6 C). Using the on-treatment strategy, the rate of change in ppFVC was -4.2% for placebo, compared with -2.5% and -1.3% for the 30 mg and 60 mg groups, respectively. The treatment difference between 60 mg compound A and placebo was 2.9% (95% CI, 0.4 to 5.5), a relative reduction of 69%( Figure 6 D).

[0205] The rate of change in FVC (mL) for the PPF cohort is shown in Figure 7 while Figure 8 shows the absolute change in FVC. At week 26, the adjusted mean treatment difference in the absolute change in FVC (mL) between the 60 mg compound A and placebo groups was 87.4 mL( Figure 8 B).

[0206] Figure 10 and Figure 11 show the observed mean change in ppFVC percentage and FVC from baseline to week 26 in the PPF cohort. As shown, both 30 mg and 60 mg showed improvement relative to placebo at week 8, but 30 mg showed more significant improvement after week 20, while 60 mg maintained improvement relative to placebo through the end of week 26. Table 18: Subgroup analysis of FVC (% predicted): Rate of decline in subjects with UIP - primary estimator - treatment policy strategy (relative reduction = 63%) Table 19: Subgroup analysis of FVC (% predicted): decline rate in subjects without UIP - primary estimand - treatment policy strategy (relative reduction = 83.6%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 20) -4.56(1.48) 30 mg (n = 17) -2.31(1.53) 30 mg - Placebo 2.25(2.13) [-1.95，6.44] 60 mg (n = 21) -0.75(1.38) 60 mg - Placebo 3.81(2.02) [-0.18，7.79] Table 20: Subgroup analysis of FVC (% predicted): decline rate in subjects with UIP - supplementary estimand - on-treatment strategy (relative reduction = 54%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 21) -3.94(1.16) 30 mg (n = 22) -2.66(1.12) 30 mg - Placebo 1.28(1.61) [-1.89，4.46] 60 mg (n = 21) -1.82(1.12) 60 mg - Placebo 2.12(1.62) [-1.06，5.31] Table 21: Subgroup analysis of FVC (% predicted): decline rate in subjects without UIP - supplementary estimand - on-treatment strategy (relative reduction = 84.4%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 20) -4.5(1.55) 30 mg (n = 17) -2.24(1.68) 30 mg - Placebo 2.26(2.28) [-2.24，6.77] 60 mg (n = 21) -0.7(1.53) 60 mg - Placebo 3.8(2.17) [-0.48，8.09]

[0207] Figure 12 and Figure 13 shows the ppFVC percentages and the observed mean change in FVC from baseline to week 26 in patients with and without UIP within the PPF cohort, while Figure 14 shows the rate of change in ppFVC in PPF patients with and without UIP. As shown, a treatment difference was observed in the PPF cohort, independent of the presence or absence of the UIP pattern. Acute exacerbation of pulmonary fibrosis was observed in 6 patients with IPF (2%) (placebo: n = 2; 30 mg: n = 3; 60 mg: n = 1) and in 3 patients with PPF (2%) (all in the placebo group). Table 22: Subgroup analysis of FVC (% predicted): decline rate in subjects receiving anti-fibrotic treatment - primary estimand - treatment policy (relative reduction = 85%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 15) -4.42(1.55) 30 mg (n = 14) -2.43(1.44) 30 mg - Placebo 1.99(2.12) [-2.19，6.18] 60 mg (n = 15) -0.68(1.37) 60 mg - Placebo 3.74(2.1) [-0.35，7.83] Table 23: Subgroup analysis of FVC (% predicted): decline rate in subjects not receiving anti-fibrotic treatment - primary estimand - treatment policy (relative reduction = 68.5%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 26) -4.16(1.15) 30 mg (n = 25) -2.88(1.15) 30 mg - Placebo 1.28(1.63) [-1.93，4.5] 60 mg (n = 27) -1.31(1.11) 60 mg - Placebo 2.85(1.6) [-0.3，6.01] Table 24: Subgroup analysis of FVC (% predicted): decline rate in subjects receiving anti-fibrotic treatment - supplementary estimand - on-treatment strategy (relative reduction = 74.9%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 15) -4.38(1.61) 30 mg (n = 14) -1.8(1.58) 30 mg - Placebo 2.58(2.25) [-1.87，7.03] 60 mg (n = 15) -1.1(1.53) 60 mg - Placebo 3.28(2.21) [-1.1，7.66] Table 25: Subgroup analysis of FVC (% predicted): decline rate in subjects not receiving anti-fibrotic treatment - supplementary estimand - on-treatment strategy (relative reduction = 62.6%) Treatment Slope (S.E.) Difference Difference (S.E.) 95% C.I. Placebo (n = 26) -4.17(1.16) 30 mg (n = 25) -2.83(1.2) 30 mg - Placebo 1.34(1.66) [-1.94，4.61] 60 mg (n = 27) -1.56(1.15) 60 mg - Placebo 2.61(1.63) [-0.6，5.82]

[0208] Figure 15 and Figure 16Shows the mean observed change in ppFVC percentage and FVC from baseline to week 26 in patients within the PPF cohort with and without additional antifibrotic therapy, while Figure 9 shows the rate of change of ppFVC in subjects within the PPF cohort with and without background antifibrotic therapy. The treatment differences in the rate of change of ppFVC in the PPF cohort with or without background antifibrotic drug were consistent ( Figure 9 C and Figure 9 D). Table 26: Summary of Selected Safety Data COVID-19, Coronavirus disease 2019; IPF, Idiopathic pulmonary fibrosis; PPF, Progressive pulmonary fibrosis; TEAE, Treatment-emergent adverse event; TESAE, Treatment-emergent serious adverse event. Summary of Adverse Events · Subjects with at least one treatment-emergent adverse event (TEAE): PBO - 24%, 30mg - 10%, 60mg - 24% · Subjects with at least one treatment-emergent serious adverse event (TESAE): PBO - 32%, 30mg - 10%, 60mg - 12% · Subjects with at least one TEAE due to investigational medicinal product (IMP): PBO - 17%, 30mg - 18%, 60mg - 26% · Seven subjects had adverse outcomes leading to treatment discontinuation · 6 were in the PBO group and 1 was in the 30mg dose group (due to hypotension) · Three subjects died due to TEAE; all 3 were in the PBO group · 1 case of infectious pneumonia, 1 case of PE, 1 case of respiratory failure · Dose-dependent BP findings reconfirmed the low BP safety risk of Compound A · Blood pressure decreased after dosing on Day 1; no clinical consequences · Dose-dependent low BP threshold (“events”): PBO - 24%, 30mg - 30%, 60mg - 41% · Dose reduction: PBO - 2%, 30mg - 15%, 60mg - 12% · AESI due to low BP: PBO - 24%, 30mg - 10%, 60mg - 24% · There was no significant imbalance in significant laboratory abnormalities between treatment groups · No hepatobiliary toxicity

[0209] In patients with PPF, the mean sitting systolic blood pressure at Day 1 in the placebo, 30 mg, and 60 mg Compound A groups decreased by -4.2 mmHg, -10.7 mmHg, and -12.7 mmHg, respectively, from the nadir after dosing relative to baseline. The pre-specified blood pressure reduction criteria (shown below) increased in a dose-dependent manner among the PPF cohort groups (Table 27). Asymptomatic blood pressure reduction criteria

[0210] The patient is experiencing any of the following, confirmed by retesting within 15 minutes: · Sitting systolic blood pressure < 85 mmHg · Sitting diastolic blood pressure < 55 mmHg · Orthostatic hypotension Symptomatic blood pressure reduction criteria

[0211] The patient is experiencing symptoms that the investigator believes may be related to blood pressure reduction and is also experiencing at least one of the following, confirmed by retesting within 15 minutes: · Sitting systolic blood pressure < 100 mmHg or sitting diastolic blood pressure < 60 mmHg · Sitting systolic blood pressure has decreased by ≥ 20 mmHg from the last visit or sitting diastolic blood pressure has decreased by ≥ 10 mmHg from the last visit · Orthostatic hypotension · Orthostatic tachycardia Table 27: Summary of pre-specified criteria for asymptomatic or symptomatic blood pressure reduction and dose reduction *The pre-specified criteria defining asymptomatic versus symptomatic blood pressure reduction are shown in the Supplementary Methods. Orthostatic hypotension is defined as a decrease in systolic blood pressure of ≥ 20 mmHg or a decrease in diastolic blood pressure of ≥ 10 mmHg upon assuming an upright posture from supine or sitting to standing. IPF, idiopathic pulmonary fibrosis; PPF, progressive pulmonary fibrosis.

[0212] Compound A was well tolerated, did not exhibit unexpected safety findings, and had an overall profile similar to that observed in the IPF cohort. Except for hypotension, the adverse event profile generally favored the 60 mg group compared to placebo.

[0213] There was a dose-dependent Day 1 blood pressure reduction in the PPF cohort, with an amplitude similar to that observed in the IPF cohort. The orthostatic hypotension (asymptomatic and symptomatic) was higher in the 60 mg group than in the other groups. There were 2 cases of syncope and 1 case of pre-syncope, but both were in the placebo group.

[0214] It should be understood that the detailed description section, rather than the summary and abstract sections, is intended to be used to interpret the claims. The summary and abstract sections may set forth one or more but not all exemplary aspects of the present disclosure as contemplated by the inventors, and are thus not intended to limit the present disclosure and the appended claims in any way.

[0215] The present disclosure has been described above by means of functional building blocks that illustrate the implementation of specified functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined as long as the specified functions and their relationships are appropriately performed.

[0216] The foregoing description of the specific aspects will so fully disclose the general nature of the present disclosure that others can, by applying knowledge within the scope of the art, readily modify and / or adapt such specific aspects for various applications without undue experimentation and without departing from the general concept of the present disclosure. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed aspects based on the teachings and guidance presented herein. It should be understood that the terminology or phraseology herein is for the purpose of description and not of limitation, and thus the terminology or phraseology of this specification will be interpreted by those skilled in the art in light of the teachings and guidance.

[0217] The breadth and scope of the present disclosure should not be limited by any of the above exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A method for treating interstitial lung disease, the method comprising administering to a subject in need thereof about 120 mg / day of Compound A: or an equivalent amount of a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein Compound A or a pharmaceutically acceptable salt thereof is administered once daily.

3. The method according to claim 1, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily.

4. The method according to claim 3, wherein about 60 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily.

5. The method according to any one of claims 1 to 4, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally.

6. The method according to claim 5, wherein Compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

7. The method according to any one of claims 1 to 6, wherein the subject is concurrently being treated with one or more therapies for interstitial lung disease.

8. The method according to claim 7, wherein the one or more therapies is pirfenidone.

9. The method according to claim 7, wherein the one or more therapies is nintedanib.

10. The method according to any one of claims 1 to 9, wherein Compound A or a pharmaceutically acceptable salt thereof is administered with food.

11. The method according to any one of claims 1 to 9, wherein Compound A or a pharmaceutically acceptable salt thereof is administered without food.

12. The method according to any one of claims 1 to 11, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

13. The method according to any one of claims 1 to 11, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

14. The method according to any one of claims 1 to 13, wherein Compound A comprises a crystalline form characterized by at least one of the following: a) a single crystal structure having unit cell parameters substantially equal to the following: Crystal system, triclinic, P1 Unit cell size α = 92.8 ± 1.0° β＝95.5±1.0° γ = 93.0 ± 1.0° Volume Density (calculated value) 1.239 g / cm 3 Temperature room temperature wherein the measurement of the single crystal structure is carried out at room temperature; b) a powder x-ray diffraction pattern substantially the same as that shown in Figure 1; c) A powder X-ray diffraction pattern comprising two or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 19.9 ± 0.2, 21.6 ± 0.2, 24.8 ± 0.2 and 26.8 ± 0.2 (obtained at room temperature and below); d) A powder X-ray diffraction pattern comprising three or more peaks at 2θ values selected from: 6.4 ± 0.2, 6.8 ± 0.2, 9.6 ± 0.2, 13.6 ± 0.2, 14.1 ± 0.2, 14.5 ± 0.2, 14.7 ± 0.2, 15.7 ± 0.2, 18.2 ± 0.2, 18.7 ± 0.2, 19.2 ± 0.2, 19.9 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, 22.5 ± 0.2, 23.1 ± 0.2, 24.1 ± 0.2, 24.8 ± 0.2, 25.6 ± 0.2, 26.8 ± 0.2, 27.1 ± 0.2 and 27.8 ± 0.2 (obtained at room temperature and below); e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram having an endotherm starting at about 152 °C; and / or g) a thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

15. The method according to any one of claims 1 to 14, wherein the subject experiences a smaller decline in forced vital capacity (FVC) after the treatment period compared to an untreated subject.

16. The method according to any one of claims 1 to 15, wherein the subject experiences a longer time to the first disease progression event after the treatment period compared to an untreated subject, wherein the first disease progression event is selected from: Absolute predicted forced vital capacity (ppFVC) decline relative to baseline ≥ 10%; Acute exacerbation of pulmonary fibrosis; Hospitalization related to pulmonary fibrosis; and All-cause death.

17. The method according to any one of claims 1 to 16, wherein the subject experiences a smaller increase in the cough domain score, as measured by the Lung-PF (Lung Fibrosis Quality of Life) questionnaire, during the treatment period compared to an untreated subject.

18. The method according to any one of claims 1 to 17, wherein the subject experiences a smaller increase in the dyspnea score, as measured by the Lung-PF (Lung Fibrosis Quality of Life) questionnaire, during the treatment period compared to an untreated subject.

19. Compound A at about 120 mg / day: or a pharmaceutically acceptable salt thereof in an equivalent amount for use in the treatment of interstitial lung disease.

20. Compound A at about 120 mg / day: or a pharmaceutically acceptable salt thereof in an equivalent amount for use in the manufacture of a medicament for the treatment of interstitial lung disease.

21. The use according to claim 19 or 20, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

22. The use according to claim 19 or 20, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

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