Treatment of systemic sclerosis and idiopathic pulmonary fibrosis

Abstract

Described herein is the use of a crystalline form of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid in the treatment of a disease or condition that would benefit from the administration of an LPA1 receptor antagonist compound.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 315,793, filed March 2, 2022, which is incorporated by reference in its entirety.

[0002] Described herein is a method for the treatment of lysophosphatidic acid receptor 1 (LPA 1 In the treatment of diseases or conditions (e.g., fibrotic diseases or conditions) that would benefit from treatment with an LPA receptor, also known as LPAR1, endothelial differentiation gene 2 or EDG-2) antagonist compound, 1 Receptor antagonist compounds, and crystalline forms thereof, and methods of using these pharmaceutical compositions. [Background technology]

[0003] LPA 1 The LPA receptor (LPAR1) is a member of the G protein-coupled receptor family of integral membrane proteins important in lipid signaling. 1 Receptor antagonists are being investigated as potential novel therapeutic agents for diseases or conditions involving aberrant LPA signaling (e.g., systemic sclerosis, pulmonary fibrosis, atherosclerosis, myocardial infarction, and heart failure). Summary of the Invention [Means for solving the problem]

[0004] This disclosure relates to LPA 1 The present invention relates to various methods of treating systemic sclerosis and pulmonary diseases (eg, pulmonary fibrosis) with the receptor antagonist 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I).

[0005] In one aspect, disclosed herein is a method of treating systemic sclerosis or a pulmonary disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) or a pharma- ceutically acceptable salt thereof, wherein Compound I or a pharma- ceutically acceptable salt thereof is administered at a daily dose equivalent to at least about 300 mg / day of Compound I. In some embodiments, Compound I is Crystalline Form 1 of Compound I, characterized by having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, as measured using Cu(Kα) radiation. In some embodiments, crystalline Form 1 of Compound I is substantially free of crystalline Form 2 of Compound I. In some embodiments, crystalline Form 1 of Compound I contains less than 1 w / w% crystalline Form 2 of Compound I. In some embodiments, Compound I has an X-ray powder diffraction (XRPD) pattern that is an amorphous phase of Compound I and shows a lack of crystallinity, and a solid form substantially identical to that shown in FIG. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0006] In some embodiments, the systemic sclerosis is selected from limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis sine scleroderma. In some embodiments, the systemic sclerosis is diffuse cutaneous systemic sclerosis. In some embodiments, the systemic sclerosis is early diffuse cutaneous systemic sclerosis. In some embodiments, treatment with Compound I or a pharmaceutically acceptable salt thereof results in a CRISS score of 0.60 or greater. In some embodiments, treatment with Compound I or a pharmaceutically acceptable salt thereof results in a reduction in skin fibrosis as measured by a mRSS change of 5 or greater. In some embodiments, treatment with Compound I or a pharmaceutically acceptable salt thereof results in an improvement in HAQ-DI of 0.14 or greater.

[0007] In some embodiments, the pulmonary disease is pulmonary fibrosis. In some embodiments, the pulmonary disease is interstitial lung disease (ILD). In some embodiments, the pulmonary disease is idiopathic interstitial pneumonia, connective tissue disease-associated interstitial lung disease (CTD-ILD), sarcoidosis, hypersensitivity pneumonitis, eosinophilic ILD, or familial pulmonary fibrosis. In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP), respiratory bronchiolitis interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), or lymphocytic interstitial pneumonia (LIP). In some embodiments, the pulmonary disease is an autoimmune ILD (e.g., rheumatoid arthritis-ILD, systemic sclerosis-ILD, Sjogren's syndrome-ILD, dermatomyositis-ILD, lupus-ILD, polymyositis-ILD, sarcoidosis-ILD). In some embodiments, the pulmonary disease is unclassifiable ILD, hypersensitivity pneumonitis-ILD, or drug-induced ILD. In some embodiments, the pulmonary disease is radiation-induced lung injury (RILI). In some embodiments, the pulmonary disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary disease is a chronic fibrotic interstitial lung disease (ILD). In some embodiments, the pulmonary disease is a chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype. In some embodiments, the pulmonary disease is a progressive phenotype that is usual interstitial pneumonia (UIP) or a UIP-like high-resolution computed tomography (HRCT) fibrosis pattern. In some embodiments, the pulmonary disease is systemic sclerosis-related interstitial lung disease (SSc-ILD). In some embodiments, the pulmonary disease is systemic sclerosis-related interstitial lung disease (SSc-ILD), and treating the pulmonary disease comprises reducing the rate of decline in pulmonary function in subjects suffering from SSc-ILD.

[0008] In some embodiments, treating the pulmonary disease comprises slowing the decline in pulmonary function, reducing the frequency of exacerbations of the pulmonary disease, reducing the hospitalization rate of patients suffering from the pulmonary disease, improving survival of subjects suffering from the pulmonary disease, or a combination thereof.

[0009] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered for a period of at least about 24 consecutive weeks. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered for a period of at least about 36 weeks. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered for a period of at least about 52 weeks.

[0010] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered orally. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered once a day at a dose equivalent to about 300 mg of compound I. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered twice a day at a dose equivalent to about 300 mg of compound I, with a total daily dose equivalent to about 600 mg / day of compound I.

[0011] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with a cough suppressant, a corticosteroid, an immunosuppressant, N-acetylcysteine ​​(NAC), an antifibrotic therapeutic, or a combination thereof. In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is administered in combination with N-acetylcysteine, a corticosteroid, an immunosuppressant, pirfenidone, nintedanib, imatinib, a tyrosine kinase inhibitor, PBI-4050, recombinant pentraxin-2 / SAP (PRM-151), aerosol IFN-γ, a CTGF activity inhibitor, an LPA receptor antagonist, an autotaxin inhibitor, a galectin-3 inhibitor, a LOXL2 inhibitor, tipelukast, an integrin antagonist, a PI3K inhibitor, Administered in combination with a JNK inhibitor, a ROCK inhibitor, an anti-IL-13 compound, a CCL2 antagonist, a CCR2 antagonist, an anti-CD20 compound, an anticoagulant, a collagen V treatment, an ASK1 inhibitor, belimumamb, a B-cell activating factor inhibitor, belmosudil, a Rho-associated coiled-coil kinase 2 (Rock2) inhibitor, a NO-independent soluble guanylate cyclase (sGC) activator, a transforming growth factor beta 1 antagonist, a PDE-4b inhibitor, or a combination thereof.

[0012] In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered in combination with nintedanib or a pharmaceutically acceptable salt thereof. In some embodiments, nintedanib or a pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to about 200mg / day or about 300mg / day of nintedanib. In some embodiments, nintedanib or a pharmaceutically acceptable salt thereof is administered orally at a dose equivalent to about 150mg twice a day, with each dose administered about 12 hours apart. In some embodiments, nintedanib or a pharmaceutically acceptable salt thereof is administered orally at a dose equivalent to about 100mg twice a day, with each daily dose administered about 12 hours apart.

[0013] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered in combination with pirfenidone. In some embodiments, pirfenidone is administered at a dose of about 801 mg / day to about 2403 mg / day. In some embodiments, pirfenidone is administered at a dose of about 267 mg three times a day. In some embodiments, pirfenidone is administered at a dose of about 534 mg three times a day.

[0014] In some embodiments, pirfenidone is administered at a dose of about 801 mg three times daily.

[0015] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered in the form of a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is a tablet, pill, or capsule. In some embodiments, the solid pharmaceutical composition is a tablet.

[0016] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered in the form of one or more tablets. In some embodiments, each tablet contains about 50 mg to about 300 mg of Compound I. In some embodiments, each tablet contains about 50 mg to about 150 mg of Compound I.

[0017] In some embodiments, the subject is an adult, hi some embodiments, the subject is an adult male.

[0018] Also described herein, in some embodiments, is a pharmaceutical composition comprising a crystalline form of Compound I and at least one pharma- ceutically acceptable excipient. For example, in some embodiments, described herein is a pharmaceutical composition comprising crystalline Form 1 and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration in the form of a tablet, pill, capsule, suspension, or solution. In some embodiments, the pharmaceutical composition is in the form of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. In some embodiments, the pharmaceutical composition is substantially free of impurities of Compound I. In some embodiments, the pharmaceutical composition comprises less than about 1 w / w% impurities of Compound I. In some embodiments, the impurities of Compound I include one or more degradants of Compound I, one or more intermediates used in the synthesis of Compound I, or a combination thereof. In some embodiments, the impurities of Compound I include one or more intermediates used in the synthesis of Compound I.

[0019] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it should be understood that this detailed description and the specific examples, while indicating specific embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description. [Brief description of the drawings]

[0020] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1. [Diagram 2] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 1. [Diagram 3]1 shows the thermogravimetric analysis (TGA) pattern of Form 1. [Figure 4] The solid-state carbon-13 NMR spectrum of Form 1 is shown. [Diagram 5] 1 shows an X-ray powder diffraction (XRPD) pattern of Form 2. [Figure 6] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 2. [Figure 7] The solid-state carbon-13 NMR spectrum of Form 2 is shown. [Figure 8] 1 shows an X-ray powder diffraction (XRPD) pattern for Form 3. [Figure 9] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 3. [Figure 10] The solid-state carbon-13 NMR spectrum of Form 3 is shown. [Figure 11] 1 shows an X-ray powder diffraction (XRPD) pattern for Form 4. [Figure 12] 1 shows a differential scanning calorimetry (DSC) thermogram of Form 4. [Figure 13] 1 shows an overlay of Fourier transform IR spectroscopy (FTIR) patterns of Forms 1, 2, 3, and 4. [Figure 14] The solid-state carbon-13 NMR spectrum of the amorphous form is shown. [Figure 15] 1 shows the XRPD pattern of Form 1 obtained on a Malvern Panalytical Empyrean diffractometer. [Figure 16] 1 shows the XRPD pattern of Form 2 obtained on a Malvern Panalytical Empyrean diffractometer. [Figure 17] 1 shows the XRPD pattern of Form 1 obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 18] 1 shows the XRPD pattern of Form 2 obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 19]1 shows an overlay of an XRPD pattern of Form 1 (top XRPD) and an XRPD pattern of Form 2 (bottom XRPD) obtained on a Stoe Stadi P,G.52.SYS.S072 diffractometer. [Figure 20] 1 shows the XRPD pattern of Form 1 obtained on a PANalytical X'Pert PRO MPD diffractometer. [Figure 21] 1 shows the XRPD pattern of Form 2 obtained on a PANalytical X'Pert PRO MPD diffractometer. [Figure 22] A comparison of the XRPD pattern of Form 1 (top XRPD) and Form 2 (bottom XRPD) is shown, highlighting the Form 2 peaks used to quantitate Form 2 in Form 1. [Diagram 23] 1 shows the XRPD overlay of the calibration standards used in the development of the XRPD limit test for the determination of Form 2 in Form 1 bulk. [Figure 24] 1 shows the calibration curve used in the development of the XRPD limit test for the determination of Form 2 in Form 1 bulk. [Diagram 25] The Raman spectrum of Form 1 is shown. [Figure 26] The Raman spectrum of Form 2 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Compound I refers to "2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid" or "2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-indane-2-carboxylic acid", which is shown below: [ka] It has the chemical structure shown below.

[0022] See U.S. Patent Nos. 9,328,071 and 8,362,073, each of which is incorporated herein by reference in its entirety. Compound I may also be referred to as CZN001, SAR100842, or HZN-825.

[0023] Compound I is a potent and selective antagonist of lysophosphatidic acid receptor 1 (LPAR1). LPAR1 signaling is involved in fibrosis and inflammation. Specifically, animal models of fibrosis have demonstrated that LPAR1 is involved in fibrosis of the skin, lung, kidney, and heart. LPAR1 deletion in mice was found to prevent fibrosis of the skin and lung. In an experimental model of pulmonary inflammation, LPAR1 antagonism reduced immune cell infiltration into the lung. Patients suffering from systemic sclerosis have elevated serum lysophosphatidic acid (LPA) levels. Fibroblasts derived from patients show higher LPAR1 levels and higher sensitivity to LPAR1 antagonists compared to normal fibroblasts.

[0024] In vivo, Compound I reversed dermal hypertrophy, significantly inhibited myofibroblast differentiation, and reduced collagen content in a mouse model of skin fibrosis. 1 It has been shown that the antifibrotic effect of blockade may be mediated in part by inhibition of the Wnt signaling pathway.In clinical settings, Compound I has been well tolerated in patients with diffuse cutaneous systemic sclerosis SSc (dcSSc), demonstrating target engagement and improving outcome measures (Y.Allanore et al. Arthritis & Rheumatology, Vol.70, No.10, October 2018, pp 1634-1643).

[0025] Scleroderma Scleroderma, or systemic sclerosis, is a potentially fatal autoimmune disease of unknown etiology characterized by progressive multiorgan fibrosis that is largely refractory to currently available drug therapies. Systemic sclerosis is thought to be initiated by tissue injury, and dysregulated wound healing processes in response to this injury are thought to contribute to the development of fibrosis.

[0026] In some embodiments, disclosed herein is the use of compound I or a pharmaceutically acceptable salt thereof in the treatment of scleroderma. There are two main forms of scleroderma: limited systemic sclerosis (also known as localized scleroderma or cutaneous scleroderma) and diffuse systemic sclerosis. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to treat limited systemic sclerosis. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to treat diffuse systemic sclerosis.

[0027] As used herein, "localized systemic sclerosis" refers to a disorder characterized by thickening and hardening of the skin and subcutaneous tissue due to excessive deposition of collagen. Localized systemic sclerosis is often accompanied by the following: calcification, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. In addition, individuals with localized systemic sclerosis may present with pulmonary arterial hypertension.

[0028] As used herein, "diffuse systemic sclerosis" refers to a disorder of the skin and internal organs characterized by thickening and hardening of the skin and subcutaneous tissues due to excessive deposition of collagen. In certain cases, diffuse systemic sclerosis is associated with Raynaud's phenomenon and calcification.

[0029] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is used in the treatment or prevention of any one of the following in a mammal: localized cutaneous scleroderma, localized morphea, morphea-lichen sclerosus atrophicus overlap, generalized morphea, atrophoderma of Pasini and Pierini, generalized morphea, profunda morphea, linear sclerosis, systemic scleroderma, CREST syndrome, sclerodactyly, systemic sclerosis, progressive systemic sclerosis.

[0030] Systemic sclerosis without scleroderma is a rare disorder in which patients develop vascular and fibrotic damage to the internal organs without any hardening of the skin.

[0031] In a Phase 2a study evaluating 32 subjects suffering from diffuse cutaneous SSc, administration of Compound I at a dose of about 300 mg BID numerically improved clinical outcomes (e.g., modified Rodnan skin score (mRSS), Health Assessment Questionnaire-Disability Index (HAQ-DI), and other components of the Scleroderma Health Assessment Questionnaire (SHAQ), total disease severity (visual analog scale [VAS]), and pruritus (VAS)) (Y. Allanore et al. Arthritis & Rheumatology, Vol. 70, No. 10, October 2018, pp 1634-1643). In this study, Compound I was administered at a dose of about 300 mg BID for up to 24 weeks and was well tolerated. During the 8-week double-blind period, the most frequent treatment-emergent adverse events (TEAEs) in the Compound I group were headache, diarrhea, nausea, and falls.

[0032] Pulmonary fibrosis In a phase 2 clinical trial for IPF, an LPAR1 antagonist significantly reduced the rate of forced vital capacity (FVC) decline compared to placebo [Palmer et al., Randomized, double-blind, placebo-controlled, phase 2 trial of BMS-986020, a lysophosphatidic acid receptor antagonist for the treatment of idiopathic pulmonary fibrosis. Chest.2018;154:1061-9]. This finding suggests a role for LPAR1 antagonists as therapeutic agents for various fibrotic conditions.

[0033] Idiopathic pulmonary fibrosis (IPF) is a special form of chronic progressive fibrotic interstitial pneumonia of unknown etiology confined to the lungs. Well over 100 different forms of interstitial lung disease (ILD) have been described. This diffuse infiltrative lung disorder is typically characterized by the presence of inflammation and changes in the pulmonary interstitium. The histopathological changes in the lungs of patients with ILD can vary from granulomatous inflammation without parenchymal fibrosis in patients with sarcoidosis to extensive pulmonary fibrosis with architectural distortion of the lungs in patients with idiopathic pulmonary fibrosis (IPF). Some forms of ILD are associated with specific genetic abnormalities (e.g., Hermansky-Pudlak syndrome, familial pulmonary fibrosis), and many genetic variants are associated with an increased risk of developing ILD disorders such as IPF, sarcoidosis, or chronic beryllium disease (CBD).

[0034] Interstitial lung disease may also occur in association with connective tissue disorders (CTDs), and in CTD-associated ILD, the pulmonary histopathological changes may have the pattern of usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP).

[0035] In some embodiments, interstitial lung diseases (ILDs) include, but are not limited to, idiopathic interstitial pneumonia, scleroderma-associated ILD, connective tissue disease-associated interstitial lung disease (CTD-ILD), sarcoidosis, hypersensitivity pneumonitis, iatrogenic interstitial pneumonia / fibrosis (drug-induced ILD, radiation injury), eosinophilic ILD (e.g., eosinophilic pneumonia), occupational lung disease, genetic disorders (e.g., familial pulmonary fibrosis, Hermansky-Pudlak syndrome), and primary disorders (e.g., pulmonary Langerhans cell histiocytosis). In some embodiments, idiopathic interstitial pneumonias include, but are not limited to, idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), lymphocytic interstitial pneumonia (LIP).

[0036] In some embodiments, the pulmonary fibrosis is idiopathic interstitial pneumonia, CTD-ILD, sarcoidosis, hypersensitivity pneumonitis, eosinophilic ILD, or familial pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is IPF, NSIP, COP, RBILD, DIP, AIP, or LIP. In some embodiments, the pulmonary fibrosis is autoimmune ILD (e.g., rheumatoid arthritis-ILD, systemic sclerosis-ILD, Sjogren's syndrome-ILD, dermatomyositis-ILD, lupus-ILD, polymyositis-ILD, sarcoidosis-ILD). In some embodiments, the pulmonary fibrosis is unclassified ILD, hypersensitivity pneumonitis-ILD, or drug-induced ILD. In some embodiments, the pulmonary fibrosis is radiation-induced lung injury (RILI). In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is chronic fibrotic interstitial lung disease (ILD). In some embodiments, the pulmonary fibrosis is a chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype. In some embodiments, the pulmonary fibrosis is a progressive phenotype with usual interstitial pneumonia (UIP) or UIP-like high-resolution computed tomography (HRCT) fibrosis pattern. In some embodiments, the pulmonary fibrosis is systemic sclerosis-associated interstitial lung disease (SSc-ILD). In some embodiments, the pulmonary fibrosis is SSc-ILD, and treating the pulmonary fibrosis comprises reducing the rate of decline in pulmonary function in a subject suffering from SSc-ILD.

[0037] IPF is a progressive and ultimately fatal disease of the lung that involves airway epithelial cell injury, fibroblast activation and proliferation, and excessive deposition of collagen and other extracellular matrix (ECM) components. These changes in ECM composition and organization alter the biomechanical properties of the lung parenchyma and increase local tensions that are important in IPF disease pathogenesis.

[0038] IPF is a specific form of chronic progressive fibrotic interstitial pneumonia of unknown etiology that is confined to the lungs and is associated with UIP or UIP-like histopathological and / or radiological patterns. It is a disease characterized clinically by dyspnea and progressive deterioration of pulmonary function and pathologically by the formation of scar tissue within the lungs in the absence of any known precipitating factor.

[0039] In 2018, the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) jointly updated their recommendations to reach a consensus on the diagnosis of IPF [Raghu et al., Am J Respir Crit Car Med. 2018;198:e44-68]. IPF is the most common type of ILD, affecting an estimated 132,000 to 200,000 people in the United States. In the United States, approximately 50,000 new cases are diagnosed each year, and as many as 40,000 patients die from IPF each year, according to the Pulmonary Fibrosis Foundation. IPF is diagnosed more frequently in men than women, and patients usually present with IPF symptoms between the ages of 40 and 70, with the median age at onset being 66 years. IPF is characterized by progressive dyspnea, dry cough, and progressive pulmonary dysfunction consistent with increasing fibrosis.

[0040] Evidence suggests that the incidence of IPF is increasing [Hutchinson et al.,Eur Respir J.2015;46:795-806]. Mortality after diagnosis of IPF is high, with median survival after diagnosis being 2-3 years [Raghu et al.,Am J Respir Crit Care Med. 2011;1 83:788-824].

[0041] IPF is characterized by a decline in lung function over time. The most prominent symptoms of IPF are exercise-induced dyspnea and chronic dry cough, which interfere with the patient's daily activities. Besides restrictive deficits in lung function, other frequent clinical features of IPF include bibasilar inspiratory rales and hypoxemia-induced clubbing. Retrospective studies suggest that symptoms may appear 6 months to 2 years prior to the diagnosis of IPF. Although the onset of symptoms is slow, symptoms may worsen over a period of months to years, resulting in a gradual decline in lung function, hypoxia, and ultimately death from respiratory failure. IPF has three potential clinical courses: a) gradual physiologic deterioration with worsening severity of dyspnea (this is the most common); b) rapid deterioration and progression to death; or c) periods of relative stability interspersed with periods of acute respiratory collapse that may manifest as hospitalization for respiratory failure.

[0042] Although IPF is by definition considered a disorder of unknown etiology, several potential risk factors have been identified. Smoking is strongly associated with IPF. In addition, various other environmental and occupational exposures to metal dust, wood dust, agriculture, hairdressing, stone cutting / polishing, livestock, and vegetable / animal dust have been associated with an increased risk of developing IPF.

[0043] The pathogenesis of most pulmonary fibrosis diseases, including those mentioned above, is poorly understood, but all are characterized by the influx of inflammatory cells followed by increased synthesis and deposition of collagen-rich extracellular matrix.

[0044] IPF is characterized by inflammation and eventually fibrosis of lung tissue, but these two conditions can also be separated. IPF has an unknown cause and can result from autoimmune disorders or infection. Symptoms of IPF include dyspnea (i.e., shortness of breath), which becomes the main symptom as the disease progresses, and dry cough. Death can result from hypoxemia, right heart failure, heart attack, pulmonary embolism, stroke, or lung infection, all of which can be caused by this disease.

[0045] In some embodiments, compound I or a pharma- ceutically acceptable salt thereof is used to treat pulmonary fibrotic conditions. In some embodiments, the pulmonary fibrotic conditions are selected from one or more of the following: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, idiopathic fibrosing alveolitis (CFA), acute respiratory distress syndrome (ARDS), diffuse parenchymal lung disease (DPLD), bronchiolitis obliterans, or bronchiectasis. In some embodiments, the pulmonary fibrosis is secondary to disease, toxins, insults, medical treatment, or a combination thereof. In some embodiments, the pulmonary fibrosis is associated with one or more of the following: disease processes such as asbestosis and silicosis; occupational hazards; environmental pollutants; smoking; autoimmune connective tissue disorders (e.g., rheumatoid arthritis, scleroderma, and systemic lupus erythematosus (SLE)); connective tissue disorders such as sarcoidosis; infectious diseases, e.g., infections, particularly chronic infections; medical treatments, such as, but not limited to, radiation therapy, and drug therapies, e.g., chemotherapy (e.g., treatment with bleomycin, methotrexate, amiodarone, busulfan, and / or nitrofurantoin). In some embodiments, the pulmonary fibrotic condition treated by the methods of the invention is associated with (e.g., secondary to) cancer treatment, e.g., treatment of cancer (e.g., squamous cell carcinoma with bleomycin, testicular cancer, Hodgkin's disease).

[0046] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to an adult suffering from pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is IPF. In some embodiments, the adult is over 18 years old, over 20 years old, over 25 years old, over 30 years old, over 35 years old, over 40 years old, over 45 years old, over 50 years old, over 55 years old, over 60 years old, over 65 years old, over 70 years old, over 75 years old, over 80 years old, or over 85 years old. In some embodiments, the adult is 30-85 years old, 35-85 years old, 40-85 years old, 45-85 years old, or 40-80 years old.

[0047] Idiopathic pulmonary fibrosis is more prevalent in adult males than in females. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered to an adult male suffering from pulmonary fibrosis.

[0048] Compound I The preparation and use of Compound I has been previously described (see WO 2009 / 135590; U.S. Pat. Nos. 8,362,073, 8,445,530, 8,802,720, and 9,328,071, each of which is incorporated by reference in its entirety).

[0049] In some embodiments provided herein, Compound I is crystalline.

[0050] In some embodiments provided herein, compound I is in a single crystalline form. In some embodiments provided herein, compound I is in a single crystalline form that is substantially free of any other crystalline form. In some embodiments, the crystalline solid form is a single solid form, for example, crystalline form 1. In some embodiments, "substantially free" refers to less than about 10 w / w%, less than about 9 w / w%, less than about 8 w / w%, less than about 7 w / w%, less than about 6 w / w%, less than about 5 w / w%, less than about 4 w / w%, less than about 3 w / w%, less than about 2.5 w / w%, less than about 2 w / w%, less than about 1.5 w / w%, less than about 1 w / w%, less than about 0.75 w / w%, less than about 0.50 w / w%, less than about 0.25 w / w%, less than about 0.10 w / w%, or less than about 0.05 w / w% of any other crystalline form (e.g., Form 2) in a sample of crystalline form 1. In some embodiments, "substantially free" means an undetectable amount (eg, by XPRD analysis).

[0051] In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD). In some embodiments, the crystallinity of the solid form is determined by solid state NMR. In some embodiments, the crystallinity of the solid form is determined by Fourier transform IR spectroscopy (FTIR).

[0052] Crystalline form 1 of compound I In one aspect, provided herein is crystalline Form 1 of Compound I. In some embodiments, a composition is provided comprising crystalline Form 1 of Compound I. In some embodiments, crystalline Form 1 of Compound I is characterized by having: · An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 1, when measured using Cu (Kα) radiation; · an X-ray powder diffraction (XRPD) pattern obtained using Cu(Kα) radiation showing peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, when measured using Cu(Kα) radiation; Approx. 1739.6cm -1 Fourier transform IR spectroscopy (FTIR) pattern showing a peak at; Unit cell parameters at 293 K essentially equal to:

[0053] [Table 5]

[0054] A solid body substantially identical to that shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum; A solid characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm 13 Carbon nuclear magnetic resonance (ssNMR) spectrum; or A combination of these.

[0055] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, as measured using Cu(Kα) radiation.

[0056] In some embodiments, the crystalline form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, and a peak at about 1739.6 cm, as measured using Cu(Kα) radiation. -1 and a Fourier transform IR spectroscopy (FTIR) pattern showing a peak at

[0057] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern showing peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, and a differential scanning calorimetry (DSC) thermogram showing three endothermic events with an onset at about 198.5° C. and a peak at about 200.4° C.; an onset at about 204.8° C. and a peak at about 205.8° C.; and an onset at about 213.9° C. and a peak at about 216.3° C., as measured using Cu(Kα) radiation.

[0058] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, and resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm, as measured using Cu(Kα) radiation. 13 and a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0059] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, and resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm, as measured using Cu(Kα) radiation. 13It has a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram that shows three endothermic events with an onset at about 198.5°C and a peak at about 200.4°C; an onset at about 204.8°C and a peak at about 205.8°C; and an onset at about 213.9°C and a peak at about 216.3°C.

[0060] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1, as measured using Cu(Kα) radiation.

[0061] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1 and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 2, when measured using Cu(Kα) radiation.

[0062] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1 and a peak at about 1739.6 cm when measured using Cu(Kα) radiation. -1 In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1 and a Fourier transform IR spectroscopy (FTIR) pattern showing a peak at about 1739.6 cm when measured using Cu(Kα) radiation. -1 2. The compound has a Fourier transform IR spectroscopy (FTIR) pattern showing a peak at and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG.

[0063] In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 1 and a solid state diffraction pattern substantially identical to that shown in FIG. 4, as measured using Cu(Kα) radiation. 13In some embodiments, crystalline Form 1 of Compound I has an X-ray powder diffraction (XRPD) pattern, measured using Cu(Kα) radiation, substantially identical to that shown in FIG 1, and a solid state diffraction (SSR) spectrum, measured using Cu(Kα) radiation, substantially identical to that shown in FIG 4. 13 It has a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG.

[0064] In some embodiments, crystalline Form 1 of Compound I is substantially the same solid form as shown in FIG. 13 In some embodiments, crystalline Form 1 of Compound I is a solid form substantially identical to that shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1739.6 cm -1 and a Fourier transform IR spectroscopy (FTIR) pattern exhibiting a peak at 1000 nm. In some embodiments, crystalline Form 1 of Compound I is substantially the same solid form as that shown in FIG. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG.

[0065] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0066] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG.

[0067] In some embodiments, crystalline Form 1 of Compound I is a solid state crystalline form characterized by resonances (δc) at about 23.35 ppm, about 124.43 ppm, about 126.78 ppm, about 127.42 ppm, and about 136.47 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1739.6 cm -1 and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0068] In some embodiments, the crystalline form 1 of Compound I has a molecular weight of about 1739.6 cm -1 In some embodiments, crystalline Form 1 of Compound I is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern exhibiting a peak at about 1739.6 cm -1 and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 2.

[0069] In some embodiments, the crystalline form 1 of Compound I has a molecular weight of about 1739.6 cm -1 and a differential scanning calorimetry (DSC) thermogram showing three endothermic events with an onset at about 198.5° C. and a peak at about 200.4° C.; an onset at about 204.8° C. and a peak at about 205.8° C.; and an onset at about 213.9° C. and a peak at about 216.3° C.

[0070] In some embodiments, crystalline form 1 of Compound I has a DSC thermogram substantially identical to that shown in Figure 2. In some embodiments, crystalline form 1 has a DSC thermogram that exhibits one or more endothermic events with an onset at about 198.5°C and a peak at about 200.4°C; an onset at about 204.8°C and a peak at about 205.8°C; and / or an onset at about 213.9°C and a peak at about 216.3°C. In some embodiments, crystalline form 1 has a DSC thermogram that exhibits three endothermic events with an onset at about 198.5°C and a peak at about 200.4°C; an onset at about 204.8°C and a peak at about 205.8°C; and an onset at about 213.9°C and a peak at about 216.3°C.

[0071] In some embodiments, crystalline Form 1 of the compound has a TGA pattern substantially identical to that shown in Figure 3. In some embodiments, crystalline Form 1 has a TGA pattern that exhibits a 15.4 w / w % loss from about 287.9°C to about 298.9°C. In some embodiments, crystalline Form 1 has a TGA pattern that exhibits less than 1% weight loss up to 200°C.

[0072] In some embodiments, crystalline form 1 of Compound I has no reversible water uptake (about -0.1 w / w%) at 0-95% relative humidity (RH). In some embodiments, crystalline form 1 of Compound I has no reversible water uptake at 0-95% relative humidity (RH). In some embodiments, crystalline form 1 of Compound I has a reversible water uptake of less than 1 w / w% at 0-95% relative humidity (RH). In some embodiments, crystalline form 1 of Compound I has a reversible water uptake of about -0.1 w / w% at 0-95% relative humidity (RH).

[0073] In some embodiments, the crystalline form 1 of Compound I has a molecular weight of about 1739.6 cm -1 The FTIR spectrum shows a peak at

[0074] In some embodiments, crystalline Form 1 of Compound I has an unchanged FTIR after storage at 75% RH and 80° C. for 7 days.

[0075] In some embodiments, crystalline Form 1 of Compound I has a crystal structure characterized by atomic coordinates substantially as set forth in Table 2, the crystal structure being measured at 293 K. In some embodiments, crystalline Form 1 has a crystal structure characterized by unit cell parameters substantially equal to a=6.521(6) Å; b=10.548(9) Å; c=17.453(15) Å; α=104.080(16)°; β=92.430(16)°; γ=101.081(17)°, and a triclinic space group=P1(Z=2), the crystal structure being measured at 293 K. In some embodiments, crystalline Form 1 has a crystalline structure characterized by unit cell parameters substantially equal to a=6.521(6) Å; b=10.548(9) Å; c=17.453(15) Å; α=104.080(16)°; β=92.430(16)°; γ=101.081(17)°, and a triclinic space group=P1(Z=2), the measurement of which was performed at 293 K, and is characterized by atomic coordinates substantially as set forth in Table 2.

[0076] In some embodiments, crystalline Form 1 of Compound I has a ssNMR spectrum substantially identical to that shown in Figure 4. In some embodiments, crystalline Form 1 has a ssNMR spectrum characterized by resonances (δc) at 23.35, 124.43, 126.78, 127.42, and 136.47 ppm. In some embodiments, crystalline Form 1 has a ssNMR spectrum further characterized by resonances (δc) at 54.41, 65.40, 138.94, 142.61, 148.68, 152.19, and 174.59 ppm. In some embodiments, crystalline Form 1 has a ssNMR spectrum characterized by resonances (δc) at 23.35, 36.40, 44.12, 45.70, 54.41, 65.40, 71.58, 110.97, 114.45, 121.00, 124.43, 126.78, 127.42, 131.27, 136.47, 138.94, 142.61, 148.68, 152.19, 172.07, and 174.59 ppm.

[0077] In some embodiments, crystalline form 1 of Compound I converts to crystalline form 2 when slurried in a solvent at a temperature of 60° C. or greater. In some embodiments, crystalline form 1 converts to crystalline form 2 when slurried in MEK or 1-pentanol at a temperature of 60° C. or 70° C. In some embodiments, the conversion of Form is determined by FTIR.

[0078] In some embodiments, crystalline Form 1 of Compound I is anhydrous.

[0079] Crystalline form 2 of compound I Also provided herein is crystalline Form 2 of Compound I. In some embodiments, a composition is provided comprising crystalline Form 2 of Compound I. In some embodiments, crystalline Form 2 of Compound I is characterized as having: · An X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 5, when measured using Cu(Kα) radiation; · An X-ray powder diffraction (XRPD) pattern showing peaks at 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 9.4±0.2° 2-θ, 15.5±0.2° 2-θ, and 16.3±0.2° 2-θ, when measured using Cu(Kα) radiation; · Approximately 1731.7cm -1 Fourier transform IR spectroscopy (FTIR) pattern showing a peak at; Unit cell parameters at 293 K essentially equal to:

[0080] [Table 6]

[0081] A solid body substantially identical to that shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum; A solid characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm 13 Carbon nuclear magnetic resonance (ssNMR) spectrum; or A combination of these.

[0082] In some embodiments, crystalline Form 2 of Compound I is characterized by having an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 5, as measured using Cu(Kα) radiation.

[0083] In some embodiments, crystalline Form 2 of Compound I has an XRPD pattern substantially identical to that shown in FIG. 5 and a peak at about 1731.7 cm when measured using Cu(Kα) radiation. -1 and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0084] In some embodiments, crystalline Form 2 of Compound I has an XRPD pattern substantially identical to that shown in FIG. 5 and a solid state image substantially identical to that shown in FIG. 7, when measured using Cu(Kα) radiation. 13 and a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0085] In some embodiments, crystalline form 2 of compound I is characterized by having an XRPD pattern substantially identical to that shown in FIG. 5 and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 6, when measured using Cu(Kα) radiation.

[0086] In some embodiments, crystalline Form 2 of Compound I is characterized by having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 9.4±0.2° 2-θ, 15.5±0.2° 2-θ, and 16.3±0.2° 2-θ, as measured using Cu(Kα) radiation.

[0087] In some embodiments, crystalline Form 2 of Compound I is characterized by having an XRPD pattern exhibiting peaks at 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 9.4±0.2° 2-θ, 15.5±0.2° 2-θ, and 16.3±0.2° 2-θ and a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event with an onset at about 215.3° C. and a peak at about 216.4° C., as measured using Cu(Kα) radiation.

[0088] In some embodiments, the crystalline form 2 of Compound I has an XRPD pattern exhibiting peaks at 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 9.4±0.2° 2-θ, 15.5±0.2° 2-θ, and 16.3±0.2° 2-θ, and a peak at about 1731.7 cm, as measured using Cu(Kα) radiation. -1 and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0089] In some embodiments, crystalline Form 2 of Compound I is a solid state compound characterized by an XRPD pattern exhibiting peaks at 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 9.4±0.2° 2-θ, 15.5±0.2° 2-θ, and 16.3±0.2° 2-θ, and resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm, as measured using Cu(Kα) radiation. 13 and a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0090] In some embodiments, crystalline Form 2 of Compound I is substantially the same solid form as shown in FIG. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0091] In some embodiments, crystalline Form 2 of Compound I is substantially the same solid form as shown in FIG. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1731.7 cm -1and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0092] In some embodiments, crystalline form 2 of compound I is a solid state compound characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0093] In some embodiments, crystalline form 2 of compound I is a solid state compound characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 The crystalline form 2 of Compound I is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum and a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event with an onset at about 215.3° C. and a peak at about 216.4° C. In some embodiments, the crystalline form 2 of Compound I is a solid state crystalline form characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. 13 Carbon nuclear magnetic resonance (ssNMR) spectrum and approximately 1731.7 cm -1 and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0094] In some embodiments, the crystalline form 2 of Compound I has a molecular weight of about 1731.7 cm -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern exhibiting a peak at

[0095] In some embodiments, crystalline form 2 has a TGA pattern that exhibits less than 1% weight loss up to 200° C. In some embodiments, crystalline form 2 of Compound I has a DSC thermogram substantially identical to that shown in Figure 6. In some embodiments, crystalline form 2 has a DSC thermogram that exhibits an endothermic event with an onset at about 215.3° C. and a peak at about 216.4° C.

[0096] In some embodiments, the crystalline form 2 of Compound I has a molecular weight of about 1731.7 cm -1In some embodiments, crystalline Form 2 of Compound I has an FTIR spectrum that exhibits a peak at 75% RH and 80° C. for 7 days.

[0097] In some embodiments, crystalline Form 2 of Compound I has a crystalline structure characterized by atomic coordinates substantially as set forth in Table 4, the crystal structure being measured at 293 K. In some embodiments, crystalline Form 2 has a crystalline structure characterized by unit cell parameters substantially equal to a=6.2823(10) Å; b=23.285(4) Å; c=31.614(6) Å; α=90.00°; β=90.00°; γ=90.00°, and an orthorhombic space group=Pbca(Z=8), the crystal structure being measured at 293 K.

[0098] In some embodiments, crystalline form 2 of compound I has a ssNMR spectrum substantially identical to that shown in Figure 7. In some embodiments, crystalline form 2 has a ssNMR spectrum characterized by resonances (δc) at 20.59, 126.39, 128.34, and 137.69 ppm. In some embodiments, crystalline form 2 has a ssNMR spectrum further characterized by resonances (δc) at 55.25, 66.34, 136.78, 141.73, 149.44, 153.68, and 175.49 ppm. In some embodiments, crystalline form 2 has a ssNMR spectrum characterized by resonances (δc) at 20.59, 37.04, 44.03, 46.84, 55.25, 66.34, 71.74, 111.25, 116.90, 122.48, 123.63, 126.39, 128.34, 131.33, 136.78, 137.69, 141.73, 149.44, 153.68, 172.82, and 175.49 ppm.

[0099] In some embodiments, crystalline form 2 of Compound I converts to crystalline form 1 when slurried in a solvent at a temperature of 50° C. or less. In some embodiments, crystalline form 2 converts to crystalline form 1 when slurried in MEK or methanol at a temperature of 40° C. or 50° C. In some embodiments, crystalline form 2 converts to crystalline form 1 when slurried in MEK at room temperature (about 25° C.). In some embodiments, the conversion of Form is determined by FTIR.

[0100] Crystalline form 3 of compound I Also provided herein is crystalline Form 3 of Compound I. In some embodiments, compositions are provided that include crystalline Form 3 of Compound I. In some embodiments, crystalline Form 3 of Compound I is characterized as having: an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 8, as measured using Cu(Kα) radiation; an X-ray powder diffraction (XRPD) pattern showing peaks at 4.2±0.2° 2-θ, 6.8±0.2° 2-θ, 15.1±0.2° 2-θ, 25.0±0.2° 2-θ, 25.5±0.2° 2-θ, and 26.4±0.2° 2-θ, as measured using Cu(Kα) radiation; -1 Fourier transform infrared spectroscopy (FTIR) pattern showing peaks at 0.15%; 13 Carbon nuclear magnetic resonance (ssNMR) spectrum; solid characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm 13 carbon nuclear magnetic resonance (ssNMR) spectra; or a combination thereof.

[0101] In some embodiments, crystalline Form 3 of Compound I is characterized by having an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG. 8, as measured using Cu(Kα) radiation.

[0102] In some embodiments, crystalline Form 3 of Compound I is characterized by having an XRPD pattern substantially identical to that shown in FIG. 8 and a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in FIG. 9, when measured using Cu(Kα) radiation.

[0103] In some embodiments, crystalline Form 3 of Compound I has an XRPD pattern substantially identical to that shown in FIG. 8 and a peak at about 1722.0 cm when measured using Cu(Kα) radiation. -1 and a Fourier transform infrared spectroscopy (FTIR) pattern showing a peak at

[0104] In some embodiments, crystalline Form 3 of Compound I is characterized by having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 4.2±0.2° 2-θ, 6.8±0.2° 2-θ, 15.1±0.2° 2-θ, 25.0±0.2° 2-θ, 25.5±0.2° 2-θ, and 26.4±0.2° 2-θ, as measured using Cu(Kα) radiation.

[0105] In some embodiments, crystalline Form 3 of Compound I is characterized by having an XRPD pattern exhibiting peaks at 4.2±0.2° 2-θ, 6.8±0.2° 2-θ, 15.1±0.2° 2-θ, 25.0±0.2° 2-θ, 25.5±0.2° 2-θ, and 26.4±0.2° 2-θ and a Differential Scanning Calorimetry (DSC) thermogram exhibiting one or more endothermic events with an onset at about 204.2° C. and a peak at about 205.3° C.; and / or an onset at about 213.6° C. and a peak at about 215.8° C., as measured using Cu(Kα) radiation.

[0106] In some embodiments, the crystalline Form 3 of Compound I has an XRPD pattern exhibiting peaks at 4.2±0.2° 2-θ, 6.8±0.2° 2-θ, 15.1±0.2° 2-θ, 25.0±0.2° 2-θ, 25.5±0.2° 2-θ, and 26.4±0.2° 2-θ, as measured using Cu(Kα) radiation, and a peak at about 1722.0 cm-1 In some embodiments, the crystalline form 3 of Compound I is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern exhibiting a peak at about 1722.0 cm. -1 It is characterized by having a Fourier transform IR spectroscopy (FTIR) pattern exhibiting a peak at

[0107] In some embodiments, crystalline Form 3 of Compound I is substantially the same solid form as shown in FIG. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0108] In some embodiments, crystalline Form 3 of Compound I is a solid state compound characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. 13 9. In some embodiments, crystalline form 3 has a DSC thermogram substantially identical to that shown in FIG. 9. In some embodiments, crystalline form 3 has a DSC thermogram that exhibits one or more endothermic events with an onset at about 204.2° C. and a peak at about 205.3° C.; and / or an onset at about 213.6° C. and a peak at about 215.8° C. In some embodiments, crystalline form 3 has a DSC thermogram that exhibits two endothermic events with an onset at about 204.2° C. and a peak at about 205.3° C.; and an onset at about 213.6° C. and a peak at about 215.8° C. In some embodiments, crystalline form 3 has a DSC thermogram that exhibits a peak at about 1722.0 cm -1 In some embodiments, crystalline Form 3 of Compound I has an FTIR spectrum that exhibits a peak at 75% RH and 80° C. for 7 days.

[0109] In some embodiments, crystalline form 3 of compound I has a ssNMR spectrum substantially identical to that shown in Figure 10. In some embodiments, crystalline form 3 has a ssNMR spectrum characterized by resonances (δc) at 64.56, 67.67, 122.99, and 126.71 ppm. In some embodiments, crystalline form 3 has a ssNMR spectrum further characterized by resonances (δc) at 110.33, 146.87, 150.90, and 176.47 ppm. In some embodiments, crystalline form 3 has a ssNMR spectrum characterized by resonances (δc) at 43.81, 46.00, 54.01, 64.56, 67.67, 109.22, 110.33, 119.58, 122.99, 126.71, 139.68, 140.34, 143.63, 144.25, 146.87, 150.90, 168.32, and 176.47 ppm. In some embodiments, crystalline form 3 has a ssNMR spectrum characterized by resonances (δc) at 21.72, 22.23, 43.81, 46.00, 54.01, 64.56, 67.67, 109.22, 110.33, 119.58, 122.99, 126.71, 130.28, 138.46, 139.68, 140.34, 143.63, 144.25, 146.87, 150.90, 168.32, and 176.47 ppm.

[0110] In some embodiments, crystalline Form 3 of Compound I converts to crystalline Form 1 when slurried in a solvent at room temperature (about 25° C.). In some embodiments, crystalline Form 3 converts to crystalline Form 1 when slurried in methanol, MEK, methyl-THF, or ethyl acetate at room temperature (about 25° C.). In some embodiments, the conversion of Form is determined by FTIR.

[0111] Crystalline form 4 of compound I Also provided herein is crystalline Form 4 of Compound I. In some embodiments, a composition is provided comprising crystalline Form 4 of Compound I. In some embodiments, crystalline Form 4 of Compound I is characterized as having: an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 11; a differential scanning calorimetry (DSC) thermogram substantially identical to that shown in Figure 12; and a crystalline form of about 1743.9 cm -1 or a combination thereof.

[0112] In some embodiments, crystalline Form 4 of Compound I has an XRPD pattern substantially identical to that shown in Figure 11. In some embodiments, crystalline Form 4 of Compound I has a DSC thermogram substantially identical to that shown in Figure 12. In some embodiments, crystalline Form 4 has a DSC thermogram substantially identical to that shown in Figure 13. -1 In some embodiments, crystalline form 4 has a TGA pattern that exhibits less than 1% weight loss up to 200° C.

[0113] Amorphous phase of compound I Also provided herein is an amorphous phase of Compound I. In some embodiments, a composition is provided that includes an amorphous phase of Compound I. In some embodiments, the amorphous phase of Compound I is characterized by having an XRPD pattern that indicates a lack of crystallinity. In some embodiments, the amorphous phase of Compound I is substantially the same solid phase as shown in FIG. 13 It is characterized by having a carbon nuclear magnetic resonance (ssNMR) spectrum.

[0114] Described herein are pharmaceutical compositions of Compound I that are substantially free of impurities. In some embodiments, the pharmaceutical compositions are substantially free of impurities of Compound I. In some embodiments, the pharmaceutical compositions contain less than about 1 w / w% impurities of Compound I. In some embodiments, the pharmaceutical compositions contain less than about 1 w / w%, less than about 0.75 w / w%, less than about 0.50 w / w%, less than about 0.25 w / w%, less than about 0.20 w / w%, less than about 0.15 w / w%, less than about 0.10 w / w%, or less than about 0.05 w / w% impurities of Compound I. In some embodiments, the amount of impurities of Compound I is undetectable. In some embodiments, the amount of impurities of Compound I is undetectable by NMR, HPLC, or the like.

[0115] "Pharmaceutically acceptable," as used herein, refers to a substance (e.g., a carrier or diluent) that does not destroy the biological activity or biological properties of the compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0116] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, a form of a therapeutically active agent that consists of the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J.Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble and dissolve rapidly in gastric and intestinal fluids than non-ionic species, making them useful in solid dosage forms. Furthermore, since solubility is often a function of pH, selective dissolution in certain parts of the gastrointestinal tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, thereby regulating passage through biological membranes.

[0117] In some embodiments, the pharma- ceutically acceptable salt of compound I is obtained by reacting compound I with a base. In some embodiments, the base is an inorganic base. In such a situation, the acidic proton of compound I is replaced with a metal ion, for example, lithium, sodium, potassium, magnesium, or calcium. Acceptable inorganic bases used to form a base with compound I include, but are not limited to, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, or magnesium salts. In some embodiments, the compounds described herein are sodium salts of compound I.

[0118] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, hydrates are formed, and when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0119] Unless otherwise stated, the following terms used in this application have the definitions set forth below. Use of the term "comprising" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0120] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it has no lasting detrimental effects on the overall health of the subject being treated.

[0121] The term "modulate," as used herein, means to directly or indirectly interact with a target to alter the activity of that target (by way of example only, enhancing the activity of that target, inhibiting the activity of that target, limiting the activity of that target, or prolonging the activity of that target).

[0122] The term "modulator," as used herein, refers to a molecule that interacts with a target directly or indirectly. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0123] The terms "administer", "administering", "administration" and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0124] The term "co-administration," or the like, as used herein, is meant to encompass the administration of more than one selected therapeutic agent to a single patient, and is 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.

[0125] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount of an agent or compound administered, which alleviates to some extent one or more symptoms of the disease or condition being treated. This can result in the reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to cause a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0126] The terms "enhance" or "enhancing," as used herein, mean to increase or prolong either in potency or duration a desired effect. Thus, in terms of enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0127] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the following mammalian classes: humans, non-human primates, such as chimpanzees, and other ape and monkey species; farm animals, such as cows, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, such as rodents, such as rats, mice, and guinea pigs, and the like. In one aspect, the mammal is a human.

[0128] The terms "treat", "treating" or "treatment" as used herein include prophylactic and / or therapeutic alleviation, amelioration, or amelioration of at least one symptom of a disease or condition, prevention of further symptoms, inhibition of a disease or condition, e.g., halting the progression of a disease or condition, relieving a disease or condition, inducing regression of a disease or condition, alleviating conditions induced by a disease or condition, or halting the symptoms of a disease or condition.

[0129] Pharmaceutical Compositions In some embodiments, the compounds disclosed herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharma- ceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. The appropriate formulation depends on the route of administration selected. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0130] In some embodiments, the compounds described herein are administered in a pharmaceutical composition, either alone or in combination with a pharma- ceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein may be by any method that allows delivery of the compound to the site of action.

[0131] In some embodiments, pharmaceutical compositions suitable for oral administration are provided as discrete units (e.g., capsules, cachets, or tablets), each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0132] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

[0133] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0134] Methods of Administration and Treatment Regimens In one embodiment, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, are administered with LPA. 1In the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from modulation of receptor activity. A method of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to said mammal a pharmaceutical composition comprising a therapeutically effective amount of at least one compound disclosed herein, or a pharma- ceutical acceptable salt thereof.

[0135] In certain embodiments, compositions comprising the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0136] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, such as the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0137] In general, however, doses used for adult human treatment typically range from 25 mg to 1000 mg per day. In one embodiment, the desired dose is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals (e.g., two, three, four or more partial doses per day).

[0138] In one embodiment, a suitable daily dosage for the compounds disclosed herein or pharma- ceutically acceptable salts thereof is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the amount of active agent in a daily dosage or dosage form is lower or higher than the ranges indicated herein, based on several variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage amount will vary depending on various variables, including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the professional.

[0139] Any of the above aspects are further embodiments, wherein an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal.

[0140] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered at a dose selected from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, and about 400 mg. In some embodiments, this dose is administered once a day. In some embodiments, this dose is administered twice a day.

[0141] Provided is a method of treating systemic sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound I, or a pharma- ceutically acceptable salt thereof, for an administration period of at least about 24 consecutive weeks.

[0142] Also provided is a method of reducing fibrosis in a cell or tissue, comprising contacting the cell or tissue with Compound I or a pharma- ceutically acceptable salt thereof in an amount and for a time sufficient to reduce or inhibit the fibrosis.

[0143] In certain embodiments, the systemic sclerosis is selected from localized cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis without scleroderma.

[0144] In certain embodiments, the systemic sclerosis is localized cutaneous systemic sclerosis.

[0145] In certain embodiments, the systemic sclerosis is systemic sclerosis without scleroderma.

[0146] In certain embodiments, the systemic sclerosis is diffuse cutaneous systemic sclerosis.

[0147] In certain embodiments, the systemic sclerosis is early diffuse cutaneous systemic sclerosis (i.e., less than 5 years since the subject showed signs or symptoms of non-Raynaud's phenomenon).

[0148] In certain embodiments, the administration period is at least 36 weeks, e.g., at least 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51 weeks. In certain embodiments, the administration period is at least 1 year (52 weeks), e.g., at least 2, at least 3, or at least 4 years. In certain embodiments, the compound is administered chronically.

[0149] In certain embodiments, Compound I, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0150] In one particular embodiment, 300 mg (free acid equivalent basis) of Compound I or a pharma- ceutically acceptable salt thereof is administered twice daily.

[0151] In certain embodiments, 300 mg (free acid equivalent basis) of Compound I or a pharma- ceutically acceptable salt thereof is administered once daily.

[0152] In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof improves forced vital capacity (FVC) %.

[0153] In certain embodiments, treatment with compound I or a pharma- ceutically acceptable salt thereof improves HAQ-DI. HAQ-DI is a 0-3 scale that measures eight areas of daily functioning (dressing, rising, eating, walking, hygiene, stretching, grip strength, and general daily activities). A score of 3 represents severe disability, and a score of 0 represents no disability. It has been suggested that the minimal clinically important difference for systemic sclerosis is 0.14 or greater. See Sultan et al. (2004) Rheumatology 43:472-8 (incorporated herein by reference for all purposes).

[0154] In certain embodiments, treatment with compound I or a pharma- ceutically acceptable salt thereof improves MDGA. The Physician Global Assessment (MDGA) is an 11-point Likert scale ranging from 0 to 10 (0=very good to 10=very bad) where the physician grades the subject's overall health over the past week. There is also a 5-point scale (1 to 5; 1=very good to 5=very bad) where the physician grades the subject's overall scleroderma condition compared to the last visit.

[0155] In certain embodiments, treatment with compound I or a pharma- ceutically acceptable salt thereof improves PTGA. The Physician Global Assessment (PTGA) is an 11-point Likert scale ranging from 0 to 10 (0=very good to 10=very bad) where the subject grades his / her overall health and disease-related pain level over the past week, how much the skin complications caused by scleroderma interfere with daily activities, and how rapidly the skin disease has progressed over the past month. There is also a 5-point Likert scale (1 to 5; 1=very good to 5=very bad) where the subject grades the overall scleroderma skin improvement compared to the last visit.

[0156] In certain embodiments, treatment with compound I or its pharma- ceutically acceptable salt improves the Physical Effects subscale of the SSPRO-18. Developed through concept elicitation of patients with diffuse cutaneous systemic sclerosis (dcSSc) and localized cutaneous systemic sclerosis (lcSSC) based on three focus groups, the Scleroderma Skin Patient-reported Outcome Instrument (SSPRO-18) is an 18-item patient-reported outcome instrument that specifically assesses the skin-related quality of life of patients with systemic sclerosis (SSc). The SSPRO-18 includes four main conceptual constructs (physical impact, emotional impact, physical limitations, and social impact) and has reproducibility and high internal consistency. This instrument reflects how subjects feel and function from several different health perspectives.

[0157] In certain embodiments, treatment with Compound I, or a pharma- ceutically acceptable salt thereof, improves the Physical Limitations subscale of the SSPRO-18.

[0158] In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof reduces mRSS by 5 points or more and 25% from baseline. The modified Rodnan skin score (mRSS) is a valid method for estimating skin thickening. Seventeen different body parts are scored as normal (0), mildly thickened (1), moderately thickened (2), and severely thickened (3), with a maximum score of 51.

[0159] In certain embodiments, treatment with compound I or a pharma- ceutically acceptable salt results in a CRISS score of 0.60 or greater. See Khanna et al. (2016) Arthritis Rheumatol. 68(2):299-311 (incorporated by reference in its entirety for all purposes). Subjects are assessed using the American College of Rheumatology-Composite Response Index in Systemic Sclerosis (CRISS), an outcome measure for dcSSc. CRISS includes core items that assess changes in two hallmarks of early dcSSc (skin and ILD), functional disability (HAQ-DI), and patient and physician global assessment. In addition, this score captures clinically meaningful deterioration of visceral disease that requires treatment.

[0160] In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof results in a reduction in skin fibrosis as measured by an mRSS change of 5 or greater.

[0161] In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof improves the HAQ-DI by 0.14 or more. In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof improves the HAQ-DI by about 0.14 and 0.3.

[0162] In certain embodiments, treatment with Compound I or a pharma- ceutically acceptable salt thereof results in an improvement from baseline in three or more of the following five core measures: 20% or more in predicted mRSS, 20% or more in HAQ-DI, 20% or more in PTGA, 20% or more in MDGA, and 5% or more in FVC%.

[0163] In some embodiments, the severity of idiopathic pulmonary fibrosis is assessed by symptoms, pulmonary function tests, exercise capacity, assessment of lung structure using CT scans, and by the use of questionnaires.

[0164] Pulmonary function tests (PFTs) are important tools in the assessment of IPF severity. The easiest test to perform is spirometry, which involves a maximal expiration through a mouthpiece followed by a maximal inspiration. The result is the forced vital capacity (FVC), which is the volume of air exhaled from a maximal inhalation. The result is compared to age-, sex-, and race-matched norms. The result is expressed as a volume of air and a percentage of predicted. Normative values ​​are approximately 80% predicted or greater. There is no single agreed cutoff for staging IPF by FVC, but many clinicians use the following: mild IPF is an FVC greater than approximately 75% predicted, moderate IPF is an FVC of approximately 50-75% predicted, severe IPF is an FVC of approximately 25-49% predicted, and very severe IPF is an FVC of less than approximately 25% predicted. Of importance relative to the specific value of FVC is the change in FVC over time. A decline in FVC of more than 5-10% is associated with an increased risk of mortality.

[0165] In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof to a human suffering from pulmonary fibrosis increases the FVC of the human. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof increases the FVC of a human suffering from pulmonary fibrosis by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than 100%.

[0166] Diffusion capacity is another type of pulmonary function test. It is an indication of how gases are exchanged through the lungs. Results are reported as a predicted percentage. Lower values ​​indicate more advanced disease. Values ​​below 40% are associated with worse survival. Decreased diffusion capacity is also associated with worse outcomes. The diffusing capacity of the lungs for carbon monoxide (DLCO) determines how much oxygen moves from the alveoli into the bloodstream.

[0167] In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof to a human suffering from pulmonary fibrosis increases DLCO. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof increases DLCO in a human suffering from pulmonary fibrosis by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more than 100%.

[0168] Exercise capacity (distance walked, oxygen saturation during exercise, heart rate, and blood pressure) is measured using a 6-minute walk test.

[0169] High-resolution CT scans assess the structural extent of fibrosis (how much fibrosis is present). More advanced radiological fibrosis is associated with worse outcomes. Increasing degrees of fibrosis over time are also associated with poorer prognosis.

[0170] Other factors associated with poor prognosis include older age, sex, heavy past smoking, low body weight, development of pulmonary hypertension, and exacerbation of underlying disease. Patients with IPF are also at increased risk of developing lung cancer, which has a significant impact on prognosis.

[0171] Questionnaires have been used to measure patient-reported outcome (PRO) assessments and include: Living with IPF questionnaire (L-IPF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), Leicester Cough Questionnaire (LCQ), and SF-12 Health Survey (SF-12).

[0172] Living with IPF (L-IPF) is a validated questionnaire assessing symptoms, disease impact, and health-related quality of life in patients with IPF. The questionnaire includes two modules: a 15-item Symptoms module (all 24-hour recall) with three domains (dyspnea, cough, and energy), and a 20-item Impact module with 1-week recall. All items in both modules have response options in a 5-point (0-4) numeric rating scale format.

[0173] The King's Brief Interstitial Lung Disease Questionnaire (K-BILD) is a self-administered health status questionnaire with 15 items and a 7-point Likert response scale that was developed and validated specifically for patients with IPF. The questionnaire has three domains: mood, dyspnea and activity, and chest symptoms. The K-BILD domains and total scores range from 0 to 100, with 100 representing the best health status. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof to a human suffering from pulmonary fibrosis increases the K-BILD score. In some embodiments, the K-BILD score increases by at least 1 unit, at least 2 units, at least 3 units, at least 4 units, at least 5 units, at least 6 units, at least 7 units, at least 8 units, at least 9 units, at least 10 units, at least 11 units, at least 12 units, or increases by more than 12 units.

[0174] The Leicester Cough Questionnaire (LCQ) is a patient-reported questionnaire that assesses the impact of cough on quality of life. The LCQ includes 19 items and takes 5-10 minutes to complete. Each item assesses symptoms or the impact on symptoms over the past two weeks on a 7-point Likert scale. Scores for the three domains (physical, psychological, and social) are calculated as the average of each domain (range: 1-7). A total score (range: 3-21) is also calculated by adding together these domain scores. A higher score indicates a better quality of life. In some embodiments, administration of Compound I or a pharma- ceutically acceptable salt thereof to a human suffering from pulmonary fibrosis increases the LCQ score. In some embodiments, the LCQ score increases by at least 1 unit, at least 2 units, at least 3 units, at least 4 units, at least 5 units, at least 6 units, at least 7 units, at least 8 units, at least 9 units, at least 10 units, at least 11 units, at least 12 units, or increases by more than 12 units.

[0175] The SF-12 Health Survey (SF-12) is a 12-item survey used to assess overall health-related quality of life. SF-12 items are scored to generate a subject-perspective physical component score (PCS) and mental component score (MCS). The SF-12 explores eight domains of health outcomes including physical functioning, role physical, bodily pain, overall health, vitality, social functioning, role emotional, and mental health. The SF-12 is a shortened version of the SF-36 and has been validated for use in patients with IPF [Swigris et al.,Respir Med. 2010;104:296-304;Tomioka et al.,Intern Med. 2007;46:1533-42], and is one of four questionnaires used in IPF Prospective Outcomes (IPF-PRO), a prospective observational US registry of patients with confirmed IPF that records patient-reported outcomes.

[0176] In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to delay the decline of lung function in a person suffering from pulmonary fibrosis. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to reduce the frequency of disease exacerbations in a person suffering from pulmonary fibrosis. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to improve the survival rate of a person suffering from pulmonary fibrosis. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is used to delay the decline of lung function, reduce the frequency of exacerbations, and improve the survival rate of a person suffering from pulmonary fibrosis.

[0177] When normal lungs are replaced with scar tissue, the lungs' ability to exchange gases and deliver oxygen to the blood is compromised. If the lungs are sufficiently affected, the level of oxygen in the blood can decrease. This is called hypoxemia or hypoxia. Blood oxygen levels are measured in two ways:

[0178] Noninvasive oxygen monitoring is done with a pulse oximeter, which reads saturation, a measure of the percentage of hemoglobin that is carrying oxygen. Normal values ​​are between 96 and 100%.

[0179] A more accurate way to measure the amount of oxygen in the blood is by arterial blood gases. This requires inserting a needle into an artery in the wrist to draw a few milliliters of blood. The oxygen pressure is then measured directly.

[0180] In some embodiments, oxygen is administered to a human if the saturation is less than 88-89% during rest, activity, or sleep. Oxygen saturation during rest is generally higher than oxygen saturation during exercise. Oxygen saturation during sleep is usually somewhere between these levels.

[0181] Oxygen is delivered via a nasal cannula from a tank or concentrator. Typical flow rates start at 2 liters per minute, but can be increased as needed. Advanced delivery systems, such as oximizer pendants, can improve oxygen delivery to patients who require higher flow rates.

[0182] Combination treatment In certain circumstances, it may be appropriate or beneficial to administer Compound I or a pharma- ceutically acceptable salt thereof in combination with one or more other therapeutic agents selected from the following: immunosuppressants (e.g., methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, and cyclophosphamide), T cell directed therapy (e.g., halofuginone, basiliximab, alemtuzumab, abatacept, rapamycin), B cell directed therapy (e.g., rituximab), autologous hematopoietic stem cell transplantation, chemokine ligand receptor antagonists (e.g., agents targeting the CXCL12 / CSCR4 axis (e.g., AMD3100)), DNA methylation inhibitors (5-azacytidine), histone deacetylase inhibitors (e.g., cyclosporine, mycophenolate mofetil, and cyclophosphamide), and / or other therapeutic agents. cetylation enzyme inhibitors (e.g., trichostatin A), statins (e.g., atorvastatin, simvastatin, pravastatin), endothelin receptor antagonists (e.g., bosentan), phosphodiesterase type V inhibitors (e.g., sildenafil), prostacyclin analogs (e.g., trepostinil), inhibitors of cytokine synthesis and / or signaling (e.g., imatinib mesylate, rosiglitazone, rapamycin, anti-transforming growth factor beta 1 (anti-TGFβ1) antibodies, mycophenolate mofetil, anti-IL-6 antibodies (e.g., tocilizumab)), corticosteroids, nonsteroidal anti-inflammatory drugs, phototherapy, and blood pressure medications (e.g., ACE inhibitors).

[0183] In some embodiments, gastroesophageal reflux disease (GERD) is involved in the development and progression of IPF. In some embodiments, acid suppression therapy is co-administered with compound I or its pharma- ceutically acceptable salt. Acid suppression therapy includes, but is not limited to, H2 blockers (e.g., cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine) and proton pump inhibitors (e.g., omeprazole).

[0184] In some embodiments, vaccination against pneumonia is co-administered with compound I or a pharma- ceutically acceptable salt thereof. Suitable vaccines include, but are not limited to, polysaccharide vaccines and conjugate vaccines. The currently most commonly used polysaccharide vaccine (PneumoVax) consists of purified polysaccharides from 23 serotypes (1, 2, 3, 4, 5, 6b, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F). Conjugate vaccines consist of capsular polysaccharides covalently linked to the diphtheria toxoid CRM197. An example of a conjugate vaccine is Prevnar 13. PneumoVax is administered in two doses, at least 5 years apart, and at least 1 year apart from Prevnar. Prevnar is administered in a single dose.

[0185] In some embodiments, the administration of Compound I or a pharma- ceutically acceptable salt thereof is combined with pulmonary rehabilitation, which is a structured exercise program that focuses on both aerobic and strength training.

[0186] In some embodiments, one or more antitussives are co-administered with Compound I or a pharma- ceutically acceptable salt thereof. Coughing can be one of the most bothersome symptoms of IPF. Treatments for coughing include, but are not limited to, expectorants, antitussives, cough suppressants, antihistamines, decongestants, steroids, benzonatate, honey, and liquid sugar.

[0187] Expectorants include, but are not limited to, acetylcysteine ​​and guaifenesin.

[0188] Antitussives or cough suppressants include, but are not limited to, codeine, pholcodine, dextromethorphan, noscapine, and butamirate.

[0189] Antihistamines include, but are not limited to, mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine (chlorpheniramine), dexchlorpheniramine, brompheniramine, triprolidine, cetirizine, cyclizine, chlorcyclizine, hydroxyzine, meclizine, loratadine, desloratidine, promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine, ketotifen, acrivastine, astemizole, cetirizine, mizolastine, terfenadine, azelastine, levocabastine, olopatadine, levocetirizine, fexofenadine.

[0190] Decongestants include, but are not limited to, ephedrine.

[0191] Steroids include, but are not limited to, betamethasone, prednisone, alclometasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortivazol, deflazacort, deoxycorticosterone, desonide, desoxymethasone, desoxycortone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorone, fludrocortisone, fludroxycortide, flumethasone, flunisolide, fluocinolone Acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, fluticasone, lumocortal, halcinonide, halometasone, hydrocortisone / cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone / prednisolone, rimexolone, tixocortol, triamcinolone, and urobetasol.

[0192] In one embodiment, honey or liquid sugar soothes a cough.

[0193] In yet another embodiment described herein, Compound I, or a pharma- ceutically acceptable salt thereof, is co-administered with at least one agent used in the treatment of a respiratory condition. Medications used in the treatment of respiratory conditions include, but are not limited to, bronchodilators (e.g., sympathomimetics and xanthine derivatives), leukotriene receptor antagonists, leukotriene formation inhibitors, leukotriene modulators, nasal decongestants, respiratory enzymes, pulmonary surfactants, antihistamines (e.g., mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine (chlorpheniramine), dexchlorpheniramine, brompheniramine, triprolidine, cetirizine, cyclizine, chlorcyclizine, hydroxyzine, meclizine, loratadine, desloratidine, promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine, ketotif cetearyl, acrivastine, astemizole, cetirizine, mizolastine, terfenadine, azelastine, levocabastine, olopatadine, levocetirizine, fexofenadine), mucolytics, corticosteroids, anticholinergics, antitussives, analgesics, expectorants, albuterol, ephedrine, epinephrine, fomoterol, metaproterenol, terbutaline, budesonide acetaminophen, ciclesonide, dexamethasone, flunisolide, fluticasone propionate, triamcinolone acetonide, ipratropium bromide, pseudoephedrine, theophylline, montelukast, zafirlukast, ambrisentan, bosentan, enrasentan, sitaxsentan, tezosentan, iloprost, treprostinil, pirfenidone, nintedanib, and 5-LO inhibitors.

[0194] In specific embodiments described herein, compound I or a pharmaceutically acceptable salt thereof is co-administered with at least one anti-inflammatory agent.In certain embodiments, compound I or a pharmaceutically acceptable salt thereof is co-administered with at least one additional agent selected from, but not limited to, epinephrine, isoproterenol, orciprenaline, bronchodilator, glucocorticoid, leukotriene modifier, mast cell stabilizer, xanthine, anticholinergic, beta-2 agonist, or 5-LO inhibitor.Beta-2 agonist includes, but is not limited to, short-acting beta-2 agonist (e.g., salbutamol (albuterol), levalbuterol, terbutaline, pirbuterol, procaterol, metaproterenol, fenoterol, and bitolterol mesylate), and long-acting beta-2 agonist (e.g., salmeterol, formoterol, bambuterol, and clenbuterol). Glucocorticoids include, but are not limited to, beclomethasone, budesonide, ciclesonide, fluticasone, and mometasone. Anticholinergics include, but are not limited to, ipratropium and tiotropium. Mast cell stabilizers include, but are not limited to, cromoglycate and nedocromil. Xanthines include, but are not limited to, amminophylline, theobromine, and theophylline. Leukotriene antagonists include, but are not limited to, montelukast, tomelukast, pranlukast, and zafirlukast. 5-LO inhibitors include, but are not limited to, zileuton.

[0195] In one embodiment, Compound I or a pharma- ceutically acceptable salt thereof is co-administered with one or more agents used to treat asthma, including, but not limited to, combination inhalants (fluticasone and salmeterol oral inhalants (e.g., Advair)); inhaled beta-2 antagonists (albuterol inhalant; albuterol nebulizer solution; formoterol; isoproterenol oral inhalant; levalbuterol; metaproterenol inhalant; pirbuterol acetate oral inhalant; salmeterol aerosol inhalant; salmeterol powder inhalant; terbutaline inhalant); inhaled corticosteroids. amides (beclomethasone oral inhalation; budesonide inhalation solution; budesonide inhalation; flunisolide oral inhalation; fluticasone inhalation aerosol; fluticasone powder for oral inhalation; mometasone powder for inhalation; triamcinolone oral inhalation); leukotriene modifiers (montelukast; zafirlukast; zaylton); mast cell stabilizers (cromolyn inhalation; nedocromil oral inhalation); monoclonal antibodies (omalizumab); oral beta-2 antagonists (albuterol oral syrup; albuterol oral tablets; metaproterenol; terbutaline); bronchodilators (aminophylline; oxtriphylline; theophylline).

[0196] In one embodiment, Compound I or a pharma- ceutically acceptable salt thereof is co-administered with one or more agents used to treat chronic obstructive pulmonary disease (COPD), including, but not limited to, anticholinergics (ipratropium bromide oral inhalant); combination inhalants (albuterol and ipratropium (e.g., Combivent, DuoNeb); fluticasone and salmeterol oral inhalant (e.g., Advair)); corticosteroids (dexamethasone tablets; fludrocortisone acetate; hydrocortisone tablets; methylprednisolone; prednisolone liquid; prednisone oral; triamcinolone oral); inhaled beta 2 agonists (albuterol inhalant; albuterol nebulizer solution;formoterol;isoproterenol oral inhalation;levalbuterol;metaproterenol inhalation;pirbuterol acetate oral inhalation;salmeterol aerosol inhalation;salmeterol powder inhalation;terbutaline inhalation);inhaled corticosteroids (beclomethasone oral inhalation;budesonide inhalation solution;budesonide inhalation;flunisolide oral inhalation;fluticasone inhalation aerosol;fluticasone powder for oral inhalation;triamcinolone oral inhalation);mucolytics (guaifenesin);oral beta2 agonists (albuterol oral syrup;albuterol oral tablets;metaproterenol;terbutaline);bronchodilators (aminophylline;oxtriphylline;theophylline).

[0197] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered in combination with a cough suppressant, a corticosteroid, an immunosuppressant, N-acetylcysteine ​​(NAC), an anti-fibrotic therapeutic agent, or a combination thereof. In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is administered in combination with N-acetylcysteine, a corticosteroid, an immunosuppressant, pirfenidone, nintedanib, imatinib, a tyrosine kinase inhibitor, PBI-4050, recombinant pentraxin-2 / SAP (PRM-151), aerosol IFN-γ, a CTGF activity inhibitor, an LPA receptor antagonist, an autotaxin inhibitor, a galectin-3 inhibitor (GB0139, GB1211), a LOXL2 inhibitor (GB2064, PAT1251), tipelukast, an integrin antagonist, a PI3K inhibitor, a JNK inhibitor, a ROCK inhibitor, an anti-IL-13 compound, a CCL2 antagonist, a CCR2 antagonist, an anti-CD20 compound, an anticoagulant, a collagen V treatment, an ASK1 inhibitor, a B-cell activating factor inhibitor (belimumab), a Rho related coiled-coil kinase 2 (Rock2) inhibitors (belmosudil), NO-independent soluble guanylate cyclase (sGC) activators (riociguat, cinaciguat, vericiguat, ataciguat, nelociguat, lificiguat), prostanoids (epoprostenol, treprostinil, iloprost), non-prostanoid prostacyclin (IP) receptor antagonists (ralnepag, selexipag), endothelin receptor antagonists (sitaxentan, ambrisentan, macitentan, bosentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), transforming growth factor beta 1 antagonists, PDE-4b inhibitors, or combinations thereof.

[0198] In one embodiment, Compound I or a pharma- ceutically acceptable salt thereof is co-administered with an inhaled corticosteroid. In some embodiments, a low dose of prednisone is co-administered with Compound I or a pharma- ceutically acceptable salt thereof.

[0199] In some embodiments, an immunosuppressant is co-administered with Compound I or a pharma- ceutically acceptable salt thereof. Immunosuppressants include, but are not limited to, prednisone and azathioprine.

[0200] In some embodiments, N-acetylcysteine ​​(NAC) is co-administered with Compound I or a pharma- ceutically acceptable salt thereof.

[0201] In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is used in combination with pirfenidone and / or nintedanib. Additional therapeutic agents contemplated for combination with Compound I or a pharmaceutically acceptable salt thereof include imatinab and other tyrosine kinase inhibitors, PBI-4050, recombinant pentraxin-2 / SAP (PRM-151), aerosol IFN-γ, CTGF activity inhibitors (FG-3019), autotaxin inhibitors (GLPG-1690, PAT-409), galectin-3 inhibitors (TD139; GB0139; GB1211), LOXL2 inhibitors (GB2064; PAT1251; PXS-5382), SSAO inhibitors (PXS-4728), Tipeluk ast (MN-001), integrin antagonists (STX-100 / BG00011, GSK3008348), PI3K inhibitors (GSK2126458), JNK inhibitors (CC-90001), ROCK inhibitors (KD025), anti-IL-13 compounds (Tralokinumab, Lebrikizumab, QAX-576), CCL2 antagonists (CNTO888), CCR2 antagonists (Cenicriviroc), anti-CD20 compounds (Rituximab), anticoagulants (Dabigatran), collagen V treatment (IW001), and ASK1 inhibitors (GS4997).

[0202] In some embodiments, Compound I, or a pharma- ceutically acceptable salt thereof, is used in combination with imatinib.

[0203] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is used in combination with pirfenidone. In some embodiments, pirfenidone is co-administered with Compound I or a pharma- ceutically acceptable salt thereof at a maximum daily dose of 2,403 mg.

[0204] In some embodiments, Compound I or a pharma- ceutically acceptable salt thereof is used in combination with nintedanib. In some embodiments, nintedanib is co-administered with Compound I or a pharma- ceutically acceptable salt thereof at a maximum daily dose of 300 mg. EXAMPLES

[0205] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0206] Example 1: Preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) The preparation of Compound I has been described in WO 2009 / 135590, U.S. Patent Nos. 8,362,073, 8,445,530, 8,802,720, and 9,328,071, each of which is incorporated herein by reference in its entirety. The preparation of Compound I as described above has yielded Form 2.

[0207] Example 2: Preparation of 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I, Form 1) Compound I (Form 2) was suspended in THF (minimal THF was used (5 v / w)) and stirred at about 22° C. for about 5 to about 7 days. The vessel or cake was not washed with additional solvent. Compound I (Form 1) was obtained. No conversion of Form 2 to Form 1 occurred over about 2 to 4 days.

[0208] Example 3: Alternative Preparation of 2-(4-Methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I, Form 1) An alternative preparation of compound 1 is now described. [ka]

[0209] a) Saponification: Methyl 2-(4-methoxy-3-(3-methylphenethoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylate (6a, 10 g, 22 mmol, 1 eq) was dissolved in methanol (164 mL, 1.64 vol) and heated to 50° C. with stirring. To the stirred solution was added aqueous NaOH (1 M, 26 mL, 1.21 eq) over 30 min, followed by water (3 mL, 0.3 vol). The reaction was stirred at 60° C. for 3 h, at which point LCMS indicated complete reaction of 6a. The reaction mixture was cooled to 20° C. and filtered to remove insoluble material. The pH of the resulting solution was 13.2.

[0210] b) Acidification / Crystallization: The solution was acidified to pH 7.5 with 1M citric acid (aqueous). The solution was seeded with Form 1 crystals (2% by weight), cooled to 10° C. over 3 hours, and held at 10° C. for 1 hour. The resulting suspension was filtered and the solid was washed with 1:1 water-methanol (2×5 volumes) followed by methanol (2×5 volumes). The solid was dried in a vacuum oven at 40° C. to give compound I (9.2 g, 95%, Form 1 by XRPD).

[0211] Example 4: X-ray Powder Diffraction (XRPD) The diffractometer described below was used, although other types of diffractometers could be used. Additionally, other wavelengths could be used and converted to Cu Kα. In some embodiments, synchrotron radiation X-ray powder diffraction (SR-XRPD) was used to characterize the crystalline forms.

[0212] "Characteristic peaks", to the extent they exist, are a subset of the observed peaks that are used to distinguish one polymorph from another (polymorphs are crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which peaks, if any, are observed in one polymorph of a compound relative to all other known polymorphs of that compound, within ±0.2° 2-θ.

[0213] STOE Stadi-P Transmission Diffractometer X-ray powder diffraction was performed using Cu-Kα 1 The measurements were performed on a STOE Stadi-P transmission diffractometer using radiation. A linear position sensitive detector was used for capillary measurements and samples in planar preparations, and an image plate position sensitive detector (IP-PSD) was used for temperature-resolved XRPD, humidity-resolved XRPD, and robotic samples in 96-well plates. The measurement data were visualized and evaluated with the Software WinXPOW V2.12.

[0214] XRPD 2-θ peak values ​​are within ±0.2° 2-θ.

[0215] Characterization of the solid forms of compound I The X-ray powder diffraction pattern of crystalline form 1 of compound I is shown in Figure 1. The X-ray powder diffraction pattern of crystalline form 2 of compound I is shown in Figure 5. The X-ray powder diffraction pattern of crystalline form 3 of compound I is shown in Figure 8. The X-ray powder diffraction pattern of crystalline form 4 of compound I is shown in Figure 11.

[0216] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 1. Characteristic XRPD peaks include: 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ.

[0217] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 5. Characteristic XRPD peaks include: 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 8.1±0.2° 2-θ, 9.4±0.2° 2-θ, 14.9±0.2° 2-θ, and 16.3±0.2° 2-θ.

[0218] Characterization of Crystalline Form 3 of Compound I The X-ray powder diffraction pattern of crystalline Form 3 of Compound I is shown in Figure 8. Characteristic XRPD peaks include: 4.2±0.2° 2-θ, 6.8±0.2° 2-θ, 15.1±0.2° 2-θ, 25.0±0.2° 2-θ, 25.5±0.2° 2-θ, and 26.4±0.2° 2-θ.

[0219] In some embodiments, measurements of independently prepared samples on different instruments may result in variations of more than ±0.2° 2-θ. Independently prepared samples of crystalline forms 1 and 2 were characterized on three additional diffractometers.

[0220] Malvern Panalytical Empyrean Diffractometer Instrument: Malvern Panalytical

[0221] Type: Empyrean equipped with Pixcel 1D Detector, Copper XRD tube, Theta-Theta goniometer, and sample changer.

[0222] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 15. Characteristic XRPD peaks include: 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ.

[0223] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 16. Characteristic XRPD peaks include: 5.6±0.2° 2-θ, 7.6±0.2° 2-θ, 8.1±0.2° 2-θ, 9.4±0.2° 2-θ, 14.8±0.2° 2-θ, and 16.2±0.2° 2-θ.

[0224] Stoe Stadi P, G.52.SYS.S072 Instrumentation and Measurement Parameters

[0225] [Table 7]

[0226] Sample preparation: A cylindrical volume defined by a washer and two foil sheets was slightly overfilled with a small amount of sample and then smoothed with two glass slides to obtain a disk of powder, which was then fixed onto a Ni-coated metal sample holder.

[0227] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 17. Characteristic XRPD peaks include: 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ.

[0228] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 18. Characteristic XRPD peaks include: 5.5±0.2° 2-θ, 7.5±0.2° 2-θ, 8.0±0.2° 2-θ, 9.4±0.2° 2-θ, 14.8±0.2° 2-θ, and 16.2±0.2° 2-θ.

[0229] An overlay of the XRPD of Form 1 (top spectrum) and Form 2 (bottom spectrum) is shown in FIG.

[0230] PANalytical X'Pert PRO MPD Diffractometer X-ray powder diffraction (XRPD, transmission mode): XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptical tilted multilayer mirror was used to focus the Cu Kα X-rays through the sample and onto the detector. The samples were sandwiched between 3 μm thick films and analyzed in transmission geometry. Prior to this analysis, a silicon sample (NIST SRM 640f) was analyzed to confirm that the position of the observed Si 111 peak matched the position certified by NIST. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position highly sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.5.5.

[0231] X-ray powder diffraction peak identification process: Depending on the instrument used for data collection and / or the inherent peak resolution, a rounding algorithm was used to round each peak to the nearest 0.1° or 0.01° 2θ. Peak positions along the x-axis (° 2-θ) in both figures and tables were determined using TRIADS® v2.1.1 software and rounded to one or two significant digits after the decimal point based on the criteria above. The variability in peak positions was determined according to the USP discussion of variability in X-ray powder diffraction (USP-NF 2021, Issue 2, <941> ,Characterization of Crystalline and Partially Crystalline Solids by X-Ray Powder Diffraction (XRPD),1_GUID-14EBB55E-0D24-45A1-A84F-FE4DCAAEE3E8_1_en-US,official prior to 2013) within ±0.2° 2-θ. In some embodiments, measurements of independently prepared samples with different instruments may result in variations of more than ±0.2° 2-θ. In the case of d-space listings, the wavelength used to calculate d-spacings was 1.5405929 Å, the Cu-Kα1 wavelength (Phys. Neurol.,A56(6):4554-4568,1997).

[0232] Characterization of Crystalline Form 1 of Compound I The X-ray powder diffraction pattern of crystalline Form 1 of Compound I is shown in Figure 20. Characteristic XRPD peaks include: 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ.

[0233] Characterization of Crystalline Form 2 of Compound I The X-ray powder diffraction pattern of crystalline Form 2 of Compound I is shown in Figure 21. Characteristic XRPD peaks include: 5.5±0.2° 2-θ, 7.5±0.2° 2-θ, 8.0±0.2° 2-θ, 9.4±0.2° 2-θ, 14.8±0.2° 2-θ, and 16.2±0.2° 2-θ.

[0234] XRPD Limit Testing Method with the PANalytical X'Pert PRO MPD Diffractometer A non-limiting method development of XRPD limit testing to determine Form 2 in Form 1 bulk is described. Specificity, i.e., the ability to clearly evaluate an analyte in the presence of components that might be expected to be present, was evaluated by comparing the XRPD patterns of Form 1 and Form 2. The specificity of Form 2 is good in Form 1 bulk, as several peaks highlighted in Figure 22 can be used to quantify Form 2 (lower spectrum) in Form 1 (upper spectrum).

[0235] Calibration model generation: Calibration standards containing 0-10% Form 2 in Form 1 were prepared by geometric mixing of the components without any extra sample handling.

[0236] [Table 8]

[0237] The XRPD overlay of the calibration standards is shown in Figure 23. The peaks specific to Form 2 are highlighted (by the dotted line) and showed good linearity based on visual assessment.

[0238] A spreadsheet was developed to calculate the peak areas at approximately 5.6°, 7.6°, and 8.1° (normalized to the total peak area in the range 4.0-25.5°).

[0239] The calibration curve is shown in Figure 24. A summary of the regression statistics is provided below along with the limits of detection (LOD) and quantitation (LOQ).

[0240] [Table 9]

[0241] [Table 10]

[0242] [Table 11]

[0243] The LOD and LOQ are calculated using the following equation: LOD = (3.3 × σ) / S LOQ = (10 × σ) / S where σ is the standard error of the linear regression and S is the slope of the calibration curve. The LOD and LOQ were calculated to be 1.0% and 2.8% (w / total), respectively.

[0244] Example 5: Differential Scanning Calorimetry (DSC) 9.1 Mettler DSC822e DSC measurements are carried out on a Mettler DSC822e (module DSC822e / 700 / 109 / 414935 / 0025). 40 μl Al crucibles with sealed lids and pinholes are used. All measurements are carried out with a nitrogen gas flow of 50 mL / min and a typical heating rate of 10° C. / min. Measurement data are evaluated by the software STARe V8.10.

[0245] 9.2 Perkin Elmer Diamond DSC DSC scans were performed using a Perkin Elmer Diamond DSC. Samples were sealed in aluminum pans with holes so that residual solvent could be released. Scans were performed from 25 to 240° C. at 10° C. / min. The system was calibrated with indium (MP 156.6° C.) and tin (MP 231.9° C.) prior to use.

[0246] Characterization of the solid forms of compound I The DSC thermogram of crystalline Form 1 of Compound I is shown in FIG.

[0247] The DSC thermogram of crystalline form 2 of Compound I is shown in FIG.

[0248] The DSC thermogram of crystalline form 3 of Compound I is shown in FIG.

[0249] The DSC thermogram of crystalline form 4 of Compound I is shown in FIG.

[0250] The thermal events of the Differential Scanning Calorimetry (DSC) thermogram of this solid form are as set forth in the table below.

[0251] [Table 12]

[0252] Example 6: Thermogravimetric Analysis (TGA) Method 10.1: Mettler TGA851e Thermogravimetric analysis is carried out on a Mettler TGA851e (module TGA / SDTA851e / SF1100 / 042). 100 μl Al crucibles with sealed lids and holes are used and the measurements are carried out with a nitrogen gas flow of 50 mL / min. The measurement data are evaluated by the software STARe V8.10.

[0253] Method 10.2: Perkin Elmer Pyris System TGA was performed using either a Perkin Elmer Pyris System. Samples were run from 25 to 200° C. at 10° C. / min. The accuracy of the system was verified using barium chloride dihydrate.

[0254] Characterization of the solid forms of compound I The TGA pattern of crystalline Form 1 of Compound I is shown in FIG.

[0255] The thermogravimetric analysis (TGA) pattern of this solid form is as set forth in the table below.

[0256] [Table 13]

[0257] Example 7: Dynamic Vapor Sorption (DVS) Moisture sorption / desorption isotherms are recorded with a DVS-1 from SURFACE MEASUREMENT SYSTEMS. Two cycles are carried out at 25° C., increasing the relative humidity (RH) from 0 to 95% and back to 0%. The data are evaluated with the software DVSWin V.2.15.

[0258] The reversible water uptake of Compound I Form 1 as determined by DVS is less than 1% (approximately −0.1 w / w% from 0 to 95% RH).

[0259] Example 8: Fourier Transform Infrared (FTIR) Spectroscopy A Nicolet Magna 750 system was used to collect FTIR of various solid forms of Compound I. Samples were prepared at 1% concentration in KBr and compressed at 10,000 lbs.

[0260] A partial Fourier transform infrared (FTIR) pattern overlay of crystalline forms 1, 2, 3, and 4 of Compound I is shown in Figure 13. The FTIR spectrum of crystalline form 1 has a peak at about 1739.6 cm -1 The FTIR spectrum of crystalline form 2 shows a peak at approximately 1731.7 cm -1The FTIR spectrum of crystalline form 3 shows a peak at about 1722.0 cm -1 The FTIR spectrum of crystalline form 4 shows a peak at about 1743.9 cm -1 The peak is indicated by .

[0261] Example 9: Fourier transform Raman spectroscopy Raman spectra were acquired with a Raman module connected to a Nicolet 6700 IR spectrophotometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing and flattening the sample in a 13 mm diameter stainless steel cup. The cup was rotated during data acquisition using a Thermo Nicolet Step-and-Repeat accessory. Three spectra were collected for each sample, from the outer ring to the inner ring of the sample cup. Approximately 0.5 W of Nd:YVO4 laser power (excitation wavelength of 1064 nm) was used to irradiate the sample. Each spectrum was captured using a 2 cm -1 The data consisted of 512 co-added scans with a spectral resolution of 100 kHz. Three spectra for each sample were averaged using Omnic v7.2 (ThermoElectron).

[0262] The variation in Raman peak positions is based on the observed sharpness of the selected peaks and the -1 Data point interval (2cm -1 Resolution) based on data acquisition and ±2cm -1 Peak selection was performed using OMNIC software, version 7.2, Thermo Electron Corporation. The observed peaks include all Raman peaks of a given Form, but peaks with very low intensity and broad peaks with poorly defined maxima are removed.

[0263] The Raman spectrum of Form 1 is shown in Figure 25.

[0264] The Raman spectrum of Form 2 is shown in Figure 26.

[0265] Example 10: Solid-state nuclear magnetic resonance (ssNMR) spectroscopy All spectra were acquired using a Bruker DRX500 spectrometer equipped with an 11.7 Tesla magnet and a 4 mm diameter solid probe, with the following parameters:

[0266] [Table 14]

[0267] All spectra are indirectly referenced to tetramethylsilane using the high frequency signal of adamantane. All samples were packed into 4 mm OD rotors made of zirconia fitted with Kel-F drive caps. A Gaussian convolution was applied to the free induction decays prior to Fourier transformation; GB=0.035, and LB=-10.0 Hz.

[0268] Characterization of Crystalline Form 1 of Compound I The ssNMR spectrum of crystalline Form 1 of Compound I is shown in Figure 4. Resonances characteristic of Form 1 are listed below. δc / ppm:23.35,36.40,44.12,45.70,54.41,65.40,71.58,110.97,114.45,121.00,124 .43,126.78,127.42,131.27,136.47,138.94,142.61,148.68,152.19,172.07,174.59

[0269] Characterization of Crystalline Form 2 of Compound I The ssNMR spectrum of crystalline Form 2 of Compound I is shown in Figure 7. Resonances characteristic of Form 2 are listed below. δc / ppm:20.59,37.04,44.03,46.84,55.25,66.34,71.74,111.25,116.90,122.48,123 .63,126.39,128.34,131.33,136.78,137.69,141.73,149.44,153.68,172.82,175.49

[0270] Characterization of Crystalline Form 3 of Compound I The ssNMR spectrum of crystalline Form 3 of Compound I is shown in Figure 10. Resonances characteristic of Form 3 are listed below. δc / ppm:21.72 # ,22.23 # ,43.81,46.00,54.01,64.56,67.67,109.22,110.33,119.58,122.99,126.71,130.28 # ,138.46 # ,139.68,140.34,143.63,144.25,146.87,150.90,168.32,176.47 # Broad or resolved signals that may vary in shape or chemical shift.

[0271] Characterization of the amorphous form of Compound I The ssNMR spectrum of the amorphous form of Compound I is shown in FIG.

[0272] Example 11: Stability of solid forms The physical stability of Forms 1, 2, and 3 was investigated at 80° C. / 75% RH to determine if interconversion was observed. After one week of stress in open glass vials, samples were examined by FTIR.

[0273] No changes were observed in the FTIR spectra for any of the forms, suggesting that these forms are relatively stable in the solid state.

[0274] Example 12: Solubility test The solubility of the various polymorphs was determined in phosphate buffer at pH 7.4 at 25° C. Samples were analyzed as a function of time for each form to determine the equilibrium value. The residual solids of each sample were analyzed to ensure that the form was unchanged during the experiment. The concentration (mg / mL) versus time data for each form is listed below.

[0275] [Table 15]

[0276] The equilibrium solubility values ​​at 24 hours show that Forms 3 and 4 are more than twice as soluble as Form 1. The 24 hour result for Form 2 was more than 30% compared to Form 1.

[0277] It should be noted that analysis of the residual solids showed no polymorphic conversion over the duration of the experiment. The data for Forms 3 and 4 are comparable within experimental error.

[0278] Example 13: Single Crystal X-ray Diffraction (SCXRD) of Crystalline Form 1 of Compound I Crystallization of compound I from propyl acetate yielded a crystal of 0.5*0.04*0.02 mm 3 Crystals of size 0.01 mm were obtained and sealed in Lindemann-glass capillaries. A SMART APEX area detector, a cryostat (model LT 2), and a molybdenum-K α Equipped with a rotating anode generator, it is operated at 50kV / 120mA and has a 0.5×5mm 2 X-ray diffraction data were collected on a Bruker / AXS three-circle diffractometer adjusted to a fine focus of 100 nm. Data frames were collected using the program package SMART V 5.628 (Bruker AXS, 2001), applying an ω-scan with a step width of 0.3° and an exposure time of 60 s. Data processing with the program SAINT+Release 6.45 (Bruker AXS, 2003) yielded 6452 reflections (

number

[0279] The structure was refined by the least-squares method ((F o 2 - F c 2 ) 2 ) using the XL module of SHELXTL 6.14 (Bruker AXS, 2000). The positions of all H atoms were determined experimentally from a difference Fourier synthesis map, S goodness of fit t = 0.780, R all data = 0.2189 (|F obs | > 4σ, wR2 all data = 0.1080, wR2 obs. data = 0.0759 for 1479 reflections with R obs. data = 0.0536). The largest unassigned peak in this difference map corresponds to -0.193 to +0.162 electrons per Å 3 . The average estimated standard deviation (e.s.d.) of C-C bonds is 0.005 Å, that of O-C bonds is 0.004 Å, that of N-C bonds is 0.004 Å, and that of C-H bonds is 0.03 Å. The average e.s.d. of C-C-C bond angles is 0.4, and the average e.s.d. of C-C-C-C torsion angles is 0.5°.

[0280] The crystal structure of crystalline form 1 of compound I was determined at 293 K, and the summary of the structure data can be found in Tables 1 and 2.

[0281]

Table 1

[0282]

Table 2-1

[0283]

Table 2-2

[0284] Example 14: Single Crystal X-ray Diffraction (SCXRD) of Crystal Form 2 of Compound I Crystallization of Compound I from N-methyl-2-pyrrolidone / methanol gave crystals of size 0.6 * 0.2 * 0.2 mm 3 which were sealed in a Lindemann-glass capillary. X-ray diffraction data were collected on a Bruker / AXS three-circle diffractometer equipped with a SMART APEX area detector, a cryogenic device (model LT 2), and a copper-K α microfocus generator, operating with a focused beam Montel multilayer lens at 45 kV / 650 μA and an image focus spot diameter of approximately 250 μm (Wiesmann et al., 2007). Data frames were collected using the program package SMART V 5.628 (Bruker AXS, 2001), applying an ω scan with a step width of 0.3° and an exposure time of 5 s. Data processing by the program SAINT+ Release 6.45 (Bruker AXS, 2003) gave 23,571 reflections (

Number

[0285] The least squares method ((F o 2 -F c 2 ) 2 The structure was refined by minimizing the σ(σ) of the σ(σ) and ... goodness of fit = 1.039, R all data =0.0490(|F obs |>4σ, wR2 all data =0.1041, wR2 obs. data R for 3283 reflections at =0.0971 obs. data = 0.0379). The largest unassigned peak in this difference map is located at 1 Å 3 This corresponds to -0.179 vs. +0.185 electrons per unit mass. The average estimated standard deviation (esd) for CC bonds is 0.002 Å, the esd for OC bonds is 0.002 Å, the esd for NC bonds is 0.002 Å, and the esd for CH bonds is 0.02 Å. The average esd for CCC bond angles is 0.2 and the average esd for CCCC torsion angles is 0.2°.

[0286] The crystal structure of crystalline Form 2 of Compound I was determined at 293 K and a summary of the structural data can be found in Tables 3 and 4.

[0287] [Table 3]

[0288] [Table 4-1]

[0289] [Table 4-2]

[0290] The experimentally determined powder diffraction pattern is in agreement with that calculated from the crystal structure.

[0291] Example A-1: ​​Tablet formulation Film-coated tablets were prepared containing 10 mg, 100 mg, 150 mg, or 200 mg of Compound I and the following excipients: mannitol, microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate, povidone, macrogol, titanium dioxide, sodium lauryl sulfate, and docusate sodium.

[0292] Example B-1: Antifibrotic effect of Compound I The activity of Compound I, a selective LPAR1 receptor antagonist, was evaluated in skin fibroblasts from patients with systemic sclerosis, as well as in several models of skin, kidney, and cardiac fibrosis.

[0293] Using two models of skin fibrosis, the effect of Compound I was evaluated in comparison with imatinib mesylate used as a standard. In a model of bleomycin-induced skin fibrosis, Compound I at 50 mg / kg / day was able to restore mouse skin thickness, myofibroblast differentiation, and collagen content using a treatment protocol. The effects on these markers were comparable to those of imatinib. In tight skin (Tsk-1) mice, heterozygous for a mutation in the fibrillin gene that leads to overproduction of matrix proteins despite the absence of inflammatory infiltration, Compound I at 30 mg / kg / day was also able to inhibit the progression of skin fibrosis at a level comparable to that of imatinib.

[0294] In addition to this effect on skin fibrosis, Compound I also improved renal function in models of hypertension- or nephrotoxicity-induced renal failure and showed beneficial effects on cardiac function and structure in various models of hypertension- or diabetes-associated cardiac hypertrophy, fibrosis, and heart failure. In parallel, Compound I showed modest but significant antithrombotic activity in acute models of coagulation and arterial thrombosis. All these pathological events were observed at various levels in SSc patients, further supporting the use of Compound I in these patients.

[0295] Finally, compound I has a significant inhibitory effect on the accumulation of leukocytes and total inflammatory cells in the bronchoalveolar lavage of presensitized mice treated with ovalbumin.

[0296] In conclusion, compound I inhibits fibrosis in various organs (skin, kidney, and heart). Compound I improves cardiac systolic and diastolic function, positively affects arteriosclerosis with little change in blood pressure, and shows antithrombotic activity in two thrombosis models in rats and one model in mice. In addition, compound I reduces inflammation in a model of lung injury that shows a predominant Th2-type response.

[0297] Example B-2: An 8-week, double-blind, randomized, placebo-controlled study in patients with cutaneous systemic sclerosis (dcSSc) An 8-week double-blind, randomized, placebo-controlled study of Compound I was conducted in patients with early dcSSc with a baseline modified Rodnan skin thickness score (mRSS) of at least 15, followed by a 16-week open-label extension. The primary endpoint was safety during the double-blind phase of the study. Exploratory endpoints included the identification of LPA-induced gene signatures in patients' skin.

[0298] Of the 32 patients, 17 were randomly assigned to receive placebo and 15 to receive Compound I. Thirty patients participated in this open-label extension study. The most frequent adverse events reported with Compound I during the blinded phase were headache, diarrhea, nausea, and falls, and the safety profile was tolerable during the open-label extension. At week 8, the reduction in MRSS was numerically greater in the Compound I group compared to the placebo group (mean ± SD change -3.57 ± 4.18 vs. -2.76 ± 4.85; treatment effect -1.2 [95% confidence interval -4.37, 2.02]). A greater reduction in LPA-related genes was observed in skin samples from the Compound I group at week 8, suggesting that LPA 1 Target engagement was demonstrated.

[0299] Clinical outcomes from the 16-week open-label extension study are shown below.

[0300] [Table 16]

[0301] Biomarker analysis of skin biopsies showed reductions in LPA-related genes.Numerical improvements over baseline in several disease biomarkers (COMP and TSP1) were observed in the initial Compound I group when treatment was extended up to 24 weeks.

[0302] Compound I was well tolerated in patients with dcSSc. MRSS improved during the study, but this difference was not significant, and additional gene signature analysis suggested target engagement. In addition, clinically significant improvements were observed in HAQ-DI (assessing functional impairment) at 24 weeks.

[0303] Example B-3: A 52-week, double-blind, randomized, placebo-controlled study in patients with cutaneous systemic sclerosis (dcSSc) The overall objective is to investigate the efficacy, safety, and tolerability of two dose regimens of Compound I administered once daily (QD) or twice daily (BID) for 52 weeks in treating patients with diffuse cutaneous systemic sclerosis (diffuse cutaneous SSc).

[0304] Main purpose The primary objective is to demonstrate the efficacy of one or two dose regimens of Compound I compared with placebo in subjects with diffuse cutaneous SSc, as determined by a comparison of the change in % predicted forced vital capacity (FVC) after 52 weeks of treatment.

[0305] Secondary Objectives To evaluate the effect of two dose regimens of Compound I compared with placebo on the Health Assessment Questionnaire-Disability Index [HAQ-DI] after 52 weeks of treatment.

[0306] To evaluate the effect of two dose regimens of Compound I compared to placebo on Physician Global Assessment (MDGA) after 52 weeks of treatment.

[0307] To evaluate the effect of two dose regimens of Compound I compared to placebo on Patient Global Assessment (PTGA) after 52 weeks of treatment.

[0308] To evaluate the effect of two dose regimens of Compound I compared with placebo on the Physical Effects subscale of the Scleroderma Skin Patient-Reported Outcome (SSPRO-18) after 52 weeks of treatment.

[0309] To evaluate the effect of two dose regimens of Compound I compared to placebo on the Physical Limitations subscale of the SSPRO-18 after 52 weeks of treatment.

[0310] The effect of two dose regimens of Compound I compared to placebo on modified Rodnan Skin Score (mRSS) after 52 weeks of treatment is evaluated.

[0311] To evaluate the effect of two dose regimens of Compound I compared to placebo on American College of Rheumatology-Composite Response Index Systemic Sclerosis (ACR-CRISS), defined as improvement from baseline in mRSS, HAQ-DI, PTGA, MDGA, and FVC% predicted after 52 weeks of treatment.

[0312] The effect of two dose regimens of Compound I compared to placebo on ACR-CRISS-20, defined as improvement from baseline of three or more core set measures: ≥20% in mRSS, ≥20% in HAQ-DI, ≥20% in PTGA, ≥20% in MDGA, and ≥5% in FVC%, predicted after 52 weeks of treatment, will be evaluated.

[0313] The safety and tolerability of Compound I will be evaluated for adverse events (AEs), adverse events of special interest (AESIs) (orthostatic hypotension), concomitant medication use, vital signs, 12-lead electrocardiogram (ECG), and clinical safety laboratory assessments (hematology, chemistry, inflammatory parameters, coagulation panel, and urinalysis).

[0314] The pharmacokinetics (PK) of Compound I and its metabolites will be evaluated.

[0315] exploratory purpose To evaluate the effect of two dose regimens of Compound I compared to placebo on SSPRO-18 after 52 weeks of treatment.

[0316] To evaluate the effects of two dose regimens of Compound I compared to placebo on the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 2.0) after 52 weeks of treatment.

[0317] The Raynaud's Assessment is used to evaluate the effect of two dose regimens of Compound I compared to placebo on Raynaud's phenomenon.

[0318] To evaluate the effect of two dose regimens of Compound I compared to placebo on the Scleroderma HAQ (SHAQ) at 52 weeks.

[0319] To evaluate the effect of two dose regimens of Compound I compared with placebo on change from baseline in Systemic Sclerosis Quality of Life Questionnaire (SScQoL) scores.

[0320] The effect of two dose regimens of Compound I compared to placebo on change from baseline in SF-12® Health Survey (SF-12) scores is evaluated.

[0321] The effect of two dose regimens of Compound I compared to placebo on change from baseline in pain and pain component scale scores is evaluated.

[0322] To evaluate the effect of two dose regimens of Compound I compared to placebo on the change from baseline in fatigue based on the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) score.

[0323] The effect of two dose regimens of Compound I compared to placebo on the change from baseline in protein expression of markers of inflammation and fibrosis in skin biopsies is evaluated.

[0324] The effect of two dose regimens of Compound I compared to placebo on changes from baseline in transcriptomics associated with the LPAR1 pathway, inflammation, and fibrosis in skin biopsies will be evaluated.

[0325] To evaluate the effect of two dose regimens of Compound I compared to placebo on the change from baseline in pulmonary fibrosis after 52 weeks of treatment in subjects with adequate baseline high-resolution computed tomography (HRCT).

[0326] To evaluate the effect of two dose regimens of Compound I compared to placebo on the change from baseline in diffusing capacity of the lung for carbon monoxide (DLCO) after 52 weeks of treatment.

[0327] The effect of two dose regimens of Compound I compared to placebo on change from baseline in serum and plasma biomarkers associated with the LPAR1 pathway, inflammation, and / or fibrosis will be evaluated.

[0328] Study design: This is a randomized, double-blind, placebo-controlled, repeated-dose, multicenter study. Subjects are screened within 4 weeks prior to the baseline (Day 1) visit. Approximately 300 subjects who meet the study eligibility criteria will be randomized on Day 1 in a 1:1:1 ratio to receive Compound I 300 mg QD, Compound I 300 mg BID, or placebo for 52 weeks. Randomization will be stratified according to the use of mycophenolate mofetil at screening (yes / no) and the presence of interstitial lung disease (ILD) based on HRCT scan at screening (yes / no).

[0329] The study will include a screening period of up to 4 weeks and a double-blind treatment period of 52 weeks. Subjects will receive their first dose of study drug at the clinic and will attend the clinic for study visits at week 4 and every 6 weeks thereafter until week 52. All subjects who complete the double-blind treatment period (week 52) will be eligible to participate in a 52-week extension study. Subjects who do not participate in this extension will attend the clinic for safety follow-up 4 weeks after their last dose of study drug.

[0330] If a subject discontinues study medication early, he / she will be asked to remain in the study and attend scheduled study visits through Week 52. If a subject discontinues study medication early and does not wish to continue in the study, he / she will be asked to return to the clinic for the Week 52 evaluation.

[0331] Inclusion Criteria: Eligible subjects must meet all of the following criteria:

[0332] Written informed consent. Male or female, aged 18-75 years at screening. Meet the 2013 American College of Rheumatology / European League Against Rheumatism classification criteria for SSc with a total score of ≥9 (Van den Hoogen et al., 2013). Classified as having skin involvement proximal to the elbow and / or knee (diffuse cutaneous SSc subset according to LeRoy and Medsger, 2001). <36 months from onset of first SSc sign other than Raynaud's phenomenon at enrollment. SSc skin thickening in the forearm suitable for repeat biopsy. ≥15 mRSS units at screening. FVC ≥45% predicted at screening as determined by spirometry. Willingness and ability to comply with prescribed treatment protocols and evaluations during the treatment period.

[0333] Exclusion criteria: Subjects are ineligible for study participation if they meet any of the following criteria:

[0334] Positive for anticentromere antibodies. Diagnosed with SSc without scleroderma or localized cutaneous SSc. Diagnosed with other autoimmune connective tissue disease except fibromyalgia, scleroderma-associated myopathy, and secondary Sjögren's syndrome. Diagnosed scleroderma renal crisis within 6 months of screening. Any of the following cardiovascular diseases: severe uncontrolled hypertension (≥160 / 100 mmHg) or persistent hypotension (systolic blood pressure <90 mmHg) within 6 months of screening, myocardial infarction within 6 months of screening, unstable angina within 6 months of screening. DLCO (hemoglobin adjusted) less than 40% predicted. For any subject, DLCO should be considered for up to 6 months prior to the screening visit if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern. Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with multiple oral PHA approved therapies or any parenteral therapy. Treatment for erectile dysfunction and / or Raynaud's phenomenon / digital ulcers is permitted. Use of corticosteroids for conditions other than SSc within 4 weeks prior to screening (topical steroids for skin conditions and inhaled / intranasal / intraarticular steroids are permitted). Use of any other nonsteroidal immunosuppressants, small biomolecules, cytotoxic agents, or antifibrotic agents (e.g., cyclophosphamide, azathioprine (Imuran®), other immunosuppressants, or cytotoxic agents) within 4 weeks of screening. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate, and low-dose prednisone as follows: CellCept 3g / day or less, Myfortic 2.14g / day or less, methotrexate 15mg / week or less, and prednisone 10mg / day or less (or equivalent doses of glucocorticoids) are permitted. See Table 9.1 for complete details. Subjects receiving CellCept, Myfortic, or methotrexate must have been receiving the drug for ≥6 months prior to the Day 1 visit and the dose must have been stable for ≥16 weeks.Prednisone must be stable at dose for ≥8 weeks prior to the Day 1 visit. Low-dose prednisone and antimalarials may be given in background along with CellCept, Myfortic, or methotrexate. Rituximab must not have been used within 6 months of the Day 1 visit. Known active bacterial, viral, fungal, mycobacterial, or other infection (e.g., tuberculosis, or atypical mycobacteria) (fungal infections of the nail bed are permitted). Use of a US Food and Drug Administration-approved drug for SSc within 90 days or 5 half-lives (whichever is longer) prior to screening, or an investigational drug for any condition, or expected use during the course of the study. Malignancy in the past 5 years (except for successful treatment of in situ basal / squamous cell carcinoma of the skin or cervical cancer). Women of childbearing potential (WOCBP) or male subjects who do not agree to use highly effective contraception during the study and for 1 month after the last dose of study drug. Pregnant or breastfeeding women.

[0335] Previous enrollment in this study or participation in a previous clinical trial of Compound I. Any other condition that, in the opinion of the Investigator, would preclude participation in this study.

[0336] Dosage forms, strengths, dosage regimens, and routes of administration: The study uses Compound I 150 mg tablets and matching placebo tablets.

[0337] Subjects will take two tablets of study medication orally with meals in the morning and evening.

[0338] Compound I 300mg QD regimen: 2 tablets of Compound I in the morning and 2 tablets of placebo in the evening. Compound I 300mg BID regimen: 2 tablets of Compound I in the morning and 2 tablets of Compound I in the evening.

[0339] Placebo regimen: 2 placebo tablets in the morning and 2 placebo tablets in the evening.

[0340] Treatment and follow-up period: The planned duration of the double-blind treatment period is 52 weeks. All subjects who complete the double-blind treatment period are eligible to participate in a 52-week extension study. Subjects who do not participate in this extension will attend a safety follow-up clinic 4 weeks after their last dose of study drug.

[0341] Evaluation criteria: Efficacy will be assessed by FVC% predicted, MDGA, mRSS, ACR-CRISS, patient-reported outcomes (HAQ-DI, SHAQ global question, PTGA, SSPRO-18, UCLA SCTC GIT2.0, and Raynaud's Assessment), quality of life, health status, and fatigue assessments (SScQoL, SF-12, pain score, and fatigue score [FACIT-F]), HRCT, and DLCO.

[0342] Blood samples will be collected for PK assessment of Compound I and metabolites, pharmacogenetic assessment (assessment of drug metabolizing enzymes and / or transporters), autoantibodies, and biomarkers associated with the LPAR1 pathway, inflammation, or fibrosis.

[0343] A total of four 3 mm biopsies (two pre-dose at baseline [day 1] and two at week 16) will be taken from the forearm (lesion) and analyzed for transcriptomics and protein expression in the skin for markers of the LPAR pathway, fibrosis, and inflammation. Lesioned skin should be used if it is located in this area.

[0344] Safety will be assessed by AEs, concomitant medication use, physical examination, vital signs, orthostatic hypotension assessment, laboratory evaluations, and 12-lead ECG.

[0345] Efficacy variables Spirometry Spirometry, including FVC% predicted, will be assessed using equipment provided by the Sponsor. Spirometry should be performed only by experienced assessors, and unless not possible, the same assessor should complete the procedure on a given subject throughout the entire study period.

[0346] Spirometry should be performed according to the American Thoracic Society (ATS) / European Respiratory Society (ERS) 2019 guidelines [Graham et al., Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200:e70-e88]. The test is performed in triplicate (three curves are provided) and the best result is selected according to the guidelines. The best of three efforts is defined as the highest FVC obtained in any of the three puffs that meets the ATS / ERS criteria in a maximum of eight procedures.

[0347] Spirometry should be attempted at approximately the same time since baseline. On the day of the visit, subjects must refrain from strenuous exercise for at least 12 hours prior to pulmonary function testing. Smoking should be abstained throughout the entire day of the visit, and smoking is not permitted for 30 minutes prior to spirometry. Subjects should also avoid cold temperatures, environmental smoke, dust, or strong odors (e.g., perfume). If treated with bronchodilators, a 24-hour washout period for long-acting bronchodilators and an 8-hour washout period for short-acting bronchodilators must be observed prior to spirometry.

[0348] Physician Global Assessment The MDGA is an 11-point Likert scale ranging from 0 to 10 (0=very good to 10=very poor) on which the physician grades the subject's overall health over the past week, and a 5-point scale (1 to 5; 1=much ​​better to 5=much ​​worse) on which the physician grades the subject's overall scleroderma condition compared to the last visit.

[0349] Modified Rodnan Skin Score The mRSS is a validated method for estimating skin thickening. Seventeen different body sites are scored as normal (0), mildly enlarged (1), moderately enlarged (2), and severely enlarged (3), with a maximum score of 51. Assessments should be performed by an investigator (or designee) trained in skin scoring. Unless unavoidable, the same person should perform assessments at each evaluation during the course of the study.

[0350] American College of Rheumatology-Composite Response Index in Systemic Sclerosis Subjects are assessed using the ACR-CRISS, an outcome measure for diffuse cutaneous SSc. The ACR-CRISS includes core items assessing change in two hallmarks of early diffuse cutaneous SSc (skin and ILD), functional disability (HAQ-DI), and patient and physician global assessment. In addition, the score captures clinically meaningful worsening of visceral disease requiring treatment.

[0351] The ACR-CRISS is a two-step process that assigns a subject's likelihood of improvement ranging from 0.0 (no improvement) to 1.0 (marked improvement). Step 1 is assessed as part of the AE evaluation, during which the investigator evaluates whether the subject has new-onset or worsening cardiopulmonary and / or renal impairment due to SSc, as outlined below.

[0352] A new scleroderma renal crisis defined as follows (Source: Steen et al., Assessment of kidney involvement. Clin Exp Rheumatol. 2003;21(3Suppl29):S29-31): Scleroderma hypertensive renal crisis: 1. New onset of hypertension defined as any of the following: systolic blood pressure 2140mmHg; diastolic blood pressure 290mmHg; increase in systolic blood pressure 230mmHg or increase in diastolic blood pressure 220mmHg and 2. One of the following five features: serum creatinine increased 250% above baseline or serum creatinine 21-20% of ULN by local laboratory; proteinuria 22+ by urine dipstick; hematuria 22+ by urine dipstick or 210 red blood cells / high power field; thrombocytopenia: <100,000 platelets / mm3; hemolysis (defined as anemia not attributable to other causes and is any of the following: i) schistocytes or other red blood cell fragments seen on blood smear, or ii) elevated reticulocyte count Normotensive renal crisis due to scleroderma: 1. Increase in serum creatinine >50% from baseline or serum creatinine 21-20% of the ULN by local laboratory: and 2. One of the following five features: proteinuria 22+ by urine dipstick; hematuria 22+ by urine dipstick or 210 red blood cells / high power field; thrombocytopenia: <100,000 platelets / mm3; hemolysis (defined as anemia not attributable to other causes and consisting of either i) schistocytes or other red blood cell debris seen on blood smear or ii) elevated reticulocyte count; renal biopsy findings consistent with scleroderma renal crisis (microangiopathy).

[0353] A decline in predicted FVC% of 15% or more (relative) confirmed by another FVC% within 1 month, HRCT to confirm ILD (if ILD was not detected on previous testing), and a predicted FVC% of less than 80%.

[0354] New onset of left heart failure (defined as ejection fraction ≤45%) requiring treatment.

[0355] New onset of PAH by right heart catheterization requiring treatment.

[0356] Gastrointestinal motility disorders requiring enteral nutrition (tube feeding) or parenteral nutrition.

[0357] Digital ischemia with gangrene, amputation, or hospitalization requiring treatment.

[0358] If a subject meets some of these criteria, the subject is assigned a probability of 0. Otherwise, in step 2, the probability of improvement is calculated based on the five core measures incorporated in the ACR-CRISS (e.g., change in mRSS, FVC% predicted, HAQ-DI, PTGA, and MDGA) [Khanna and Berrocal et al., The American College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 2016;68(2):299-311].

[0359] Skin (lesion) biopsy Skin (lesion) biopsies are taken from the mid-dorsal surface of the forearm (150±20 mm proximal to the ulnar styloid process). If lesional skin is located in this area, lesional skin should be used. Biopsies should be performed with or without lesional skin. This biopsy is used to analyze for transcriptomics and to analyze cutaneous protein expression for markers of the LPAR pathway, fibrosis, and inflammation.

[0360] On each biopsy collection day, two 3 mm skin punch biopsies are taken adjacent to each other. The biopsies are obtained according to standard dermatology practice. After the biopsy is performed, the investigator will advise the subject on the care of the site. The biopsy should be taken from the same arm, approximately 25 mm away from the previous biopsy, so that the healing of the previous biopsy does not interfere with the analysis.

[0361] The location of the biopsy (right or left arm) and distance from the ulnar styloid process will be recorded. If the investigator is of the opinion that the mid-dorsal forearm is not suitable, the ventral forearm may be selected as the biopsy site. Alternate sites and reasons for changing site will be recorded.

[0362] The investigator has the discretion to manage the occlusion of the biopsy site according to standard care, although the use of sutures or gel foam is recommended.

[0363] Only the first 110 consenting subjects completed this biopsy.

[0364] Plasma and serum biomarkers Blood samples are collected pre-dose at days 1, 4, and 28, and at the week 52 visit, and analyzed for plasma and serum biomarkers associated with the LPAR1 pathway, inflammation, or fibrosis. Examples of biomarkers that may be measured include, but are not limited to, proteins associated with the complement pathway, and components of the extracellular matrix pathway.

[0365] Only subjects who had baseline blood samples available for serum and plasma biomarkers completed this assessment.

[0366] Pulmonary high-resolution computed tomography Lung HRCT will be reviewed by a central reader. The results must be available prior to randomization. If an HRCT has been performed for clinical care within 3 months prior to screening and has been reviewed and deemed acceptable by the central reader, an HRCT does not need to be performed at screening.

[0367] Pulmonary Diffusing Capacity for Carbon Monoxide At the site, their own DLCO device is used, and if several devices are available at the site, all measurements are made with the same DLCO device. Single-breath DLCO measurements are performed according to the ATS guidelines for DLCO measurement [Graham et al.,Executive Summary:2017 ERS / ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017;49:16E0016].

[0368] DLCO values ​​are adjusted for altitude, carboxyhemoglobin, and the most recent hemoglobin value. DLCO assessments should always be performed after FVC measurements and should always begin at approximately the same time each day.

[0369] Patient-reported outcome measures Health Assessment Questionnaire-Disability Index The HAQ-DI, which is a part of the SHAQ, assesses the subject's functional ability level and includes questions on fine movements of the upper limbs, spontaneous movements of the lower limbs, and activities involving both the upper and lower limbs. There are 20 questions in eight categories of function (e.g., dressing, getting up, eating, walking, hygiene, stretching, grip strength, and general activities) [Cole et al., Single-factor scoring validation for the Health Assessment Questionnaire-Disability Index (HAQ-DI) in patients with systemic sclerosis and comparison with early rheumatoid arthritis patients. Qual Life Res. 2006;15(8):1383-94]. The subject's ability to accomplish each activity in the past week is indicated as follows: easily, with some difficulty, with a lot of difficulty, and unable to do it. Also evaluate any equipment typically used to complete the activity and any categories that require assistance from others.

[0370] Patient Global Assessment The PTGA is an 11-point Likert scale ranging from 0 to 10 (0=very good to 10=very bad) on which the subject grades his / her overall health over the past week, as well as disease-related pain levels, the extent to which skin complications due to scleroderma are interfering with daily activities, and how rapidly the skin disease has progressed over the past month. There is also a 5-point Likert scale (1 to 5; 1=much ​​better to 5=much ​​worse) on which the subject grades the overall scleroderma skin improvement compared to the last visit.

[0371] Scleroderma Skin Patient-reported Outcome Instrument Developed through concept elicitation of patients with diffuse and localized cutaneous SSc based on three focus groups, the SSPRO-18 is an 18-item patient-reported outcome instrument that specifically assesses skin-related quality of life in patients with SSc and was developed with extensive patient input and in accordance with FDA patient-reported outcome guidance [Man et al., Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis. Ann Rheum Dis. 2017;76:1374-80]. The SSPRO-18 includes four major conceptual constructs (physical impact, emotional impact, physical limitations, and social impact) and has high reproducibility and internal consistency. The instrument reflects how subjects feel and function from several different health perspectives. Good test-retest reliability and construct validity have been demonstrated. Responsiveness has been shown for lenabasum compared with placebo [Spiera et al., Safety and efficacy of lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol. 2020;72(8):1350-60].

[0372] Scleroderma Health Assessment Questionnaire The SHAQ consists of the HAQ-DI (8 domains), a VAS for pain, and the following scleroderma-specific VAS: Patient Global Assessment, Deficits, Digital Ulcers, Pulmonary Lesions, and Gastrointestinal Lesions [Steen and Medsger, 1997]. The developers added a global question to the HAQ-DI based on the evaluation of SSc patients at the University of Pittsburgh Scleroderma Clinic, their HAQ scores, patient reports of symptoms, and clinical examinations. The five scleroderma-specific VAS address the extent to which symptoms interfere with daily activities and are scored similarly to the pain VAS. Each VAS score is reported separately. Studies support excellent test-retest reliability of abatacept versus placebo on the SHAQ global question, and construct validity (correlation with other measures in the expected direction and magnitude) [Johnson et al.,The Health Assessment Questionnaire Disability Index and Scleroderma Health Assessment Questionnaire in scleroderma trials:an evaluation of their measurement properties. Arthritis Rheum. 2005;53:256-62;Smyth et al.,A cross-sectional comparison of three self-reported functional indices in scleroderma. Rheumatology. 2003;42(6):732-8;Khanna et al.,Abatacept in early diffuse cutaneous systemic sclerosis:results of a phase 2 investigator-initiated,multicenter,double-blind,randomized,placebo-controlled trial. Arthritis Rheumatol. 2020;72:125-36].

[0373] UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument The UCLA SCTC GIT 2.0 captures SSc-related gastrointestinal activity and severity. This instrument is an improvement over the Scleroderma Gastrointestinal Tract (SSC-GIT 1.0) instrument because it is shorter (34 items vs. 52 items) but still a reliable and valid instrument that distinguishes between reflux and distension / bloating symptoms, adds a scale to assess anal incontinence due to its high prevalence in SSc, and develops a composite score that captures the overall gastrointestinal burden associated with SSc [Khanna et al., Reliability and validity of UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT 2.0) instrument. Arthritis Rheumatol. 2009;61(9):1257-63].

[0374] The UCLA SCTC GIT 2.0 has seven scales (reflux, distension / bloating, distension / fullness, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning) and a total GIT score is also calculated to capture the overall burden of SSc-related gastrointestinal disorders. Items are scored from 0 to 3 and do not need to be converted to a 0 to 100 scale.

[0375] Raynaud's Assessment The Raynaud's Condition Score Diary captures the frequency, duration, and severity of Raynaud's phenomenon activity and has face, content, criterion, discriminant, and construct validity in subjects with SSc. [Merkel et al., J Rheumatol. 2003;30:1630-47] Subjects are provided with an electronic device to capture daily symptoms for up to 52 weeks.

[0376] Systemic Sclerosis Quality of Life Questionnaire Developed through concept elicitation interviews of patients affected by diffuse and limited cutaneous SSc, the SScQoL is a validated tool with 29 questions divided into five subscales related to the important disease-specific factors associated with quality of life in SSc: physical functioning, emotional functioning, social functioning, sleep, and pain [Sierakowska et al.,Factors associated with quality of life in systemic sclerosis:a cross-sectional study. Qual Life Res. 2019;28:3347-54]. It has shown good test-retest reliability and construct validity [Reay N.The quality of life in patients with diffuse and limited systemic sclerosis. Published online in 2008. https: / / etheses.whiterose.ac.uk / 26111 / 1 / 503274.pdf]. To date, no studies have yet determined responsiveness.

[0377] SF-12 Health Survey The SF-12 [Ware et al., A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34:220-33] is a 12-item survey used to assess overall health-related quality of life. Items on the SF-12 are scored to generate a subject-perspective physical component score (PCS) and mental component score (MCS). The SF-12 explores eight domains of health outcomes including physical functioning, role physical, bodily pain, overall health, vitality, social functioning, role emotional, and mental health.

[0378] pain questionnaire Subjects complete a pain questionnaire with three questions regarding the severity of pain experienced during the past week due to Raynaud's disease, arthritis, and digital ulcers and / or calcifications. Subjects grade pain from 0 (no pain) to 10 (very severe pain).

[0379] Functional Assessment of Chronic Illness Therapy-Fatigue Scale The FACIT-F is a 13-item scale assessing self-reported fatigue and its impact on daily activities and function. The FACIT-F was developed in the mid-1990s to meet the growing demand for a more accurate assessment of fatigue associated with anemia in cancer patients. Since its development, it has been employed in over 150 published studies involving over 40,000 patients. Study populations have included patients with cancer, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, multiple sclerosis, psoriasis, and SSc. The FACIT-F is reliable and validated in subjects with SSc [Harel et al., Canadian Scleroderma Research Group. Measuring fatigue in SSc: a comparison of the Short Form-36 Vitality subscale and Functional Assessment of Chronic Illness Therapy-Fatigue scale. Rheumatology (Oxford) 2012:51:2177-85;Strickland et al.,Predictors of health-related quality of life and fatigue in systemic sclerosis: evaluation of the EuroQol-5D and FACIT-F assessment tools. Clin Rheumatol. 2012;31:1215-22].

[0380] Example B-4: Pharmacokinetics (PK) and food effect of Compound I in healthy adult subjects The PK and food effect of Compound I were evaluated in an open-label study in healthy volunteers to inform the dose and administration conditions of the tablet formulation used in clinical trials. Dose proportionality and food effect were evaluated using a two-way, two-period crossover design in two cohorts: single doses of 150 mg and 300 mg under fasting conditions in Cohort 1, and a single dose of 450 mg under fasting and high-fat high-calorie meal conditions in Cohort 2. The PK of multiple doses was evaluated using a two-period fixed-sequence crossover design. Subjects were administered Compound I twice daily (BID), 300 mg (Cohort 3) or 450 mg (Cohort 4), with a low-fat meal in Period 1 and with a high-fat meal in Period 2.

[0381] PK Sample Collection: For cohorts 1 and 2, blood samples were collected pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post-dose. For cohorts 3 and 4, blood samples were collected pre-dose and 0.5, 1, 2, 4, 5, and 12 hours after the first dose on day 1. After the last dose on day 5, PK samples were collected pre-dose, 0.5, 1, 2, 4, 6, 12, 24, 36, 60, 84, and 108 hours in period 1 and pre-dose and 0.5, 1, 2, 4, 6, and 12 hours after the last dose in period 2.

[0382] Plasma concentrations of Compound I were determined using a validated high performance liquid chromatography-tandem mass spectrometry (HPLC MS / MS) method. The analytical ranges for Compound I were 250-50,000 ng / mL (high range) and 25-25,000 ng / mL (low range). Dose proportionality of pharmacokinetic parameters was evaluated. AUC 0-last , AUC 0-inf , and C max Parameters were examined by dose-normalized analysis of variance (ANOVA). 90% confidence intervals (CI) were derived by exponentiation of the CI obtained for the differences between treatment LSMs (least squares means). Dose proportionality was established when the 90% CI of the ratio of the geometric means of dose-normalized parameters was within the range of (0.7, 1.43).

[0383] The effect of food was evaluated using ANOVA on the ln-transformed PK parameters. The ANOVA model included sequence, treatment, and period as fixed effects, with subject nested within sequence as a random effect. From this ANOVA model, geometric least squares means, geometric mean ratios (high fat vs. fasted), and 90% confidence intervals of PK parameters (AUC and Cmax) were calculated.

[0384] The Cmax and AUC of Compound I increased less than dose proportionally from 150 mg to 450 mg, and the exposure increased slightly from 300 mg to 450 mg (see table below). Less than dose proportional PK by ANOVA analysis.

[0385] PK parameters following doses of 150, 300, and 450 mg administered under fasting conditions

[0386] [Table 17]

[0387] At 450 mg, a high-fat, high-calorie meal increased the exposure of Compound I. The AUC 0-last , AUC 0-inf , and C max The GMRs for were approximately 212%, 212%, and 191%, respectively (see table below).

[0388] Summary of statistical comparison of pharmacokinetic parameters of Compound I at 450mg following fed and fasted conditions.

[0389] [Table 18]

[0390] 1. Geometric least squares means (LSM) are calculated by exponentiating the LSM from the ANOVA. 2. Geometric mean ratio (GMR) = 100 x (Test / Reference). 3. A high-fat, high-calorie diet as per FDA guidance, including 55-65g fat, 800-1000 total calories, and 50% calories from fat.

[0391] Compared with the results seen in Example B-3 study, similar Compound I exposure was achieved after administration of 300mg BID with food.Therefore, 300mg BID with food was selected as the highest dose in the following study, and 300mg QD dose was also included to know the dose-response relationship of Compound I.

[0392] Pharmacokinetic parameters of compound I at steady state following fed conditions

[0393] [Table 19]

[0394] 1. A low-fat diet as per FDA guidance, containing 11-14g fat, 400-500 total calories, and 25% calories from fat. 2. A high-fat, low-calorie diet, containing 33-44g fat, 600-800 total calories, and 50% calories from fat. 3. A high-fat, high-calorie diet as per FDA guidance, containing 55-65g fat, 800-1000 total calories, and 50% calories from fat. Data are presented as medians. 1 / 2 are expressed as mean (%CV), except for .

[0395] Example B-5: A multicenter, open-label extension study to evaluate the efficacy, safety, and tolerability of Compound I in subjects with diffuse cutaneous systemic sclerosis This is an open-label, repeated-dose, multicenter extension study of Example B-3. Subjects who complete the double-blind treatment period (week 52) in Study Example B-3 are eligible to participate in this 52-week extension study.

[0396] On Day 1 (Week 52 visit in Example B-3), subjects will receive their first dose of Compound I in this extension study at the clinic, and will return to the clinic for study visits at Week 4 and every 6 weeks thereafter until Week 52.

[0397] If a subject discontinues study medication early, he / she will be asked to remain in the study and participate in scheduled study visits through week 52. If a subject discontinues study medication early and does not wish to continue in the study, he / she will attend the clinic for an evaluation at week 52. Subjects will attend the clinic for safety follow-up 4 weeks after their last dose of Compound I.

[0398] Target population: Inclusion Criteria: Written informed consent. Completion of the double-blind treatment period (Week 52) of Study B-3; subjects who prematurely discontinue study drug in Study B-3 for reasons other than safety or toxicity may be enrolled at the investigator's discretion after completion of scheduled visits in Study B-3 (including the Week 52 evaluation). Willingness and ability to comply with prescribed treatment protocols and evaluations during the treatment period.

[0399] Exclusion criteria: Anticipated use of another investigational drug for any condition during the course of this study. New diagnosis of malignancy after enrollment in Study B-3 (except for successful treatment of in situ basal / squamous cell carcinoma of the skin or cervical cancer). Women of childbearing potential (WOCBP) or male subjects who do not agree to use highly effective contraception during the study and for one month after the last dose of study drug. Pregnant or lactating women. Any new onset of the subject's disease or condition, or any significant clinical laboratory abnormality, during the course of Study B-3 that, in the opinion of the Investigator, would place the subject at unacceptable risk. Subjects will be ineligible if they have an intercurrent disease or condition that, in the opinion of the Investigator, would make them unlikely to comply with the study protocol or that may interfere with the performance of the study.

[0400] Dosage forms, strengths, dosage regimens, and routes of administration: This study uses Compound I 150 mg tablets. The dose regimen for all subjects is Compound I 300 mg BID. Subjects take two Compound I 150 mg tablets orally with meals in the morning and evening.

[0401] Endpoints Two baselines are defined: Study Baseline (defined as the most recent measurement prior to the first dose of Compound I in the extension study). Compound I Baseline (defined as the most recent measurement prior to the first dose of Compound I in either Study Example B-3 or the extension study). For subjects who received placebo in Study Example B-3, the Study Baseline will be the same as the Compound I Baseline.

[0402] Primary Efficacy Endpoint The primary efficacy endpoints were change from baseline in FVC% predicted at week 52.

[0403] Exploratory Efficacy Endpoints Changes from baseline in both HAQ-DI scores at week 52. Changes from baseline in both MDGAs at week 52. Changes from baseline in both PTGA at week 52. Changes from both baselines in the SSPRO-18 Physical Effects subscale at week 52. Changes from both baselines in the SSPRO-18 Physical Limitations subscale at week 52. Proportion of subjects achieving a ≥5-point and 25% reduction from baseline in mRSS at Week 52. Response rate at 52 weeks (defined as an ACR-CRISS [predicted probability] of at least 0.6). Percentage of subjects achieving improvement in ≥ 3 of 5 core measures from baseline: ≥ 20% in mRSS predicted at Week 52, ≥ 20% in HAQ-DI, ≥ 20% in PTGA, ≥ 20% in MDGA, and ≥ 5% in FVC% (ACR-CRISS-20). Changes from baseline in both SSPRO-18 at week 52. Change from baseline in both UCLA SCTC GIT 2.0 and total GIT score scales at week 52. Change from both baselines in Raynaud's phenomenon using the Raynaud's Assessment at week 52. Changes from baseline in both SHAQ measures at week 52. Changes from both baselines in SScQoL scores at week 52. Changes from both baselines in SF-12 scores at week 52. Change from baseline in both pain and pain component scale scores at week 52. Changes from baseline in both FACIT-F scores at week 52. Changes from baseline in both mRSS at week 52. Changes from both baselines in HRCT-based pulmonary fibrosis at week 52. Changes from baseline in DLCO at week 52 for both. Changes from baseline in both serum and plasma biomarkers associated with the LPAR1 pathway, inflammation, and / or fibrosis at week 52.

[0404] Safety and Tolerability Endpoints Incidence of TEAEs and AESIs (orthostatic hypotension). Use of concomitant medications. Changes from baseline in vital signs at both ends. Changes from baseline in 12-lead ECG measurements at both ends. Changes from baseline in clinical safety study outcomes at both ends.

[0405] Pharmacokinetic endpoints Pre-dose and post-dose concentrations of Compound I and metabolites.

[0406] Rescue medications permitted due to clinically significant deterioration Dose initiation / modification permitted in the event of clinically significant deterioration as defined below may be appropriate (should be discussed in advance with the medical monitor): absolute decline from study baseline in FVC% predicted of 10% or more with a decline in DLCO of 15% or more from study baseline in FVC% predicted of 5-9% or more; or relative change from study baseline in mRSS of 25% or more and absolute change from study baseline of 5 points or more; or clinically significant deterioration in other organ systems as assessed by the investigator, or clinically significant deterioration not meeting the above criteria.

[0407] Other causes of decreased FV (i.e. respiratory infection) should be ruled out. If, in the Investigator's clinical judgment, well-founded doubts regarding the quality of the test and the subject's well-being justify the associated delay in the subject's care and increased risk to the subject, FVC / spirometry should be repeated to confirm prior to initiation of rescue medication.

[0408] Compound I is an in vitro inhibitor of organic anion transporters 1 and 3 (OAT1 and OAT3) and may increase the systemic exposure of methotrexate.

[0409] DLCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; mRSS = modified Rodnan skin score; OATP = organic anion transporter polypeptide.

[0410] [Table 20]

[0411] Example B-6: Phase 2b Study to Evaluate the Efficacy, Safety, and Tolerability of Compound I in Subjects with Idiopathic Pulmonary Fibrosis (IPF) The study will be conducted in two parts: Part 1 (core phase), followed by Part 2 (extension phase). The core phase will include a 52-week randomized, double-blind, placebo-controlled treatment period, and the extension phase will include a 52-week open-label extension (OLE).

[0412] Part 1 (Core Phase) The overall objective of the core phase is to investigate the efficacy, safety, and tolerability of two dose regimens of Compound I, a selective antagonist of LPAR1, administered QD or BID for 52 weeks in the treatment of subjects with IPF.

[0413] Main purpose The primary objective is to demonstrate the efficacy of two dose regimens of Compound I compared to placebo in subjects with IPF, as determined by a comparison of change in predicted FVC% after 52 weeks of treatment.

[0414] Secondary Objectives The effect of two dose regimens of Compound I compared to placebo on the proportion of subjects with a ≥10% decline from baseline in predicted FVC% after 52 weeks of treatment is evaluated.

[0415] To evaluate the effect of two dose regimens of Compound I compared to placebo on the change from baseline in the 6-Minute Walk Test (6MWT) after 52 weeks of treatment.

[0416] To evaluate the effect of two dose regimens of Compound I compared to placebo on the King's Brief Interstitial Lung Disease Questionnaire (K-BILD) after 52 weeks of treatment.

[0417] To evaluate the effect of two dose regimens of Compound I compared to placebo on L-IPF after 52 weeks of treatment.

[0418] To evaluate the effect of two dose regimens of Compound I compared to placebo on the Leicester Cough Questionnaire (LCQ) after 52 weeks of treatment.

[0419] The effect of two dose regimens of Compound I compared to placebo on the rate of hospitalization due to dyspnea over up to 52 weeks of treatment is evaluated.

[0420] To evaluate the effect of two dose regimens of Compound I compared to placebo on the composite endpoint of progression-free survival (PFS) (progression includes a decline in predicted FVC% of 10% or more from baseline or death over 52 weeks of treatment).

[0421] The safety and tolerability of Compound I will be evaluated, including but not limited to adverse events (AEs), SAEs, and AESIs.

[0422] The PK of Compound I is evaluated.

[0423] exploratory purpose The effect of two dose regimens of Compound I compared to placebo on the change from baseline in SF-12® Health Survey (SF-12) scores after 52 weeks of treatment is evaluated.

[0424] The effect of two dose regimens of Compound I compared with placebo on the change from baseline in titrated oxygen requirement (TOR) after 52 weeks of treatment is evaluated.

[0425] The effect of two dose regimens of Compound I compared to placebo on the change from baseline in DLCO after 52 weeks of treatment is evaluated.

[0426] To evaluate the effect of two dose regimens of Compound I compared to placebo on time from baseline to first IPF-related acute exacerbation (defined by: Collard et al., Acute exacerbation of idiopathic pulmonary fibrosis. an international working group report. Am J Respir Crit Care Med. 2016;194(3):265-75) over up to 52 weeks of treatment.

[0427] The effect of two dose regimens of Compound I compared to placebo on all-cause mortality over up to 52 weeks of treatment is evaluated.

[0428] The effect of two dose regimens of Compound I compared to placebo on mortality due to respiratory deterioration over up to 52 weeks of treatment is evaluated.

[0429] The effect of two dose regimens of Compound I compared to placebo on mortality due to IPF disease-related events over up to 52 weeks of treatment will be evaluated.

[0430] In subjects with adequate baseline (at screening or within 6 months prior to screening) and 52-week HRCT scans, the effects of two dose regimens of Compound I compared to placebo on the following after 52 weeks of treatment will be evaluated: change from baseline in total lung volume by high resolution computed tomography (HRCT); change from baseline in volume of pulmonary fibrosis score by HRCT; percent change from baseline in total lung volume by pulmonary fibrosis score by HRCT; change from baseline in normal lung volume by HRCT; percent change from baseline in FVC% predicted; and relationship to the mean percent change from baseline in pulmonary fibrosis score.

[0431] Part 2 (extension phase) The overall objective of the extension phase is to examine the long-term efficacy, safety, and tolerability of Compound I administered at a dose of 300 mg BID to subjects with IPR at an OLE of 52 weeks following completion of the core phase of the study. The dose in the extension phase may be modified based on the results of the core phase.

[0432] For this extension phase, two baselines are defined: OLE baseline (defined as the most recent measurement prior to the first dose of Compound I in the extension phase); or Compound I baseline (defined as the most recent measurement prior to the first dose of Compound I in either the core phase or the extension phase). For subjects who received placebo in the core phase, the OLE baseline is the same as the Compound I baseline.

[0433] Main purpose The primary efficacy objective is to evaluate the efficacy of Compound I in subjects with IPF after 52 weeks of open-label treatment.

[0434] safety purpose Safety objectives are to determine the safety and tolerability of 52 weeks of open-label treatment with Compound I based on TEAE assessments; concomitant medication use; vital signs; 12-lead electrocardiograms (ECGs); and clinical safety laboratory results.

[0435] exploratory purpose Exploratory efficacy objectives are to evaluate the efficacy of open-label treatment with Compound I for 52 weeks with the following additional efficacy measures: proportion of subjects with a ≥10% decline in predicted FVC%; 6MWT; K-BILD; L-IPF; LCQ; SF-12 score; hospitalization due to respiratory distress; a composite endpoint of PFS with exacerbations including a ≥10% decline in predicted FVC% or death; TOR; DLCO; IPF-related acute exacerbation; all-cause mortality; mortality due to IPF disease-related events; HRCT scan; total lung volume, pulmonary fibrosis score volume, total lung volume with pulmonary fibrosis score, and normal lung volume by HRCT.

[0436] The exploratory PK objective was to evaluate the PK of Compound I.

[0437] Overall Study Design and Plan This is a randomized, squared-blind, placebo-controlled, repeated-dose, multicenter study to evaluate the efficacy, safety, and tolerability of Compound I in subjects with IPF. Subjects will be screened within 8 weeks prior to the baseline (Day 1) visit. Approximately 135 subjects who meet the study eligibility criteria will be randomly assigned in a 1:1:1 ratio on Day 1 to receive Compound I 300 mg once daily (QD), Compound I 300 mg twice daily (BID), or placebo for 52 weeks using the following two stratification factors: Previous use of approved IPF therapies (i.e., nintedanib or pirfenidone): yes or no Baseline predicted FVC%: ≥70% or <70%.

[0438] The core phase includes a screening period of up to 8 weeks and a double-blind treatment period of 52 weeks. Subjects will receive their first dose of study drug at the clinic on Day 1 (Week 0), and will participate in study visits at Week 4 and every 6 weeks thereafter until Week 52. Subjects who complete the 52-week double-blind treatment period may be eligible to participate in the extension phase of this study. If subjects do not participate in this extension phase, they will visit for safety follow-up 4 weeks after their last dose of study drug.

[0439] If a subject discontinues study medication early, he / she will be asked to remain in the study and attend scheduled study visits through Week 52. If a subject discontinues study medication early and does not wish to continue in the study, he / she will be asked to return to the clinic for the Week 52 evaluation.

[0440] The extension phase of the study is an optional open-label, repeated-dose, multicenter extension of the core phase. Subjects who have completed the double-blind treatment period (week 52) in the core phase of this study may be eligible to participate in this 52-week extension phase. Subjects who participate in the extension phase will complete the week 52 visit, which is considered as day 1 of the extension phase, will be administered the first dose of open-label Compound I in the extension phase at the clinic, and will visit the clinic for study visits at weeks 56, 62, and 68, and then every 12 weeks until week 104. The week 52 visit activity will serve as the baseline for the extension phase. Subjects will visit the clinic for a safety follow-up visit 4 weeks after the last dose of Compound I.

[0441] If a subject prematurely discontinues Compound I, he / she will be asked to remain in the study and attend scheduled study visits through Week 104. If a subject prematurely discontinues Compound I and does not wish to continue in the study, he / she will be asked to return to the clinic for the Week 104 evaluation.

[0442] Core Phase Inclusion Criteria Eligible subjects must meet all of the following criteria:

[0443] Written informed consent.

[0444] Male or female, aged 18 years or older at the time of screening.

[0445] Current diagnosis of IPF as defined by the ATS / ERS / JRS / ALAT guidelines [Raghu et al.,Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults:an official ATS / ERS / JRS / ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022;205(9):e18-47]; first diagnosis of IPF should be within 7 years prior to screening.

[0446] No recent or planned changes to IPF therapy dose or regimen, as defined below: receiving a stable dose of an approved IPF therapy (i.e., nintedanib or pirfenidone) for at least 3 months prior to Day 1 with no planned changes to background regimen during study participation; or not currently receiving background approved IPF therapy at screening (either naïve to approved IPF therapy or any approved IPF therapy has been discontinued for at least 4 weeks prior to Day 1, or an exclusion period of 5 drug-specific half-lives if more than 4 weeks) and no current plans to resume treatment during study participation. Subjects receiving any additional agent for IPF therapy must be receiving a stable regimen for at least 3 months prior to Day 1 with no current plans to change treatment regimen during study participation. Any previously discontinued therapy used to treat IPF must have been discontinued for at least 4 weeks prior to Day 1 with no plans to resume this therapy during study participation, or 5 half-lives of this particular treatment must have elapsed (whichever is longer).

[0447] A lung HRCT performed within 6 months prior to the screening visit and performed according to the minimum requirements for a diagnosis of IPF by central review based on the subject's HRCT. If an evaluable HRCT is not available within 6 months prior to screening, an HRCT will be performed at screening according to the same requirements as the previous HRCT to determine eligibility. The HRCT must show a pattern of usual interstitial pneumonia or probably usual interstitial pneumonia based on the interpretation of the central review vendor. Histopathology combined with HRCT results supporting a diagnosis of IPF or likely IPF according to Raghu et al.,2022 may be submitted to support subject eligibility.

[0448] HRCT shows parenchymal fibrosis (reticulosis) of 10% to less than 50%, and the degree of fibrotic changes is greater than the degree of emphysema seen on the most recent HRCT scan.

[0449] Meet all of the following criteria during the screening period as determined by central review: FVC ≥ 45% predicted of normal; forced expiratory volume in 1 second (FEV1) / FVC ≥ 0.7; DLCO corrected for hemoglobin ≥ 25% and ≤ 90% predicted of normal.

[0450] A minimum estimated life expectancy of 30 months or more for non-IPF-related disease in the opinion of the investigator.

[0451] Vaccinations are up to date.

[0452] Willingness and ability to comply with prescribed treatment protocols and evaluations during treatment.

[0453] Core Phase Exclusion Criteria Subjects are ineligible for study participation if they meet any of the following criteria: any of the following cardiovascular disease: severe uncontrolled hypertension (≥160 / 100 mmHg) within 6 months of screening; myocardial infarction within 6 months of screening; unstable angina within 6 months of screening.

[0454] ILD associated with a known primary disease (e.g., sarcoidosis, amyloidosis, and coronavirus disease 2019 [COVID-19]), connective tissue disorder (e.g., rheumatoid arthritis, systemic lupus erythematosus, Sjogren's disease, dermatomyositis, scleroderma), exposure (e.g., radiation, silica, asbestos, and coal dust), or medication (e.g., amiodarone).

[0455] Known active bacterial, viral, fungal, mycobacterial, or other infection (e.g., tuberculosis, or atypical mycobacteriosis) (fungal infections of the nail bed are permitted). Subjects must be >3 months from any acute infection with COVID-19 if previously infected.

[0456] Clinically significant pulmonary hypertension requiring chronic medical therapy.

[0457] Use of any of the following therapies within 4 weeks prior to screening, during the screening period, or planned during the study: prednisone at a stable dose greater than 10 mg / day or equivalent, or cyclosporine. Any changes in the regimen or dosage of immunosuppressants from the screening period through the end of study participation require consultation with and approval by the Study Medical Monitor. Avoidance of use of the prohibited treatments listed must not be considered detrimental and must be ordered by the treating physician. Subjects may not withdraw from any standard of care treatments deemed necessary for the subject's clinical management in order to meet study eligibility requirements.

[0458] Use of rifampin within 2 weeks prior to Day 1 or planned during the study.

[0459] Malignant disease in the past 5 years (excluding successful treatment of in situ basal / squamous cell carcinoma of the skin or cervical cancer).

[0460] Women of childbearing potential (WOCBP) or male subjects who do not agree to use highly effective contraception during the study and for 4 weeks after the last dose of study medication. Pregnant or breastfeeding women, and women who plan to become pregnant or breastfeed during the study and within 4 weeks after the last dose of study medication.

[0461] Current drug or alcohol abuse, or a history of either within the past 2 years, in the opinion of the investigator or as reported by the subject.

[0462] Previous enrollment in this study or participation in a previous Compound I clinical trial. Exposure to an experimental drug or vaccine within 30 days prior to Day 1, within 5 half-lives of the study drug, or within 2 times the duration of the biological effect of the study drug (whichever is longest).

[0463] Known positive test for Human Immunodeficiency Virus (HIV). Active hepatitis.

[0464] Current alcoholic liver disease, primary biliary cirrhosis, or primary sclerosing cholangitis.

[0465] Previous organ transplant (including allogeneic or autologous bone marrow transplant).

[0466] International normalized ratio greater than 2, prothrombin time prolonged greater than 1.5 × upper limit of normal (ULN), or partial thromboplastin time greater than 1.5 × ULN at screening. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.0 × ULN. Estimated glomerular filtration rate greater than 30 mL / min / 1.73 m2 at screening.

[0467] Any confirmed clinical laboratory abnormality of grade 3 or greater. Any laboratory abnormality at screening that, in the opinion of the Investigator, would preclude the subject from participating in the study.

[0468] Any other condition that, in the opinion of the investigator, would prevent enrollment in the study.

[0469] Inclusion criteria for the extension phase Eligible subjects must meet all of the following criteria:

[0470] Written informed consent.

[0471] Completion of the double-blind treatment period (Week 52) of the core phase of the study; subjects who prematurely discontinue study drug during the core phase of the study for reasons other than safety or tolerability may be enrolled at the investigator's discretion after completion of scheduled visits (including the Week 52 evaluation).

[0472] Willingness and ability to comply with prescribed treatment protocols and evaluations for the duration of the extension phase of the study.

[0473] Exclusion Criteria for the Extension Phase A subject will be ineligible for study participation if they meet any of the following criteria: anticipated use of another investigational drug for any condition during the course of the study; new diagnosis of malignancy after enrollment in the core phase (excluding successful treatment of in situ basal / squamous cell carcinoma of the skin or cervical cancer); estimated minimum life expectancy of 18 months or less, in the opinion of the investigator; WOCBP or male subjects who do not agree to use highly effective contraception during the study and for one month after the last dose of Compound I; pregnant or lactating women; any other new onset of a disease / condition / significant clinical laboratory abnormality during the course of the core phase of the study that, in the opinion of the investigator, may place the subject at unacceptable risk; intercurrent diseases or conditions that, in the opinion of the investigator, may make them unlikely to comply with the study protocol or may interfere with the performance of the study.

[0474] Treatment taken During the core phase of the study, on Day 1 of the double-blind treatment period, subjects will be randomized in a 1:1:1 ratio to receive Compound I 300 mg QD, or Compound I 300 mg BID, or placebo for 52 weeks.

[0475] During the extension phase, all subjects will receive open-label Compound I 300 mg BID for 52 weeks. The dose in the extension phase may be modified based on the results of the core phase.

[0476] Compound I is provided as film-coated 150 mg tablets for oral administration.

[0477] The placebo tablets are matched in appearance to the active tablets.

[0478] Subjects will take two 150 mg tablets of Compound I orally in the morning and evening with meals. The dose in the extension phase may be modified based on the results of the core phase.

[0479] Concomitant Therapies and Drug Restrictions The use of medications restricted during this study is presented in the table below.

[0480] [Table 21]

[0481] In the event of clinically significant deterioration in pulmonary function, initiation of additional therapy is permitted after Week 28, as outlined in the table below. Clinically significant deterioration includes: an absolute decline from baseline in FVC% predicted of ≥10% with a decline in DLCO of ≥15% from baseline, or an absolute decline from baseline in FVC% predicted of ≥5-9%, or clinically significant deterioration in other organ systems as assessed by the investigator.

[0482] DLCO = diffusing capacity of the lungs for carbon monoxide; FVC = forced vital capacity.

[0483] Other causes of decreased FV (i.e. respiratory infection) should be ruled out. If, in the Investigator's clinical judgment, well-founded doubts regarding the quality of the test and the subject's well-being justify the associated delay in the subject's care and increased risk to the subject, FVC / spirometry should be repeated to confirm prior to initiation of rescue medication.

[0484] Rescue medications permitted after week 28 due to clinically significant deterioration

[0485] [Table 22]

[0486] Efficacy variables Spirometry Spirometry, including FVC% predicted, will be assessed using equipment provided by the Sponsor. Spirometry should be performed only by experienced assessors, and unless not possible, the same assessor should complete the procedure on a given subject throughout the entire study period.

[0487] Spirometry should be performed according to the ATS / ERS 2019 guidelines [Graham et al., Am J Respir Crit Care Med. 2019;200:e70-e88]. The test is performed in triplicate (three curves are provided) and the best result is selected according to the guidelines. The best of three efforts is defined as the highest FVC obtained in any of the three puffs that meets the ATS / ERS criteria in a maximum of eight procedures.

[0488] Spirometry should be attempted at approximately the same time since baseline. On the day of the visit, subjects must refrain from strenuous exercise for at least 12 hours prior to pulmonary function testing. Smoking should be abstained throughout the entire day of the visit, and smoking is not permitted for 30 minutes prior to spirometry. Subjects should also avoid cold temperatures, environmental smoke, dust, or strong odors (e.g., perfume). If treated with bronchodilators, a 24-hour washout period for long-acting bronchodilators and an 8-hour washout period for short-acting bronchodilators must be observed prior to spirometry.

[0489] Spirometry results are transmitted electronically. Central review of spirometry is performed to ensure the quality of the primary endpoint measurements. Results are read by a central radiologist, confirmed at the clinical site, and data are transferred to a clinical database.

[0490] Grade the severity of breathing problems during the past week: 0: no breathing problems; 1: mild breathing problems; 2: moderate breathing problems; 3: severe breathing problems; 4: very severe breathing problems.

[0491] How has your breathing problem changed since the start of the study? +3: much better; 2+: a lot better; 1: a little better; 0: no change; -1: a little worse; -2: a lot worse; -3: a lot worse.

[0492] 6-minute Walk Test The 6MWT measures the distance a subject can walk briskly on a flat, hard surface in 6 minutes (6-minute walk distance). The test evaluates the global and integrated response of all systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular unit, and muscle metabolism. The 6MWT is performed according to the ATS guidelines for the 6MWT [Lancaster,Multidiscip Respir Med. 2018;13;13:45].

[0493] Titrable Oxygen Demand Oxygen titration was performed and oxygen saturation (Sp ,O2 Determine the minimum oxygen flow rate required to maintain a SpO2 concentration of 296%. Titration begins with the subject breathing room air. ,O2 is monitored for 1 min. ,O2 If the Sp is 296%, the test is terminated. ,O2 If Sp is less than 96%, use the following titration steps to reach the target Sp of 296%: ,O2 Increase the oxygen flow rate every minute to achieve: 1, 2, 3, 4, 5, 6, 8, 12, and 15 L min -1 .

[0494] Pulmonary Diffusing Capacity for Carbon Monoxide At the site, their own DLCO device is used, and if several devices are available at the site, all measurements are performed with the same DLCO device. Single-breath DLCO measurements are performed according to the ATS guidelines for DLCO measurement [Graham et al.,Eur Respir J.2017;49:16E00 16].

[0495] DLCO values ​​are adjusted for altitude, carboxyhemoglobin, and the most recent hemoglobin value. DLCO assessments should always be performed after FVC measurements and should always begin at approximately the same time each day.

[0496] Pulmonary high-resolution computed tomography Lung HRCT will be reviewed by a central radiologist and must be available prior to randomization. If an HRCT has been performed for clinical care in the 6 months prior to screening and has been reviewed and deemed acceptable, an HRCT does not need to be performed at screening.

[0497] Patient-reported outcome measures Living with IPF The L-IPF is a validated questionnaire that assesses symptoms, disease impact, and health-related quality of life in patients with IPF [Swigris et al., 2020]. The questionnaire was developed with input from the FDA and includes two modules: a 15-item symptom module (all 24-hour recall) with three domains (dyspnea, cough, and energy), and a 20-item impact module with 1-week recall. All items in both modules have response options in a 5-point (0-4) numeric rating scale format.

[0498] King's Brief Interstitial Lung Disease Questionnaire K-BILD is a self-administered health status questionnaire with 15 items and a 7-point Likert response scale developed and validated specifically for patients with IPF [Patel et al., 2012]. The questionnaire has three domains: Psychology, Dyspnea and Activity, and Chest Symptoms. K-BILD domain and total scores range from 0 to 100, with 100 representing the best health status. K-BILD scoring has been modified in recent years with the introduction of a logit transformation step. The minimal clinically important difference in the K-BILD total score (logit version) is a 5-unit change, as determined by both the anchor and distribution-based methods [Sinha et al., 2019].

[0499] Leicester Cough Questionnaire The LCQ is a patient-reported questionnaire assessing the impact of cough on quality of life. The questionnaire was originally developed for use in patients with idiopathic chronic cough and has since been validated for use in patients with bronchiectasis and chronic obstructive pulmonary disease [Birring et al.,Thorax. 2003;58:339-43].

[0500] The LCQ contains 19 items and takes 5-10 minutes to complete. Each item rates symptoms or symptom impact over the past 2 weeks on a 7-point Likert scale. Scores for the three domains (physical, psychological, and social) are calculated as the average of each domain (range: 1-7). A total score (range: 3-21) is also calculated by adding up these domain scores. Higher scores indicate better quality of life.

[0501] SF-12 Health Survey The SF-12 [Ware et al., Med Care. 1996;34:220-33] is a 12-item survey used to assess overall health-related quality of life. Items on the SF-12 are scored to generate a subject-perspective physical component score (PCS) and mental component score (MCS). The SF-12 explores eight domains of health outcomes including physical functioning, role physical, bodily pain, overall health, vitality, social functioning, role emotional, and mental health. The SF-12 is a shortened version of the SF-36 that has been validated for use in patients with IPF [Swigris et al., Respir Med. 2010;104:296-304; Tomioka et al., Intern Med. 2007;46:1533-42] and is one of four questionnaires used in IPF Prospective Outcomes (IPF-PRO), a prospective, observational US registry of patients with confirmed IPF that records patient-reported outcomes.

[0502] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are within the spirit and scope of this application and the scope of the appended claims.

Claims

1. 1. A composition comprising 2-(4-methoxy-3-(3-methylphenetoxy)benzamido)-2,3-dihydro-1H-indene-2-carboxylic acid (Compound I) or a pharmaceutically acceptable salt thereof for treating systemic sclerosis or a pulmonary disease in a subject in need thereof, wherein Compound I or a pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to at least about 300 mg / day of Compound I.

2. 2. The composition of claim 1, wherein Compound I is a crystalline form (Form 1) of Compound I and is characterized by having an X-ray powder diffraction (XRPD) pattern exhibiting peaks at 5.2±0.2° 2-θ, 9.0±0.2° 2-θ, 14.4±0.2° 2-θ, and 17.7±0.2° 2-θ, as measured using Cu(Kα) radiation.

3. 3. The composition of claim 2, wherein the crystalline form 1 of Compound I is substantially free of crystalline form 2 of Compound I.

4. 3. The composition of claim 2, wherein the crystalline form 1 of Compound I contains less than 1 wt. % of crystalline form 2 of Compound I.

5. Compound I was synthesized using an X-ray powder diffraction (XRPD) pattern showing the amorphous phase of Compound I and lack of crystallinity, and a solid substantially identical to that shown in FIG. １３ 10. The composition of claim 1, characterized by a carbon nuclear magnetic resonance (ssNMR) spectrum:

6. 2. The composition of claim 1, wherein the systemic sclerosis is selected from localized cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis without scleroderma.

7. The composition of claim 1 , wherein the systemic sclerosis is diffuse cutaneous systemic sclerosis.

8. The composition of claim 1 , wherein the systemic sclerosis is early diffuse cutaneous systemic sclerosis.

9. The composition of claim 6, wherein treatment with the composition results in an American College of Rheumatology-Composite Response Index in Systemic Sclerosis (CRISS) score of 0.60 or greater.

10. The composition described in claim 6, wherein treatment with the composition results in a reduction in skin fibrosis as measured by a change in modified Rodnan skin score (mRSS) of 5 or more.

11. The composition of claim 6, wherein treatment with the composition improves the Health Assessment Questionnaire-Disability Index (HAQ-DI) by 0.14 or more.

12. The composition of claim 1 , wherein the lung disease is pulmonary fibrosis.

13. 10. The composition of claim 1, wherein the pulmonary disease is an interstitial lung disease (ILD).

14. 2. The composition of claim 1, wherein the pulmonary disease is idiopathic interstitial pneumonia, connective tissue disease-associated interstitial lung disease (CTD-ILD), sarcoidosis, hypersensitivity pneumonitis, eosinophilic ILD, or familial pulmonary fibrosis.

15. 2. The composition of claim 1, wherein the lung disease is idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP), acute interstitial pneumonia (AIP), or lymphocytic interstitial pneumonia (LIP).

16. 2. The composition of claim 1, wherein the lung disease is idiopathic pulmonary fibrosis (IPF).

17. 2. The composition of claim 1, wherein the lung disease is chronic fibrotic interstitial lung disease (ILD).

18. 2. The composition of claim 1, wherein the pulmonary disease is a chronic fibrotic interstitial lung disease (ILD) with a progressive phenotype.

19. 2. The composition of claim 1, wherein the lung disease is a progressive phenotype with a usual interstitial pneumonia (UIP)-like high-resolution computed tomography (HRCT) fibrosis pattern.

20. The composition of claim 1, wherein the lung disease is systemic sclerosis-related interstitial lung disease (SSc-ILD).

21. 2. The composition of claim 1, wherein the pulmonary disease is systemic sclerosis-related interstitial lung disease (SSc-ILD) and treating the pulmonary disease comprises reducing the rate of decline in pulmonary function in a subject afflicted with SSc-ILD.

22. 10. The composition of claim 1, wherein treating the pulmonary disease comprises slowing the decline in lung function, reducing the frequency of exacerbations of the pulmonary disease, improving survival of a subject afflicted with the pulmonary disease, or a combination thereof.

23. 10. The method of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered for a period of at least about 24 consecutive weeks.

24. 10. The composition of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered for a period of at least about 36 weeks.

25. 10. The composition of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered for a period of at least about 52 weeks.

26. 2. The composition of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered orally.

27. 2. The composition of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered once a day at a dose equivalent to about 300 mg of Compound I.

28. 2. The composition of claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered in a dose equivalent to about 300 mg of Compound I twice daily, for a total daily dose equivalent to about 600 mg / day of Compound I.

29. The composition described in claim 1, characterized in that the composition is administered in combination with a cough suppressant, a corticosteroid, an immunosuppressant, N-acetylcysteine ​​(NAC), an anti-fibrotic therapeutic agent, or a combination thereof.

30. The composition of claim 1, wherein the composition is administered in combination with N-acetylcysteine, a corticosteroid, an immunosuppressant, pirfenidone, nintedanib, imatinib, a tyrosine kinase inhibitor, PBI-4050, recombinant pentraxin-2 / SAP (PRM-151), aerosol IFN-γ, a CTGF activity inhibitor, an LPA receptor antagonist, an autotaxin inhibitor, a galectin-3 inhibitor, a LOXL2 inhibitor, tipelukast, an integrin antagonist, a PI3K inhibitor, a JNK inhibitor, a ROCK inhibitor, an anti-IL-13 compound, a CCL2 antagonist, a CCR2 antagonist, an anti-CD20 compound, an anticoagulant, a collagen V treatment agent, an ASK1 inhibitor, or a combination thereof.

31. The composition described in claim 1, characterized in that the composition is administered in combination with nintedanib or a pharmaceutically acceptable salt thereof.

32. 32. The composition of claim 31, wherein nintedanib or a pharmaceutically acceptable salt thereof is administered at a daily dose equivalent to about 200 mg / day or about 300 mg / day of nintedanib.

33. 32. The composition of claim 31, wherein nintedanib or a pharmaceutically acceptable salt thereof is orally administered twice daily at a dose equivalent to about 150 mg, with each dose administered about 12 hours apart.

34. 32. The composition of claim 31, wherein nintedanib or a pharmaceutically acceptable salt thereof is orally administered twice daily at a dose equivalent to about 100 mg, with each daily dose administered about 12 hours apart.

35. The composition described in claim 1, characterized in that the composition is administered in combination with pirfenidone.

36. 36. The composition of claim 35, wherein pirfenidone is administered at a dose of about 801 mg / day to about 2403 mg / day.

37. 36. The composition of claim 35, wherein pirfenidone is administered at a dose of about 267 mg three times a day.

38. 36. The composition of claim 35, wherein pirfenidone is administered at a dose of about 534 mg three times a day.

39. 36. The composition of claim 35, wherein pirfenidone is administered at a dose of about 801 mg three times a day.

40. The composition of claim 1, wherein the composition is administered in the form of a solid pharmaceutical composition.

41. 41. The composition of claim 40, wherein the solid pharmaceutical composition is a tablet, pill, or capsule.

42. 41. The composition of claim 40, wherein the solid pharmaceutical composition is a tablet.

43. The composition of claim 1, wherein the composition is administered in the form of one or more tablets.

44. 44. The composition of claim 43, wherein each tablet contains from about 50 mg to about 300 mg of Compound I.

45. 44. The composition of claim 43, wherein each tablet contains from about 50 mg to about 150 mg of Compound I.

46. The composition of any one of claims 1 to 45, wherein the subject is an adult.

47. The composition of any one of claims 1 to 45, wherein the subject is an adult male.

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