LPA1 antagonists for treating interstitial lung disease

Abstract

The present disclosure relates to a method of treating interstitial lung disease by administering Compound A to a subject at one or more daily doses lower than the standard daily dose during a dose escalation treatment period, followed by escalating the dose to the standard daily dose of Compound A, wherein the standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 476,997, filed December 23, 2022, and U.S. Provisional Patent Application No. 63 / 519,723, filed August 15, 2023, each of which is incorporated by reference in its entirety.

[0002] The present disclosure relates to a method of treating interstitial lung disease by administering Compound A to a subject at one or more daily doses lower than the standard daily dose during a dose escalation treatment period, followed by escalating the dose to the standard daily dose of Compound A, wherein the standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Interstitial lung diseases (ILDs) are a heterogeneous group of lung diseases classified based on common clinical features, including scarring (fibrosis) and / or inflammation of the lung parenchyma, with various patterns of lung damage by imaging or histopathology. ILDs can arise from identifiable causes, such as underlying systemic autoimmune diseases (e.g., systemic sclerosis or rheumatoid arthritis), environmental exposures (e.g., asbestos or silica), or drug toxicity, but are often idiopathic in nature. Idiopathic pulmonary fibrosis (IPF), one of the more common and most devastating types of ILD, is a chronic, progressive, and typically fatal lung disease of unknown etiology characterized by worsening dyspnea, cough, and loss of lung function due to scarring in the lungs, and must have a pathological and radiographic pattern known as usual interstitial pneumonia (UIP) (Non-Patent Document 1). Besides IPF, some patients with other forms of ILD develop a progressive fibrosis phenotype characterized by respiratory symptoms, worsening lung function, progressive fibrosis on imaging, and premature death.

[0004] To date, two approved therapeutic agents, pirfenidone and nintedanib, significantly reduce the decline in lung function in patients with IPF, and both appear to have a modest effect on progression-free survival (Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). However, many patients progress despite treatment. Another treatment option is lung transplantation, which has been shown to improve mortality in carefully selected patients, but is not without complications (Non-Patent Document 5). Despite these advances, there remains a significant unmet need for safe, well-tolerated, and effective IPF therapies that improve lung function, delay disease progression, and reduce mortality.

[0005] Clinical and pathophysiological similarities between IPF and other progressive pulmonary fibrosis (PPF) have suggested that such disorders, regardless of etiology, share common pathobiological mechanisms, resulting in progressive pulmonary fibrosis and therefore may have similar therapeutic responses to IPF (Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8). Indeed, in the recently published INBUILD trial, patients with PPF of various etiologies were treated with nintedanib or placebo. Patients treated with nintedanib experienced slower progression of pulmonary fibrosis than patients receiving placebo, as demonstrated by a lower annual rate of decline in forced vital capacity (FVC) over the 52-week study period (Non-Patent Document 8). The absolute treatment effect in the PPF trial was similar in magnitude to that observed in the pivotal IMPULSIS trial, which led to the approval of nintedanib for the treatment of IPF. Furthermore, the IMPULSIS and INBUILD trials demonstrated that IPF and PPF patients had similar rates of FVC decline. Based on data from the INBUILD trial, health authorities have also approved nintedanib for patients with PPF. Nevertheless, many patients cannot tolerate nintedanib due to gastrointestinal side effects, and some patients may progress despite treatment with nintedanib, so there remains an unmet need for a well-tolerated and effective therapy for PPF (Non-Patent Document 8).

[0006] Overall, there is a high unmet need for effective and tolerable treatments for patients with IPF and non-IPF PPF who show disease progression. Such fibrotic diseases involve the activation of six LPA receptors (LPA 1~6 ), signaling through LPA1 is thought to be fundamental in the pathogenesis of fibrotic diseases.

[0007] Patent Document 1 (Patent Document 2) discloses specific antagonists of lysophosphatidic acid (LPA) receptors for use in the treatment of LPA-dependent or LPA-mediated conditions or diseases, such as fibrosis of various organs, including the lung.

[0008] The compound (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (hereinafter referred to as "Compound A") is described in Patent Document 1. [ka]

[0009] Compound A is a potent LPA1 antagonist in vitro (LPA1K in CHO cells overexpressing human LPA1). b = 6.9 nM, LPA1K in normal human lung fibroblasts b =5.9 nM). Compound A is currently in clinical development for the treatment of IPF and PF-ILD. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US Patent Application Publication No. 2017 / 0360759 [Patent Document 2] International Publication No. 2017 / 223016 Brochure [Non-patent literature]

[0011] [Non-Patent Document 1] Meltzer et al.,Orphanet J.Rare Dis.2008,3:8 [Non-patent document 2] Noble et al.,Lancet 2011,377(9779),1760-1769 [Non-patent document 3] King et al.,N.Engl.J.Med.2014,370(22),2083-2092 [Non-patent document 4] Richeldi et al.,New Engl J Med 2014,370(22),2071-2082 [Non-patent document 5] Kistler et al.,BMC Pulmonary Med.2014;14:139 [Non-patent document 6] Raghu et al.,Am.J.Respir.Crit.Care Med.2022,205,e18-e47 [Non-Patent Document 7] du Bois et al.,Am.J.Respir.Crit.Care Med.2012,186,712-715 [Non-patent document 8] Flaherty et al.,N.Engl.J.Med.2019,381(18),1718-1727 Summary of the Invention [Means for solving the problem]

[0012] The present disclosure provides methods of treating interstitial lung disease using LPA1 antagonists. [Brief explanation of the drawings]

[0013] [Figure 1] 1 shows the powder X-ray diffraction (PXRD) pattern of Form A. [Figure 2]1 shows a differential scanning calorimetry (DSC) thermogram of Form A. [Figure 3] 1 shows a thermogravimetric analysis (TGA) thermogram of Form A. [Figure 4] 1 shows the moisture sorption isotherm of Form A. [Figure 5] An overview of the phase 2 trial is shown below. [Figure 6] Figure 1 shows the percent change in ppFVC in patients treated with placebo or Compound A. [Figure 7] Figure 1 shows the change in FVC (mL) in patients treated with placebo or Compound A. [Figure 8] Absolute change from baseline in FVC (mL) in patients treated with placebo or Compound A is shown. [Figure 9] Figure 1 shows the percent change in ppFVC according to the use of background antifibrotic agents in patients treated with placebo or Compound A. [Figure 10] Figure 1 shows the change from baseline in ppFVC percentage (primary estimate) in PPF subjects treated with placebo or Compound A. [Figure 11] Figure 1 shows the change from baseline in FVC (mL) (primary estimate) in PPF subjects treated with placebo or Compound A. [Figure 12] Figure 1 shows the change from baseline in ppFVC percentage (primary estimate) in PPF subjects with UIP treated with placebo or Compound A. [Figure 13] Figure 1 shows the change from baseline in FVC (mL) (primary estimate) in PPF subjects without UIP treated with placebo or Compound A. [Figure 14] Figure 1 shows the percent change in ppFVC in PPF subjects with and without UIP treated with placebo or Compound A. [Figure 15] Figure 1 shows the change from baseline in ppFVC percentage (primary estimate) in placebo- and Compound A-treated PPF subjects taking antifibrotic agents. [Figure 16]Figure 1 shows the change from baseline in FVC (mL) (primary estimate) in PPF subjects taking antifibrotic agents treated with placebo or Compound A. DETAILED DESCRIPTION OF THE INVENTION

[0014] In some aspects, the disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to a subject in need thereof Compound A: [ka] or a pharmaceutically acceptable salt thereof to a subject at one or more daily doses lower than the standard daily dose during a dose escalation treatment period, followed by increasing the daily dose to the standard daily dose of Compound A, wherein the standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the dose escalation treatment period is completed within 21 days. In some embodiments, the dose escalation treatment period is completed within 14 days. In some embodiments, the dose escalation treatment period is completed within 10 days. In some embodiments, the dose escalation treatment period is completed within 7 days. In some embodiments, the dose escalation treatment period is completed within 5 days.

[0016] In some embodiments, the dose-escalation treatment period comprises an initial treatment period and a second treatment period. In some embodiments, the initial treatment period is completed within 7 days. In some embodiments, the initial treatment period is completed within 4 days. In some embodiments, the initial treatment period is completed within 3 days. In some embodiments, the initial treatment period is completed within 2 days. In some embodiments, the initial treatment period is completed within 1 day.

[0017] In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day.

[0018] In some embodiments, the dose escalation treatment period further comprises a third treatment period. In some embodiments, the third treatment period is completed within 7 days. In some embodiments, the fourth treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 2 days. In some embodiments, the third treatment period is completed within 1 day.

[0019] In some aspects, the disclosure provides a method of treating an interstitial lung disease in a subject in need thereof, the method comprising administering to the subject Compound A: [ka] at a daily dose lower than the standard daily dose during a first treatment period, followed by a daily dose higher than the first period but lower than the standard daily dose for a second treatment period, followed by increasing the dose to the standard daily dose, wherein the standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the first treatment period and the second treatment period are each independently completed within 7 days. In some embodiments, the first treatment period and the second treatment period are each independently completed within 4 days. In some embodiments, the first treatment period and the second treatment period are each independently completed within 3 days. In some embodiments, the first treatment period and the second treatment period are each independently completed within 2 days. In some embodiments, the first treatment period and the second treatment period are each independently completed within 1 day.

[0021] In some embodiments, increasing the dosage comprises administering a dosage at a lower daily dosage than the standard daily dosage for a third treatment period, followed by administering the standard daily dosage for a fourth treatment period. In some embodiments, the third treatment period is completed within seven days. In some embodiments, the fourth treatment period is completed within three days. In some embodiments, the third treatment period is completed within three days. In some embodiments, the third treatment period is completed within two days. In some embodiments, the third treatment period is completed within one day.

[0022] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered twice daily.

[0023] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

[0024] In some embodiments, the subject is treated with one or more additional therapies for interstitial lung disease. In some embodiments, the one or more additional therapies are pirfenidone. In some embodiments, the one or more additional therapies are nintedanib.

[0025] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered with food. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered without food.

[0026] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0027] In some embodiments, the standard daily dose of Compound A is about 120 mg twice daily or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, about 20 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered during the first treatment period. In some embodiments, about 10 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily is administered during the first treatment period. In some embodiments, about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered during the second treatment period. In some embodiments, about 30 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof twice daily is administered during the second treatment period.

[0028] In some embodiments, about 120 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered during the third treatment period.

[0029] In some embodiments, about 60 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily during the third treatment period.

[0030] In some embodiments, Compound A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å alpha=92.8±1.0° b=13.06±0.10Å beta=95.5±1.0° c=14.04±0.10Å gamma=93.0±1.0° Volume 1189(20)Å 3 Density (calculated value) 1.239g / cm 3 temperature room temperature and the measurement of the single crystal structure is at room temperature. b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2 and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2 and 27.8±0.2; e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an onset endotherm at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 The present invention includes crystalline forms characterized by at least one of the following:

[0031] In some embodiments, subjects experience a smaller decline in forced vital capacity (FVC) after a period of treatment compared to untreated subjects.

[0032] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after absolute % predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Respiratory-related hospitalization Lung transplants, and All-cause mortality is selected from.

[0033] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after a decline in absolute predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Pulmonary fibrosis-related hospitalization, and All-cause mortality is selected from.

[0034] In some embodiments, the subject experiences a smaller increase in cough domain score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects. In some embodiments, the subject experiences a smaller increase in dyspnea score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects.

[0035] In some embodiments, subjects experience a decrease in distance traveled compared to baseline as measured by the 6-minute walk test (6MWT) over the treatment period that is less than untreated subjects.

[0036] In some aspects, the present disclosure provides a method for treating interstitial lung disease in a subject in need thereof, comprising administering to a subject a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein Compound A is administered to a subject at a dose lower than the standard daily dose during an initial treatment period, and thereafter the dose is increased to the standard daily dose of Compound A, the standard daily dose of Compound A being about 240 mg / day. In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0037] In some embodiments, the disclosure provides a method of treating interstitial lung disease, the method comprising administering to a subject in need thereof about 240 mg of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, about 120 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily.

[0039] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

[0040] In some embodiments, the subject is simultaneously treated with one or more therapies for interstitial lung disease.In some embodiments, one or more pharmacological therapies are pirfenidone.In some embodiments, one or more pharmacological therapies are nintedanib.

[0041] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered with food. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered without food.

[0042] In some embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrosis is progressive pulmonary fibrosis (PPF).

[0043] In some embodiments, Compound A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å alpha=92.8±1.0° b=13.06±0.10Å beta=95.5±1.0° c=14.04±0.10Å gamma=93.0±1.0° Volume 1189(20)Å 3 Density (calculated value) 1.239g / cm 3 temperature room temperature and the measurement of the single crystal structure is at room temperature. b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more 2θ peaks selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more 2θ peaks selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2 and 27.8±0.2; e) A differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an onset endotherm at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3 The present invention includes crystalline forms characterized by at least one of the following:

[0044] In some embodiments, subjects experience a smaller decline in forced vital capacity (FVC) after a period of treatment compared to untreated subjects.

[0045] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after absolute % predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Respiratory hospitalization Lung transplants, and All-cause mortality is selected from.

[0046] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after a decline in absolute predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Pulmonary fibrosis-related hospitalization, and All-cause mortality is selected from.

[0047] In some embodiments, the subject experiences a smaller increase in cough domain score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects. In some embodiments, the subject experiences a smaller increase in dyspnea score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than untreated subjects.

[0048] In some embodiments, the disclosure provides a method for treating interstitial lung disease using about 240 mg / day of Compound A: [ka] or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the interstitial lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease is progressive pulmonary fibrosis (PPF).

[0050] The present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering to a subject in need thereof Compound A: [ka] or a pharmaceutically acceptable salt thereof to a subject at one or more daily doses lower than the standard daily dose during a dose escalation treatment period, followed by increasing the daily dose to the standard daily dose of Compound A, wherein the standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

[0051] In order that this description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout this detailed description.

[0052] I. Definition Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions set forth below. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed unless otherwise indicated. Furthermore, the use of the term "comprising" and other forms such as "include," "includes," and "comprised" is not intended to be limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0053] All measurements are subject to experimental error, which is within the scope of the present invention.

[0054] The term "about," when used throughout this specification and claims in connection with numerical values, indicates an interval of accuracy well known and accepted by those skilled in the art. Such interval of accuracy is ±10%.

[0055] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject being treated.

[0056] The terms "administration" and / or "administering" a compound or composition should be understood to mean providing a compound or composition described herein to one or more subjects.

[0057] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0058] The term "antagonist," as used herein, refers to a molecule, such as a compound, that reduces, inhibits, or prevents the action of another molecule or the activity of a receptor site. Antagonists include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists.

[0059] As used herein, the term "BP" refers to blood pressure, the term "SBP" refers to systolic blood pressure, and the term "DBP" refers to diastolic blood pressure.

[0060] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single subject, and is intended to include therapeutic regimens in which agents are administered by the same or different routes of administration or at the same or different times.

[0061] As used herein, the term "DSC" refers to differential scanning calorimetry. The term "TGA" refers to thermogravimetric analysis.

[0062] The term "effective amount" or "therapeutically effective amount," as used herein, refers to a sufficient quantity of an agent or compound being administered that will alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change to a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case can be determined using techniques such as a dose escalation study.

[0063] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0064] As used herein, "polymorph" refers to crystalline forms that have the same chemical structure but differ in the spatial arrangement of the molecules and / or ions that form the crystals.

[0065] The term "room temperature" generally means about 22°C, but can vary up to 7°C above or below.

[0066] The terms "subject" and "participant" are used interchangeably and include mammals. Examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, etc. In some embodiments, the mammal is a human.

[0067] As used herein, "substantially pure," when used in reference to a crystalline form, means a compound having a purity of greater than 90% by weight (including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight) based on the weight of the compound, including equal to about 100% by weight of the crystalline form of Compound A. The remaining material includes other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound A may be considered substantially pure in having a purity of greater than 90% by weight as measured by means currently known and generally accepted in the art, with the remaining less than 10% by weight of the material including other forms of Compound A and / or reaction and / or processing impurities.

[0068] When the term "substantially identical" is used in reference to a PXRD or XRPD pattern, it is understood that measurements of peak positions for a given crystalline form of the same compound will vary within a margin of error. It is also understood that the intensities of peaks may vary between different PXRD scans of the same crystalline form of the same compound. The relative intensities of different peaks are not meant to be limited to comparisons of different PXRD scans.

[0069] The terms "treat," "treating," or "treatment," as used herein, include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting the onset of a disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating conditions caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of a disease or condition.

[0070] II. Compound A Compound A is described in U.S. Patent Application Publication No. 2017 / 0360759. [ka]

[0071] In some embodiments, Compound A comprises a crystalline form "Form A." The crystalline forms of Compound A lose their crystalline structure upon dissolution and are therefore referred to as solutions of Compound A. However, all forms of the present invention can be used to prepare liquid formulations in which the drug is dissolved or suspended. Additionally, crystalline Form A of Compound A can be incorporated into solid formulations.

[0072] As used herein, a PXRD (X-ray powder diffraction) or XRPD (X-ray powder diffraction) pattern that "comprises" or has peaks selected from a particular set of peaks is intended to include PXRD patterns having additional peaks not included in the particular set of peaks. For example, a PXRD pattern that includes four or more peaks, preferably five or more peaks, at 2θ values ​​selected from A, B, C, D, E, F, G, and H is intended to have the following PXRD pattern: (a) four or more peaks, preferably five or more peaks, at 2θ values ​​selected from A, B, C, D, E, F, G, and H, and (b) zero or more peaks that are not peaks A, B, C, D, E, F, G, or H.

[0073] In some embodiments, Form A is a single crystalline structure having Crystal system, space group triclinic system, P1 Unit cell dimensions a=6.53±0.10Å alpha=92.8±1.0° b=13.06±0.10Å beta=95.5±1.0° c=14.04±0.10Å gamma=93.0±1.0° Volume 1189(20)Å 3 Density (calculated value) 1.239g / cm 3 temperature room temperature and the single crystal structure measurements are at room temperature.

[0074] In some embodiments, Form A has a powder X-ray diffraction pattern substantially the same as that shown in FIG.

[0075] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2. In some embodiments, Form A has a powder X-ray diffraction (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2. In some embodiments, Form A has a powder X-ray diffraction (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2.

[0076] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising five or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2.

[0077] In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2. In some embodiments, Form A has an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2. In some embodiments, Form A has a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising four or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 13.6±0.2, 15.7±0.2, and 21.6±0.2.

[0078] In some embodiments, Form A has a differential scanning calorimetry thermogram substantially similar to that shown in FIG.

[0079] In some embodiments, Form A has a differential scanning calorimetry thermogram with an endotherm onset at about 152°C.

[0080] In some embodiments, Form A has a thermogravimetric analysis thermogram substantially similar to that shown in FIG.

[0081] III. Composition In some embodiments, the disclosure provides a composition comprising Compound A. In some embodiments, the disclosure provides a composition comprising a crystalline form of Compound A. In some embodiments, the disclosure provides a composition comprising Form A of Compound A. As used herein, the term "composition" is intended to encompass a product comprising specific ingredients in specific amounts, as well as any product resulting directly or indirectly from combining specific ingredients in specific amounts. Such terms, with respect to pharmaceutical composition, are intended to encompass a product comprising one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant that the carrier, diluent, or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0082] In some embodiments, the compositions of the present disclosure are suitable for oral administration. These compositions may comprise solid, semi-solid, gel matrix, or liquid dosage forms suitable for oral administration. As used herein, oral administration includes buccal administration, lingual administration, and sublingual administration. Suitable oral dosage forms include, without limitation, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, syrups, or any combination thereof. In some embodiments, the compositions of the present disclosure suitable for oral administration are in the form of tablets or capsules. In some embodiments, the compounds of the present disclosure may be in the form of capsules. In some embodiments, the capsules may be immediate-release capsules.

[0083] The compositions of the present disclosure may be in the form of compressed tablets, molded tablets, chewable tablets, fast-dissolving tablets, multi-layer compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings can have the same general characteristics as sugar coatings. Multilayer compressed tablets are compressed tablets made by more than one compression cycle, including multilayer tablets and compression-coated or dry-coated tablets.

[0084] In some embodiments, the compounds of the present disclosure can be in the form of tablets. In some embodiments, the compounds of the present disclosure can be in the form of compressed tablets. In some embodiments, the compounds of the present disclosure can be in the form of film-coated compressed tablets. In some embodiments, the compositions of the present disclosure can be in the form of film-coated compressed tablets.

[0085] In some embodiments, the compositions of the present disclosure can be prepared by fluidized bed granulation, combining a compound of the present disclosure with one or more pharmaceutically acceptable carriers, vehicles, and / or excipients. In some embodiments, the compositions of the present disclosure can be prepared by a fluidized bed granulation process, which can provide tablet formulations with good flowability, good compressibility, rapid dissolution, good stability, and / or minimal to no cracking. In some embodiments, the fluidized bed granulation process can enable the preparation of formulations with high drug loadings, such as greater than 70% or greater than 75% of the compound of the present disclosure.

[0086] In some embodiments, the compositions of the present disclosure may be in the form of soft or hard capsules, which may be made of gelatin, methylcellulose, starch, and / or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), may contain two sections, one sliding over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells, plasticized by adding glycerin, sorbitol, or similar polyols. In some embodiments, soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including, but not limited to, methylparaben and propylparaben, sorbic acid, and combinations thereof. Liquid, semi-solid, and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions of propylene carbonate, vegetable oils, triglycerides, and combinations thereof. The capsules may also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0087] In some embodiments, compositions of the present disclosure may be in liquid or semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. In some embodiments, emulsions may be two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may include pharmaceutically acceptable acetals, such as di-(lower alkyl) acetals of lower alkyl aldehydes (the term "lower" refers to alkyls having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs may be clear, sweetened, hydroalcoholic solutions. Syrups may be concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. For a liquid dosage form, for example, the solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0088] In some aspects, compositions of the present disclosure for oral administration may also be provided in the form of liposomes, micelles, microspheres, or nanosystems.

[0089] In some embodiments, the compositions of the present disclosure can be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders can include, but are not limited to, diluents, sweeteners, humectants, and mixtures thereof. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders can include, but are not limited to, organic acids, carbon dioxide sources, and mixtures thereof.

[0090] Coloring and flavoring agents can be used in any of the above dosage forms. Additionally, flavoring and sweetening agents can be particularly useful in the formation of chewable tablets and lozenges.

[0091] In certain aspects, the compositions of the present disclosure may be formulated as immediate or modified release dosage forms, including delayed-, extended-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0092] The compositions of the present disclosure may include additional active ingredients that do not confer therapeutic or prophylactic efficacy on the composition and / or may include substances that enhance or supplement the efficacy of the composition.

[0093] In certain embodiments, Compound A or a pharmaceutically acceptable salt thereof can be administered orally. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof can be administered in a capsule. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof can be administered in a tablet.

[0094] Compound A is typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) suitably selected based on the intended form of administration, i.e., oral tablet, capsule, elixir, syrup, etc., and consistent with conventional pharmaceutical practice.

[0095] For example, when administered orally in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, sucrose, dextrose, dextrates, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, etc. When administered orally in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Moreover, when desired or necessary, suitable binders, lubricants, disintegrants, flow agents, flavoring agents, and coloring agents can also be incorporated into the mixture.

[0096] In still other embodiments, a film coating is provided around the Compound A formulation using standard coating procedures such as those described in Remingon's Pharmaceutical Sciences, 20th Edition (2000).

[0097] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 300 milligrams of active ingredient per dosage unit. In such pharmaceutical compositions, the active ingredient will typically be present in an amount of from about 0.5 to 95% by weight, based on the total weight of the composition. In some embodiments, dosage forms suitable for administration may contain from about 10 to about 240 milligrams of active ingredient per dosage unit. In some embodiments, dosage forms suitable for administration may contain about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, or 240 mg of active ingredient or an equivalent amount of a pharmaceutically acceptable salt thereof per dosage unit.

[0098] In some aspects, the present disclosure provides pharmaceutical compositions comprising Compound A described herein and at least one pharmaceutically acceptable carrier.

[0099] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration comprising: (a) about 5% by weight to about 40% by weight of compound A; (b) about 30% to about 90% by weight of a diluent or mixture of diluents; (c) about 0% to about 2% by weight of a superplasticizer; (d) about 2% to about 10% by weight of a disintegrant, and (e) about 0.25% to about 4% by weight of a lubricant.

[0100] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0101] In some aspects, the present disclosure provides a pharmaceutical formulation for oral administration comprising: (a) about 10% by weight to about 30% by weight of compound A; (b) about 40% to about 85% by weight of a diluent or mixture of diluents; (c) about 0% to about 2% by weight of a superplasticizer; (d) about 2% to about 10% by weight of a disintegrant, and (e) about 0.25% to about 4% by weight of a lubricant.

[0102] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0103] In some aspects, the diluents described herein are selected from lactose, sucrose, dextrose, dextrates, glucose, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, methylcellulose, microcrystalline cellulose, microcellulose, talc, and combinations thereof. In some aspects, the diluent or mixture of diluents is selected from microcrystalline cellulose and anhydrous lactose.

[0104] As used herein, the term "flow agent" refers to a substance that, when added to a powder, improves the flowability of the powder, such as by reducing interparticle friction. In some embodiments, the flow agent described herein is selected from silica, silicon dioxide, CAB-O-SILM-SP, AEROSIL, talc, starch, magnesium aluminum silicate, and combinations thereof. In some embodiments, the flow agent is silicon dioxide.

[0105] In some embodiments, the disintegrant described herein is selected from natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clays, gums, and combinations thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0106] In some aspects, the surfactant described herein is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide, propylene oxide, and combinations thereof. In some aspects, the surfactant is sodium lauryl sulfate.

[0107] In some aspects, the lubricant described herein is selected from stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, magnesium stearate, zinc stearate, waxes, and combinations thereof, hi some aspects, the lubricant is magnesium stearate.

[0108] In some aspects, provided herein is a pharmaceutical formulation for oral administration comprising: (a) about 5% by weight to about 40% by weight of compound A; (b) about 15% to about 70% by weight of microcrystalline cellulose and about 15% to about 70% by weight of anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium, and (e) about 0.25% to about 1.5% by weight of magnesium stearate.

[0109] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet.

[0110] In some aspects, provided herein is a pharmaceutical formulation for oral administration comprising: (a) about 10% by weight to about 30% by weight of compound A; (b) about 25% to about 70% by weight of microcrystalline cellulose and about 25% to about 70% by weight of anhydrous lactose; (c) about 0% to about 2% by weight of silicon dioxide; (d) about 2% to about 6% by weight of croscarmellose sodium, and (e) about 0.25% to about 1.5% by weight of magnesium stearate.

[0111] In some embodiments, Compound A of the pharmaceutical formulation comprises crystalline Form A. In some embodiments, the pharmaceutical formulation for oral administration is a tablet. In some embodiments, the tablet can be prepared using the ingredients provided in Tables 1 and / or 2.

[0112] [Table 1]

[0113] [Table 2]

[0114] In some embodiments, pharmaceutical compositions for oral administration may be preformed by direct compression or granulation (dry, wet, or melt granulation).

[0115] IV. Treatment method The present disclosure provides a method for treating interstitial lung disease by administering Compound A, an LPA1 antagonist. Lysophospholipids are membrane-derived bioactive lipid mediators. Examples of lysophospholipids include, but are not limited to, lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate (S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine (SPC). Lysophospholipids affect fundamental cellular functions, such as cell proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes, such as neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis.

[0116] LPA acts through a set of specific G protein-coupled receptors (GPCRs) in an autocrine and paracrine manner. Binding of LPA to its cognate GPCRs (LPA1, LPA2, LPA3, LPA4, LPA5, and LPA6) activates intracellular signaling pathways, resulting in a variety of biological responses.

[0117] Lysophospholipids, such as LPA, are a quantitatively minor class of lipids compared to their major counterparts, phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPA plays a role as a biological effector molecule, exerting a wide range of cellular effects, including, but not limited to, effects on various physiological functions, such as blood pressure, platelet activation, and smooth muscle contraction, as well as cell growth, cell rounding, neurite retraction, actin stress fiber formation, and cell migration. The effects of LPA are primarily receptor-mediated.

[0118] Activation of LPA receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) by LPA mediates various downstream signaling cascades. These include mitogen-activated protein kinase (MAPK) activation, adenylate cyclase (AC) inhibition / activation, phospholipase C (PLC) activation / Ca 2+These include, but are not limited to, mobilization, arachidonic acid release, Akt / PKB activation and activation of small GTPases, Rho, ROCK, Rac and Ras. Other pathways affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42 / GTP-binding protein (Cdc42), proto-oncogene serine / threonine protein kinase Raf (c-RAF), proto-oncogene tyrosine protein kinase Src (c-src), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchange factors (GEFs), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminal kinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB (NF-kB), N-methyl-D-aspartate (NMDA) receptor activation, phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), protein kinase C (PKC), and ras-related C3 botulinum toxin substrate 1 (RAC1). The actual pathway and realized endpoint depend on various variables, such as receptor usage, cell type, receptor or signaling protein expression level, and LPA concentration. Nearly all mammalian cells, tissues, and organs co-express several LPA receptor subtypes, indicating that LPA receptor signaling is cooperative. LPA1, LPA2, and LPA3 share high amino acid sequence similarity.

[0119] LPA is produced by activated platelets, activated adipocytes, neurons, and other cell types. Serum LPA is produced by multiple enzymatic pathways involving lysophospholipase D (lysoPLD), such as monoacylglycerol kinase, phospholipase A1, secretory phospholipase A2, and autotaxin. Several enzymes are involved in LPA degradation: lysophospholipase, lipid phosphate phosphatase, and LPA acyltransferases such as endophilin. The LPA concentration in human serum is estimated to be 1–5 μM. Serum LPA binds to albumin, low-density lipoprotein, or other proteins, which may protect LPA from rapid degradation. Naturally occurring LPA species have different acyl chain lengths and saturations, including 1-palmitoyl (16:0), 1-palmitoleoyl (16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and 1-arachidonyl (20:4) LPA. A quantitatively small number of alkyl LPAs have similar biological activity to acyl LPAs, and different LPA species activate LPA receptor subtypes with varying efficiencies.

[0120] LPA1 (previously called VZG-1 / EDG-2 / mrec1.3) binds three types of G proteins: G i / o , G q and G 12 / 13 Through activation of these G proteins, LPA induces various cellular responses via LPA1, including but not limited to: cell proliferation, serum response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation, adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, and Ca 2+ Recruitment, Akt activation and Rho activation.

[0121] Widespread expression of LPA1 has been observed in adult mice, with distinct localization in the testes, brain, heart, lungs, small intestine, stomach, spleen, thymus, and skeletal muscle. Similarly, human tissues also express LPA1, with localization in the brain, heart, lungs, placenta, colon, small intestine, prostate, testes, ovaries, pancreas, spleen, kidneys, skeletal muscle, and thymus.

[0122] The term "LPA-dependent," as used herein, refers to a condition or disorder that does not occur, or does not occur to the same extent, in the absence of LPA.

[0123] The term "LPA-mediated," as used herein, refers to conditions or disorders that can occur in the absence of LPA, but can occur in the presence of LPA.

[0124] As used herein, the terms "fibrosis" and "fibrotic disease" refer to a condition associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, skin, cornea, retina, musculoskeletal and gastrointestinal tract.

[0125] Examples of diseases, disorders, or conditions associated with fibrosis include, but are not limited to, pulmonary diseases associated with fibrosis, such as rheumatoid arthritis, scleroderma, lupus, idiopathic interstitial pneumonia, radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), chronic asthma, silicosis, asbestos-induced pulmonary or pleural fibrosis, acute lung injury and acute respiratory distress (bacterial pneumonia-induced, trauma-induced, viral pneumonia-induced, ventilator-induced, non-pulmonary sepsis-induced, and aspiration-induced), e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic inflammatory diseases; chronic nephropathy associated with injury / fibrosis (renal fibrosis), such as lupus and scleroderma, diabetes, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy, hypertension, allograft, and Alport; intestinal fibrosis, such as scleroderma and radiation-induced intestinal fibrosis; liver fibrosis, such as cirrhosis, alcohol-induced liver fibrosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infectious or virally induced liver fibrosis (e.g., chronic HCV infection), and autoimmune hepatitis; radiation-induced head and neck fibrosis; corneal scarring, such as LASIK (laser-assisted in situ keratomileusis), corneal transplantation, and trabeculectomy; burn-induced or surgical hypertrophic scars and keloids; and other fibrotic diseases, such as sarcoidosis, scleroderma, spinal cord injury / fibrosis, myelofibrosis, vascular restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

[0126] Other diseases, disorders, or conditions in which the LPA1 receptor may be associated include atherosclerosis, thrombosis, heart disease, vasculitis, scar tissue formation, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, intestinal adhesions, bladder fibrosis and cystitis, nasal fibrosis, sinusitis, neutrophil-mediated inflammation and fibroblast-mediated fibrosis, skin disorders such as proliferative or inflammatory disorders of the skin, e.g., atopic dermatitis, bullous disorders, collagen fibrosis, psoriasis, and the like. eczema, psoriasis lesions, dermatitis, contact dermatitis, eczema, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjögren-Larsson syndrome and urticaria, etc. Respiratory diseases such as asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, etc., capneic hyperventilation, childhood-onset asthma , adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, e.g., chronic bronchitis or emphysema, pulmonary hypertension, interstitial pulmonary fibrosis and / or airway inflammation, and cystic fibrosis, and hypoxia, and inflammatory / immune disorders, e.g., psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle diseases, allergic rhinitis, vaginitis, interstitial bladder disease, These include cystitis, scleroderma, eczema, allo- or xenotransplant (organ, bone marrow, stem cell and other cell and tissue) graft rejection, graft versus host disease, lupus erythematosus, inflammatory diseases, type 1 diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, and atopic dermatitis.

[0127] In certain aspects, the present disclosure provides a method of treating interstitial lung disease in a subject in need thereof, the method comprising administering Compound A or a pharmaceutically acceptable salt thereof to the subject at one or more daily doses lower than the standard daily dose during a dose-escalation treatment period, and then increasing the daily dose to the standard daily dose. In some aspects, the term "dose-escalation treatment period" refers to a period during which Compound A or a pharmaceutically acceptable salt thereof is administered at one or more daily doses lower than the standard daily dose. In certain aspects, the dose-escalation treatment period is completed within a specified number of days. In certain aspects, as used herein, "a dose-escalation treatment period is completed within X days" (where X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof at a daily dose lower than the standard daily dose on day 1 of the dose-escalation period, and is administered the standard daily dose of Compound A or a pharmaceutically acceptable salt thereof on or before day X+1. For example, if the dose escalation treatment period is described as being completed within 21 days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof at a daily dose that is lower than the standard daily dose on day 1 of the dose escalation treatment period, and will be administered the standard daily dose of Compound A or a pharmaceutically acceptable salt thereof on or before day 22.

[0128] In certain aspects of the present disclosure, the dose escalation treatment period is completed within 21 days. In some aspects, the dose escalation treatment period is completed within 14 days. In some aspects, the dose escalation treatment period is completed within 10 days. In some aspects, the dose escalation treatment period is completed within 7 days. In some aspects, the dose escalation treatment period is completed within 5 days. In some aspects, the dose escalation treatment period is completed within 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 days.

[0129] In certain embodiments, the methods described herein include an initial treatment period. In some embodiments, the dose-escalation treatment periods described herein include an initial treatment period in which a subject is administered a first daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose. In certain embodiments, the initial treatment period is completed within a specified number of days. In certain embodiments, as used herein, "the initial treatment period is completed within X days" (X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof at a daily dose lower than the standard daily dose on day 1 of the initial treatment period, and on or before day X+1, is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose of the LPA1 antagonist but higher than the daily dose administered during the initial treatment period. For example, if the initial treatment period is described as being completed within 7 days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof at a daily dose lower than the standard daily dose on day 1 of the initial treatment period, and will be administered Compound A or a pharmaceutically acceptable salt thereof at a daily dose lower than the standard daily dose but higher than the daily dose administered during the initial period on or before day 7.

[0130] In some embodiments, the initial treatment period is completed within 7 days. In some embodiments, the initial treatment period is completed within 4 days. In some embodiments, the initial treatment period is completed within 3 days. In some embodiments, the initial treatment period is completed within 2 days. In some embodiments, the initial treatment period is completed within 1 day. In some embodiments, the initial treatment period is completed within 7, 6, 5, 4, 3, 2, or 1 day.

[0131] In certain embodiments, the methods described herein include a second treatment period. In some embodiments, the dose-escalation treatment period includes a second treatment period, in which the subject is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose but higher than the daily dose administered during the first treatment period. In certain embodiments, the second treatment period is completed within a specified number of days. In certain embodiments, as used herein, "the second treatment period is completed within X days" (X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the second treatment period at a daily dose that is higher than the daily dose administered during the first treatment period but lower than the standard daily dose, and is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is higher than the daily dose administered during the second treatment period on or before day X+1. For example, if the second treatment period is described as being completed within 7 days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof on day 1 at a daily dose higher than the daily dose administered during the first treatment period but lower than the standard daily dose, and will be administered Compound A or a pharmaceutically acceptable salt thereof on or before day 7 at a daily dose higher than the daily dose administered during the second treatment period.

[0132] In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day. In some embodiments, the second treatment period is completed within 7, 6, 5, 4, 3, 2, or 1 day.

[0133] In some embodiments, the dose-escalation treatment period includes a third treatment period, in which the subject is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose but higher than the daily dose administered during the second treatment period. In certain embodiments, the third treatment period is completed within a specified number of days. In certain embodiments, as used herein, "the third treatment period is completed within X days" (X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the third treatment period at a daily dose that is higher than the daily dose administered during the second treatment period but lower than the standard daily dose, and is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is higher than the daily dose administered during the third treatment period on or before day X+1. For example, if the third treatment period is described as being completed within seven days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the third treatment period at a daily dose higher than the daily dose administered during the second treatment period but lower than the standard daily dose, and will be administered Compound A or a pharmaceutically acceptable salt thereof on or before day 7 at a daily dose higher than the daily dose administered during the third treatment period.

[0134] In some embodiments, the third treatment period is completed within 7 days. In some embodiments, the fourth treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 2 days. In some embodiments, the third treatment period is completed within 1 day. In some embodiments, the third treatment period is completed within 7, 6, 5, 4, 3, 2, or 1 day.

[0135] In some embodiments, the dose-escalation treatment period includes a fourth treatment period, in which the subject is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose but higher than the daily dose administered during the third treatment period. In certain embodiments, the fourth treatment period is completed within a specified number of days. In certain embodiments, as used herein, "the fourth treatment period is completed within X days" (X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the fourth treatment period at a daily dose that is higher than the daily dose administered during the third treatment period but lower than the standard daily dose, and is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is higher than the daily dose administered during the fourth treatment period on or before day X+1. For example, if the fourth treatment period is described as being completed within seven days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the fourth treatment period at a daily dose higher than the daily dose administered during the third treatment period, but lower than the standard daily dose, and will be administered Compound A or a pharmaceutically acceptable salt thereof on or before day 7 at a daily dose higher than the daily dose administered during the fourth treatment period.

[0136] In some embodiments, the fourth treatment period within a dose escalation period is completed within 7 days. In some embodiments, the fourth treatment period within a dose escalation period is completed within 4 days. In some embodiments, the fourth treatment period within a dose escalation period is completed within 3 days. In some embodiments, the fourth treatment period within a dose escalation period is completed within 2 days. In some embodiments, the fourth treatment period within a dose escalation period is completed within 1 day. In some embodiments, the fourth treatment period within a dose escalation period is completed within 7, 6, 5, 4, 3, 2, or 1 day.

[0137] In some embodiments, the dose-escalation treatment period includes a fifth treatment period, in which the subject is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is lower than the standard daily dose but higher than the daily dose administered during the fourth treatment period. In certain embodiments, the fifth treatment period is completed within a specified number of days. In certain embodiments, as used herein, "the fifth treatment period is completed within X days" (X is an integer) means that the subject is administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the fifth treatment period at a daily dose that is higher than the daily dose administered during the fourth treatment period but lower than the standard daily dose, and is administered a daily dose of Compound A or a pharmaceutically acceptable salt thereof that is higher than the daily dose administered during the fifth treatment period on or before day X+1. For example, if the fifth treatment period is described as being completed within seven days, the subject will be administered Compound A or a pharmaceutically acceptable salt thereof on day 1 of the fifth treatment period at a daily dose that is higher than the daily dose administered during the fourth treatment period but lower than the standard daily dose, and will be administered Compound A or a pharmaceutically acceptable salt thereof on or before day 7 at a daily dose that is higher than the daily dose administered during the fifth treatment period.

[0138] In some embodiments, the fifth treatment period is completed within 7 days. In some embodiments, the fifth treatment period is completed within 4 days. In some embodiments, the fifth treatment period is completed within 3 days. In some embodiments, the fifth treatment period is completed within 2 days. In some embodiments, the fifth treatment period is completed within 1 day. In some embodiments, the fifth treatment period is completed within 7, 6, 5, 4, 3, 2, or 1 day.

[0139] Currently, there are two approved therapeutic agents for interstitial lung disease: nintedanib and perfenidone, but several compounds are currently under development.In certain embodiments of the present disclosure, the subject receiving an LPA1 antagonist is receiving one or more concurrent treatments for interstitial lung disease.In some embodiments, one or more treatments are selected from nintedanib and perfenidone.

[0140] In some embodiments, the subject is administered the LPA1 antagonist with food. In some embodiments, the subject is administered the LPA1 antagonist without food.

[0141] In some embodiments, subjects administered an LPA1 antagonist experience slower disease progression than untreated subjects. In some embodiments, disease progression is measured by a decrease in the subject's forced vital capacity (FVC). In some embodiments, subjects treated with an LPA1 antagonist experience a smaller decrease in forced vital capacity (FVC) after a treatment period compared to untreated subjects. FVC is the amount of air that can be forcibly exhaled from a subject's lungs after the subject has inhaled as deeply as possible. FVC is typically measured using a spirometry test, which involves placing a special mask on the subject's face and having the subject inhale and exhale as forcefully as possible, while measurements are collected. The assessment is typically performed according to a manual provided by a central vendor. In some embodiments, the subject is seated in a chair and asked to breathe comfortably. A clip is placed on the subject's nose, and the subject tightly seals the spirometer tube with their lips, inhales as deeply as possible, and exhales as forcefully as possible into the spirometer tube. In some embodiments, spirometry testing is performed at approximately the same time (+ / - 2 hours) prior to the morning dose at all visits where spirometry is performed.

[0142] In some embodiments, disease progression is measured by the subject's diffusing capacity for carbon monoxide (DLCO). DLCO is a measure of the rate at which oxygen passes from the alveoli into the blood. This test typically involves measuring the partial pressure difference between inhaled and exhaled carbon monoxide, demonstrating capillary gas absorption that is less dependent on cardiac output, relying on the strong affinity and large absorption capacity of red blood cells for carbon monoxide.

[0143] In general, the single-breath diffusing capacity test is the most common method for determining DLCO. Typically, the test is performed by having the subject exhale as much air as possible, leaving only the remaining volume of air in the lungs. The subject then rapidly and completely inhales the test gas mixture, reaching as close to total lung capacity as possible. The test gas mixture typically contains a small amount of carbon monoxide (usually 0.3%) and a tracer gas (helium or methane) that distributes freely throughout the alveolar space but does not cross the alveolar-capillary membrane. The test gas is held in the lungs for approximately 10 seconds, during which time carbon monoxide (but not the tracer gas) continuously moves from the alveoli into the blood. The subject then exhales into an analysis tube. By analyzing the concentrations of carbon monoxide and inert gases in the inspired and expired gases, the single-breath diffusing capacity of the lung for carbon monoxide (DLCO SB) can be calculated.

[0144] In some embodiments, disease progression can be measured by HRCT. IPF is a specific form of chronic progressive fibrotic interstitial pneumonia of unknown etiology, limited to the lungs, and is associated with the histopathological and / or radiological patterns of UIP. The hallmark pathological feature of UIP is a heterogeneous, variegated appearance with alternating areas of healthy lung, interstitial inflammation, fibrosis, and honeycombing, with fibrosis predominating over inflammation. Characteristic HRCT findings of IPF consist of symmetric bilateral plexiform structures, architectural distortion, and honeycombing, primarily involving the subpleural lung regions and lower lobes. As IPF progresses, honeycombing becomes more pronounced.

[0145] Although identification of UIP on surgical lung biopsy has been used for diagnosis, typical clinical and HRCT features are sufficient for a definitive diagnosis and may eliminate the need for surgical lung biopsy. Therefore, HRCT evaluation has been adopted as an important diagnostic criterion in the 2018 ATS / ERS / JRS / ALAT Clinical Practice Guidelines. The degree of reticulation and honeycombing on HRCT findings is considered to be an important independent predictor of mortality in patients with IPF. HRCT has been applied in multiple clinical trials of pulmonary fibrosis for drug development, serving as an inclusion criterion, a predictive marker of positive treatment response, and a readout of efficacy.

[0146] A computer-aided diagnosis (CAD) score, which quantifies pulmonary fibrosis as the percentage of reticular pattern involvement based on texture measurements from HRCT, has been developed and validated as a measure of quantitative pulmonary fibrosis (QLF) and a potential surrogate imaging marker. Computer-aided diagnosis scores for QLF have been successfully applied as outcome measures for testing treatment efficacy in ILD trials. Compared with visual assessment, CAD scores have been shown to improve objectivity, sensitivity, and reproducibility in measuring quantitative changes in lung characteristics.

[0147] In some embodiments, HRCT may be performed on study participants in the Phase 3 studies described herein during the screening period, at Week 52, and annually thereafter. To ensure comparability, the same scans, equipment, methods, and techniques used during the baseline HRCT scan may be used for the follow-up HRCT scan (at Week 52). In some embodiments, the screening HRCT scan may be performed using a low-dose protocol, with reconstructions at 1-1.5 mm intervals at the total lung volume and residual volume without contrast administration. In some embodiments, HRCT may be performed at the total lung volume at Week 52 and annually thereafter. Residual volume HRCT is optional at Week 52 and annually thereafter. For efficacy assessment, HRCT images from both the screening period and the follow-up scan (at Week 52) may be analyzed with a central blinded review.

[0148] HRCT analysis focuses on visual and CAD scores for regional pulmonary fibrosis assessment. Changes in pulmonary fibrosis scores from HRCT during the screening period are used to assess treatment response. In some embodiments, correlation of HRCT data with other efficacy readings and biomarker data can be performed, if applicable.

[0149] In some embodiments, disease progression can be measured by the time it takes for a subject to experience a disease progression event. In some embodiments, subjects administered an LPA1 antagonist have a longer time to the first disease progression event after a treatment period than untreated subjects. In some embodiments, the first disease progression event is an absolute percentage predicted forced vital capacity (ppFVC) of 10% or more from baseline. An absolute or relative decline in predicted FVC% of 10% or more is associated with mortality. In some embodiments, subjects treated with Compound A have a longer time to reach an absolute percentage predicted forced vital capacity (ppFVC) of 10% or more from baseline than untreated subjects.

[0150] In some embodiments, the first disease progression event is an acute exacerbation (e.g., a sudden worsening) of the subject's pulmonary fibrosis. In some embodiments, subjects treated with Compound A experience a longer time to an acute exacerbation of pulmonary fibrosis than untreated subjects.

[0151] In some embodiments, the first disease progression event is a respiratory hospitalization. In some embodiments, subjects treated with Compound A have a longer time to respiratory hospitalization than untreated subjects.

[0152] In some embodiments, the first disease progression event is lung transplantation. In some embodiments, subjects treated with an LPA1 antagonist have a longer time to lung transplantation than untreated subjects.

[0153] In some embodiments, the first disease progression event is death. In some embodiments, subjects treated with an LPA1 antagonist experience a longer time to death from all causes than untreated subjects.

[0154] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after absolute % predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, respiratory hospitalization, Lung transplants, and All-cause mortality is selected from.

[0155] In some embodiments, subjects experience a longer time to first disease progression event after a period of treatment than untreated subjects, and the first disease progression event occurs after a decline in absolute predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Pulmonary fibrosis-related hospitalization, and All-cause mortality is selected from.

[0156] In some embodiments, subjects in the Phase 3 trials described herein may be required to complete clinical outcome assessment (5L) measures, including the Pulmonary Fibrosis Living Questionnaire (L-PF), EQ-5D-CoA, and perform a 6-minute walk test (6MWT) at visits at Day 1 (baseline), Week 28, and Week 52. The L-PF questionnaire assesses symptoms and quality of life in patients with fibrotic interstitial lung disease (ILDS). Its dyspnea and cough domains are based on item responses over a 24-hour period and have a score range of 0 to 100, with higher scores indicating greater symptom severity (see, e.g., Swigris JJ, et al. BMJ Open Resp Res 2022;9:e001167. doi:10.1136 / bmjresp-2021-001167). In some embodiments, disease progression may be measured by change in score on the L-PF questionnaire.

[0157] The EQ-5D-5L is a standardized instrument used to measure self-reported general health status. This instrument has two components: a descriptive scale and a visual analog scale (VAS). The descriptive scale is composed of five dimensions: exercise, self-care, daily activities, pain / discomfort, and anxiety / depression. Each dimension has five levels, reflecting no problems, mild problems, moderate problems, severe problems, and extreme problems. A no-problem perspective is referred to as level 1, and an extreme problem perspective as level 5. Thus, the vectors 11111 and 55555 represent the best and worst health states, respectively. Collectively, this instrument describes 3,125 different health states. Individual responses to the EQ-5D-5L narrative system can be weighted empirically to generate a utility index using a flexible copula-based model developed by Hernandez-Alava and Pudney, a system of ordinal regression with a flexible copula mixture residual distribution, or a model recommended by the National Institute for Health and Care Excellence during data analysis. EQ-5D-5L value sets have been derived for the UK, the US, France, Germany, Spain, Europe, and several other countries. The EQ-5D-5L VAS allows participants to rate their current health status on a 0-100 scale ranging from "worst imaginable health" to "best imaginable health." The minimum amount of significant change is a 7-point change in the EQ-5D-5L VAS score, and a utility index of 0.08 is used, as recommended in the literature, for within-group, within-person, and between-group differences. The EQ-5D-5L uses a "today" recall period.

[0158] The 6MWT is a submaximal exercise test used to assess aerobic capacity and endurance. Before starting the test, participants should be informed that the goal is to walk as far as possible in 6 minutes. The test should be conducted on a hard, flat surface, such as a hallway. If participants become short of breath or fatigue, they may slow down, stop, or rest as needed. Participants may lean against a wall or use a mobility aid during breaks, but they must resume walking as soon as possible. The remaining time should be communicated to participants every minute and 15 seconds before the end of the test. At the end of 6 minutes, participants are instructed to stop, and the distance traveled should be measured and recorded on the eCRF. For patients with IPF, the threshold for clinically meaningful change in 6MWT results has been estimated to be in the range of 24 to 45 meters, with a more recent estimate of 21.7 meters for patients with IPF. The 6MWT should be administered after a spirometry assessment and, if possible, after an eCOA. Further details of the 6MWT assessment and the associated oxygen titration walk test are provided in the Guidance Manual for Performing the 6MWT.

[0159] An electronic diary device will be available to subjects in the Phase 3 study described herein at screening, and subjects will be trained on using the eCOA device to complete daily PRO assessments. Each day from day -14 through day -1, subjects will complete the L-PF cough and dyspnea daily questionnaire for 14 consecutive days (2 weeks) prior to the day 1 visit. Subjects will also complete the Patient Global Impression of Pulmonary Fibrosis Symptom Severity (PGI-S) cough and dyspnea questionnaires using the eCOA device on days -8 and -1.

[0160] On Day 1, eligible subjects return to the site with their eCOA device. Subjects will complete the L-PF Fatigue and Impact domain items, Cough NRS (Cough Severity Numeric Rating Scale, 11-point scale, 0-10), and EQ-5D-5L questionnaire on the eCOA device, whenever possible, before receiving any other procedures and before having any meaningful discussions about the study or IMP with study site staff. Subjects will complete PGI-S and PGI-C assessments for shortness of breath (dyspnea), cough, and overall disease symptoms on the eCOA device the day before visits at Weeks 16, 28, 40, and 52.

[0161] Additionally, all subjects in the Phase 3 trials described herein will be asked to perform an oxygen titration test only at screening. The oxygen levels established at screening should be used for the 6MWT test at screening and the 28- and 52-week visits. COA measurements other than the 6MWT (including the oxygen titration walk test) will be performed electronically, and responses entered by study participants into the source record cannot be overwritten by site staff or investigators. If possible, eCOA measurements should be performed using an electronic device before other study-related procedures and before any meaningful discussion with study site staff about the study or IMP. If a participant refuses to complete all or part of the questionnaire, this will be recorded. If exceptional circumstances make it impossible to continue measurements using the planned method, an alternative implementation method may be necessary after consultation with the sponsor.

[0162] In some embodiments, subjects administered Compound A experience a smaller increase in cough domain score as determined by the Lung Fibrosis Life (L-PF) questionnaire over the treatment period than untreated subjects. In some embodiments, subjects experience a smaller increase in dyspnea score as determined by the Lung Fibrosis Life (L-PF) questionnaire over the treatment period than untreated subjects. The L-PF is a multidimensional measure of health-related quality of life for patients with pulmonary fibrosis. The L-PF was adapted from the Idiopathic Pulmonary Fibrosis Patient Questionnaire (L-IPF), which was developed from the previous "Tool for Assessing Quality of Life in IPF." The L-PF is currently undergoing review through the Food and Drug Administration Drug Development Tool (DDT) certification process (DDT COA #000027). The L-PF was adapted from the L-IPF by removing the word "idiopathic" from the L-IPF title and the patient-completed instructions for the L-IPF measurement. This adaptation allows the same questionnaire to be used in IPF and PPF patient populations to assess the symptoms and impact of progressive fibrosis. The L-PF conceptual framework consists of two modules: disease symptoms and impact. The symptom module is measured using a 24-hour recall period and is composed of three domains: shortness of breath (dyspnea), cough, and fatigue. The impact module measures activities of daily living, including physical and mental health, sleep, and social aspects, using a 7-day recall period. Scores are assigned for each symptom domain and for the impact module on a 0-100 scale, with higher scores indicating greater disability. While all domains are assessed over the course of the study, only the cough and dyspnea domains are considered key secondary endpoints because these domains are most important to patients with IPF. Validation of the L-PF's psychometric properties is ongoing, but the instrument has been used in trials of treatments for patients with PF-ILD.

[0163] In some embodiments, the LPA1 antagonist is the compound (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid (hereinafter referred to as "Compound A"), which is described in U.S. Patent Application Publication No. 2017 / 0360759. [ka]

[0164] Compound A is a potent LPA1 antagonist in vitro (LPA1K in CHO cells overexpressing human LPA1). b = 6.9 nM, LPA1K in normal human lung fibroblasts b =5.9 nM). Compound A is currently in clinical development for the treatment of IPF and PF-ILD.

[0165] In certain embodiments, the standard daily dose of Compound A is about 121 mg to about 250 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day. In some embodiments, the standard daily dose of Compound A is about 150 mg to about 250 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day. In some embodiments, the standard daily dose of Compound A is about 175 mg to about 245 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day. In some embodiments, the standard daily dose of Compound A is about 121, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, or about 250 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day. In some embodiments, the standard daily dose of Compound A is 125 mg to about 250 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day. In some embodiments, the standard daily dosage of Compound A is about 240 mg of Compound A or the equivalent amount of a pharmaceutically acceptable salt thereof per day.

[0166] In some embodiments, the subject is administered Compound A or a pharmaceutically acceptable salt thereof once daily. In some embodiments, the subject is administered Compound A or a pharmaceutically acceptable salt thereof twice daily. In some embodiments, the subject is administered Compound A or a pharmaceutically acceptable salt thereof three times daily. In some embodiments, the subject is administered Compound A or a pharmaceutically acceptable salt thereof four times daily. In some embodiments, the subject is administered Compound A or a pharmaceutically acceptable salt thereof five times daily.

[0167] In some embodiments, during the dose escalation treatment period, the subject is administered about 10 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the dose escalation treatment period, the subject is administered about 20 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the dose escalation treatment period, the subject is administered about 30 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the dose escalation treatment period, the subject is administered about 40 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the dose escalation treatment period, the subject is administered about 50 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 70 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 80 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 90 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 100 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 110 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose escalation treatment period, the subject is administered about 120 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose-escalation treatment period, the subject is administered about 130 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose-escalation treatment period, the subject is administered about 140 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt of Compound A. In some embodiments, during the dose-escalation treatment period, the subject is administered about 150 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt of Compound A.

[0168] In some embodiments, the dose escalation treatment period is completed within 21 days. In some embodiments, the dose escalation treatment period is completed within 14 days. In some embodiments, the dose escalation treatment period is completed within 10 days. In some embodiments, the dose escalation treatment period is completed within 7 days. In some embodiments, the dose escalation treatment period is completed within 5 days.

[0169] In some embodiments, during the initial treatment period, the subject is administered about 10 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 20 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 30 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 40 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 50 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 70 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 80 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 90 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 100 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the initial treatment period, the subject is administered about 110 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the initial treatment period is completed within 7 days. In some embodiments, the initial treatment period is completed within 4 days. In some embodiments, the initial treatment period is completed within 3 days. In some embodiments, the initial treatment period is completed within 2 days. In some embodiments, the initial treatment period is completed within 1 day.

[0171] In some embodiments, during the second treatment period, the subject is administered about 20 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 30 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 40 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 50 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 70 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 80 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 90 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 100 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 110 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the second treatment period, the subject is administered about 110 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day.

[0173] In some embodiments, during the third treatment period, the subject is administered about 30 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 40 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 50 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 70 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 80 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 90 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 100 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 110 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, during the third treatment period, the subject is administered about 120 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the subject is administered about 20 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period, and about 120 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period. In some embodiments, the subject is administered about 30 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period, and about 120 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period. In some embodiments, the subject is administered about 40 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period, and about 120 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period. In some embodiments, the subject is administered about 50 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period, and about 120 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period. In some embodiments, the subject is administered about 60 mg / day of Compound A, or the equivalent of a pharmaceutically acceptable salt thereof, during a first period, and about 120 mg / day of Compound A, or the equivalent of a pharmaceutically acceptable salt thereof, during a second period.

[0175] In some embodiments, the first treatment period is completed within 7 days. In some embodiments, the first treatment period is completed within 4 days. In some embodiments, the first treatment period is completed within 3 days. In some embodiments, the first treatment period is completed within 2 days. In some embodiments, the first treatment period is completed within 1 day. In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day.

[0176] In some embodiments, the subject is administered about 10 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period of time, about 30 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period of time, and about 60 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a third period of time. In some embodiments, the subject is administered about 20 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period of time, about 40 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period of time, and about 80 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a third period of time. In some embodiments, the subject is administered about 20 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period of time, about 60 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period of time, and about 120 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a third period of time. In some embodiments, the subject is administered about 40 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a first period of time, about 90 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a second period of time, and about 150 mg / day of Compound A or the equivalent of a pharmaceutically acceptable salt thereof during a third period of time.

[0177] In some embodiments, the first treatment period is completed within 7 days. In some embodiments, the first treatment period is completed within 4 days. In some embodiments, the first treatment period is completed within 3 days. In some embodiments, the first treatment period is completed within 2 days. In some embodiments, the first treatment period is completed within 1 day. In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day. In some embodiments, the third treatment period is completed within 7 days. In some embodiments, the third treatment period is completed within 4 days. In some embodiments, the third treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 2 days. In some embodiments, the third treatment period is completed within 1 day.

[0178] In some embodiments, during the first treatment period of the dose-escalation treatment period, the subject is administered a dose of about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof, and during the second treatment period of the dose-escalation treatment period, about 120 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof, followed by a standard daily dose of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the standard daily dose of Compound A is 240 mg / day or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dose-escalation treatment period is completed within 21 days. In some embodiments, the dose-escalation treatment period is completed within 14 days. In some embodiments, the dose-escalation treatment period is completed within 10 days. In some embodiments, the dose-escalation treatment period is completed within 7 days. In some embodiments, the dose-escalation treatment period is completed within 5 days. In some embodiments, the first treatment period is completed within 7 days. In some embodiments, the first treatment period is completed within 4 days. In some embodiments, the first treatment period is completed within 3 days. In some embodiments, the first treatment period is completed within 2 days. In some embodiments, the first treatment period is completed within 1 day. In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day.

[0179] In some embodiments, during the first treatment period of the dose-escalation treatment period, the subject is administered a dose of about 20 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof, during the second treatment period of the dose-escalation treatment period, about 60 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof, during the third treatment period of the dose-escalation treatment period, about 120 mg / day of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof, and thereafter a standard daily dose of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered. In some embodiments, the standard daily dose of Compound A is 240 mg / day or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the dose-escalation treatment period is completed within 21 days. In some embodiments, the dose-escalation treatment period is completed within 14 days. In some embodiments, the dose-escalation treatment period is completed within 10 days. In some embodiments, the dose-escalation treatment period is completed within 7 days. In some embodiments, the dose-escalation treatment period is completed within 5 days. In some embodiments, the first treatment period is completed within 7 days. In some embodiments, the first treatment period is completed within 4 days. In some embodiments, the first treatment period is completed within 3 days. In some embodiments, the first treatment period is completed within 2 days. In some embodiments, the first treatment period is completed within 1 day. In some embodiments, the second treatment period is completed within 7 days. In some embodiments, the second treatment period is completed within 4 days. In some embodiments, the second treatment period is completed within 3 days. In some embodiments, the second treatment period is completed within 2 days. In some embodiments, the second treatment period is completed within 1 day. In some embodiments, the third treatment period is completed within 7 days. In some embodiments, the third treatment period is completed within 4 days. In some embodiments, the third treatment period is completed within 3 days. In some embodiments, the third treatment period is completed within 2 days. In some embodiments, the third treatment period is completed within 1 day. [Example]

[0180] Example 1: Preparation of crystalline form A of Compound A Crystalline forms can be prepared in a variety of ways, such as crystallization or recrystallization from a suitable solvent, sublimation, crystal growth from the melt, solid-state transformation from another phase, crystallization from supercritical fluids, and jet atomization. Techniques for crystallization or recrystallization of co-crystals from solvent mixtures include, for example, evaporation of the solvent, cooling the temperature of the solvent mixture, seeding a supersaturated solvent mixture with crystals of the molecule and / or salt, freeze-drying the solvent mixture, and adding an anti-solvent (counter-solvent) to the solvent mixture.

[0181] In solvent-selective crystallization techniques, the choice of solvent or solvent mixture is generally influenced by one or more factors (e.g., the solubility of the compound, the crystallization method, and the vapor pressure of the solvents). A solvent mixture can be used, for example, by dissolving a compound in a first solvent to obtain a solution, followed by adding an antisolvent to reduce the solubility of the compound in the solution so that crystals can form. An antisolvent is a solvent in which the compound has low solubility.

[0182] In one method of forming crystals, the compound can be suspended and / or stirred in a suitable solvent to form a slurry, which can be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which may also include additional compounds to form a heterogeneous mixture of the compound and solvent at a given temperature.

[0183] Seed crystals can be added to any mixture to be crystallized to promote crystallization. Seeding can be used to control the growth of a specific polymorph or the particle size distribution of the crystalline product. The calculated amount of seeds required will therefore vary depending on the size of the seeds used and the desired average size of the product particles, as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. Generally, small-sized seeds are required to effectively control the growth of crystals in the batch. Small-sized seeds can be produced by sieving, crushing, or micronizing large crystals or by microcrystallizing a solution. Care must be taken to ensure that the desired crystalline form is not altered (i.e., converted to amorphous or another polymorph) by crushing or microcrystallizing the crystals.

[0184] The cooled crystallization mixture can be vacuum filtered, and the isolated solid can be washed with an appropriate solvent (e.g., a cooled recrystallization solvent) and dried under a nitrogen purge to obtain the desired crystalline form. The isolated solid can be analyzed by an appropriate spectroscopic or analytical method (e.g., solid-state nuclear magnetic resonance, differential scanning calorimetry, powder X-ray diffraction, etc.) to confirm the formation of the desired crystalline form of the product. The resulting crystalline form is generally purified to an isolated yield of about 70% by weight or greater, preferably 90% by weight or greater, based on the weight of the original compound used in the crystallization step. The resulting product can be co-milled or passed through a mesh screen to break down the product, if necessary.

[0185] The presence of more than one polymorph in a sample can be determined by various techniques (e.g., powder X-ray diffraction (PXRD), Raman or IR spectroscopy, solid-state nuclear magnetic resonance). For example, the presence of extra peaks in a comparison of an experimentally determined PXRD pattern with a simulated PXRD pattern can indicate more than one polymorph in a sample. Simulated PXRD can be calculated from single crystal X-ray data. See Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0186] The crystalline form of Compound A according to the present invention can be characterized using various techniques whose operation is well known to those skilled in the art.Crystalline forms can be characterized and identified using single crystal X-ray diffraction, which is based on the unit cell measurement of a single crystal of the form at a fixed analysis temperature.A detailed description of the unit cell is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference.Alternatively, the characteristic spatial arrangement of atoms in the crystal lattice can be characterized according to the observed fractional atomic coordinates.Another method for characterizing crystalline structure is powder X-ray diffraction analysis, in which the diffraction profile measured at the same analysis temperature is compared with a simulated profile representing a pure powder material, and the measured value of the form of interest is characterized by a series of 2q values ​​(usually four or more).

[0187] Other means of characterizing forms can be used, such as solid-state nuclear magnetic resonance (SSNMR), differential scanning calorimetry, thermogravimetric analysis, and FT-Raman and FT-IR. These techniques can also be used in combination to characterize the form of interest. In addition to the techniques specifically described herein, the presence of a particular crystalline form can be determined by other suitable analytical methods.

[0188] Example 1A 150 mg of Compound A was dissolved in 1.5 mL of tetrahydrofuran (THF) at 20° C. 0.5 mL of this solution was subjected to flash evaporation using a centrifugal evaporator to obtain a solid of Form A. 0.5 mL of the same solution was subjected to slow evaporation at 20° C. to obtain a solid of Form A.

[0189] Example 1B 200 mg of Compound A was dissolved in 1 mL of dichloromethane (DCM) at 20° C. 0.5 mL of this solution was subjected to flash evaporation using a centrifugal evaporator to obtain a solid of Form A. 0.5 mL of the same solution was subjected to slow evaporation at 20° C. to obtain a solid of Form A.

[0190] Example 1C 100 mg of Compound A was dissolved in 0.5 mL of THF at 50° C. and kept stirring at 20° C. 0.5 mL of water was added to the clear solution to obtain Form A solid.

[0191] Example 1D 100 mg of Compound A was dissolved in 1 mL of 2-methyl THF at 50° C. and kept stirring at 20° C. 1 mL of n-heptane was added to the clear solution to obtain Form A solid.

[0192] Example 1E A solution of Compound A in tert-amyl alcohol (t-AmOH) was concentrated under vacuum to 4 L / kg, followed by the addition of 15 L / kg DCM and 10 L / kg water. The layers were separated, and the DCM layer was concentrated under vacuum to 4 L / kg. The DCM layer was charged with 8-10 L / kg ethyl acetate (EtOAc) and concentrated under vacuum to 4 L / kg. An additional 8-10 L / kg EtOAc was added and concentrated under vacuum to 4 L / kg. 6-8 L / kg EtOAc was added and warmed to 70-83 °C until completely dissolved. The resulting slurry was cooled to 0-10 °C over at least 2 hours and then aged for at least an additional 12 hours. The slurry was filtered. The wet cake was washed with 3-5 L / kg EtOAc and dried under vacuum at 55-60 °C to obtain Form A solid.

[0193] Example 1F A solution of Compound A in t-AmOH was concentrated under vacuum at 55°C to 4 L / kg, then 5 L / kg of 2-propanol (IPA) was added and concentrated under vacuum at 55°C to 4 L / kg. This process was repeated two more times using 2 x 5 L / kg of IPA. The batch was cooled to 30°C, then 1.3 L / kg of water was added and heated to 45-55°C. The resulting warm solution was filtered through a polishing filter and seeded with 1 wt% Form A crystals cooled to 30°C, followed by 2 L / kg of water. After at least 6 hours, an additional 8.7 L / kg of water was added. The resulting slurry was cooled to 20°C over at least 30 minutes, and the slurry was aged for at least 3 hours. The solid was filtered and the wet cake was washed successively with 3 L / kg of a water:IPA:t-AmOH mixture (volume ratio 11:3:1) and 3 L / kg of water, and dried under vacuum at 50-60°C to give Form A solid.

[0194] Example 1G To a solution of isopropyl (1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate (500 mg, 1.025 mmol) in 1:1 THF / MeOH (10 mL) was added aqueous LiOH (1.538 mL of a 2 M solution, 3.08 mmol). The reaction mixture was stirred at 50 °C for 1 h, then cooled to room temperature and the organic volatiles removed in vacuo. The concentrated solution was washed with EtOAc and then acidified (1 N aqueous HCl) to pH 6-7. The aqueous layer was extracted several times with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), and the MgSO4 was filtered off. The EtOAc solution was concentrated in vacuo to give Form A solid.

[0195] Analytical data for crystalline Compound A described herein was obtained using the following procedures.

[0196] Single crystal Single crystal X-ray data were collected using a Bruker X8 Kappa diffractometer equipped with an APEX II CCD detector and a MICROSTAR microfocus rotating anode X-ray generator with monochromatic Cu Kα radiation. The single crystal was at room temperature during data collection.

[0197] Indexing and processing of the measured intensity data was performed using the APEX2 program suite (Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison, WI 53711 USA). Final unit cell parameters were determined using the complete data set. The structure was solved by direct methods and refined by full-matrix least-squares using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA). Structural refinement involved minimizing a function defined by Σw(|Fo|-|Fc|), where w is an appropriate weighting factor based on the observed intensity error, Fo is a structure coefficient based on the measured reflections, and Fc is a structure coefficient based on the calculated reflections. The agreement between the refined crystal structure model and the experimental X-ray diffraction data was evaluated using the residual coefficients R = Σ||Fo|-|Fc|| / Σ|Fo| and wR = [Σw(|Fo|-|Fc|)2 / Σw|Fo|]1 / 2. Difference Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were introduced using an idealized geometry with isotropic temperature factors and were included in the structure coefficient calculations using fixed parameters.

[0198] Powder X-ray diffraction (PXRD) PXRD diffractograms were acquired over the 2θ range of 2–40° on a Bruker D8 Advance system using Cu Kα (40 kV / 40 mA) radiation and a LynxEye detector with a step size of 0.03° 2θ. The incident beam configuration was a Göbel mirror, a 0.2 mm mirror exit slit, a 2.5° Soller slit, and a beam knife. The diffracted beam configuration was an 8 mm anti-scatter slit and a 2.5° Soller slit. Samples were mounted flat on a zero-background Si wafer.

[0199] Differential scanning calorimetry (DSC) DSC was performed using a TA Instruments Q2000 differential scanning calorimeter equipped with an autosampler and a cooling system under a 40 mL / min N purge for the Q2000. DSC thermograms were acquired at 15 °C / min in crimped Al pans.

[0200] Thermogravimetric analysis (TGA) TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer with a 40 mL / min N purge for the balance and 60 mL / min for the samples in the Al pans. TGA thermograms were obtained at 15 °C / min.

[0201] Moisture sorption isotherm Moisture sorption isotherms were collected on a TA Instruments VTI-SA vapor sorption analyzer using approximately 270 mg of sample in a 250 μL ceramic pan. Samples were dried at 30°C until a loss rate of 0.005 wt% / min was obtained in 10 minutes. Samples were tested at 25°C and 4, 5, 15, 25, 35, 45, 50, 65, 75, 85, and 95% RH. Equilibrium at each RH was achieved when a rate of 0.01 wt% / min was achieved for 35 minutes or for a maximum of 600 minutes.

[0202] Example 2. A double-blind, placebo-controlled, randomized, single- and multiple-ascending-dose study of the safety, pharmacokinetics, and exploratory pharmacodynamics of oral administration of Compound A in healthy participants The study was conducted in three parts with 112 healthy male and female participants, including 24 Japanese participants. Female participants were not of childbearing potential. This study was designed to evaluate the safety and tolerability, PK, and exploratory PD of Compound A oral suspension. Parts A and B (Cohort B1 only) enrolled healthy participants and were conducted at sites in the Netherlands. Part B (Cohorts B2-B5) enrolled healthy non-Japanese participants and were conducted at sites in the United Kingdom (UK). Part C enrolled healthy Japanese participants and was conducted at the same sites in the UK.

[0203] Part A was a SAD study conducted under fasting conditions in six planned sequential dose-escalation cohorts (3, 10, 30, 100, 150, or 250 mg) in eight healthy participants (six active, two placebo). Eligible participants in Part A (excluding participants in Cohort A7 [food effect (FE) / pH cohort]) received a single dose of study drug (Compound A or placebo) under fasting conditions. Cohorts A1 through A6 employed sentinel dosing (active 1 + placebo 1, followed 48 hours later by the remaining cohort participants [active 5 + placebo 1]). However, in Cohort A6 (250 mg), a dose-limiting event was observed in one sentinel participant, and further enrollment was discontinued after dosing only two sentinel participants. In addition to the six ascending dose cohorts, a cohort of six healthy participants (Cohort A7; active 6, 100 mg Compound A) evaluated the effects of food and pH on the bioavailability of Compound A in a three-period, open-label, fixed-sequence, crossover design (FE / pH cohort).

[0204] Part B was a multi-agent controlled trial conducted under fasting conditions in eight healthy participants (six active, two placebo) in six planned sequential dose-escalation cohorts (10 mg QD, 30 mg QD, 30 mg BID, 60 mg BID, 125 mg BID, and ≤250 mg BID). However, cohort B6 (≤250 mg BID) was discontinued due to sufficient safety and PK data available at doses up to 125 mg BID. Eligible participants received oral study drug (Compound A or placebo) for 14 days.

[0205] Part C was a MAD study in three sequential dose-escalation cohorts (30 mg BID, 60 mg BID, and 90 mg BID) of eight healthy Japanese participants each (six active, two placebo). Eligible participants in cohorts C1-C3 received oral administration of the study drug (Compound A or placebo) for 14 days.

[0206] During the study, physical examinations, vital sign measurements (including orthostatic control tests in Cohort A6, Cohorts B3-B5, and Cohorts C1-C3 at selected time points), 12-lead electrocardiograms (ECGs), and clinical laboratory assessments were performed at selected time points. Additionally, Holter ECG monitoring was performed for the first 24 hours after dosing on Day 1 in Part A (but not in the FE / pH cohorts) and for the first 24 hours after dosing on Days 1 and 14 in Parts B and C. Participants were closely monitored for adverse events (AEs). Blood samples were collected for up to 14 days (follow-up visits) after the (last) study drug dose for PK analysis. Additionally, blood and urine samples were collected for exploratory biomarker evaluation and biobanking of samples for potential analyses. For potential PK analysis, urine was collected up to 96 hours after a single dose of Compound A or placebo in the SAD part, and up to 24 hours after the first (morning) dose of study drug on Day 1 and up to 24 hours after the last (morning) dose of study drug on Day 14 in the MAD part.

[0207] Compound A was generally safe and well tolerated after single and multiple oral dose administration to healthy participants. Compound A was generally associated with a reversible reduction in BP that reached a maximum 4-8 hours after administration and was not associated with significant changes in heart rate. BP reductions were largely asymptomatic.

[0208] In the SAD cohort, Compound A dose-dependently, reversibly, and largely asymptomatically reduced SBP and DBP with minimal effect on heart rate. Changes in blood pressure are shown in Tables 3 and 4 below.

[0209] [Table 3]

[0210] [Table 4]

[0211] In the MAD cohort, reversible reductions in mean SBP and DBP were observed in all groups except the placebo QD group, which showed no change in BP. In the QD group, reductions generally occurred in a dose-dependent manner with Compound A. In the BID group, both the placebo and Compound A groups reduced BP, with no clear difference between the placebo and Compound A groups. There was no clear change in the magnitude of BP reduction with repeated administration over the 14-day treatment period. In the Japanese MAD cohort, reversible reductions in mean BP occurred in all groups, including placebo. No clear dose-dependent trend toward BP reduction with Compound A was observed. Blood pressure changes can be seen in Tables 5–7 below.

[0212] [Table 5]

[0213] [Table 6]

[0214] [Table 7]

[0215] [Table 8]

[0216] Example 3. A double-blind, placebo-controlled, randomized, single- and multiple-ascending-dose study of the safety, tolerability, and pharmacokinetics of oral administration of Compound A in healthy Chinese participants In this Chinese PK bridging study, a single dose of 60 mg and multiple doses of 60 mg BID were selected to confirm the PK, safety, and tolerability of clinically relevant doses. This study examines the effects of genetic variations in genes related to drug absorption, distribution, metabolism, excretion, and transport on the PK of Compound A in healthy Chinese subjects.

[0217] Single dose On Day 1, eligible subjects will be randomized in a 3:1 ratio to receive a single oral dose of Compound A or matching placebo. Participants will fast for at least 10 hours prior to dosing, and will remain fasted until at least 4 hours after dosing.

[0218] Multiple doses On days 5-10, subjects will receive Compound A BID or matching placebo. On day 11, subjects will receive a morning dose (last dose) of Compound A or matching placebo.

[0219] On days 5 and 11, participants fast for at least 10 hours prior to dosing, and participants remain fasted until at least 4 hours after administration of the morning dose.

[0220] On the mornings of days 6-10, participants will also receive a fasted dose, with breakfast provided to participants approximately 2 hours after dosing on these days.

[0221] In the evenings of days 5-10, participants will receive a second oral dose of Compound A or placebo 12 hours after the morning dose. The evening dose will be administered approximately 2 hours after the start of dinner.

[0222] The study treatment will be administered with 240 mL of water.

[0223] Example 4: A multicenter, randomized, double-blind, placebo-controlled, phase 2 study of the efficacy, safety, and tolerability of Compound A in participants with pulmonary fibrosis The topline safety and efficacy data from the final analysis of the IPF cohort of the Phase 2 study support the continued development of Compound A in both IPF and PPF. A schematic overview of both cohorts of the study is shown in Figure 5.

[0224] Example 4A: IPF Cohort A total of 278 participants with IPF were randomized, and 276 participants were treated as of the final analysis data cutoff (August 4, 2022). Male and female participants aged 40 years or older with IPF, a percent predicted forced vital capacity (ppFVC) of 40% or greater, and a percent predicted pulmonary pulmonary sufficiency (PPDLCO) of 25% or greater, who were diagnosed within 7 years of screening and had a centrally read chest HRCT scan at screening consistent with UIP or possible UIP, or a lung biopsy consistent with UIP, were eligible to participate in the study. The mean baseline ppFVC for all subjects was 76.5%. In the primary IPF cohort, participants were randomized (1:1:1) to receive 30 mg or 60 mg of Compound A or placebo (PBO) twice daily for 26 weeks. Participants were stratified by standard of care (SoC) IPF therapy (pirfenidone vs. nintedanib, none) and region (Japan vs. other countries) at randomization.

[0225] The primary objective of the study was to determine the percent change in ppFVC from baseline to week 26. The primary objective was evaluated in two estimation frameworks to address the intervention event of dose reduction to 10 mg BID or matching PBO if pre-specified low BP criteria were met. The primary estimate was employed to estimate the treatment effect when dose reduction was implemented. The supplementary estimate was employed to estimate the treatment effect without dose reduction.

[0226] Of the 276 treated participants who contributed to these analyses, 90% (n=248) completed the 26-week treatment period, and 10% (n=28) discontinued treatment. Discontinuations due to TEAEs were evenly balanced between treatment groups (PBO: 9.8%; 30mg: 9.9%; 60mg: 6.5%).

[0227] Table 8 shows the baseline demographic and clinical characteristics of the subject population in the IPF cohort.

[0228] [Table 9]

[0229] A summary of the results is provided in Tables 9–12, and additional results from the final analysis of the IPF cohort are described below.

[0230] Key estimates: Analytical strategy: The primary inference was to assess the efficacy of Compound A at 30 mg or 60 mg compared with PBO in participants with IPF who met the enrollment criteria, with or without SoC use. The percent decline in ppFVC from baseline to week 26 was compared, regardless of dose reduction or treatment discontinuation for any reason (treatment-directed strategy), using the difference between each dose and PBO as a population-level summary.

[0231] Primary efficacy results: In the overall population, the 60 mg dose group demonstrated a favorable treatment response at week 26, measured as the rate of decline in ppFVC and decline in FVC (mL), compared with PBO under both the primary and supplemental estimate frameworks (Table 9). The 30 mg dose group demonstrated no efficacy (data not shown).

[0232] In the overall population, the 60 mg dose demonstrated a treatment difference in the rate of decline in ppFVC of 1.45 ± 0.81 (mean ± standard error of the mean [SEM]) [95% CI -0.133, 3.028], corresponding to an overall relative decline of 54% compared with the decline slope for PBO (-2.67 ± 0.57).

[0233] When analyzing the rate of decline in FVC (adjusted for age, sex, and height, measured as the slope difference for the 60 mg group [-54.3 ± 20.76] and the slope difference for the PBO group [-101.2 ± 20.45]) in mL, the 60 mg dose corresponded to a relative treatment difference of 46.9 mL compared with PBO (46.9 ± 29.14 (mean ± SEM) [95% CI -10.3, 104.1]).

[0234] Subgroup analysis of background SoC (SoC vs. no SoC) showed a favorable response to the primary endpoint in the 60 mg group in contrast to the PBO group.

[0235] Among the background SoC (68% of the total population), the 60 mg dose showed a treatment difference compared with PBO of 1.22 ± 0.87 (mean ± SEM) [95% CI −0.486, 2.929], corresponding to a relative treatment benefit of 39% compared with PBO.

[0236] Among background SoC (32% of the total population), the 60 mg dose demonstrated a treatment difference compared with PBO of 2.01 ± 1.7 (mean ± SEM) [95% CI −1.327, 5.355], corresponding to a relative treatment benefit of 113% compared with PBO.

[0237] Supplementary estimates: Analytical strategy: The supplemental estimate for the primary objective was to assess the efficacy of Compound A at 30 mg or 60 mg twice daily without dose reduction compared with PBO in IPF participants who met the enrollment criteria, with or without SoC use. The percent decline in ppFVC from baseline to week 26 was compared using the difference between each dose and PBO as a population-level summary, regardless of treatment discontinuation for any reason (treat-to-treat strategy). In the case of dose reduction, data collected after the dose reduction were not considered relevant to the treatment effect of interest and were therefore treated as missing values ​​(on-treatment strategy).

[0238] Protocol-defined hypotension criteria led to a dose reduction to Compound A 10 mg BID and corresponding PBO in 18 (6.5%) participants, which was distributed approximately evenly between groups (PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%)).

[0239] In the overall population, the 60 mg dose demonstrated a treatment difference in the rate of decline in ppFVC of 1.77 ± 0.82 (mean ± SEM) [95% CI 0.162, 3.370], corresponding to an overall relative decline of 62% compared with the decline slope for PBO (-2.84 ± 0.57).

[0240] When FVC (adjusted for age, sex, and height, measured as the slope difference for the 60 mg group [-47.2 ± 20.92] and the slope difference for the PBO group [-108.7 ± 20.58]) was analyzed in mL, the 60 mg dose represented a relative treatment difference of 61.4 mL compared with PBO.

[0241] Subgroup analysis of background SoC (SoC vs. no SoC) showed a favorable response to the primary endpoint in the 60 mg group in contrast to the PBO group.

[0242] Among those with background SoC (68% of the total population), the 60 mg dose demonstrated a treatment difference compared with PBO of 1.41 ± 0.89 (mean ± SEM) [95% CI −0.341, 3.151] for the primary endpoint (percent change in ppFVC), corresponding to a 44% relative treatment benefit compared with PBO.

[0243] Among those without background SoC (32% of the total population), the 60 mg dose demonstrated a treatment difference of 2.55 ± 1.73 (mean ± SEM) [95% CI −0.84, 5.948] compared with PBO for the primary endpoint (percent change in ppFVC), corresponding to a relative treatment benefit of 123% compared with PBO.

[0244] Subgroup analyses of participants enrolled with stable background SoC (defined as either nintedanib or pirfenidone) (68% of the total population) and participants enrolled without SoC (no SoC; 32% of the total population) showed favorable efficacy with 60 mg compared with PBO (Table 10).

[0245] Subgroup analysis based on gender revealed different rates of decline (data not shown).

[0246] [Table 10]

[0247] [Table 11]

[0248] Additional data from the IPF cohort are presented in Figures 6-9. As shown in Figure 6, with the treatment-at-treatment strategy, the percent change in ppFVC over 26 weeks in patients with IPF was -2.7% for placebo and -2.8% and -1.2% for the 30 mg and 60 mg Compound A groups, respectively. The treatment difference between the 60 mg group and the placebo group was 1.4% (95% CI, -0.1 to 3.0), a relative decline of 54% (Figure 6A). With the treatment-at-treatment strategy, the percent change in ppFVC was -2.8% for placebo and -3.2% and -1.1% for the 30 mg and 60 mg Compound A groups, respectively. The treatment difference between the 60 mg Compound A group and the placebo group was 1.8% (95% CI, 0.2 to 3.4), a relative decline of 62% (Figure 6B). In Bayesian analyses, the posterior probability of a positive treatment difference for 60 mg Compound A versus placebo was greater than 95% under both estimation strategies.

[0249] The percent change in FVC (mL) for the IPF cohort is shown in Figure 7, and the absolute change in FVC is shown in Figure 8. The adjusted mean treatment difference in absolute change in FVC (mL) between the 60 mg Compound A group and the placebo group at week 26 was 45.5 mL (Figure 8A).

[0250] Figure 9 shows the percent change in ppFVC in subjects with and without background antifibrotic therapy in the IPF cohort. Treatment differences in percent change in ppFVC were consistent between both groups (Figures 9A and 9B).

[0251] Summary of efficacy results: - The 30 mg dose group showed no efficacy compared with PBO in the overall population with and without SoC (data not shown). - The 60 mg dose group demonstrated a favorable treatment response to PBO in the overall population with and without SoC, as well as in the subgroups of participants receiving background SoC and participants not receiving SoC. - These results demonstrate that Compound A, when used alone or with background therapy with nintedanib or pirfenidone, has a favorable effect on FVC compared with PBO.

[0252] In general, overall adverse events in subjects with at least one TEAE were observed more frequently in the PBO group (Table 11). Discontinuations due to TEAEs were evenly balanced between treatment groups (PBO: 9.8%; 30 mg: 9.9%; 60 mg: 6.5%).

[0253] [Table 12]

[0254] Safety rating: - In general, overall safety events were more common in the PBO group. Treatment-emergent adverse events (TEAEs): ·PBO:74(80.4%);30mg:69(75.8%);60mg:69(74.2%)) - Adverse Events of Special Interest (AESI): ·PBO:19(20.7%);30mg:18(19.8%);60mg:9(9.7%)) Treatment-emergent serious adverse events (TESAEs): ·PBO:16(17.4%);30mg:10(11.0%);60mg:10(10.8%)) - Discontinuation due to TEAEs: ·PBO:9(9.8%);30mg:9(9.9%);60mg:6(6.5%)) - TEAEs related to study treatment: ·PBO:20(21.7%);30mg:23(25.3%);60mg:25(26.9%)) - No major system organ classes or preferred terms were reported for treatment interruptions - Total deaths: 13 ·PBO:4(4.4%);30mg:4(4.4%);60mg:5(5.4%)). Causes of death were disease progression in 9 cases, pneumonia in 3 cases, and congestive heart failure in 1 case. TEAE-related deaths: 9 (3.3%) participants experienced TEAE-related deaths during the study or within 28 days of the last dose of treatment. ·PBO:2(2.2%);30mg:3(3.3%);60mg:4(4.3%)). After the 28-day TEAE period, four additional participants died.

[0255] Blood Pressure Monitoring: Based on protocol-prespecified safety monitoring and criteria for hypotension, patients receiving the 60 mg dose had the lowest frequency of orthostatic intolerance, orthostatic hypotension, or prespecified symptomatic or asymptomatic hypotension criteria. In the overall population, the following orthostatic intolerance, orthostatic hypotension, or symptomatic or asymptomatic hypoBP events were observed: Orthostatic intolerance was observed in 19 participants (6.9%). ·PBO:7(7.6%);30mg:10(11.0%);60mg:2(2.2%)) Orthostatic hypotension was observed in 54 participants (19.6%) with asymptomatic low BP. Orthostatic hypotension was defined as a decrease in systolic blood pressure of 20 mmHg or more or a decrease in diastolic blood pressure of 10 mmHg or more when moving from a supine or sitting position to a standing position. ·PBO:19(20.7%);30mg:21(23.1%);60mg:14(15.1%)) - Orthostatic hypotension was observed in 21 (7.5%) participants with symptomatic low BP. ·PBO:7(7.6%);30mg:9(9.9%),60mg:5(5.4%)) - Asymptomatic hypotension was observed in 59 participants (21.4%). ·PBO:20(21.7%);30mg:22(24.2%);60mg:17(18.3%)) Symptomatic hypotension was observed in 27 (9.8%) participants. ·PBO:10(10.9%);30mg:11(12.1%);60mg:6(6.5%)) Protocol-defined hypotension criteria (listed below) led to a dose reduction to Compound A 10 mg BID and corresponding PBO in 18 participants (6.5%), which was distributed approximately evenly between groups: PBO: 5 (5.4%); 30 mg: 7 (7.7%); 60 mg: 6 (6.5%).

[0256] Asymptomatic hypotension criteria Patients experience one of the following, confirmed by retest within 15 minutes: Sitting systolic blood pressure less than 85mmHg Sitting diastolic blood pressure less than 55mmHg Orthostatic hypotension

[0257] Symptomatic hypotension criteria Patients will experience symptoms that, in the opinion of the investigator, may be related to a drop in blood pressure and will also experience at least one of the following, confirmed by retest within 15 minutes: Sitting systolic blood pressure less than 100mmHg or sitting diastolic blood pressure less than 60mmHg - Sitting systolic blood pressure has decreased by 20mmHg or more since the previous visit, or sitting diastolic blood pressure has decreased by 10mmHg or more since the previous visit Orthostatic hypotension Orthostatic tachycardia

[0258] Based on the pre-specified blood pressure monitoring and hypotension criteria in the protocol, these data indicate that Compound A 60 mg twice daily (BID) administration is not associated with an increased risk of orthostatic intolerance, orthostatic hypotension, orthostatic tachycardia, or symptomatic or asymptomatic hypotension compared with PBO (Table 12). However, post-dose reductions in SBP were observed with 30 mg and 60 mg on the first day of dosing. Two hours post-dose, a nadir mean reduction from baseline in sitting systolic blood pressure was recorded (PBO: -2.1 mmHg; Compound A 30 mg: -10.5 mmHg; Compound A 60 mg: -14.1 mmHg). These reductions were not associated with any clinical sequelae and were essentially self-limiting.

[0259] [Table 13]

[0260] The number of dose reductions (% of all subjects in the group) in the IPF cohort was as follows: placebo, 5 (5.4); 30 mg Compound A, 7 (7.7); and 60 mg Compound A, 6 (6.5).

[0261] The number of dose reductions (% of all subjects in the group) in the IPF cohort was as follows: placebo, 5 (5.4); 30 mg Compound A, 7 (7.7); and 60 mg Compound A, 6 (6.5).

[0262] Example 4B: PPF Cohort A total of 123 participants with PPF were randomized. Participants (aged 21 years or older) were randomized (1:1:1) to receive 30 mg or 60 mg of Compound A or PBO twice daily for 26 weeks. Centrally read HRCT scans at screening showed evidence of parenchymal fibrosis in greater than 10% of the lung. (a) Evidence of ILD progression within 24 months prior to screening, defined as any of the following: a ≥10% decline in relative ppFVC, or a ≥5% but <10% decline in relative ppFVC with increasing fibrosis compared to the previous image on a pre-screening chest computed tomography scan, or increasing fibrosis compared to the previous image on a pre-screening chest computed tomography scan with symptoms associated with ILD progression; (b) Subjects with interstitial lung disease of various etiologies, excluding connective tissue disease-associated interstitial lung disease (excluding rheumatoid arthritis-associated interstitial lung disease) and sarcoid, were enrolled. Immunosuppressants (mycophenolate mofetil, mycophenolic acid, azathioprine, and / or tacrolimus) were permitted only if the dose was stable for at least 6 months before screening. If patients were receiving the antifibrotic agents pirfenidone or nintedanib, they had to have received a stable dose for at least 3 months before and during the screening period. If patients were not receiving pirfenidone or nintedanib, they had to have received neither drug or neither drug for at least 4 weeks prior to Day 1. A total of 47 subjects (38.2%) were receiving antifibrotic treatment (with or without immunosuppressive therapy). Of these subjects, 34 were receiving nintedanib and 13 were receiving pirfenidone. Participants were stratified by usual interstitial pneumonia (UIP) pattern (yes vs. no) and background therapy (antifibrotic agents + / - ILD-targeted immunosuppression, ILD-targeted immunosuppression alone, or no). UIP pattern was present in 52% of subjects, with unclassifiable ILD being the most common disease classification.

[0263] The study was not powered to detect statistical significance (no formal testing). The target effect size was not defined in the study design. There were two estimation approaches for the analysis: Treatment strategy: Effect of dose reduction as part of the treatment regimen. During treatment: Effect of treatment without dose reduction.

[0264] Of the 123 treated participants who contributed to these analyses, 90.2% (n=111) completed the 26-week treatment period, and 9.8% (n=12) discontinued treatment (6 (4.9%) discontinued due to adverse events). Treatment discontinuation was across treatment groups (PBO: 17.1%; 30mg: 7.5%; 60mg: 4.8%). A total of 91 (74%) subjects continued in the 26-week optional treatment extension (OTE).

[0265] The primary efficacy endpoint, the rate of decline in FVC (% predicted) from baseline to week 26 in the PPF cohort, was estimated using a linear mixed-effects model utilizing all FVC time points. This was analyzed under the primary (using all data, treatment-directed strategy) and supplementary (using all data up to the dose reduction time point, on-treatment strategy) assumptions. Analyses were performed in the overall population and in subgroups by 1) background antifibrotic therapy and 2) UIP radiological pattern (yes / no). Mean baseline ppFVC was 66.7% in the PPF cohort.

[0266] Table 13 shows the baseline demographic and clinical characteristics of the subjects in the PPF cohort, and Table 14 shows their baseline disease characteristics.

[0267] [Table 14]

[0268] [Table 15]

[0269] A summary of the results is provided in Tables 15-26, and additional results from the final analysis of the PPF cohort are described below.

[0270] [Table 16]

[0271] [Table 17]

[0272] [Table 18]

[0273] Additional data for the PPF cohort are shown in Figures 6-16. As shown in Figure 6, following the treatment-to-treatment strategy, the percent change in ppFVC over 26 weeks in patients with PPF was -4.3% for placebo and -2.7% and -1.1% for the 30 mg and 60 mg Compound A groups, respectively. The treatment difference between 60 mg Compound A and placebo was 3.2% (95% CI, 0.7-5.6), a relative decline of 74% (Figure 6C). Using the treatment-to-treatment strategy, the percent change in ppFVC was -4.2% for placebo and -2.5% and -1.3% for the 30 mg and 60 mg groups, respectively. The treatment difference between 60 mg Compound A and placebo was 2.9% (95% CI, 0.4-5.5), a relative decline of 69% (Figure 6D).

[0274] The percent change in FVC (mL) for the PPF cohort is shown in Figure 7, and the absolute change in FVC is shown in Figure 8. The adjusted mean treatment difference in absolute change in FVC (mL) between the 60 mg Compound A group and the placebo group at week 26 was 87.4 mL (Figure 8B).

[0275] 10 and 11 show the mean observed change in ppFVC percentage and FVC in the PPF cohort from baseline to week 26. As can be seen, both 30 mg and 60 mg show improvement over placebo at week 8, but 30 mg shows a more significant improvement from week 20 onwards, and 60 mg maintains improvement over placebo through the end of week 26.

[0276] [Table 19]

[0277] [Table 20]

[0278] [Table 21]

[0279] [Table 22]

[0280] Figures 12 and 13 show the mean observed change in ppFVC percentage and FVC from baseline to week 26 in patients with and without UIP within the PPF cohort, and Figure 14 shows the percent change in ppFVC in PPF patients with and without UIP. As shown in the figures, treatment differences were observed in the PPF cohort, independent of the presence or absence of UIP. Acute exacerbations of pulmonary fibrosis were observed in 6 IPF patients (2%) (placebo: n=2; 30 mg: n=3; 60 mg: n=1) and 3 PPF patients (2%) (all placebo-treated).

[0281] [Table 23]

[0282] [Table 24]

[0283] [Table 25]

[0284] [Table 26]

[0285] Figures 15 and 16 show the mean observed change in ppFVC percentage and FVC from baseline to week 26 in patients with and without additional antifibrotic therapy within the PPF cohort, and Figure 9 shows the percent change in ppFVC in subjects with and without background antifibrotic therapy in the PPF cohort. Treatment differences in percent change in ppFVC were consistent in the PPF cohort with and without background antifibrotic use (Figures 9C and 9D).

[0286] [Table 27]

[0287] Summary of adverse events Subjects with at least one treatment-emergent adverse event (TEAE): PBO-24%, 30mg-10%, 60mg-24% Subjects with at least one treatment-emergent serious adverse event (TESAE): PBO-32%, 30mg-10%, 60mg-12% Subjects with at least one TEAE due to the investigational drug (IMP): PBO-17%, 30mg-18%, 60mg-26% Seven subjects had adverse outcomes leading to treatment discontinuation Six patients were in the PBO group and one in the 30 mg group (due to hypotension). Three subjects died from TEAEs, all in the PBO group. 1 case of infectious pneumonia, 1 case of PE, 1 case of respiratory failure Dose-dependent BP findings reaffirmed the low BP safety risk of Compound A. Decreased blood pressure on day 1 of treatment; no clinical effect Dose-dependent low BP threshold ("event"): PBO-24%, 30mg-30%, 60mg-41% ·Dose reduction: PBO-2%, 30mg-15%, 60mg-12% AESI due to low BP: PBO-24%, 30mg-10%, 60mg-24% No significant disparities in significant laboratory abnormalities between treatment groups No hepatobiliary toxicity.

[0288] In patients with PPF, the nadir post-dose reduction from baseline in mean sitting systolic blood pressure on Day 1 was -4.2 mmHg, -10.7 mmHg, and -12.7 mmHg in the placebo, 30 mg, and 60 mg Compound A groups, respectively. Pre-specified blood pressure reduction criteria (shown below) increased dose-dependently across PPF cohorts (Table 26).

[0289] Asymptomatic hypotension criteria Patients experience one of the following, confirmed by retest within 15 minutes: Sitting systolic blood pressure less than 85mmHg Sitting diastolic blood pressure less than 55mmHg Orthostatic hypotension

[0290] Symptomatic hypotension criteria Patients will experience symptoms that, in the opinion of the investigator, may be related to a drop in blood pressure and will also experience at least one of the following, confirmed by retest within 15 minutes: Sitting systolic blood pressure less than 100mmHg or sitting diastolic blood pressure less than 60mmHg - Sitting systolic blood pressure has decreased by 20mmHg or more since the previous visit, or sitting diastolic blood pressure has decreased by 10mmHg or more since the previous visit Orthostatic hypotension Orthostatic tachycardia

[0291] [Table 28]

[0292] Compound A was well tolerated, had no unexpected safety findings, and had an overall profile similar to that seen in the IPF cohort. Other than hypotension, the adverse event profile generally favored the 60 mg group compared with placebo.

[0293] The PPF cohort experienced a dose-dependent reduction in blood pressure on day 1, which was similar in magnitude to that seen in the IPF cohort. Orthostatic hypotension (asymptomatic and symptomatic) was higher in the 60 mg group than in the other groups. There were two cases of syncope and one case of presyncope, all in the placebo group.

[0294] Example 5: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy, safety, and tolerability of Compound A in participants with progressive pulmonary fibrosis (PPF) Scientific basis for study design Rationale for dose escalation phase: In a Phase 2 study, Compound A was initially administered at 30 mg or 60 mg twice daily (BID), resulting in a reduction in blood pressure. In a Phase 1 study, Compound A was administered at the same dose and at higher doses. PK / PD modeling and simulations (based on Phase 1 and Phase 2 blood pressure results) suggest that the BP reduction observed in the study on day 1 may be mitigated by dose escalation. Therefore, a dose-escalation plan with BP monitoring is being implemented to ensure safety and assess the impact of dose escalation on BP and clinical events associated with low BP.

[0295] Study design rationale: The primary endpoint for Cohort 1 was the number of spontaneous syncope episodes occurring in the Compound A 120 mg and PBO groups from the first dose of Compound A 120 mg through the Week 4 visit. No syncope events occurred in the Compound A 30 and 60 mg groups in the Phase 2 study. Post-dose decreases in SBP were observed in these groups on Day 1 of dosing; these decreases were self-limiting and not associated with any clinical sequelae. Spontaneous syncope is a clinically meaningful indicator of hypotension and will be monitored and reviewed in Cohort 1 of the study to allow for a decision to advance the 120 mg dose of the compound.

[0296] The primary endpoint selected for Cohort 2 in this phase 3 trial is similar to that of other IPF and PPF trials of approved therapies. Phase 3 pirfenidone and nintedanib IPF trials demonstrated a benefit in FVC in actively treated patients compared with PBO after 72 and 52 weeks of treatment, respectively. Furthermore, an absolute decline in FVC of 10% or more over a 6-month period has been shown to be associated with a nearly fivefold increase in the risk of death over the following 1-year period. Even a decline in FVC of just 10% was predictive, more than doubling the risk of death over the following year. In summary, FVC has been established to represent a robust clinical measure that is the gold standard for determining disease progression, and categorical declines in FVC are a strong predictor of mortality.

[0297] The secondary endpoints selected for Cohort 2 in this Phase 3 study are similar to those in other IPF and PPF studies and are well suited to robustly assessing efficacy and safety. In this Phase 3 study, the placebo-controlled study period will be extended beyond 52 weeks to increase the likelihood that Compound A will demonstrate clinically meaningful benefits beyond FVC, such as pulmonary fibrosis-related hospitalizations, acute exacerbations, patient-reported outcomes (PRO) data, and potentially survival, adverse events (AEs), serious adverse events (SAEs), and other safety measures.

[0298] Given that the placebo-controlled period will extend beyond 52 weeks and that this participant population may require urgent treatment, and that disease worsening criteria have been built into the study, participants who experience a disproportionate decline in FVC over time or an acute exacerbation or hospitalization related to progression of pulmonary fibrosis may be transitioned to double-blind active investigational treatment.

[0299] Study population Key selection criteria Participants were eligible for inclusion in the study if all of the following criteria were met: 1) Aged 21 or older at the time of signing the informed consent form (ICF). 2) Clinical diagnosis of ILD and one of the following PPF progression criteria: a) Imaging and evidence of prior progression by FVC and / or symptoms: centrally read HRCT with >10% parenchymal fibrosis throughout the lung at screening and features consistent with progressive ILD within the 24 months prior to screening, defined as: i) A decrease of 10% or more in relative ppFVC, or ii) A pre-screening chest computed tomography scan showing a 5% to less than 10% decrease in relative ppFVC compared to the previous scan and an increase in the degree of fibrosis; or iii) A 5% to less than 10% decline in relative ppFVC and symptoms associated with progression of ILD, or iv) symptoms associated with progression of ILD and an increase in the degree of fibrosis on pre-screening chest computed tomography compared with previous images. 3) Predicted forced vital capacity (ppFVC) ≥ 40%. 4) Forced expiratory volume in 1 second (FEV1) / FVC≧0.7. 5) Single-breath, hemoglobin-corrected, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 25%. 6) If using pirfenidone or nintedanib, participants must have been on a stable dose for at least 3 months (90 days) prior to screening, during the screening period, and until randomization (Day 1). 7) If not currently using pirfenidone or nintedanib, participants must not have received either of these medications within 4 weeks prior to screening. 8) Participants with rheumatoid arthritis-ILD. Participants with sarcoidosis and other CTD-ILD will be allowed per DMC recommendation after initial safety review. 9) Women of childbearing potential must use highly effective contraception (if using hormonal methods, a barrier method must also be used). a) A negative pregnancy serum test prior to Day 1 and a negative pregnancy urine / serum test prior to study treatment administration on Day 1. 10) Men who have sexual contact with women of childbearing potential agree to use male barrier contraception.

[0300] In the PPF study, participants will be randomized in a 1:1:1 ratio to receive either 60 mg or 120 mg of Compound A or matching placebo orally twice daily (BID). Approximately equal numbers of participants will be randomized to each treatment group. Stable background antifibrotic therapy with nintedanib or pirfenidone will be permitted. Similarly, specific background immunosuppressive therapy targeting ILD will be permitted. The study will use a two-cohort design.

[0301] Cohort 1 will be a single-blind design. The research team, investigators, participants, and families will be blinded to participant-level treatment assignment, but the Internal Review Committee (IRC) will not be blinded to all Cohort 1 data. Cohort 1 will enroll approximately 60 participants with PPF to evaluate the safety and tolerability of Compound A. During the first 4 weeks of treatment, the IRC will closely monitor the occurrence of spontaneous syncopal events in the Compound A 120 mg treatment group in both Phase 3 studies. These episodes are defined as a clinical syndrome in which a period of insufficient cerebral blood flow and oxygen supply causes a temporary loss of consciousness, most often resulting from a sudden drop in systemic blood pressure, with spontaneous recovery in participants without a history of syncope. After reviewing all available data, the IRC will determine whether: Continue Cohort 1 without modification (fewer than two spontaneous syncopal events without alternative etiology in the Compound A 120 mg group compared with PBO, and no unfavorable safety profile compared with PBO occurring in Cohort 1 of this study or the IPF study; evaluation will be performed by the IRC), and initiate Compound A 60 mg, 120 mg, and PBO groups in Cohort 2, or Terminate the Compound A 120 mg group in Cohort 1 (two or more spontaneous syncopal events without another possible etiology in the Compound A 120 mg group compared to PBO, or an unfavorable safety profile compared to PBO occurring in Cohort 1 of this study or the IPF study; evaluation will be performed by the IRC). All participants in the Compound A 120 mg group in Cohort 1 are encouraged to complete an early termination visit and a safety follow-up visit approximately 28 days after their last dose of investigational drug (IMP). Cohort 1 participants in the blinded Compound A 60 mg or PBO groups will continue in Cohort 1 until EOS. If the IRC decides to discontinue the Compound A 120 mg group in Cohort 1, this dose will not be initiated in Cohort 2, which will include only the Compound 60 mg and PBO groups.

[0302] Subsequently, Cohort 2 will enroll PPF participants based on IRC assessment of spontaneous syncopal events occurring in Cohort 1 from either the PPF or IPF trial, whichever completes enrollment first.

[0303] Cohort 2 will be a registrational, double-blind design, whereby the sponsor, investigators, participants, and families will remain blinded to treatment assignment. Cohort 2 will investigate the efficacy, safety, and tolerability of Compound A compared to PBO. The treatment arm for Cohort 2 will be determined by the results of the IRC review of Cohort 1 data and will be one of the following options: Approximately 1,032 participants with PPF will be randomized 1:1:1 to Compound A 60 mg, 120 mg, or PBO BID in three treatment arms; or Approximately 688 participants with PPF will be randomized 1:1 to Compound A 60 mg or PBO BID in two treatment arms.

[0304] Screening period (maximum 6 weeks) Treatment Duration The treatment duration will be approximately 4 years from the Day 1 visit of the first randomized participant in Cohort 1 to the End of Treatment (EOT) visit of the last participant in Cohort 2 (participants' individual study duration can be a minimum of 52 weeks to a maximum of approximately 4 years, depending on when the last participant completes the 52-week endpoint visit).

[0305] From day 1 to the 52-week visit Titration Period: A minimum of 2 consecutive days of dosing is required between titration visits from Day 1 (the day of the first dose of IMP) through Day 16. If any low BP criteria are met during titration, participants must either rechallenge at the next visit or discontinue treatment.

[0306] Post-titration period to EOT EOT is defined as when the last participant completes their last scheduled treatment visit according to the activity schedule. The last participant's EOT visit is defined as the completion of the 52-week visit. Once the last participant's scheduled 52-week visit date is known, an EOT visit will be triggered for all participants on treatment. The primary endpoint will be obtained at 52 weeks.

[0307] The last participant is defined as the participant who completed the last safety follow-up visit. Post-Treatment Safety Follow-Up (SFU) period (28 days after the last dose of IMP)

[0308] Objectives and Endpoints The primary objective of Cohort 1 is to evaluate the safety of Compound A 120 mg BID dose through the Week 4 visit. The primary endpoint for Cohort 1 is the number of spontaneous syncope episodes occurring in the Compound A and PBO groups during the period beginning with the first dose of Compound A and ending with the Week 4 visit.

[0309] Secondary objectives for Cohort 1 are to evaluate the safety and tolerability of Compound A 60 mg and 120 mg BID compared with PBO until the end of the study. Secondary endpoints include discontinuation rates due to any AEs related to low BP and safety assessment of Compound A 60 mg and 120 mg until the end of the study.

[0310] The primary, key secondary, secondary and exploratory objectives for Cohort 2 are listed below.

[0311] [Table 29]

[0312] [Table 30]

[0313] [Table 31]

[0314] Treatment period (Day 1 - End of treatment) The study will end when the last participant reaches week 52. Treatment duration can be up to approximately 3.5 years for any one participant, depending on when the participant enrolls.

[0315] Randomization All participants will be randomized in a blinded manner using the Interactive Response Technology (IRT) system. Two separate randomization sequences will be performed for the two cohorts. In Cohort 1, participants will be randomized before Cohort 2. In Cohort 1, eligible participants will be randomized 1:1:1 to Compound A 60 mg, 120 mg, and PBO, BID. Safety data from Cohort 1 will be reviewed at Week 4.

[0316] If the decision is made to continue Compound A 120 mg in Cohort 1, eligible participants will be enrolled in Cohort 2 and randomized 1:1:1 to Compound A 60 mg, 120 mg, and PBO BID. If the decision is made to discontinue Compound A 120 mg in Cohort 1, eligible participants will be enrolled in Cohort 2 and randomized 1:1 to Compound A 60 mg and PBO BID.

[0317] Stratification Randomization will be stratified by the following factors for both Cohort 1 and Cohort 2: UIP pattern (present vs. absent) (UIP pattern will be verified during screening by centrally read screening HRCT or verified by surgical lung biopsy or transbronchial cryobiopsy previously obtained during a previous clinical diagnostic evaluation for ILD). Identification of UIP pattern by cryobiopsy or by genomic typing will be considered on a case-by-case basis (in collaboration with medical monitor and central study team). UIP confirmation by genomic typing will be considered on a case-by-case basis. The study will enroll approximately 60% of participants with a verified UIP pattern at screening across all treatment arms. · Background therapy: antifibrotic therapy (pirfenidone or nintedanib with or without immunosuppression) vs. immunosuppression alone (mycophenolate mofetil [MMF], mycophenolic acid [MA], azathioprine [AZA], or tacrolimus), none.

[0318] Key components from Day 1 to Week 52 include: Primary endpoint at Week 52. No initiation or switch of antifibrotic therapy within the first 52 weeks.

[0319] Visit 1 (Day 1 / Week 1) includes randomization, first dose, spirometry, BP monitoring and other safety and clinical assessments.

[0320] Visits 2-4 (Weeks 1-2) are dose adjustment visits, 2-4 days apart, that include dose titration, BP monitoring, and overall safety assessment. Visits 2 and 3 may be on-site or remote visits (e.g., telephone, video, or virtual platform, depending on local and national capabilities or regulations). See below for details on the BP titration phase.

[0321] Visits 5-13 (Weeks 4 through 52) will occur at 6-week intervals starting at Week 4 and will include spirometry, regular BP monitoring, and other safety and clinical assessments according to the assessment schedule (included in the full protocol). Post-dose adjustment visits will include visits at the following weeks (W): W4, W10, W16, W22, W28, W34, W40, W46, and W52. See below for details on the blood pressure (BP) monitoring plan (including dose titration, BP assessments, and low BP criteria).

[0322] Key components from week 52 onwards include: From week 52 until the end of the study, visits will occur every 12 weeks with spirometry, regular BP monitoring and other safety and clinical assessments according to the schedule of assessments (included in the full protocol).

[0323] Participants will continue double-blind, placebo-controlled treatment beyond week 52 to obtain clinical efficacy and safety outcomes.

[0324] The study allows potential escape to double-blind active treatment due to progressive disease based on the following escape criteria: Any absolute ppFVC decline: ≥ 10% within the past 6 months, or ≥ 15% within the past 12 months Confirmed at the second visit between 4 and 12 weeks (including scheduled outpatient visits or the next scheduled visit), or respiratory-related respiratory hospitalization due to disease progression, or Acute exacerbation.

[0325] If a participant meets the eligibility criteria for escape, under blinded conditions the participant may escape to the double-blind active treatment as follows: PBO participants: randomized to 60 mg or 120 mg BID dose 60 mg participants: Titrate to 120 mg BID dose 120mg participants: Continue with 120mg BID dose

[0326] After week 52, initiation of or switching to currently approved antifibrotic therapy (nintedanib or pirfenidone) is permitted at the discretion of the PI.

[0327] New antifibrotic therapies that may become available after the start of this study will not be permitted at any time during this study.

[0328] All participants who complete the study have the option to participate in a separate rollover study with long-term active treatment.

[0329] Blood Pressure Monitoring Plan BP assessment: Sitting SBP measurements will be assessed pre-dose and 1, 2, and 4 hours post-dose according to the titration schedule (see below). BP monitoring will be performed in this study and will be feasible at the site if the following BP criteria are met at specific visits:

[0330] Low BP criteria definition: Low BP criteria for Visits 1, 2, and 3 (i.e., initiation of 10, 30, and 60 mg, respectively): Sitting systolic blood pressure less than 85 mmHg 4 hours after administration, or There are clinically significant events of BP reduction that, in the opinion of the investigator, justify a pause in dose escalation.

[0331] Visit 4 Low BP Criteria (i.e., starting 120 mg): Sitting systolic blood pressure less than 85 mmHg 4 hours after administration, or A decrease in systolic blood pressure from pre- to post-administration of at least 25% and a post-administration systolic blood pressure of less than 95 mmHg, or There are clinically significant events of BP reduction that, in the opinion of the investigator, justify a pause in dose escalation.

[0332] 4 dose escalation phases (Days 1-10*): The titration period is intended to be completed in 7-16 days, with at least 2 consecutive days of administration between titration visits. Overall, the titration period may be extended up to 21 days to accommodate unforeseen circumstances or logistics. If low BP criteria are met during titration, refer to the titration plan or discontinue treatment.

[0333] [Table 32]

[0334] Incremental Plan: Visit 1 / Day 1 (Blinded 10 mg or PBO): Participants will receive their first dose of blinded IMP (10 mg / PBO) on Day 1.

[0335] If low BP criteria are not met 4 hours after administration, proceed to the next titration visit (Visit 2, completed 2–3 days later).

[0336] If low BP criteria are met 4 hours after administration, the evening dose will be withheld, no further doses will be administered, and the patient will be rechallenged with blinded 10 mg / PBO at the next visit (Visit 1A to be completed within 14 days).

[0337] If low BP criteria are not met 4 hours after rechallenge, participants will continue blinded 10 mg / PBO and proceed to the next titration at Visit 2, which will be completed 2–3 days later.

[0338] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0339] Visits 2 and 3 (V2: blinded 30 mg or PBO; V3: blinded 60 mg or PBO): Participants will receive the escalated, blinded dose level of IMP (V2: 30 mg / PBO; V3: 60 mg / PBO) for the first time. Either in-person or remote visits will be conducted at the discretion of the site, investigator, and / or participant. For remote visits, home BP assessments will be performed with a standardized BP cuff provided by the sponsor vendor.

[0340] If the post-dose low BP criterion is not met at 4 hours, proceed to the next titration visit (Visit 3 or Visit 4, completed in 2-3 days).

[0341] If hypotension criteria were met 4 hours after administration, participants received the previous blinded IMP (from V1: 10 mg / PBO in the evening of V2; from V2: 30 mg / PBO in the evening of V3) in the evening dose and on subsequent days, and the blinded IMP (for V2A: 30 mg / PBO; for V3A: 60 mg / PBO) was rechallenged at the next visit (Visit 2A or 3A completed within 7 days).

[0342] If the low BP criteria are not met 4 hours after rechallenge, participants will continue on the blinded IMP and proceed to the next titration at Visit 3 or Visit 4, which will be completed 2–3 days later.

[0343] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0344] Visit 4 (blinded 120 mg or 60 mg or PBO): Some participants will receive increased blinded IMP at 120 mg for the first time, while others will continue to receive 60 mg or PBO.

[0345] If low BP criteria are not met 4 hours after administration, proceed to the next scheduled visit (Visit 5 completed at Week 4).

[0346] If hypotension criteria are met 4 hours after administration, participants will receive the previous blinded IMP (60 mg / PBO) in the evening dose and on subsequent days, and will be rechallenged with blinded IMP (120 mg / 60 mg / PBO) at the next visit (Visit 4A to be completed within 7 days).

[0347] If low BP criteria are not met 4 hours after rechallenge, participants will continue blinded 60 mg / PBO and proceed to Week 4 at Visit 5, which will be completed 2–3 days later.

[0348] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0349] *If a participant needs to be rechallenged more than once over the course of the titration plan, the sponsor's medical monitor or study director must be consulted.

[0350] *At each titration visit, participants are encouraged to eat a snack or light meal prior to dosing.

[0351] [Table 33]

[0352] Example 6: A multicenter, randomized, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy, safety, and tolerability of Compound A in participants with idiopathic pulmonary fibrosis (IPF) Scientific basis for study design Rationale for dose escalation phase: In a Phase 2 study, Compound A was shown to reduce blood pressure when initially administered at 30 mg or 60 mg, and in a Phase 1 study at the same and higher doses. PK / PD modeling and simulations suggest that the BP reduction observed on day 1 after dosing in the study may be mitigated by dose escalation. Therefore, a dose-escalation plan with BP monitoring is being implemented to ensure safety and evaluate the impact of dose escalation on BP and clinical events related to low BP.

[0353] Study design rationale: The primary endpoint for Cohort 1 was the number of spontaneous syncope episodes occurring in the Compound A 120 mg and PBO groups from the first dose of Compound A 120 mg through the Week 4 visit. No syncope events occurred in the Compound A 30 and 60 mg groups in the Phase 2 study. Post-dose decreases in SBP were observed in these groups on Day 1 of dosing; these decreases were self-limiting and not associated with any clinical sequelae. Spontaneous syncope is a clinically meaningful indicator of hypotension and will be monitored and reviewed in Cohort 1 of the study to allow for a decision to advance the 120 mg dose of the compound.

[0354] The primary endpoint selected for Cohort 2 in this phase 3 trial, specifically the absolute decline in FVC (mL), is similar to that of other IPF trials involving approved therapies. Phase 3 pirfenidone and nintedanib IPF trials demonstrated a benefit in FVC in actively treated patients compared with PBO after 72 and 52 weeks of treatment, respectively. Furthermore, a 10% or greater absolute decline in FVC over a 6-month period has been shown to be associated with a nearly fivefold increase in the risk of death over the subsequent 1-year period. Even a decline of just 10% FVC was predictive, resulting in a more than twofold increase in the risk of death over the following year. In summary, it has been established that FVC represents a robust clinical measure that is the gold standard for determining disease progression, and categorical declines in FVC are a strong predictor of mortality.

[0355] The secondary endpoints selected for Cohort 2 in this Phase 3 study are similar to those in other IPF studies and are well suited to robustly assessing efficacy and safety. In this Phase 3 study, the placebo-controlled study period will be extended beyond 52 weeks to increase the likelihood that Compound A will demonstrate clinically meaningful benefits beyond FVC, such as respiratory-related respiratory hospitalizations, acute exacerbations, patient-reported outcomes (PROs), and potentially survival, adverse events (AEs), serious adverse events (SAEs), and other safety measures.

[0356] Given that the placebo-controlled period will extend beyond 52 weeks and that this participant population may require urgent treatment, and that disease worsening criteria have been built into the study, participants who experience a disproportionate decline in FVC over time or an acute exacerbation or hospitalization related to progression of pulmonary fibrosis may be transitioned to double-blind active investigational treatment.

[0357] Study population Key selection criteria Participants were eligible for inclusion in the study if all of the following criteria were met: 1) Age 40 or older at the time of signing the informed consent form (ICF). 2) Diagnosis of IPF within 7 years prior to screening. 3) The diagnosis of IPF is supported by a centrally read chest high-resolution computed tomography (HRCT) obtained at screening: HRCT interpretation is consistent with definite or probable UIP. If central HRCT interpretation is inconsistent with UIP (most consistent with an indeterminate or non-IPF diagnosis), surgical lung biopsy histopathology should be confirmed to be consistent with UIP. Identification of UIP pattern by frozen biopsy or genomic typing will be considered on a case-by-case basis (in collaboration with medical monitors and central testing teams). 4) Predicted forced vital capacity (ppFVC) ≥ 40. 5) Forced expiratory volume in 1 second (FEV1) / FVC≧0.7. 6) Single-breath, hemoglobin-corrected, percent predicted diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 25%. 7) If using pirfenidone or nintedanib, participants must have been on a stable dose for at least 90 days prior to screening. 8) If not currently using pirfenidone or nintedanib, participants must not have received either of these medications within 28 days prior to screening. 9) Women of childbearing potential must use highly effective contraception (if using hormonal methods, a barrier method must also be used). Negative pregnancy serum test prior to Day 1 and negative pregnancy urine / serum test prior to study treatment administration on Day 1. 10) Men who have sexual contact with women of childbearing potential agree to use male barrier contraception.

[0358] A total of approximately 1,125 participants with IPF will be randomized in a 1:1:1 ratio to receive either 60 mg or 120 mg of Compound A or matching placebo orally twice daily (BID). Approximately 375 participants will be randomized to each treatment group. Stable background standard of care (SOC) therapy for IPF with nintedanib or pirfenidone will be permitted. Similarly, specific background immunosuppressive therapy targeting ILD will be permitted.

[0359] The study will use a two-cohort design.

[0360] Cohort 1 will be a single-blind design. The research team, investigators, participants, and families will be blinded to participant-level treatment assignment, but the Internal Review Committee (IRC) will not be blinded to all Cohort 1 data. Cohort 1 will enroll approximately 60 participants with IPF to evaluate the safety and tolerability of Compound A. Eligible participants will be randomized 1:1:1 to Compound A 60 mg or 120 mg or PBO BID. Cohort 1 will enroll and randomize participants before Cohort 2. Cohort 2 will then enroll and randomize participants with IPF based on the evaluation of spontaneous syncopal events (defined as a clinical syndrome in which a period of insufficient cerebral blood flow and oxygen supply causes a temporary loss of consciousness, most often resulting from a sudden drop in systemic blood pressure, with spontaneous recovery in participants without a history of syncope) from Cohort 1. Spontaneous syncopal episodes will be evaluated in the Compound A 120 mg treatment group compared to PBO to determine one of the following: Continue Cohort 1 without modification (fewer than two spontaneous syncopal episodes without alternative etiology in the Compound A 120 mg group compared to PBO, and no unfavorable safety profile compared to PBO; evaluation will be performed by the IRC) and initiate Compound A 60 mg, 120 mg, and PBO groups in Cohort 2, or Terminate the Compound A 120 mg group in Cohort 1 (two or more spontaneous syncopal episodes without another possible etiology in the Compound A 120 mg group compared to PBO, or an unfavorable safety profile compared to PBO; assessment will be performed by the IRC). All participants in the Compound 120 mg group in Cohort 1 are encouraged to complete an early termination visit and a safety follow-up visit approximately 28 days after the last dose of IMP. Cohort 1 participants in the blinded Compound A 60 mg or PBO groups will continue in Cohort 1 until EOS. If the IRC decides to discontinue the Compound A 120 mg group in Cohort 1, this dose will not be initiated in Cohort 2, which will include only the Compound A 60 mg and PBO groups.

[0361] Cohort 2 will be a registrational, double-blind design, whereby the sponsor, investigators, participants, and families will remain blinded to treatment assignment. Cohort 2 will investigate the efficacy, safety, and tolerability of Compound A compared to PBO. The treatment arm for Cohort 2 will be determined by the results of the IRC review of Cohort 1 data and will be one of the following options: Three treatment arms: Approximately 1,125 participants with IPF will be randomized 1:1:1 to Compound A 60 mg or 120 mg or PBO BID; or Approximately 750 participants with IPF will be randomized 1:1 to Compound A 60 mg or PBO BID in two treatment arms.

[0362] Screening period (maximum 6 weeks) Treatment Duration The treatment duration will be approximately 4 years from the Day 1 visit of the first randomized participant in Cohort 1 to the End of Treatment (EOT) visit of the last participant in Cohort 2 (participants' individual study duration can be a minimum of 52 weeks to a maximum of approximately 4 years, depending on when the last participant completes the 52-week endpoint visit).

[0363] A minimum of 2 consecutive days of dosing is required between titration visits from Titration Day 1 (the day of the first dose of IMP) through Day 16. If any low BP criteria are met during titration, participants must be rechallenged at the next visit or discontinue treatment.

[0364] Post-titration period to EOT EOT is defined as when each participant completes their last scheduled treatment visit according to their activity schedule. The last participant's EOT visit is defined as the completion of the 52-week visit. Once the last participant's scheduled 52-week visit date is known, an EOT visit will be triggered for all participants in treatment.

[0365] The primary endpoint will be obtained at 52 weeks.

[0366] The last participant is defined as the participant who completed the last safety follow-up visit.

[0367] Visit to participate in the rollover study or for a safety follow-up visit.

[0368] Post-treatment safety follow-up (SFU) period (28 days after the last dose of IMP). Objectives and Endpoints The primary objective of Cohort 1 is to evaluate the safety of Compound A 120 mg BID dose through the Week 4 visit. The primary endpoint for Cohort 1 is the number of spontaneous syncope episodes occurring in the Compound A and PBO groups during the period beginning with the first dose of Compound A and ending with the Week 4 visit.

[0369] Secondary objectives for Cohort 1 are to evaluate the safety and tolerability of Compound A 60 mg and 120 mg BID compared with PBO until the end of the study. Secondary endpoints include discontinuation rates due to any AEs related to low BP and safety assessment of Compound A 60 mg and 120 mg until the end of the study.

[0370] The primary, key secondary, secondary and exploratory objectives for Cohort 2 are listed below.

[0371] [Table 34]

[0372] [Table 35]

[0373] [Table 36]

[0374] [Table 37]

[0375] [Table 38]

[0376] Treatment period (Day 1 to end of treatment) The study will end when the last participant reaches week 52. Treatment duration can be up to approximately 3.5 years for any one participant, depending on when the participant enrolls.

[0377] Randomization All participants will be randomized in a blinded manner using the Interactive Response Technology (IRT) system. Two separate randomization sequences will be performed for the two cohorts. In Cohort 1, participants will be randomized before Cohort 2. In Cohort 1, eligible participants will be randomized 1:1:1 to Compound A 60 mg, 120 mg, and PBO, BID. Safety data from Cohort 1 will be reviewed at Week 4.

[0378] If the decision is made to continue Compound A 120 mg in Cohort 1, eligible participants will be enrolled in Cohort 2 and randomized 1:1:1 to Compound A 60 mg, 120 mg, and PBO BID. If the decision is made to discontinue Compound A 120 mg in Cohort 1, eligible participants will be enrolled in Cohort 2 and randomized 1:1 to Compound A 60 mg and PBO BID.

[0379] Stratification Randomization will be stratified by the following factors for both Cohort 1 and Cohort 2: - Approved combinations with both IPF drugs (pirfenidone, nintedanib, none) Gender (male vs. female)

[0380] Key components from Day 1 to Week 52 include: Primary endpoint at Week 52. No initiation or switch of antifibrotic therapy within the first 52 weeks.

[0381] Visit 1 (Day 1 / Week 1) includes randomization, first dose, spirometry, BP monitoring and other safety and clinical assessments.

[0382] Visits 2-4 (Weeks 1-2) are dose adjustment visits, 2-4 days apart, that include dose titration, BP monitoring, and overall safety assessment. Visits 2 and 3 may be on-site or remote visits (e.g., telephone, video, or virtual platform, depending on local and national capabilities or regulations). See below for details on the BP titration phase.

[0383] Visits 5-13 (Weeks 4 through 52) will occur at 6-week intervals starting at Week 4 and will include spirometry, regular BP monitoring, and other safety and clinical assessments according to the assessment schedule (included in the full protocol). Post-dose adjustment visits will include visits at the following weeks (W): W4, W10, W16, W22, W28, W34, W40, W46, and W52.

[0384] For details on the blood pressure (BP) monitoring plan (including dose titration, BP assessment, and low BP criteria), see below.

[0385] Key components from week 52 onwards include: From week 52 until the end of the study, visits will occur every 12 weeks with spirometry, regular BP monitoring and other safety and clinical assessments according to the schedule of assessments (included in the full protocol).

[0386] Participants will continue double-blind, placebo-controlled treatment beyond week 52 to obtain clinical efficacy and safety outcomes.

[0387] The study allows for potential escape to double-blind active IMP treatment due to progressive disease, based on the following escape criteria: Any absolute ppFVC decline: ≥ 10% within the past 6 months, or ≥ 15% within the past 12 months and confirmed at the second visit (scheduled outpatient or next scheduled visit) between weeks 4 and 12, or IPF-related respiratory hospitalization due to disease progression, or Acute exacerbation.

[0388] If a participant meets the eligibility criteria for escape, under blinded conditions the participant may escape to the double-blind active treatment as follows: PBO participants: randomized to 60 mg or 120 mg BID dose 60 mg participants: Titrate to 120 mg BID dose 120mg participants: Continue with 120mg BID dose

[0389] After week 52, initiation of or switching to currently approved antifibrotic therapy (nintedanib or pirfenidone) is permitted at the discretion of the PI.

[0390] New antifibrotic therapies that may become available after the start of this study will not be permitted at any time during this study.

[0391] All participants who complete the study have the option to participate in a separate rollover study with long-term active treatment.

[0392] Blood Pressure Monitoring Plan BP assessment: Sitting SBP measurements will be assessed pre-dose and 1, 2, and 4 hours post-dose according to the titration schedule (see below). BP monitoring will be performed in this study and will be feasible at the site if the following BP criteria are met at specific visits:

[0393] Low BP criteria definition: Low BP criteria for Visits 1, 2, and 3 (i.e., initiation of 10, 30, and 60 mg, respectively): Sitting systolic blood pressure less than 85 mmHg 4 hours after administration, or There are clinically significant events of BP reduction that, in the opinion of the investigator, justify a pause in dose escalation.

[0394] Visit 4 Low BP Criteria (i.e., starting 120 mg): Sitting systolic blood pressure less than 85 mmHg 4 hours after administration, or A decrease in systolic blood pressure from pre- to post-administration of at least 25% and a post-administration systolic blood pressure of less than 95 mmHg, or There are clinically significant events of BP reduction that, in the opinion of the investigator, justify a pause in dose escalation.

[0395] 4 dose escalation phases (Days 1-10*): The titration period is intended to be completed in 7-16 days, with at least 2 consecutive days of administration between titration visits. Overall, the titration period may be extended up to 21 days to accommodate unforeseen circumstances or logistics. If low BP criteria are met during titration, refer to the titration plan or discontinue treatment.

[0396] [Table 39]

[0397] Incremental Plan: Visit 1 / Day 1 (Blinded 10 mg or PBO): Participants will receive their first dose of blinded IMP (10 mg / PBO) on Day 1.

[0398] If the post-dose low BP criterion is not met at 4 hours, proceed to the next titration visit (Visit 2 is completed 2–3 days later).

[0399] If low BP criteria are met 4 hours after administration, the evening dose will be withheld, no further doses will be administered, and the patient will be rechallenged with blinded 10 mg / PBO at the next visit (Visit 1A to be completed within 14 days).

[0400] If low BP criteria are not met 4 hours after rechallenge, participants will continue blinded 10 mg / PBO and proceed to the next titration at Visit 2, which will be completed 2–3 days later.

[0401] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0402] Visits 2 and 3 (V2: blinded 30 mg or PBO; V3: blinded 60 mg or PBO): Participants will receive the escalated, blinded dose level of IMP (V2: 30 mg / PBO; V3: 60 mg / PBO) for the first time. Either in-person or remote visits will be conducted at the discretion of the site, investigator, and / or participant. For remote visits, home BP assessments will be performed with a standardized BP cuff provided by the sponsor vendor.

[0403] If the post-dose low BP criterion is not met at 4 hours, proceed to the next titration visit (Visit 3 or Visit 4, completed in 2-3 days).

[0404] If hypotension criteria were met 4 hours after administration, participants received the previous blinded IMP (from V1: 10 mg / PBO in the evening of V2; from V2: 30 mg / PBO in the evening of V3) in the evening dose and on subsequent days, and the blinded IMP (for V2A: 30 mg / PBO; for V3A: 60 mg / PBO) was rechallenged at the next visit (Visit 2A or 3A completed within 7 days).

[0405] If the low BP criteria are not met 4 hours after rechallenge, participants will continue on the blinded IMP and proceed to the next titration at Visit 3 or Visit 4, which will be completed 2–3 days later.

[0406] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0407] Visit 4 (blinded 120 mg or 60 mg or PBO): Some participants will receive increased blinded IMP at 120 mg for the first time, while others will continue to receive 60 mg or PBO.

[0408] If low BP criteria are not met 4 hours after administration, proceed to the next scheduled visit (Visit 5 completed at Week 4).

[0409] If hypotension criteria are met 4 hours after administration, participants will receive the previous blinded IMP (60 mg / PBO) in the evening dose and on subsequent days, and will be rechallenged with blinded IMP (120 mg / 60 mg / PBO) at the next visit (Visit 4A to be completed within 7 days).

[0410] If low BP criteria are not met 4 hours after rechallenge, participants will continue blinded 60 mg / PBO and proceed to Week 4 at Visit 5, which will be completed 2–3 days later.

[0411] If the rechallenge met the low BP criteria 4 hours after administration, the participant could rechallenge again at the discretion of the PI, or else treatment would be discontinued.

[0412] *If a participant needs to be rechallenged more than once over the course of the titration plan, the sponsor's medical monitor or study director must be consulted.

[0413] *At each titration visit, participants are encouraged to eat a snack or light meal prior to dosing.

[0414] [Table 40]

[0415] It is understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections are not intended to limit the scope of the disclosure and the appended claims in any way, as they may set forth one or more, but not all, exemplary aspects of the disclosure contemplated by the inventors.

[0416] This disclosure has been described above in terms of functional building blocks that illustrate implementations of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for convenience of description. Alternate boundaries may be defined so long as the specified functions and relationships thereof are appropriately performed.

[0417] The foregoing description of the specified embodiments fully reveals the general nature of the present disclosure so that others can readily modify and / or adapt such specific embodiments for various uses by applying knowledge within the skill of the art without undue experimentation and without departing from the general concepts of the present disclosure. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description, rather than limitation, as the terminology or terminology used herein can be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0418] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A method of treating interstitial lung disease in a subject in need thereof, comprising administering to the subject in need thereof Compound A: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof to the subject at one or more daily doses lower than a standard daily dose during a dose escalation treatment period, thereafter increasing said daily dose to said standard daily dose of Compound A, wherein said standard daily dose is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the dose-escalation treatment period is completed within 21 days.

3. 3. The method of claim 1 or 2, wherein the dose-escalation treatment period is completed within 14 days.

4. 4. The method of any one of claims 1 to 3, wherein the dose-escalation treatment period is completed within 10 days.

5. 5. The method of any one of claims 1 to 4, wherein the dose-escalation treatment period is completed within 7 days.

6. 6. The method of any one of claims 1 to 5, wherein the dose-escalation treatment period is completed within 5 days.

7. 7. The method of any one of claims 1 to 6, wherein the dose-escalating treatment period comprises a first treatment period and a second treatment period.

8. 8. The method of claim 7, wherein the initial treatment period is completed within seven days.

9. 9. The method of claim 7 or 8, wherein the initial treatment period is completed within 4 days.

10. 10. The method of any one of claims 7 to 9, wherein the initial treatment period is completed within 3 days.

11. The method of any one of claims 7 to 10, wherein the initial treatment period is completed within 2 days.

12. The method of any one of claims 7 to 11, wherein the initial treatment period is completed within one day.

13. 13. The method of any one of claims 7 to 12, wherein the second treatment period is completed within 7 days.

14. 14. The method of any one of claims 7 to 13, wherein the second treatment period is completed within four days.

15. 15. The method of any one of claims 7 to 14, wherein the second treatment period is completed within 3 days.

16. 16. The method of any one of claims 7 to 15, wherein the second treatment period is completed within 2 days.

17. 17. The method of any one of claims 7 to 16, wherein the second treatment period is completed within one day.

18. 18. The method of any one of claims 7 to 17, wherein the dose-escalation treatment period further comprises a third treatment period.

19. 20. The method of claim 18, wherein the third treatment period is completed within seven days.

20. 20. The method of claim 18 or 19, wherein the third treatment period is completed within four days.

21. 21. The method of any one of claims 18 to 20, wherein the third treatment period is completed within 3 days.

22. 22. The method of any one of claims 18 to 21, wherein the third treatment period is completed within 2 days.

23. 23. The method of any one of claims 18 to 22, wherein the third treatment period is completed within one day.

24. 1. A method of treating interstitial lung disease in a subject in need thereof, comprising administering to the subject Compound A: 【Chemistry 2】 at a daily dosage lower than a standard daily dosage during a first treatment period, followed by a daily dosage higher than during said first period but lower than said standard daily dosage, for a second treatment period, followed by increasing said dosage to said standard daily dosage, wherein said standard daily dosage is the equivalent of about 240 mg / day of Compound A or a pharmaceutically acceptable salt thereof.

25. 25. The method of claim 24, wherein the first treatment period and the second treatment period are each independently completed within seven days.

26. 26. The method of claim 24 or 25, wherein the first treatment period and the second treatment period are each independently completed within four days.

27. 27. The method of any one of claims 24 to 26, wherein the first treatment period and the second treatment period are each independently completed within 3 days.

28. 28. The method of any one of claims 24 to 27, wherein the first treatment period and the second treatment period are each independently completed within two days.

29. 29. The method of any one of claims 24 to 28, wherein the first treatment period and the second treatment period are each independently completed within one day.

30. 25. The method of claim 24, wherein increasing the dosage comprises administering the dosage at a daily dosage lower than the standard daily dosage for a third treatment period, followed by administering the standard daily dosage for a fourth treatment period.

31. 31. The method of claim 30, wherein the third treatment period is completed within seven days.

32. 32. The method of claim 30 or 31, wherein the third treatment period is completed within four days.

33. 33. The method of any one of claims 30 to 32, wherein the third treatment period is completed within 3 days.

34. 34. The method of any one of claims 30 to 33, wherein the third treatment period is completed within 2 days.

35. 35. The method of any one of claims 30 to 34, wherein the third treatment period is completed within one day.

36. 36. The method of any one of claims 1 to 35, wherein Compound A or a pharmaceutically acceptable salt thereof is administered once daily.

37. 37. The method of any one of claims 1 to 36, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily.

38. 38. The method of any one of claims 1 to 37, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally.

39. 39. The method of any one of claims 1 to 38, wherein Compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

40. 40. The method of any one of claims 1 to 39, wherein the subject is being treated with one or more additional therapies for interstitial lung disease.

41. 41. The method of claim 40, wherein the one or more additional therapies is pirfenidone.

42. 41. The method of claim 40, wherein the one or more additional therapies is nintedanib.

43. 43. The method of any one of claims 1 to 42, wherein Compound A or a pharmaceutically acceptable salt thereof is administered with food.

44. 44. The method of any one of claims 1 to 43, wherein Compound A or a pharmaceutically acceptable salt thereof is administered without food.

45. 45. The method of any one of claims 1 to 44, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

46. 45. The method of any one of claims 1 to 44, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

47. 47. The method of any one of claims 1 to 46, wherein the standard daily dose of Compound A is about 120 mg twice daily, or an equivalent amount of a pharmaceutically acceptable salt thereof.

48. 48. The method of any one of claims 7 to 47, wherein about 20 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered during the initial treatment period.

49. 49. The method of any one of claims 7 to 48, wherein about 10 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily during the initial treatment period.

50. 50. The method of any one of claims 7 to 49, wherein about 60 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered during said second treatment period.

51. 51. The method of any one of claims 7 to 50, wherein about 30 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily during the second treatment period.

52. 52. The method of any one of claims 18-23 or 31-51, wherein about 120 mg / day of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered during the third treatment period.

53. 53. The method of any one of claims 18-23 or 31-52, wherein about 60 mg of Compound A, or an equivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily during the third treatment period.

54. Compound A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a = 6.53 ± 0.10 Å alpha = 92.8 ± 1.0° b = 13.06 ± 0.10 Å beta = 95.5 ± 1.0° c = 14.04 ± 0.10 Å gamma = 93.0 ± 1.0° Volume 1189 (20) Å ３ Density (calculated value) 1.239 g / cm ３ temperature room temperature a single crystal structure having unit cell parameters substantially equal to b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more peaks at 2θ values ​​selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more peaks at 2θ values ​​selected from: 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2 and 27.8±0.2; e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an onset endotherm at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

54. The method of any one of claims 1 to 53, comprising a crystalline form characterized by at least one of:

55. 55. The method of any one of claims 1-54, wherein the subject experiences a smaller decline in forced vital capacity (FVC) after a period of treatment compared to an untreated subject.

56. The subject experiences a longer time to a first disease progression event after a treatment period than an untreated subject, and the first disease progression event is a decrease in absolute predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, respiratory-related hospitalizations, and All-cause mortality 56. The method of any one of claims 1 to 55, wherein the method is selected from:

57. 57. The method of any one of claims 1-56, wherein the subject experiences an increase in cough domain score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period that is less than an untreated subject.

58. 58. The method of any one of claims 1-57, wherein the subject experiences an increase in dyspnea score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period that is less than an untreated subject.

59. 1. A compound of formula I for use in treating interstitial lung disease in a subject in need thereof: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein Compound A is administered to the subject at a dosage lower than a standard daily dosage during an initial treatment period, thereafter the dosage is increased to the standard daily dosage of Compound A, wherein the standard daily dosage of Compound A is about 240 mg / day.

60. 64. The use of claim 62 or 63, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

61. 64. The use of claim 62 or 63, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

62. 1. A method for treating interstitial lung disease, comprising administering to a subject in need thereof about 240 mg / day of Compound A: 【Chemistry 4】 or an equivalent amount of a pharmaceutically acceptable salt thereof.

63. 63. The method of claim 62, wherein Compound A or a pharmaceutically acceptable salt thereof is administered once daily.

64. 63. The method of claim 62, wherein Compound A or a pharmaceutically acceptable salt thereof is administered twice daily.

65. 65. The method of claim 64, wherein about 120 mg of Compound A or an equivalent amount of a pharmaceutically acceptable salt thereof is administered twice daily.

66. 66. The method of any one of claims 62 to 65, wherein Compound A or a pharmaceutically acceptable salt thereof is administered orally.

67. 67. The method of claim 66, wherein Compound A or a pharmaceutically acceptable salt thereof is administered as a tablet.

68. 68. The method of any one of claims 62-67, wherein the subject is being concurrently treated with one or more therapies for interstitial lung disease.

69. 69. The method of claim 68, wherein the one or more pharmacological therapies is pirfenidone.

70. 69. The method of claim 68, wherein the one or more pharmacological therapies is nintedanib.

71. 71. The method of any one of claims 62 to 70, wherein Compound A or a pharmaceutically acceptable salt thereof is administered with food.

72. 72. The method of any one of claims 62 to 71, wherein Compound A or a pharmaceutically acceptable salt thereof is administered without food.

73. 73. The method of any one of claims 62 to 72, wherein the fibrosis is idiopathic pulmonary fibrosis (IPF).

74. 73. The method of any one of claims 62 to 72, wherein the fibrosis is progressive pulmonary fibrosis (PPF).

75. Compound A is a) a single crystal structure, Crystal system, space group triclinic system, P1 Unit cell dimensions a = 6.53 ± 0.10 Å alpha = 92.8 ± 1.0° b = 13.06 ± 0.10 Å beta = 95.5 ± 1.0° c = 14.04 ± 0.10 Å gamma = 93.0 ± 1.0° Volume 1189 (20) Å ３ Density (calculated value) 1.239 g / cm ３ temperature room temperature a single crystal structure having unit cell parameters substantially equal to b) a powder X-ray diffraction pattern substantially the same as that shown in Figure 1; c) a powder X-ray diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising two or more 2θ peaks selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 15.7±0.2, 18.2±0.2, 19.9±0.2, 21.6±0.2, 24.8±0.2, and 26.8±0.2; d) an X-ray powder diffraction pattern (obtained at room temperature and CuKα λ=1.5418 Å) comprising three or more 2θ peaks selected from 6.4±0.2, 6.8±0.2, 9.6±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 14.7±0.2, 15.7±0.2, 18.2±0.2, 18.7±0.2, 19.2±0.2, 19.9±0.2, 20.5±0.2, 21.6±0.2, 22.5±0.2, 23.1±0.2, 24.1±0.2, 24.8±0.2, 25.6±0.2, 26.8±0.2, 27.1±0.2, and 27.8±0.2; e) a differential scanning calorimetry thermogram substantially similar to that shown in Figure 2; f) a differential scanning calorimetry thermogram with an onset endotherm at about 152°C, and / or g) Thermogravimetric analysis thermogram substantially similar to that shown in Figure 3.

75. The method of any one of claims 62 to 74, comprising a crystalline form characterized by at least one of:

76. 76. The method of any one of claims 62-75, wherein the subject experiences a smaller decline in forced vital capacity (FVC) after a period of treatment compared to an untreated subject.

77. The subject has a longer time to a first disease progression event after a treatment period than an untreated subject, and the first disease progression event is: a decrease in absolute predicted forced vital capacity (ppFVC) of 10% or more from baseline; acute exacerbation of pulmonary fibrosis, Pulmonary fibrosis-related hospitalization, and All-cause mortality 77. The method of any one of claims 62 to 76, wherein the method is selected from:

78. 78. The method of any one of claims 62-77, wherein the subject experiences a smaller increase in cough domain score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than an untreated subject.

79. 79. The method of any one of claims 62-78, wherein the subject experiences a smaller increase in dyspnea score as determined by the Living with Pulmonary Fibrosis (L-PF) questionnaire over the treatment period than an untreated subject.

80. About 240 mg / day of Compound A for treating interstitial lung disease: 【Transformation 5】 or an equivalent amount of a pharmaceutically acceptable salt thereof.

81. 81. The use of claim 80, wherein the interstitial lung disease is idiopathic pulmonary fibrosis (IPF).

82. 81. The use of claim 80, wherein the interstitial lung disease is progressive pulmonary fibrosis (PPF).

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