Integrin inhibitors for reversal of fibrosis and collagen deposition

Abstract

The disclosure relates to methods of reversing or retarding progression of fibrosis in a subject (such as a human) in need thereof, and methods of reversing or retarding collagen deposition in a subject (such as a human) in need thereof, comprising administering to the subject a therapeutically effective amount of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject has a lung fibrotic disease, such as idiopathic pulmonary fibrosis, or a liver fibrotic disease such as primary sclerosing cholangitis. Methods of determining changes in collagen deposition in a subject following administration of a dual αvβ1 / αvβ6 integrin inhibitor, such as (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, are also disclosed herein.

Description

INTEGRIN INHIBITORS FOR REVERSAL OF FIBROSIS AND COLLAGENDEPOSITIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 646,901, filed on May 13, 2024, and U.S. Provisional Application No. 63 / 691,961, filed on September 6, 2024, the contents of each of which are incorporated by reference herein in their entirety.FIELD OF THE INVENTION

[0002] The disclosure relates to methods for reversing progression of fibrosis, retarding progression of fibrosis, reversing collagen deposition, and retarding collagen deposition in fibrotic diseases, such as idiopathic pulmonary fibrosis or primary sclerosing cholangitis.BACKGROUND OF THE INVENTION

[0003] Fibrosis, a pathologic feature of many diseases, is caused by a dysfunction in the body’s natural ability to repair damaged tissues. If left untreated, fibrosis can result in scarring of vital organs causing irreparable damage and eventual organ failure.

[0004] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing disease of unknown etiology, occurring in adults and limited to the lungs. In IPF, the lung tissue becomes thickened, stiff, and scarred. As lung fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the bloodstream and the organs do not receive the oxygen needed to function properly. IPF currently affects approximately 200,000 people in the U.S., resulting in 40,000 deaths per year. Patients diagnosed with IPF experience progressive breathlessness and eventually, complete respiratory failure.

[0005] Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is a chronic disease of the liver that causes damage and fibrosis in the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Over time, this leads to scarring and fibrosis in both the liver and biliary tract.

[0006] Available courses of treatment are scarce, as there are currently no options on the market proven to have an effect on long-term patient survival or symptomatology. For example, agents such as pirfenidone and nintedanib have been studied for treatment of fibrosis. In the treatment of IPF, pirfenidone and nintedanib have been used, but have shown less therapeutic efficacy than desired while also exhibiting numerous side effects. There remains a need for treatment of fibrotic diseases.

[0007] Several integrins, including avPi and avPe, have been proposed as mediators of TGF-P activation in fibrosis. The avPe integrin is expressed in epithelial cells and binds to the latency- associated peptide of transforming growth factor-pi (TGFpi) and mediates TGFpi activation. The expression level of avPe is significantly increased after injury to lung and cholangiocytes and it plays a critical in vivo role in tissue fibrosis. Increased levels of avPe are also associated with increased mortality in IPF and NSIP patients. A significant increase in levels of avpi has also been shown in lung tissue from patients with IPF (Decaris et al.. Respir Res. 2021; 22(I):265).

[0008] Primary sclerosing cholangitis (PSC) involves bile duct inflammation, and fibrosis that obliterates the bile ducts. The resulting impediment to the flow of bile to the intestines can lead to cirrhosis of the liver and subsequent complications such as liver failure and liver cancer. Expression of avPe is elevated in liver and bile duct of PSC patients.

[0009] To date, reversing fibrosis is recognized as a difficult endeavor, and achieving such a reversal would be of immense benefit to patients suffering from fibrotic diseases.BRIEF SUMMARY OF THE INVENTION

[0010] As detailed herein, the dual avPi / avPe integrin inhibitor (S)-4-((2-m ethoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, was demonstrated to reverse collagen deposition in human subjects with idiopathic pulmonary fibrosis (IPF). This is the first known demonstration of this striking result. Prior to this discovery, tissue damage from IPF was believed to be irreversible. The American Lung Association states that “[l]ung damage from IPF is irreversible and progressive, meaning it gets worse over time” (www.lung.org / lung-health-diseases / lung- disease-lookup / idiopathic-pulmonary-fibrosis). The National Health Service of the United Kingdom states that “[s]everal treatments can help reduce the rate at which IPF gets worse, but there's currently no treatment that can stop or reverse the scarring of the lungs”(www.nhs.uk / conditions / idiopathic-pulmonary-fibrosis / ). The reversal of collagen deposition demonstrated herein constitutes a tremendous advance in the treatment of IPF.

[0011] The disclosure provides a method of reversing progression of fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0012] The disclosure also provides a method of retarding progression of fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0013] The disclosure also provides a method of reversing collagen deposition in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0014] The disclosure also provides a method of retarding collagen deposition in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0015] In the method of reversing collagen deposition or the method of retarding collagen deposition, the collagen deposition may be in the subpleural region of a lung of the subject.

[0016] In the method of reversing collagen deposition or the method of retarding collagen deposition, collagen deposition after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be reduced relative to collagen deposition prior toa first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. For example, collagen deposition may be reduced at about 12 weeks after the first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0017] In any embodiments of the methods of reversing progression of fibrosis, retarding progression of fibrosis, reversing collagen deposition, or retarding collagen deposition, the subject may have a fibrotic disease. The fibrotic disease may be pulmonary fibrosis. The fibrotic disease may be idiopathic pulmonary fibrosis. The fibrotic disease may be liver fibrosis. The fibrotic disease may be primary sclerosing cholangitis.

[0018] In any embodiments of the methods of reversing progression of fibrosis, retarding progression of fibrosis, reversing collagen deposition, or retarding collagen deposition, the (S)- 4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, may be administered over at least about 12 weeks.

[0019] In any embodiments of the method of reversing progression of fibrosis, progression may be reversed after about 12 weeks following a first administration of the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof.

[0020] In any embodiments of the method of retarding progression of fibrosis, progression may be retarded after about 12 weeks following a first administration of the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof.

[0021] In any embodiments of the methods of reversing progression of fibrosis, retarding progression of fibrosis, reversing collagen deposition, or retarding collagen deposition, wherein the subject has lung fibrosis, cough severity in the subject after a first administration of (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, may be reduced relative to cough severity prior to the first administration of (S)-4-((2 -methoxy ethyl)(4-(5, 6,7, 8-tetrahydro- 1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or apharmaceutically acceptable salt thereof. Cough severity can be measured by the Cough Visual Analog Scale, as described further herein.

[0022] In any of the embodiments disclosed herein, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered orally.

[0023] In any of the embodiments disclosed herein, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered daily. Daily administration may be once daily administration, such as once daily oral administration.

[0024] In any of the embodiments disclosed herein, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered in an amount of about 160 mg to about 320 mg daily. In some embodiments, the daily administration is once daily oral administration in an amount of about 160 mg to about 320 mg daily.

[0025] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered in an amount of about 160 mg daily. In some embodiments, (S)- 4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered in an amount of about 240 mg daily. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may be administered in an amount of about 320 mg daily. Any such embodiments may employ once daily oral administration of the stated dosage amount.

[0026] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid may be administered as a phosphate salt, such as a crystalline Form I phosphate salt.

[0027] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid may be administered as a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, or a crystalline Form III naphthalenedisulfonic acid salt.

[0028] In any of the embodiments disclosed herein, the subject may be a human.

[0029] In some embodiments, the subject may be concurrently being treated with a standard of care for fibrosis. In some embodiments, the subject may not be concurrently treated with a standard of care for fibrosis. In some embodiments, the subject may not have been previously treated with a standard of care for fibrosis. In some embodiments, the standard of care for fibrosis comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

[0030] The disclosure also provides a method of determining a change in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor, comprising: a. administering a first dose of a collagen-binding probe to the subject; b. measuring the amount of the probe in a lung of the subject following administration of the first dose of the probe; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the probe to the subject; e. measuring the amount of the probe in the lung of the subject following administration of the second dose of the probe; and f. comparing the amount of the probe measured in the lung of the subject after administration of the first dose to the amount of the probe measured in the lung of the subject after administration of the second dose.

[0031] The disclosure also provides a method of determining a change in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor, comprising: a. administering a first dose of a collagen-binding probe to the subject; b. measuring the amount of the probe in a lung of the subject following the first administration of the probe; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the probe to the subject; e. measuring the amount of the probe in the lung of the subject following the second dose of the probe; and f. comparing the amount of the probe measured in the lung of the subject after the first dose to the amount of the probe measured in the lung of the subject after the second dose.

[0032] In some embodiments, the collagen-binding probe may be a radiotracer. The radiotracer may be a gallium-68-labeled peptide-based collagen binding probe (68GA-CBP). In some embodiments, the second dose of the probe may be administered at about 12 weeks afteradministration of the dual avPi / avPe integrin inhibitor. In some embodiments, the dual avPi / avPe integrin inhibitor may be administered over at least about 12 weeks. In some embodiments, the dual avPi / avPe integrin inhibitor may be administered over about 12 weeks. In some embodiments, the dual avPi / avPe integrin inhibitor may be (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0033] Also provided is (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in reversing progression of fibrosis in a subject in need thereof.

[0034] Also provided is (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in retarding progression of fibrosis in a subject in need thereof, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0035] Also provided is (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in reversing collagen deposition in a subject in need thereof.

[0036] Also provided is (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in retarding collagen deposition in a subject in need thereof, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)- 2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof .

[0037] Also provided is use of (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reversing progression of fibrosis in a subject in need thereof.

[0038] Also provided is use of (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for retarding progression of fibrosisin a subject in need thereof, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0039] Also provided is use of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reversing collagen deposition in a subject in need thereof.

[0040] Also provided is use of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for retarding collagen deposition in a subject in need thereof, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0041] Also provided are pharmaceutical compositions comprising (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use according to a method described herein, such as reversing fibrosis in a subject in need thereof.

[0042] Further provided is a kit comprising (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises instructions for use according to a method described herein, such as reversing fibrosis in a subject in need thereof. In some embodiments, the kit further comprises instructions for use according to a method described herein, such as reversing collagen deposition in a subject in need thereof.

[0043] In any of the methods or uses detailed herein, in some embodiments the subject is a human.BRIEF DESCRIPTION OF THE FIGURES

[0044] FIG. 1 depicts a schematic diagram of a study design associated with a randomized, double-blind, placebo-controlled Phase 2a collagen positron emission tomography (PET) imaging clinical trial of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast) in subjects with idiopathic pulmonary fibrosis (IPF).

[0045] FIG. 2 depicts a schematic diagram of the subject disposition associated with the study design of FIG. 1.

[0046] FIG. 3 depicts a graph showing the mean standard error (SE) change from the baseline in the top quartile standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with Gallium-68 radioisotope (68GA-CBP8) for treatment with 160 mg of bexotegrast and placebo at week 12.

[0047] FIG. 4 depicts a graph showing the least squares (LS) mean SE change from the baseline in forced vital capacity (FVC) (mL) for treatment with 160 mg of bexotegrast and placebo over a twelve-week time period.

[0048] FIG. 5 depicts a graph showing the LS mean SE change from the baseline in forced vital capacity percent predicted (FVCPP) (%) for treatment with 160 mg of bexotegrast and placebo at week 12.

[0049] FIG. 6 depicts a graph showing the mean SE change from the baseline in the visual analog scale (VAS) score for treatment with 160 mg of bexotegrast and placebo over a 12-week time period.

[0050] FIG. 7 depicts a graph showing the LS mean SE change from the baseline and the placebo (ng / mL) for N-terminal type III collagen propeptide (PRO-C3) associated with treatment with 160 mg of bexotegrast at 4 weeks and at 12 weeks, where * p < 0.05 vs. placebo.

[0051] FIG. 8 depicts a graph showing the LS mean SE change from the baseline and the placebo (pg / mL) for integrin beta-6 (ITGB6) associated with treatment with 160 mg of bexotegrast at 4 weeks and at 12 weeks.

[0052] FIG. 9 depicts a schematic diagram of the idiopathic pulmonary fibrosis (IPF) signaling pathway and the study objectives associated with the randomized, double-blind, placebo- controlled Phase 2 collagen deposition by PET imaging clinical trial of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid (bexotegrast) in subjects with IPF. “COL1 Al” refers to collagen type I alpha 1; “COL3A1” refers collagen type III alpha 1; “CTGF” refers to connective tissue growth factor; “ITGB6” refers to integrin beta-6; “LAP” refers to latency-associated peptide; “SMAD” refers to a family of proteins similar to the gene products of the Drosophila gene “mothersagainst decapentaplegic” (Mad) and the C elegans gene Sma; “TGF-P” refers to transforming growth factor-beta; “TIMP1” refers to tissue inhibitor matrix metalloproteinase 1.

[0053] FIG. 10 depicts a schematic diagram of the study design and subject disposition associated with the study objectives of FIG. 9. One participant in the bexotegrast group was non-adherent to the study drug (65%) and contracted COVID-19 during the first month on the study.

[0054] FIG. 11 depicts a graph showing the observed change in whole lung from baseline in top quartile standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with68GA-CBP8 for treatment with 160 mg of bexotegrast and placebo at week 12. Individual, median, and percentage change in top quartile SUV shown. The length of the box represents the interquartile range, and the vertical lines represent the maximum and minimum. Change in central region was of smaller magnitude than subpleural regions. The non-adherent / COVID-19 participant in the bexotegrast group is noted using dots in circles.

[0055] FIG. 12 depicts a graph showing the observed changes in subpleural lung regions from baseline in top quartile SUV of peptide-based collagen binding probe 8 tagged with68GA-CBP8 for treatment with 160 mg of bexotegrast and placebo at week 12. Individual, median, and percentage change in top quartile SUV shown. The length of the box represents the interquartile range, and the vertical lines represent the maximum and minimum. Change in central region was of smaller magnitude than subpleural regions. The non-adherent / COVID-19 participant in the bexotegrast group is noted using dots in circles.

[0056] FIG. 13 depicts PET images showing the observed changes within the lung from baseline in top quartile standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with Gallium-68 radioisotope (68GA-CBP8) for treatment with 160 mg of bexotegrast and placebo at week 12.

[0057] FIG. 14 depicts a graph showing the observed change from baseline in peak enhancement associated with treatment with 160 mg of bexotegrast and placebo. “DCE-MRI,” dynamic-contrast enhanced magnetic resonance imaging, was used to assess peak enhancement changes; Kwashout, washout rate of contrast from the lung. Contrast agent was gadoterate meglumine. Individual and mean change shown. The non-adherent / COVID-19 participant in the bexotegrast group is noted using dots in circles.

[0058] FIG. 15 depicts a graph showing the observed change from baseline in contrast washout rate associated with treatment with 160 mg of bexotegrast and placebo. “DCE-MRI,”dynamic-contrast enhanced magnetic resonance imaging, was used to assess peak enhancement changes; Kwashout, washout rate of contrast from the lung. Contrast agent was gadoterate meglumine. Individual and mean change shown. The non-adherent / COVID-19 participant in the bexotegrast group is noted using dots in circles.

[0059] FIG. 16 depicts a graph showing the LS (least squares) mean SE change from the baseline in FVC (forced vital capacity) (mL) for treatment with 160 mg of bexotegrast and placebo at week 12.

[0060] FIG. 17 depicts a graph showing the mean SE change from the baseline in the VAS (visual analog scale) score for treatment with 160 mg of bexotegrast and placebo over a 12-week time period.DETAILED DESCRIPTION OF THE INVENTION

[0061] The present disclosure provides, inter alia, a demonstration that collagen deposition in the lungs of subjects suffering from idiopathic pulmonary fibrosis (IPF) can be reversed, a surprising result for a disease symptom that has been considered irreversible up until this time. In the words of one researcher, “[i]diopathic pulmonary fibrosis (IPF) is a rare, chronic, progressive, irreversible and usually fatal disease” (Costabel, U. European Respiratory Revie , Mar 2015, 24 (135) 65-68, incorporated herein by reference in its entirety), indicating the grim outlook for this disease. Reversing fibrosis will be of tremendous benefit for subjects suffering from IPF.

[0062] The present disclosure provides, inter alia, a method of reversing a fibrotic disease in a subject, such as a human, in need thereof, comprising administering to the subject a therapeutically effective amount of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. Also provided is, inter alia, a method of reversing collagen deposition caused by a fibrotic disease in a subject, such as a human, in need thereof, comprising administering to the subject a therapeutically effective amount of (S)-4-((2 -methoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.Definitions

[0063] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

[0064] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0065] Unless clearly indicated otherwise, “a subject” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the subject is a human.

[0066] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include, but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of fibrosis. The methods of the invention contemplate any one or more of these aspects of treatment.

[0067] As used herein, “reversing fibrosis” means at least reversing collagen deposition in a subject, and may also include reversal of a fibrosis-associated symptom, such as reversing the loss of forced vital capacity in a subject who has idiopathic pulmonary fibrosis, or reversing the stiffening of an organ.

[0068] As used herein, “reversing collagen deposition” or “reversing deposition of collagen” signifies that the amount of collagen in a region of a subject has decreased. The region may be a location such as the lungs, the subpleural region of the lungs, the liver, or the bile ducts of the liver.

[0069] As used herein, the term “effective amount” intends such amount that should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, z.e., a single dose or multiple doses may be required to achieve the desiredtreatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or a pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0070] A “therapeutically effective amount” refers to an amount sufficient to produce a desired therapeutic outcome.

[0071] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0072] As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, z.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0073] As used herein, the term “composition” or “pharmaceutical composition” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. Pharmaceutical compositions may be prepared by known pharmaceutical methods. Suitable compositions, excipients, or carriers can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21sted. (2005), which is incorporated herein by reference in its entirety.

[0074] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g, the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of theother components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration, herein incorporated by reference in its entirety.

[0075] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to a subject. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), hereby incorporated by reference in its entirety. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0076] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or a pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. See, e.g., Handbook of Pharmaceutical Excipients. 6thEdition, Pharmaceutical Press (2008), hereby incorporated by reference in its entirety. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose de (de = “directly compressible”), honey de, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystallinecellulose), starch de, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0077] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments. The features of any specific embodiment can be applied to any other embodiments disclosed herein where practical.Compounds

[0078] (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid (bexotegrast) and pharmaceutically acceptable salts thereof are disclosed herein for use in the methods described herein. The structure of (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid is:

[0079] (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid inhibits both avPe integrin and avPi integrin. The synthesis of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid is disclosed in US Patent No. 10,793,564, which is incorporated by reference herein in its entirety, as Compound 5 of that patent, and specifically for methods of making the compound. Salts and polymorphs of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acidare disclosed in US Patent Application Publication No. 2022 / 0177468, which is incorporated by reference herein in its entirety and specifically for methods of making the salts and polymorphs of the compound. Dosages, dosage forms and methods of administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, including salts thereof and polymorphs thereof, are disclosed in US Patent No. 11,419,869 and US Patent Application Publication No. US 2023 / 0028658, each of which is incorporated by reference herein in its entirety and specifically for methods of making dosages and dosage forms of the compound.

[0080] The disclosure also includes all salts of compounds referred to herein, such as pharmaceutically acceptable salts. All forms of the compounds are also embraced, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the disclosure are also intended.

[0081] In some embodiments, the (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including crystalline Form I phosphate salt, crystalline Form IV phosphate salt, crystalline Form II fumarate salt, or crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is Form I phosphate salt. In some embodiments, the Form I phosphate salt of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid can have any one or more of the following characteristics: a. an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 4.31 (e.g., 4.31±0.2), about 6.76 (e.g., 6.76±0.2), about 18.89 (e.g., 18.89±0.2), about 21.29 (e.g., 21.29±0.2), and about 23.16 (e.g., 23.16±0.2) degrees; b. an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about 4.31 (e.g., 4.31±0.2), about 6.76 (e.g., 6.76±0.2), about 11.25 (e.g., 11.25±0.2), about 12.75 (e.g., 12.75±0.2), about 18.89 (e.g., 18.89±0.2), about 20.38 (e.g., 20.38±0.2), about 21.29(e.g., 21.29±0.2), about 23.16 (e.g., 23.16±0.2), about 23.97 (e.g., 23.97±0.2), and about 24.68 (e.g., 24.68±0.2) degrees; c. an X-ray powder diffraction (XRPD) pattern comprising peaks at angles 2-theta of about4.31 (e.g., 4.31±0.2), about 6.76 (e.g., 6.76±0.2), about 8.55 (e.g., 8.55±0.2), about 10.04 (e.g., 10.04±0.2), about 11.25 (e.g., 11.25±0.2), about 12.75 (e.g., 12.75±0.2), about 13.76(e.g., 13.76±0.2), about 17.20 (e.g., 17.20 ±0.2), about 18.02 (e.g., 18.02 ±0.2), about 18.89 (e.g., 18.89±0.2), about 20.38 (e.g., 20.38±0.2), about 21.29 (e.g., 21.29±0.2), about 23.16(e.g., 23.16±0.2), about 23.97 (e.g., 23.97±0.2), about 24.68 (e.g., 24.68±0.2), about 25.50(e.g., 25.50±0.2), about 26.18 (e.g., 26.18±0.2), about 29.88 (e.g., 29.88±0.2), and about33.49 (e.g., 33.49±0.2) degrees; d. endotherm peaks at about 88.3 °C, about 136.3 °C, and / or about 197.6 °C, as determined by differential scanning calorimetry (DSC); e. endotherm peaks at about 86.1 °C, about 140.8 °C, and / or about 197.0 °C, as determined by DSC; f. endotherm peaks at about 77.3 °C, 132.2 °C, and / or about 197.0 °C, as determined by DSC; g. endotherm peaks at about 95.2 °C, about 134.1 °C, and / or about 200.9 °C, as determined by DSC; h. a weight loss of about 5.21% after heating from about 26.5 °C to about 150.0 °C, as determined by thermogravimetric analysis (TGA); i. a weight loss of about 5.04% after heating from about 27.0 °C to about 110.0 °C, as determined by TGA; j. a weight loss of about 10.32% after heating from about 30.0 °C to about 150.0 °C, as determined by TGA; or k. a weight loss of about 7.37% after heating from about 27.0 °C to about 150.0 °C, as determined by TGA.

[0082] In some embodiments, the Form II fumarate salt of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid can have any one or more of the following characteristics: a. an XRPD pattern comprising peaks at angles 2-theta of about 8.47 (e.g., 8.47±0.2), about 10.51 (e.g., 10.51±0.2), about 13.98 (e.g., 13.98±0.2), about 23.70 (e.g., 23.70±0.2), and about 24.43 (e.g., 24.43±0.2) degrees;b. an XRPD pattern comprising peaks at angles 2-theta of about 8.47 (e.g., 8.47±0.2), about 9.37 (e.g., 9.37±0.2), about 10.51 (e.g., 10.51±0.2), about 13.98 (e.g., 13.98±0.2), about 16.20 (e.g., 16.20±0.2), about 17.26 (e.g., 17.26±0.2), about 23.70 (e.g., 23.70±0.2), about 24.01 (e.g., 24.01±0.2), about 24.43 (e.g., 24.43±0.2), and about 25.59 (e.g., 25.59±0.2) degrees; c. an XRPD pattern comprising peaks at angles 2-theta of about 6.87 (e.g., 6.87±0.2), about8.47 (e.g., 8.47±0.2), about 9.37 (e.g., 9.37±0.2), about 10.51 (e.g., 10.51±0.2), about 12.20 (e.g., 12.20±0.2), about 12.63 (e.g., 12.63±0.2), about 13.34 (e.g., 13.34±0.2), about 13.98(e.g., 13.98±0.2), about 16.20 (e.g., 16.20±0.2), about 17.26 (e.g., 17.26±0.2), about 18.11(e.g., 18.11±0.2), about 18.72 (e.g., 18.72±0.2), about 19.42 (e.g., 19.42±0.2), about 20.46(e.g., 20.46±0.2), about 21.87 (e.g., 21.87±0.2), about 22.15 (e.g., 22.15±0.2), about 23.70(e.g., 23.70±0.2), about 24.01 (e.g., 24.01±0.2), about 24.43 (e.g., 24.43±0.2), and about 25.59 (e.g., 25.59±0.2) degrees; d. an endotherm peak at about 95.4 °C, as determined by DSC; or e. a weight loss of about 13.02% after heating from about 26.0 °C to about 125.0 °C, as determined by TGA.

[0083] In some embodiments, the Form III 1,5-naphthalenedisulfonate salt of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid can have any one or more of the following characteristics: a. an XRPD pattern comprising peaks at angles 2-theta of about 15.87 (e.g., 15.87±0.2) and about 23.85 (e.g., 23.85±0.2) degrees; b. an XRPD pattern comprising peaks at angles 2-theta of about 12.58 (e.g., 12.58±0.2), about 15.87 (e.g., 15.87±0.2), about 16.77 (e.g., 16.77±0.2), about 23.85 (e.g., 23.85±0.2), and about 31.95 (e.g., 31.95±0.2) degrees; c. an XRPD pattern comprising peaks at angles 2-theta of about 3.17 (e.g., 3.17±0.2), about12.58 (e.g., 12.58±0.2), about 15.87 (e.g., 15.87±0.2), about 16.77 (e.g., 16.77±0.2), about18.78 (e.g., 18.78±0.2), about 23.85 (e.g., 23.85±0.2), about 25.30 (e.g., 25.30±0.2), about27.34 (e.g., 27.34±0.2), about 29.61 (e.g., 29.61±0.2), about 31.95 (e.g., 31.95±0.2), about38.05 (e.g., 38.05±0.2), and about 38.63 (e.g., 38.63±0.2) degrees; d. an endotherm peak at about 103.4 °C, as determined by DSC; or e. a weight loss of about 11.11% after heating from about 23.0 °C to about 150.0 °C, as determined by TGA.

[0084] In some embodiments, the Form IV phosphate salt of (S)-4-((2-m ethoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid can have any one or more of the following characteristics: a. an XRPD pattern comprising one or more (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten) peaks each assigned at angles 2-theta in degrees of about 4.14 (e.g., 4.14±0.2), about 20.02 (e.g., 20.02±0.2), about 21.57 (e.g., 21.57±0.2), about 6.64 (e.g., 6.64±0.2), about 25.22 (e.g., 25.22±0.2), about 15.18 (e.g., 15.18±0.2), about 21.79 (e.g., 21.79±0.2), about 11.20 (e.g., 11.20±0.2), about 11.65 (e.g., 11.65±0.2), and about 24.86 (e.g., 24.86±0.2). b. an XRPD pattern comprising one or more (e.g., at least one, at least two, at least three, at least four, or at least five) peaks each assigned at angles 2-theta in degrees of about 4.14 (e.g., 4.14±0.2), about 20.02 (e.g., 20.02±0.2), about 21.57 (e.g., 21.57±0.2), about 6.64 (e.g., 6.64±0.2), and about 25.22 (e.g., 25.22±0.2) c. an XRPD pattern comprising peaks assigned at angles 2-theta in degrees of about 4.14±0.2, about 6.64±0.2, and about 11.20±0.2. d. an XRPD pattern comprising peaks assigned at angles 2-theta in degrees of about 4.14±0.2, about 6.64±0.2, and about 15.18±0.2 e. an XRPD pattern comprising peaks assigned at angles 2-theta in degrees of about 4.14±0.2 and about 6.64±0.2.

[0085] Further characteristics of salts and polymorphs of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid are disclosed in US Patent Application Publication No. 2022 / 0177468, incorporated by reference herein in its entirety.

[0086] The disclosure also contemplates isotopically-labeled and / or isotopically-enriched forms of compounds described herein. The compounds described herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, wherein one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as2H,3H,nC,13C,14C,13N,15O,170,32P,35S,18F,36C1. Incorporation of heavier isotopes such as deuterium (2H or D) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosagerequirements and, hence may be preferred in some instances. As used herein, each instance of replacement of a hydrogen by deuterium is also a disclosure of replacing that hydrogen with tritium. As used herein, each instance of enrichment, substitution, or replacement of an atom with corresponding isotope of that atom encompasses isotopic enrichment levels of one of about: 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99,6%, 99.7%, 99.8%, 99.9%, or 100%, or a range between any two of the preceding percentages.

[0087] Isotopically-labeled compounds of the present disclosure can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described herein substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.

[0088] Preferably, the compounds detailed herein are administered orally. However, the compounds may also be formulated for parenteral (e.g., intravenous) administration.Pharmaceutical Compositions and Formulations

[0089] Pharmaceutical compositions of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a salt thereof, are embraced by this disclosure. Thus, the disclosure includes pharmaceutical compositions comprising (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.Pharmaceutical compositions according to the disclosure may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is a composition for controlled release of any form of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or salt thereof, detailed herein.

[0090] A compound detailed herein, or salt thereof, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or salt thereof, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories,ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs.

[0091] A compound detailed herein, or salt thereof, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21sted. (2005), which is incorporated herein by reference in its entirety.

[0092] Compounds as described herein, or salts thereof, may be administered to subjects (e.g., humans) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0093] Compositions comprising a compound provided herein, or salt thereof, are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in a method of reversing a disease or disorder as described herein.Methods of Use

[0094] Compounds and compositions as disclosed herein, such as a pharmaceutical composition containing (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a salt thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.

[0095] In one aspect, provided is a method of reversing progression of fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0096] In one aspect, provided is a method of retarding progression of fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0097] In one aspect, provided is a method of reversing collagen deposition in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0098] In one aspect, provided is a method of retarding collagen deposition in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, collagen deposition is in the subpleural region of a lung. In some embodiments, collagen deposition after a first administration of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to collagen deposition prior to a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, collagen deposition is reduced at about 12 weeks after the first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, collagen deposition is in the subpleural region of a lung of the subject. In some embodiments, collagen deposition in the subject after a first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to collagen deposition in the subject prior to the first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, collagen deposition in the subject is reduced at about 12 weeks after the first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the subject has a fibrotic disease. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the fibrotic disease is primary sclerosing cholangitis.

[0101] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered over at least about 12 weeks. In some embodiments, (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is administered over about 12 weeks.

[0102] In some embodiments, progression of fibrosis is reversed after about 12 weeks following a first administration of the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, progression of fibrosis is retarded after about 12 weeks following a first administration of the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, progression of collagen deposition is reversed after about 12 weeks following a first administration of the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, progression of collagen deposition is retarded after about 12 weeks following a first administration of the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the subject suffers from lung fibrosis. In certain embodiments, cough severity in the subject is reduced after a first administration of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, relative to cough severity in the subject prior to the first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity is measured by the Cough Visual Analog Scale, as described elsewhere herein. In some embodiments, the subject has lung fibrosis and cough severity after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to cough severity prior to a first administration of (S)- 4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity is measured by the Cough Visual Analog Scale.

[0107] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered daily.

[0108] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered as a phosphate salt. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered as a crystalline Form I phosphate salt. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered as a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, or a crystalline Form III naphthalenedisulfonic acid salt

[0109] In some embodiments, the subject is concurrently being treated with a standard of care for fibrosis. Thus, in some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered to the subject as an add-on therapy. In some embodiments, the standard of care for fibrosis comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the subject who is administered (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is also administered pirfenidone and / or nintedanib, such as concurrently or sequentially. In some other embodiments, the subject is not concurrently treated with a standard of care for fibrosis. In some embodiments, the subject has not been previously treated with a standard of care for fibrosis. Thus, in some embodiments, (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid is administered to a subject whose fibrosis is treatment naive. In some embodiments, the subject who is administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is treatment naive and is not concurrently or sequentially administered pirfenidone and / or nintedanib.

[0110] In some embodiments, the subject is a human. The subject, such as a human, may be in need of treatment, such as a human who has or is suspected of having a fibrotic disease.[OHl] In some embodiments, the fibrotic disease is fibrosis of the lung (pulmonary fibrosis) or of the liver (liver fibrosis).

[0112] In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is primary sclerosing cholangitis (PSC).

[0113] In some embodiments, the subject with IPF has a gender-age-physiology (GAP) stage, based on the gender-age-physiology (GAP) index system, of GAP Stage I. In some embodiments, the subject with IPF has a GAP stage of GAP Stage II. In some embodiments, the subject with IPF has a GAP stage of GAP Stage III. GAP stages are described in Lee SH et al., Respir Res. 2016 Oct 18; 17(1): 131, which is incorporated by reference herein in its entirety.

[0114] In any of the methods described herein, in one aspect, the subject is a human, such as a human in need of the method. The subject may be a human who has been diagnosed with having a fibrotic disease. The subject may be a human who is suspected of having a fibrotic disease.

[0115] The methods described herein may employ dosage forms, comprising a pharmaceutically acceptable carrier or excipient, and (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0116] In various embodiments, a dose, e.g., a dose for daily administration, can include (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of one of, or one of about: 160, 170, 175, 180, 190, 200, 225, 240, 250, 275, 300, or 320 milligrams. For example, a dose can include the compound in an amount of, or of about, 160 mg. A dose can include the compound in an amount of, or of about, 240 mg. A dose can include the compound in an amount of, or of about, 320 mg.

[0117] When (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is in a salt form, the weight of the salt is adjusted to administer the same amount of active agent on a molar basis as would be administered if the non-salt compound were used. For example, as used herein, “160 mg of (S)- 4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid,” refers to 160 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid. If a salt form is used, the appropriate amount would be administered to provide 160 mg of (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid in the non-salt form.

[0118] In some embodiments, the amount of the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, may include the compound in a percentage range about any of the individual values in milligrams recited in the preceding paragraphs, for example, any percentage range independently selected from one of, or one of about: ± 1%, ± 2%, ± 2.5%, ± 5%, ± 7.5%, or ± 10. For example, the range may be, or be about, ± 1%. The range may be, or be about, ± 2%. The range may be, or be about, ± 2.5%. The range may be, or be about, ± 5%. The range may be, or be about, ± 7.5%. The range may be, or be about, ± 10%.

[0119] Further, for example, the dose may include the compound in an amount of one of: 160 mg ± 1%; 160 mg ± 2%; 160 mg ± 2.5%; 160 mg ± 5%; 160 mg ± 7.5%; or 160 mg ± 10%. The dose may include the compound in an amount of one of: 240 mg ± 1%; 240 mg ± 2%; 240 mg ± 2.5%; 240 mg ± 5%; 240 mg ± 7.5%; or 240 mg ± 10%. The dose may include the compound in an amount of one of: 320 mg ± 1%; 320 mg ± 2%; 320 mg ± 2.5%; 320 mg ± 5%; 320 mg ± 7.5%; or 320 mg ± 10%.

[0120] For numerical values indicated herein with “about,” the numerical value can be replaced by plus or minus 10%, plus or minus 5%, plus or minus 2%, or plus or minus 1%. For example, “about 100” can be replaced by 90-110, 95-105, 98-102, or 99-101.

[0121] (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof once daily. That is, the total amount of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, which is to be administered each day, can be administered all together at one time daily. Alternatively, if it is desirable that the total amount is to be administered in two or more portions daily, the dosage form containing the appropriate amount of compound can be administered two times or more daily, such as twice a day, three times a day, or four times a day.

[0122] The present disclosure further contemplates combination administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, with a second drug, e.g., pirfenidone, a salt thereof, pharmaceutical formulations or dosage forms thereof, and related methods as described in U.S. Pat. Nos. 7,566,729, 7,635,707, 7,696,236, 7,767,225, 7,767,700, 7,816,383, 7,910,610, 7,988,994, 8,013,002, 8,084,475, 8,318,780, 8,383,150, 8,420,674,8,592,462, 8,609,701, 8,648,098, 8,753,679, 8,754,109, 8,778,947, 9,561,217, 10,188,637, and in each of the FDA approvals / labels / inserts for New Drug Application 208780 for ESBRIET® (pirfenidone) oral capsules and oral film-coated tablets, the approvals / labels / inserts dating fromJanuary 11, 2017 to July 31, 2019, accessed October 1, 2021 at URL. www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=overview.process&ApplNo=208780.The entire contents of each of the preceding documents are incorporated herein by reference.

[0123] A deuterated analog of pirfenidone has been reported to have a more favorable adverse event profile than pirfenidone (Chen el aC Clin Pharmacol Drug Dev. 2022 Feb;l l(2):220-234, doi: 10.1002 / cpdd.l040; herein incorporated by reference in its entirety). Deuterated pirfenidone analogs as disclosed in that publication, and in U.S. Patent Application PublicationNos. 2020 / 0093810 and 2021 / 0205283 and International Patent ApplicationNo. WO 2020 / 056430, can be used as the pirfenidone component in any of the compositions disclosed herein. In particular, the following deuterated analog can be used:pharmaceutically acceptable salt thereof. U.S. Patent ApplicationPublication Nos. 2020 / 0093810 and 2021 / 0205283 and International Patent Application No. WO 2020 / 056430 are incorporated herein by reference in their entireties.

[0124] The disclosure further contemplates combination administration of (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, with a second drug, e.g., nintedanib, salts thereof, pharmaceutical formulations or dosage forms thereof, and related methods as described in U.S. Pat. Nos. 6,762,180, 7,119,093, 9,907,756, 10,105,323, or 10,154,990, and in each of the FDA-approved labels or inserts for New Drug Application 205832 for OFEV® (nintedanib) oral capsules, the labels dating from October 15, 2014 to October 28, 2020, accessed October 1, 2021 at URL www.accessdata.fda.gov / scripts / cder / daf / index.cfm?event=overview.process&ApplNo=205832. The entire contents of each of the preceding documents are incorporated herein by reference in their entireties.

[0125] Administration of any drug, such as pirfenidone or nintedanib, can be associated with adverse events (AEs), which may rise to the level of serious adverse events (SAEs). A common AE associated with pirfenidone and nintedanib is gastrointestinal distress, such as diarrhea, which in many patients rises to the level of an SAE. An adverse event (AE) is considered a serious adverse event (SAE) when the patient outcome is death, life-threatening, hospitalization (initial or prolonged), disability or permanent damage, congenital anomaly / birth defect, required intervention to prevent permanent impairment or damage (due to the use of a medical product), or is otherwise considered an important medical event (see URL www.fda.gov / safety / reporting- serious-problems-fda / what-serious-adverse-event; herein incorporated by reference in its entirety; see also Kizer K.W, Stegun MB. Serious Reportable Adverse Events in Health Care. In: Henriksen K, Battles JB, Marks ES, Lewin DI, editors. Advances in Patient Safety: From Research to Implementation (Volume 4: Programs, Tools, and Products). Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Feb. PMID: 21250024, herein incorporated by reference in its entirety).

[0126] In some embodiments, no SAEs are observed. In some embodiments, no SAEs are observed over about 12 weeks.

[0127] In some embodiments, the subject does not require treatment for an adverse event up to 12 weeks. In some embodiments, the subject does not require treatment for an adverse event up to 24 weeks. In some embodiments, adverse events are selected from diarrhea, abdominal discomfort, and acute respiratory failure. In some embodiments, the subject does not require treatment for a severe adverse event up to 12 weeks. In some embodiments, the subject does not require treatment for a severe adverse event up to 24 weeks. In some embodiments, severe adverse events are selected from acute respiratory failure, pneumonia, acute exacerbation of idiopathic pulmonary fibrosis, and atrial flutter. In some embodiments, the subject does not require treatment for a gastrointestinal adverse event. In some embodiments, there is no dose relationship for adverse events.

[0128] In some embodiments, the method comprising administering to the subject (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is not accompanied by a serious adverse event. In some embodiments, the method comprises administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, wherein anincidence of adverse events is lower than an incidence of adverse events for a standard of care for a lung disorder. In some embodiments, the method comprises administering to the subject (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, wherein an incidence of adverse events is lower than an incidence of adverse events for a standard of care for a lung disorder, and wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the method comprises administering to the subject (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, wherein an incidence of adverse events is lower than an incidence of adverse events for a standard of care for a lung disorder, and wherein the adverse events are gastrointestinal adverse events. In some embodiments, the method comprises administering to the subject (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, wherein an incidence of adverse events is lower than an incidence of adverse events for a standard of care for a lung disorder, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib, and wherein the adverse events are gastrointestinal adverse events. In some embodiments, the (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0129] In some embodiments, the subject is undergoing concurrent treatment with standard of care therapy for fibrosis. In some embodiments, the subject is not undergoing concurrent treatment with standard of care therapy for fibrosis. In some embodiments, the subject is undergoing concurrent treatment with standard of care therapy for IPF. In some embodiments,the subject is not undergoing concurrent treatment with standard of care therapy for IPF. In some embodiments, standard of care therapy for IPF comprises administration of pirfenidone or nintedanib to the subject. In some embodiments, standard of care therapy for IPF comprises administration of pirfenidone and nintedanib to the subject. In some embodiments, standard of care therapy for IPF comprises administration of pirfenidone to the subject. In some embodiments, standard of care therapy for IPF comprises administration of nintedanib to the subject. In some embodiments, the pirfenidone is deuterated pirfenidone.

[0130] In various embodiments, a dose, e.g., a unit dose, such as a unit dose for daily administration, can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of one of, or one of about: 1, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 225, 240, 250, 275, 300, 320, 325, 350, 375, 400, 425, 450, 475, 480, 500, 525, 550, 560, 575, 600, 625, 640, 650, 675, 700, 720, 725, 750, 775, 800, 825, 850, 875, 880, 900, 925, 950, 960, 975, 1000, 1025, or 1040 milligrams. For example, a dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 10 mg. A dose can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 15 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 20 mg. A dose can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 30 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 40 mg. A dose can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 50 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or ofabout, 75 mg. A dose can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 80 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 100 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 120 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 160 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 240 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 320 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 400 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 480 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 560 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 640 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 720 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 800 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceuticallyacceptable salt thereof, in an amount of, or of about, 880 mg. A dose can include (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 960 mg. A dose can include (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount of, or of about, 1040 mg.

[0131] In various embodiments, a dose, e.g., a unit dose, such as a unit dose for daily administration, can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount in mg of about: 320, 400, 480, 560, 640, 720, 800, 880, 960, or 1040, or a range between any two of the preceding values.

[0132] In various embodiments, a dose, e.g., a unit dose, such as a unit dose for daily administration, can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount, in mg of about: 400, 480, 560, 640, 720, 800, 880, 960, or 1040.

[0133] In various embodiments, a dose, e.g., a unit dose, such as a unit dose for daily administration, can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount in mg of a range between about 320 and any one of about 400, 480, 560, 640, 720, 800, 880, 960, or 1040.

[0134] In various embodiments, a dose, e.g., a unit dose, such as a unit dose for daily administration, can include (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in an amount in mg of about: 400, 480, 560, 640, 720, 800, 880, 960, or 1040, or a range between any two of the preceding values.

[0135] In some embodiments, (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed at about 160 mg, about 240 mg, or about 320 mg. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed at about 160 mg. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or apharmaceutically acceptable salt thereof, is dosed at about 240 mg. In some embodiments, (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed at about 320 mg. In some embodiments, (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed at about 320 mg. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed BID or QD. As used herein, “BID” refers to dosing twice a day and “QD” refers to dosing once a day. In some embodiments, (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed for at least 4 weeks. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed for at least 8 weeks. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed for at least 12 weeks. In some embodiments, (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is dosed for at least 24 weeks. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt.

[0136] In some embodiments, the (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered in an amount of about 160 mg daily, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg of (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid daily. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered in an amount of about 240 mg daily, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 240 mg of (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid daily. In some embodiments, the (S)- 4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid is administered in an amount of about 320 mg daily, or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid daily. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0137] In some embodiments, the subject who has been administered (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has a fibrotic disease. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has a fibrotic lung disease. In some embodiments, the subject who has been administered (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has a fibrotic lung disease, wherein the fibrotic lung disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the subject who has been administered (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, has a fibrotic liver disease. In some embodiments, the subject who has been administered (S)-4-((2 -methoxy ethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has a fibrotic liver disease, wherein the fibrotic liver disease is primary sclerosing cholangitis (PSC). In some embodiments, the (S)-4-((2-methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0138] In some embodiments, the subject who has been administered (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a human. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is concurrently being treated with a standard of care. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is concurrently being treated with a standard of care, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has not been previously treated with a standard of care for a lung disorder. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has not been previously treated with a standard of care for a lung disorder, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is not being concurrently treated with a standard ofcare. In some embodiments, the subject who has been administered (S)-4-((2 -methoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is not being concurrently treated with a standard of care, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the subject who has been administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is not being concurrently treated with a standard of care comprising administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib. In some embodiments, the subject is not administered any treatment for a lung disorder other than (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0139] In some embodiments, cough severity in the subject is reduced following administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity in the subject is reduced following administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, wherein cough severity is determined by visual analog scale, as described further herein. In some embodiments, cough severity is reduced following the administering of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid or a pharmaceutically acceptable salt thereof. In some embodiments,cough severity is reduced following the administering of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, wherein cough severity is determined by visual analog scale. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0140] In some embodiments, cough severity in the subject is reduced through application of the methods described herein. In some embodiments, the reduction of cough severity is determined by patient reported cough severity over a two-week period. In some embodiments, cough severity is determined by mean change in visual analog scale (VAS) from baseline. In some embodiments, reduction of cough severity is a mean change in VAS of about 25 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 20 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 15 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 10 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 5 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 3 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 2 mm or less. In some embodiments, reduction of cough severity is a mean change in VAS of about 0%, that is, the cough severity remains about the same (remains stable). In some embodiments, reduction of cough severity is measured at about 4 weeks, 8 weeks, and / or 12 weeks after initial administration. In some embodiments, reduction of cough severity is measured at about 4 weeks, 8 weeks, 12 weeks, and / or 24 weeks after initial administration. In some embodiments, reduction of cough severity is measured at about 4 weeks after initial administration. In some embodiments, reduction of cough severity is measured at about 8 weeks after initial administration. In some embodiments, reduction of cough severity ismeasured at about 12 weeks after initial administration. In some embodiments, reduction of cough severity is measured at about 24 weeks after initial administration. In some embodiments, reduction of cough severity is measured at about 4 weeks, 8 weeks, 12 weeks, and / or 24 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, reduction of cough severity is measured at about 4 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, reduction of cough severity is measured at about 8 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, reduction of cough severity is measured at about 12 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, reduction of cough severity is measured at about 24 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. The cough severity visual analog scale (VAS) records patients' assessment of cough severity on a 100-mm linear scale ranging from "no cough" (0 mm) to "worst cough" (100 mm) (Nguyen, A. M. et cd.. “Validation of a visual analog scale for assessing cough severity in patients with chronic cough,” Ther Adv Respir Dis. 2021 Jan-Dec; 15: 17534666211049743. doi: 10.1177 / 17534666211049743; herein incorporated by reference in its entirety). See also page 3 1 oi Next-Generation Interstitial Lung Disease, An Issue of Clinics in Chest Medicine EBook, (2021), Netherlands: Elsevier Health Sciences, Sato, R., Han da, T., Matsumoto, H. el al. Clinical significance of self-reported cough intensity and frequency in patients with interstitial lung disease: a cross-sectional study, BMCPulmMed. 19, 247 (2019), doi.org,'' 10.1 186 / s 12890-019- 1012-6; and Birring SS, Spinou A. How best to measure cough clinically, Curr Opin Pharmacol. 2015 Jun; 22:37-40, doi: 10.1016 / j. coph.2015.03.003. Epub 2015 Mar 25. PMID: 25819594, all of which are herein incorporated by reference in their entirety.

[0141] In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises amean change in VAS of about 65 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 60 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 55 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 50 mm or less relative to cough severity in a subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 45 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 40 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 35 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 30 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 25 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 20 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 15 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 10 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, reduction of cough severity in a subject after administration of (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, comprises a mean change in VAS of about 5 mm or less relative to cough severity in the subject after administration of a placebo. In some embodiments, the (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, wherein the phosphate salt is crystalline. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a crystalline Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is selected from a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, a crystalline Form III naphthalenedisulfonic acid salt, a zwitterionic form, and an amorphous form.

[0142] In some embodiments, reduction of cough severity after administration of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 65 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 60 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 55 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 50 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 45 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 40 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 35 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 30 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity afteradministration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 25 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 20 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 15 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 10 mm or less relative to cough severity after administration of placebo. In some embodiments, reduction of cough severity after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a mean change in VAS of about 5 mm or less relative to cough severity after administration of placebo. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, wherein the phosphate salt is crystalline. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a crystalline Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is selected from a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, a crystalline Form III naphthalenedisulfonic acid salt, a zwitterionic form, and an amorphous form.

[0143] Forced vital capacity (FVC) is the maximum volume of air that a person can exhale from their lungs after taking the deepest breath possible. Lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease, asbestosis, and many other disorders can affect FVC. The decrease in FVC in a subject over time is used to measure the progression of diseases such as idiopathic pulmonary fibrosis.

[0144] Reducing or slowing the decline in forced vital capacity is a measure of treatment efficacy in a subject who has idiopathic pulmonary fibrosis. Increasing FVC would provide even more benefit to the subject.

[0145] In some embodiments, forced vital capacity (FVC) is increased following administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC is increased between about 0 mL and about 50 mL. In some embodiments, FVC is increased relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 150 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 140 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 130 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 120 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 110 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 100 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 90 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 80 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 70 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 60 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 50 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 40 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 30 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 20 mL relative to placebo. In some embodiments, FVC is increased about, up to about, or at least about, 10 mL relative to placebo. In some embodiments, FVC increase is dosedependent. In some embodiments, FVC increase is measured at about 4 weeks, 8 weeks, and / or 12 weeks after initial administration. In some embodiments, FVC increase is measured at about4 weeks, 8 weeks, 12 weeks, and / or 24 weeks after initial administration. In some embodiments, FVC increase is measured at about 4 weeks after initial administration. In some embodiments, FVC increase is measured at about 8 weeks after initial administration. In some embodiments, FVC increase is measured at about 12 weeks after initial administration. In some embodiments, FVC increase is measured at about 24 weeks after initial administration. In some embodiments, forced vital capacity (FVC) in a subject is increased following administration of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC in a subject is increased between about 0 mL and about 50 mL. In some embodiments, FVC in a subject is increased relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 150 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 140 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 130 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 120 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 110 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 100 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 90 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 80 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 70 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 60 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 50 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 40 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 30 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 20 mL relative to placebo. In some embodiments, FVC in a subject is increased about, up to about, or at least about, 10 mL relative to placebo. In some embodiments, FVC increase is measured at about 4 weeks, 8 weeks, and / or 12 weeks after initial administration of (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC increase is measured at about 4 weeks, 8weeks, 12 weeks, and / or 24 weeks after initial administration of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC increase is measured at about 4 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC increase is measured at about 8 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC increase is measured at about 12 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC increase is measured at about 24 weeks after initial administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount sufficient to increase FVC in a subject as compared to a subject who has not been administered (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro- 1,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for at least about 4 weeks. In some embodiments, administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro- 1,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is for at least about 8 weeks. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for at least about 12 weeks. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for about a 4-week period. In some embodiments, administration of (S)-4-((2-methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for about an 8-week period. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for about a 12-week period. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is daily. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is once daily. In some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is by oral administration. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0147] In some embodiments, the increase in FVC following administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, or about 60 mL or more. In some embodiments, the increase in FVC following administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, or about 120 mL or more. In some embodiments, the increase in FVC following administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is up to about 10 mL, up to about 20 mL, up to about 30 mL, up to about 40 mL, up to about 50 mL, up to about 60 mL, up to about 70 mL, up to about 80 mL, up to about 90 mL, up to about 100 mL, up to about 110 mL, up to about 120 mL, up to about 130 mL, up to about 140 mL, up to about 150 mL, up to about 160 mL, up to about 170 mL, up to about 180 mL, or up to about 185 mL. In some embodiments, the increase in FVC following administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0148] In some embodiments, the administering of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is for about a 12 week period and the increase in FVC is about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, or about 60 mL or more from the start of the period to the end of the period. In some embodiments, the increase in FVC following administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, or about 120 mL or more from the start of the period to the end of the period. In some embodiments, the increase in FVC following the administering of (S)-4-((2 -methoxy ethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid,or a pharmaceutically acceptable salt thereof, is about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more from the start of the period to the end of the period. In some embodiments, the increase in FVC following administration of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is up to about 10 mL, up to about 20 mL, up to about 30 mL, up to about 40 mL, up to about 50 mL, up to about 60 mL, up to about 70 mL, up to about 80 mL, up to about 90 mL, up to about 100 mL, up to about 110 mL, up to about 120 mL, up to about 130 mL, up to about 140 mL, up to about 150 mL, up to about 160 mL, up to about 170 mL, up to about 180 mL, or up to about 185 mL from the start of the period to the end of the period. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a Form I phosphate salt. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form.

[0149] In some embodiments, FVC is increased by about 150 mL. In some embodiments, FVC is increased by about 140 mL. In some embodiments, FVC is increased by about 130 mL. In some embodiments, FVC is increased by about 120 mL. In some embodiments, FVC is increased by about 110 mL. In some embodiments, FVC is increased by about 100 mL. In some embodiments, FVC is increased by about 90 mL. In some embodiments, FVC is increased by about 80 mL. In some embodiments, FVC is increased by about 70 mL. In some embodiments, FVC is increased by about 60 mL. In some embodiments, FVC is increased by about 50 mL. In some embodiments, FVC is increased by about 40 mL. In some embodiments, FVC is increased by about 30 mL. In some embodiments, FVC is increased by about 25 mL. In some embodiments, FVC is increased by about 20 mL. In some embodiments, FVC is increased by about 15 mL. In some embodiments, FVC is increased by about 10 mL. In some embodiments, FVC is increased by about 5 mL. In some embodiments, FVC is measured at about 4 weeks, 8weeks, and / or 12 weeks after initial administration. In some embodiments, FVC is measured at about 4 weeks, 8 weeks, 12 weeks, and / or 24 weeks after initial administration. In some embodiments, FVC is measured at about 4 weeks after initial administration. In some embodiments, FVC is measured at about 8 weeks after initial administration. In some embodiments, FVC is measured at about 12 weeks after initial administration. In some embodiments, FVC is measured at about 24 weeks after initial administration. In some embodiments, FVC in the subject is increased by about 150 mL. In some embodiments, FVC in the subject is increased by about 140 mL. In some embodiments, FVC in the subject is increased by about 130 mL. In some embodiments, FVC in the subject is increased by about 120 mL. In some embodiments, FVC in the subject is increased by about 110 mL. In some embodiments, FVC in the subject is increased by about 100 mL. In some embodiments, FVC in the subject is increased by about 90 mL. In some embodiments, FVC in the subject is increased by about 80 mL. In some embodiments, FVC in the subject is increased by about 70 mL. In some embodiments, FVC in the subject is increased by about 60 mL. In some embodiments, FVC in the subject is increased by about 50 mL. In some embodiments, FVC in the subject is increased by about 40 mL. In some embodiments, FVC in the subject is increased by about 30 mL. In some embodiments, FVC in the subject is increased by about 25 mL. In some embodiments, FVC in the subject is increased by about 20 mL. In some embodiments, FVC in the subject is increased by about 15 mL. In some embodiments, FVC in the subject is increased by about 10 mL. In some embodiments, FVC in the subject is increased by about 5 mL. In some embodiments, FVC is measured at about 4 weeks, 8 weeks, and / or 12 weeks after initial administration. In some embodiments, FVC is measured at about 4 weeks, 8 weeks, 12 weeks, and / or 24 weeks after initial administration of S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC is measured at about 4 weeks after initial administration of S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC is measured at about 8 weeks after initial administration of S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin- 4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC is measured at about 12 weeks after initial administration of S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid,or a pharmaceutically acceptable salt thereof. In some embodiments, FVC is measured at about 24 weeks after initial administration of S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0150] Increase in forced vital capacity can be an increase in forced vital capacity of about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, about 60 mL or more, about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, about 120 mL or more, about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more, or between a range of any two of the foregoing values. An increase in forced vital capacity in the subject can comprise an increase by about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, about 60 mL or more, about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, about 120 mL or more, about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more, or between a range of any two of the foregoing values. The increase in forced vital capacity can be about 10 mL or more, about 20 mL or more, about 30 mL or more, about 40 mL or more, about 50 mL or more, about 60 mL or more, about 70 mL or more, about 80 mL or more, about 90 mL or more, about 100 mL or more, about 110 mL or more, about 120 mL or more, about 130 mL or more, about 140 mL or more, about 150 mL or more, about 160 mL or more, about 170 mL or more, about 180 mL or more, or about 185 mL or more, or between a range of any two of the foregoing values, over a period of about 12 weeks. The increase in forced vital capacity can be about 10 mL to about 30 mL, about 10 mL to about 50 mL, about 10 mL to about 75 mL, about 10 mL to about 100 mL, about 10 mL to about 125 mL, about 10 mL to about 150 mL, about 10 mL to about 175 mL, about 10 mL to about 185 mL, about 20 mL to about 40 mL, about 30 mL to about 50 mL, about 30 mL to about 75 mL, about 30 mL to about 100 mL, about 30 mL to about 125 mL, about 30 mL to about 150 mL, about 30 mL to about 175 mL, about 30 mL to about 185 mL, about 50 mL to about 75 mL, about 50 mL to about 100 mL, about 50 mL to about 125 mL, about 50 mL to about 150 mL, about 50 mL to about 175 mL, about 50 mL to about 185 mL, about 75 mL to about 100 mL, about 75 mL to about 125 mL, about 75 mL to about 150 mL, about 75 mL to about 175 mL, or about 75 mL to about 185 mL. The increase in forced vital capacity can beabout 10 mL to about 30 mL, about 10 mL to about 50 mL, about 10 mL to about 75 mL, about 10 mL to about 100 mL, about 10 mL to about 125 mL, about 10 mL to about 150 mL, about 10 mL to about 175 mL, about 10 mL to about 185 mL, about 20 mL to about 40 mL, about 30 mL to about 50 mL, about 30 mL to about 75 mL, about 30 mL to about 100 mL, about 30 mL to about 125 mL, about 30 mL to about 150 mL, about 30 mL to about 175 mL, about 30 mL to about 185 mL, about 50 mL to about 75 mL, about 50 mL to about 100 mL, about 50 mL to about 125 mL, about 50 mL to about 150 mL, about 50 mL to about 175 mL, about 50 mL to about 185 mL, about 75 mL to about 100 mL, about 75 mL to about 125 mL, about 75 mL to about 150 mL, about 75 mL to about 175 mL, or about 75 mL to about 185 mL over a period of about 12 weeks.

[0151] The increase in forced vital capacity in a subject in accordance with the methods of treatment described herein can be compared to any increase in forced vital capacity in a subject who is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, such as a phosphate salt thereof, a polymorph thereof (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form thereof, or an amorphous form thereof, or compared to any average increase in forced vital capacity in a group of subjects who are not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, such as a phosphate salt thereof, a polymorph thereof (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form thereof, or an amorphous form thereof. The increase in forced vital capacity can be as compared to the increase in a subject who is not treated by administration of (S)-4-((2 -methoxy ethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, such as a phosphate salt thereof, a polymorph thereof (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form thereof, or an amorphous form thereof, or compared to an average increase in a group of subjects who are not treated by administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid or apharmaceutically acceptable salt thereof, such as a phosphate salt thereof, a polymorph thereof (including a crystalline Form I phosphate salt, a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, and a crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form thereof, or an amorphous form thereof. By way of illustration, if a subject who is administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)- 2-(quinazolin-4-ylamino)butanoic acid or a pharmaceutically acceptable salt thereof, has an increase of forced vital capacity over a certain period, such as about 12 weeks, of about 30 mL, and a subject who is not administered (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, has an increase of forced vital capacity over the same period of about 5 mL, then the increase of forced vital capacity is 25 mL over the period. Alternatively, an increase in forced vital capacity in a subject at the end of a certain period of administration, such as 12 weeks, can be compared to the forced vital capacity of the subject measured at the start of the period. Alternatively, the increase of forced vital capacity at the end of a certain period of administration such as 12 weeks, to a subject, can be compared to the forced vital capacity of the subject at the start of the period.

[0152] In some embodiments, treatment effect is driven by standardized uptake values (SUVs) of a collagen-binding probe. In some embodiments, treatment effect is driven by standardized uptake values (SUVs) of a collagen-binding radiotracer such as a Ga-labeled probe. In some embodiments, SUV is reduced in the lung of a subject after administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to SUV increases in the lung of a subject not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, SUV is reduced in the lung of a subject at about 12 weeks after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to SUV increases in the lung of a subject not administered (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)- 2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, about 160 mg to about 320 mg of (S)-4-((2 -methoxy ethyl)(4-(5, 6,7, 8-tetrahydro- 1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or apharmaceutically acceptable salt thereof, is administered. In some embodiments, about 160 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 240 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered.

[0153] In some embodiments, SUV is reduced in the subpleural lung region of a subject after administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to SUV increases in the subpleural lung region of a subject not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, SUV is reduced in the subpleural lung region of a subject at about 12 weeks after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 160 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 240 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 160 mg to about 320 mg of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in reduced SUV in the subpleural lung region of the subject. In some embodiments, about 160mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in reduced SUV in the subpleural lung region of the subject. In some embodiments, about 240 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in reduced SUV in the subpleural lung region of the subject. In some embodiments, about 320 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in reduced SUV in the subpleural lung region of the subject.

[0154] The reduction in SUV indicates reduced total lung collagen. Thus, in some embodiments, administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, reduces total lung collagen. In some embodiments, total lung collagen in a subject is reduced after administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin- 2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to total lung collagen in a subject not administered (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, total lung collagen in a subject is reduced after administration of (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to an increase of total lung collagen in a subject not administered (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, total lung collagen in a subject is reduced at about 12 weeks after a first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to total lung collagen in a subject not administered (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, total lung collagen in a subject is reduced at about 12 weeks after a first administration of (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, compared to an increase of total lung collagen in a subject not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro- 1,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 160 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 240 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in a reduction of total lung collagen. In some embodiments, about 160 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in a reduction of total lung collagen. In some embodiments, about 240 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in a reduction of total lung collagen. In some embodiments, about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered, resulting in a reduction of total lung collagen.

[0155] Total lung collagen levels can be measured with a probe that binds to collagen, such as radiotracers or MRI contrast agents. Total lung collagen levels can be measured by PET imaging via a collagen-binding radiotracer, such as, e.g., a PET ligand or Ga-labeled probe. In some embodiments, the PET ligand is68GA-CBP8 (see Montesi SB et al.. Am. J. Respir. Crit. Care Med. 2019; 200(2):258-261, the entire contents of which are hereby incorporated by reference). In some embodiments, the Ga-labeled probe is68GA-CBP8. Subjects with increasedtotal lung collagen levels, as measured by PET, have been shown to have an increased risk of death. See A. Justet, el al. (2017) Respir Res 18(74), doi.org / 10.1186 / sl2931-017-0556-3, the entire contents of which are hereby incorporated by reference.

[0156] In some embodiments, cough severity and total lung collagen are reduced following administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are reduced at about 12 weeks following a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are reduced at about 12 weeks following a first administration of about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are reduced at about 12 weeks following a first administration of about 160 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are reduced at about 12 weeks following a first administration of about 240 mg of (S)-4-((2- methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are reduced at about 12 weeks following a first administration of about 320 mg of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, FVC and FVCpp (forced vital capacity percent predicted) are increased following administration of (S)-4-((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro- 1,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC and FVCpp are increased at about 12 weeks following a first administration of (S)-4-((2 -methoxy ethyl)(4-(5, 6,7, 8-tetrahydro- 1, 8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC and FVCpp are increased at about 12 weeks following a first administration of about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC and FVCpp are increased at about 12 weeks following a first administration of about 160 mg of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC and FVCpp are increased at about 12 weeks following a first administration of about 240 mg of (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, FVC and FVCpp are increased at about 12 weeks following a first administration of about 320 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased following administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-1, 8-naphthyri din-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased at about 12 weeks following a first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased at about 12 weeks following a first administration of about 160 mg to about 320 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased at about 12 weeks following a first administration of about 160 mg of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased at about 12 weeks following a first administration of about 240 mg of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, cough severity and total lung collagen are decreased, and FVC and FVCpp are increased atabout 12 weeks following a first administration of about 320 mg of (S)-4-((2-methoxyethyl)(4- (5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0159] In another aspect, methods of determining changes in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor are provided, comprising: a. administering a first dose of a collagen-binding probe to the subject; b. measuring the amount of said probe in a lung of the subject following administration of the first dose of said probe; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the probe to the subject; e. measuring the amount of said probe in the lung of the subject following administration of the second dose of said probe; and f. comparing the amount of said probe measured in the lung of the subject after administration of the first dose to the amount of said probe measured in the lung of the subject after administration of the second dose.

[0160] In another aspect, methods of determining changes in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor are provided, comprising: a. administering a first dose of collagen-binding radiotracer to the subject; b. measuring the amount of said radiotracer in a lung of the subject following administration of the first dose of said radiotracer; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the radiotracer to the subject; e. measuring the amount of said radiotracer in the lung of the subject following administration of the second dose of said radiotracer; and f. comparing the amount of said radiotracer measured in the lung of the subject after administration of the first dose to the amount of said radiotracer measured in the lung of the subject after administration of the second dose.

[0161] In another aspect, methods of determining changes in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor are provided, comprising: a. administering a first dose of a collagen-binding probe to the subject; b. measuring the amount of said probe in a lung of the subject following the first administration of said probe;c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the probe to the subject; e. measuring the amount of said probe in the lung of the subject following the second dose of said probe; and f. comparing the amount of said probe measured in the lung of the subject after the first dose to the amount of said probe measured in the lung of the subject after the second dose.

[0162] In another aspect, methods of determining changes in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor are provided, comprising: a. administering a first dose of collagen-binding radiotracer to the subject; b. measuring the amount of said radiotracer in a lung of the subject following the first administration of said radiotracer; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the radiotracer to the subject; e. measuring the amount of said radiotracer in the lung of the subject following the second dose of said radiotracer; and f. comparing the amount of said radiotracer measured in the lung of the subject after the first dose to the amount of said radiotracer measured in the lung of the subject after the second dose.

[0163] In some embodiments, the subject has a fibrotic disease. In some embodiments, the fibrotic disease is pulmonary fibrosis. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis. In some embodiments, the fibrotic disease is liver fibrosis. In some embodiments, the fibrotic disease is primary sclerosing cholangitis.

[0164] In some embodiments, the radiotracer is a Ga-labeled probe. In some embodiments, the Ga-labeled probe is gallium-68-labeled peptide-based collagen binding probe (68GA-CBP).

[0165] In some embodiments, the second dose of the radiotracer is administered at about 12 weeks after administration of the dual avPi / avPe integrin inhibitor.

[0166] In some embodiments, the dual avPi / avPe integrin inhibitor is administered over at least about 12 weeks. In some embodiments, the dual avPi / avPe integrin inhibitor is administered over about 12 weeks.

[0167] Dual avPi / avPe integrin inhibitors are disclosed in US Patent No. 10,793,564, which is incorporated by reference herein in its entirety.

[0168] In some embodiments, the dual avPi / avPe integrin inhibitor is (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt, a polymorph (including crystalline Form I phosphate salt, crystalline Form IV phosphate salt, crystalline Form II fumarate salt, or crystalline Form III naphthalenedisulfonic acid salt), a zwitterionic form, or an amorphous form. In some embodiments, the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is a phosphate salt. In some embodiments, the (S)-4-((2 -m ethoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is Form I phosphate salt.

[0169] In some embodiments, about 160 mg of the dual avPi / avPe integrin inhibitor is administered to the subject. In some embodiments, about 240 mg of the dual avPi / avPe integrin inhibitor is administered to the subject. In some embodiments, about 320 mg of the dual avPi / avPe integrin inhibitor is administered to the subject.

[0170] In some embodiments, the dual avPi / avPe integrin inhibitor reduces standardized uptake values (SUVs) of the radiotracer relative to placebo at about 12 weeks after a first dose of the radiotracer.Kits

[0171] The disclosure further provides kits for carrying out the methods of the invention, which comprise one or more compounds described herein, or a salt thereof, or a pharmaceutical composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a fibrotic disease.

[0172] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined inone container where cross-reactivity and shelf-life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.

[0173] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., fibrosis) to provide effective treatment of the subject for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0174] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to a subject.

[0175] The kits may optionally further comprise instructions for daily administration of the dosage form to a subject in need thereof, such as instructions for administration of the dosage form to a subject in need thereof one, two, three, or four times daily, for example, instructions for administration of the dosage form to a subject in need thereof once daily.Enumerated Embodiments

[0176] Embodiment 1. A method of reversing or retarding progression of fibrosis or collagen deposition in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

[0177] Embodiment 2. The method of embodiment 1, wherein fibrosis in the subject is reversed.

[0178] Embodiment 3. The method of embodiment 1, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0179] Embodiment 4. The method of embodiment 1, wherein collagen deposition in the subject is reversed.

[0180] Embodiment 5. The method of embodiment 1, wherein progression of collagen deposition in the subject is retarded relative to progression of collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0181] Embodiment 6. The method of any one of embodiments 1, 4 or 5, wherein collagen deposition is in the subpleural region of a lung of the subject.

[0182] Embodiment 7. The method of any one of embodiments 1-5, wherein collagen deposition after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to collagen deposition prior to the first administration.

[0183] Embodiment 8. The method of any one of embodiments 1, or 4-7, wherein collagen deposition is reduced at about 12 weeks after the first administration of (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof.

[0184] Embodiment 9. The method of any one of embodiments 1-8, wherein the subject has a fibrotic disease.

[0185] Embodiment 10. The method of embodiment 9, wherein the fibrotic disease is pulmonary fibrosis.

[0186] Embodiment 11. The method of embodiment 9, wherein the fibrotic disease is an interstitial lung disease.

[0187] Embodiment 12. The method of embodiment 9, wherein the fibrotic disease is idiopathic pulmonary fibrosis.

[0188] Embodiment 13. The method of embodiment 9, wherein the fibrotic disease is liver fibrosis.

[0189] Embodiment 14. The method of embodiment 9, wherein the fibrotic disease is primary sclerosing cholangitis.

[0190] Embodiment 15. The method of any one of embodiments 1-14, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6,7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered over at least about 12 weeks.

[0191] Embodiment 16. The method of any one of embodiments 1-15, wherein progression is reversed after about 12 weeks following a first administration of the (S)-4-((2-methoxyethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0192] Embodiment 17. The method of any one of embodiments 1-15, wherein progression is retarded after about 12 weeks following a first administration of the (S)-4-((2 -methoxy ethyl)(4- (5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0193] Embodiment 18. The method of any one of embodiments 1-12 or 15-17, wherein the subject has lung fibrosis and cough severity after a first administration of (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to cough severity prior to the first administration.

[0194] Embodiment 19. The method of embodiment 18, wherein cough severity is measured by Cough Visual Analog Scale.

[0195] Embodiment 20. The method of any one of embodiments 1-19, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is administered orally.

[0196] Embodiment 21. The method of any one of embodiments 1-20, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is administered daily.

[0197] Embodiment 22. The method of any one of embodiments 1-21, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg to about 320 mg daily.

[0198] Embodiment 23. The method of any one of embodiments 1-22, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg daily.

[0199] Embodiment 24. The method of any one of embodiments 1-22, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 240 mg daily.

[0200] Embodiment 25. The method of any one of embodiments 1-22, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg daily.

[0201] Embodiment 26. The method of any one of embodiments 1-25, wherein the administration is once daily.

[0202] Embodiment 27. The method of any one of embodiments 1-26, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid is administered as a phosphate salt.

[0203] Embodiment 28. The method of any one of embodiments 1-27, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid is administered as a crystalline Form I phosphate salt.

[0204] Embodiment 29. The method of any one of embodiments 1-26, wherein the (S)-4-((2- methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4- ylamino)butanoic acid is administered as a crystalline Form IV phosphate salt, a crystalline Form II fumarate salt, or a crystalline Form III naphthalenedisulfonic acid salt.

[0205] Embodiment 30. The method of any one of embodiments 1-29, wherein the subject is a human.

[0206] Embodiment 31. The method of any one of embodiments 1-30, wherein the subject is concurrently being treated with a standard of care for fibrosis.

[0207] Embodiment 32. The method of any one of embodiments 1-30, wherein the subject is not concurrently being treated with a standard of care for fibrosis.

[0208] Embodiment 33. The method of any one of embodiments 1-30, wherein the subject has not been previously treated with a standard of care for fibrosis.

[0209] Embodiment 34. The method of any one of embodiments 31-33, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

[0210] Embodiment 35. A method of determining a change in collagen deposition in a subject following administration of a dual avPi / avPe integrin inhibitor, comprising: a. administering a first dose of a collagen-binding probe to the subject; b. measuring the amount of the probe in a lung of the subject following the first administration of the probe; c. administering the dual avPi / avPe integrin inhibitor to the subject; d. administering a second dose of the probe to the subject; e. measuring the amount of the probe in the lung of the subject following the second dose of the probe; and f. comparing the amount of the probe measured in the lung of the subject after the first dose to the amount of the probe measured in the lung of the subject after the second dose.

[0211] Embodiment 36. The method of embodiment 35, wherein the collagen-binding probe is a radiotracer.

[0212] Embodiment 37. The method of embodiment 36, wherein the radiotracer is gallium-68- labeled peptide-based collagen binding probe (68GA-CBP).

[0213] Embodiment 38. The method of any one of embodiments 35-37, wherein the second dose of the probe is administered at about 12 weeks after administration of the dual avPi / avPe integrin inhibitor.

[0214] Embodiment 39. The method of any one of embodiments 25-38, wherein the dual avPi / avPe integrin inhibitor is administered over at least about 12 weeks.

[0215] Embodiment 40. The method of any one of embodiments 35-39, wherein the dual avPi / avPe integrin inhibitor is administered over about 12 weeks.

[0216] Embodiment 41. The method of any one of embodiments 35-40, wherein the dual avPi / avPe integrin inhibitor is (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0217] Embodiment 42. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in reversing progression of fibrosis in a subject in need thereof.

[0218] Embodiment 43. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in retarding progression of fibrosis in a subject in need thereof, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0219] Embodiment 44. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in reversing collagen deposition in a subject in need thereof.

[0220] Embodiment 45. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in retarding collagen deposition in a subject in need thereof, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)- 2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof .

[0221] Embodiment 46. Use of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reversing progression of fibrosis in a subject in need thereof.

[0222] Embodiment 47. Use of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for retarding progression of fibrosis in a subject in need thereof, wherein progression of fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0223] Embodiment 48. Use of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for reversing collagen deposition in a subject in need thereof.

[0224] Embodiment 49. Use of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for retarding collagen deposition in a subject in need thereof, wherein collagen deposition in the subject is retarded relative to collagen deposition in a subject that is not administered (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyri din-2 -yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

[0225] Embodiment 50. The method of any one of embodiments 1-41, or the use of any one of embodiments 42-49, wherein the collagen is Type I collagen.EXAMPLES

[0226] The following examples are set forth to enable this disclosure to be more fully understood. The examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner.Example 1 - Randomized, double-blind, placebo-controlled Phase 2a collagen positron emission tomography (PET) imaging clinical trial of (S)-4-((2-methoxyethyl)(4-(5, 6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid (bexotegrast) in subjects with idiopathic pulmonary fibrosis (IPF)

[0227] IPF is a disease characterized by excessive collagen deposition in the lung. As described elsewhere herein, subjects with increased total lung collagen levels, as measured by PET, have been shown to have an increased risk of death. See A. Justet, et al. (2017) Respir Res 18(74), doi.org / 10.1186 / sl2931-017-0556-3, the entire contents of which are hereby incorporated by reference.

[0228] The Phase 2a, 12-week, single-center, randomized, double-blinded, placebo-controlled trial evaluated bexotegrast at a once-daily dose of 160 mg or placebo on levels of total collagen deposition (type 1 collagen deposition) in the lungs of participants with IPF. PET and architectural changes by DCE-MRI were used to evaluate the treatment. Subject inclusion criteria included diagnosis of IPF (within 8 years), forced vital capacity (FVC) percent predicted > 45%, DLCO > 30%, and estimated glomerular filtration rate > 50mL / min. Bexotegrast wasdosed as its phosphate salt. Weights of bexotegrast refer to the amount of active agent (i.e., free base) present in the dose.

[0229] Patients were randomized in a 2: 1 ratio of (active:placebo) and were stratified based on use of standard of care IPF therapy. The trial enrolled 7 subjects in the active arm and 3 in the placebo arm. Eight out of 10 enrolled subjects were on standard of care, with the majority on nintedanib. FIG. 1 depicts a schematic diagram of the study design associated with this study and FIG. 2 depicts a schematic diagram of the subject disposition associated with this study design. The subjects underwent positron emission tomography (PET) imaging with a radiotracer,68Ga-CBP8, that binds to total collagen at baseline and at week 12.

[0230] The baseline demographics for the study are shown in Table 1. “IQR” refers to interquartile range (QI, Q3) and “BMI” refers to body mass index.Table 1. Baseline Demographics

[0231] The baseline disease characteristics are shown in Table 2. The GAP index score for the GAP Stage is derived from gender, age, FVC, % predicted and DLCO, % predicted. “IQR” refers to interquartile range (QI, Q3) and “DLCO” refers to diffusing capacity for carbon monoxide.Table 2. Baseline Disease Characteristics

[0232] The primary endpoint of the trial included an evaluation of the change in standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with Gallium-68 radioisotope (68GA-CBP8).68GA-CBP8 is a PET ligand that binds to type 1 collagen. Type 1 collagen is the predominant collagen type produced in the lungs as a result of IPF.68GA-CBP8 was developed as a non-invasive means to detect and stage pulmonary fibrosis. See P. Desogere, et al. (2017) Sci TranslMed. 9(394): eaaf4696. doi: 10.1126 / scitranslmed.aaf4696, the entire contents of which are hereby incorporated by reference. An increase in SUV of68GA-CBP8 in the lung indicates higher total lung collagen and potential progression of the disease. IPF patients have been shown to exhibit higher SUV values compared to healthy subjects. See S.Montesi (2019) Am J Respir Crit Care Med. 200(2):258-61, doi: 10.1164 / rccm.201903-0503LE, the entire contents of which are hereby incorporated by reference. Patients with increased SUV mean levels have an increased risk of death. See A. Justet, et al. (2017) Respir Res 18(1):74, doi: 10.1186 / s 12931 -017-0556-3, the entire contents of which are hereby incorporated by reference.

[0233] The secondary endpoint of this trial was the evaluation of the safety and tolerability of bexotegrast.

[0234] Exploratory endpoints of the trial included assessing changes in FVC, forced vital capacity percent predicted (FVCPP), fibrosis biomarkers, and visual analog scale (VAS) for cough severity.Bexotegrast reduced SUVs of68GA-CBP8 compared to an increase on placebo at Week 12 in the intent-to-treat (ITT) population

[0235] SUV (standardized uptake values) measure the ratio of the uptake of a radiotracer in tissue. IPF patients have been shown to have higher68Ga-CBP8 SUVs as compared to healthy subjects. See Montesi, el al. (2019) AJRCCM 200(2):258-61, doi: 10.1164 / rccm.201903- 0503LE, the entire contents of which are hereby incorporated by reference.

[0236] FIG. 3 depicts a graph showing the mean standard error (SE) change from the baseline in the top quartile SUV of68GA-CBP8 for treatment with 160 mg of bexotegrast and the placebo.

[0237] As shown in FIG. 3, after 12 weeks of treatment, bexotegrast-treated subjects showed SUV reductions in the lung compared to SUV increases seen in the placebo. The reduction in post-treatment SUV indicates reduced total lung collagen.Bexotegrast improved lung function over 12 weeks of treatment in the ITT population

[0238] FIG. 4 depicts a graph showing the least squares (LS) mean SE change from the baseline in forced vital capacity (FVC) (mL) for treatment with 160 mg of bexotegrast and the placebo over a twelve-week time period. FIG. 5 depicts a graph showing the LS mean SE change from the baseline in forced vital capacity percent predicted (FVCPP) (%) for treatment with 160 mg of bexotegrast and the placebo at week 12. One placebo subject did not have FVC that meet quality standards per ATS guidelines at weeks 4, 8 and 12. As shown in FIG. 4 and in FIG. 5, bexotegrast-treated subjects experienced improved lung function, as measured by FVC and FVCpp, with a clear separation from the placebo across all timepoints.Bexotegrast improved cough severity at week 12 in the ITT population

[0239] Chronic cough in IPF is often refractory, debilitating, and is an independent predictor of disease progression, and may predict time to death or lung transplantation. See van Manen, et al. (2016) Eur Respir Rev. 25(141):278-86, doi: 10.1183 / 16000617.0090-2015 and Ryerson, et al. (2011) Respirology 16(6):969-75, doi: 10.1111 / j.1440-1843.2011.01996.x, the entire contents of which are hereby incorporated by reference.

[0240] Cough VAS measures subject reported cough severity over the last 2 weeks on scale of 0-100 mm. FIG. 6 depicts a graph showing the mean SE change from the baseline in the visual analog scale (VAS) score for treatment with 160 mg of bexotegrast and the placebo over atwelve-week time period. After post-treatment discontinuation, cough worsened in several bexotegrast-treated subjects.Bexotegrast reduced biomarkers of collagen synthesis and interstitial lung disease (ILD) progression in the ITT population

[0241] Elevated integrin beta-6 plasma (ITGB6) levels have been associated with ILD progression as defined by mortality, transplant or > 10% relative reduction in FVC (mL) over 12 months. Bowman, etal. (2022) Lancet Respir Med. 10(6):593-602; doi: 10.1016 / S2213- 2600(21)00503-8 and Organ, et al. (2019) Respir Res. 20(l):148, doi: 10.1186 / sl2931-019- 1118-7, the entire contents of which are hereby incorporated by reference. PRO-C3, a serum biomarker of type III collagen synthesis, is elevated in patients with IPF and is associated with progressive disease. See Organ, et al. (2019) Respir Res. 20(l): 148, doi: 10.1186 / sl2931-019- 1118-7, the entire contents of which are hereby incorporated by reference.

[0242] FIG. 7 depicts a graph showing the LS mean SE change from the baseline and the placebo (ng / mL) for N-terminal type III collagen propeptide (PRO-C3) associated with treatment with 160 mg of bexotegrast at 4 weeks and at 12 weeks, where * p < 0.05 vs. placebo. FIG. 8 depicts a graph showing the LS mean SE change from the baseline and the placebo (pg / mL) for ITGB6 associated with treatment with 160 mg of bexotegrast at 4 weeks and at 12 weeks. Bexotegrast reduced circulating PRO-C3 and ITGB6 levels at weeks 4 and 12 when compared to the placebo.Conclusions

[0243] Bexotegrast demonstrated a favorable safety and tolerability profile in the IPF subjects. PET imaging with68Ga-CBP8, supported by changes in DCE-MRI, detected apparent antifibrotic effects of bexotegrast, resulting in potential lung remodeling. Treatment with bexotegrast numerically improved FVC, cough severity, and prognostic biomarkers, highlighting its potential for disease modification (FIG. 9, FIG. 10, FIG. 11, FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16, FIG. 17).

[0244] Shown in FIG. 9 is a schematic of the idiopathic pulmonary fibrosis (IPF) signaling pathway. Briefly, avpe and avpi integrins promote fibrosis through activation of TGF-P (see Desogere P., et al. Sci Trans Med. 2017; 9(384):eaaf4696; 2; Aschner Y and Downey GP. Am J. Respir Cell Mol Bio. 2016; 54(5):647-655, each of which is incorporated by reference herein inits entirety). IPF is primarily a basilar, subpleural disease characterized by excessive deposition of type 1 collagen (Desogere P., et al. In patients with IPF, avpe and avpi integrins are overexpressed in the lungs, activating TGF-P, which drives collagen synthesis (see Decaris ML et al. Respir Res. 2021; 22(1):265, incorporated by reference herein in its entirety). Bexotegrast is an oral, once-daily, selective dual inhibitor of avpe and avpi integrins for patients with IPF.68Ga-CBP8, a type 1 collagen PET probe, measures both new synthesized collagen accumulation and cross-linked collagen and showed increased uptake in patients with IPF (see Montesi S, et al. Am J Respir Crit Care Med. 2019;200(2):258-261, incorporated by reference herein in its entirety).

[0245] The graph in FIG. 11 shows observed changes in whole lung from baseline in top quartile standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with68GA-CBP8 for treatment with 160 mg of bexotegrast and placebo at week 12. Bexotegrast 160 mg reduced the68GA-CBP8 PET ligand SUV from baseline, indicating a reduction in total lung collagen. Moreover, as shown in FIG. 12, the SUV changes with bexotegrast at week 12 were consistent across participants and largest in the subpleural lung regions.

[0246] Shown in FIG. 13 are PET images of observed changes within the lung from baseline in top quartile standardized uptake value (SUV) of peptide-based collagen binding probe 8 tagged with Gallium-68 radioisotope (68GA-CBP8). PET images at baseline and week 12 are compared for “Participant A,” who received 160 mg of bexotegrast, with “Participant B,” who received a placebo. “Participant A” experienced a decrease from baseline to Week 12 in the top quartile SUV of -0.17, representing a -15.5% change in top quartile SUV. Meanwhile, “Participant B” experienced an increase from baseline to Week 12 in the top quartile SUV of 0.21, representing an 18.4% change in the top quartile SUV.

[0247] The observed change from baseline in peak enhancement associated with treatment with 160 mg of bexotegrast and placebo is shown in FIG 14. Reduced peak enhancement has been associated with increased vascular permeability. See, e.g., Montesi, S., et al. Am J Respir Crit Care Med. 2019;200(2):258-261; Zhang W-J et al. Radiology. 2016;278(3):906-916; Amundsen T et al. , J. Magn Reson Imaging. 2000; 12(2):224-231 ; Kehr E, et al. Int J Cardiovasc Imaging. 2008;24(l): 61-68, each of which is incorporated herein by reference in its entirety.

[0248] The observed change from baseline in contrast wash-out rate associated with treatment with 160 mg of bexotegrast and placebo is shown in FIG. 15. Without wishing to be bound by theory, slower Kwashout rates may be due to expanded volume as a result of replacement ofcellular components with fibrosis. See, e.g., Montesi, S., et al. Am J Respir Crit Care Med. 2019;200(2):258-261; Zhang W-J et al. Radiology. 2016;278(3):906-916; Amundsen T et al., J. Magn Reson Imaging. 2000;12(2):224-231; Kehr E, et al. Int J Cardiovasc Imaging. 2008;24(l): 61-68, each of which is incorporated herein by reference in its entirety.

[0249] A graph showing the LS mean SE change from the baseline in FVC (mL) for treatment with 160 mg of bexotegrast and placebo at week 12 is shown in FIG. 16. Treatment with bexotegrast resulted in a numerically reduced FVC decline over 12 weeks with the bexotegrast group maintaining a clear separation from placebo at all time points. Of note, the correlation in change in SUV and change in FVC was p=-0.57.

[0250] Provided in FIG. 17 is a graph showing the mean SE change from the baseline in the VAS score for treatment with 160 mg of bexotegrast and placebo over a 12-week time period. Participants in the bexotegrast group reported decreased cough severity across all on-treatment timepoints compared with placebo. Of note, the change in cough severity predicted by the change in FVC was p<0.05; R2=0.77.

[0251] Changes in the PET ligand68Ga-CBP8 correlated with disease progression and may therefore be a sensitive measure of active disease and a useful tool to assess early therapeutic effects of antifibrotic drugs. No new safety concerns were identified over 12 weeks of treatment. Most frequently reported treatment emergent adverse events (TEAEs) were mild in severity (Table 3) with no trial discontinuations occurring. Further, no serious adverse events (SAEs) were observed. Overall, bexotegrast demonstrated a favorable safety and tolerability profile over 12 weeks.Table 3. Treatment-emergent adverse events as a result of treatment with bexotegrast and placebo over 12-week period

[0252] Bexotegrast improved both lung function and cough severity over 12 weeks of treatment. Further, twelve-week treatment with 160 mg of bexotegrast resulted in a reduction of total lung collagen as measured by PET imaging compared to an increase in the placebo. An improvement in FVC and a reduction in both cough severity and fibrosis biomarkers was shown in the bexotegrast-treated subjects compared to the placebo-treated subjects at all timepoints.

[0253] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.

[0254] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. A method of reversing or retarding progression of collagen deposition or fibrosis in a subject in need thereof, comprising administering a therapeutically effective amount of (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof, to the subject.

2. The method of claim 1, wherein progression of collagen deposition or fibrosis in the subject is reversed.

3. The method of claim 1, wherein progression of collagen deposition or fibrosis in the subject is retarded relative to progression of fibrosis in a subject that is not administered (S)-4- ((2 -methoxy ethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4- ylaminojbutanoic acid, or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein collagen deposition is in the subpleural region of a lung of the subject.

5. The method of any one of claims 1-4, wherein collagen deposition after a first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to collagen deposition prior to the first administration.

6. The method of claim 5, wherein collagen deposition is reduced at about 12 weeks after the first administration of (S)-4-((2-methoxyethyl)(4-(5, 6, 7, 8-tetrahydro-l, 8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1-6, wherein the subject has a fibrotic disease.

8. The method of claim 7, wherein the fibrotic disease is pulmonary fibrosis or liver fibrosis.

9. The method of claim 7, wherein the fibrotic disease is an interstitial lung disease.

10. The method of claim 7, wherein the fibrotic disease is idiopathic pulmonary fibrosis or primary sclerosing cholangitis.

11. The method of any one of claims 1-10, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered over at least about 12 weeks.

12. The method of any one of claims 1-11, wherein the subject has lung fibrosis, and wherein cough severity in the subject after a first administration of (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is reduced relative to cough severity in the subject prior to the first administration.

13. The method of claim 12, wherein cough severity is measured by Cough Visual Analog Scale.

14. The method of any one of claims 1-13, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered orally.

15. The method of any one of claims 1-14, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg to about 320 mg daily.

16. The method of claim 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg daily.

17. The method of claim 15, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8- naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg daily.

18. The method of any one of claims 1-17, wherein the administration is once daily.

19. The method of any one of claims 1-18, wherein the (S)-4-((2-methoxyethyl)(4-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid is administered as a phosphate salt.

20. The method of any one of claims 1-19, wherein the subject is concurrently being treated with a standard of care for fibrosis.

21. The method of claim 20, wherein the standard of care comprises administration of pirfenidone, administration of nintedanib, or administration of pirfenidone and nintedanib.

22. (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)butyl)amino)-2- (quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, for use in reversing or retarding progression of collagen deposition or fibrosis in a subject in need thereof.

23. Use of (S)-4-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-l,8-naphthyridin-2- yl)butyl)amino)-2-(quinazolin-4-ylamino)butanoic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reversing or retarding progression of collagen deposition or fibrosis in a subject in need thereof.

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