Methods of Treating Interstitial Lung Disease and Other Fibrosis-Mediated Pulmonary Diseases and Disorders with Dupirfenidone - Patent application

Abstract

Disclosed herein are methods of treating interstitial lung disease and other fibrosis-mediated pulmonary diseases or disorders, comprising administering to a subject in need thereof deuterium-enriched pirfenidone, LYT-100, in a total daily dose of about 825 mg to about 2475 mg.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 432,208, filed December 13, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 431,530, filed December 9, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 403,481, filed September 2, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 374,362, filed September 1, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 356,653, filed June 29, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 352,107, filed June 14, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 352,107, filed May 13, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 352,207, filed May 13, 2022, which claims the benefit of U.S. Provisional Application No. 63 / 352,1 ...207, filed May 13, 2022, which claims the benefit of U No. 63 / 341,828, filed May 12, 2022, claims the benefit of U.S. Provisional Application No. 63 / 341,269, filed May 12, 2022, claims the benefit of U.S. Provisional Application No. 63 / 341,279, filed May 12, 2022, claims the benefit of U.S. Provisional Application No. 63 / 341,281, filed May 12, 2022, claims the benefit of U.S. Provisional Application No. 63 / 326,132, filed March 31, 2022, and claims the benefit of U.S. Provisional Application No. 63 / 326,129, filed March 31, 2022, all of which are incorporated by reference in their entireties for all purposes. [Background technology]

[0002] Current antifibrotic agents suffer from poor drug tolerability problems, including dose-limiting side effects and toxicities, particularly those associated with gastrointestinal intolerance (e.g., nausea, diarrhea, and other gastrointestinal events), headaches, and photosensitivity, as well as other adverse side effects, which significantly limit current treatments for interstitial lung disease and other fibrosis-mediated lung diseases and disorders. These dose-limiting side effects and / or toxicities typically require, and are therefore managed by, one or more of the following treatment options: administration of lower, less effective doses, periodic reduction(s) of the effective dose, periodic or permanent withdrawal of the drug (interruption or discontinuation of treatment), and / or inability of the patient to maintain a continuous treatment program or long-term maintenance dose (e.g., without treatment interruption). For example, pirfenidone, one of only two drugs currently approved in the United States by the FDA for the treatment of idiopathic pulmonary fibrosis (IPF), suffers from poor tolerability problems, which significantly limit the use of this drug, leading to dose reductions, drug switching, and / or interruption or discontinuation of antifibrotic therapy. Studies have shown that only 21% of patients who initiate pirfenidone therapy remain on the recommended dose after 2 years (see, e.g., Dempsey, 2021). Poor tolerability and its management, including significant incidence of permanent dose reductions and treatment discontinuation, are associated with reduced clinical efficacy and missed opportunity to achieve full clinical benefit.

[0003] Thus, there is a need for therapies that have a better tolerability profile than current antifibrotic agents for the treatment of interstitial lung disease and other fibrosis-mediated lung diseases and disorders. In particular, there is a need for treatment options that allow dosing that can achieve higher drug exposure than current treatment options that are limited by dose-limiting side effects and / or toxicity so that continuous (e.g., uninterrupted) treatment can be maintained, or that have a better tolerability profile than current antifibrotic agents, or both. Summary of the Invention

[0004] In one aspect, a method of treating interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder is provided, the method comprising administering to a subject in need thereof a compound having the structure: [ka] The present invention relates to a method for treating interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder in a subject, the method comprising administering deuterium-enriched pirfenidone having the formula:

[0005] In some embodiments, the total daily dose is 1650 mg.

[0006] In some embodiments, the total daily dose is 2475 mg.

[0007] In some embodiments, the total daily dose is administered in three equal doses.

[0008] In some embodiments, the total daily dose is administered in three equal doses of 825 mg each (825 mg TID).

[0009] In some embodiments, the total daily dose is administered in three equal doses of 550 mg each (550 mg TID).

[0010] In some embodiments, LYT-100 is administered without regard to food.

[0011] In some embodiments, LYT-100 is administered without food.

[0012] In some embodiments, LYT-100 is administered with food.

[0013] In some embodiments, LYT-100 is administered without dose escalation.

[0014] In some embodiments, administering comprises titrating from an initial total daily dose that is less than the total daily dose up to the total daily dose.

[0015] In some embodiments, administering comprises titrating from an initial total daily dose below the total daily dose to a total daily dose, where titrating comprises administering LYT-100 at three doses per day of 550 mg each for an initial period, followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, titrating comprises administering LYT-100 at three doses per day of 275 mg each for an initial period, followed by LYT-100 at three doses per day of 550 mg each for a period, optionally followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, the initial period is 3-14 days. In some embodiments, the initial period is 3-7 days.

[0016] In some embodiments, the fibrosis-mediated lung disease or disorder is interstitial lung disease (ILD).In some embodiments, the ILD is exposure-related ILD, drug-induced ILD, autoimmune interstitial lung disease, unclassifiable interstitial lung disease (uILD), progressive fibrosing interstitial lung disease (pfILD), respiratory bronchiolitis ILD (RB-ILD), connective tissue disease-associated ILD (CTD-ILD), rheumatoid arthritis (RA-ILD), systemic sclerosis (SSc-ILD), mixed connective tissue disease ILD, scleroderma-associated ILD, or chronic sarcoidosis-associated ILD.In some embodiments, the ILD is progressive fibrosing ILD (PF-ILD).

[0017] In some embodiments, the interstitial lung disease or disorder is not idiopathic pulmonary fibrosis (IPF).

[0018] In some embodiments, interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder is alleviated.

[0019] In some embodiments, the progression of interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder is delayed, slowed, or prevented.

[0020] In another aspect, there is provided a method of treating interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder, comprising administering to a subject in need thereof a compound having the structure: [ka] The method includes administering deuterium-enriched pirfenidone having the formula:

[0021] In some embodiments, the dose of LYT-100 is a total daily dose of 1650 mg.

[0022] In some embodiments, the total daily dose is administered in three equal doses.

[0023] In some embodiments, the total daily dose is administered in three equal doses of 550 mg each (550 mg TID).

[0024] In some embodiments, LYT-100 is administered without regard to food.

[0025] In some embodiments, LYT-100 is administered without food.

[0026] In some embodiments, LYT-100 is administered with food.

[0027] In some embodiments, LYT-100 is administered without dose escalation.

[0028] In some embodiments, the fibrosis-mediated lung disease or disorder is interstitial lung disease (ILD).In some embodiments, the ILD is exposure-related ILD, drug-induced ILD, autoimmune interstitial lung disease, unclassifiable interstitial lung disease (uILD), progressive fibrosing interstitial lung disease (pfILD), respiratory bronchiolitis ILD (RB-ILD), connective tissue disease-associated ILD (CTD-ILD), rheumatoid arthritis (RA-ILD), systemic sclerosis (SSc-ILD), mixed connective tissue disease ILD, scleroderma-associated ILD, or chronic sarcoidosis-associated ILD.In some embodiments, the ILD is progressive fibrosing ILD (PF-ILD).

[0029] In some embodiments, the interstitial lung disease or disorder is not idiopathic pulmonary fibrosis (IPF). In some embodiments, the interstitial lung disease or other fibrosis-mediated lung disease or disorder is alleviated.

[0030] In some embodiments, the progression of interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder is delayed, slowed, or prevented.

[0031] In yet another aspect, a method of treating interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder is provided, comprising administering to a subject in need thereof a compound having the structure: [ka] The method includes administering deuterium-enriched pirfenidone having the formula:

[0032] In some embodiments, administration is performed at a dose that achieves a systemic exposure of LYT-100 in the subject that exceeds the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, and the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID).

[0033] In some embodiments, pirfenidone is administered at a dose that achieves a systemic exposure of LYT-100 in the subject that is about 1.1 to about 1.9 times the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0034] In some embodiments, the dose is administered to achieve in the subject a systemic exposure of LYT-100 that is about 1.25 to about 1.75 times the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0035] In some embodiments, the dose of LYT-100 administered achieves a systemic exposure of pirfenidone that is 1.25-1.75-fold that achieved when pirfenidone is administered at a total daily dose of 2403 mg.

[0036] In some embodiments, the dose is administered to achieve in the subject a systemic exposure of LYT-100 that is about 1.4-1.6 times the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0037] In some embodiments, the dose is administered to achieve in the subject a systemic exposure of LYT-100 that is 1.4-1.5 times the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0038] In some embodiments, administration is at a dose that achieves a systemic exposure of LYT-100 in the subject that is about 1.5 times the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally administered in three doses of 801 mg each (801 mg TID).

[0039] In some embodiments, pirfenidone is administered at a dose that achieves a systemic exposure of LYT-100 in the subject that is about 85% to about 125% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0040] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is 125% to 175% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0041] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is 140% to 160% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0042] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is 140% to 150% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0043] In some embodiments, administration is at a dose that achieves a systemic exposure of LYT-100 in the subject that is about 150% of the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0044] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is about 10% to about 90% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0045] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is about 25% to about 75% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0046] In some embodiments, pirfenidone is administered at a dose that achieves a systemic exposure of LYT-100 in the subject that is 25% to 75% greater than the systemic exposure of pirfenidone achieved when administered at a total daily dose of 2403 mg, optionally divided into three doses of 801 mg each (801 mg TID). In some embodiments, pirfenidone is administered at a dose that achieves a systemic exposure of LYT-100 in the subject that is 40% to 60% greater than the systemic exposure of pirfenidone achieved when administered at a total daily dose of 2403 mg, optionally divided into three doses of 801 mg each (801 mg TID).

[0047] In some embodiments, the dose is administered to achieve a systemic exposure of LYT-100 in the subject that is 40% to 50% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0048] In some embodiments, administration is performed at a dose that achieves a systemic exposure of LYT-100 in the subject that is about 50% greater than the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg, optionally with the total daily dose of pirfenidone administered in three doses of 801 mg each (801 mg TID).

[0049] In some embodiments, a dose of LYT-100 that achieves a systemic exposure of LYT-100 in a subject that exceeds the systemic exposure of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg is a total daily dose of 2475 mg.

[0050] In some embodiments, the total daily dose is administered in three equal doses.

[0051] In some embodiments, the total daily dose is administered in three equal doses of 825 mg each (825 mg TID).

[0052] In some embodiments, LYT-100 is administered without regard to food.

[0053] In some embodiments, LYT-100 is administered without food.

[0054] In some embodiments, LYT-100 is administered with food.

[0055] In some embodiments, LYT-100 is administered without dose escalation.

[0056] In some embodiments, administering comprises titrating from an initial total daily dose that is less than the total daily dose up to the total daily dose.

[0057] In some embodiments, administering comprises titrating from an initial total daily dose below the total daily dose to a total daily dose, where titrating comprises administering LYT-100 at three doses per day of 550 mg each for an initial period, followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, titrating comprises administering LYT-100 at three doses per day of 275 mg each for an initial period, followed by LYT-100 at three doses per day of 550 mg each for a period, optionally followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, the initial period is 3-14 days. In some embodiments, the initial period is 3-7 days.

[0058] In some embodiments, the fibrosis-mediated disease or disorder or collagen-mediated disease or disorder is interstitial lung disease (ILD).In some embodiments, the ILD is exposure-related ILD, drug-induced ILD, autoimmune interstitial lung disease, unclassifiable interstitial lung disease (uILD), progressive fibrosing interstitial lung disease (pfILD), respiratory bronchiolitis ILD (RB-ILD), connective tissue disease-associated ILD (CTD-ILD), rheumatoid arthritis (RA-ILD), systemic sclerosis (SSc-ILD), mixed connective tissue disease ILD, scleroderma-associated ILD, or chronic sarcoidosis-associated ILD.In some embodiments, the ILD is progressive fibrosing ILD (PF-ILD).

[0059] In some embodiments, the fibrosis-mediated or collagen-mediated disease or disorder is not idiopathic pulmonary fibrosis (IPF).

[0060] In some embodiments, the fibrosis-mediated or collagen-mediated disease or disorder is alleviated.

[0061] In some embodiments, the progression of a fibrosis-mediated or collagen-mediated disease or disorder is delayed, slowed, or prevented. [Brief description of the drawings]

[0062] [Figure 1] 1 is a diagram of a crossover clinical trial study design according to a non-limiting embodiment of the present disclosure. [Diagram 2] 1 is an illustration of a study design for another crossover clinical trial according to a non-limiting embodiment of the present disclosure. [Diagram 3] 1 is a table showing the extrapolated steady-state exposure (AUC24ss) and steady-state Cmax values ​​for LYT-100 administered at 450 mg to 550 mg TID based on PK data from two separate cohorts (12A and 12B) and the combined data set. Pharmacokinetic parameters were calculated using steady-state AUC0-24 following administration of LYT-100 at a dose of 1000 mg BID or pirfenidone at a dose of 801 mg TID. The data show that the 550 mg TID dose of LYT-100 has a steady-state exposure (AUC) calculated to be 98.5% of the steady-state exposure (AUC) of pirfenidone administered at 801 mg TID and a Cmax calculated to be 67.4% of the Cmax of pirfenidone administered at 801 mg TID. [Figure 4]1 is a table showing extrapolated steady state exposure (AUC24ss) and steady state Cmax values ​​for LYT-100 administered at 700mg-1000mg BID (1400mg-2000mg daily doses) versus 450mg-850mg TID (1350mg-2550mg daily doses). The data show that an 825mg BID (1650mg daily dose) dose of LYT-100 is calculated to have a steady state exposure (AUC) equivalent to 98.5% of the steady state exposure (AUC) and 101.1% of the steady state Cmax of pirfenidone administered at 801mg TID. In contrast, a dose of 550 mg TID (1650 mg daily dose) of LYT-100 has been calculated to have a steady-state exposure (AUC) equivalent to 98.5% of the steady-state exposure (AUC) and 67.4% of the steady-state Cmax of pirfenidone administered at 801 mg TID. [Figure 5A] Summary of pharmacokinetic and tolerability results from a Phase 1 crossover study of healthy adults receiving 850 mg BID of LYT-100. [Figure 5B] 1 is a table showing the incidence of treatment-emergent adverse events (TEAEs) in a crossover study in healthy elderly subjects comparing LYT-100 850 mg BID versus pirfenidone 801 mg TID. The data show that the incidence of gastrointestinal AEs with LYT-100 was 37.1% for LYT-100 versus 29.7% for pirfenidone, the incidence of neurological AEs was 45.7% for LYT-100 versus 35.1% for pirfenidone, and the incidence of nausea was increased for both LYT-100 and pirfenidone when administered after a fast. [Figure 6] FIG. 1 is a graphical representation of adverse events occurring in a healthy elderly patient population with LYT-100 at 550 mg TID and pirfenidone at 801 mg TID. [Figure 7A] 1 is a graphical representation of LYT-100 exposure versus time for a dose of 550 mg TID. [Figure 7B] 1 is a graphical representation of LYT-100 exposure versus time for a dose of 824 mg TID. [Figure 7C] 1 is a graphical representation of exposure to major metabolites versus time for a dose of 550 mg TID. [Figure 7D] 1 is a graphical representation of exposure to major metabolites versus time for a dose of 824 mg TID. [Figure 8] 1 is a table showing pharmacokinetic parameters of LYT-100 and major metabolites for doses of 550 mg TID and 824 mg TID. [Figure 9A] FIG. 1 is a graphical representation of LYT-100 exposure versus time for doses of 550 mg TID and 824 mg TID in the crossover study of Example 1 and two lead-in studies. [Figure 9B] FIG. 1 is a graphical representation of exposure to major metabolites versus time for doses of 550 mg TID and 824 mg TID in the crossover study and two lead-in studies of Example 1. [Figure 10] 1 is a graphic representation of mean plasma concentrations over time of pirfenidone administered at 801 mg TID, and LYT-100 administered at 550 mg TID and 824 mg TID. [Figure 11] 1 is a graphical representation of the mean plasma concentrations of major metabolites over time for pirfenidone administered at 801 mg TID, and LYT-100 administered at 550 mg TID and 824 mg TID. [Figure 12] 1 is a graphic representation of plasma concentrations versus time of pirfenidone, 550 mg TID, and LYT-100, 824 mg TID, after day 3 in the crossover study of Example 1. [Figure 13A] FIG. 1 is a graphical representation of subject weight versus exposure for LYT-100 at doses of 550 mg TID and 824 mg TID in the crossover study of Example 1 and the three lead-in dose studies. [Figure 13B] FIG. 1 is a graphical representation of subject weight versus exposure to major metabolites at doses of 550 mg TID and 824 mg TID in the crossover study and three lead-on dose studies of Example 1. [Figure 14A]FIG. 1 is a graphical representation of subject age versus exposure to LYT-100 normalized to 550 mg TID in the crossover study of Example 1 and three prior dosing studies. [Figure 14B] FIG. 1 is a graphical representation of subject age versus exposure to major metabolites of LYT-100 normalized to 550 mg TID in the crossover study of Example 1 and three prior dosing studies. [Figure 15A] FIG. 1 is a graphical summary of exposure versus dose for the crossover and lead-in studies of Example 1, showing that 550 mg TID of LYT-100 achieves bioequivalence to 801 mg TID of pirfenidone. [Figure 15B] FIG. 1 is a graphical summary of exposure versus dose for the crossover and lead-in studies of Example 1, showing that 550 mg TID of LYT-100 achieves bioequivalence to 801 mg TID of pirfenidone. [Figure 15C] FIG. 1 is a graphical summary of exposure versus dose for the crossover and lead-in studies of Example 1, showing that 550 mg TID of LYT-100 achieves bioequivalence to 801 mg TID of pirfenidone. [Figure 15D] FIG. 1 is a graphical summary of exposure versus dose for the combined data from the crossover and lead-in studies of Example 1, showing that 550 mg TID of LYT-100 achieves bioequivalence to 801 mg TID of pirfenidone. [Figure 16] FIG. 13 is a graphical summary of exposure versus dose for the combined data from the crossover study of Example 1 and the three prior dosing studies, showing that LYT-100 at 550 mg TID and 687 mg TID achieved bioequivalence to pirfenidone at 801 mg TID. [Figure 17] 1 is a table showing the predicted bioequivalence for various TID doses of LYT-100 using data from the crossover study of Example 1 and three prior dosing studies. [Figure 18A] 1 is a pictorial representation of predicted plasma concentrations over time for pirfenidone 801 mg TID, LYT-100 550 mg TID, and LYT-100 825 mg TID. [Figure 18B] 1 is a table showing the percentage of predicted plasma concentrations of LYT-100 administered at 550 mg TID and 825 mg TID compared to pirfenidone at 801 mg TID. [Figure 19] FIG. 1 is a table outlining the baseline demographic characteristics of subjects in the COVID-19 clinical trial of Example 3 with respect to age and sex. [Figure 20] FIG. 1 is a table outlining baseline demographic characteristics of subjects in the COVID-19 clinical trial of Example 3 with respect to ethnicity, race, and time since COVID diagnosis. [Figure 21] FIG. 1 is a table outlining the subject breakdown of the population enrolled in the COVID-19 clinical trial of Example 3. [Figure 22] FIG. 1 is a table summarizing treatment-emergent adverse events determined to be at least possibly related to LYT-100 in the COVID-19 clinical trial of Example 3. [Figure 23] 1 is a table showing the metabolism of pirfenidone and LYT-100 in the presence of individual CYP isoenzymes in the assay of Example 4. [Figure 24] FIG. 13 is a graphical representation of the activity results of LYT-100 and pirfenidone in the BioMap Fibrosis Panel of Example 5. [Figure 25A] FIG. 1 is a graph showing that the TNF-α response to LPS was reduced by pretreatment with both pirfenidone and LYT-100. [Figure 25B] FIG. 1 is a graph showing that the IL-6 response to LPS was reduced by pretreatment with both pirfenidone and LYT-100. [Figure 26] Representative photomicrographs of Sirius Red stained liver sections are shown, demonstrating that LYT-100 significantly reduced areas of fibrosis. [Figure 27]FIG. 1 is a graphic representation showing the percentage of areas of fibrosis for LYT-100 versus vehicle and control. [Figure 28A] 1 is a diagram showing that LYT-100 does not induce survival of primary mouse lung fibroblasts (PMFL). [Figure 28B] FIG. 1 is a graph showing that LYT-100 reduced TGF-β-induced total collagen levels in PMFLs in a 6-well format. [Figure 28C] FIG. 1 is a graph showing that LYT-100 reduced TGF-β-induced total collagen levels in PMFLs in a 96-well format. [Figure 28D] 1 is a diagram showing that LYT-100 reduced TGF-β-induced soluble fibronectin levels. [Figure 28E] 1 is a diagram showing that LYT-100 reduced TGF-β-induced soluble collagen levels. [Figure 29A] 1 is a diagram showing that LYT-100 does not affect the viability of L929 cells. [Figure 29B] 1 is a diagram showing that LYT-100 inhibits TGF-induced collagen synthesis. [Figure 29C] 1 is a graph showing that LYT-100 significantly suppresses TGF-β-induced total collagen levels. [Figure 29D] 1 is a diagram showing that LYT-100 significantly suppresses TGF-β-induced soluble collagen levels. [Figure 29E] FIG. 1 is a graph showing that LYT-100 significantly reduces soluble fibronectin levels in the absence and presence of TGF-β induction. [Figure 30A] 1 shows the results of once-daily administration of LYT-100 to reduce swelling in a mouse lymphedema model. [Figure 30B] 1 shows the results of once-daily administration of LYT-100 to reduce swelling in a mouse lymphedema model. [Figure 30C]1 shows the results of once-daily administration of LYT-100 to reduce swelling in a mouse lymphedema model. [Figure 30D] 1 shows the results of once-daily administration of LYT-100 to reduce swelling in a mouse lymphedema model. [Diagram 31] 1 is a graphical representation of the percent weight change over time in rats in Phase I of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 32A] 1 is a graphical representation of the percentage of lung weight to body weight over time in rats in Phase I of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 32B] 1 is a graphical representation of the percentage of lung weight to body weight over time in rats in Phase I of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 33A] 1 is a graphical representation of rat body weight over time in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 33B] 1 is a graphical representation of the percent weight change over time in rats in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 34A] 1 is a graphical representation of lung weight over time in rats in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 34B] 1 is a graphical representation of lung weight over time in rats in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 35A] 1 is a graphical representation of the percentage of lung weight to body weight over time in rats in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 35B] 1 is a graphical representation of the percentage of lung weight to body weight over time in rats in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 36A] 1 is a graphical representation of hydroxyproline content in left lung tissue of rats in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 36B]1 is a graphical representation of hydroxyproline content in left lung tissue of rats in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 37] 1 is a table showing hydroxyproline content in left lung tissue of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 38A] FIG. 13 is a graphical representation of hydroxyproline content in lung tissue of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 38B] FIG. 13 is a graphical representation of hydroxyproline content in lung tissue of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 39] 1 is a table showing hydroxyproline content in lung tissue of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 40A] FIG. 13 is a graphical representation of the mean pulmonary fibrosis scores of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 40B] FIG. 13 is a graphical representation of the mean pulmonary fibrosis scores of various treatment groups in phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 40C] FIG. 13 is a graphical representation of the median lung fibrosis scores for various treatment groups in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Figure 40D] FIG. 13 is a graphical representation of the median lung fibrosis scores for various treatment groups in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. [Diagram 41] FIG. 13 is a graphical representation of the frequency of pulmonary fibrosis scores in various treatment groups in Phase II of the bleomycin-induced pulmonary fibrosis model of Example 11. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] Disclosed herein is a method for treating interstitial lung disease or other fibrosis-mediated lung disease or disorder, comprising administering LYT-100 to a subject in need thereof.In some embodiments, the method comprises administering a total daily dose of LYT-100 that achieves a systemic exposure equivalent (e.g., the same or approximately the same) to the systemic exposure of 2403 mg of pirfenidone administered daily (e.g., 801 mg TID administration).In some embodiments, the method comprises administering a total daily dose of LYT-100 that achieves a systemic exposure that is greater than the systemic exposure of pirfenidone administered at a dose of 2403 mg daily (e.g., 801 mg TID administration). This method, in some embodiments, may result in improved patient compliance, may provide higher LYT-100 exposure than that achieved with the currently approved dose of pirfenidone (801 mg TID), or both, and may ultimately result in more effective therapeutic agents that address the underlying mechanisms of fibrosis- or collagen-mediated diseases and disorders.

[0064] Overall, the results disclosed herein show that LYT-100 can be used in the treatment of indications where pirfenidone has been shown to be beneficial, but where tolerability concerns may limit its dosage and its effectiveness.Therefore, the disclosed method can be beneficial in the treatment of various interstitial lung diseases and other fibrosis-mediated lung diseases and disorders.The characteristics, advantages and usefulness of this method are each described further below in this specification.

[0065] definition Although the terms used herein are believed to be well understood by those of skill in the art, definitions are provided herein to facilitate description of the subject matter disclosed in the present application.

[0066] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0067] The term "about" used throughout this specification is used to represent and take into account small variations. For example, the term "about" can refer to greater than, less than, or equal to ±10%, for example, greater than, less than, or equal to ±5%, greater than, less than, or equal to ±2%, greater than, less than, or equal to ±1%, greater than, less than, or equal to ±0.5%, greater than, less than, or equal to ±0.2%, greater than, less than, or equal to ±0.1%, or greater than, less than, or equal to ±0.05%. Any numerical value in this specification is modified by the term "about", whether or not it is explicitly stated. Values ​​modified by the term "about" should include the specified value. For example, "about 5.0" should include 5.0.

[0068] The term "adverse event" refers to any event, side effect, or other untoward medical occurrence occurring with the use of a medicinal product in humans, whether or not it is considered causally related to this treatment. Thus, an AE can be any untoward, unintended sign (which may include clinically significant laboratory abnormalities), symptom, or disease that is temporally related to the use of a medicinal product, whether or not it is considered drug-related. Events that meet the definition of an AE include: chronic or intermittent worsening of a pre-existing condition (including an increase in the frequency and / or intensity of that condition); a new condition that occurs during the reporting period and is detected or diagnosed after administration of the study drug, even if it may have been present before the start of the study; signs, symptoms, or clinical sequelae of a suspected interaction; signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a concomitant drug (overdose itself is not reported as an AE / SAE). An AE may be causally related, potentially related, or unrelated to the treatment. The severity of an AE is classified as one of the following:Mild (Grade 1): a type of AE that is usually transient and may require only minimal treatment or intervention. The event generally does not interfere with normal activities of daily living;Moderate (Grade 2): a type of AE that is usually mitigated by additional specific intervention. The event interferes with normal activities of daily living and causes discomfort to the study participant, but does not pose a risk of serious or permanent harm;Severe (Grade 3): a type of AE that interferes with normal activities of daily living or has a significant impact on clinical status or may require intensive intervention;Life-threatening (Grade 4): a type of AE that poses an immediate risk of death to the participant;Death (Grade 5): an event that leads to death.

[0069] As used herein, the terms "clinically effective amount," "clinically proven effective amount," and the like refer to an effective amount of an API as demonstrated by clinical trials, e.g., U.S. Food and Drug Administration (FDA) clinical trials.

[0070] The term "deuterium" when used to represent a given variable position in a molecule or formula, or the symbol "D" when used to represent a given position in a molecular structure diagram, means that the designated position is enriched with deuterium above the naturally occurring deuterium distribution. In some embodiments, the deuterium enrichment is about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 98% or more, or in some embodiments, about 99% or more deuterium at the designated position. In some embodiments, the deuterium enrichment is greater than 90% at each designated position. In some embodiments, the deuterium enrichment is greater than 95% at each designated position. In some embodiments, the deuterium enrichment is about 99% at each designated position.

[0071] The term "deuterium enrichment" refers to the percentage of deuterium incorporation in place of hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring deuterium distribution is approximately 0.0156%, the deuterium enrichment at any position of a compound synthesized using a non-enriched starting material is approximately 0.0156%. Deuterium enrichment can be determined using conventional analytical methods such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0072] The term "fibrosis" refers to the deposition of extracellular matrix components, excess fibrous connective tissue, or scarring within an organ or tissue.

[0073] The term "idiopathic pulmonary fibrosis (IPF)" refers to a type of lung disease that causes scarring in the lungs (pulmonary fibrosis) for which the cause of the condition may be unknown.

[0074] Terms such as "treating" or "treatment" or "treat" or "alleviating" or "alleviating" refer to a therapeutic measure that cures, slows, relieves or alleviates, halts the progression of, and / or alleviates one or more symptoms of a diagnosed pathological condition or disorder. Thus, those in need of treatment include those who already have the disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay recurrence. In some embodiments, a subject has been successfully "treated" for a disease or disorder according to the methods provided herein, e.g., when the patient exhibits a total, partial, or temporary alleviation or disappearance of symptoms associated with the disease or disorder. "Treating" may include, but is not limited to, reducing or alleviating one or more symptoms of a disease or disorder; delaying, slowing, halting, remission, attenuation, and / or reducing fibrosis; slowing, slowing, halting, remission, or attenuation of the progression of a disease or disorder; delaying, slowing, halting, remission, or attenuation of the onset of a disease or disorder; reducing swelling, inflammation, fibrosis, and / or pain; and / or improving pulmonary or respiratory function.

[0075] The term "pirfenidone administered at a dose or dosage that achieves the same or approximately the same systemic exposure" used in comparison with LYT-100 refers to a dose, dosage, or administration of pirfenidone such that the AUC of pirfenidone in a subject is the same or approximately the same as the AUC achieved by LYT-100 at a given dose of LYT-100 in the subject.In some cases, "pirfenidone administered at a dose or dosage that achieves the same or approximately the same systemic exposure" can refer to pirfenidone administered to a subject at a total daily dose of 2403 mg.In some cases, "pirfenidone administered at a dose or dosage that achieves the same or approximately the same systemic exposure" can refer to pirfenidone administered to a subject at 801 mg TID.

[0076] The term "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional components that are unacceptably toxic to the subject to which the composition is administered. Pharmaceutical compositions can be in a number of dosage forms, such as tablets, capsules, liquids, solutions, softgels, suspensions, emulsions, syrups, elixirs, tinctures, films, powders, hydrogels, ointments, pastes, creams, lotions, gels, mousses, foams, lacquers, sprays, aerosols, inhalers, nebulizers, eye drops, patches, suppositories, and / or enemas. Pharmaceutical compositions typically include a pharmaceutical acceptable carrier and may include one or more of a buffer (e.g., acetate buffer, phosphate buffer, or citrate buffer), a surfactant (e.g., polysorbate), a stabilizer (e.g., human albumin), a preservative (e.g., benzyl alcohol), a penetration enhancer, an absorption promoter to enhance bioavailability, and / or other conventional solubilizing or dispersing agents. The choice of dosage form and excipients depends on the active agent to be delivered and the disease or disorder to be treated or prevented, and is routine for those skilled in the art.

[0077] The terms "subject" and "patient" refer to a mammalian subject, including a human subject. In some embodiments, the patient is a human subject.

[0078] The term "LYT-100" refers to a selectively deuterium enriched form of pirfenidone. Specifically, LYT-100 is 5-(methyl-d3)-1-phenylpyridin-2-(1H)-one (CAS number 1093951-85-9), also known as dupirfenidone or 2(1H)-pyridinone, 5-(methyl-d3)-1-phenyl. LYT-100 has the following structure: [ka] References herein to "LYT-100" further include 5-(methyl-d3)-1-phenylpyridin-2-(1H)-one, any hydrates, solvates, crystalline polymorphs, amorphous forms, and the like. LYT-100 can be prepared by methods known to those of skill in the art and routine modifications thereof, and / or procedures found in Esaki et al., Tetrahedron 2006, 62, 10954-10961, Smith et al., Organic Syntheses 2002, 78, 51-56, U.S. Pat. No. 3,974,281, U.S. Pat. No. 8,680,123, WO2003 / 014087, WO2008 / 157786, WO2009 / 035598, WO2012 / 122165, or WO2015 / 112701, each of which is incorporated herein by reference in its entirety, and references cited therein and routine modifications thereof.

[0079] Methods for treating interstitial lung disease and other fibrosis-mediated pulmonary diseases and disorders - Patents.com Pirfenidone Pirfenidone (Deskar®), CAS#53179-13-8, Pirespa, AMR-69, Pirfenidona, Pirfenidonum, Esbriet, Pirfenex, 5-methyl-1-phenyl-1H-pyridin-2-one, 5-methyl-1-phenyl-2-(1H)-pyridone, 5-methyl-1-phenylpyridin-2(1H)-one is an orally administered small molecule with antifibrotic activity and has been approved in the United States and elsewhere for the treatment of idiopathic pulmonary fibrosis (IPF). [ka]

[0080] Pirfenidone has established anti-inflammatory and anti-fibrotic properties. Multiple mechanisms likely contribute to the unique profile of pirfenidone. Pirfenidone attenuates fibroblast proliferation, fibrosis-related protein and cytokine production, and extracellular matrix biosynthesis and accumulation in response to cytokine growth factors such as TGF-β and platelet-derived growth factor, or PDGF (Schaefer et al., Eur Respir Rev. 2011; 20: 85-97; InterMune UK, Ltd. Esbriet® Summary of Product Characteristics, 2011). Specifically, pirfenidone blocks the production and activity of TGF-β, a key growth factor that increases collagen production and decreases its degradation. In addition, administration of pirfenidone reduces the production of other fibrogenic factors induced by TGF-β, such as fibronectin and connective tissue growth factor (Schaefer et al., 2011). Pirfenidone can block bleomycin-induced PDGF production and proliferation of fibroblasts and hepatic stellate cells in response to PDGF (DiSario et al., J.Hepatol.2002 Nov.37.5.584-591). Pirfenidone inhibits the expression of TNF-α, IL-6, IL-1, and intercellular adhesion molecule 1 (ICAM-1) (Schaefer et al., 2011). In mouse macrophage-like cell lines, pirfenidone suppressed the production or secretion of TNF-α and increased the levels of the anti-inflammatory cytokine IL-10 through a mitogen-activated protein kinase and c-Jun N-terminal kinase-independent mechanism (Schaefer et al., 2011).

[0081] In clinical trials for IPF, the most common adverse reactions were gastrointestinal (nausea, abdominal pain, diarrhea, dyspepsia, vomiting, and gastroesophageal reflux disease), in addition to fatigue, rash, and photosensitivity reactions. The frequency of these adverse effects led to discontinuation in 14.6% of patients enrolled in those trials. In a prospective, real-world, observational study of 1009 patients with IPF who initiated pirfenidone, 35% of patients experienced adverse reactions leading to dose adjustments, 28% discontinued, and 11% discontinued after dose adjustment (Cottin, ERJ Open Res, 2018, 4(4)). As a result, the overall adoption rate of antifibrotic agents, including pirfenidone, remains low. One study used the US OptumLabs Data Warehouse to identify 10,996 patients with IPF who had medical and drug claims between October 1, 2014 and July 31, 2019. The study showed that 73.6% of IPF patients had never received antifibrotic agents (pirfenidone or nintedanib) during the observation period (Dempsey et al. Ann Am Thorac Soc. 2021;18(7):1121-1128). In a large post-marketing analysis of 10,996 patients diagnosed with IPF, only 13.2% were treated with pirfenidone during a 5-year follow-up period, the same percentage as those treated with another marketed antifibrotic drug, nintedanib (Dempsey, 2021). AEs were identified as a barrier to both adoption and persistence of pirfenidone and nintedanib in IPF patients.

[0082] Nintedanib (Ofev; Boehringer Ingelheim) was approved by the FDA in 2014 for the treatment of patients with idiopathic pulmonary fibrosis. It has since been approved to slow the progression of pulmonary fibrosis in patients with systemic sclerosis (scleroderma) as well as other rheumatic diseases with progressive pulmonary fibrosis (progressive fibrosing interstitial lung disease). Nintedanib is a small molecule that inhibits multiple receptor and non-receptor tyrosine kinases. Specifically, nintedanib inhibits platelet-derived growth factor (PDGF) receptors α and β, fibroblast growth factor (FGF) receptors 1-3, vascular endothelial growth factor (VEGF) receptors 1-3, and fms-like tyrosine kinase 3. Of these tyrosine kinase receptors, FGF, PDGF, and VEGF have been implicated in the pathogenesis of idiopathic pulmonary fibrosis. Nintedanib competitively binds to the adenosine triphosphate-binding pocket of these receptors, blocking intracellular signaling essential for fibroblast proliferation, migration, and transformation, which represent an essential mechanism of the pathology of idiopathic pulmonary fibrosis.

[0083] As reported in the Ofev prescribing information, nintedanib was associated with numerous side effects in the studies leading to its FDA approval. The most common adverse reactions (≥5%) with nintedanib therapy included diarrhea (62%), nausea (24%), abdominal pain (15%), vomiting (12%), elevated liver enzymes (14%), decreased appetite (11%), headache (8%), weight loss (10%), and hypertension (5%). Overall, 21% of patients receiving nintedanib and 15% of patients receiving placebo discontinued treatment due to adverse events. The most frequent adverse reactions leading to discontinuation of nintedanib were diarrhea, nausea, and decreased appetite. A 2019 retrospective study reported that nausea, vomiting, or thrombocytopenia led to permanent discontinuation of nintedanib, and temporary discontinuation due to adverse effects was common (Nakamura et al. Ann Transl Med. 2019 Jun;7(12):262). Nintedanib may have adverse effects on the liver, and blood tests for liver enzymes are recommended when dosing is started and at regular intervals during the first 3 months of treatment.

[0084] Pirfenidone has not been tested for clinical efficacy at doses above 801 mg TID due to poor tolerability, including gastrointestinal adverse effects, nausea, weight loss, and photosensitive skin rash (among other AEs). Although some studies have been conducted using higher doses of pirfenidone, no well-controlled efficacy studies have been conducted with doses of pirfenidone higher than 2403 mg daily. Thus, although high doses of pirfenidone (up to 801 mg TID pirfenidone) are associated with improved efficacy in IPF (compared to doses below 2403 mg daily), no upper limit for improved clinical efficacy has been achieved to date, as doses higher than 801 mg TID have not been tested in well-controlled clinical efficacy studies due to poor tolerability. Thus, there is a clear need for novel therapies that improve the AE profile of pirfenidone while maintaining its anti-inflammatory and anti-fibrotic activity for the treatment of interstitial lung disease or other fibrosis-mediated lung diseases and disorders.

[0085] Pharmacology of LYT-100 As disclosed herein, LYT-100 retains the pharmacology of pirfenidone. In particular, LYT-100 has anti-inflammatory and anti-fibrotic properties consistent with pirfenidone. Preclinical data disclosed herein demonstrates the anti-fibrotic and anti-inflammatory activities of LYT-100 (see, e.g., Examples 6-11). For example, pretreatment with LYT-100 at oral doses of 100 and 300 mg / kg inhibited TNFα and IL-6 in a rat lipopolysaccharide (LPS) model of systemic inflammation (Example 6), and a dose of 60 mg / kg / day of LYT-100 significantly reduced sites of liver fibrosis in a streptozocin-induced nonalcoholic steatohepatitis (NASH) mouse model (Example 7).

[0086] LYT-100 also reduced proinflammatory cytokines and suppressed TGF-β and downstream signaling to inhibit fibrosis in primary mouse lung fibroblasts (Example 8). In particular, LYT-100 was found to (i) reduce TGF-β-induced cell proliferation, (ii) reduce both background and TGF-β-induced levels of insoluble (structural) collagen, (iii) reduce both background and TGF-β-induced levels of soluble collagen, and (iv) reduce both background and TGF-β-induced levels of soluble fibronectin in primary mouse lung fibroblasts (Example 8).

[0087] With reference to Example 9, LYT-100 (i) inhibits collagen synthesis in the absence or presence of TGF-β induction, (ii) suppresses total collagen levels in the absence or presence of TGF-β induction, (iii) suppresses soluble collagen levels in the absence or presence of TGF-β induction, and (iv) reduces soluble fibronectin levels in the absence or presence of TGF-β induction.

[0088] Additionally, LYT-100 and pirfenidone were evaluated using the DiscoverX BioMAP Fibrosis Panel, as described in Example 5. Similar results were observed with both compounds in the three systems, indicating that the anti-fibrotic profile of pirfenidone is retained in LYT-100.

[0089] LYT-100 demonstrated activity in a mouse model of lymphedema (Example 10) and a rat model of bleomycin-induced pulmonary fibrosis (Example 11).

[0090] LYT-100 maintains the pharmacological profile of pirfenidone and has a differentiated pharmacokinetic profile compared to pirfenidone due to deuterium kinetic isotope effects on enzyme kinetics. In addition, LYT-100 is unexpectedly well tolerated, including relatively high gastrointestinal tolerability. Deuteration of pirfenidone to create LYT-100 slows down its metabolism (Chen et al., Clinical Phar, in Drug Dev. 2021, 11(2), 220-234), and the metabolic changes may be associated with reduced adverse effects and improved tolerability observed with LYT-100, which allows for increased dosage and improved efficacy without the adverse effects seen for comparable doses of pirfenidone. This discovery also allows for administration to treat patients immediately, and potentially more effectively, without dose adjustments.

[0091] Thus, in one aspect, there is provided a method of treating interstitial lung disease or other fibrosis-mediated pulmonary disease or disorder, the method comprising administering to a subject in need thereof a compound having the structure: [ka] The present invention relates to a method for treating interstitial lung disease or other fibrosis-mediated lung disease or disorder in a subject, the method comprising administering deuterium-enriched pirfenidone having the formula:

[0092] To arrive at the methods (i.e., dose ranges) disclosed herein, multiple dose-ranging PK studies of LYT-100 were conducted (e.g., several dose-ranging MAD studies ranging from 1000 mg to 4000 mg total daily doses of LYT-100). To reduce the variability inherent in multiple studies with small sample sizes, the results of the various MAD PK studies were incorporated into the PK modeling data. The results of the pooled data from these various dose-ranging studies are shown in Table 18 below and indicate that 1) at a dose of 550 mg TID, the systemic exposure (AUC) was about 90-98% (mean about 95%) of the AUC achieved with pirfenidone (2403 mg dose, 801 mg TID) and the Cmax was about 73-80% (mean about 77%) of the Cmax achieved with pirfenidone (2403 mg dose, 801 mg TID), and 2) at a dose of 825 mg TID, the systemic exposure (AUC) was about 139-148% (mean about 143%) of the AUC achieved with pirfenidone (2403 mg dose, 801 mg TID) and the Cmax was about 109-121% (mean about 115%) of the Cmax achieved with pirfenidone (2403 mg dose, 801 mg TID). Notably, pirfenidone has not previously been tested for clinical efficacy at doses greater than 801 mg TID due to poor tolerability.

[0093] Pharmacokinetic results of the crossover study comparing doses of 550 mg TID LYT-100 and 801 mg TID pirfenidone are summarized in Table 1. Results are presented as mean (SD) and showed that at the 550 mg TID dose, the AUC of LYT-100 was similar to that of 801 mg TID pirfenidone, and the C max The AUC of LYT-100 is lower. 0-24 met the criteria for bioequivalence with pirfenidone 801 mg TID (geometric mean ratio = 0.875; 90% confidence interval = 0.842 to 0.910), C max5-Carboxypirfenidone, the major metabolite of both pirfenidone and LYT-100, showed a lower C after LYT-100 at 550 mg TID compared with pirfenidone at 801 mg TID. max and AUC 0-24 The C of parent and 5-carboxypirfenidone in the case of LYT-100 was max The reduction in C-terminal lysine may be responsible for the reduced gastric side effects of pirfenidone, while similar levels of total exposure (AUC) are expected to result in efficacy in interstitial lung disease and other fibrotic mediated lung diseases and disorders. Similar results were seen on days 4 or 14 after a single dose of 550 mg LYT-100 or 801 mg pirfenidone administered in the fasted state (Table 2). C-terminal lysine of the parent and 5-carboxy metabolites max was slightly increased after administration of LYT-100 compared with that after administration of pirfenidone.

[0094] [Table 1]

[0095] [Table 2]

[0096] Additionally, further PK studies were performed to determine the dosing frequency and dose associated with improved tolerability (compared to currently approved IPF treatments, e.g., pirfenidone 801 mg TID).The dose that minimized AEs and provided similar overall exposure levels (AUC) to pirfenidone 801 mg TID was LYT-100 550 mg TID.

[0097] As shown in Table 3, PK and AE data for LYT-100 550 mg TID and pirfenidone 801 mg TID were compared in fed and fasted states (LYT-100-2021-103 Part 2). At 550 mg TID (e.g., similar drug exposure levels to approved pirfenidone 801 TID), lower AEs were observed with LYT-100 compared to pirfenidone in both fed and fasted states. Specifically, at a daily dose of 1650 mg of LYT-100, 550 mg TID of LYT-100 was demonstrated to be associated with improved tolerability, such as a 50% reduction in gastrointestinal-related AEs and a 45% reduction in CNS-related AEs, compared to pirfenidone (see LYT-100-2021-103 Part 2 results shown in Example 1 and Table 3).

[0098] Although AEs observed with LYT-100 administered at 550 mg TID in the fasted state were higher than those seen in the fed state, AEs with LYT-100 administered at 550 mg TID in the fasted state are still much lower than those seen with pirfenidone administered at 801 mg TID in the fasted state. These results indicate that at the same / similar drug exposure levels of pirfenidone administered at 801 TID, LYT-100 administered at 550 TID is better tolerated (fewer AEs) and has the option to administer in the fasted state, e.g., with individualized changes in meal timing, if necessary. These data provide a rationale for the selection of LYT-100 at a dose of 550 mg TID in the treatment of interstitial lung disease and other fibrosis-mediated lung diseases and disorders. When the incidence of AEs was ranked from lowest to highest, the Cmax values ​​of the parent compound for each of these conditions were similarly ranked from lowest to highest, i.e., lowest AE incidence and Cmax to highest AE and Cmax, the order was LYT-100 550 mg (fed), LYT-100 550 mg (fasted), pirfenidone 801 mg (fed), pirfenidone 801 mg (fasted) (Table 3 (LYT-100-2021-103 Part 2)). The levels of the 5-carboxy metabolite were also ranked from lowest to highest in the above order (Table 3) (LYT-100-2021-103 Part 2).

[0099] [Table 3]

[0100] Table 4 summarizes the pharmacokinetic results and shows that at a dose of 550 mg TID, the PK parameters of LYT-100 and the metabolite 5-carboxypirfenidone were similar to those seen in part 2 of the study at a dose of 550 mg TID of LYT-100. At the higher dose of 824 mg TID, the AUC 0-24 and C maxwere higher than those seen with pirfenidone, while the corresponding parameters for the metabolite 5-carboxypirfenidone were similar / slightly lower. Adverse event data (Table 6) show that even at a dose of 824 mg TID, the frequency of the most common adverse events was very low. The low frequency of adverse events in conjunction with the higher exposure provides a rationale for the use of the 825 mg TID dose of LYT-100 in the treatment of interstitial lung disease and other fibrosis-mediated lung diseases and disorders.

[0101] [Table 4]

[0102] The LYT-100 dose was optimized to achieve a systemic exposure (AUC) similar to pirfenidone 801 mg TID. The LYT-100 dose was also optimized to achieve a Cmax similar to pirfenidone 801 mg TID while maximizing exposure (AUC). The Cmax and AUC values ​​obtained using the pooled PK data for LYT-100 compared to pirfenidone 801 mg TID were confirmed in subsequent individual studies of LYT-100 550 mg TID and LYT-100 824 mg TID, confirming confidence in the modeling data and the use of the LYT-100 doses of 550 mg TID and 825 mg TID.

[0103] The dose of LYT-100 was optimized to achieve a similar Cmax to 801 mg TID pirfenidone while maximizing drug exposure (AUC). Study LYT-100-2021-103 Part 3 was a randomized, double-blind, parallel-group, placebo-controlled study in healthy older adults to evaluate the safety and tolerability of a titrated high dose of LYT-100 compared to placebo under fed conditions. Based on the observation in Part 2 (550 TID LYT-100) of improved tolerability at lower TID doses of LYT-100 compared to pirfenidone (but with similar total exposure), it was decided to test the safety and tolerability of a higher TID dose of LYT-100 to achieve a higher overall predicted AUC or total exposure than the approved dose of pirfenidone (801 mg TID). Subjects aged 60-80 years were randomized to receive LYT-100 or placebo. Subjects were dosed with up to 550 mg of LYT-100 TID for 3 days (until steady state [days 1-3]) compared to placebo TID for 3 days until steady state. From days 4-6, subjects were dosed with 824 mg of LYT-100 TID for 3 days compared to placebo TID for 3 days until steady state. A summary of the dosing scheme is provided in the Examples section below (Example 2).

[0104] Table 5 summarizes the pharmacokinetic results and shows that at a dose of 550 mg TID, the PK parameters of LYT-100 and the metabolite 5-carboxypirfenidone were similar to those seen in part 2 of the study at a dose of 550 mg TID of LYT-100. At the higher dose of 824 mg TID, the AUC 0-24 and C maxwere higher than those seen with 801 mg TID pirfenidone, while the corresponding parameters for the metabolite 5-carboxypirfenidone were similar or slightly lower. Adverse event data (Table 6) show that even at a dose of 824 mg TID, the frequency of the most common adverse events was very low. The low frequency of adverse events combined with the higher exposure provides a rationale for the use of the 825 mg TID dose of LYT-100 in treating interstitial lung disease and other fibrosis-mediated lung diseases and disorders.

[0105] [Table 5]

[0106] LYT-100 824 mg TID achieved approximately 25% higher AUC and slightly higher Cmax compared to historical pirfenidone PK values. Surprisingly, this high dose of LYT-100 (825 mg TID) was well tolerated, as shown in Table 6. Prior to the completion of the tolerability study shown in Table 6, it was unclear that such a high dose (825 mg TID of LYT-100, corresponding to approximately 120-150% exposure of pirfenidone 801 TID) would be tolerated well enough to be included in a clinical efficacy study.

[0107] [Table 6]

[0108] Table 7 summarizes the pharmacokinetic results of the 550 mg TID dose and the 825 mg TID dose, along with observed adverse events and frequency, and further provides comparative data for pirfenidone in related studies.

[0109] [Table 7]

[0110] 550 mg TID and 825 mg TID doses of LYT-100 were optimized for key PK parameters and surprisingly demonstrated improved tolerability compared to pirfenidone at a 2304 mg daily dose (801 mg TID), even at higher systemic exposure to the drug. This improved tolerability of LYT-100 compared to pirfenidone was unexpected and may significantly improve compliance at sustained high effective doses (e.g., by reducing the frequency of dose reductions, treatment interruptions, and / or temporary or permanent discontinuation experienced with the use of pirfenidone).

[0111] Overall, as described in Examples 1 and 2 of the present disclosure, in parts 1 and 2 of the clinical trial, 850 mg BID LYT-100 had a similar AUC and slightly higher Cmax to pirfenidone 801 mg TID, and a 550 mg TID LYT-100 dose had a matched AUC (within BE) and lower Cmax compared to pirfenidone 801 mg TID. With continued reference to the Examples, on day 3 of the first study, LYT-100 550 mg TID administered in the fed state had a significantly higher Cmax compared to pirfenidone 801 mg TID administered in the fed state. max On day 4, both pirfenidone and 550 mg TID LYT-100 administered in the fasted state had higher drug exposure and C max On the third day, in the fed state, the increase in the metabolite C of LYT-100 was greater than that of pirfenidone. max The AE rate was 46% lower than that of pirfenidone. max (AE rates were GI 28.3%, 10.6%, 11.1%, and 6.5%; CNS 21.7%, 14.9%, 8.9%, and 8.7% for fasted pirfenidone, fed pirfenidone, fasted LYT-100, and fed LYT-100, respectively). Continuing with the Examples, on day 3 of the second study, LYT-100 at 824 mg TID resulted in significantly greater CNS AEs than LYT-100 at 550 mg. max was 57% higher, and AUC0-24 AEs were low and similar between LYT-100 824 mg TID and placebo (GI 0%, CNS 0%, infection (COVID-19) 16.7% in both groups).

[0112] With further reference to the Examples, the results of Part 3 of this study were unexpected in light of expectations based on Parts 1 and 2 of the study. Specifically, 1) LYT-100 550 mg TID had a significantly lower AUC but similar Cmax compared to part 2; 2) LYT-100 824 mg TID had a lower than predicted AUC and a 17% higher Cmax than pirfenidone; 3) relatively high variability in LYT-100 PK parameters was observed in part 3, but metabolite / parent ratios were consistently lower with LYT-100 compared to pirfenidone (i.e., lower 5-carboxy metabolite exposure when comparing the same doses of LYT-100 and pirfenidone); 4) GI AEs and nausea were significantly lower with LYT-100 (550 mg TID) compared to pirfenidone 801 mg TID; 5) dosing in the fed state reduced GI-related AEs, especially with pirfenidone, but had less impact on AEs with LYT-100; 6) GI AEs emerged earlier during treatment; and 7) 550 mg Improved tolerability of LYT-100 at TID doses may improve subject adherence to the full dose and, consequently, improve clinical outcomes in various interstitial lung diseases and other fibrosis-mediated pulmonary diseases and disorders.

[0113] In the disclosed methods, the dose and frequency of administration may vary based on the disease or disorder and its severity, as well as the desired pharmacokinetic parameters and tolerability profile. In particular, improved tolerability (e.g., reduced adverse side effects) of LYT-100 may allow for administration at therapeutic (effective) levels, including administration at currently approved therapeutic doses of pirfenidone, with reduced or no treatment interruptions, reduced or no treatment discontinuations, and reduced or no dose reductions in the treatment of interstitial lung disease and other fibrosis-mediated lung diseases or disorders. This increased tolerability of deuterium-enriched pirfenidone LYT-100 may allow for sustained or long-term treatment with therapeutic administration, thereby allowing for effective treatment of patients suffering from various interstitial lung diseases and other fibrosis-mediated lung diseases and disorders. Improved tolerability also provides the possibility of administration without dose adjustment or with a reduced dose adjustment period, to more quickly and effectively treat patients with various interstitial lung diseases and other fibrosis-mediated lung diseases and disorders. Improved tolerability also offers the potential for greater efficacy at higher dosages (systemic exposure) without the adverse effects seen with comparable doses (systemic exposure) of pirfenidone.

[0114] As described above, the method generally involves administering LYT-100 at a total daily dose of about 825 mg to about 2550 mg of LYT-100. In some embodiments, LYT-100 is administered at a daily dose that achieves the same or approximately the same systemic exposure as pirfenidone administered at a dose of 2403 mg / day. In some embodiments, the method involves administering a total daily dose of LYT-100 that achieves a systemic exposure that is greater than the systemic exposure of pirfenidone administered at a dose of 2403 mg per day (e.g., 801 mg TID).

[0115] In some embodiments, the total daily dose is about 825 to about 1650 mg, e.g., about 825, about 1100, about 1375, or about 1650 mg. In some embodiments, the total daily dose is 825 mg.

[0116] In some embodiments, the total daily dose is about 1650 to about 2550 mg of LYT-100, for example, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2475 mg, about 2500 mg, or about 2550 mg. In some embodiments, the total daily dose is about 1650 mg to about 2475 mg. In some embodiments, the total daily dose is 1650 mg. In some embodiments, the total daily dose is 2475 mg.

[0117] In some embodiments, the total daily dose is administered in three equal doses. In some embodiments, LYT-100 is administered in three equal doses of 550 mg each (550 mg TID). In some embodiments, LYT-100 is administered in three equal doses of 825 mg each (825 mg TID). In some embodiments, LYT-100 is administered in three equal doses of 275 mg each (275 mg TID).

[0118] In some embodiments, LYT-100 is administered without regard to food. In some embodiments, LYT-100 is administered without food. In some embodiments, LYT-100 is administered with food.

[0119] In some embodiments, LYT-100 is administered orally without food in three doses of 550 mg per day.In some embodiments, LYT-100 is administered orally with food in three doses of 550 mg per day.

[0120] In some embodiments, LYT-100 is administered orally without food in three doses of 825 mg per day.In some embodiments, LYT-100 is administered orally with food in three doses of 825 mg per day.

[0121] In some embodiments, LYT-100 is administered orally without food in three doses of 275 mg per day.In some embodiments, LYT-100 is administered orally with food in three doses of 275 mg per day.

[0122] In some embodiments, LYT-100 is administered without dose escalation. In some embodiments, LYT-100 is administered in three equal doses of 550 mg each, without dose escalation. In some embodiments, LYT-100 is administered in three equal doses of 825 mg each, without dose escalation.

[0123] In some embodiments, LYT-100 is administered in an escalating dose. In some embodiments, LYT-100 is administered at a dose of 825 mg TID after three doses of 550 mg per day for three days. With reference to the crossover study described in Example 2, early data on the occurrence of adverse events in healthy elderly subjects receiving a dose of 550 mg TID (1650 mg / day) followed by a dose of 824 TID (2472 mg / day) show that with this titration scheme, adverse events (particularly gastrointestinal (GI) and nervous system disorders) are not increased, but may be reduced or even eliminated.

[0124] In some embodiments, administering comprises titrating from an initial total daily dose below the total daily dose to a total daily dose, where titrating comprises administering LYT-100 at three doses per day of 550 mg each for an initial period, followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, titrating comprises administering LYT-100 at three doses per day of 275 mg each for an initial period, followed by LYT-100 at three doses per day of 550 mg each for a period, optionally followed by LYT-100 at three doses per day of 825 mg each for a period. In some embodiments, the initial period is 3-14 days. In some embodiments, the initial period is 3-7 days.

[0125] In comparison, as reported in the regulatory review leading to the approval of Esbriet (pirfenidone), ascending daily doses of pirfenidone (801 mg / day, 1602 mg / day, 2403 mg / day, 3204 mg / day, and 4005 mg / day, administered in three equal doses) were tested in a cohort of healthy elderly subjects (PIPF-005). The number of reported AEs (headache, dyspepsia, nausea, back pain) increased as the total daily dose increased. At higher doses, C max Higher values ​​were associated with increased odds of experiencing gastrointestinal (GI) AEs, which is consistent with previous studies of pirfenidone. As reported in study PIPF-005, at a dose of 801 mg three times daily (2403 mg / day), C max was 11.85 μg / mL, which is the C reported for 550 mg TID and 824 mg TID in Example 2. max It will be halfway between the values.

[0126] In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of time and at a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period of time and at a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of time and at a second total daily dose of 1650 mg for a second period of time and at a total maintenance dose of 2475 mg thereafter. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of time of about 7 days and at a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period of about 7 days and at a second total daily maintenance dose of 2475 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of about 7 days, at a second total daily dose of 1650 mg for a second period of about 7 days, and at a total maintenance dose of 2475 mg thereafter. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 825 mg for a first period of about 14 days and at a second total daily maintenance dose of 1650 mg. In some embodiments, the method comprises administering LYT-100 at a first total daily dose of 1650 mg for a first period of about 14 days and at a second total daily maintenance dose of 2475 mg. In some embodiments, the method includes administering LYT-100 at a first total daily dose of 825 mg for a first period of about 14 days, at a second total daily dose of 1650 mg for a second period of about 14 days, and at a total maintenance dose of 2475 mg thereafter. In some embodiments, the method includes administering LYT-100 at a first total daily dose of 825 mg for a first period of 7-14 days, and at a second total daily maintenance dose of 1650 mg. In some embodiments, the method includes administering LYT-100 at a first total daily dose of 1650 mg for a first period of 7-14 days, and at a second total daily maintenance dose of 2475 mg.In some embodiments, the methods include administering LYT-100 at a first total daily dose of 825 mg for a first period of 7 to 14 days, at a second total daily dose of 1650 mg for a second period of 7 to 14 days, and at a total maintenance dose of 2475 mg thereafter.

[0127] In some embodiments, the method comprises administering LYT-100 at three doses per day of 275 mg each for a first period of time and three doses per day of 550 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 at three doses per day of 550 mg each for a first period of time and three doses per day of 825 mg each for a second maintenance dose. In some embodiments, the method comprises administering LYT-100 at three doses per day of 275 mg each for a first period of time and three doses per day of 550 mg each for a second period of time and three doses per day of 825 mg each for a maintenance dose thereafter. In some embodiments, the method comprises administering LYT-100 at three doses per day of 275 mg each for a first period of time and three doses per day of 550 mg each for a second maintenance dose. In some embodiments, the method includes administering LYT-100 at three doses per day of 550 mg each for a first period of about 7 days, and at three doses per day of 825 mg each for a second maintenance dose. In some embodiments, the method includes administering LYT-100 at three doses per day of 275 mg each for a first period of about 7 days, at three doses per day of 550 mg each for a second period of about 7 days, and at three doses per day of 825 mg each for a second maintenance dose thereafter. In some embodiments, the method includes administering LYT-100 at three doses per day of 275 mg each for a first period of about 14 days, and at three doses per day of 550 mg each for a second maintenance dose. In some embodiments, the method includes administering LYT-100 at three doses per day of 550 mg each for a first period of about 14 days, and at three doses per day of 825 mg each for a second maintenance dose. In some embodiments, the method includes administering LYT-100 in three doses of 275 mg per day for a first period of about 14 days, three doses of 550 mg per day for a second period of about 14 days, and three doses of 825 mg per day thereafter as maintenance doses. In some embodiments, the method includes administering LYT-100 in three doses of 275 mg per day for a first period of 7-14 days, and three doses of 550 mg per day as a second maintenance dose.In some embodiments, the methods include administering LYT-100 three times a day at 550 mg doses for a first period of 7-14 days, and three times a day at 825 mg doses as a second maintenance dose. In some embodiments, the methods include administering LYT-100 three times a day at 275 mg doses for a first period of 7-14 days, three times a day at 550 mg doses for a second period of 7-14 days, and three times a day at 825 mg doses as a maintenance dose thereafter.

[0128] In any of the above embodiments, LYT-100 is administered orally without food. In any of the above embodiments, LYT-100 is administered orally with food. In any of the above embodiments, LYT-100 is administered orally without food. In any of the above embodiments, the total daily dose, e.g., 825 mg, 1650 mg, or 2475 mg, may be adjusted to a lower daily dose, e.g., as described elsewhere herein.

[0129] In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in improved tolerability compared to pirfenidone administered at 801 mg TID. In some embodiments, the improved tolerability is due to a reduction in one or more adverse events or side effects. In some embodiments, the one or more adverse events are neurological side effects. In some embodiments, the one or more adverse events are gastrointestinal events. In some embodiments, LYT-100 is administered in three doses per day of 550 mg each.

[0130] In some embodiments, LYT-100 administered at a total daily dose of 1650-2475 mg three times daily results in a lower steady-state C compared to pirfenidone administered at 801 mg TID. max In some embodiments, LYT-100 is administered in three doses of 550 mg per day.

[0131] In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in a steady state exposure (AUC) of LYT-100 that is the same or nearly the same as the steady state exposure (AUC) of pirfenidone achieved when pirfenidone is administered at 801 mg TID. In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in a steady state exposure (AUC) of LYT-100 that is bioequivalent to the steady state exposure (AUC) of pirfenidone when pirfenidone is administered at 801 mg TID. In some embodiments, LYT-100 is administered at three doses per day of 550 mg each.

[0132] In some embodiments, administration of LYT-100 at a total daily dose of 1650-2475 in three doses per day provides a steady state exposure of LYT-100 that is the same or approximately the same as the steady state exposure (AUC) achieved with pirfenidone when pirfenidone is administered at 801 mg TID, and provides a steady state C of 1650-2475 that is approximately the same as the steady state exposure (AUC) achieved with pirfenidone when pirfenidone is administered at 801 mg TID. max A lower steady-state Cmax of LYT-100 is achieved. In some embodiments, the steady-state exposure of LYT-100 is about 90% of the AUC of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg and the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID). In some embodiments, the lower steady-state Cmax of LYT-100 is achieved when pirfenidone is administered at a total daily dose of 2403 mg and the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID). max is the C of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg and when the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID). maxThe efficacy of LYT-100 is approximately 75-80% of that of pirfenidone administered at 801 mg TID. In some embodiments, at this dosage, LYT-100 is more or better tolerated with a reduction in one or more adverse events or side effects compared to pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses of 550 mg per day.

[0133] In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in the same or nearly the same steady state exposure (AUC) as pirfenidone administered at 801 mg TID, and improved or improved tolerability as compared to pirfenidone administered at 801 mg TID. In some embodiments, the improved or improved tolerability is due to a reduction in one or more adverse events or side effects. In some embodiments, LYT-100 is administered in three doses per day of 550 mg each.

[0134] In some embodiments, LYT-100 is administered in three doses per day at a total daily dose of 1650-2475 mg, resulting in higher steady-state exposure (AUC) compared to pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses per day at 825 mg each.

[0135] In some embodiments, LYT-100 is administered in three doses per day at a total daily dose of 1650-2475 mg, resulting in the same or nearly the same steady state Cmax as pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses per day at 825 mg each.

[0136] In some embodiments, LYT-100 is administered in three doses per day at a total daily dose of 1650-2475, resulting in a higher steady state exposure (AUC) compared to pirfenidone administered at 801 mg TID, and the same or nearly the same steady state Cmax compared to pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses per day of 825 mg each.

[0137] In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in a higher steady-state exposure (AUC) compared to pirfenidone administered at 801 mg TID, and is similarly or similarly tolerable (e.g., no significant difference in incidence of adverse events) compared to pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered at a total daily dose of 1650-2475 in three doses per day, resulting in a higher steady-state exposure (AUC) compared to pirfenidone administered at 801 mg TID, and is more tolerable or improved with reduced one or more adverse events or side effects. In some embodiments, LYT-100 is administered at three doses per day of 825 mg each.

[0138] In some embodiments, LYT-100 is administered in three doses per day at a total daily dose of 1650-2475 mg, resulting in the same or approximately the same steady-state Cmax as pirfenidone administered at 801 mg TID, and is similarly or approximately the same tolerable (e.g., no significant difference in incidence of adverse events) as pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses per day at a total daily dose of 1650-2475 mg, resulting in the same or approximately the same steady-state Cmax as pirfenidone administered at 801 mg TID, and is similarly or approximately the same tolerable due to a reduction in one or more adverse events or side effects. In some embodiments, LYT-100 is administered in three doses per day at 825 mg each.

[0139] In some embodiments, LYT-100 is administered at a dose that achieves in the subject about 85-125% of the systemic exposure of pirfenidone that would be achieved if pirfenidone was administered at a total daily dose of 2403 mg and the total daily dose of pirfenidone was administered in three doses of 801 mg each (801 mg TID).

[0140] In some embodiments, the dose of LYT-100 that achieves a systemic exposure of LYT-100 in a subject that is about 85-125% of the systemic exposure of pirfenidone is 825 mg TID.

[0141] In some embodiments, a dose of LYT-100 that achieves a systemic exposure of LYT-100 in a subject that is about 85-125% of the systemic exposure of pirfenidone also achieves a C of pirfenidone that is about 85-125% of the C of pirfenidone achieved when pirfenidone is administered at a total daily dose of 2403 mg and the total daily dose of pirfenidone is administered in three doses of 801 mg each (801 mg TID). max The C of LYT-100 is about 115-125% of max In some embodiments, at this dosage, LYT-100 is as well tolerated or similarly tolerated (e.g., no significant difference in incidence of adverse events) as pirfenidone administered at 801 mg TID. In some embodiments, at this dosage, LYT-100 is more or less tolerated or improved by reducing one or more adverse events or side effects as pirfenidone administered at 801 mg TID. In some embodiments, LYT-100 is administered in three doses of 825 mg per day.

[0142] As noted above, in some embodiments, administration of LYT-100 in accordance with the disclosed methods results in increased or improved tolerability due to a reduction in one or more adverse events or side effects in a subject compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same systemic exposure.

[0143] In any of these embodiments in which one or more side effects are reduced, the incidence, severity, or both may be reduced.In some embodiments, the incidence of side effects (i.e., the frequency with which side effects occur) in an individual patient or patient population is reduced by at least 30% compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same total body exposure.For example, in some embodiments, the incidence of side effects is reduced by at least 35%, at least 40%, or at least 50% compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same total body exposure.In some embodiments, the incidence of side effects is reduced by at least 30% compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same total body exposure.

[0144] In some embodiments, the incidence of side effects is reduced when administered in a fed state, compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same total body exposure in a fed state.In some embodiments, the incidence of side effects is reduced when administered in a fasted state, compared to pirfenidone administered at a dose or dosage that achieves the same or approximately the same total body exposure in a fasted state.

[0145] In some embodiments, the one or more side effects are gastrointestinal side effect(s). In some embodiments, the one or more side effects are nervous system side effect(s). In some embodiments, the one or more side effects are a combination of gastrointestinal side effect(s) and nervous system side effect(s). Examples of gastrointestinal side effects include nausea, vomiting, and abdominal pain or bloating.

[0146] In some embodiments, neurological and / or gastrointestinal side effects in a subject are reduced by administration of a total daily dose of 1650 mg of LYT-100, optionally administered TID. In some embodiments, neurological and / or gastrointestinal side effects in a subject are reduced by administration of a total daily dose of 2475 mg of LYT-100, optionally administered TID.

[0147] Interstitial Lung Disease and Other Fibrosis-Mediated Lung Diseases and Disorders The disclosed method generally treats interstitial lung disease and other fibrosis-mediated lung diseases and disorders. Thus, the method may treat various diseases and disorders of fibrotic and / or inflammatory nature. In some embodiments, interstitial lung disease or other fibrosis-mediated lung disease or disorder or its symptoms are alleviated. In some embodiments, the onset of interstitial lung disease or other fibrosis-mediated lung disease or disorder is delayed, slowed, or prevented. In some embodiments, the progression of interstitial lung disease or other fibrosis-mediated lung disease or disorder is delayed, slowed, or prevented.

[0148] Interstitial Lung Disease and Other Fibrosis-Mediated Lung Disorders In some embodiments, the method treats interstitial lung disease (ILD). ILD encompasses a large, heterogeneous group of lung disorders with overlapping clinical symptoms and patterns of lung damage. ILD is commonly characterized by destruction of the distal lung parenchyma, which leads to changes in the interstitial space, leading to clinical symptoms such as dyspnea and cough, and resulting in restrictive ventilation and defective gas exchange on pulmonary function tests. ILD includes several diseases of unknown cause, as well as ILDs known to be associated with other diseases or environmental exposures. Although the cause of many ILDs is unknown, the disease typically involves some form of damage to alveolar epithelial cells that initiate an inflammatory response in conjunction with repair mechanisms. The damage repair process is reflected pathologically as inflammation, fibrosis, or a combination of both. A common feature of ILD is lung scarring (pulmonary fibrosis) and / or inflammation. The interstitium is a fine, interconnected network of tissue that extends through each lung and supports the alveoli (air sacs) of the lungs. Under normal conditions, the interstitium is so thin that it does not show up on x-rays or CT scans. All forms of ILD result in interstitial thickening, for example, through inflammation, scarring, or fluid accumulation. There is no single, universally accepted classification of ILD. They can generally be classified based on etiology (idiopathic or ILD with known association or cause), clinical course (acute (transient), subacute, or chronic (long-term) ILD), and primary pathological features (inflammatory or fibrotic ILD). A wide variety of substances and conditions can lead to ILD. Yet, in some cases, the cause is never known. Such disorders with unknown causes are lumped together under the name idiopathic interstitial pneumonias, the most common and fatal of which is idiopathic pulmonary fibrosis (IPF).

[0149] During the progression of ILDs such as IPF, accumulation of extracellular matrix components such as collagen and an increase in fibroblast population are observed. Sustained proliferation of fibroblasts is thought to be an important contributor to lung structure in IPF, including the reduction of alveolar interstitial space. Thus, reducing TGF-β-induced proliferation of fibroblasts and structural collagens by LYT-100 has the potential to prolong lung function in IPF. In addition to suppressing TGF-β-induced insoluble collagen levels, LYT-100 also inhibits TGF-β-induced secreted collagen and fibronectin β. Secreted collagen and fibronectin not only increase the rate of formation of fibrotic lesions in the lung, but these proteins can also act as ligands for integrin receptors. When integrin receptors are activated, they not only induce proliferation of lung epithelial cells and fibroblasts, but also induce epithelial-mesenchymal transition (EMT) of lung epithelial cells together with TGF-β. EMT allows these cells to migrate to different regions of the lung. This translocation is thought to be a critical contributor to the generation of new fibrotic lesions in the lung and the progression of IPF.LYT-100 has the potential to inhibit the profibrotic process induced by TGF-β and reduce underlying factors that may exacerbate ongoing fibrosis.

[0150] Progressive fibrosing ILDs can be divided into three groups based on disease behavior, including those that are essentially non-progressive, e.g., drug-induced lung disease after removal of the drug or some cases of hypersensitivity pneumonitis (HP) after removal of the trigger, those that are progressive but stabilized by immune modulation, e.g., some cases of connective tissue disease (CTD)-ILD, and those that are progressive despite treatment deemed appropriate for the individual ILD, e.g., idiopathic pulmonary fibrosis (IPF).

[0151] Although IPF is the best-known and most representative form of progressive fibrosing ILD (PF-ILD), there exists a group of patients with distinct clinical ILD diagnoses other than IPF who express a progressive fibrotic phenotype during the course of their disease. These patients show many similarities to IPF patients, whose disease is defined by increasing degrees of pulmonary fibrosis on imaging, declining lung function, worsening respiratory symptoms and quality of life regardless of treatment of the individual ILD, and ultimately premature death. Similar to IPF, declining FVC predicts mortality in patients with these other fibrosing ILDs.

[0152] Non-limiting examples of ILD include non-idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia (iNSIP), autoimmune or connective tissue disease (CTD)-ILD, unclassifiable ILD (uILD), chronic hypersensitivity pneumonitis (HP), interstitial pneumonia with an autoimmune component (IPAF), hereditary and / or familial idiopathic pulmonary fibrosis (g / f IPF), chronic sarcoidosis, exposure-related ILD, and drug-induced ILD.

[0153] In some embodiments, the ILD is iNSIP, or interstitial pneumonia with an autoimmune component (IPAF). In some embodiments, the ILD is chronic HP. Chronic HP is a complex syndrome caused by sensitization to inhaled antigens, resulting in an abnormal immune response in the small airways and lung parenchyma. Susceptibility is thought to be influenced by genetics, antigen concentration and frequency of exposure, and immune tolerance.

[0154] In some embodiments, the ILD is an autoimmune or CTD-ILD. Autoimmune diseases are frequently associated with pulmonary complications, including ILD. Patients with a wide range of CTDs are at risk for developing ILD. In some embodiments, the autoimmune or CTD-ILD is systemic sclerosis ILD (SSc-ILD). In some embodiments, the ILD is rheumatoid arthritis ILD (RA-ILD). In some embodiments, the ILD is lupus-induced pulmonary fibrosis. In some embodiments, the ILD is scleroderma interstitial lung disease. In some embodiments, the ILD is mixed CTD-associated ILD.

[0155] In some embodiments, the ILD is pediatric interstitial lung disease (chILD), which is a broad term for a group of rare lung diseases that can affect infants, children, and teenagers. These diseases have some similar symptoms, such as chronic coughing, rapid breathing, and shortness of breath. These diseases also harm the lungs in a similar way. For example, they can damage the tissue surrounding the alveoli and bronchi of the lungs, and can also directly damage the air sacs and airways. Various types of chILD can reduce lung function, reduce blood oxygen levels, and disrupt the breathing process. In some embodiments, the chILD is a surfactant dysfunction mutation, a childhood lung development disorder such as alveolar capillary dysplasia, a lung growth abnormality, neuroendocrine hyperplasia of infancy (NEHI), pulmonary interstitial glycogen storage disease (PIG), idiopathic interstitial pneumonia (e.g., nonspecific interstitial pneumonia, idiopathic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia), alveolar hemorrhage syndrome, aspiration syndrome, hypersensitivity pneumonitis, infectious or post-infectious diseases (e.g., bronchiolitis obliterans), ), eosinophilic pneumonia, pulmonary alveolar proteinosis, pulmonary infiltrates with eosinophilia, pulmonary lymphatic disorders (lymphangiomatosis, lymphangiectasia), pulmonary vascular disorders (hemangiomatosis), interstitial lung diseases associated with a systemic disease process (e.g., connective tissue diseases, histiocytosis, malignancy-associated lung disease, sarcoidosis, storage diseases), or disorders of the immune deficiency system (e.g., opportunistic infections, disorders associated with therapeutic interventions, lung and bone marrow transplant-associated lung disease, diffuse alveolar damage of unknown etiology).

[0156] In some embodiments, the ILD is chronic sarcoidosis or sarcoidosis-associated pulmonary fibrosis. Sarcoidosis is an inflammatory disease characterized by the formation of granulomas in one or more organs of the body. If left untreated, this chronic inflammation can lead to fibrosis. Sarcoidosis can affect almost any organ in the body, although approximately 90% of cases affect the lungs.

[0157] In some embodiments, the method treats an ILD that is an exposure-related ILD or a drug-induced ILD. In some embodiments, the exposure-related ILD is pneumoconiosis. Pneumoconiosis is a group of ILDs caused by inhaling certain types of dust particles, such as asbestos, coal, or silica. In some embodiments, the exposure-related ILD is asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, coal-induced pulmonary fibrosis, or other environmentally induced pulmonary fibrosis.

[0158] In some embodiments, the ILD is acute interstitial pneumonia (AIP, also known as Hamman-Rich syndrome). AIP is an acute, rapidly progressive, idiopathic lung disease that often leads to fulminant respiratory failure and acute respiratory distress syndrome (ARDS). In some embodiments, the ILD is alveolitis, including chronic fibrosing alveolitis and fibrosing alveolitis.

[0159] In some embodiments, the ILD is unclassifiable ILD (uILD). The term "unclassifiable interstitial lung disease" was introduced in 2002 in the American Thoracic Society / European Respiratory Society consensus classification of idiopathic interstitial pneumonias (IIPs) to encompass a subset of ILDs that cannot be classified within the current diagnostic framework. The paradoxical classification of "unclassifiable" arises from the impossibility of a specific ILD diagnosis due to 1) insufficient or 2) discordant clinical, radiological, and pathological data.

[0160] Many ILDs are characterized by inflammation and chronic fibrosis. Patients with certain types of chronic fibrotic ILDs are at risk of developing progressive phenotypes. These include, but are not limited to, iNSIP, uILD, autoimmune ILD, chronic sarcoidosis, HP, g / f IPF, and exposure-related diseases such as asbestosis and silicosis.

[0161] Because these various pathologies share similarities regarding pathogenesis and clinical behavior, they are increasingly described under the collective term “progressive fibrosing ILD” (PF-ILD) or “fibrosing ILD with a progressive phenotype.” The progressive phenotype is histologically characterized by autonomous fibrosis, a process common to the various pathologies, leading to poor quality of life, decreased lung function, and ultimately premature death. The term “progressive phenotype” means that disease progression has occurred despite state-of-the-art management, including, for example, the use of corticosteroids and / or immunosuppressive therapy. One of the most common types of progressive fibrosing ILD is idiopathic pulmonary fibrosis (IPF). IPF is, by definition, a progressive fibrosing ILD of unknown etiology, characterized by decreased lung function and premature death. The prognosis of IPF is poor, with a median survival time after diagnosis generally estimated at 2–5 years.

[0162] In addition to IPF, PF-ILD also includes non-IPF ILD. Estimates based on surveys and insurance claims in the United States indicate that 18-32% of patients diagnosed with non-IPF ILD will develop progressive fibrosis (Wijsenbeek et al. “Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management” Curr Med Res Opin 2019:1-10). In the same study, the time from symptom onset to death was estimated to be 61-80 months, with poor survival rates but better than those of IPF. The incidence and prevalence of PF-ILD are not well defined, in part due to the heterogeneous nature of this group. It is estimated that there are approximately 140,000-250,000 patients in the United States with PF-ILD, including IPF. Currently, there are no drugs approved for the treatment of progressive fibrosing ILD, other than nintedanib and pirfenidone for the treatment of IPF. Thus, LYT-100 may be particularly advantageous in the treatment of PF-ILD, as improved tolerability allows for higher dosages than pirfenidone.

[0163] In some embodiments, the ILD is PF-ILD. In some embodiments, the PF-ILD is iNSIP, CTD-ILD, uILD, chronic fibrotic HP, g / f IPF, sarcoidosis, exposure-related ILD, or drug-induced ILD.

[0164] In some embodiments, the fibrosis-mediated pulmonary disease or disorder is not idiopathic pulmonary fibrosis (IPF).

[0165] In treating any of the interstitial lung diseases and other fibrosis-mediated lung diseases or disorders disclosed herein, LYT-100 is administered as disclosed herein above. In some embodiments, LYT-100 is administered at a total daily dose of about 825 to about 2475 mg, e.g., 825 mg, 1650 mg, or 2475 mg. In some embodiments, administration is in three equal doses. In some embodiments, LYT-100 is administered at three equal doses of 550 mg each. In some embodiments, LYT-100 is administered at three equal doses of 825 mg each.

[0166] Clinical Endpoints and Biomarkers In some embodiments, therapeutic efficacy may be assessed by reference to various clinical endpoints or biomarkers indicative of fibrotic and inflammatory processes, many of which are described above with respect to particular diseases or disorders.

[0167] Suitable types of biomarkers include, but are not limited to, markers of alveolar epithelial cell injury and epithelial cell dysfunction, markers of alveolar macrophage activation, markers of TGF-β activation, markers of fibroblast proliferation and extracellular matrix production or turnover, markers of immune dysregulation, markers of ECM production and turnover. In some embodiments, the biomarker is Krebs von den Lungen-6 antigen (KL-6), surfactant proteins (e.g., SP-A or SP-D), matrix metalloproteases (e.g., MMP-1, MMP-7, MMP-8), PP1, YKL-40, IGFBP-1, TNFRSA1F, ICAM-1, IL-6, IL-8, CC chemokine ligands (e.g., CCL 16 and CCL 18), insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), vascular endothelial growth factors (VEGFs), periostin, or combinations thereof.

[0168] In any of the methods described herein, the treatment method prevents, delays, or slows the progression of respiratory dysfunction in a subject. In some embodiments, the progression of ILD is delayed, slowed, or stopped.

[0169] Respiratory function, for example, respiratory dysfunction, can be measured using various methods.In some embodiments, respiratory function is determined by measuring the forced vital capacity (FVC) of the subject.In some embodiments, the progression of respiratory dysfunction in the subject is determined by measuring the change in FVC over the course of treatment.

[0170] In some embodiments, the change in FVC is measured as a percentage decline in FVC (mL). In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 825 mg in three equal doses of 275 mg each, wherein the percentage decline in FVC (mL) is less than a subject naive to LYT-100. In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 1650 mg in three equal doses of 550 mg each, wherein the percentage decline in FVC (mL) is less than a subject naive to LYT-100. In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 2475 mg in three equal doses of 825 mg each, wherein the percentage decline in FVC (mL) is less than a subject naive to LYT-100. In some embodiments, the treatment period for measuring the rate of decline in FVC (mL) is at least 26 weeks. In some embodiments, the treatment period for measuring the rate of decline in FVC (mL) is at least 52 weeks. In some embodiments, the rate of decline in FVC (mL) over a treatment period of at least 26 weeks is less than the rate of decline exhibited by a subject naive to LYT-100. In some embodiments, the rate of decline in FVC (mL) over a treatment period of at least 52 weeks is less than the rate of decline exhibited by a subject naive to LYT-100.

[0171] In some embodiments, the change in FVC is measured as a change in FVC% predicted (FVCpp). In some embodiments, the change in FVC is measured as a decline in FVC% predicted (FVCpp). In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 825 mg in three equal doses of 275 mg each, wherein the rate of decline in FVCpp is less than in a LYT-100-naive subject. In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 1650 mg in three equal doses of 550 mg each, wherein the rate of decline in FVCpp is less than in a LYT-100-naive subject. In one aspect, a method of treating ILD is provided, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 2475 mg administered in three equal doses of 825 mg each, wherein the rate of decline in FVCpp is less than in a subject who has not received LYT-100.

[0172] In some embodiments, the treatment of ILD is demonstrated or indicated by a delay in the time to progression of ILD in a subject. In some embodiments, the treatment of ILD is demonstrated or indicated by a slowing in the rate of progression of ILD in a subject. In any of the methods disclosed herein, the time to progression of ILD is prolonged (prolonged, exceeded) in subjects treated with LYT-100 compared to subjects who have never received LYT-100. ILD progression can be determined using various methods, for example, by measuring the change in FVC, for example, a decline in FVC (mL) or FVCpp. In some embodiments, IPF progression is determined by a decline of 5% or more in FVCpp. In some embodiments, IPF progression is determined by a decline of 10% or more in FVCpp. In any of the methods disclosed herein, the time to progression of ILD, as determined by a decline of 5% or more in FVCpp, is prolonged (prolonged, exceeded) in subjects treated with LYT-100 compared to subjects who have never received LYT-100. In any of the methods disclosed herein, the time to progression of ILD as determined by a 10% or greater decline in FVCpp is prolonged (extended, greater) in subjects treated with LYT-100 compared to subjects who have not received LYT-100.

[0173] In any of the methods disclosed herein, the subject exhibits a prolonged time to hospitalization due to respiratory dysfunction compared to a subject who has not received LYT-100. In some cases, the prolonged time to hospitalization is a prolonged time to first hospitalization due to respiratory dysfunction. In some cases, the prolonged time to hospitalization is not a first hospitalization, but is, for example, a prolonged time to re-hospitalization(s) due to respiratory dysfunction.

[0174] In any of the methods disclosed herein, the subject is hospitalized less frequently for respiratory dysfunction compared to a subject who has never been administered LYT-100. Thus, in some embodiments, the subject is hospitalized less frequently for respiratory dysfunction compared to a subject who has never been administered LYT-100. In any of the methods disclosed herein, the subject has a shorter length of hospitalization for respiratory dysfunction(s) compared to a subject who has never been administered LYT-100.

[0175] In any of the methods disclosed herein, the subject exhibits a prolonged time to death from respiratory dysfunction compared to a subject who has not been administered LYT-100.In any of the methods disclosed herein, the subject exhibits a prolonged time to death from IPF compared to a subject who has not been administered LYT-100.

[0176] In any of the methods disclosed herein, the subject has an alteration in one or more serum biomarker(s) associated with respiratory dysfunction compared to a subject who has not received LYT-100. In some embodiments, the serum biomarker is type 4 collagen.

[0177] In any of the methods disclosed herein, a subject is treated as determined by one or more of the King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score, the St. George's Respiratory Questionnaire (SGRQ-I) domain score, the EuroQol 5 Item (EQ5D) questionnaire score, and the cough visual analog scale (VAS) compared to subjects who have not received LYT-100.

[0178] In any of the methods disclosed herein, the subject is treated throughout the treatment period without dose reduction of the daily dose administered.In any of the methods disclosed herein, the subject is treated throughout the treatment period without interruption or temporary cessation of treatment.In any of the methods disclosed herein, the subject is treated throughout the treatment period without stopping treatment.

[0179] In one embodiment, a method is provided for reducing the number of one or more adverse event(s) (AEs) in the treatment of ILD, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 825 mg in three equal doses of 275 mg each. In one embodiment, a method is provided for reducing the number of one or more adverse event(s) (AEs) in the treatment of ILD, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 1650 mg in three equal doses of 550 mg each. In one embodiment, a method is provided for reducing the number of one or more adverse event(s) (AEs) in the treatment of ILD, comprising administering to a subject in need thereof LYT-100 at a total daily dose of 2475 mg in three equal doses of 825 mg each.

[0180] In any of the above methods, the one or more adverse event(s) is a gastrointestinal-related adverse event selected from nausea, vomiting, abdominal pain or bloating, dyspepsia, diarrhea, decreased appetite, and constipation. In any of the above methods, the one or more adverse event(s) is a nervous system-related adverse event selected from headache, dizziness, and somnolence. In any of the above methods, the one or more adverse event(s) is selected from fatigue, drug intolerance, and photosensitivity. In any of the above methods, the one or more adverse event(s) is selected from elevated AST, ALT, GGT, and hepatotoxicity.

[0181] Pharmaceutical Compositions In another aspect, a pharmaceutical composition is provided for administration in the methods described herein. The pharmaceutical composition comprises an active compound, e.g., LYT-100, and one or more pharma- ceutically acceptable excipients or carriers. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0182] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0183] Embodiments of the present disclosure can be further defined by reference to the following non-limiting examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the disclosure. EXAMPLES

[0184] Examples 1 and 2 describe a crossover study comparing the safety, tolerability, and pharmacokinetics of deupirfenidone (LYT-100) and pirfenidone. Example 3 describes a study exploring the tolerability of deuterated pirfenidone LYT-100 in patients with COVID-19 respiratory disease. Example 4 describes the CYP isoenzyme profile of pirfenidone and LYT-100. Example 5 describes a BioMAP Fibrosis panel screening study of LYT-100 and pirfenidone on a range of fibrosis biomarkers. Example 6 describes a rat lipopolysaccharide (LPS) model of systemic inflammation. Example 7 describes a streptozocin-induced nonalcoholic steatohepatitis (NASH) mouse model. Example 8 describes a study of LYT-100 inhibition of fibrosis in primary mouse lung fibroblasts. Example 9 describes the study of collagen synthesis inhibition by LYT-100. Example 10 describes a mouse model of lymphedema. Example 11 describes a rat bleomycin-induced pulmonary fibrosis model.

[0185] Example 1: Crossover administration study This was a double-blind, randomized, two-period crossover study in healthy elderly subjects to compare the safety, tolerability, and pharmacokinetics of dupirfenidone (LYT-100) and pirfenidone. The crossover study was conducted in the United States at one study site per part.

[0186] Exam details The study was conducted in two parts: Part 1 and Part 2.

[0187] Part 1 was a randomized, double-blind, two-period crossover study in healthy older adults comparing the safety, tolerability, and pharmacokinetics of dupirfenidone (LYT-100) administered twice daily (BID) with pirfenidone.

[0188] Part 2 was a randomized, double-blind, two-period crossover study in healthy older adults to compare the safety, tolerability, and pharmacokinetics of dupirfenidone (LYT-100) administered three times daily (TID) with pirfenidone. Study endpoints ·Safety: - Treatment-emergent adverse events (TEAEs) (including severity and relationship to study drug) -Physical examination -Vital signs -Electrocardiogram (ECG) - Clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis) -Newly started concomitant medications Pharmacokinetics: - The main PK parameters (C max,ss , C min,ss , and AUC 0-24,ss ) comparison. Other PK parameters were derived and compared. - Comparison of urinary major PK parameters (Ae t1-t2 , C.L. R , Fe t1-t2 ) for comparison. Other urinary PK parameters were derived and compared. -Evaluation of the effect of food on LYT-100 and pirfenidone (C max,ss and AUC 0-6,ss ) (fed and fasted).

[0189] Study design Part 1: Part 1 was a double-blind, randomized, two-period crossover study in elderly healthy subjects to determine the safety, tolerability, and PK of LYT-100 administered twice daily (BID) for 3 days (until steady state [days 1-3 and 11-13]) compared with pirfenidone administered three times daily (TID) for 3 days (until steady state) under fed conditions. To determine the effect of food on steady-state PK parameters, the final single dose of study medication (LYT100 or pirfenidone) was administered on the morning of day 4 (day 4 / 14) of each treatment period after an overnight fast of at least 8 hours.

[0190] An encapsulation method was used to match the TID administration of pirfenidone and the number of LYT-100 capsules administered for each dose. Thus, during LYT-100 treatment, the midday dose was placebo. Pirfenidone was administered at the current marketed dose of 801 mg TID (2403 mg daily dose).

[0191] Approximately 40 elderly healthy female and male adult subjects (1:1 target ratio) were randomized into one of two cohorts: Cohort 1 or Cohort 2 (N=20 subjects per cohort; minimum 8 per gender per cohort). Subjects in each cohort were randomized to the following treatment sequences: Sequence A: pirfenidone to LYT-100; Sequence B: LYT-100 to pirfenidone. Dosing is outlined in Table 8. A schematic of the study design for Part 1 is shown in Figure 1.

[0192] [Table 8]

[0193] The initial dose of LYT-100 in this crossover study comparing LYT-100 head-to-head against pirfenidone in healthy adults was 850 mg BID LYT-100 (1700 mg daily dose) versus 801 mg TID pirfenidone (2403 mg daily dose). 850 mg BID LYT-100 (1700 mg daily dose) was selected based on PK results from a previous study. PK modeling work using data from a multiple-dose titration study of LYT-100 and pirfenidone and a single-dose crossover study showed that a dose of LYT-100 of approximately 800-850 mg BID (1600-1700 mg daily dose) would result in a similar systemic exposure to the marketed dose of pirfenidone (2403 mg daily dose). Based on these data, a randomized, blinded crossover study was conducted in older healthy adults (N=37) comparing LYT-100 850 mg BID for 3 days (fed) with pirfenidone 801 mg TID for 3 days (fed). The study was blinded with placebo for the midday dose of LYT-100 to match the TID pirfenidone dose. A single morning fasting dose was administered on day 4 for both drugs. A 6-day washout period was allowed between drug crossovers. The 850 mg BID dose was selected to match the exposure of pirfenidone based on the results of a previous PK crossover study, which showed that a daily dose of LYT-100 850 mg BID was approximately 102% of the steady-state systemic exposure of pirfenidone administered 801 mg TID daily.

[0194] Part 2: Part 2 was a double-blind, randomized, two-period crossover study in elderly healthy subjects to determine the safety, tolerability, and PK of LYT-100 administered three times daily (TID) for 3 days (until steady state [days 1-3 and 11-13]) compared with pirfenidone administered TID for 3 days (until steady state) under fed conditions. The final single dose of study drug (LYT-100 or pirfenidone) was administered on the morning of day 4 (day 4 / 14) of each treatment period after at least an 8-hour overnight fast to determine the effect of food on steady-state PK parameters. Encapsulation methods were used to maintain the blindness of the study. Screening was performed up to 28 days prior to administration of the first dose of LYT-100 / pirfenidone. Only subjects who met all applicable inclusion criteria and none of the applicable exclusion criteria were randomized. Approximately 50 elderly healthy female and male adult subjects (1:1 ratio) were randomized into one of two cohorts: Cohort 1 or Cohort 2 (N=approximately 25 subjects per cohort). Subjects in each cohort were randomized to the following treatment sequence: Sequence A: Pirfenidone to LYT-100 Sequence B: LYT-100 to Pirfenidone

[0195] A schematic of the Part 2 study design is shown in Figure 2. Dosing is outlined in Table 9. [Table 9] ^Pirfenidone: AM dose: 3 x 267 mg, midday dose: 3 x 267 mg, PM dose: 3 x 267 mg. Each AM, midday, and PM dose will be encapsulated to maintain the blinding of the study. Placebo capsules will be administered as needed to match the number of LYT-100 capsules to maintain blinding. Each cohort will start at the same time or with a slight time stagger.

[0196] The LYT-100 doses for this crossover study comparing LYT-100 head-to-head against pirfenidone in healthy adults were 550 mg TID LYT-100 (1650 mg daily dose) versus 801 mg TID pirfenidone (2403 mg daily dose). LYT-100 550 mg TID (1650 mg daily dose) was selected based on PK results from previous studies and PK results obtained in part 1 of this study. PK modeling work using data from a multiple-dose titration study of LYT-100 and pirfenidone, a single-dose crossover study, and part 1 of this study demonstrated that a dose of 550 mg TID LYT-100 (1650 mg daily dose) results in similar systemic exposure to the marketed dose of pirfenidone (2403 mg daily dose). In particular, it was predicted that a dose of 550 TID LYT-100 (total daily dose of 1650 mg) would achieve a steady-state systemic exposure that was approximately 99% of the steady-state systemic exposure observed with pirfenidone administered at 801 mg TID.

[0197] Based on these data, a randomized, blinded crossover study was conducted in healthy older adults (N=49) comparing LYT-100 550 mg TID for 3 days (fed) with pirfenidone 801 mg TID for 3 days (fed). A single morning fasting dose was administered on day 4 for both drugs. There was a 6-day washout period between drug crossovers. The 550 mg TID dose was selected to match the exposure of pirfenidone based on the results of a previous PK crossover study.

[0198] 3 and 4, the predicted steady-state systemic exposure (AUC24ss) of LYT-100 administered at 550 mg TID is shown to be 98.5% of the steady-state systemic exposure (AUC24ss) of pirfenidone administered at 801 mg TID. However, surprisingly, the C of LYT-100 administered at 550 mg TID was 98.5% of the steady-state systemic exposure (AUC24ss) of pirfenidone administered at 801 mg TID. max is the C of pirfenidone obtained from pirfenidone administered at 801 mg TID. maxFigure 4 shows the predicted steady-state C max However, the steady-state C max Without wishing to be bound by any particular theory, the C of LYT-100 is 67.4%. max It is possible that the lower creatinine concentration may contribute to the improved tolerability of LYT-100 compared with pirfenidone.

[0199] Treatment Period 1 (Day -1 to Day 4) Part 1 and Part 2 Subjects were admitted to the Clinical Research Unit (CRU) on day -1 of Treatment Period 1 and received their assigned study medication (pirfenidone or LYT-100 with or without matching placebo) under fed conditions every 6 hours for 3 days (days 1-3) until steady state was achieved. Subjects then received a single dose of their randomized treatment (pirfenidone or LYT-100 with or without matching placebo) on the morning of day 4 after an overnight fast of at least 8 hours. Subjects were discharged on day 4 after all evaluations had been successfully completed, at the discretion of the investigator.

[0200] Treatment Period 2 (Days 11-14) Part 1 and Part 2 After a minimum washout period of at least 7 days, subjects were admitted back to the CRU on the evening of day 10 and crossed over to receive the alternative study medication (pirfenidone or LYT-100 with or without a matching placebo) every 6 hours for 3 days (days 11-13) under fed conditions. Subjects then received a single dose of their randomized treatment on the morning of day 14 after an overnight fast of at least 8 hours. Subjects were discharged on day 14 after all evaluations had been successfully completed, at the discretion of the investigator.

[0201] On days 1-3 (treatment period 1) and days 11-13 (treatment period 2), subjects received their assigned study medication TID every 6 hours ± 0.25 hours (with approximately 240 mL of noncarbonated water), 30 minutes after the start of their respective standardized breakfast, lunch, or dinner meals (6-hour intervals). An evening snack was served at least 3 hours after the evening study medication administration. On days 4 (treatment period 1) and 14 (treatment period 2), subjects received their assigned study medication once in the morning (with approximately 240 mL of noncarbonated water), after an overnight fast of at least 8 hours. No additional fluid intake was permitted for 1 hour before or after dosing.

[0202] On feeding days, meals were provided as follows: Breakfast: A meal was served 30 minutes before the morning dose. Breakfast was completed within 30 minutes of the start time. Lunch: A meal was served at least 4 hours after the morning study drug administration and 30 minutes before the midday dose in Part 5 (restricted). -Dinner: A meal was served at least 11.5 hours after the morning dose and 30 minutes before the afternoon study drug dose. Evening snack: A snack was served at least 15 hours after the morning dose (at least 3 hours after the afternoon dose).

[0203] On fasting days, meals were provided as follows: On Day 4 (Period 1) and Day 14 (Period 2), breakfast was served at least 4 hours after study drug administration.

[0204] Number of subjects: Part 1 The aim was to recruit approximately 40 healthy elderly female and male adult subjects (target ratio male:female = 1:1, minimum 8 per sex per cohort), unless additional subjects were required to support statistical analyses. Part 1 was conducted with 37 subjects who completed the study.

[0205] Part 2 The aim was to recruit approximately 50 healthy elderly female and male adult subjects (target ratio male:female = 1:1, minimum 15 per sex per cohort), unless additional subjects were required to support statistical analyses. Part 1 was conducted with 49 subjects who completed the study. Main inclusion and exclusion criteria Selection criteria: 1. Male or female aged ≥60 years and ≤80 years at screening. 2. Subjects must have a body mass index (BMI) of 18.0 kg / m2 or greater and 35.0 kg / m2 or greater at screening. 2 The following is the result. 3. Willingness and ability to refrain from total body direct sunlight exposure from 2 days prior to dosing until the final study procedure was performed. Subjects were instructed to avoid or minimize exposure to sunlight (including sunlamps), use a sunscreen with SPF 50 or higher, wear clothing that protects against sun exposure, and avoid concomitant medications known to cause photosensitivity (including, but not limited to, tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine, and thioridazine). Exclusion criteria: 1. Pregnant or lactating at screening or baseline, or planning pregnancy (self or partner) at any time during the study period, including the specified follow-up period. 2. History or presence of malignancy at screening or baseline, except adequately treated localized skin cancer (basal cell carcinoma or squamous cell carcinoma) or cervical intraepithelial neoplasia. 3. Clinically significant infection within 28 days of initiating treatment or infection requiring parenteral antibiotics within 3 months prior to screening. Confirmed exposure to another COVID-19 patient within the past 14 days or a positive COVID test within 5 days prior to treatment are also exclusion criteria. 4.Has undergone major surgery (e.g., requiring general anesthesia) within 3 months prior to screening or is scheduled for surgery during the period in which the participant is expected to participate in the study, as determined by the study investigator. 5. Has clinically significant systemic allergic disease at screening or baseline, or has a history of significant drug allergy, including anaphylactic reactions (especially reactions to general anesthetics); allergic reactions to any drug that have resulted in significant pathology; or a history of a past allergic reaction to pirfenidone. 6. Chronic use (defined as >14 consecutive days) of immunosuppressants or other immune-modulating drugs within 3 months prior to study drug administration. Corticosteroids are permitted at the investigator's discretion. 7. History or presence of conditions associated with significant immunosuppression at screening or baseline. 8. Test positive for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at screening. 9. Dysphagia symptoms or known difficulty swallowing capsules at screening or baseline. 10. Any condition at screening or baseline that would interfere with drug absorption (e.g., chronic diarrhea, inflammatory bowel disease, or previous gastrointestinal surgery) or any disease or condition that, in the judgment of the investigator, would affect drug metabolism or excretion. 11. History or presence of cardiac arrhythmias or congenital long QT syndrome at screening or baseline. 12. QT interval corrected using the Fridericia formula (QTcF) >450 msec. An ECG may be repeated with an interval of 30-60 minutes from the first one collected at screening. If the repeat ECG is ≤450 msec, the second ECG may be used to determine patient eligibility. However, if the repeat ECG confirms that the QTcF remains >450 msec, the subject will be ineligible. 13. Use of tobacco or nicotine-containing products in the past 3 months prior to dosing or a positive urine cotinine test at screening or baseline. 14. Unwilling to abstain from consumption of tobacco or nicotine-containing products throughout the entire study period and until completion of the final follow-up visit. 15. Regular alcohol consumption defined as more than 21 alcohol units per week (1 unit = 284 mL of beer, 25 mL of 40% distilled spirits, or a 125 mL glass of wine) or the participant is unwilling to abstain from alcohol for 48 hours prior to admission and 48 hours prior to the study visit. 16. Use of any of the following medications within 30 days or within 5 half-lives of the medication (whichever is longer) prior to study drug administration: Fluvoxamine, enoxacin, ciprofloxacin; b. Other CYP1A2 inhibitors (including but not limited to methoxsalen or mexiletine); c. Contraceptives containing estradiol, ethinylestradiol or gestodene; d. Inducers of CYP1A2 (such as phenytoin), CYP2C9 or 2C19 (including but not limited to carbamazepine or rifampicin); e. Any drug associated with prolongation of the QTc interval, including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol. 17. Received any live vaccine within 4 weeks prior to screening or scheduled within 4 weeks of administration, and any non-live vaccine within 2 weeks prior to screening or scheduled within 2 weeks of administration (including against COVID). 18. Use of any investigational drug or device within 30 days or 5 half-lives prior to screening, whichever is longer. 19. Consumption of grapefruit, grapefruit juice, bitter orange, bitter orange juice, or any food containing these ingredients within 7 days prior to dosing, or unwillingness to abstain from these throughout the study period.

[0206] Dosage and Method of Administration: This was a crossover study in which subjects received both the test treatment (LYT-100) and the reference (pirfenidone). All subjects received LYT-100 (BID or TID) or pirfenidone (TID) for 3 days during each treatment period, with placebo encapsulation to maintain blinding. Part 1 subjects received LYT-100 850 mg BID. Part 2 subjects received LYT-100 550 mg TID. In parts 1 and 2, all subjects also received a single dose of either LYT-100 or pirfenidone on the morning of day 4 during each treatment period, with placebo encapsulation to maintain blinding. LYT-100 (dupirfenidone) was provided as a hard gelatin capsule. LYT-100 was stored at controlled room temperature between 15°C and 25°C. Pirfenidone (Esbriet) comes as a white to off-white, hard gelatin capsule containing 267 mg of pirfenidone. Both LYT-100 and pirfenidone were encapsulated to maintain the blinded nature of the study.

[0207] Treatment duration: Part 1 and Part 2 The study included a 28-day screening period, two treatment periods (each 4 days in duration) with a 7-day washout period between treatment periods, and a safety follow-up visit 3 days (± 1 day) after the last dose. Thus, the total duration of participation in the study for each subject was approximately 50 days. Treatment with the double-blind study drug was for 4 days in each of the two treatment periods, for a total of 8 days.

[0208] Evaluation criteria Safety: Safety and tolerability were assessed by monitoring for AEs, physical examination, vital signs, 12-lead electrocardiogram, clinical laboratory values ​​(hematology panel, multiphasic chemistry panel, and urinalysis), and evaluation of concomitant treatments / medications.

[0209] Pharmacokinetics: Part 1 and Part 2 To support exploratory PK analyses, blood samples for CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotype determination were obtained from subjects pre-treatment, i.e., on day -1 or day 1 of treatment period 1. Subjects were asked to provide consent for genotyping.

[0210] Blood samples for PK were collected at specific times during both periods in Cohort 1 and Cohort 2 as follows: Days 1 and 11: 0 (before morning dose) Days 2 and 12: No blood sampling Days 3 and 13: 0 (before the morning dose), and 1, 2, 3, 4, 6 (before the midday dose), 7, 8, 9, 10, 12 (before the evening dose), 13, 14, 15, 16, and 17 hours after the morning dose. Days 4 and 14: 0 (before the morning dose) and 1, 2, 3, 4, 6 (after the dose),

[0211] Plasma PK parameters at steady state dosing (Days 1-3 and Days 11-13) include, but are not limited to, the following: AUC 0-tau,ss (Area under the time-concentration curve from time zero to tau at steady state) AUC 0-24,ss (Area under the time-concentration curve from time zero to 24 hours at steady state) λz (terminal elimination rate constant / terminal rate constant) t1 / 2 (elimination half-life) C max,ss (Maximum concentration during dosing interval) T max (Time to maximum concentration, reported relative to the start of the dosing interval in which the maximum concentration occurred) C min,ss (Minimum concentration during dosing interval) C av,ss (average concentration during dosing interval) C max,ss -C min,ss / C av,ss (Degree of fluctuation) C max,ss -C min,ss / C min,ss (swing) PTF% (Peak-Trough Variation)

[0212] Plasma PK parameters from food effect analysis (Day 4 and Day 14) included, but were not limited to, the following: AUC 0-tau,ss (Area under the time-concentration curve from time zero to tau at steady state) AUC 0-6,ss (Area under the time-concentration curve from time 0 to 6 hours at steady state) AUC 0-∞ (area under the time-concentration curve from time zero to infinity) + AUC 0-∞ / D %AUC ext (Percentage of total AUC, area under the time-concentration curve extrapolated from time t to infinity) λz (terminal elimination rate constant / terminal rate constant) ·CL / F (apparent total clearance) Vz / F (apparent volume of distribution) T max (Time to maximum concentration) t lag (Ragtime)

[0213] Part 1 only Urine samples for PK were collected at specific intervals during both treatment periods in Cohort 1 and Cohort 2 as follows: Days 1 and 11: Pre-dose (subjects were instructed to empty their bladders approximately 30 minutes prior to dosing) Days 2 and 12: No urine collection Days 3 and 13: Pre-dose (subjects were instructed to empty their bladders approximately 30 minutes prior to dosing), 0-4 hours, 4-8 hours, 8-12 hours, 12-16 hours, and 16-24 hours after the morning dose. Days 4 and 14: 0 to 3 hours and 3 to 6 hours after the morning dose

[0214] Urine samples for urinary excretion analysis were collected, separated and analyzed at specific time intervals. The total volume of urine collected at each interval (t1-t2) was noted. Urinary PK parameters included, but were not limited to: Ae t1 / 2 (urinary excretion over time) ·CLR (renal clearance) The proportion of total body clearance (CL / F) represented by renal clearance (CLR / [CL / F]) Fet1-t2 (proportion of the administered dose excreted in urine during the dosing interval) The study endpoints were defined as follows: ·Safety - AEs (type, severity, and relationship to study drug) -Physical examination -Vital signs -Electrocardiogram (ECG) - Clinical test items (hematology, serum chemistry, coagulation, and urinalysis) -Newly started concomitant medications Pharmacokinetics: - The main plasma PK parameters (C max,ss , C min,ss , and AUC 0-24,ss ) compared. Other plasma PK parameters will also be derived and compared. - Comparison of urinary major PK parameters (Ae t1-t2 , C.L. R , Fe t1-t2 ) for comparison. Other urinary PK parameters may be derived and compared. -Evaluation of the food effect of LYT-100 and pirfenidone in a fed vs fasted state (C max,ss , and AUC 0-6,ss ).

[0215] result Part 1 It was confirmed that 1000 mg BID of LYT-100 provides LYT-100 exposure (AUC) that exceeds the exposure of pirfenidone obtained from the approved dose of pirfenidone (801 mg TID). Furthermore, based on the dosing schedule, doses of LYT-100 ranging from 800 to 850 mg BID provided exposure (AUC) values ​​and maximum concentration (C) values ​​equivalent to those of pirfenidone administered at 801 mg TID (2403 mg daily). max ) values ​​could be obtained with LYT-100.

[0216] Part 1 of the study was conducted in healthy elderly subjects, an age group associated with IPF. Overall, the Part 1 head-to-head crossover study was designed, at least in part, to evaluate the impact on tolerability of reduced exposure to the major metabolite. To this end, 37 subjects were randomized in a blinded crossover study to receive 850 mg BID LYT-100 or 801 mg TID pirfenidone, administered fed for 3 days and fasted on the morning of the fourth day. Referring to Figure 5A, the C of the parent drug for 850 mg BID LYT-100 was 0.01 mg TID. max The steady-state AUC and AUC were very similar to those of the parent drug for pirfenidone at 801 mg TID. Specifically, the steady-state AUC for administration of 850 mg BID was 102% of the AUC for pirfenidone administered at 801 mg TID, and the steady-state C max is the steady-state C of pirfenidone administered at 801 mg TID. max C max Fasting increased C max Exposure to the major metabolite (5-carboxypirfenidone) was reduced with LYT-100 at 850 mg BID compared with pirfenidone at 801 mg TID.

[0217] Adverse events occurring in each treatment group are shown in Figure 5B, indicating that there were no serious adverse events in either group, and similar types of AEs were observed across both groups, with no clinically meaningful differences in the overall incidence of AEs between LYT-100 and pirfenidone.

[0218] Referring to Figure 5B, adverse events in both groups were primarily gastrointestinal and neurological, with neurological AEs including headache and dizziness. As mentioned above, fasting was associated with a decreased risk of C max It was hypothesized that cefotaxime would increase the incidence of GI AEs and increase the overall incidence of GI AEs. Consistent with this hypothesis, there was an increase in nausea in both groups when administered after fasting, and the timing and duration of AEs were significantly greater than those of cefotaxime. max As shown in Figure 5B (also see Figure 5A), the results of this study indicate that reducing exposure to the major metabolite did not improve tolerability.

[0219] Part 2 Part 2 was a double-blind, randomized, two-period crossover study in elderly healthy subjects to determine the safety, tolerability, and PK of 550 mg LYT-100 administered three times daily (TID) for 3 days (until steady state [days 1-3 and 11-13]) compared with pirfenidone administered at 801 mg TID for 3 days (until steady state) under fed conditions. To determine the effect of food on steady-state PK parameters, the final single dose of study medication (LYT-100 or pirfenidone) was administered on the morning of day 4 (day 4 / day 14) of each treatment period after an overnight fast of at least 8 hours.

[0220] Overall, 49 subjects were enrolled and included in the safety population (24 subjects in Sequence A and 25 subjects in Sequence B). Five subjects (10.2%) did not complete the study. Two subjects in Cohort 2 discontinued due to TEAEs (one subject in Sequence A (LYT-100) and one subject in Sequence B (pirfenidone)). Two subjects in Cohort 2 discontinued due to investigator decision (one subject in Sequence A (LYT-100) and one subject in Sequence B (pirfenidone)). One subject in Cohort 1 randomized to Sequence A withdrew consent while taking LYT-100.

[0221] The mean age for the entire population was 67.7 years; mean ages were similar in cohort 1 and cohort 2 (68.5 and 66.9 years, respectively). The majority of subjects were female (53.1%; 52.2% in cohort 1 and 53.8% in cohort 2), primarily white (81.6%), and had a mean BMI of 27.9 kg / m 2 The overall mean number of days of LYT-100 administration was 4.0 days (4.0 days in cohort 1 and 3.9 days in cohort 2). The mean number of days of pirfenidone administration was 3.9 days (4.0 days in cohort 1 and 3.9 days in cohort 2).

[0222] Preliminary PK analyses were performed to assess comparability of exposure to the parent (pirfenidone or deupirfenidone) and metabolite (5-carboxypirfenidone, regardless of treatment) following LYT-100 administration to pirfenidone administration. Summary statistics for key PK parameters by analyte, fed state, and treatment are shown in Table 10. Overall, exposure (AUC 0-24 and C max ) was slightly lower after administration of LYT-100 compared with pirfenidone, and C max The time to C was slightly longer (median 3 hours for LYT-100 vs. 2 hours for pirfenidone). max The concentrations of the main metabolites were substantially lower after administration of LYT-100, as expected.

[0223] [Table 10] Summary statistics are T max are expressed as geometric mean (CV%) or median (min-max) of Note: Only subjects with sufficient concentration data for all time periods / analytes were included.

[0224] The results of the bioequivalence evaluation when treatment was administered in the fed state (Day 3 or Day 13) are shown in Table 11. Despite a slightly lower exposure observed following administration of LYT-100 in the fed state, the 550 mg TID dose of LYT-100 showed AUC 0-24 The bioequivalence criteria based on the above were met.

[0225] [Table 11] Note: Only subjects with sufficient data for all time periods / analytes concentrations were included. Bioequivalence assessment was performed using the method of Chow et al. as implemented in the BE package in R.

[0226] Further simulations were performed using the crossover data described above. The simulations showed that the AUC 0-24 After dose normalization, the predicted AUC after administration of a hypothetical dose of 550 mg TID was 0-24 Then, the obtained AUC 0-24 , and the AUC observed after administration of 801 mg TID pirfenidone. 0-24The individual ratios of LYT-100 to pirfenidone were calculated by comparing the ratios. These ratios were then evaluated using the same process described in Chow (Design and Analysis of Bioavailability and Bioequivalence Studies; Chapman & Hall / CRC Biostatistics Series, Chapman; Hall / CRC 2008) and CDER (Guidance for Industry Statistical Approaches to Establishing Bioequivalence Center for Drug Evaluation and Research [CDER], FDA, 2001). The results of the simulation are shown in Table 12. Based on these evaluations, the LYT-100 dosage regimen of 550 mg TID is predicted to provide parent drug exposure comparable to pirfenidone administered at 801 mg TID.

[0227] [Table 12]

[0228] Summary of adverse events Overall, 28 subjects (57.1%) experienced at least one TEAE, 14 (30.4%) on LYT-100 versus 23 (48.9%) on pirfenidone. The most common TEAEs (overall >5%) were nausea, headache, dizziness, vomiting, and somnolence. A summary of these TEAEs (overall and by study drug) is provided in Table 13.

[0229] [Table 13]

[0230] Overall TEAEs during LYT-100 were mild in 10 subjects (21.7%; 19 events) and moderate in 4 subjects (8.7%; 10 events). Overall TEAEs during pirfenidone were mild in 17 subjects (36.2%; 42 events) and moderate in 6 subjects (12.8%; 8 events). Overall, TEAEs leading to study discontinuation were reported in 2 subjects (4.1%) in cohort 2, 1 during LYT-100 (nausea) and 1 during pirfenidone (headache and dizziness). No deaths or serious AEs were reported.

[0231] In this elderly group (mean age 68 years), across the two treatment groups (550 mg TID LYT-100 vs. 801 mg TID pirfenidone, fed and fasted), there was a significant reduction in the incidence of TEAEs (nausea and dizziness) in the LYT-100 treatment group compared to the pirfenidone group. Overall, among subjects experiencing at least one TEAE, the incidence was substantially lower in the LYT-100 group than in the pirfenidone group. Specifically, there was a 38% reduction in the overall incidence of TEAEs in the comparison of LYT-100 to pirfenidone (30.4% vs. 48.9%, respectively).

[0232] Figure 6 is a graphical representation of the reduction in gastrointestinal and nervous system symptoms in this patient population with LYT-100 at 550 mg TID compared to pirfenidone at 801 mg TID. Referring to Figure 6, 50 percent fewer subjects experienced gastrointestinal-related AEs with LYT-100 compared to pirfenidone (17.4% vs. 34.0%, respectively), including 50% less nausea (15.2% vs. 29.8%). Fewer subjects experienced nervous system AEs with LYT-100 compared to pirfenidone (17.4% vs. 31.9%), especially less dizziness (2.2% vs. 14.9% with LYT-100 vs. pirfenidone). These study results indicate that substantially fewer subjects taking LYT-100 experienced AEs compared to pirfenidone, and approximately 50% fewer subjects experienced gastrointestinal-related AEs with LYT-100 compared to pirfenidone. There was no difference in the incidence of study discontinuation between treatment arms. The results suggest that 550 mg TID of LYT-100 may be better tolerated than 801 mg TID of pirfenidone in this subject population.

[0233] Regarding TEAE incidence comparing fed and fasted conditions, there were 8 (17.4%) LYT-100-treated subjects who experienced at least one TEAE under fed conditions and 8 (17.8%) subjects under fasted conditions. Ten (21.3%) pirfenidone-treated subjects experienced at least one TEAE under fed conditions and 17 (37.0%) subjects under fasted conditions. A summary of the most common TEAEs (≥10%) under fed and fasted conditions for each study drug is provided in Table 14.

[0234] [Table 14]

[0235] In this study, fed conditions reduced the incidence of TEAEs in both treatment groups. Furthermore, LYT-100 was better tolerated than pirfenidone in both fed and fasted conditions within these two dose groups. This improved tolerability of LYT-100 also appears to be amplified in the fasted state. Without wishing to be bound by any particular theory, it is possible that the higher incidence of TEAEs experienced by fasted subjects in both treatment groups may be due to more rapid and extensive absorption of the parent molecule (pirfenidone or deupirfenidone) during fasting than when taken with food, resulting in a higher peak plasma concentration (C max Fasting days were associated with higher C max The observation that the incidence of TEAEs was substantially higher in both treatment groups than on fed days suggested a high C-value for tolerability. max Furthermore, the fasting-induced C max It is noteworthy that elevated C-reactive protein levels were associated with a higher incidence of TEAEs during the study. Overall, the Part 2 head-to-head crossover study demonstrated that the efficacy and safety of C-reactive protein levels was, at least in part, due to the parental C-reactive protein levels. max As described herein thus far, the results of this study were designed to assess the impact of the reduction in C of the parent drug on tolerability. max This indicates that reduction improves tolerability.

[0236] Example 2: LYT-100 Crossover Study - 550mg TID and 824mg TID This was a double-blind, randomized, two-period crossover study in healthy elderly subjects to compare the safety, tolerability, and pharmacokinetics of dupirfenidone (LYT-100) and pirfenidone. The crossover study was conducted in the United States at one study site per part.

[0237] Exam details This was a randomized, double-blind, parallel-group, placebo-controlled study in healthy older adults to evaluate the safety and tolerability of a dose of LYT-100 compared to placebo that provided an exposure of LYT-100 that was approximately 150% of the exposure of pirfenidone when administered at 801 mg TID and not to exceed 850 mg TID LYT-100. Study endpoints ·Safety: - Treatment-emergent adverse events (TEAEs) (including severity and relationship to study drug) -Physical examination -Vital signs -Electrocardiogram (ECG) - Clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis) -Newly started concomitant medications Pharmacokinetics: - The main PK parameters (C max,ss , C min,ss , and AUC 0-24,ss ) compared. Other PK parameters will also be derived and compared. - Urinary primary PK parameters (Ae t1-t2 , C.L. R , Fe t1-t2 ) for comparison. Other urinary PK parameters may be derived and compared. -Evaluation of the effect of food on LYT-100 and pirfenidone (C max,ss and AUC 0-6,ss ) (fed and fasted).

[0238] Study design This was a randomized, double-blind, parallel-group, placebo-controlled study in healthy older adults to evaluate the safety and tolerability of a titrated high-dose LYT-100 compared to placebo under fed conditions. Thirty healthy older adults, 60-80 years of age, were randomized to receive LYT-100 or placebo. Subjects received 550 mg LYT-100 three times a day (TID) for 3 days (until steady state [days 1-3]) compared with 550 mg placebo TID for 3 days until steady state. On days 4-6, subjects received 824 mg LYT-100 TID for 3 days until steady state compared with 824 mg placebo TID for 3 days. Informed consent was obtained prior to initiating the study. Screening was performed up to 28 days prior to administration of the first dose of LYT-100 / placebo. Only subjects who met all applicable inclusion criteria and none of the applicable exclusion criteria were randomized. The dosing schedule is outlined in Table 15.

[0239] [Table 15]

[0240] Number of subjects: Thirty healthy elderly female and male adult subjects (target male:female ratio 1:1, minimum 10 per gender per cohort) Main inclusion and exclusion criteria Selection criteria: 1. Male or female aged ≥60 years and ≤80 years at screening. 2. Subjects must have a body mass index (BMI) of 18.0 kg / m2 or greater and 35.0 kg / m2 or greater at screening. 2 The following is the result. 3. Willing and able to refrain from total body direct sunlight exposure from 2 days prior to dosing until the final study procedure is performed. Subjects should be instructed to avoid or minimize exposure to sunlight (including sunlamps), use a sunscreen with SPF 50 or higher, wear clothing that protects against sun exposure, and avoid concomitant medications known to cause photosensitivity (including, but not limited to, tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine, and thioridazine). Exclusion criteria: 1. Pregnant or lactating at screening or baseline, or planning pregnancy (self or partner) at any time during the study period, including the specified follow-up period. 2. History or presence of malignancy at screening or baseline, except adequately treated localized skin cancer (basal cell carcinoma or squamous cell carcinoma) or cervical intraepithelial neoplasia. 3. Clinically significant infection within 28 days of initiating treatment or infection requiring parenteral antibiotics within 3 months prior to screening. Confirmed exposure to another COVID-19 patient within the past 14 days or a positive COVID test within 5 days prior to treatment are also exclusion criteria. 4.Has undergone major surgery (e.g., requiring general anesthesia) within 3 months prior to screening or is scheduled for surgery during the period in which the participant is expected to participate in the study, as determined by the study investigator. 5. Currently have any clinically significant systemic allergic disease at screening or baseline, or have a history of significant drug allergy, including anaphylactic reactions (especially reactions to general anesthetics); allergic reactions to any drug that have resulted in significant morbidity; or a history of a past allergic reaction to pirfenidone. 6. Chronic use (defined as >14 consecutive days) of immunosuppressants or other immune-modulating drugs within 3 months prior to study drug administration. Corticosteroids are permitted at the investigator's discretion. 7. History or presence of conditions associated with significant immunosuppression at screening or baseline. 8. Test positive for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), or human immunodeficiency virus (HIV) antibody at screening. 9. Dysphagia symptoms or known difficulty swallowing capsules at screening or baseline. 10. Any condition at screening or baseline that would interfere with drug absorption (e.g., chronic diarrhea, inflammatory bowel disease, or previous gastrointestinal surgery) or any disease or condition that, in the judgment of the investigator, would affect drug metabolism or excretion. 11. History or presence of cardiac arrhythmias or congenital long QT syndrome at screening or baseline. 12. QT interval corrected using the Fridericia formula (QTcF) >450 msec. An ECG may be repeated with an interval of 30-60 minutes from the first one collected at screening. If the repeat ECG is ≤450 msec, the second ECG may be used to determine patient eligibility. However, if the repeat ECG confirms that the QTcF remains >450 msec, the subject will be ineligible. 13. Use of tobacco or nicotine-containing products in the past 3 months prior to dosing or a positive urine cotinine test at screening or baseline. 14. Unwilling to abstain from consumption of tobacco or nicotine-containing products throughout the entire study period and until completion of the final follow-up visit. 15. Regular alcohol consumption defined as more than 21 alcohol units per week (1 unit = 284 mL of beer, 25 mL of 40% distilled spirits, or a 125 mL glass of wine) or the participant is unwilling to abstain from alcohol for 48 hours prior to admission and 48 hours prior to the study visit. 16. Use of any of the following medications within 30 days or within 5 half-lives of the medication (whichever is longer) prior to study drug administration: Fluvoxamine, enoxacin, ciprofloxacin; b. Other CYP1A2 inhibitors (including but not limited to methoxsalen or mexiletine); c. Contraceptives containing estradiol, ethinylestradiol or gestodene; d. Inducers of CYP1A2 (such as phenytoin), CYP2C9 or 2C19 (including but not limited to carbamazepine or rifampicin); e. Any drug associated with prolongation of the QTc interval, including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol. 17. Received any live vaccine within 4 weeks prior to screening or scheduled within 4 weeks of administration, and any non-live vaccine within 2 weeks prior to screening or scheduled within 2 weeks of administration (including against COVID). 18. Use of any investigational drug or device within 30 days or 5 half-lives prior to screening, whichever is longer. 19. Consumption of grapefruit, grapefruit juice, bitter orange, bitter orange juice, or any food containing these ingredients within 7 days prior to dosing, or unwillingness to abstain from these throughout the study period.

[0241] Dosage and Method of Administration: This was a crossover study in which subjects received both the test treatment (LYT-100) and the reference (pirfenidone). LYT-100 (dupirfenidone) is supplied as a hard gelatin capsule. LYT-100 should be stored at controlled room temperature between 15°C and 25°C. Pirfenidone (Esbriet) is supplied as a white to off-white hard gelatin capsule containing 267 mg of pirfenidone. The capsule cap is printed with "PFD 267 mg" in brown ink. Pirfenidone should be stored at 15°C to 25°C. Both LYT-100 and pirfenidone were encapsulated to maintain the blinded nature of the study.

[0242] Treatment duration: The study included a 28-day screening period, followed by a 6-day treatment period consisting of up to 550 mg TID LYT-100 for 3 days, followed immediately by 824 mg TID LYT-100 for 3 days, or placebo. There was a safety follow-up visit 3 days (± 1 day) after the last dose. Thus, the total duration of participation in the study for each subject was a maximum of 40 days.

[0243] Evaluation criteria Safety: Safety and tolerability were assessed by monitoring for AEs, physical examination, vital signs, 12-lead electrocardiogram, clinical laboratory values ​​(hematology panel, multiphasic chemistry panel, and urinalysis), and evaluation of concomitant treatments / medications.

[0244] Pharmacokinetics: To support exploratory PK analyses, blood samples for genotyping of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 were obtained from subjects prior to treatment, i.e., on day -1 or day 1. Subjects were asked to provide consent for genotyping. Blood samples for PK were collected at specific times as follows: Day 1: 0 (before morning dose) Day 2: No blood sampling Day 3: 0 (before the morning dose), and 1, 2, 3, 4, 6 (before the midday dose), 7, 8, 9, 10, 12 (before the afternoon dose), 13, 14, 15, 16, and 17 hours after the morning dose. Day 4: 0 (before morning dose) Day 5: No blood draw Day 6: 0 (before the morning dose), and 1, 2, 3, 4, 6 (before the midday dose), 7, 8, 9, 10, 12 (before the afternoon dose), 13, 14, 15, 16, and 17 hours after the morning dose. Day 7: 0 (same time as day 6 before the morning dose, discharged)

[0245] Plasma concentration-time data for LYT-100 and its metabolite(s) were analyzed using non-compartmental methods. Plasma PK parameters at steady state dosing (Days 1-3 and Days 4-7) included, but were not limited to, the following: AUC 0-tau,ss (Area under the time-concentration curve from time zero to tau at steady state) AUC 0-24,ss (Area under the time-concentration curve from time zero to 24 hours at steady state) λ z (Terminal elimination rate constant / Terminal rate constant) t 1 / 2 (elimination half-life) C max,ss (Maximum concentration during dosing interval) T max (Time to maximum concentration, reported relative to the start of the dosing interval in which the maximum concentration occurred) C min,ss (Minimum concentration during dosing interval) C av,ss (average concentration during dosing interval) C max,ss -C min,ss / C av,ss (Degree of fluctuation) C max,ss -C min,ss / C min,ss (swing) PTF% (Peak-Trough Variation)

[0246] Urine samples for PK were collected at specific intervals as follows: Days 1 and 4: Pre-dose (subjects should be instructed to empty their bladder approximately 30 minutes prior to dosing) Days 2 and 5: No urine collection Days 3 and 6: Pre-dose (subjects should be instructed to empty their bladder approximately 30 minutes prior to dosing), 0-4 hours, 4-8 hours, 8-12 hours, 12-16 hours, and 16-24 hours after the morning dose.

[0247] Urine samples for urinary excretion analysis are collected, separated and analyzed at specific time intervals. The total volume of urine collected at each interval (t1-t2) is noted. Urinary PK parameters included, but were not limited to: Ae t1-t2 (urinary excretion over time) ·CLR (renal clearance) The proportion of total body clearance (CL / F) represented by renal clearance (CLR / [CL / F]) Fe t1-t2 (Percentage of the administered dose excreted in urine during the dosing interval) The study endpoints are defined as follows: ·Safety - AEs (type, severity, and relationship to study drug) -Physical examination -Vital signs -Electrocardiogram (ECG) - Clinical test items (hematology, serum chemistry, coagulation, and urinalysis) -Newly started concomitant medications Pharmacokinetics: - The main plasma PK parameters (C max,ss , C min,ss , and AUC 0-24,ss ) compared. Other plasma PK parameters were also derived and compared. - Urinary primary PK parameters (Ae t1-t2 , C.L. R , Fe t1-t2 ) for comparison. It was also possible to derive and compare other urinary PK parameters. -Evaluation of the food effect of LYT-100 and pirfenidone in a fed vs fasted state (C max,ss , and AUC 0-6,ss ).

[0248] Results – Pharmacokinetics Based on the observation in Example 1 of improved tolerability at lower TID doses of LYT-100 compared to pirfenidone (but similar total exposure), the safety and tolerability of a higher TID dose of LYT-100 was evaluated in this study (to achieve a higher overall predicted AUC or total exposure than the approved dose of pirfenidone (801 mg TID) and to explore the possibility of evaluating that dose in future efficacy studies).

[0249] Subjects aged 60-80 years were randomized to receive LYT-100 or placebo. Subjects received up to 550 mg LYT-100 TID for 3 days (until steady state [days 1-3]) compared to placebo TID for 3 days until steady state. From days 4-6, subjects received 824 mg LYT-100 TID for 3 days compared to placebo TID for 3 days until steady state. The dosing scheme is outlined in Table 16.

[0250] [Table 16]

[0251] Overall, 30 subjects were enrolled and included in the safety population (24 subjects in LYT-100 and 6 subjects in placebo). Seven subjects (23.3%) did not complete the study. The mean age of the entire population was 64.9 years; mean ages were similar in the LYT-100 and placebo groups, 65.0 and 64.5 years, respectively. The majority of subjects were male (56.7%; 66.7% in the LYT-100 group and 16.7% in the placebo group). The mean number of days of LYT-100 administration overall was 5.5 days. The mean number of days of placebo administration was 5.8 days.

[0252] Data were available for 30 subjects. Eight subjects reported all values ​​below the level of quantification (assuming BLQ; six placebo subjects and two active subjects with only a day 1 predose sample). One additional subject was excluded due to a high number of BLQ samples on both days 3 and 4 and days 6 and 7. Thus, sufficient PK data were available to calculate PK parameters at the low dose (550 mg TID on days 3 and 4) for 21 subjects. Three subjects only had data on days 3 and 4, and therefore PK parameters at the high dose (824 mg TID on days 6 and 7) were missing.

[0253] The results of the pharmacokinetic evaluation are shown in Figures 7A-18B. Referring to Figures 7A-7D, the plasma concentrations of both the parent drug (LYT-100; SD-560) and the major metabolite (5-carboxypirfenidone; SD-789) were higher in the 824 mg TID dose cohort (Figures 7B and 7D) compared to the 550 mg TID dose cohort (Figures 7A and 7C). The fed-state C of LYT-100 and the major metabolite for the 550 mg and 824 mg TID doses was 0.01 mg / kg / day. max value, AUC value, and T max The values ​​are shown in Figure 89. Referring to Figure 8, for LYT-100, the C of 824 mg TID versus the 550 mg TID dose was max The ratio was 1.45 and the AUC ratio was 1.44, indicating a nearly linear dose-exposure relationship. max and AUC ratios were slightly lower, 1.32 and 1.42, respectively.

[0254] The results of this study were compared to those obtained in a prior 850 mg BID study and a prior 550 mg TID study (described in Example 1 herein). As shown in Figures 10A and 10B (LYT-100 and major metabolites, respectively), the AUCs from the present 550 mg TID (days 1-3) study closely matched the AUCs of 550 mg TID from the prior 550 mg TID study (Part 2; solid blue and green lines, respectively; see also Example 1, Table 13), although slightly lower, and the AUCs and Cs of the 824 mg TID dose were significantly higher than those of the prior 550 mg TID study (Part 2; solid blue and green lines, respectively; see also Example 1, Table 13). max shows a significant / linear increase over that of the 550 mg TID dose.

[0255] FIG. 10 shows a comparison of plasma concentrations of LYT-100 (administered at 550 mg and 824 mg TID) and pirfenidone (administered at 801 mg TID) versus time after dosing on day 3. Referring to FIG. 10, the concentration peak of pirfenidone is higher than that of 550 mg LYT-100. FIG. 11 shows a comparison of plasma concentrations of the main metabolite of LYT-100 (administered at 550 mg and 824 mg TID) and pirfenidone (administered at 801 mg TID) versus time after dosing on day 3. FIG. 12 shows a comparison of plasma concentrations of pirfenidone 801 mg TID and LYT-100 550 mg TID versus time after dosing on day 3.

[0256] Figure 13A shows the AUC 0-24 Figure 13B shows the AUC for the main metabolites of LYT-100 across the current and previous studies. 0-24 13A and 13B, a similar trend was observed for the effects on body weight across the three groups, with a clear difference in exposure between those above and those below the 70-75 kg threshold.

[0257] Figures 14A and 14B show the AUC values ​​of LYT-100 and its main metabolites versus subject age across the current and previous studies, respectively. 0-2414A and 14B, age appears to affect the AUC, as exposure increases with age.

[0258] AUC for this treatment study and the three preceding treatment studies 24ss A bioequivalence simulation was performed for LYT-100 at 550 mg TID and 801 mg TID with pirfenidone. The results are shown in Figures 15A-15D and 16 and show that bioequivalence was achieved with 550 mg TID of LYT-100 using the combined data from the study, with bioequivalence observed at the theoretical 687 mg TID dose (Figure 16). Simulation results for the current study and across the three prior studies are shown in tabular form in Figure 17. Exemplary predictions of plasma concentrations over time for theoretical 550 mg TID and 825 mg TID doses of LYT-100, and 801 mg TID dose of pirfenidone, are shown in Figure 18A. With reference to Figure 18A, it is predicted that at 550 mg TID, the maximum plasma concentration (Cmax) achieved for LYT-100 is lower than the maximum plasma concentration of pirfenidone achieved at 801 mg TID, but exposure (AUC) is similar. In contrast, at 825 mg TID, the achieved Cmax of LYT-100 is only slightly higher than the peak plasma concentration of pirfenidone achieved at 801 mg TID, but the AUC is predicted to be higher. The estimated Cmax and AUC ratios of LYT-100 to pirfenidone are shown in Figure 18B.

[0259] Results – Tolerability Four subjects discontinued due to TEAEs (3 (12.5%) in the LYT-100 group and 1 (16.7%) in the placebo group). Three (12.5%) subjects withdrew consent, all in the LYT-100 group. Overall, 9 subjects (30.0%) experienced at least one TEAE, 8 (33.3%) while taking LYT-100 and 1 (16.7%) while taking placebo. The most common TEAEs (>5% overall) were COVID-19 and headache. A summary of these TEAEs (overall and by study drug) is provided in Table 17.

[0260] [Table 17]

[0261] Overview of TEAEs stratified by onset of symptoms on days 1-3 or 4-6 showed that onset of COVID-19 events occurred between days 4-6; onset of headache events occurred between days 1-3. Overall, the majority of TEAEs were considered mild. Thirteen mild events were reported in eight (26.7%) subjects, seven (29.2%) in the LYT-100 group and one (16.7%) in the placebo group. Two moderate TEAEs were reported in one (3.3%) subject in the LYT-100 group. None of the TEAEs were severe. Five (16.7%) TEAEs were unrelated and six (13.3%) were possibly related. No events were probably related. Overall, TEAEs leading to study discontinuation were reported in four (13.3%) subjects, all of which were due to Covid-19. Of these four TEAEs, three (12.5%) occurred in the LYT-100 group and one (16.7%) occurred in the placebo group. No deaths or SAEs were reported during the study.

[0262] Based on prior PK modeling studies, the AUC of LYT-100 at 824 mg TID is expected to be approximately 150% of the AUC at 801 mg TID, the approved dose of pirfenidone. Within the 824 mg TID LYT-100 group (mean age = 65), the dose was well tolerated over the 3-day treatment period. In this dose group, the most common TEAE was headache, with the majority of events being mild.

[0263] Further simulations were performed using the crossover data described above. The simulations showed that the AUC 0-24 The predicted AUC after administration of various hypothetical TID doses was normalized to0-24 Then, the obtained AUC 0-24 The AUC observed after administration of 801 mg TID pirfenidone 0-24 The individual ratios of LYT-100 to pirfenidone were calculated by comparing the ratios. These ratios were then evaluated using the same process described in Chow (Design and Analysis of Bioavailability and Bioequivalence Studies; Chapman & Hall / CRC Biostatistics Series, Chapman; Hall / CRC 2008) and CDER (Guidance for Industry Statistical Approaches to Establishing Bioequivalence Center for Drug Evaluation and Research [CDER], FDA, 2001). The results of the simulation are shown in Table 18. Based on these evaluations, the LYT-100 dosage regimen of 550 mg TID is predicted to provide parent drug exposure comparable to pirfenidone administered at 801 mg TID. The LYT-100 dosage regimen of 825 mg TID is predicted to provide parent drug exposure that is approximately 150% of the parent drug exposure following pirfenidone administered at 801 mg TID. Notably, the slower absorption of LYT-100 compared to pirfenidone resulted in a predicted C of LYT-100 at a dose of 825 mg TID. max is the corresponding C for pirfenidone at a dose of 801 mg TID. max It is only 15% higher than

[0264] Actual and extrapolated exposure and C for LYT-100 administered at 550 mg TID and 824 / 825 mg TID max The values, combined with the tolerability data, support these two doses for investigating efficacy, safety, and dose-response in idiopathic pulmonary fibrosis, as described in Example 3 below.

[0265] [Table 18]

[0266] Example 3: Tolerability of LYT-100 in Patients with COVID-19 Respiratory Disease A Phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled study was conducted to evaluate the safety and efficacy of dupirfenidone (LYT-100) compared to placebo in adult patients with post-acute COVID-19 respiratory disease who had received at least 1 day of treatment with supplemental oxygen (including MV, ECMO, or any other means of oxygen administration) in a hospital and who had only required low-flow nasal oxygen or had not required supplemental oxygen for at least 72 hours prior to screening. Patients received LYT-100 (dupirfenidone) formulated as a powder in a 250 mg capsule or a matching placebo. Dosing was as shown in Table 19. An initial dose of 500 mg BID was administered for the first 3 days of administration, followed by 750 mg BID thereafter. Patients received LYT-100 study drug, or placebo (Part A), orally, preferably with food (solid food or dietary supplements, if available), twice daily with approximately 10-12 hours between doses.

[0267] [Table 19]

[0268] One hundred and seventy-seven patients, with a mean age of 55 years, who experienced persistent respiratory complications following hospitalization for acute COVID-19 infection requiring treatment with supplemental oxygen were enrolled in the study and randomized 1:1 to receive LYT-100 or placebo, respectively. Baseline demographic characteristics and subject distribution of enrolled subjects are shown in Figures 19-21.

[0269] Tolerability results LYT-100 was well tolerated in this relatively sick patient population with multiple comorbidities and concomitant medications. There were no drug-related serious adverse events (SAEs) or deaths. Treatment-emergent AEs occurring at a frequency of 5% or greater in the LYT-100 group are summarized in Table 20. Referring to Table 20, nausea was the only AE judged to be at least possibly related to LYT-100, with an incidence of 5% or greater (8.7% vs. 2.4% (placebo)). Referring further to Table 20, other AEs frequently associated with pirfenidone that were considered at least possibly related to LYT-100 treatment in this study included headache (4.3% vs. 1.2% (placebo)), dizziness (3.3% vs. 1.2% (placebo)), fatigue (2.2% vs. 0% (placebo)), and rash (3.3% vs. 1.2% (placebo)). Discontinuation rates due to AEs considered at least possibly related to LYT-100 were low in both groups (8.6% (LYT-100) vs. 2.4% (placebo)), with the majority of discontinuations in the LYT-100 group due to idiosyncratic events and not AEs commonly associated with pirfenidone. A summary of all treatment-emergent adverse events judged at least possibly related to LYT-100 is shown in Figure 22.

[0270] [Table 20]

[0271] Overall, the safety and tolerability results of this study reaffirm the strong safety and tolerability profile characteristics of LYT-100 observed in previous studies, such as those described herein in Examples 1 and 2. The safety and tolerability of the 750 mg BID dose in this relatively sick patient population suggests that it may be similarly well tolerated in other patient populations, such as those with interstitial lung disease or other fibrotic mediated pulmonary diseases.

[0272] Example 4: In vitro stability of pirfenidone and LYT-100 in the presence of recombinant human CYP isoenzymes The metabolism of LYT-100 by isolated CYP isoenzyme preparations was evaluated and compared to that of pirfenidone (Figure 27). Pirfenidone and LYT 100 were incubated with recombinant human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 expressed in heterologous cell systems, respectively. The half-life (t1 / 2) of each test article was determined.

[0273] Referring to Figure 23, the concentrations of pirfenidone and LYT-100 were decreased by at least 15% during incubation with recombinantly expressed human CYP1A2, CYP2D6 and CYP2C19 isoenzymes. The t 1 / 2 The t of LYT-100 after incubation with CYP1A2, CYP2C19, and CYP2D6 were 3.18, 2.13, and 2.30 hours, respectively. 1 / 2 were 9.08, 3.67, and 2.72 h, respectively. There was no significant metabolism by the CYP2C8, CYP2C9, CYP3A4, or CYP3A5 isoenzymes, with more than 92% of the compound remaining at the end of the incubation. Thus, the t 1 / 2 These results confirm the stabilization of LYT-100 and pirfenidone against metabolism. Metabolism by CYP1A2 was most affected by deuteration (t compared to pirfenidone). 1 / 2 This result demonstrates the effect of deuteration of LYT-100 on the overall metabolism of pirfenidone, as the CYP1A2 isoenzyme plays a major role in the metabolism of pirfenidone.

[0274] Example 5: Activity Screening LYT-100 and pirfenidone were evaluated using the DiscoverX BioMAP Fibrosis panel. The panel contains readouts of 54 biomarkers (cell surface receptors, cytokines, chemokines, matrix molecules, and enzymes) that capture biological changes occurring within the physiological context of a particular BioMAP system. LYT-100 and pirfenidone were tested in the BioMAP Fibrosis panel at various dilutions starting from the highest dose of 1700 μM in three cell / stimulus systems (myofibroblasts [MyoF], consisting of lung fibroblasts treated with TNF-α and TGF-β; renal proximal tubular epithelial cells (RE) MyoF, which includes renal tubular epithelial cells and lung fibroblasts treated with TNF-α and TGF-β; and small airway epithelial cells (SAE) MyoF, which includes small airway epithelial cells and lung fibroblasts treated with TNF-a and TGF-β). Similar results were observed for both compounds in the three systems (Figure 24).

[0275] Example 6: Suppression of lipopolysaccharide (LPS)-induced plasma TNF-α and IL-6 concentrations following oral administration of LYT-100 in male Sprague-Dawley rats Dosing solutions of LYT-100 and pirfenidone were prepared by dissolving each in a vehicle of water containing 1% carboxymethylcellulose and 0.2% Tween-80. LPS was diluted to 2 mg / mL in sterile saline and sonicated for 20 minutes at 40° C. to generate a stock solution that was stored at 4° C. On each day of use, the stock solution was further diluted to 0.03 mg / mL in sterile saline.

[0276] Male Sprague-Dawley rats (n = 6–8 per dose and test article group) with catheters in the femoral and jugular veins were used in this study. Rats were administered either vehicle (dosing solution, 10 mL / kg), LYT-100, or pirfenidone at concentrations of 30, 100, or 300 mg / kg via a syringe attached to an oral gavage needle. Sixty minutes after oral dosing, 0.03 mg / kg LPS in 1 mL / kg saline was injected into the jugular vein.

[0277] Blood samples were collected from the femoral vein into heparin-coated syringes 15 min prior to LPS injection (45 min after oral administration of the test substance), 90 min after LPS injection, and 4 h after LPS injection. Plasma was prepared by centrifuging the blood samples at 14,000 rpm for 10 min. Plasma samples were stored at -70°C until analysis.

[0278] LPS stimulated a strong inflammatory response, including the cytokines TNF-α and IL-6 (FIGS. 25A and 25B, respectively). Referring to FIG. 25A, in vehicle-pretreated rats, LPS increased plasma TNF-α concentrations from undetectable to approximately 75,000 pg / mL 90 minutes after injection. This TNF-α response to LPS was reduced by pretreatment with both pirfenidone and LYT-100. 90 minutes after LPS injection, pretreatment with oral administration of 100 and 300 mg / kg LYT-100 inhibited TNFα. At 100 mg / kg, TNF-α levels were 70 percent lower than those obtained using an equivalent oral dose of vehicle control, and the reduction in TNF-α response in rats pretreated with LYT-100 was greater than that of pirfenidone (Table 21, Table 22, and FIG. 25A). Oral pretreatment with 100 and 300 mg / kg LYT-100 also inhibited IL-6 similarly to pirfenidone (Table 23, Table 24, and FIG. 25B). Thus, LYT-100 retains the activity of pirfenidone in attenuating LPS-induced TNF-α and exhibits additional potency at comparable doses, likely due to the pharmacokinetic effects of deuteration.

[0279] [Table 21]

[0280] [Table 22]

[0281] [Table 23]

[0282] [Table 24]

[0283] Example 7: LYT-100 significantly reduced areas of fibrosis in a mouse model Nonalcoholic steatohepatitis (NASH) is characterized by lobular inflammation, hepatocyte hypertrophy, and progression to hepatic fibrosis. NASH mice were induced by a single subcutaneous injection of 200 μg of streptozotocin solution on the second day of life and a high-fat diet from 4 weeks of age onwards. 18 male mice were orally administered LYT-100 at 0 mL / kg (vehicle only: 0.5% carboxymethylcellulose) or 10 mL / kg twice daily from 6–9 weeks of age. LYT-100 was administered at an oral dose of 30 mg / kg twice daily (60 mg / kg / day). In addition, 9 non-NASH mice were fed a normal diet and monitored.

[0284] Figure 26 shows representative photomicrographs of Sirius red stained liver sections, showing that LYT-100 significantly reduced the area of ​​fibrosis. Specifically, the liver sections of the vehicle group showed collagen deposition in the pericentral area of ​​the liver lobule. Furthermore, the LYT-100 group showed a significant reduction in the area of ​​fibrosis compared to the vehicle group. These results indicate that LYT-100 has the potential to inhibit the progression of fibrosis. Figure 27 shows the percentage of area of ​​fibrosis of LYT-100 relative to vehicle and control. The results are also summarized in Table 25 below.

[0285] [Table 25]

[0286] Liver sections from the vehicle group showed severe microdroplet and macrodroplet steatosis, hepatocyte hypertrophy and inflammatory cell infiltration. LYT-100 had similar hepatocyte hypertrophy to vehicle, but lower scores for lobular inflammation and steatosis (Table 26). The components of the NAS score are shown in Table 27.

[0287] [Table 26]

[0288] [Table 27]

[0289] As demonstrated above, LYT-100 significantly reduced areas of fibrosis, reduced inflammation, and reduced fat accumulation (steatosis) compared to untreated NASH mice.

[0290] Example 8: Reduction of TGF-β-induced proliferation and collagen levels in primary mouse lung fibroblasts by LYT-100 LYT-100 was evaluated for its ability to reduce TGF-β-induced proliferation of primary mouse lung fibroblasts (PMLF) and collagen levels in PMLF.

[0291] Inhibition of p38 members by LYT-100 is important because p38 members are activated by the TGF-β signaling pathway. Activation of TGF-β then plays a key role in the transcriptional induction of type IA2 collagen. Type IA2 collagen, for example, constitutes the majority of the extracellular matrix that accumulates during the progression of fibrotic lung disease. Collagen deposition is one of the most important components of fibrotic lung tissue, a process that is primarily induced by TGF-β. Accumulation of insoluble collagen invades the alveolar space, and therefore plays a pivotal role in the deformation of lung structure and the progression of fibrotic lung disease. In addition to insoluble (structural) collagen, fibrotic lungs of IPF patients also show high levels of nonstructural (soluble) collagen. This type of collagen can eventually become insoluble collagen, but until then, soluble collagen can function as a ligand for integrin receptors on lung fibroblasts and epithelial cells. Binding of soluble collagen to these receptors induces the proliferation and migration of these cells. Fibronectin is another important component of fibrotic lungs, as it is induced by TGF-β and functions both as a structural component of the extracellular matrix (ECM) and as a ligand for integrin receptors. Similar to soluble collagens, fibronectin binding to integrin receptors induces proliferation of lung fibroblasts and epithelial cells, playing an important role in the progression of IPF. Therefore, inhibition of TGF-β-induced collagen synthesis is an important target for fibrotic lung diseases.

[0292] Preparation of primary mouse lung fibroblasts Primary mouse lung fibroblasts were prepared as follows: one lung was removed from a 2-month-old male BalbC mouse, perfused with sterile PBS, minced, and incubated in 2 ml of serum-free Dulbecco's Modified Eagle Medium (DMEM) containing 100 μg / ml collagenase I for 1 hour at 37°C. Each sample was centrifuged at 1500 rpm (revolutions per minute) for 5 minutes, washed three times with PBS, and the final cell pellet was resuspended in DMEM supplemented with 10% serum and Pen / Strep and incubated in a 150 mm plate at 37°C with 80% humidity and 10% CO2. Growth medium was removed and fresh medium was added daily for 10 days.

[0293] Examining the effect of LYT-100 on the survival of primary mouse lung fibroblasts LYT-100 was evaluated for its ability to alter TGF-β-induced proliferation of PMLFs. At the end of the 10-day incubation period described above, lung fibroblasts were confluent. Before examining the effect of LYT-100 on the survival of these cells, fibroblasts were trypsinized and 5000 cells were seeded in 200 μL of complete DMEM in 96-well plates and incubated until the cells reached 95-100% confluency, after which the medium was removed and complete DMEM containing proline (10 μM) and ascorbic acid (20 μg / mL) was added. LYT-100 dissolved in pure ethanol was added to the plates at a final concentration of 500 μM 1 h before the addition of TGF-β (5 ng / mL) and the cells were incubated for a further 72 h. 100 μL of growth medium was removed and 20 μL of MTT stock solution (prepared in PBS at a concentration of 5.5 mg / mL) was added and the cells were incubated for 4 h, after which 100 μL of dimethyl sulfoxide was added and the absorbance of the resulting color was monitored at 540-690 nm.

[0294] As shown in Figure 28A, LYT-100 alone did not affect PMLF survival. TGF-β (5 ng / mL) significantly induced PMLF proliferation by nearly 45% (p=0.001), and LYT-100 appeared to reduce TGF-β-induced PMLF proliferation by 10%, although this effect was not statistically significant (p=0.19).

[0295] TGF-β-induced synthesis of insoluble collagen using a 6-well plate format The effect of LYT-100 on the inhibition of TGF-β-induced collagen synthesis was evaluated in PMLFs in a 6-well format. One hundred thousand primary mouse lung fibroblasts were seeded in 6-well plates and incubated in complete DMEM until confluency was reached. The incubation medium was removed and complete DMEM containing proline (10 μM) and ascorbic acid (20 μg / mL) was added. LYT-100 was added to the plates at a final concentration of 500 μM 1 h prior to the addition of TGF-β (5 ng / mL) and the cells were incubated for an additional 72 h.

[0296] The supernatant was removed, the cells were washed with cold PBS, and 1 mL of Sircol reagent was added. Sircol reagent contains Sirius Red, a collagen-binding dye. The cells were scraped with Sircol reagent, the samples were shaken for 5 h at room temperature (RT), centrifuged at 10,000 rpm for 5 min, the supernatant was removed, the pellet was washed with 0.5 M acetic acid to remove unbound dye, centrifuged again at 10,000 rpm for 5 min, the supernatant was removed, and the final pellet was dissolved in 1 mL of 0.5 M NaOH and shaken for 5 h at RT. Samples of 100 μL of the resulting solution were placed in 96-well plates. The color reaction was evaluated by optical density at a wavelength of 600 nm.

[0297] As shown in Figure 28B, PMLFs responded to TGF-β with an increase in total collagen levels (21% increase, p=0.0087). LYT-100 inhibited this induction by 15% compared to TGF-β alone (p=0.026) without reducing background collagen levels.

[0298] TGF-β-induced synthesis of insoluble collagen using a 96-well plate format The effect of LYT-100 on collagen under TGF-β induction was confirmed in a high-throughput collagen assay using a 96-well plate format. Approximately 5,000 primary mouse fibroblasts were seeded in complete DMEM in 96-well plates and incubated for 3 days, at which point the cultures achieved confluency. After the cells reached confluency, the medium was removed and fresh DMEM supplemented with ascorbic acid (20 μg / mL) and proline (10 μMol) was added. LYT-100 was then added to the appropriate cultures at a final incubation concentration of 500 μM. One hour later, TGF-β was added to the appropriate cultures at a final concentration of 5 ng / ml. After 72 hours, the medium was replaced with a 0.5% glutaraldehyde solution. After 30 minutes, the attached cells were washed and subsequently incubated with acetic acid at a final concentration of 0.5 M. After a 30-minute room temperature incubation and subsequent washing step, the wells were incubated with Sircol reagent. After 5 hours, unbound dye was removed and the plate was washed and dried. To extract collagen-bound Sircol, 100 μL of alkaline solution (0.5 M NaOH) was added and the plate was shaken on a rotary shaker at room temperature for 1 hour. Bound collagen was detected by determining absorbance at 600 nm.

[0299] As shown in FIG. 28C, in a 6-well format, TGF-β induced insoluble collagen levels by 40% (p=0.0002), and LYT-100 reduced this TGF-β-stimulated collagen accumulation by 24% (p=0.0003) without reducing background collagen levels.

[0300] TGF-β-induced synthesis of soluble fibronectin and collagen Selective ELISA was used to evaluate LYT-100 for its ability to modify TGF-β-induced synthesis of soluble fibronectin and soluble collagen. Approximately 5,000 primary mouse lung fibroblasts were seeded in complete DMEM in 96-well plates and incubated for 3 days, at which point the cultures achieved confluency. After the cells reached confluency, the medium was removed and fresh DMEM supplemented with ascorbic acid (20 μg / mL) and proline (10 μM) was added. LYT-100 was then added to the appropriate cultures at a final incubation concentration of 500 μM. One hour later, TGF-β (5 ng / ml) was added to the appropriate cultures at a final concentration. After 72 hours, 200 μL samples of the supernatants were placed in ELISA plates and incubated overnight. After blocking with 1% BSA for 2 hours, the plates were incubated with either anti-type I collagen antibody or anti-fibronectin antibody.

[0301] After 1 h, the plates were washed and incubated with horseradish peroxidase-conjugated secondary antibodies (anti-goat for collagen antibodies and anti-rabbit for fibronectin antibodies). After a series of washing steps, the color reagent TMB (3,3',5,5'-tetramethylbenzidine) was added and the reaction was stopped after 15 min with an equal volume of 2N H2SO4. The levels of soluble collagen and fibronectin were determined by assessing the absorbance at 450 nm.

[0302] Referring to Figure 28D, TGF-β induced soluble fibronectin levels by 16% (p=0.0021). LYT-100 inhibited TGF-β-dependent fibronectin induction by 11% (p=0.0185). In addition, LYT-100 also inhibited background levels of soluble fibronectin by 10% (p=0.03).

[0303] As shown in Figure 28E, TGF-β induced soluble collagen levels by 20% (p=0.0185). LYT-100 inhibited this TGF-β-dependent increase by 36% (p=0.0001). In addition, it also inhibited background levels of soluble collagen by 23% (p=0.0115).

[0304] In summary, LYT-100 was found to (i) reduce TGF-β-induced cell proliferation, (ii) reduce both background and TGF-β-induced levels of insoluble (structural) collagen, (iii) reduce both background and TGF-β-induced levels of soluble collagen, and (iv) reduce both background and TGF-β-induced levels of soluble fibronectin.

[0305] During the progression of fibrotic lung diseases such as IPF, accumulation of extracellular matrix components such as collagen and an increase in fibroblast population are observed. Sustained proliferation of fibroblasts is thought to be an important contributor to lung structure in fibrotic lung diseases, including the reduction of alveolar interstitial space. Thus, reducing TGF-β-induced proliferation of fibroblasts and structural collagens by LYT-100 has the potential to prolong lung function in fibrotic lung diseases. In addition to suppressing TGF-β-induced insoluble collagen levels, LYT-100 also inhibits TGF-β-induced secreted collagen and fibronectin β. Secreted collagen and fibronectin not only increase the rate of formation of fibrotic lesions in the lung, but these proteins can also act as ligands for integrin receptors. When integrin receptors are activated, they not only induce proliferation of lung epithelial cells and fibroblasts, but also induce epithelial-mesenchymal transition (EMT) of lung epithelial cells together with TGF-β. EMT allows these cells to migrate to different regions of the lung. This translocation is believed to be a critical contributor to the generation of new fibrotic lesions in the lung and the progression of fibrotic lung diseases such as IPF. LYT-100 has the ability to inhibit the profibrotic process induced by TGF-β and reduce underlying factors that may exacerbate ongoing fibrosis.

[0306] Example 9: Effect of LYT-100 on L929 cells The effect of LYT-100 on L929 cell viability was determined. 5,000 L929 cells were seeded in complete DMEM and incubated for 3 days until confluent. The medium was removed and complete DMEM containing proline (20 μg / mL) and ascorbic acid (10 uM) was added. LYT-100 was given at 500 μM 1 hour before the addition of TGFβ (5 ng / ml) and cells were incubated for an additional 72 hours. An aliquot of 100 μL of medium was removed and 20 μL of MTT solution was added for 4 hours, followed by 100 μl of DMSO, and the absorbance of the resulting deep pink color was determined from 54 to 690 nM. Figure 29A shows that LYT-100 does not affect L929 cell viability.

[0307] The effect of LYT-100 on TGF-induced collagen synthesis in 6-well plates was determined. 100,000 L929 cells were seeded in complete DMEM and incubated for 3 days until confluent. The medium was removed and complete DMEM containing proline (20 μg / mL) and ascorbic acid (10 μM) was added. LYT-100 was added at 500 μM 1 hour before the addition of TGF-β (5 ng / mL). The cells were further incubated for 72 hours. The supernatant was removed, the cells were washed with cold PBS, 1 mL of Sircol reagent was added to the cells, the cells were scraped off, the samples were shaken for 5 hours at RT, centrifuged at 10,000 rpm for 5 minutes, the supernatant was removed, the pellet was dissolved in 0.5 M acetic acid to remove unbound dye, centrifuged again at 10,000 rpm for 5 minutes, the supernatant was removed, the final pellet was dissolved in 1 mL of 0.5 M NaOH, shaken for 5 hours at RT, 100 μL of the resulting solution was placed in a 96-well plate, and the absorbance was determined at 600 nM. The results showing that LYT-100 inhibits TGF-induced collagen synthesis are summarized in Figure 29B. LYT-100 significantly inhibits collagen synthesis even in the absence of added TGF-β.

[0308] Next, the effect of LYT-100 on TGF-induced collagen synthesis was confirmed using a 96-well plate format. 5,000 L929 cells were seeded in complete DMEM and incubated for 3 days until confluent. The medium was removed and complete DMEM containing proline (20 μg / mL) and ascorbic acid (10 μM) was added. LYT-100 was added at 500 μM 1 hour before the addition of TGF-β (5 ng / mL). The cells were further incubated for 72 hours. The supernatant was removed, 0.5% glutaraldehyde was added for 30 minutes at RT, removed, washed three times with water, 0.5 M acetic acid was added for 30 minutes at RT, removed, washed with water, air-dried, and 100 μL of Sircol dye was added for 5 hours at RT. The dye was removed, the plates were washed thoroughly with running water, air-dried, 200 μL of 0.5 M NaOH was added, the plates were shaken for 1 h at RT, and the absorbance was determined at 600 nm. The results summarized in FIG. 29C show that LYT-100 significantly inhibited or reduced total collagen levels under TGF-β induction. LYT-100 also significantly inhibited or reduced total collagen levels in the absence of TGF-β induction.

[0309] A 96-well plate format was used to determine the effect of LYT-100 on TGF-induced synthesis of soluble collagen. 5,000 L929 cells were seeded in complete DMEM and incubated for 3 days until confluent. The medium was removed and complete DMEM containing proline (20 μg / mL) and ascorbic acid (10 μM) was added. LYT-100 was added at 500 μM 1 hour before the addition of TGF-β (5 ng / mL). The cells were incubated for an additional 72 hours. 200 μl of the supernatant from the 96-well Sircol plate was placed on the ELISA plate and incubated overnight. The next day, the supernatant was removed, 100ul of 1% BSA in PBST was added, incubated at RT for 2 hours, the BSA was removed, the plate was washed 3 times with 200ul of PBST, anti-type I collagen antibody (ab) was added at a dilution of 1:2000 (prepared in 1% BSA in PBST), incubated at RT for 1 hour, the primary antibody was removed, the plate was washed 3 times with 200ul of PBST, secondary anti-goat HRP was added at a dilution of 1:2000, incubated at room temperature for 1 hour, removed, the plate was washed 3 times with 200ul of PBST, 100ul of TMB solution was added to develop for 15 minutes, then 100ul of 2N H2SO4 was added to stop the reaction, and the absorbance of the resulting yellow color was determined at 450nm.

[0310] As shown in Figure 29D, LYT-100 significantly suppresses soluble collagen levels under TGF-β induction. LYT-100 also significantly reduced soluble collagen levels in the absence of TGF-β induction.

[0311] Fibronectin is another important component of fibrotic lungs, as it is induced by TGF-β and functions as both a structural component of the extracellular matrix as well as a ligand for integrin receptors. Like soluble collagen, fibronectin binding to integrin receptors induces proliferation of lung fibroblasts and epithelial cells. Using a process similar to that described in the paragraph above for soluble collagen synthesis, except that a fibronectin ELISA was used, the effect of LYT-100 on soluble fibronectin synthesis under TGF induction was determined. As shown in Figure 29E, LYT-100 significantly reduced the levels of soluble fibronectin in the absence and presence of TGF-β induction.

[0312] Example 10: Testing of LYT-100 in a Mouse Model of Lymphedema In this experiment, we investigated the effects of LYT-100 in a mouse tail model of lymphedema. LYT-100 or control (carboxymethylcellulose) was delivered by oral gavage once daily to mice in which the tail lymphatics had been severed via circumferential resection and transection of the collecting lymphatic trunk. Tail volume measurements of all animals were taken weekly beginning before surgery and continued until the COVID19 outbreak necessitated termination of the study at 6 weeks. At the time of sacrifice, tails were harvested for histology and immunofluorescence imaging to characterize tissue changes due to surgery and treatment with LYT-100 or control. Tail volume, as well as markers of lymphatics, fibrosis, and inflammation, were compared between LYT-100 and control groups.

[0313] Animals: 14 adult C57BL / 6 J mice (10–14 weeks old), 7 per group.

[0314] Surgery: The superficial and deep collecting lymphatics in the mid-tail were excised using a 2 mm full thickness cutaneous and subcutaneous excision performed at a distance of 15 mm from the base of the tail. The lymphatic trunks (collecting lymphatics) adjacent to the lateral veins were identified and severed by controlled, focal application of cautery under a surgical microscope. The doses, routes and schedules of administration are shown in Table 28.

[0315] [Table 28]

[0316] The measurement method is shown in Table 29. [Table 29]

[0317] The test procedures and timing are shown in Table 30. [Table 30]

[0318] Figures 30A-D show the results of once-daily administration of LYT-100 to reduce swelling in a mouse lymphedema model over a six-week period. The mouse lymphedema model is illustrated in Figure 30A. As shown in Figure 30B, daily administration of LYT-100 significantly reduced swelling compared to the carboxymethylcellulose control by week 5. The images in Figures 30C and 30D show the difference in swelling at week 6.

[0319] Example 11: Evaluation of the efficacy of LYT-100 in a rodent bleomycin-induced fibrosis model The rodent bleomycin-induced fibrosis model (BLM) is commonly used in preclinical settings because it appears to be clinically relevant as an animal model of human fibrosis (e.g., idiopathic pulmonary fibrosis) based on the pulmonary pathophysiology observed after bleomycin administration in rats. See, for example, Corboz et al.,Pumonary Pharm.& Ther.49 (2018),95-103). Bleomycin is a metabolite of the bacterium Streptomyces verticillus that was first identified in 1962. Specifically, bleomycin is a nonribosomal hybrid peptide-polyketide natural product with the following structure:

[0320] [ka]

[0321] Although bleomycin has antibacterial activity, its toxicity prevents its use as an antibiotic. It is used as a chemotherapeutic agent in the treatment of various cancers, particularly Hodgkin's lymphoma, non-Hodgkin's lymphoma, testicular cancer, ovarian cancer, and cervical cancer. Bleomycin acts by inducing DNA strand breaks and may also inhibit the incorporation of thymidine into DNA strands. DNA cleavage by bleomycin is dependent on oxygen and metal ions, at least in vitro, but the exact mechanism of DNA strand breakage has not been elucidated.

[0322] Common side effects associated with bleomycin chemotherapy include fever, weight loss, vomiting, rash, and severe anaphylaxis. The most serious complication of bleomycin treatment, which occurs with increasing doses, is pulmonary fibrosis and impaired pulmonary function. At high concentrations, bleomycin induces DNA strand breaks, generates free radicals, and causes oxidative stress, resulting in cellular necrosis and / or apoptosis. Recent studies support a role for the proinflammatory cytokines IL-18 and IL-1 beta in the mechanism of bleomycin-induced lung injury. Bleomycin is normally metabolized by the enzyme bleomycin hydrolase, but the lung lacks this enzyme, making the lung particularly susceptible to bleomycin toxicity. Pulmonary inflammation, fibrosis, reduced lung compliance, and impaired gas exchange are the effects of bleomycin administration.

[0323] In assessing the antifibrotic potential of compounds of interest, evaluations are generally performed at the established fibrotic stage, i.e., 10-15 days after the onset, rather than early in bleomycin-induced inflammation. The conversion of proline to hydroxyproline and its incorporation into lung collagen occurs as early as 4 days after bleomycin administration. The switch between inflammation and fibrosis occurs in rats around day 9 after bleomycin administration. It was considered desirable to evaluate the activity of LYT-100 during both the inflammatory and fibrotic stages of the model. Therefore, LYT-100 was administered starting from day 8 after bleomycin administration.

[0324] Phase I First, a Phase I study was conducted to evaluate the effects of bleomycin and LYT-100 on body and lung weight in a rat BLM-induced pulmonary fibrosis model. The Phase I study design is shown in Table 31.

[0325] [Table 31]

[0326] Groups 1, 2, and 3 received bleomycin and vehicle as indicated in Table 31 (0.45 mg / kg, 1696 IU / mg bleomycin, or saline on days 1, 2, 3, 6, and 7). LYT-100 was administered by oral gavage once daily on days 8-13.

[0327] observation Animals were observed for various clinical signs and symptoms following administration of bleomycin and LYT-100. All animals administered bleomycin or saline had a 100% incidence of abnormal sounds on days 1, 2, 3, 6, and 7, which abated by the next test day, confirming pulmonary administration. Respiratory signs were observed in all animals administered bleomycin (groups 2 and 3) beginning on day 3, with a 100% incidence of increased respiratory rate by day 5. No increased respiratory rate was observed in group 1. Respiratory signs are indicative of acute inflammation secondary to bleomycin administration. Gait abnormalities were observed in some animals following the initiation of LYT-100 administration on day 8. Signs disappeared in animals that exhibited them approximately 5 hours after they were recorded, and did not appear on subsequent occasions of administration. Sluggishness and hypoactivity were observed in almost all animals after LYT-100 administration on days 8, 9, and 10, and after that time, signs only appeared in group 3 (bleomycin / 400 mg / kg LYT-100) on day 13. When this sign appeared, it disappeared about 5 hours after it was recorded. In all animals, eyelid closure was observed after initiation of LYT-100 administration on day 8. The sign disappeared in animals that showed it about 5 hours after it was recorded and did not appear on subsequent dosing occasions. In some animals of groups 1 and 2, piloerection was observed after initiation of LYT-100 administration on day 8 and again on day 11. The sign disappeared in animals that showed it about 5 hours after it was recorded and did not appear on subsequent dosing occasions. In almost all animals, salivation was observed after initiation of LYT-100 administration on day 11. Symptoms disappeared in animals that exhibited them approximately 5 hours after they were recorded and did not appear on subsequent dosing occasions.

[0328] result To determine the effect of bleomycin and LYT-100 in the model, body weight and lung weight were evaluated over the course of the study. Weight gain was prevented in Groups 2 and 3 receiving bleomycin from days 1-9 (Figure 31). With continued reference to Figure 31, from day 10 until the end of phase 1 on day 14, weight gain in Groups 2 and 3 resumed at a similar rate to Group 1 receiving saline. Weight gain (expressed as % of body weight compared to day -1) Weight gain was prevented in Groups 2 and 3 receiving bleomycin from days 1-9. From day 10 until the end of phase 1 on day 14, weight gain in Groups 2 and 3 resumed at a similar rate to Group 1 receiving saline.

[0329] Lung weights were higher in bleomycin-treated animals (groups 2 and 3 compared to group 1), as predicted by the model. Lung weight ratios (expressed as % of body weight; Figures 32A and 32B) were higher in bleomycin-treated animals (groups 2 and 3 compared to group 1), as predicted by the model.

[0330] Overall, phase 1 was performed according to protocol, with no deviations deemed to affect the integrity of the results of this phase of the study. In phase 1 (tolerability), LYT-100 was administered once daily (QD) at high (400 mg / kg) and low (250 mg / kg) dose levels from days 8 through 13 (including day 13) in healthy rats (high dose) and bleomycin-challenged rats (low and high doses). LYT-100 was well tolerated in all animals, with no clear correlation between dose level and the presence of side effects. Any side effects observed resolved within approximately 5 hours after they were noted and did not reoccur until subsequent dosing sessions. Based on animal weight progression, clinical signs, lung weights, and lung to body weight ratios, it was determined during the tolerability phase that LYT-100 administered QD at 400 mg / kg was well tolerated in both healthy and bleomycin-treated rats, and that this dose level would be used to explore the therapeutic potential of LYT-100 in Phase 2 (efficacy).

[0331] Phase II A Phase II study was then conducted to evaluate the efficacy of LYT-100 in a rat BLM-induced pulmonary fibrosis model. The Phase II study design is shown in Table 32.

[0332] [Table 32]

[0333] Groups 4, 5, 6, and 7 received bleomycin and vehicle as indicated in Table 32 (0.45 mg / kg, 1696 IU / mg bleomycin or saline on days 1, 2, 3, 6, and 7). LYT-100 was administered by gavage once daily and nintedanib was administered by gavage twice daily from days 8 to 27.

[0334] observation Animals were observed for various clinical signs and symptoms following administration of bleomycin, saline, and LYT-100. All animals administered bleomycin or saline had a 100% incidence of dysthymia on days 1, 2, 3, 6, and 7, which abated by the next study day, confirming pulmonary administration. Respiratory signs were observed in all animals administered bleomycin (groups 5-7) from day 2, with a 100% incidence of increased respiratory rate from day 4 to day 28, when the study was terminated. No increased respiratory rate was observed in group 4, which received saline. Respiratory signs are indicative of acute inflammation secondary to bleomycin administration.

[0335] result To determine the impact of bleomycin and LYT-100 in the model, body weight and lung weight were evaluated over the study period. Weight gain was prevented from days 1 to 9 in groups 5, 6, and 7 receiving bleomycin (Figure 33A). With continued reference to Figure 33A, from day 10 to day 28, when the efficacy phase of the study ended, weight gain resumed in groups 5 (bleomycin / vehicle) and 6 (bleomycin / LYT-100) at a rate similar to that of group 4 receiving saline / vehicle. Weight gain in group 7 (bleomycin / nintedanib) showed moderate improvement after day 8, with weight gain rates remaining slower compared to the other groups. Weight gain (expressed as % of body weight compared to body weight on day 1) was prevented from days 1 to 9 in groups 5, 6, and 7 receiving bleomycin (Figure 33B). With continued reference to Figure 33B, from Day 10 through Day 28, when the efficacy phase of the study ended, percent body weight gain in Groups 5 (bleomycin / vehicle) and 6 (bleomycin / LYT-100) resumed rates similar to Group 4, which received saline / vehicle. Percent body weight gain in Group 7 (bleomycin / nintedanib) showed a moderate improvement after Day 8, with weight gain rates remaining slower compared to the other groups.

[0336] Mean lung weight was increased in bleomycin-treated rats (Group 4 (Saline) vs. Group 5 (Bleomycin); Figures 34A and 34B). With continued reference to Figures 34A and 34B, LYT-100 treatment did not affect mean lung weight in bleomycin-treated rats (Group 5 (Bleomycin / Vehicle) vs. Group 6 (Bleomycin LYT-100)). Lung weights were reduced in nintedanib-treated rats (Group 7 vs. Group 5) and were similar to untreated rats (Group 7 vs. Group 4). Lung weight ratios (expressed as a percentage (%) of body weight; Figures 35A and 35B) were increased in bleomycin-treated rats (Group 4 (Saline) vs. Group 5 (Bleomycin)). LYT-100 treatment did not affect lung weight ratios in bleomycin-treated rats (Group 5 (bleomycin / vehicle) vs. Group 6 (bleomycin / LYT-100)). Nintedanib-treated rats tended to have lower lung weight ratios (Group 5 vs. Group 7), but these lung ratios were still higher than those of untreated rats (Group 7 vs. Group 4).

[0337] Hydroxyproline content of lungs was measured for all groups (Figure 36A, Figure 36B, Figure 37, Figure 38A, Figure 38B, Figure 39). Referring to Figure 36A, Figure 36B, Figure 37, Figure 38A, Figure 38B, and Figure 39, total hydroxyproline (μg per left lung) in the left lung was higher in bleomycin-treated rats (Group 4 (Saline) vs. Group 5 (Bleomycin)). LYT-100 treatment did not affect total hydroxyproline levels in bleomycin-treated rats (Group 5 (Bleomycin / Vehicle) vs. Group 6 (Bleomycin / LYT-100)). Lungs from animals treated with nintedanib had lower levels of total hydroxyproline (Group 7 vs. Group 5) but higher than untreated rats (Group 7 vs. Group 4). Hydroxyproline content (μg per mg of wet lung) was higher in bleomycin-treated rats (Group 4 (Saline) vs. Group 5 (Bleomycin)). LYT-100 treatment reduced hydroxyproline content in bleomycin-treated rats (Group 5 (Bleomycin / Vehicle) vs. Group 6 (Bleomycin / LYT-100)). Nintedanib treatment also reduced hydroxyproline content (Group 7 vs. Group 5).

[0338] Histopathological studies were performed to assess the degree of lung fibrosis (Figures 40A-D and 41). The mean and median fibrosis scores were increased in bleomycin-treated rats (Group 4 (Saline) vs. Group 5 (Bleomycin)). Treatment with LYT-100 or nintedanib did not affect the fibrosis scores (Group 5 (Bleomycin / Vehicle) vs. Group 6 (Bleomycin / LYT-100) or Group 7 (Bleomycin / Nintedanib)). Treatment with LYT-100 and nintedanib reduced the median fibrosis scores (Groups 6 and 7 vs. Group 5). The majority of fibrosis scores in group 5 (bleomycin / vehicle) were distributed around scores of 2 (39% of lung sections) and 3 (32% of lung sections). With LYT-100 and nintedanib treatment (groups 6 and 7, respectively), the distribution of lung section fibrosis scores shifted towards scores of 1 (33% and 37%, respectively) and 2 (36% and 33%, respectively).

[0339] Overall, phase 2 was performed according to protocol, with no deviations deemed to affect the integrity of the results of this phase of the study. As in phase 1, LYT-100 administered QD at 400 mg / kg from day 8 through day 27 (including day 27) was well tolerated in all animals, and any side effects observed resolved within approximately 5 hours after they were noted and did not reoccur until a subsequent dosing session. Nintedanib administered at 60 mg / kg twice daily (BID) was used as a reference. In contrast to nintedanib, LYT-100 did not adversely affect body weight progression. LYT-100 reduced lung hydroxyproline content, suggesting a reduced presence of connective tissue in the lungs. Consistent with the latter, median fibrosis scores were also reduced in the lungs of LYT-100-treated rats compared to vehicle controls.

[0340] Example 12: Exploring the efficacy of LYT-100 in treating myocardial fibrosis and heart failure Patients with heart failure (HF) and evidence of myocardial fibrosis will be randomized to receive LYT-100 or placebo for a fixed period of time.

[0341] Selection criteria may include one or more of the following: HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction, HF with intermediate ejection fraction, elevated levels of natriuretic peptides, increased left ventricular end-diastolic diameter, systolic dyssynchrony, and elevated filling pressures. The degree of myocardial fibrosis may be measured using one or more of cardiovascular magnetic resonance, myocardial extracellular volume, and load-independent intrinsic left ventricular myocardial stiffness.

[0342] Evaluation endpoints may include one or more of the following: reduction in myocardial extracellular volume (ECV), improvement in the 6-minute walk test (6MWT); improved KCCQ score (0-100); improved KCCQ clinical summary score (0-100); improved KCCQ total symptom score (0-100); improved left ventricular EDVi, ml m -2 Improved left ventricular ESVi, ml m -2;Improved left ventricular EF, %;Improved left ventricular mass index, gm -2 ;Improved Native T1, ms;Improved Absolute Myocardial ECM Volume, ml;Improved Absolute Myocardial Cell Volume, ml;Improved E / A Ratio;Improved Lateral e', cm s -1 ;septum e', cm s -1 , Improved average E / e', cm s -1 Improved GLS, % Improved PCr:ATP ratio (BCPSC) Improved right ventricular EDVi, ml m -2 ;Improved right ventricular EF (%);Improved right ventricular PAP, mm Hg;Improved left atrial volume, ml;Improved left atrial volume index, ml m -2 ;Improved Left Atrial Strain (Reservoir), %;Improved Left Atrial Strain (Booster), %;Improved Left Atrial Strain (Conduit), %.

Claims

1. 1. A method for treating a fibrosis-mediated pulmonary disease or disorder, comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 1】 at a total daily dose of about 825 mg to about 2475 mg of deuterium-enriched pirfenidone having the formula:

2. 2. The method of claim 1, wherein the total daily dose is 1650 mg.

3. 2. The method of claim 1, wherein the total daily dose is 2475 mg.

4. The method of any one of claims 1 to 3, wherein the total daily dose is administered in three equal doses.

5. 13. The method of claim 1, wherein the total daily dose is administered in three equal doses of 825 mg each (825 mg TID).

6. 10. The method of claim 1, wherein the total daily dose is administered in three equal doses of 550 mg each (550 mg TID).

7. The method of any one of claims 1 to 6, wherein the LYT-100 is administered without regard to food.

8. The method of any one of claims 1 to 6, wherein the LYT-100 is administered without food.

9. The method of any one of claims 1 to 6, wherein the LYT-100 is administered with food.

10. The method of any one of claims 1 to 9, wherein the LYT-100 is administered without dose escalation.

11. 10. The method of any one of claims 1-9, wherein said administering comprises titrating from an initial total daily dose that is less than said total daily dose to said total daily dose.

12. 6. The method of claim 5, wherein said administering comprises titrating from an initial total daily dose less than said total daily dose to said total daily dose, and said titrating comprises administering said LYT-100 in three daily doses of 550 mg each for three days, followed by administering said LYT-100 in three daily doses of 825 mg each.

13. The method of any one of claims 1 to 12, wherein the fibrosis-mediated pulmonary disease or disorder is an interstitial lung disease (ILD).

14. 14. The method of claim 13, wherein the ILD is exposure-related ILD, drug-induced ILD, autoimmune interstitial lung disease, unclassifiable interstitial lung disease (uILD), progressive fibrosing interstitial lung disease (pfILD), respiratory bronchiolitis ILD (RB-ILD), connective tissue disease-associated ILD (CTD-ILD), rheumatoid arthritis (RA-ILD), systemic sclerosis (SSc-ILD), mixed connective tissue disease ILD, scleroderma-associated ILD, or ILD associated with chronic sarcoidosis.

15. The method of claim 13 or 14, wherein the ILD is progressive fibrosing ILD (PF-ILD).

16. The method of any one of claims 1 to 15, wherein the fibrosis-mediated or collagen-mediated disease or disorder is alleviated.

17. The method of any one of claims 1 to 16, wherein the progression of the fibrosis-mediated or collagen-mediated disease or disorder is delayed, slowed or prevented.

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