Deupirfenidone for use for treating idiopathic pulmonary fibrosis

Abstract

Disclosed herein are methods of stabilizing or improving lung function in subjects with idiopathic pulmonary fibrosis by orally administering a daily amount of between 1600 mg and 2500 mg deupirfenidone. Also disclosed are methods of dose escalation for initial titration, methods of reducing the incidence of emerging adverse events, and methods of directly transitioning patients from other drugs to deupirfenidone without titration.

Description

LYT100-IPF-2-WOMETHODS OF TREATING IDIOPATHIC PULMONARY FIBROSIS WITH DEUPIRFENIDONETECHNICAL FIELD

[0001] The present disclosure is directed to methods for treating Idiopathic Pulmonary Fibrosis (IPF) with the anti-fibrotic agent LYT-100.BACKGROUND

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and ultimately fatal lung disease characterized by the scarring and thickening of lung tissue resulting in the irreversible loss of lung function. The clinical presentation of IPF may be gradual, with symptoms developing over months to years. The most common initial symptom is exertional dyspnea, which progressively worsens over time. A persistent dry cough is also frequently reported. On physical examination, fine, bibasilar “velcro-like” crackles can be heard during inspiration. As the disease advances, patients may develop other respiratory, cardiovascular, gastrointestinal, and / or neurologic symptoms. Whatever the trajectory, IPF results in mortality.

[0003] The cause of IPF is unknown and there are no curative treatments for IPF. Management of IPF focuses on slowing disease progression, alleviating symptoms, and improving the patient’s quality of life. Raghu et al. 2018 Am J Respir Crit Care Med, 198(5):44— 68; Raghu et al. 2022 Am J Respir Crit Care Med, 205(9): 18-47.

[0004] Other FDA-approved antifibrotic agents (nintedanib, pirfenidone, nerandomilast) have been shown to reduce the rate of FVC decline, a key indicator of disease progression and surrogate for survival. Maher et al. 2023 Respirology, 28(12), 1147-1153; Man et al. 2024 Cureus, 16(2). However, none of these drugs halts disease worsening or results in stabilization of lung function decline. Their limited efficacy, combined with tolerability challenges, contributes to low treatment uptake, frequent discontinuation of treatment, and impaired quality of life. As a result, IPF remains an invariably progressive and fatal disease with a significant unmet medical need for treatments that can improve patient outcomes by improving treatment efficacy without compromising tolerability. Fisher et al. 201723(3-1) Suppl): 17-24).BRIEF SUMMARY

[0005] Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-5 years after diagnosis. Nathan et al. 2011 Chest, 140, 221-229. Pirfenidone is indicated for the treatment of Idiopathic pulmonary fibrosis (IPF) at a maximum daily dose of 2403 mg in theLYT100-IPF-2-WOUinted States and a maximum daily dose of 1800 mg in certain ex-US countries (e.g., Japan, China, South Korea). Studies have indicated that the efficacy of pirfenidone is dose-dependent. King et al. 2014 N. Engl. J. Med., 370, 2083-2092. Other studies have indicated that longer duration of pirfenidone treatment provides improved therapeutic outcomes (a slower lung function decline). Kang et al. 2014 Front. Pharmacol., 15, 1451447. However, maintaining the maximal dose of pirfenidone is difficult, particularly over longer durations, due to the related adverse events, which are reported to occur in about 73% of patients on longer-term treatment and are considered to be dose-limiting. Cottin et al. ERJ Open Res. 4 doi:10.1183 / 23120541.00084-2018. In fact, in real-world practice, the percentage of patients maintaining the maximal dose of pirfenidone is less than 50%. Ogura et al. 2015 Respir. Investig. 53, 232-241.

[0006] Accordingly, the unmet medical needs for patients living with IPF include dose-limiting adverse events and toxicity associated with gastrointestinal intolerability (e.g., nausea, vomiting, diarrhea, dyspepsia, anorexia, and other GI events), dizziness, fatigue, rash and photosensitivity rash, as well as other adverse side effects, which limits current treatment tor IPF (Noble, 2016). Management of these adverse events includes dose reductions and discontinuations of pirfenidone, associated with a lost opportunity for the full clinical benefits achieved when full dose pirfenidone is maintained for longer treatment duration, and also limits the maximum dose that can be safely administered due to the observed tolerability and toxicity issues.

[0007] The present disclosure addresses the above needs and provides methods for treatment of Idiopathic Pulmonary Fibrosis (IPF) with the antifibrotic agent LYT-100 (deupirfenidone, 5-(methyl-d3)-I-phenylpyridin-2-(127)-one, CAS# 1093951-85-9). LYT-100 has the following structure:(LYT-100)LYT-100 is a selectively deuterated form of pirfenidone, which is referred to herein (interchangeably) as deupirfenidone.

[0008] Example 1 describes a clinical study in patients with IPF (ELEVATE IPF study). ELEVATE IPF was a Phase 2b trial that studied the safety, tolerability, and effectiveness of two doses of LYT-100 (550 mg and 825 mg, each three times daily (TID)) compared with placeboLYT100-IPF-2-WOand pirfenidone (801 mg TID) in patients with IPF. The results of that study are summarized here. With reference to Example 1, the study demonstrated that in the LYT- 100550 mg and 825 mg pooled arms, lung function decline was reduced compared to placebo as measured by Forced Vital Capacity (FVC) with a posterior probability value vs. placebo of 98.5%. Specifically, the posterior mean change in FVC for placebo was -110.7 ml (95% credible interval (CI), -148.75, -70.98) and for the combined deupirfenidone arms was -48.42 ml (95% CI, -87.66, -9.04) with a posterior mean difference of 62.29 ml (95% CI, -6.13, 115.73; posterior probability 0.985). Further, the pooled deupirfenidone dose arms demonstrated a similar high posterior probability of superiority (99.7%) on change in Forced Vital Capacity percent predicted (FVCpp) from baseline to week 26 compared with placebo. Specifically, the results showed an adjusted mean change in FVCpp for the placebo arm of -3.27 and for the combined deupirfenidone arms of -1.1, with an adjusted mean difference for FVCpp of 2.17 (95% CI, 0.57, 3.85).

[0009] Importantly, the rate of decline in lung function was significantly less for LYT- 100 825 mg TID compared with placebo at 26 weeks. Using a frequentist approach, the adjusted mean change in FVC for the placebo arm was -112.5 ml (95% CI, -167.2, -57.8) and forthe LYT-100 825 mg TID arm was -21.5 ml (95% CI, -78.2, 35.1) with an adjusted mean difference of of 91.0 ml (95% CI, 12.2, 169.7; p= 0.02). A similar analysis using rate of change of FVCpp also demonstrated a statistically significant decrease in the rate of lung decline in patients treated with 825 mg TID LYT-100 as compared with placebo. Specifically, the results showed an adjusted mean change in FVCpp forthe placebo arm of -3.43 (95% CI, -5.08, -1.77) and forthe LYT-100 825 mg TID arm of -0.43 (95% CI, -2.14, 1.29), with an adjusted mean difference for FVCpp of 3.00 (95% CI, 0.62, 5.38; p = 0.01), reinforcing the robustness of the LYT-100 825 mg TID treatment's impact. In fact, the rate of decline in lung function achieved with LYT-100 825 mg TID at 26 weeks was similar to the natural decline in lung function observed in healthy older adults for the same period of time. The natural decline in lung function in healthy older adults is about -30 to -50 ml as measured by FVC. Luoto et al., 2019 Eur Respir J 53(3): 1701812. The ELEVATE IPF study demonstrated that treatment with LYT-100 825 mg TID at 26 weeks resulted in a lung function decline of -21.5 ml as measured by FVC. This result was confirmed by ELEVATE Phase 2b open label extension data which showed an absolute FVC of -32.8 ml over 52 weeks in patients treated with LYT-100 825 mg TID.

[0010] In addition, LYT-100 825 mg TID also outperformed pirfenidone 801 mg TID in reducing lung function decline as measured from baseline FVC by frequentist analysis. The adjusted mean change in FVC forthe pirfenidone arm (801 mg TID) was -51.6 mL (95% CI, -108.8, 5.6) and forthe placebo arm was -112.5 mL (95% CI, -167.2, -57.8). When compared toLYT100-IPF-2-WOthe placebo arm, the adjusted mean difference for the pirfenidone 801 mg TID arm was 60.9 mL (95% CI, -18.3, 140.0; p = 0.13). In comparison, the adjusted mean change in FVC for the LYT-100825 mg TID arm was -21.5 ml (95% CI, -78.2, 35.1) with an adjusted mean difference from placebo of 91.0 ml (95% CI, 12.2, 169.7; p= 0.02). An analysis using rate of change of FVCpp demonstrated an adjusted mean change for the placebo arm of -3.43 (95% CI -5.08, -1.77) and for pirfenidone 801 mg TID of -1.46 (95% CI -3.19, 0.28). When compared to the placebo arm, the adjusted mean difference for the pirfenidone 801 mg arm was 1.97 (95% CI -0.42, 4.37; p = 0.11, relative improvement compared with placebo of 57%). In comparison, the rate of change of FVCpp demonstrated an adjusted mean change for the LYT-100 825 mg TID of -0.43 (95% CI -2.14, 1.29). When compared to the placebo arm, the adjusted mean difference for FVCpp for the LYT-100 825 mg arm was 3.00 (95% CI 0.62, 5.38; p = 0.01). In this study, neither the 801 mg TID pirfenidone dose nor the 550 mg TID dose demonstrated statistical significance in change from baseline for FVC or FVCpp versus placebo; however, treatment benefit was observed and efficacy in the 550 mg TID dose was shown to be comparable to that of 801 mg pirfenidone, the current standard of care. Specifically, LYT-100 550 mg TID provided efficacy (FVC) within one standard error of that of 801 mg TID pirfenidone. At this lower dose, patients who cannot tolerate the side effects associated with pirfenidone can still be effectively treated. Using a frequentist approach, LYT-100 550 mg TID had an adjusted mean change in absolute FVC of -80.7 mL (95% CI, -138.3, -23.1) as compared with the 825 mg TID arm of -21.5 mL (95% CI, -78.2, 35.1). Similarly, LYT-100550 mg TID had an adjusted mean change in FVCpp of -1.81 (95% CI, -3.55, -0.07) compared with 825 mg TID of -0.43 (95% CI -2.14, 1.29). These results demonstrate a dose response with LYT-100.

[0011] Both doses of LYT-100 were generally well-tolerated in the trial. The 825 mg TID dose of LYT-100 met the success criteria of less than 25% difference in AEs vs. pirfenidone (i.e., a similar tolerability profile), and the 550 mg TID dose of LYT-100 also met the success criteria of >25% reduction in AEs vs. pirfenidone. Adverse events during the treatment period from first dose through 28 days after last dose of study drug are summarized in Table 9.

[0012] Pirfenidone is known to be associated with gastrointestinal, neurologic, and cutaneous effects. As expected, adverse events in these three organ-systems were higher in the three active treatment arms compared to placebo. Specifically, gastrointestinal, neurologic, and cutaneous events were more common in the pirfenidone 801 mg and deupirfenidone 825 mg treatment arms than in placebo. The incidence of these adverse events in the deupirfenidone 550 mg arm was intermediate between placebo and the other two treatment arms. Events were generally mild to moderate in severity, were reversible, and without clinically significant sequelae.LYT100-IPF-2-WO

[0013] Gastrointestinal adverse events were the most common treatment-emergent adverse events (TEAE) reported in 16 patients (24.6%) in the placebo arm, 33 patients (52.4%) in the pirfenidone arm, 23 patients (35.4%) in the deupirfenidone 550 mg arm, and 34 patients (53.1%) in the deupirfenidone 825 mg arm, and the most common TEAE, nausea, occurred in 5 (7.7%), 17 (27.0%), 11 (16.9%) and 13 (20.3%) of patients, respectively. Liver enzyme abnormalities >5 x ULN (the threshold for permanent study drug discontinuation) were reported in one patient on placebo, one on deupirfenidone 550 mg and two on deupirfenidone 825 mg arms. The cutaneous TEAEs of photosensitivity and rash were similar for pirfenidone and deupirfenidone 825 mg. Photosensitivity was experienced by five patients each on pirfenidone (7.9%) and deupirfenidone 825 mg (7.8%). Cough, dyspnea, and worsening of IPF generally occurred more frequently with placebo.

[0014] Grade 3 or higher TEAEs were uncommon. Nine patients (13.8%) experienced at least one grade 3 or higher TEAE on placebo, ten patients (15.9%) on pirfenidone, 13 patients (20.0%) on deupirfenidone 550 mg, and eight patients (12.5%) on deupirfenidone 825 mg arms. The number (%) of patients with at least one treatment emergent-serious AE that was judged related to study drug was two (3.1%) for placebo (cholangitis, gastroenteritis), one (1.6%) for pirfenidone (vomiting and decreased oxygen saturation), zero for deupirfenidone 550 mg, and one (1.6%) for deupirfenidone 825 mg (nausea), respectively. All-cause mortality during the treatment period was lower in both deupirfenidone arms (one patient (1.6%) in the 825 mg arm and one patient (1.6%) in the 550 mg arm) compared to pirfenidone (five patients; 7.9%) and placebo (two patients; 3.2%). No deaths were considered by investigators to be related to study drug.

[0015] TEAEs that led to any dose modifications (temporary and permanent dose reductions, temporary dose interruptions, and permanent study drug discontinuations) occurred in 20 patients (30.8%) on placebo, 24 patients (38.1%) on pirfenidone 801 mg, 27 patients (41.5%) on deupirfenidone 550 mg, and 30 patients (46.9%) on deupirfenidone 825 mg. TEAES that led to treatment discontinuation occurred in eight patients (12.3%) on placebo, 11 patients (17.5%) on pirfenidone 801 mg, 16 patients (24.6%) on deupirfenidone 550 mg, and 12 patients (18.8%) on deupirfenidone 825 mg. The most common TEAEs leading to discontinuation (more than one patient by preferred term) for each treatment arm were IPF exacerbation for placebo, nausea, fatigue, headache, and pneumonia for pirfenidone, nausea, diarrhea, dyspepsia, fatigue, asthenia, IPF, and decreased appetite for deupirfenidone 550 mg, and nausea for deupirfenidone 825 mg arms, respectively.

[0016] ELEVATE-IPF demonstrated that deupirfenidone significantly slows FVC decline at 26LYT100-IPF-2-WOweeks compared with placebo. Importantly, deupirfenidone 825mg TID demonstrated a numerically superior benefit over both deupirfenidone 550 mg TID and pirfenidone 801 mg TID. Targeted deuteration has the potential to advantageously alter the pharmacokinetic properties of a drug. Deupirfenidone 550 mg TID results in plasma exposure (AUC) that is relatively lower than pirfenidone 801 mg TID, while deupirfenidone 825 mg TID provides a 50% higher dose (50% higher drug exposure), which was included in the study to determine the impact of higher exposure on efficacy and tolerability. Of the three active treatment arms, deupirfenidone 825 mg TID demonstrated the largest treatment effect compared with placebo, slowing FVC decline over 26 weeks to a level consistent with the normal physiological loss of FVC observed with aging, e.g., about -30 to -50 ml as measured by FVC (treatment with LYT-100 825 mg TID for 26 to 52 weeks resulted in a lung function decline of -21.5 ml to 32.8 ml as measured by FVC). Also, treatment with the LYT-100 825 mg TID dose resulted in a significantly longer time to IPF progression as compared to placebo (measured by >5% decline in FVCpp over 26 weeks or death; HR 0.439, 95% CI, 0.255, 0.756, p= 0.0023) and further had the greatest percentage of IPF patients with no lung function decline.

[0017] Deupirfenidone was demonstrated to be safe and generally well tolerated at both the 825 mg TID daily dosage and at the 550 mg TID daily dosage, and the safety and tolerability profile of deupirfenidone (at both doses) was consistent with that seen with pirfenidone. Indeed, the incidence of treatment emergent adverse events (TEAEs) for deupirfenidone 825 mg TID were similar to 801 mg TID pirfenidone (85.9% v. 84.1%), despite a 72 mg / day higher dose and resulting 50% higher exposure. The reported adverse events were generally mild to moderate in severity, reversible, and without clinically significant sequelae. The percentage of patients who remained on deupirfenidone 825 mg TID for 26 weeks (78.1%) was similar to the percent of patients remaining on placebo (80.0%). These data suggest that the 50% higher exposure and improved efficacy seen with deupirfenidone 825 mg TID was achieved without sacrificing tolerability.

[0018] In one aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF), the method comprising:administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),LYT100-IPF-2-WOwherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, and wherein lung function is stabilized in the patient for at least 26 weeks.

[0019] In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mb from baseline or initiation of treatment.

[0020] In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 40 mL from baseline or initiation of treatment.

[0021] In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 30 mL from baseline or initiation of treatment.

[0022] In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 5% from baseline or initiation of treatment.

[0023] In some embodiments, the subject is 75 years of age or older.

[0024] In some embodiments, the subject was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0025] In one aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF), the method comprising:administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, and wherein lung function is stabilized in the patient for at least 52 weeks.

[0026] In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment.

[0027] In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 40 mL from baseline or initiation of treatment.LYT100-IPF-2-WO

[0028] In some embodiments, the lung function stabilization is determined by a decline in Forced Vital Capacity percent predicted (FVCpp) of < 10% from baseline or initiation of treatment.

[0029] In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0030] In another aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject 75 years of age or older, the method comprising:administering to the subject a total daily dose between 1600 mg and 2500 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations and wherein the subject exhibits a smaller decline in lung function after a treatment period compared to an untreated subject.

[0031] In some embodiments, the decline in lung function is stabilized in the subject 75 years of age or older for at least 26 weeks. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mb from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 40 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 30 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 5% from baseline or initiation of treatment.

[0032] In some embodiments, the decline in lung function is stabilized in the subject 75 years of age or older for at least 52 weeks. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 40 mL from baseline or initiation of treatment. In some embodiments,LYT100-IPF-2-WOthe lung function stabilization is determined by a decline in FVCpp of < 10% from baseline or initiation of treatment).

[0033] In some embodiments, the subject 75 years of age or older is administered a daily dose of about 2500 mg deupirfenidone. In some embodiments, the subject is administered a daily dose of 2475 mg deupirfenidone. In some embodiments, the subject is administered 825 mg TID. In some emboiments, the subject is administered a daily dose of about 1600 mg deupirfenidone. In some embodiments, the subject is administered a daily dose of 1650 mg deupirfenidone. In some embodiment, the subject is administered 550 mg TID deupirfenidone.

[0034] In some embodiments, the subject 75 years of age or older was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0035] In another aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject 75 years of age or older, the method comprising:administering to the subject a total daily dose between 1600 mg and 2500 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations and wherein the subject exhibits a a longer time to IPF progression after a treatment period compared to an untreated subject.

[0036] In some embodiments, the IPF progression in the subject 75 years of age or older is measured as a decline in FVC more than -30 ml from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVC more than -50 ml from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVCpp > 5% from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVCpp > 10% from baseline or treatment initiation. In some embodiments, the subject is treated for at least 26 weeks. In some embodiments, the subject is treated at least 52 weeks.

[0037] In some embodiments, the subject 75 years of age or older is administered a daily dose of about 2500 mg deupirfenidone. In some embodiments, the subject is administered a dailyLYT100-IPF-2-WOdose of 2475 mg deupirfenidone. In some embodiments, the subject is administered 825 mg TID. In some emboiments, the subject is administered daily dose of about 1600 mg deupirefenidone. In some embodiments, the subject is administered a daily dose of 1650 mg deupirfenidone. In some embodiment, the subject is administered 550 mg TID deupirfenidone.

[0038] In some embodiments, the subject 75 years of age or older was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0039] In yet another aspect is provided a dose escalation regimen method for providing deupirfenidone therapy to a subject in need thereof, the method comprising:providing deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at a third oral daily dosage of 2475 mg for at least day fifteen of the dose escalation regimen,wherein the subject is provided deupirfenidone therapy for the treatment of idiopathic pulmonary fibrosis.

[0040] In some embodiments, the dose escalation regimen method comprises:providing deupirfenidone to the subject at the first oral daily dosage of 825 mg as one tablet comprising 275 mg of deupirfenidone three times a day for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at the second oral daily dosage of 1650 mg as two tablets comprising 275 mg of deupirfenidone three times a day for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at the third oral daily dosage of 2475 mg as three tablets comprising 275 mg of deupirfenidone three times a day for at least day fifteen of the dose escalation regimen.

[0041] In a further aspect is provided a starter pack for use in an initial dose escalation regimen which provides deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the initial dose escalation regimen; provides deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the initial dose escalation regimen; and provides deupirfenidone to the subject a third oral daily dosage of 2475 mg for at least dayLYT100-IPF-2-WOfifteen of the dose escalation regimen, the starter pack comprising a plurality of compartments for containing a dosage amount of deupirfenidone arranged within rows and columns, wherein the starter pack comprises separate rows for Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 with three separate columns for three dosage amounts to be taken each day; and wherein each of the three compartments for Days 1, 2, 3, 4, 5, 6, and 7 separately contain one pill of 275 mg deupirfenidone and each of the three compartments for Days 8, 9, 10, 11, 12, 13, and 14 separately contain two pills of 275 mg deupirfenidone; and wherein the starter pack optionally further comprises at least one additional set of compartments for Days 15, 16, 17, 18, 19, 20 and 21 in separate rows and each compartment in the additional set of compartments separately contain three pills of 275 mg deupirfenidone.

[0042] In a further aspect is provided a method for reducing the incidence of adverse events in a subject receiving oral deupirfenidone therapy for the treatment of a fibrotic disease or disorder, the method comprising a dose adjustment regimen comprising:administering deupirfenidone to the subject at an oral daily dosage of 2475 mg for a first period of time; andsubsequently administering deupirfenidone to the subject at an oral daily dosage of 1650 mg deupirfenidone for a second period of time.

[0043] In some embodiments, the oral daily dosage of 1650 mg deupirfenidone is administered as three equal daily doses of 550 mg each.

[0044] In some embodiments, the oral daily dosage of 1650 mg deupirfenidone is administered as two equal daily doses of 825 mg each.

[0045] In some embodiments, the method further comprises, after the second period of time, administering deupirfenidone to the subject as a 2475 mg total daily dose.

[0046] In some embodiments, the 2475 mg total daily dose is administered as three equal daily doses of 825 mg each.

[0047] In a still further aspect is provided a method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration thereof for a period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprising administering to said subject deupirfenidone at a total daily dose of 1650 mg, administered as two daily administration of 825 mg each.

[0048] In another aspect is provided a method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration of deupirfenidone for a period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprisingLYT100-IPF-2-WOadministering deupirfenidone at a total daily dose of 1650 mg, administered as three daily doses of 550 mg each.

[0049] In some embodiments, the intolerance is one or more of nausea, vomiting, abdominal pain or distension, dyspepsia, diarrhea, decreased appetite, constipation, headache, dizziness, somnolence, fatigue, skin rash, photosensitivity, increased AST, increased ALT, increased GGT, and liver toxicity.

[0050] In some embodiments, the subject has not received prior treatment for IPF.

[0051] In some embodiments, the subject has received prior treatment for IPF with nintedanib.

[0052] In some embodiments, the subject has received prior treatment for IPF with pirfenidone.

[0053] In some embodiments, the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

[0054] In some embodiments, the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

[0055] In some embodiments, the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.

[0056] In a further aspect is provided a method of transitioning from pirfenidone to deupirfenidone for a subject with IPF, the method comprising:a) discontinuing a daily amount of pirfenidone; andb) administering an initial daily amount of deupirfenidone the next day to the subject, wherein the daily amount of pirfenidone in a) is 801 mg and the initial total daily amount of deupirfenidone is 825 mg; orwherein the daily amount of pirfenidone in a) is 1602 mg and the initial total daily amount of deupirfenidone is 1650 mg; orwherein the daily amount of pirfenidone in a) is 2403 mg and the initial total daily amount of deupirfenidone is 2475 mg.

[0057] In a yet further aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a patient population, the method comprising administering to said patients in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, wherein the IPF is treated in the patient population, andLYT100-IPF-2-WOwherein a rate of treatment discontinuation in the patient population is less than about 20% over 52 weeks.

[0058] In some embodiments, the rate of treatment discontinuation in the patient population is less than about 12%.

[0059] In some embodiments, the subject has not received prior treatment for IPF.

[0060] In some embodiments, the subject has received prior treatment for IPF with nintedanib.

[0061] In some embodiments, the subject has received prior treatment for IPF with pirfenidone.

[0062] In some embodiments, the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

[0063] In some embodiments, the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

[0064] In some embodiments, the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIG. 1 is a high-level graphical illustration of the IPF clinical trial study design of Example 1 according to a non-limiting embodiment of the disclosure.

[0066] FIG. 2 is a graphical illustration of the double-blind portion of the IPF clinical trial study of Example 1 according to a non-limiting embodiment of the disclosure.

[0067] FIG. 3 is a graphical illustration of the open label portion of a the IPF clinical trial study of Example 1 according to a non-limiting embodiment of the disclosure.

[0068] FIG. 4 is an example of a patient reported assessment of IPF symptoms survey according to a non-limiting embodiment of the disclosure.

[0069] FIG. 5 is an example of a patient reported assessment of side effect survey according to a non-limiting embodiment of the disclosure.

[0070] FIG. 6 is an example of a patient reported satisfaction survey according to a non-limiting embodiment of the disclosure.

[0071] FIG. 7 is a graphical depiction of subject disposition in the IPF clinical trial study of Example 1.

[0072] FIG.8 is a graphical depiction providing the summary of change from baseline in Forced Vital Capacity (FVC) over 26 weeks by Bayesian analysis for placebo, pirfenidone and pooled doses of LYT-100 in the IPF clinical trial study of Example 1.LYT100-IPF-2-WO

[0073] FIG.9A is a graphical depiction providing the summary of change from baseline in FVC over 26 weeks by Bayesian analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0074] FIG.9B is a graphical depiction providing the summary of change from baseline in FVC over 26 weeks by Frequentist analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0075] FIG.9C is a graphical depiction providing the summary of change from baseline in FVC and FCVpp over 26 weeks for pirfenidone, 550 mg TID LYT-100, and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0076] FIG. 10A is a graphical depiction providing the summary of change from baseline in Forced Vital Capacity percent predicted (FVCpp) over 26 weeks by Bayesian analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0077] FIG. 10B is a graphical depiction providing the summary of change from baseline in FVCpp over 26 weeks by Frequentist analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0078] FIG. 11A is a graphical depiction providing the summary of change from baseline in FVC over 26 weeks by Bayesian analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0079] FIG. 11B is a graphical depiction providing the summary of change from baseline in FVCpp over 26 weeks by Frequentist analysis for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0080] FIG. 12 is a graphical depiction illustrating the FVC decline over 26 weeks for placebo, average healthy adults over 60 years of age, and for 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0081] FIG. 13 is a graphical depiction showing the proportion of patients showing progression-free IPF overtime for placebo, pirfenidone and 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.

[0082] FIG. 14 is a graphical depiction showing the percentage of participants with a change from baseline greater than or equal to zero at week 26 for placebo, pirfenidone, 550 mg TID LYT-100, 825 mg TID LYT-100, and pooled LYT-100 doses in the IPF clinical trial study of Example 1.

[0083] FIG. 15 is a graphical depiction showing percentage of participants with dose modification or discontinuation over 26 weeks in the IPF clinical trial study of Example 1.LYT100-IPF-2-WO

[0084] FIG. 16 is a graphical depiction of mean change in FVC over time for Part A and Part B in the IPF clinical trial study of Example 1. In Part B, participants on placebo and on pirfenidone were switched to 825 mg TID LYT-100.

[0085] FIG. 17A is a graphical depiction of change from baseline in FVC over 26 weeks for 825 mg TID LYT-100 versus placebo, categorized by subgroup, in the IPF clinical trial study of Example 1.

[0086] FIG. 17B is a graphical depiction of change from baseline in FVC over 26 weeks for 550 mg TID LYT-100 versus placebo, categorized by subgroup, in the IPF clinical trial study of Example 1.

[0087] FIG. 18A is a graphical depiction of change from baseline in FVC over 26 weeks by Frequentist analysis for placebo, pirfenidone, 550 mg TID LYT-100, and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1, specifically in regions excluding Europe and South Africa.

[0088] FIG. 18B is a graphical depiction of change from baseline in FVC%pp over 26 weeks by Frequentist analysis for placebo, pirfenidone, 550 mg TID LYT-100, and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1, specifically in regions excluding Europe and South Africa.

[0089] FIG. 19 is a graphical depiction providing the change from baseline in FVC over 52 weeks by Bayesian analysis for 825 mg TID LYT-100 in the IPF clinical trial study of Example 1, compared with the natural expected lung function decline in healthy older adults and in IPF patients based on historical data.

[0090] FIG. 20A is a graphical depiction of gastrointestinal (GI) adverse events (AEs) versus trough concentration of deupirfenidone or pirfenidone for all subjects at week four of the IPF clinical trial study of Example 1.

[0091] FIG. 20B is a graphical depiction of GI AEs versus trough concentration of deupirfenidone or pirfenidone for subjects with less than 95% adherence at week four of the IPF clinical trial study of Example 1.

[0092] FIG. 21A is a graphical depiction of GI AEs versus trough concentration of deupirfenidone or pirfenidone for all subjects at week twelve of the IPF clinical trial study of Example 1.

[0093] FIG. 21B is a graphical depiction of GI AEs versus trough concentration of deupirfenidone or pirfenidone for subjects with less than 95% adherence at week twelve of the IPF clinical trial study of Example 1.LYT100-IPF-2-WO

[0094] FIG. 22A is a graphical depiction of related AEs versus trough concentration of deupirfenidone or pirfenidone for all subjects at week twelve of the IPF clinical trial study of Example 1.

[0095] FIG. 22B is a graphical depiction of related AEs versus trough concentration of deupirfenidone or pirfenidone for subjects with less than 95% adherence at week twelve of the IPF clinical trial study of Example 1.

[0096] FIG. 23 is a graphical depiction of adjusted mean change from baseline over time of Forced Vital Capacity up to 52 weeks in the IPF clinical trial study of Example 1.

[0097] FIG. 24 is a graphical depiction of adjusted mean change from baseline over time of Forced Vital Capacity from week 26 to week 52 for subjects switching from placebo or pirfenidone to deupirfenidone 825 mg TID in the open-label portion of the IPF clinical trial study of Example 1.

[0098] FIG. 25 is a graphical depiction of adjusted mean change from baseline over time of Forced Vital Capacity from week 26 to week 52 for subjects switching from placebo to deupirfenidone 550 mg TID or 825 mg TID in the open-label portion of the IPF clinical trial study of Example 1.

[0099] FIG. 26 is a graphical depiction of adjusted mean change from baseline over time of Forced Vital Capacity from week 26 to week 52 for subjects switching from prifenidone to deupirfenidone 550 mg TID or 825 mg TID in the open-label portion of the IPF clinical trial study of Example 1.

[0100] FIG. 27 is a graphical depiction showing the proportion of patients showing IPF progression over time for 550 mg TID LYT-100 and 825 mg TID LYT-100 in the IPF clinical trial study of Example 1.DETAILED DESCRIPTION

[0101] Disclosed herein is a method stabilizing lung function in a patient suffering from Idiopathic Pulmonary Fibrosis (IPF) with LYT-100 (deupirfenidone) treatment. As exemplified below, the decline in FVC experienced by participants on deupirfenidone 825 mg TID over 6 months was in the range of the decline observed in healthy older adults without the disease. Also disclosed herein is a method treating a patient aged 75 years or older suffering from Idiopathic Pulmonary Fibrosis (IPF) with LYT-100 (deupirfenidone).

[0102] Moreover, deupirfenidone is demonstrated in the below example to be safe and generally well tolerated at both the 825 TID daily dosage and at the 550 TID daily dosage. Indeed, the treatment emergent adverse events (TEAEs) for deupirfenidone 825 mg TID are similar to 801LYT100-IPF-2-WOmg TID pirfenidone (85.9% v. 84.1%), despite a 72 mg / day higher dose and resulting 50% higher exposure.

[0103] Deupirfenidone 550 mg TID TEAEs were much lower than for 825 mg TID deupirfenidone and pirfenidone and were comparable to placebo (72.3% v. 73.8%). At this lower dose, patients who cannot tolerate the side effects associated with pirfenidone can still be effectively treated.Definitions

[0104] While the terms used herein are believed to be well understood by one of ordinary skill in the art, definitions are set forth herein to facilitate explanation of the presently disclosed subject matter.

[0105] The singular forms of articles “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0106] The term “about” used throughout this specification is used to describe and account for small fluctuations. For example, the term “about” can refer to greater than, less than or equal to ±10%, such as 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%. All numeric values herein are modified by the term “about,” whether or not explicitly indicated. A value modified by the term “about” of course includes the specific value. For instance, “about 5.0” must include 5.0.

[0107] The term “Adverse Event” refers to any event, side-effect, or other untoward medical occurrence that occurs in conjunction with the use of a medicinal product in humans, whether or not considered to have a causal relationship to this treatment. An AE can, therefore, be any unfavourable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Events meeting the definition of an AE include: Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition; New conditions detected or diagnosed after study drug administration that occur during the reporting periods, even though it may have been present prior to the start of the study; Signs, symptoms, or the clinical sequelae of a suspected interaction; Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or concomitant medications (overdose per se will not be reported as an AE / SAE). AE's may have a causal relationship with the treatment, may beLYT100-IPF-2-WOpossibly related, or may be unrelated. Severity of AEs may be graded as one of: Mild (Grade 1): A type of AE that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not generally interfere with usual activities of daily living; Moderate (Grade 2): A type of AE that is usually alleviated with additional specific therapeutic intervention. The event interferes with usual activities of daily living, causing discomfort but poses no significant or permanent risk of harm to the research participant; Severe (Grade 3): A type of AE that interrupts usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention; Life-threatening (Grade 4): A type of AE that places the participant at immediate risk of death; Death (Grade 5): Events that result in death.

[0108] As used herein, the term “clinically effective amount,” “clinically proven effective amount,” and the like, refer to an effective amount of an API as shown through a clinical trial, e.g., a U. S. Food and Drug Administration (FDA) clinical trial.

[0109] The term “is / are deuterium,” when used to describe a given variable position in a molecule or formula, or the symbol “D,” when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In some embodiments, deuterium enrichment is of no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 98%, or in some embodiments no less than about 99% of deuterium at the specified position. In some embodiments, the deuterium enrichment is above 90% at each specified position. In some embodiments, the deuterium enrichment is above 95% at each specified position. In some embodiments, the deuterium enrichment is about 99% at each specified position.

[0110] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0111] The term “fibrosis” refers to the deposition of extracellular matrix components, excessive fibrous connective tissue, or scarring within an organ or tissue.LYT100-IPF-2-WO

[0112] The term “idiopathic pulmonary fibrosis (IPF)” refers to a type of lung disease that results in scarring of the lungs (pulmonary fibrosis) for which the origin of the disease state may be unknown.

[0113] ‘ ‘Prevent” or “prevention” refers to prophylactic or preventative measures that obstruct, delay and / or slow the development of a targeted pathologic condition or disorder or one or more symptoms of a targeted pathologic condition or disorder. Thus, those in need of prevention include those at risk of or susceptible to developing the disorder.

[0114] The terms “stabilized lung function,” “stable lung function” and the like refer to a level of lung function decline consistent with the physiological loss of lung function observed in healthy people for the relevant age group, e.g., over age 60 or 75. By way of example, as exemplified herein, stabilized lung function is demonstrated by a change in Forced Vital Capacity (FVC) for the LYT-100 825 mg arm of -32.8 mL over 52 weeks. This level of FVC decline is consistent with the 25 to 50 mL decline physiological loss of lung function observed in healthy people over age 60.

[0115] In some embodiments, a change in FVC is measured as a change in FVC% predicted (FVCpp). FVCpp is the FVC predicted for an individual based on demographics (age, sex, and height). Generally, an FVC value which is greater than or equal to 80% of the predicted value is considered normal. A value of 70% for the FVCpp is average for patients with IPF, and a decline in FVCpp over time is considered a key marker for disease progression in IPF. IPF progression is generally determined by a decline in FVCpp of 5% or greater. In some embodiments, IPF progression is determined by a decline in FVCpp of 10% or greater. In any of the methods disclosed herein, the length of time to IPF progression, as determined by a decline in FVCpp of 5% or greater, is longer (increased, greater) in the subject treated with LYT-100 relative to a subject who has not received LYT-100.

[0116] Terms such as “treating” or “treatment” or “to treat” refer to therapeutic measures that avoid, delay, and / or slow the occurrence of, avoid, delay, and / or slow the progression of, prevent, cure, ameliorate or lessen one or more symptoms of a pathologic condition or disorder; and / or that avoid occurrence of, prevent, cure, ameliorate, slow progression of, and / or halt progression of, a pathologic condition or disorder.

[0117] In some embodiments, treatment may be administered after one or more symptoms have developed. Thus, those in need of treatment include those already with the disorder (e.g., IPF). In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, a subject is successfully “treated” for a disease or disorder according to the methods provided herein if the patient shows, e.g., total, partial, or transientLYT100-IPF-2-WOalleviation or elimination of one or more symptoms associated with the disease or disorder (e.g., IPF) or if the patient shows, e.g., partial or transient delay in the progression of one or more symptoms associated with the disease or disorder (e.g., IPF) and / or if the patient shows, e.g., partial, or transient decrease (reduction, lessening) in the rate of progression of one or more symptoms associated with the disease or disorder, e.g., IPF, including, for example, impaired respiratory function and pulmonary fibrosis, as well as other known symptoms of IPF.

[0118] The terms “subject” and “patient” are used interchangeably herein and refer to a mammalian subject, including a human subject. In some embodiments, the subject is a human subject. As used herein, the terms “subject” and “patient” may refer to a single subject or patient, or to more than one subject or patient, such as a population of patients or subjects as defined herein.

[0119] The term “population of subjects” refers to a group of subjects participating in a clinical trial, with all subjects suffering from the same disease or symptom to be treated (i.e., IPF), wherein the clinical trial comprises a treatment arm (a subgroup of the subjects treated with LYT-100), and one or more of a placebo arm (a subgroup of the subjects not receiving treatment) and a comparator arm (i.e., a subgroup of the subjects treated with pirfenidone).

[0120] The age of a human subject may vary. In some embodiments, the human subject is an adult (i.e., aged 18 or older). In some embodiments, the subject is at least 40 years of age, such as about 40, about 50, about 60, about 70, about 80, about 90, or about 100 years of age. In some embodiments, the subject is less than 75 years of age, such as about 40, about 45, about 50, about 55, about 60, about 65, or about 70 years of age. In some embodiments, the subject is 75 years of age or older, such as about 75, about 80, about 85, about 90, or about 95 years of age.

[0121] The methods disclosed herein comprise administering LYT-100, which is a selectively deuterated form of pirfenidone. Specifically, LYT-100 is the deuterium-enriched pirfenidone, 5-(methyl-d3)-1-phenylpyridin-2-(1H)-one (CAS# 1093951-85-9) which may alternatively be referred to as deupirfenidone or 2(1H)-Pyridinone, 5-(methyl-d3)-1-phenyl. LYT-100 has the following structure:hkLYT-100.Reference to “LYT-100” herein further includes any hydrate, solvate, crystalline polymorph, amorphous form, or the like, of 5-(methyl-d3)-1-phenylpyridin-2-(1H)-one.LYT100-IPF-2-WO

[0122] The LYT-100 as disclosed herein can be prepared by methods known to one 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, W02003 / 014087, WO 2008 / 157786, WO 2009 / 035598, WO 2012 / 122165, or WO 2015 / 112701; the entirety of each of which is hereby incorporated by reference; and references cited therein and routine modifications thereof.Methods for Treating Idiopathic Pulmonary Fibrosis

[0123] Disclosed herein are methods of treating Idiopathic Pulmonary Fibrosis (IPF). The methods generally comprise administering to a subject in need thereof deupirfenidone (LYT- 100), wherein the IPF is treated in the subject.

[0124] In one aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF), the method comprising:administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, and wherein lung function is stabilized in the patient for at least 26 weeks. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 30 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 5% from baseline or initiation of treatment.

[0125] In some embodiments, the subject is 75 years of age or older. In some embodiments, the subject was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.LYT100-IPF-2-WO

[0126] In one aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF), the method comprising:administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, and wherein lung function is stabilized in the patient for at least 52 weeks.

[0127] In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 40 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 10% from baseline or initiation of treatment. In some embodiments, the subject is 75 years of age or older. As disclosed herein, it was found in the study of Example 1 that subjects aged 75 or older exhibited a greater treatment effect with 825 mg TID deupirfenidone relative to subjects aged less than 75 years (Table 8C). Subjects 75 or older also had about the same continuation rates as subjects less than 75 years old (Table 8B).

[0128] In some embodiments, the subject was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone

[0129] In another aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject 75 years of age or older, the method comprising:administering to the subject a total daily dose between 1600 mg and 2500 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),LYT100-IPF-2-WOwherein the total daily dose of deupirfenidone is administered as three equal administrations and wherein the subject exhibits a smaller decline in lung function after a treatment period compared to an untreated subject.

[0130] In some embodiments, the decline in lung function is stabilized in the subject 75 years or older for at least 26 weeks. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 30 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 5% from baseline or initiation of treatment).

[0131] In some embodiments, the decline in lung function is stabilized in the subject 75 years or older for at least 52 weeks. In some embodiments, the lung function stabilization is determined by a decline in FVC (mL) of less than about 50 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVC of less than about 40 mL from baseline or initiation of treatment. In some embodiments, the lung function stabilization is determined by a decline in FVCpp of < 10% from baseline or initiation of treatment).

[0132] In some embodiments, the subject 75 years or older is administered a daily dose of about 2500 mg deupirfenidone. In some embodiments, the subject is administered a daily dose of 2475 mg deupirfenidone. In some embodiments, the subject is administered 825 mg TID. In some emboiments, the subject is administered daily dose of about 1600 mg deupirefenidone. In some embodiments, the subject is administered a daily dose of 1650 mg deupirfenidone. In some embodiment, the subject is administered 550 mg TID deupirfenidone.

[0133] In some embodiments, the subject 75 years or older was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0134] In another aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject 75 years of age or older, the method comprising:administering to the subject a total daily dose between 1600 mg and 2500 mg of a deuterium-enriched pirfenidone having the structure:LYT100-IPF-2-WOD3c^Ny^(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations and wherein the subject exhibits a a longer time to IPF progression after a treatment period compared to an untreated subject.

[0135] In some embodiments, the IPF progression in the subject 75 years or older is measured as a decline in FVC more than -30 ml from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVC more than -50 ml from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVCpp > 5% from baseline or treatment initiation. In some embodiments, the IPF progression is measured as a decline in FVCpp > 10% from baseline or treatment initiation. In some embodiments, the subject is treated for at least 26 weeks. In some embodiments, the subject is treated at least 52 weeks.

[0136] In some embodiments, the subject 75 years or older is administered a daily dose of about 2500 mg deupirfenidone. In some embodiments, the subject is administered a daily dose of 2475 mg deupirfenidone. In some embodiments, the subject is administered 825 mg TID. In some emboiments, the subject is administered daily dose of about 1600 mg deupirefenidone. In some embodiments, the subject is administered a daily dose of 1650 mg deupirfenidone. In some embodiment, the subject is administered 550 mg TID deupirfenidone.

[0137] In some embodiments, the subject 75 years or older was being treated with pirfenidone and transitioned to deupirfenidone. In some embodiments, the subject was being treated with a 2403 mg daily dose of pirfenidone before transitioning to deupirfenidone. In some embodiments, the subject was being treated with about 1600 mg (e.g., 1602 mg) to 2400 mg (e.g., 2403 mg) daily dose of pirfenidone before transitioning to deupirfenidone.

[0138] As disclosed herein, it was found in the study of Example 1 that subjects aged 75 or older actually demonstrated an increase in lung function relative to a baseline value. With reference to Table 8C, subjects receiving the 825 mg TID dose of LYT-100 had an FVC improvement of 13.6 mL, while subjects on placebo had a decrease of 122 mL and subjects on pirfenidone had a decrease of 58.7 mL.

[0139] In yet another aspect is provided a dose escalation regimen method for providing deupirfenidone therapy to a subject in need thereof, the method comprising:LYT100-IPF-2-WOproviding deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at a third oral daily dosage of 2475 mg for at least day fifteen of the dose escalation regimen,wherein the subject is provided deupirfenidone therapy for the treatment of idiopathic pulmonary fibrosis.

[0140] In some embodiments, the dose escalation regimen method comprises:providing deupirfenidone to the subject at the first oral daily dosage of 825 mg as one tablet comprising 275 mg of deupirfenidone three times a day for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at the second oral daily dosage of 1650 mg as two tablets comprising 275 mg of deupirfenidone three times a day for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at the third oral daily dosage of 2475 mg as three tablets comprising 275 mg of deupirfenidone three times a day for at least day fifteen of the dose escalation regimen.

[0141] In a further aspect is provided a starter pack for use in an initial dose escalation regimen which provides deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the initial dose escalation regimen; provides deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the initial dose escalation regimen; and provides deupirfenidone to the subject a third oral daily dosage of 2475 mg for at least day fifteen of the dose escalation regimen, the starter pack comprising a plurality of compartments for containing a dosage amount of deupirfenidone arranged within rows and columns, wherein the starter pack comprises separate rows for Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 with three separate columns for three dosage amounts to be taken each day; and wherein each of the three compartments for Days 1, 2, 3, 4, 5, 6, and 7 separately contain one pill of 275-mg deupirfenidone and each of the three compartments for Days 8, 9, 10, 11, 12, 13, and 14 separately contain two pills of 275 mg deupirfenidone; and wherein the starter pack optionally further comprises at least one additional set of compartments for Days 15, 16, 17, 18, 19, 20 and 21 in separate rows and each compartment in the additional set of compartments separately contain three pills of 275 mg deupirfenidone.LYT100-IPF-2-WO

[0142] In a further aspect is provided a method for reducing the incidence of adverse events in a subject receiving oral deupirfenidone therapy for the treatment of a fibrotic disease or disorder, the method comprising a dose adjustment regimen comprising:administering deupirfenidone to the subject at an oral daily dosage of 2475 mg for a first period of time; andsubsequently administering deupirfenidone to the subject at an oral daily dosage of 1650 mg deupirfenidone for a second period of time.

[0143] In some embodiments, the oral daily dosage of 1650 mg deupirfenidone is administered as three equal daily doses of 550 mg each.

[0144] In some embodiments, the oral daily dosage of 1650 mg deupirfenidone is administered as two equal daily doses of 825 mg each.

[0145] In some embodiments, the method further comprises, after the second period of time, administering deupirfenidone to the subject as a 2475 mg total daily dose.

[0146] In some embodiments, the 2475 mg total daily dose is administered as three equal daily doses of 825 mg each.

[0147] In a still further aspect is provided a method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration thereof for a period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprising administering to said subject deupirfenidone at a total daily dose of 1650 mg, administered as two daily administration of 825 mg each.

[0148] In some embodiments, the methods disclosed herein above may include temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions, drug interactions, or in response to altered liver function (e.g., as determined by a liver function test indicative of hepatic impairment). In some embodiments, the dose may be reduced from 2475 mg / day to 1650 mg / day or 825 mg / day. The reduction may be in the form of a titration down over a period of days, e.g., as described above for titration to the maintenance or full dose, but in a reverse order, or dosing may be interrupted entirely. In some embodiments, dosing may be interrupted temporarily. Following a dose reduction or temporary discontinuation, re-titration back up to 1650 mg / day or 2475 mg / day may be employed.

[0149] Accordingly, in another aspect is provided a method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration of deupirfenidone for a period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprisingLYT100-IPF-2-WOadministering deupirfenidone at a total daily dose of 1650 mg, administered as three daily doses of 550 mg each.

[0150] In some embodiments, the intolerance is one or more of nausea, vomiting, abdominal pain or distension, dyspepsia, diarrhea, decreased appetite, constipation, headache, dizziness, somnolence, fatigue, skin rash, photosensitivity, increased AST, increased ALT, increased GGT, and liver toxicity.

[0151] In some embodiments, the subject in any of the methods disclosed herein has not received prior treatment for IPF.

[0152] In some embodiments, the subject in any of the methods disclosed herein has received prior treatment for IPF with nintedanib.

[0153] In some embodiments, the subject has received prior treatment for IPF with pirfenidone.

[0154] In some embodiments, the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

[0155] In some embodiments, the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

[0156] In some embodiments, the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.

[0157] In a further aspect is provided a method of transitioning from pirfenidone to deupirfenidone for a subject in need thereof, the method comprising:a) discontinuing a daily amount of pirfenidone; andb) administering an initial daily amount of deupirfenidone the next day to the subject, wherein the daily amount of pirfenidone in a) is 801 mg and the initial total daily amount of deupirfenidone is 825 mg; orwherein the daily amount of pirfenidone in a) is 1602 mg and the initial total daily amount of deupirfenidone is 1650 mg; orwherein the daily amount of pirfenidone in a) is 2403 mg and the initial total daily amount of deupirfenidone is 2475 mg.

[0158] In a yet further aspect is provided a method of treating Idiopathic Pulmonary Fibrosis (IPF) in a patient population, the method comprising administering to said patients in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),LYT100-IPF-2-WOwherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, wherein the IPF is treated in the patient population, and wherein a rate of treatment discontinuation in the patient population is less than about 20% over 52 weeks.

[0159] In some embodiments, the rate of treatment discontinuation in the patient population is less than about 12%.

[0160] In some embodiments, the subject has not received prior treatment for IPF.

[0161] In some embodiments, the subject has received prior treatment for IPF with nintedanib.

[0162] In some embodiments, the subject has received prior treatment for IPF with pirfenidone.

[0163] In some embodiments, the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

[0164] In some embodiments, the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

[0165] In some embodiments, the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.Oral administration

[0166] As described herein above, the various disclosed methods of treating Idiopathic Pulmonary Fibrosis (IPF) comprise administering a total daily dose between 1600 mg and 2500 mg, such as about 1650 mg or 2475 mg. Such doses are generally divided into three daily doses (TID), such as 550 mg TID or 825 mg TID. Generally, the administration is by the oral route. Accordingly, in any of the foregoing aspects and embodiments, the deupirfenidone is generally administered orally in a solid dosage form. Such solid dosage forms suitable for oral administration are configured for immediate release and comprise 5-(methyl-d₃)-1-phenylpyridin-2-(1H)-one (deupirfenidone) and one or more pharmaceutically acceptable excipients. Typically, immediate release formulations comprise pharmaceutically acceptable excipients such as fillers, disintegrants, binders, glidants, lubricants, surfactants, or combinations thereof. Solid dosage forms for oral administration include capsules, dragees, tablets, pills, powders, and granules. The solid dosage form can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Oral administration of LYT-100, dosage regimens, and pharmaceutical compositions and dosage forms of LYT-100 are disclosed in, for example, Intemation Application Publication No. W02020 / 056430, incorporated by reference herein.LYT100-IPF-2-WO

[0167] In some embodiments, the deupirfenidone is administered in capsule form. In some embodiments, the deupirfenidone is administered in tablet form. In some embodiments, the deupirfenidone is administered in the form of tablets comprising 275 mg of deupirfenidone. In some embodiments, the total daily dose of deupirfenidone is administered as six or nine daily tablets comprising 275 mg of deupirfenidone. For example, in some embodiments, the total daily dose of deupirfenidone is 1650 mg, and is administered as 2x275 mg, three times daily. In some embodiments, the total daily dose of deupirfenidone is 2475 mg, and is administered as 3x275 mg, three times daily.Administration by Inhalation

[0168] While oral dosing of LYT-100 has been described throughout the present disclosure, other routes of administration are also contemplated herein. For example, LYT-100 may be administered by inhalation. Accordingly, in another aspect is provided liquid, dry powder, and metered dose formulations for therapeutic inhalation delivery of LYT-100. Such inhalation formulations may be delivered by oral or nasal inhalation, including pulmonary delivery. In some embodiments, LYT-100 is formulated for pulmonary delivery. In some embodiments, LYT-100 is formulated for nasal delivery. In some embodiments, LYT-100 is formulated for inhaled oral delivery.Liquid formulations.

[0169] In some embodiments, the inhaled formulation is a liquid. In some embodiments, the liquid formulation comprises LYT-100, water, and one or more additional components selected from co-solvents, isotonicity agents, sweeteners, surfactants, wetting agents, chelating agents, antioxidants, salts, and buffers.

[0170] In some embodiments, the inhaled formulation comprises LYT-100 at a concentration from about 10 mg / mL to about 50 mg / mL.

[0171] In some embodiments, the inhaled formulation comprises one or more co-solvents, wherein the total amount of the one or more co-solvents is about 1 to about 30% v / v. Suitable co-solvents include, but are not limited to, ethanol, propylene glycol, or a combination thereof.

[0172] In some embodiments, the inhaled formulation comprises a buffer that maintains the pH of the solution from about pH 6.0 to about pH 8.0. In some embodiments, the osmolality of the aqueous solution is from about 400 mOsmol / kg to about 6000 mOsmol / kg.

[0173] Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization. A variety of nebulizers (including small volume nebulizers) are available to aerosolize the disclosed formulations. Any known inhalation nebulizer suitableLYT100-IPF-2-WOto provide delivery of a medicament may be used in the various embodiments and methods described herein. Such nebulizers include, e.g., jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber (e.g., Pari eFlow®).

[0174] In some embodiments, the nebulizer is a jet nebulizer. A jet nebulizer utilizes air pressure breakage of an aqueous solution into aerosol droplets. Compressor-driven nebulizers incorporate jet technology and use compressed air to generate the liquid aerosol. Such devices are commercially available from, for example, Healthdyne Technologies, Inc.; Invacare, Inc.; Mountain Medical Equipment, Inc.; Pari Respiratory, Inc.; Mada Medical, Inc.; Puritan-Bennet; Schuco, Inc., DeVilbiss Health Care, Inc.; and Hospitak, Inc.

[0175] In some embodiments, the nebulizer is an ultrasonic nebulizer. Ultrasonic nebulizers rely on mechanical energy in the form of vibration of a piezoelectric crystal to generate respirable liquid droplets and are commercially available from, for example, Omron Heathcare, Inc., Boehringer Ingelheim, and DeVilbiss Health Care, Inc. Exemplary ultrasonic nebulizers suitable to provide delivery of a medicament as described herein can include Micro Air, UltraAir, Siemens Ultra Nebulizer 145, CompAir, Pulmosonic, Scout, 5003 Ultrasonic Neb, 5110 Ultrasonic Neb, 5004 Desk Ultrasonic Nebulizer, Mystique Ultrasonic, Lumiscope's Ultrasonic Nebulizer, Medisana Ultrasonic Nebulizer, Microstat Ultrasonic Nebulizer, and Mabismist Hand Held Ultrasonic Nebulizer. Other nebulizers for use herein include 5000 Electromagnetic Neb, 5001 Electromagnetic Neb 5002 Rotary Piston Neb, Lumineb I Piston Nebulizer 5500, Aeroneb Portable Nebulizer System, Aerodose Inhaler, and AeroEclipse Breath Actuated Nebulizer. Exemplary nebulizers comprising a vibrating mesh or plate with multiple apertures are described by R. Dhand in New Nebuliser Technology — Aerosol Generation by Using a Vibrating Mesh or Plate with Multiple Apertures, Long-Term Healthcare Strategies 2003, (July 2003), p. 1-4 and Respiratory Care, 47: 1406-1416 (2002), the entire disclosure of each of which is hereby incorporated by reference.

[0176] In some embodiments, a vibrating mesh nebulizer is used to deliver an aerosol of LYT-100. A vibrating mesh nebulizer comprises a liquid storage container in fluid contact with a diaphragm and inhalation and exhalation valves. Vibrating mesh nebulizers rely upon either piezoelectric or mechanical pulses to respirable liquid droplets generate. Other examples of nebulizers for use with pirfenidone or pyridone analogs described herein are described in U. S. Pat. Nos. 4,268,460; 4,253,468; 4,046,146; 3,826,255; 4,649,911; 4,510,929; 4,624,251; 5,164,740; 5,586,550; 5,758,637; 6,644,304; 6,338,443; 5,906,202; 5,934,272; 5,960,792; 5,971,951; 6,070,575; 6,192,876; 6,230,706; 6,349,719; 6,367,470; 6,543,442; 6,584,971;LYT100-IPF-2-WO6,601,581; 4,263,907; 5,709,202; 5,823,179; 6,192,876; 6,644,304; 5,549,102; 6,083,922; 6,161,536; 6,264,922; 6,557,549; and 6,612,303 all of which are hereby incorporated by reference in their entirety.

[0177] Exemplary disclosure of compositions and methods for formulation delivery using nebulizers can be found in, e.g., US 2006 / 0276483, including descriptions of techniques, protocols and characterization of aerosolized mist delivery using a vibrating mesh nebulizer. In some embodiments, the nebulizer is a commercially available unit including, but not limited to, Aeroneb®, MicroAir®, Aeroneb® Pro, and Aeroneb® Go, Aeroneb® Solo, Aeroneb® Solo / Idehaler combination, Aeroneb® Solo or Go Idehaler-Pocket® combination, PARI LC-Plus®, PARI LC-Star®, PARI Sprint®, eFlow and eFlow Rapid®, Pari Boy® N and Pari Duraneb® (PARI, GmbH), MicroAir® (Omron Healthcare, Inc.), Halolite® (Profde Therapeutics Inc.), Respimat® (Boehringer Ingelheim), Aerodose® (Aerogen, Inc, Mountain View, Calif.), Omron Elite® (Omron Healthcare, Inc.), Omron Microair® (Omron Healthcare, Inc.), Mabismist II® (Mabis Healthcare, Inc.), Lumiscope® 6610, (The Lumiscope Company, Inc.), Airsep Mystique®, (AirSep Corporation), Acom-1 and Acom-II (Vital Signs, Inc.), Aquatower® (Medical Industries America), Ava-Neb® (Hudson Respiratory Care Incorporated), Cirrus® (Intersurgical Incorporated), Dart® (Professional Medical Products), Devilbiss® Pulmo Aide (DeVilbiss Corp.), Downdraft® (Marquest), Fan Jet® (Marquest), MB-5 (Mefar), Misty Neb® (Baxter), Salter 8900 (Salter Labs), Sidestream® (Medic -Aid), Updraft-II® (Hudson Respiratory Care), Whisper Jet® (Marquest Medical Products), Aiolos® (Aiolos Medicnnsk Teknik), Inspiron® (Intertech Resources, Inc.), Optimist® (Unomedical Inc.), Prodomo®, Spira® (Respiratory Care Center), AERx® and AERx Essence™ (Aradigm), Respirgard II®, Sonik® LDI Nebulizer (Evit Labs), Swirler W Radioaerosol System (AMICI, Inc.), Maquet SUN 145 ultrasonic, Schill untrasonic, compare and compare Elite from Omron, Monoghan AeroEclipse BAN, Transneb, DeVilbiss 800, AerovectRx, Porta-Neb®, Freeway Freedom™, Sidestream, Ventstream and I-neb produced by Philips, Inc. By further non-limiting example, U. S. Pat. No. 6,196,219, is hereby incorporated by reference in its entirety. In some embodiments, the nebulizer is a commercially available unit available from, e.g., Pari GmbH (Starnberg, Germany), DeVilbiss Healthcare (Heston, Middlesex, UK), Healthdyne, Vital Signs, Baxter, Allied Health Care, Invacare, Hudson, Omron, Bremed, AirSep, Luminscope, Medisana, Siemens, Aerogen, Mountain Medical, Aerosol Medical Ltd. (Colchester, Essex, UK), AFP Medical (Rugby, Warwickshire, UK), Bard Ltd. (Sunderland, UK), Carri-Med Ltd. (Dorking, UK), Plaem Nuiva (Brescia, Italy), Henleys Medical Supplies (London, UK), Intersurgical (Berkshire, UK), Lifecare Hospital Supplies (Leies, UK), Medic -Aid Ltd. (WestLYT100-IPF-2-WOSussex, UK), Medix Ltd. (Essex, UK), Sinclair Medical Etd. (Surrey, UK), and many others. Exemplary jet nebulizers for use herein can include Pari LC plus / ProNeb, Pari LC plus / ProNeb Turbo, Pari LCPlus / Dura Neb 1000 & 2000 Pari LC plus / Walkhaler, Pari LC plus / Pari Master, Pari LC star, Omron CompAir XL Portable Nebulizer System (NE-C 18 and JetAir Disposable nebulizer), Omron compare Elite Compressor Nebulizer System (NE-C21 and Elite Air Reusable Nebulizer, Pari LC Plus or Pari LC Star nebulizer with Proneb Ultra compressor, Pulomo-aide, Pulmo-aide LT, Pulmo-aide traveler, Invacare Passport, Inspiration Healthdyne 626, Pulmo-Neb Traveler, DeVilbiss 646, Whisper Jet, Acomll, Misty-Neb, Allied aerosol, Schuco Home Care, Lexan Plasic Pocet Neb, SideStream Hand Held Neb, Mobil Mist, Up-Draft, Up-Draftll, T Up-Draft, ISO-NEB, Ava-Neb, Micro Mist, and PulmoMate. Additional suitable nebulizers include nebulizers comprising a vibration generator and an aqueous chamber such as e.g., Pari ePlow, and are described in U. S. Pat. Nos. 6,962,151, 5,518,179, 5,261,601, and 5,152,456, each of which is specifically incorporated by reference herein.

[0178] In some embodiments, the nebulizer is high efficiency liquid nebulizer. In some embodiments, the high efficiency liquid nebulizer contains a vibrating microperforated membrane of tapered nozzles against a bulk liquid will generate a plume of droplets without the need for compressed gas. In these embodiments, a solution in the microperforated membrane nebulizer is in contact with a membrane, the opposite side of which is open to the air. The membrane is perforated by a large number of nozzle orifices of an atomizing head. An aerosol is created when alternating acoustic pressure in the solution is built up in the vicinity of the membrane causing the fluid on the liquid side of the membrane to be emitted through the nozzles as uniformly sized droplets.

[0179] In some embodiments, the high efficiency liquid nebulizers use passive nozzle membranes and a separate piezoelectric transducer that are in contact with the solution. In contrast, some high efficiency liquid nebulizers employ an active nozzle membrane, which use the acoustic pressure in the nebulizer to generate very fine droplets of solution via the high frequency vibration of the nozzle membrane. Some high efficiency liquid nebulizers contain a resonant system. In some such high efficiency liquid nebulizers, the membrane is driven by a frequency for which the amplitude of the vibrational movement at the center of the membrane is particularly large, resulting in a focused acoustic pressure in the vicinity of the nozzle; the resonant frequency may be about 100 kHz. A flexible mounting is used to keep unwanted loss of vibrational energy to the mechanical surroundings of the atomizing head to a minimum. In some embodiments, the vibrating membrane of the high efficiency liquid nebulizer may be made of a nickel-palladium alloy by electroforming. Additional features of a high efficiency liquidLYT100-IPF-2-WOnebulizer with perforated membranes are disclosed in U. S. Pat. Nos. 6,962,151, 5,152,456, 5,261,601, and 5,518,179, 6,983,747, each of which is hereby incorporated by reference in its entirety. Other embodiments of the high efficiency liquid nebulizers contain oscillatable membranes. Features of these high efficiency liquid nebulizers are disclosed in 7,252,085; 7,059, 320; 6,983,747, each of which is hereby incorporated by reference in its entirety. Commercial high efficiency liquid nebulizers are available from: PARI (Germany) under the trade name eFlow®; Nektar Therapeutics (San Carlos, Calif.) under the trade names AeroNeb® Go and AeroNeb® Pro, and AeroNeb® Solo, Respironics (Murrysville, Calif.) under the trade names I-Neb®, Omron (Bannockbum, Ill.) under the trade name Micro-Air®, and Activaero (Germany) under the trade name Akita®. Commercial High Efficiency Nebulizers are also available from Aerogen (Galaway, Ireland) utilizing the OnQ® nebulizer technology.

[0180] The parameters used in nebulization, such as flow rate, mesh membrane size, aerosol inhalation chamber size, mask size and materials, valves, and power source may be varied as applicable to provide delivery of a medicament as described herein to maximize their use with different types of inhalation mixtures.

[0181] In some embodiments, the liquid nebulizer delivers the intended dosage of LYT-100 to the lungs of the subject in less than about 20 minutes.

[0182] In some embodiments, about 0.5 m to about 6 m of the formulation is administered to the subject with a liquid nebulizer.Dry powder formulations.

[0183] In some embodiments, the inhaled formulation is a dry powder. Such dry powder compositions may include, in addition to EYT-100, bulking agents, stabilizers, force control agents, and the like. Such components include, but are not limited to, sugars, salts, lubricants, amino acids, cellulose ethers, and amino acids. Further contemplated herein are spray-dried powders, nanoparticulate formulations, and liposomal compositions.

[0184] Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device. There are two major designs of dry powder inhalers. One design is the metering device in which a reservoir for the drug is placed within the device and the patient adds a dose of the drug into the inhalation chamber. The second is a factory-metered device in which each individual dose has been manufactured in a separate container. Both systems depend upon the formulation of drug into small particles of mass median diameters from about 1 to about 5 microns, and usually involve co-formulation with larger excipient particles (typically 100-micron diameter lactose particles). Drug powder isLYT100-IPF-2-WOplaced into the inhalation chamber (either by device metering or by breakage of a factory-metered dosage) and the inspiratory flow of the patient accelerates the powder out of the device and into the oral cavity. Non-laminar flow characteristics of the powder path cause the excipientdrug aggregates to decompose, and the mass of the large excipient particles causes their impaction at the back of the throat, while the smaller drug particles are deposited deep in the lungs.

[0185] In some embodiments, a dry powder inhaler (DPI) is used to dispense the LYT-100. DPIs contain the drug substance in fine dry particle form. Dry powder inhalers (DPIs), which involve deaggregation and aerosolization of dry powder particles, normally rely upon a burst of inspired air that is drawn through the unit to deliver a drug dosage. Typically, inhalation by a patient causes the dry particles to form an aerosol cloud that is drawn into the patient's lungs. The fine dry drug particles may be produced by any technique known in the art. Some well-known techniques include use of a jet mill or other comminution equipment, precipitation from saturated or super saturated solutions, spray drying, in situ micronization, or supercritical fluid methods. Typical powder formulations include production of spherical pellets or adhesive mixtures. In adhesive mixtures, the drug particles are attached to larger carrier particles, such as lactose monohydrate of size about 50 to about 100 microns in diameter. The larger carrier particles increase the aerodynamic forces on the carrier / drug agglomerates to improve aerosol formation. Turbulence and / or mechanical devices break the agglomerates into their constituent parts. The smaller drug particles are then drawn into the lungs while the larger carrier particles deposit in the mouth or throat. Some examples of adhesive mixtures are described in U. S. Pat. No. 5,478,578 and PCT Publication Nos. WO 95 / 11666, WO 87 / 05213, WO 96 / 23485, and WO 97 / 03649, all of which are incorporated by reference in their entirety. Additional excipients may also be included with the drug substance.

[0186] Exemplary DPI devices are described in, for example, U. S. Pat. No. 4,807,814, which is directed to a pneumatic powder ejector having a suction stage and an injection stage; SU 628930 (Abstract), describing a hand-held powder disperser having an axial air flow tube; Fox et al., Powder and Bulk Engineering, pages 33-36 (March 1988), describing a venturi eductor having an axial air inlet tube upstream of a venturi restriction; EP 347 779, describing a hand-held powder disperser having a collapsible expansion chamber, and U. S. Pat. No. 5,785,049, directed to dry powder delivery devices for drugs.

[0187] Examples of single-dose DPIs are described in U. S. Pat. Nos. 3,807,400; 3,906,950; 3,991,761; and 4,013,075, all of which are hereby incorporated by reference in their entirety. In a multiple unit dose DPI, a package containing multiple single dose compartments is provided.LYT100-IPF-2-WOExamples of multiple unit dose DPIs are described in EPO Patent Application Publication Nos.0211595A2, 0455463A1, and 0467172A1, all of which are hereby incorporated by reference in their entirety. In a multi-dose DPI, a single reservoir of dry powder is used. Mechanisms are provided that measure out single dose amounts from the reservoir to be aerosolized and inhaled, such as described in U. S. Pat. Nos. 5,829,434; 5,437,270; 2,587,215; 5,113,855; 5,840,279; 4,688,218; 4,667,668; 5,033,463; and 4,805,811 and PCT Publication No. WO 92 / 09322, all of which are hereby incorporated by reference in their entirety.

[0188] In some embodiments, auxiliary energy in addition to or other than a patient's inhalation may be provided to facilitate operation of a DPI. For example, pressurized air may be provided to aid in powder de-agglomeration, such as described in U. S. Pat. Nos. 3,906,950; 5,113,855; 5,388,572; 6,029,662 and PCT Publication Nos. WO 93 / 12831, WO 90 / 07351, and WO 99 / 62495, all of which are hereby incorporated by reference in their entirety. Electrically driven impellers may also be provided, such as described in U. S. Pat. Nos. 3,948,264; 3,971,377; 4,147,166; 6,006,747 and PCT Publication No. WO 98 / 03217, all of which are hereby incorporated by reference in their entirety. Another mechanism is an electrically powered tapping piston, such as described in PCT Publication No. WO 90 / 13327, which is hereby incorporated by reference in its entirety. Other DPIs use a vibrator, such as described in U. S. Pat. Nos. 5,694,920 and 6,026,809, both of which are hereby incorporated by reference in their entirety. Finally, a scraper system may be employed, such as described in PCT Publication No. WO 93 / 24165, which is hereby incorporated by reference in its entirety. Additional examples of DPIs for use herein are described in U. S. Pat. Nos. 4,811,731; 5,113,855; 5,840,279; 3,507,277; 3,669,113; 3,635,219; 3,991,761; 4,353,365; 4,889,144, 4,907,538; 5,829,434; 6,681,768; 6,561,186; 5,918,594; 6,003,512; 5,775,320; 5,740,794; and 6,626,173, all of which are hereby incorporated by reference in their entirety. In some embodiments, the DPI is a commercially available device. Commercial examples of dry powder inhalers include the Aerolizer, Turohaler, Handihaler and Discus.

[0189] In some embodiments, the dry powder formulation is delivered by a meter dose inhaler (MDI). In some embodiments, the MDI is propellant driven (pMDI). A pMDI releases a metered dose of medicine upon each actuation. The medicine (i.e., LYT-100) is formulated as a suspension or solution in a suitable propellant such as a halogenated hydrocarbon. pMDIs are described in, for example, Newman, S. P., Aerosols and the Lung, Clarke et al., eds., pp. 197-224 (Butterworths, London, England, 1984).

[0190] In some embodiments, the particle size of the drug substance in an MDI may be optimally chosen. In some embodiments, the particles of active ingredient (i.e., LYT-100) haveLYT100-IPF-2-WOdiameters of less than about 50 microns. In some embodiments, the particles have diameters of less than about 10 microns. In some embodiments, the particles have diameters of from about 1 micron to about 5 microns. In some embodiments, the particles have diameters of less than about 1 micron. In one advantageous embodiment, the particles have diameters of from about 2 microns to about 5 microns.

[0191] The LYT-100 may be soluble in the propellant, soluble in the propellant plus a cosolvent (by non-limiting example ethanol), soluble in the propellant plus an additional moiety promoting increased solubility (by non-limiting example glycerol or phospholipid), or as a stable suspension or micronized, spray-dried or nanosuspension.

[0192] The propellants for use with the MDIs may be any propellants known in the art. Examples of propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluorometbane, and dichlorotetrafluoroethane; hydrofluoroalkanes (HFAs); and carbon dioxide. It may be advantageous to use HFAs instead of CFCs due to the environmental concerns associated with the use of CFCs. Examples of medicinal aerosol preparations containing HFAs are presented in U. S. Pat. Nos. 6,585,958; 2,868,691 and 3,014,844, all of which are hereby incorporated by reference in their entirety. In some embodiments, a co-solvent is mixed with the propellant to facilitate dissolution or suspension of the drug substance.

[0193] In some embodiments, the propellant and active ingredient are contained in separate containers, such as described in U. S. Pat. No. 4,534,345, which is hereby incorporated by reference in its entirety.

[0194] In some embodiments, the MDI is activated by a patient pushing a lever, button, or other actuator. In other embodiments, the release of the aerosol is breath activated such that, after initially arming the unit, the active compound aerosol is released once the patient begins to inhale, such as described in U. S. Pat. Nos. 6,672,304; 5,404,871; 5,347,998; 5,284,133; 5,217,004; 5,119,806; 5,060,643; 4,664,107; 4,648,393; 3,789,843; 3,732,864; 3,636,949; 3,598,294; 3,565,070; 3,456,646; 3,456,645; and 3,456,644, each of which is hereby incorporated by reference in its entirety. Such a system enables more of the active compound to get into the lungs of the patient. Another mechanism to help a patient get adequate dosage with the active ingredient may include a valve mechanism that allows a patient to use more than one breath to inhale the drug, such as described in U. S. Pat. Nos. 4,470,412 and 5,385,140, both of which are hereby incorporated by reference in their entirety. Additional examples of MDIs known in the art and suitable for use herein include U. S. Pat. Nos. 6,435,177; 6,585,958; 5,642,730; 6,223,746; 4,955,371; 5,404,871; 5,364,838; and 6,523,536, all of which are hereby incorporated by reference in their entirety.LYT100-IPF-2-WO

[0195] By non-limiting example, a metered-dose LYT-100 formulation may be administered in the intended dose in 10 or fewer inhalation breaths, such as in 8 or fewer inhalation breaths, 6 or fewer inhalation breaths, 4 or fewer inhalation breaths, or 2 or fewer inhalation breaths. Dosing frequency

[0196] The frequency of dose administration of an LYT-100 inhaled formulation as described herein may vary. In some embodiments, the inhaled dose is administered once a day, twice a day, three times a day, or four time a day.

[0197] In some embodiments, the inhaled dose is administered every other day, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, or any combination thereof.

[0198] In some embodiments, the inhaled doses are delivered by nebulization using standard tidal breathing of continuous flow aerosol or breath actuated aerosol. In such embodiments of nebulized delivery, delivery times can be <20, <15, <10, <8, <6, <4, <2 and <1 minute. In some embodiments, the inhaled doses are delivered by inhalation of a dispersed dry powder aerosol using <10, <8, <6, <5, <4, <3, <2 or 1 breath of either a passive dispersion dry power inhaler or active dispersion dry powder inhaler. In some embodiments, the inhaled doses are delivered by inhalation of aerosol using <10, <8, <6, <5, <4, <3, <2 or 1 breath of a compressed gas metered dose inhaler with or without a spacer.

[0199] In some embodiments, the inhaling is performed in less than about 10 minutes, such as less than about 7.5 minutes, less than about 5 minutes, less than about 2.5 minutes, less than about 1.5 minutes, less than about 1 minute, or less than about 30 seconds. In some embodiments, the inhaling is performed in less than about 5 breaths. In some embodiments, the inhaling is performed in less than about 3 breaths, such as 2 breaths or 1 breath.

[0200] In some embodiments, administration by inhalation does not include an initial doseescalation period. In some embodiments, administration by inhalation includes a dose escalation period, such as is described herein with respect to oral dosing up-titration.

[0201] In some embodiments, the inhaled formulation is administered in a quantity and with a dosing frequency such that the administration provides a Cmax, an AUC, or both which are substantially equivalent to that provided by administration of LYT-100 as an oral tablet formulation. In some embodiments, the inhaled formulation provides a Cmax, an AUC, or both which are substantially equivalent to that provided by a total daily dose of 2475 mg of LYT- 100, or 1650 mg LYT-100, when the total daily oral dose is administered in three equal daily doses (TID).LYT100-IPF-2-WO

[0202] 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 present disclosure.EXEMPLIFICATION

[0203] Example 1 provides a study of the efficacy, tolerability and safety of the deuterated pirfenidone LYT-100 in patients with Idiopathic Pulmonary Fibrosis.Example 1: LYT-100 Efficacy, Safety, and Dose Response in Idiopathic Pulmonary Fibrosis

[0204] This study was a randomized double-blind, four-arm active and placebo-controlled dosefinding trial to evaluate the efficacy, tolerability, safety, and dose response of LYT-100 in patients with Idiopathic Pulmonary Fibrosis (IPF). Hie study was conducted at approximately 100 study centers globally. This study was conducted in two parts. A high-level graphical illustration is provided as FIG. 1.Double-blind Treatment Period (Part A)

[0205] The Double-blind Treatment Period was a multicenter, four-arm, active and placebo-controlled, randomized, double-blind, trial comparing the efficacy, tolerability, and safety of LYT-100 550 mg oral capsules three times a day (TID), LYT-100 825 mg oral capsules TID, pirfenidone 801 mg oral capsules TID, and placebo oral capsules TID over a 26-week treatment period. The primary objective was to determine the dose(s) to carry into Phase 3. This determination was based on the overall benefit risk profile of LYT-100 via decline in forced vital capacity (FVC, mL), including both efficacy and tolerability outcomes over the 26-week treatment period. Patients were randomized to one of the four treatments in a 1: 1: 1: 1 ratio and stratified based on prior exposure to nintedanib (<6 months) versus nintedanib-naive patients. Patients who completed the Double-blind Treatment Period (Part A) were offered participation in the Long-term Extension (Part B). Patients who did not participate in the Part B had a followup visit 4 weeks after their last dose of study medication. For patients who participated in Part B, the follow-up was conducted at the end of Part B. A graphical illustration of an embodiment of the tri al design is provided as FIG. 2.Long-term Extension Period (Part B)

[0206] Part B (long-term extension) evaluated the tolerability and long-term safety of LYT-100 in patients who completed the Double-blind Treatment Period. Part B had two periods. During Part 1 Period 1, patients were titrated over a period of 7 to 14 days to the target dose of either 550 or 825 mg LYT-100 TID, followed by maintenance treatment through Week 52. PatientsLYT100-IPF-2-WOcompleting Part B Period 1 continued maintenance treatment in Part B Period 2 until the study ended. Part B Period 2 continued at least until all patients who entered Part B Period 1 had the opportunity to complete Part B Period 1. Tolerability and safety during both Part B Period 1 and Part B Period 2 wase monitored by regularly scheduled review of adverse events (AEs), patient reported symptoms, concomitant medications, clinical laboratory findings, physical examinations, electrocardiograms (ECGs), and vital signs. Efficacy was assessed by evaluation of pulmonary function and monitored by spirometry' at regularly scheduled clime visits. A graphical illustration of an embodiment of the trial design is provided as FIG. 3.

[0207] The primary objective of this study was to obtain clinical data establishing the efficacy, tolerability, safety, and dosing regimen of LYT- 100 in patients with IPF. A secondary objective was to assess the relative efficacy of LYT-100 as compared to pirfenidone. For Part B, the objectives were to assess the safety and tolerability of long-term treatment with LYT- 100 in the IPF population (52 weeks) and to compare the rate of change in FVC through the end of Part B Period 1 to that observed during Part A, by Part A treatment group assignment and by Part B LYT-100 target dose.Dosing

[0208] In Part A, patients received one of two doses of LYT-100 (550 mg or 825 mg) capsules, pirfenidone (801 mg) capsules, or placebo, each TID orally with meals, with approximately 6 hours between each of the three daily doses.

[0209] At the start of Part B, all patients received LYT-100 oral tablets. Patients were titrated onto their assigned doses. Dose titration was conducted as follows.

[0210] The dosing for patients who received 550 mg LYT-100 TID in the Double-blind Treatment Period was: Days 183-189 - 1 tablet (275 mg) TID (825 mg / day); and Day 190 to end of study: 2 tablets (550 mg) TID (1,650 mg / day).

[0211] The dosing for patients who received 825 mg LYT-100 TID in the Double-blind Treatment Period: Days 183-189: 1 tablet (275 mg) TID (825 mg / day); Days 190-196: 2 tablets (550 mg) TID (1,650 mg / day): Day 197 to end of study: 3 tablets (825 mg) TID (2,475 mg / day).

[0212] The dosing for patients who received 801 mg pirfenidone in the Double-blind Treatment Period: Days 183-189: One tablet (275 mg) TID (825 mg / day); Days 190-196: Two tablets (550 mg) TID (1,650 mg / day); and Day 197 to end of study: Randomized to receive 2 tablets TID (1,650 mg / day) or three tablets (825 mg) TID (2,475 mg / day).

[0213] The dosing for patients who received placebo in the Double-blind Treatment Period: Days 183-189: One tablet (275 mg) TID (825 mg / day); Days 190-196: Two tablets (550 mg)LYT100-IPF-2-WOTID (1,650 mg / day); and Day 197 to end of study: Randomized to receive 2 tablets TID (1,650 mg / day) or three tablets (825 mg) TID (2,475 mg / day).

[0214] Approximately 240 patients with physician diagnosis of IPF who were either treatment-naive or were exposed to nintedanib for <6 months were intended to be randomized, in a 1: 1: 1: 1 ratio, to receive one of four treatments: (i) 550 mg LYT-100 (N=60); (ii) 825 mg LYT-100 (N=60); (iii) 801 mg Pirfenidone (N=60); and (v) matching placebo (N=60).

[0215] The proportion of patients with prior exposure to nintedanib was limited to 50%. Patients assigned to receive pirfenidone or placebo in Part A were re-randomized in a 1: 1 ratio to receive 550 mg LYT-100 TID or 825 mg LYT-100 TID. Following titration, all patients in Part B recieved 550 mg LYT-100 TID or 825 mg LYT-100 TID.

[0216] In each treatment group, dosing was three times a day (TID) of the indicated dosage (i.e., 550 mg of LYT-100 was administered three times daily for a total daily dose of 1650 mg; 825 mg of LYT-100 was administered three times daily for a total daily dose of 2475 mg). Patients took LYT-100, pirfenidone or placebo, orally and with food (solid or nutritional supplements, whenever possible), with approximately 6 hours between the three daily doses. Doses were adjusted according to safety and tolerability to avoid toxicity.

[0217] Table 1 below provides the dosing regimens used during the 6-month treatment period. Note that, for all treatment groups, the first 7 days of treatment, one capsule was taken TID, Day 8 through Day 14, two capsules TID., and Day 15 forward, 3 capsules TID. Each capsule was 275 mg LYT-100 (e.g., for the 550 mg TID dose at weeks 3-24, two 275 mg capsules of LYT-100 administered TID; for the 825 TID dose at weeks 3-24, three 275 mg capsules of LYT-100 administered TID).Table 1: Dosing RegimensWeek Group Dose Morning Dose (mg) Afternoon Dose (mg) Evening Dose (mg) #1 LYT- Titration 275 275 275 275100 E2 LYT- Titration 275 275 PTM 275 PTM 275 PTM 100 E *3+ LYT- Standard 550 275 275 PTM 275 275 PTM 275 275 PTM 100 E1 LYT- Titration 275 275 275 275100HighLYT100-IPF-2-WOWeek Group Dose Morning Dose (mg) Afternoon Dose (mg) Evening Dose (mg) #2 LYT- Titration 550 275 275 275 275 275 275100High3+ LYT- Standard 825 275 275 275 275 275 275 275 275 275 100High1 Pirfenid Titration 267 267 267 267one2 Pirfenid Titration 534 267 267 267 267 267 267 one3+ Pirfenid Standard 801 267 267 267 267 267 267 267 267 267 one1 Placebo N / A PT PTM PTM M2 Placebo N / A PT PTM PTM PTM PT PTMM M3+ Placebo N / A PT PTM PTM PTM PTM PTM PT PTM PTM M M*PTM: placebo trial matchDose Adjustment for Tolerability and Safety

[0218] The doses indicated (i.e., 550 mg TID and 825 mg TID) were adjusted based on any encountered adverse event or tolerability issues as follows.

[0219] Patients who experienced intolerance to therapy due to gastrointestinal side effects were reminded again to take study drug with food. If gastrointestinal events did not improve, or worsened in severity, dose reduction was considered per Investigator judgment.

[0220] Patients were instructed to avoid or minimize exposure to sunlight (including sunlamps), to use a sunblock (SPF 50 or higher), and to wear clothing that protects against sun exposure. Additionally, patients were instructed to avoid concomitant medications known to cause photosensitivity. Dose reduction was considered per investigator judgement.

[0221] If dose titration was well tolerated or the dose needed to be reduced due to tolerability or toxicity, adjustments to dosing were made as follows.

[0222] For Part A, Days 8-14: reduction from 2 capsules, TID, to 1 capsule, TID, x 2 days (longer if needed); Days 15-182: reduction from 3 capsules, TID, to 2 capsules, TID x 2 days (longer if needed); and if reduction from 3 capsules to 2 capsules of study drug TID was not sufficient to address difficulties with tolerability or toxicity, further reduction to one capsuleLYT100-IPF-2-WOTID was allowed; and Days 15-182: reevaluation for the ability to up titrate back to 3 capsules TID was performed.

[0223] For Part B, Days 183-189: reduction from 2 tablets, TID, to 1 tablet, TID, x 2 days (longer if needed); Day 190- 196; reduction from 2 tablets, TID, to 1 tablet, TID, x 2 days (longer if needed); Day 197 onward: (i) For patients receiving 550 mg TIP: reduction from 2 tablets, TID, to 1 tablet, TID, x 2 days (longer if needed); (ii) For patients receiving 825 mg TIP: reduction from 3 tablets, TID, to 2 tablets, TID x 2 days (longer if needed); and if reduction from 3 tablets to 2 tablets of study drug TID was not sufficient to address difficulties with tolerability or toxicity, further reduction to 1 tablet TID was allowed.

[0224] Following dose reductions, patients were re-evaluated for the ability to up titrate back to 2 or 3 tablets TID at each scheduled study visit at a minimum or more frequently at the discretion of the investigator. Patients who were unable to tolerate 275 mg (1 tablet) TID were discontinued from study medication but remained in the study.

[0225] In both Part A and Part B, patients who missed 14 consecutive days or more of treatment were to re-initiate therapy by undergoing the initial 2-week titration regimen up to the recommended daily dose. For treatment interruption of less than 14 consecutive days, the dose was resumed at the previous recommended daily dose without titration.

[0226] In the event of elevated liver function tests, clinical judgement was used to consider dose modifications to study medication as follows.

[0227] When ALT and / or AST are elevated >3 to <5 x upper limit of normal (ULN) without elevation of bilirubin and in the absence of symptoms that may indicate liver injury the clinician: (i) discontinued confounding medications, exclude other causes, and monitored the patient closely; (ii) repeated liver chemistry tests as clinically indicated; and / or (iii) maintianed the full daily dosage, if clinically appropriate, or reduced or interrupted (e.g., until liver chemistry tests were within normal limits). The patient was re-started on study drug at 1 capsule TID and following the up-titration schedule. If ALT and / or AST >3 but <5 x ULN was accompanied by symptoms that may indicate liver injury or hyperbilirubinemia, permanently discontinued study drug. If ALT and / or AST >5 x ULN, permanently discontinued study drug.Eligibility Criteria

[0228] Inclusion Criteria for Part A: (i) Male or female, aged >40 at the time of informed consent; (ii) Treatment naive patients or those with <6 months of exposure to nintedanib with physician diagnosed IPF based on ATSZERS / JRS / ALAT 2018 guidelines; (iii) Idiopathic Pulmonary Fibrosis on HRCT, performed within 12 months of Visit 1 as confirmed by central readers; (iv) The extent of fibrotic changes was greater than the extent of emphysema on theLYT100-IPF-2-WOmost recent HRCT scan as determined by the investigator; (v) Diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for Hemoglobin (Hb) [visit 1] > 30% and <90% of predicted ofnormal where available; and FVC > 45% of predicted normal.

[0229] Exlucusion Criteria for Part A: (i) Significant clinical worsening of IPF between Screening and Baseline Visits; (ii) AST, ALT > 1.5 x ULN at Visit; (iii) Bilirubin > 1.5 x ULN at Visit 1. Exceptions were made on a case-by-case basis for patients with Gilbert’s syndrome; (iv) Creatinine clearance <30 mL / min calculated by Cockcroft-Gault formula at Visit 1. (Laboratory' parameters from Visit 1 were used to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results were available only after randomization. In case at Visit 2 the results no longer satisfy the entry criteria, the Investigator 'as to determine whether if it is justified that the patient remains on study drug. The justification for decision was to be documented); (v) Patients with underlying chronic liver disease (Child-Pugh B or C hepatic impairment); (vi) Current or prior treatment with pirfenidone; (vii) Other investigational therapy- received within 1 month prior to randomization visit (Visit 2); (viii) Significant Pulmonary-Arterial Hypertension (PAH) defined by any of the following: previous clinical or echocardiographic evidence of significant right heart failure, history' of right heart catheterization showing a cardiac index < 2 l / mm / m2, or PAH requiring inhaled, subcutaneous or intravenous therapy with epoprostenol / Treprostinil; (ix) Primary obstructive airway physiology (pre-bronchodilator FEV1 / FVC < 0.7 at Visit 1); (x) Known explanation for interstitial lung disease, including but not limited to radiation, sarcoidosis, hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, human immunodeficiency virus (HIV), viral hepatitis, and cancer; (xi) Diagnosis of any connective tissue disease, including but not limited to scleroderma / systemic sclerosis, polymyositis / dermatomyositis, systemic lupus erythematosus, and rheumatoid arthritis; (xii) In the opinion of the Investigator, other clinically significant pulmonary' abnormalities, including poor or current lung cancer (treated within the past 5 years); (xiii) Major extrapulmonary physiological restriction (e.g., chest wall abnormality, large pleural effusion); (xiv) Cardiovascular diseases, any of the following: Uncontrolled hy pertension within 3 months months of Visit 1, Myocardial infarction within 6 months of Visit 1, or Unstable cardiac angina within 6 months of Visit 1; (xv) Prior hospitalization for severe confirmed COVID-19, acute exacerbation of IPF or any lower respiratory tract infection within 3-months of Visit 1; (xvi) Known symptoms of dysphagia or known difficulty' in swallowing tablets and / or total gastrectomy; (xvii) Use of any of the following drugs within 2 weeks prior to Visit 2 / baseline, during the screening period or planned during the duration of the study: (a) Strong and moderate CYP1A2 inhibitors (i.e. ciprofloxacin,LYT100-IPF-2-WOfluvoxamine, enoxacin, methoxsalen, mexiletine, vemurafenib) and phenytoin, rifampin, and terifluonmide (inducers of CYP1A2); (b) Medications associated with substantial risk for prolongation of the QTc interval (including but not limited to moxifloxacin, quinidine, procainamide, amiodarone, sotalol). Note that QTc prolongation is not an all / nothing drug effect, and specifically the administration drugs such as hydroxychloroquine do not preclude participation in this trial but does mandate measurement of the QTc every' 6 hours until deemed necessary in accordance with investigator judgement; (c) Immunosuppressant medications such as azathioprine, cyclophosphamide, cyclosporin A, methotrexate, prednisone at steady dose >10 mg / day or equivalent; (d) Medications used to treat pulmonary hypertension such as ambrisentan, bosentan, and phosphodiesterase-5 inhibitors (sildenafil and tadalafil used to treat erectile dysfunction are allowed); (e) Warfarin, as it may worsen IPF; and (g) Vaccination with a live vaccine is not permitted during the period from 4 weeks prior to screening to 4 weeks after the last dose; however, adenovirus and mRNA vaccines are allowed; (xviii) A current immunosuppressive condition (e.g., human immunodeficient virus); (xix) Major surgical procedures during screening or study period, wi th the exception of pre-planned procedures that will not interfere with study participation; (xx) Active alcohol or drug abuse; (xxi) Use of smoked (burnt) tobacco products; (xxii) Patients with a documented hypersensitivity' to LYT- 100; and (xxii) Patients with a documented lactose or galactose intolerance.

[0230] Tire Inclusion Criteria for Part B: The following inclusion and exclusion criteria were to be met before the patient could continue into the long-term extension (Part B): (i) Patient must have completed Part A of the study, through Day 183 of treatment; and (ii) In the opinion of the investigator, the patient was a good candidate for continued treatment.

[0231] The Exclusion Criteria for Parth B: (i) Patients must not have met any exclusion criteria listed for Part A; (ii) Patients who discontinued study medication and started receiving commercially available antifibrotic medication during Part A were not eligible for Part B; and (ii i) Patients whose treatment assignment was unblinded during Part A were not eligible for Part B.

[0232] The following drugs were not permitted during the study, and they must have been discontinued at least 14 days prior to study drug administration (Visit 2): Strong and moderate CYP1A2 inhibitors (ie, ciprofloxacin, fluvoxamine, enoxacin, methoxsalen, mexiletine, vemurafenib) and phenytoin, rifampin, and teriflunomide (inducers of CYP1A2); Any drug associated with prolongation of the QTc interval (including but not limited tomoxifloxacin, quinidine, procainamide, amiodarone, sotalol). Warfarin, imatinib, ambrisentan, azathioprine, cyclophosphamide, cyclosporin A, bosentan, methotrexate, sildenafil (except for occasionalLYT100-IPF-2-WOuse), prednisone at steady dose > 10 mg / day or equivalent; Immunosuppressant medications such as azathioprine, cyclophosphamide, cyclosporin A, methotrexate, and prednisone at steady dose >10 mg / day or equivalent; Medications used to treat pulmonary hypertension such as ambrisentan, bosentan, and sildenafil (except for occasional use); Warfarin, as it may worsen IPF; Immunosuppressants or other immune-modifying drugs were to be discussed in consultation with the sponsor; Use of concomitant pirfenidone and / or nintedanib while on study drug was prohibited. If a patient discontinued study medication and began receiving a commercially available antifibrotic medication during Part A, they were not eligible for Part B; Some concomitant medications were to be administered with care in combination with pirfenidone and as such clinical judgement should be used to consider discontinuation of a concomitant medication such as in the event of LFT elevation. Investigators were to consult the local prescribing information for pirfenidone for their country for additional information on medications to be used with caution in combination with LYT-100 or pirfenidone.Endpoints

[0233] The Part A Primary Efficacy Endpoint was the Rate of decline in Forced Vital Capacity (FVC; in ml) over 26 weeks. The Key Secondary Efficacy Endpoint was Change in FVC % predicted (FVCpp) from baseline to the end of the Double-blind Treatment Period (Week 26). Other Secondary Efficacy Endpoints were: Time to hospitalization due to respiratory causeor all-cause mortality through 26 weeks; and Time to IPF progression through 26 weeks (the end of the Double-blind Treatment Period), as defined by a decline in FVC% predicted (FVCpp) of 5% or greater, or death.

[0234] Secondary Tolerability Endpoints included: (i) Incidence of dose modifications (dose reductions and interruptions); (ii) Time to first dose modification (reduction or interruption); (iii) Duration of dose modifications (reductions and interruptions); (iv) Number of days on full assigned dose; (v) Incidence of patient-reported assessment of side effects (nausea, poor appetite, vomiting, belly discomfort, bloating, headache, tiredness (mental exhaustion), fatigue (physical exhaustion), no energy, and dizziness; (vi) incidence and duration of AEs of special interest; (vii) Time to treatment discontinuation due to an adverse event; and (viii) Change from baseline to Week 26 in PGI-C cough.

[0235] The Part A Exploratory Endpoints were: Time to hospitalization due to respiratory cause through 26 weeks; Time to all-cause mortality through 26 weeks; Change from baseline to Week 26 in King's Brief Interstitial Lung Disease Questionnaire (K BILD) total score; Change from baseline to Week 26 in St. George’s Respiratory Questionnaire - IPF Version (SGRQ-I);LYT100-IPF-2-WOChange from baseline to Week 26 in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D); Change in serum biomarkers from baseline through Week 26; Number and duration of respiratory hospitalizations or pulmonary exacerbations through 26 weeks; Changes from baseline to Week 26 in measures of fibrosis and lung structure, obtained by quantitative analysis of HRCT images; and Rate of hospitalization due to respiratory cause through 26 weeks.

[0236] The Part B Key Secondary Efficacy Endpoints were: (i) Change in FVCpp from the end of Part A (Week 26) to the end of Part B Period 1 (Week 52); and (ii) Rate of decline in FVC (in mb) from the end of Part A (Week 26) to the end of Part B Period 1 (Week 52) using the values obtained from the in-clinic spirometry assessments. An additional Secondary Efficacy Endpoints was Time to IPF progression in Part B, as defined by a decline from the end of Part A (Week 26) to the end of Part B Period 1 (Week 52) in FVCpp of 5% or greater, or death.

[0237] Secondary Tolerability Endpoints were: Incidence of dose modifications (dose reductions and interruptions); Time to first dose modification (reduction or interruption); Duration of dose modifications (reductions and interruptions); Number of days on full assigned dose; Incidence of patient-reported assessment of side effects (nausea, poor appetite, vomiting, belly discomfort, bloating, headache, tiredness [mental exhaustion], fatigue [physical exhaustion], no energy, and dizziness); Incidence and duration of AESIs; and Time to treatment discontinuation due to an AE.

[0238] Part B Exploratory Endpoints were: Time to hospitalization due to respiratory cause from the start of Part B (Week 26) through the end of Part B Period 1 (Week 52); Time to allcause mortality from the start of Part B (W eek 26) through the end of Part B Period 1 (Week 52); Time to hospitalization due to respiratory cause or all-cause mortality from the start of Part B (Week 26) through the end of Part B Period 1 (Week 52); Total duration on assigned dose from the start of Part B through the end of Part B Period 1 (Week 52); Change in EQ-5D from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52); Change in serum and plasma biomarkers from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52); Number and duration of respiratory hospitalizations or pulmonary exacerbations from the start of Part B (Week 26) through the end of Part B Period 1 (Week 52); and Rate of hospitalization due to respiratory cause from the start of Part B (Week 26) through the end of Part B Period 1 (Week 52).

[0239] Safety endpoints included: Adverse events, concomitant medications, clinical laboratory findings (chemistry, hematology, urinalysis), physical examinations, ECGs, and vital signs. These will be summarized descriptively, where appropriate.LYT100-IPF-2-WO

[0240] Tolerability endpoints included: Frequency of dose modifications (reductions and interruptions), time to first dose modification, (reduction or interruption), duration of adverse events of special interest, time to treatment discontinuation due to an adverse event of special interest and patient reported assessment of IPF symptoms, side-effects, severity, change and satisfaction.

[0241] Selected endpoints, including adverse events of special interest (AESIs) and all-cause mortality were considered efficacy outcomes in the context of the study objectives, the disease being studied, and the expected benefits of LYT-100. These endpoints were included in the overall discussion (as part of the clinical study report) of the safety and tolerability of LYT- 100, where appropriate.

[0242] For pharmacokinetic endpoints, a sparse PK sampling strategy was employed in which all patients provided pre-dose blood samples for determination of plasma concentrations of LYT-100 / pirfenidone and its metabolite(s). In addition, an intensive PK sub-study was conducted in approximately 8 patients per treatment arm in which each patient provided up to 16 blood samples for PK over a 24-hour period at Study Visits 3, 5 and 8.Table 2: Schedule of Assessments- Part AVisit 1 2 3 4 5“ 6 7“ 8A / ETbFUaWeeks of treatment Screening 0 4 8 12 16 20 26 30 Day <-28 to 0 1 29 57 85 113 141 183 211 Time window ±7 ±7 ±7 ±7 ±7 ±7 ±7 Informed consentc> uXHRCT sent to central reviewdX XsDemographics XQuestionnaires: K-BILD, EQ- X X X5D, SGRQ-PMedical history X XAdverse events, concomitant X X X X X X X X X medicationsIn / exclusion criteria X XPhysical examination, X X (including height)fVital signs (including weight) X X X X X X Resting 12-leadECG8X X XSafety Laboratory (blood and X X X X X X X Xurine)Pregnancy test11X X X Cotinine test (urine)1X X X XPK sample1X X X Genomic Analysis (DNA XSample)jLYT100-IPF-2-WOVisit 1 2 3 4 5“ 6 7a8A / ETbFUaSerum and plasma biomarker X X XsampleskHCRU assessments (including X X X X X X X X non-elective hospitalization)In-Clinic Spirometry X X X X X X (including FVC & DLCO)1Weekly Home SpirometrymXPatient-reported assessment11XPGI-S Cough / IPF Severity; XPGI-C Cough / IPF Severity11Patient Satisfaction0X X X X X X XPatient InterviewspX Randomization XAdminister 1st dose of study Xdrug in the clinicCompliance / drug X X X X X X X accountability anddispensation11Vital status assessment1XDLCO=diffusing capacity of the lungs for carbon monoxide; ECG=electrocardiogram; eCRF=electronic case report form; EQ-5D=EuroQol 5-Dimensional Quality of Life Questionnaire; FVC=forced vital capacity; FU=follow-up; HCRU=healthcare resource utilization; HRCT=high-resolution computed tomography; IPF=idiopathic pulmonary fibrosis; K-BILD=King’s Brief Interstitial Lung Disease; PGI-C=Patient Global Impression - Change; PGI-S=Patient Global Impression - Severity; PK=pharmacokinetic; SGRQ-I=St. George’s Respiratory Questionnaire - IPF VersionIn case of dose modification (reduction or re-escalation) additional visits were included. In case of premature discontinuation of study drug, the patient was expected to attend all visits as originally planned until the end of the trial.a. Visits 5 and 7 were conducted in-clinic, remote or hybrid. Follow-up visits were conducted via telephone or televisit.b. Early termination (ET) was done in cases of premature trial medication discontinuation during the study when the patient did continue all study visits along with a FU Visit 4 weeks later.c. Informed consent via written, electronic, or oral was documented before any study-specific Screening procedures were performed.d. Central review HRCT not older than 12 months was to be sent. If the patient did not have a HRCT within 12 months of Visit 1 or the available HRCT scan failed to meet the required image acquisition specification, a new HRCT could be be performed for the purposes of participation in the trial, provided the patient met all other inclusion and no exclusion criteria.e. Self-reported outcomes / Questionnaires were to be done by the patients in a quiet place prior to any other visit procedure. Order of questionnaires: 1. K-BILD, 2. EQ-5D, 3. SGRQ-I.f. Height collected at Visit 1 only.g. Resting ECGs was performed at Screening (Visit 1), Visit 2 prior to randomization, and Visit 8A / ET. h. Performed in all women of childbearing potential. Where required by local regulations, a serum pregnancy test was conducted in addition to the urine pregnancy test, (ie, in certain countries, a serum pregnancy test is required at Screening). If a urine pregnancy test was positive, a serum pregnancy test must also have been performed as confirmation. Documentation was done in patient’s notes. Where required by local regulations, an appropriate pregnancy test was performed more frequently than this schedule.i. In all patients, PK samples were obtained immediately prior to drug administration at Visits 3, 5 and 8. Date and exact clock time of drug administration and blood sampling must have been recorded on the eCRF. Patients were provided (Visits 2 and 4) with a PK-card to support the record of the exactLYT100-IPF-2-WOclock time of medication intake 3 days preceding PK sampling. Approximately 8 patients per treatment group participated in the intensive PK substudy at Visits 3, 5 and 8. PK samples were obtained from these patients immediately prior to dosing and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 15, 18 and 24 hours postdose. Pre-dose sample was collected within 30 minutes prior to dosing. Acceptable windows for PK sampling were as follows: + / - 2 minutes during 0.5 to 4-hour postdose period, + / - 5 minutes 6-16 h postdose and + / - 10 minutes 24 h postdose. Exact time of each sample collection was recorded.j. Deoxyribonucleic Acid (DNA) and serum banking samples were taken from eligible patients at Visit 2 who consented. Participation was voluntary and not a prerequisite for participation in the trial. k. Biomarker samples were taken just before dmg administration at Visits 2, 5 and 8.l. Order of lung function measurements: 1. F VC followed by patients rest at Screening (Visit 1), baseline (Visit 2) and weeks 4 (Visit 3), 8 (Visit 4), 16 (Visit 6) and 26 (Visit 8A / ET); 2. DLCO. Measurements at approximately the same time each visit. DLCO was done at Screening (Visit 1) and Week 26 (Visit 8A / ET) where available at the study site. If a patient’s in-clinic spirometry (and DLCO where applicable) assessments were conducted in a pulmonary function lab not in close proximity to the research clinic where other study assessments were performed, the sequence of assessments was modified to reduce burden on study patients as long as spirometry continued to be performed in the morning.m. Weekly spirometry was performed by patients at home weekly in the am. Site staff scheduled televisits with patients to coach the weekly FVC maneuvers, as needed. On the weeks where in-clinic spirometry is performed, home spirometry was not performed on that same day. Patients could do their weekly home spirometry assessment the following day. The final home spirometry assessment was to be performed no later than the day prior to Visit 8A (Week 26).n. Patients were asked weekly to complete ePROs to assess their symptoms, cough and IPF severity starting during Screening (Visits 1-2) and continued to assess symptoms and side effects, cough and IPF severity weekly through the 26-week treatment period (Visits 2-8). Patients were also asked to assess PGI-C Cough and PGI-C IPF Severity at Visit 8A / ET.o. Patients were asked at baseline (Visit 2) to assess satisfaction expectations with their study treatment and then access overall satisfaction with study medication weekly beginning on Day 7 through Visit 8A / ET.p. Up to 30 (English speaking) patients were asked to participate in interviews to discuss their symptoms at the end of the treatment period (either on / after the ET visit for those who discontinued treatment early or on / after Day 183 forthose who completed study treatment).q. Dispensation at Visits 2, 3, 4, and 7; Compliance / Accountability at Visits 2, 3, 4, 6, and 8 A. All unused capsules were collected at Visit 8A.r. Vital status check were done at Week 26 for randomized patients who discontinued study drug early and did not complete all study visits.s. HRCT of the lungs was performed prior to Visit 8A / ET. The CT scan was to be performed between Visit 7 and Visit 8A / ET per the vendor imaging guidelines. The HRCT was to be performed within 28 days of Visit 8A / ET whenever possible. If the Week 26 HRCT at Visit 8A / ET was less than 12 months since the baseline CT, the Visit 8 A / ET HRCT could be waived as required by local or national health authorities, ethics committees and / or imaging guidelines for this patient population.t. Cotinine testing was performed for sensitivity analysis.u. Patients must have provided a signed genetic sample informed consent form prior to blood collection at Visit 2.Table 3: Schedule of Assessments- Part BStudy Period Period 2Period 1 FU Every 13 weeks Visit SB 9a10 lla12 13a14 15+ ETbFU Weeks of treatment 26 30 34 39 42 46 52 65+Day183 211 239 274 295 323 365 456+ 28LYT100-IPF-2-WOStudy Period Period 2Period 1Every 13 weeks FU Visit window ±7 ±7 ±7 ±7 ±7 ±7 ±2 ±2 +7 days days days days days days weeks weeks days Informed consent0XIn / exclusion criteria11XAdverse events,X X X X X X X X Xconcomitant medicationPatient satisfaction X X X X X X X X HCRU assessments(including non-elective X X X X X X X X X hospitalization)Resting 12-lead ECGeX X Vital signs (includingX X X X X X X Xweight)Physical examination X X Spirometry (including FVCX X X X X± DLCO)fPregnancy test8X X X X X Cotinine test (urine) X X X X Safety laboratory (bloodX X X X X X X Xand urine)EQ-5D X X X XSerum and plasmaX X X Xbiomarker samples11Collection of all unusedcapsules and dispensationXof tablets for Long-termextension PeriodTabletcompliance / medicationX X X X Xaccountability anddispensation of tablets1Vital status (living / dead)X Xassessment1ALT=alanine aminotransferase; AST=aspartate aminotransferase; DLCO=diffusing capacity of the lungs for carbon monoxide; ECG=electrocardiogram; eCRF=electronic case report form; ET=end of treatment;FVC=forced vital capacity; FU=follow-up; HCRU=healthcare resource utilization; IPF=idiopathic pulmonary fibrosisNote: In case of dose modification (reduction or re-escalation) additional visits may be included. In case of discontinuation of study medication, the patient will be expected to attend all visits as originally planned until the end of the study.a. Visits 9, 11, and 13 could be conducted in clinic, remote, or hybrid. FU Visit could be conducted via telephone or televisit.b. Early termination was to be done in cases of study medication discontinuation during the study when the patient did not continue all study visits along with a FU Visit 4 weeks later.c. Informed consent via written, electronic, or oral must have been documented before any study-specific procedures were performed.d. Reviewed at each visit to confirm the patient’ s continued eligibility for the study. Samples were collected for ALT, AST, bilirubin and creatine as part of safety laboratory testing, but values did not need to be confirmed to proceed.e. Resting ECGs was performed at Visit 8B, Visit 14 and ET (if applicable).f. Order of lung function measurements: 1. FVC followed by patients rest at Weeks 34 (Visit 10), 42 (Visit 12), and 52 (Visit 14) during Period 1, and every 13 weeks during Period 2. DLCO. Measurements at approximately the same time each visit. Where available at the study site, DLCO was done at Week 52 (Visit 14) during Period 1 and every 13 weeks during Period 2.LYT100-IPF-2-WOg. Performed in all WOCBPs. Where required by local regulations, a serum pregnancy test was conducted in addition to the urine pregnancy test, (ie, in certain countries, a serum pregnancy test is required at enrollment.) If a urine pregnancy test was positive, a serum pregnancy must also have been performed as confirmation.h. Biomarker samples were taken just before drug administration at Visit 11 in Period 1, and every 13 weeks during Period 2.i. Dispensation at Visits 8B, 10, 12, and 14 in Period 1, and at all visits in Period 2; compliance / accountability at Visits 11, 13, and 15 in Period 1, and through the end of treatment in Period 2.j. Vital status check (living / dead) were done for all patients at Week 26 and at the end of the study for patients who discontinued study medication early and did not complete all study visits.

[0243] Weekly home FVC was assessed with an individual spirometer, which was supplied to each patient. The site used its own equipment for in-clinic FVC assessments. Spirometry measurements were performed according to the American Thoracic Society / European Respiratory Society (“An Official American Thoracic Society and European Respiratory Society Technical Statement Technical Statement” Am J Respir Crit Care Med. 2019; 200(8):e71-e83) and the study specific Pulmonary Function Manual, at timepoints specified in the Schedule of Assessments. Spirometry was conducted while the patient was in a seated position. The test was done in order to achieve three acceptable FVC measurements (three curves to be provided), and the best result selected according to the guidelines. The best of three efforts was defined as the highest FVC, obtained on any of the three blows meeting the ATS / ERS / JRS / ALAT 2019 criteria (Graham et al, 2019) with preferably a maximum of eight attempts.

[0244] For the in-clinic assessments effort was be made to schedule the spirometric measurements at approximately the same time of the day with reference to the baseline measurement (Visit 2). On days of clinic visits, patients were to refrain from strenuous activity at least 12 hours prior to pulmonary function testing. Patients were to avoid cold temperatures, environmental smoke, dust, or areas with strong odors (e.g., perfumes).

[0245] If treated with bronchodilators, patients were instructed to withhold medications as follows prior to the in-clinic spirometry assessments: (i) SABA (e.g., albuterol or salbutamol) 4-6 h; (ii) SAMA (e.g., ipratropium bromide) 12 h; (iii) LABA (e.g., formoterol or salmeterol) 24 h; (iv) Ultra-LABA (e.g., indacaterol, vilanterol, or olodaterol) 36 h; (v) LAMA (e.g., tiotropium, umeclidinium, aclidinium, or glycopyrronium) 36-48 h. LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist.

[0246] Prior to weekly home FVC, patients were advised to hold all bronchodilators on the day of the weekly FVC assessment. If rescue bronchodilator use was required during the weeklyLYT100-IPF-2-WOhome FVC assessment, the patient was to abandon the FVC assessment for that week and then perform the weekly home FVC as planned the following week.

[0247] Pulmonary function was measured in a standardized manner and results transmitted electronically during the visit immediately after performing the spirometry and evaluated by a central reader. In case the acceptability and repeatability criteria as specified by ATS / ERS / JRS / ALAT guidelines were not met, a repeat spirometry was performed during the same visit.

[0248] In-clinic spirometry was performed at the following visits: Visit 1 (Screening), Visit 2 (baseline), Visits 4, 6, and 8 / ET (premature study medication discontinuation).

[0249] The primary efficacy endpoint was the rate of decline in FVC mL over 26 weeks. In addition, decline in FVC % predicted from baseline to Week 26 and by > 10% and > 5% was assessed. The secondary endpoint was comparison of FVC % predicted change from baseline to Week 26.

[0250] All DLCO measurements at a site were conducted with the same DLCO device (i.e., if multiple devices were available, selected only one for the entire study). Single-breath DLCO measurement was carried out according to local practice at the time points specified in the Schedule of Assessments. Before beginning the test, the techniques was demonstrated, and the patient carefully instructed. The DLCO assessment was always to be performed after the FVC measurement and following a few minutes of rest.

[0251] The following parameters were measured or calculated as part of the spirometry assessment: FVC (mL) and FVC% predicted; FEV1 (mL) and percent predicted forced expiratory volume in 1 second (FEVl%p); FEV1 / FVC ratio; and Forced expiratory flow between 25% and 75% of exhaled volume (FEF25-75).

[0252] The '2012 Global Lung Function Initiative Equations' was used to calculate the predicted values (Quanjer et al, “Multi-ethnic reference values for spirometry for the 3-95 year age range: the global lung function 2012 equations: Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung Function Reference Values.,” Eur Respir J, vol.40(6), pp. 1324-1343, 2012).

[0253] Exploratory parameters included: Duration on assigned dose from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52); Number and duration of respiratory hospitalizations or pulmonary exacerbations through 26 weeks; Number and duration of respiratory hospitalizations or pulmonary exacerbations from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52); Measures of fibrosis and lung structure, obtained by quantitative analysis of HRCT images; Rate of hospitalization due to respiratory causeLYT100-IPF-2-WOthrough 26 weeks; and Rate of hospitalization due to respiratory cause from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52).

[0254] A time to (first) event analysis was conducted for each of the following endpoints: Hospitalization due to respiratory cause or all-cause mortality through 26 weeks; IPF progression through 26 weeks (the end of Part A), as defined by a decline in FVC % predicted (FVCpp) of 5% or greater, or death; IPF progression through 52 weeks (the end of Part B Period 1); Hospitalization due to respiratory cause through 26 weeks; Hospitalization due to respiratory cause from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52); All-cause mortality through 26 weeks; All -cause mortality from the end of Part A (W eek 26) through the end of Part B Period 1 (Week 52); and Hospitalization due to respiratory cause or all-cause mortality from the end of Part A (Week 26) through the end of Part B Period 1 (Week 52)

[0255] Change from baseline to week 26 was analyzed for the QOL assessments: King's Brief Interstitial Lung Disease Questionnaire (K-BILD); EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D); St. George Respiratory Questionnaire-I (SGRQ-I); Baseline Satisfaction (Visit 2 only); Patient reported assessment of IPF symptoms (Visit 8 / ET only); PGI-S Cough (Visit 8 / ET Only); PGI-C Cough (Visit 8 / ET Only); PGI-S IPF Severity (Visit 8 / ET Only); PGI-C IPF Severity (Visit 8 / ET Only); Patient reported assessment of side effects (Visit 8 / ET Only); PGI-S Side Effects (Visit 8 / ET Only); and Overall Satisfaction (Visit 8 / ET Only).

[0256] The K-BILD is a self-administered health status questionnaire that was developed and validated specifically for patients with ILD. Questionnaire development and validation included a range of ILDs, including the ILD disease types in this study population. The questionnaire consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, with a score of 100 representing the best health status. The efficacy endpoint is the change from baseline to Week 26 in the total score.

[0257] The EQ-5D was developed by the European Quality of Life Group (EuroQol Group) and is a standardized instrument for use as a measure of health outcome. The version used in this trial was the new five-level version (EQ-5D-5L). The questionnaire consists of 2 sections. The first section is the descriptive system with 5 questions regarding the patient's health state on the day of the assessment. Each question captures one dimension of health (e.g., mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Each dimension has three levels, which results in a 1 -digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5 -digit number that describes the patient’s health state) and has five levels to answer. The second section records the patient's self-rated health status on the day of the assessment on a vertical graduated (0 to 100) visualLYT100-IPF-2-WOanalogue scale. The EQ VAS records the patient’s self-rated health on a vertical VAS and can be used as a quantitative measure of health outcome that reflects the patient’s own judgment.

[0258] The SGRQ-I is an idiopathic pulmonary fibrosis disease-specific instrument designed to measure the impact of the disease on overall health, daily life, and perceived well-being in patients with interstitial lung disease. There are 34 self-completed items with 3 domain component scores (Symptoms, Activities, and Impacts). Higher scores indicate more limitations and provides a sample of the scale. Changes from baseline in the component scores of the SGRQ-I were assessed as secondary efficacy endpoint. Further, a responder analysis was performed in which the proportion ofpatients experiencing an increase of >4 units (vs < 4 units) will be assessed.

[0259] From screening to the end of treatment, patients were asked weekly to describe specific symptoms (shortness of breath, fatigue, tiredness, discomfort in the chest, loss of appetite) “In the past 7 days” how often these symptoms occurred on a scale from 0 (never) to 4 (always) and “at its worst, how bad” was the symptom from 0 (not all) to 4 (very bad). An example survey is provided as FIG. 4.

[0260] Patient Reported Assessment of Side Effects and PGI-S Side Effects. From Baseline to the end of treatment, patients were asked weekly to describe specific side effects (nausea, poor appetite, vomiting, abdominal discomfort, bloating, headache, dizziness, and fatigue) “In the past 7 days” how often these side effects occurred on a scale from 0 (never) to 4 (always) and “at its worst, how bad” was the side effect from 0 (not all) to 4 (very bad). An example survey is provided as FIG. 5. In addition, PGI-S-Side Effects asks, “Over the past 7 days, how bad were the study treatment side effects?” from 0 (not all) to 4 (very bad).

[0261] PGI-S Cough Assessment and PGI-C Cough. From screening to the end of treatment, patients were asked weekly “Over the past 7 days, how bad was your cough?” on a scale from 0 (not bad at all) to 4 (very bad). In addition, at the end of the study, the PGI-C Cough asked patients to “Compare your cough over the past 7 days to your cough at the beginning of the study?” on a scale from 0 (much better) to 6 (much worse).

[0262] PGI-S IPF Severity and PGI-C IPF Severity. From screening to the end of treatment, patients were asked weekly “Over the past 7 days, how bad was your IPF severity?” on a scale from 0 (not bad at all) to 4 (very bad). In addition, at the end of the study, the PGI-C IPF Severity asked patients to “Compare your cough over the past 7 days to your cough at the beginning of the study? on a scale from 0 (much better) to 6 (much worse).”

[0263] Patients were asked questions regarding expected satisfaction with IPF treatment and how bad side effects could be to remain satisfied. In addition, beginning on Day 7, patients wereLYT100-IPF-2-WOasked weekly through Visit 8 / ET about Overall Satisfaction “Considering your overall experience over the past 7 days, how satisfied are you with the study medication on a scale from 0 (very satisfied) to 6 (very dissatisfied). An example survey is provided as FIG. 6.

[0264] Up to thirty (30) patients were targeted to participate in the qualitative interviews. The interviews were to occur after completion of blinded treatment for patients who discontinued treatment early or who completed study treatment. The sample size was elected to be in line with evidence-based recommendations for the estimate of sample sizes for qualitative interviews. This research has demonstrated that, across a wide range of diseases, 84% of all relevant symptom concepts will emerge by the tenth interview and 97% of relevant symptom concepts will emerge by the twentieth interview. Every effort was made to address demographic representativeness in the sample, including recruiting patients across education, race / ethnicity, gender, and age range.

[0265] All interviews were conducted based on the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) task force recommendations. The interviews were based on an interview guide with open-ended questions that were used to encourage spontaneous responses and good qualitative data. For example, the interview guide included non-leading questions such as “What is a bad day like with IPF?” The interview guide included topics, questions, and probes designed to understand IPF from the patient’s perspective. The interview guide was to begin with an overall introduction about the interview and then move into a general discussion about the patient’s experience. During this concept elicitation phase of the interview, the interviewer listened for terms and wording that were spontaneously voiced by the patient when describing any problems they may have experienced (with particular reference to respiratory problems). A mix of open-ended and probing questions was to be used.

[0266] Safety laboratory tests (hematology, biochemistry, coagulation, urinalysis, and urine cotinine) were performed at the time points specified in the Schedule of Assessments (Tables 4 and 5). Additional clinical laboratory tests may have been performed at other times if deemed necessary based on the patient’s clinical condition. Each patient had blood samples taken for hematology, coagulation, biochemistry and as necessary for serum pregnancy and FSH analyses at the time points delineated in the study schedules. In addition, urine sample were taken for urinalysis at the time points delineated in the study schedules.

[0267] Safety Biomarkers assessed were: C-reactive protein (CRP - collected with biomarkers and at screening); Troponin 1 (TROP1- collected with biomarkers); Ferritin (collected withLYT100-IPF-2-WObiomarkers and at screening); Lymphocytes (LYM - collected with hematology biomarkers and at screening); and D-dimer (collected with biomarkers).

[0268] Inflammatory and Fibrotic Biomarkers assessed were: Transforming Growth Factor Beta 1 (TGF-β1); Tumor necrosis factor alpha (TNF-α); Interleukin 6 (IL-6); Interleukin 1 beta (IL-1β); Platelet-derived growth factor- β (PDGF- β); Granulocyte colony-stimulating factor (GCSF); and Vascular endothelial growth factor (VEGF).

[0269] Coagulation parameters to be tested were: INR; Prothrombin time; APTT; and D-dimer (collected with biomarkers).

[0270] Disease and / or drug-related biomarkers including, but not limited to, extracellular matrix synthesis and turnover (i.e., neo-epitopes), inflammatory cells, alveolar epithelial and oxidative stress markers, were to be assessed in plasma and / or serum, if deemed appropriate. In addition, other analytes such as metabolites or endogenous biomarkers might have been assessed in plasma and / or serum, if deemed appropriate. Blood samples for potential serum disease-specific biomarker analysis and for potential plasma disease-specific biomarker analysis were collected before study medication administration at Visits 2, 5 and 8 / ET. The details on blood sample collection, handling, storage, and shipment instructions were to be provided in a separate laboratory manual.

[0271] Safety and tolerability were assessed throughout the study by monitoring AEs, physical examination, vital signs, 12-lead ECGs, clinical laboratory values (hematology panel, multiphasic chemistry panel and urinalysis), and concomitant treatments. In this study, AEs are reported for all patients from the time of consent until the completion of the Follow-up visit. AEs reported prior to the first dose are denoted as pre-treatment. SAEs are reported for all patients (randomized or not) from the time of consent. AEs reported from the time of consent to confinement on Day 0 were recorded as pre-treatment AEs.

[0272] Treatment emergent adverse events (TEAEs) are defined as an AE that occurs following first dose of study medication and were evaluated from the first administration of study drug on Day 1 until the Follow-up visit.

[0273] Adverse Events of Special Interest (AESIs) relate to any specific AE identified at the project level as being of particular concern for prospective safety monitoring and safety assessment within this trial, (e.g., the potential for AEs based on knowledge from other compounds in the same class). AESI were to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe that applies to SAEs,

[0274] For this study, the following were considered AESIs for LYT-100: (i) General disorders: anorexia, decreased appetite, fatigue; (ii) GI disorders: diarrhea, nausea, vomiting;LYT100-IPF-2-WO(iii) investigations, e.g., hepatic laboratory abnormalities: increase in transaminases; and skin and subcutaneous tissue disorders, e.g., photosensitivity reaction and rash.

[0275] Elevations in liver enzymes as well as post-marketing reports of drug-induced liver injury have been associated with the parent compound, pirfenidone. Therefore, these were monitored as AESIs and have dose modification instructions were provided.

[0276] An SAE is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the study drug (active or placebo), that fulfils one or more of the following: results in death; immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; and an important medical event that may jeopardize the patient or may require medical intervention to prevent one of the outcomes listed above.Efficacy and Tolerability Results - Part A

[0277] Subject disposition is summarized in FIG. 7. With reference to FIG. 7, 500 potential subjects were assessed for eligibility, resulting in randomization of 257 patients. Allocation to each study arm was nearly equal. Overall, 42 patients in the 550 mg TID LYT-100 group, 50 patients in the 825 mg TID LYT-100 group, 43 patients in the 801 mg TID pirfenidone group, and 52 patients in the placebo group completed the 26-week study treatment.

[0278] Patient demographics for Part A of the study are summarized in Table 4. The population included in this study was consistent with other IPF trials. Patients were predominantly male (71.2%) and older (mean age was 70.9 years) population. There were several differences from other IPF studies, such as regional differences (relatively higher enrollment from Latin America and Asia, and relatively less enrollment from Europe in this study) and background antifibrotic therapy was not allowed.Table 4. Patient Demographics- Part ACharacteristic Placebo TID Pirfenidone Deupirfenidone 550 Deupirfenidone 825N=65) 801 mg TID mg TID mg TID N=63) (N=65) (N=64) Age (mean, 71.7 (7.27) 71.0 (8.50) 70.9 (7.89) 70.0 (8.31)SD)Age group, n(%)<65 years 8 (12.3) 14 (22.2) 13 (20.0) 17 (26.6)>65 and <75 36 (55.4) 22 (34.9) 31 (47.7) 25 (39.1)≥75 21 (32.3) 27 (42.9) 21 (32.3) 22 (34.4)Male 47 (72.3) 47 (74.6) 46 (70.8) 43 (67.2)Female 18 (27.7) 16 (25.4) 19 (29.2) 21 (32.8)LYT100-IPF-2-WOCharacteristic Placebo TID Pirfenidone Deupirfenidone 550 Deupirfenidone 825N=65) 801 mg TID mg TID mg TID N=63) (N=65) (N=64) Race, n (%)White or 38 (58.5) 42 (66.7) 40 (61.5) 42 (65.6) CaucasianAsian 22 (33.8) 21 (33.3) 22 (33.8) 21 (32.8) Black or 3 (4.6) 0 1 (1-5) 0AfricanAmericanOther 2 (3.1) 0 2 (3.1) 1 (1-6) Ethnicity, n(%)Hispanic or 23 (35.4) 14 (22.2) 16 (24.6) 14 (21.9) LatinoRegion, n (%)United States 10 (15.4) 20 (31.7) 13 (20.0) 11 (17.2) Central / South 23 (35.4) 16 (25.4) 17 (26.2) 14 (21.9) AmericaEurope and 10 (15.4) 8 (12.7) 14 (21.5) 19 (29.7) South AfricaAsia 22 (33.8) 19 (30.2) 21 (32.3) 20 (31.3) BMI (kg / m2; 27.39 (5.079) 27.60 (4.018) 26.96 (4.788) 27.12 (4.942) mean, SD)Comorbidities(>20%frequencyoverall)Prior 1 (1.5) 2 (3.2) 3 (4.6) 3 (4.7) nintedanibuse <6months, n (%)Years of IPF 1.4 (1.75) 1.8 (2.50) 1.8 (2.42) 2.1 (2.30) diagnosis(mean, SD)IPF diagnosis 51 (78.5) 45 (71.4) 46 (70.8) 39 (60.9)<2 years, n(%)HRCTpattern, n (%)Probably UIP 31 (47.7) 32 (50.8) 31 (47.7) 32 (50.0)I IP 34 (52.3) 31 (49.2) 34 (52.3) 32 (50.0) Baseline FVC 2550.5 2682.6 (729.79) 2672.9 (845.35) 2659.2 (871.70) (mL) mean, (974.01) (n=61) (n=63)SDBaseline FVC 76.74 (19.822) 79.52 (17.203) 80.11 (20.438) 79.45 (20.951) (percent (n=61) (n=63) predicted)mean, SDBaseline FVC 3 (4.6) 3 (4.9) 1 (1-5) 5 (7.9)pp <50%, n(%)LYT100-IPF-2-WO

[0279] The primary efficacy endpoint was rate of decline in FVC (in mL) over 26 weeks. The primary analysis was performed based on the full analysis set (FAS). The FAS was defined as all randomized study participants who received at least one dose of study drug and had at least one valid efficacy assessment.

[0280] The primary efficacy analysis was performed using the Bayesian linear mixed effects model, in which the two LYT-100 groups (550 mg TID and 825 mg TID) were pooled together and compared to placebo. Bayesian methods include prior elicitation utilizing historical data and the ability to update over time and test inferences as new data becomes available. Bayesian analysis provides posterior probability distributions of parameters of interest (e.g., treatment effects), allowing for direct interpretation of the probability that a treatment is effective (i.e., the analysis allows calculation of the probability of an outcome). Bayesian methods have been implemented in two previous phase 2 clinical trials in IPF. See Richeldi et al, “Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis”, NEJM, 2022; 386:2178-87) and “Bristol Myers Squibb’s Investigational LPA1 Antagonist Reduces the rate of Lung Function Decline in Patients with Idiopathic Pulmonary Fibrosis”, May 22, 2023. The FDA has issued several guidance documents relating to the use of Bayesian statistical methods in drug development. See “Adaptive Designs for Clinical Trials of Drugs and Biologies”, FDA guidance, Nov 2019, and “Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials”, Feb 2010.

[0281] Specifically, in the present study, a prespecified Bayesian analysis was utilized to assess the primary endpoint and provided the probability of a positive treatment difference for deupirfenidone compared to placebo. This also allowed for augmentation of the placebo arm with placebo data from historical IPF trials. This approach enabled a more patient-centric clinical trial design by minimizing the number of trial participants exposed to placebo — a key consideration since IPF is progressive and fatal — while delivering a robust, placebo-controlled dataset.

[0282] The primary efficacy analysis of the study assessed the superiority of LYT-100 to placebo as measured by the difference in rate of decline (θ) in FVC between the combined LYT-100 and placebo arms. The primary analysis was to be declared successful if the posterior probability Pr(0 > 0 | Data) > 0.90. The response variable was the absolute FVC over time, including baseline. The model included fixed effects for treatment, time in weeks (as a continuous covariate), and treatment by time interaction, as well as subject-level random effects for the intercept and slope.LYT100-IPF-2-WO

[0283] In addition to the Bayesian analysis, the FVC data (both pooled and individual dose) was also compared to placebo using the frequentist approach, applying a random coefficient regression model with absolute FVC as a response, including baseline. The model included fixed effects of week, treatment, and interaction between week and treatment. The random effects were subject-specific intercept and slope. The effect of interest was change from baseline in FVC at Week 26 between the combined LYT-100 and placebo arms.

[0284] The key secondary efficacy endpoint of this study was change from baseline in forced vital capacity % predicted (FVCpp). The secondary endpoint analysis was performed using a Bayesian linear mixed effects model. The response variable was the absolute FVCpp overtime, including baseline. The fixed effects included treatment, time in weeks (as a continuous covariate), and treatment by time interaction, as well as the random effects for the intercept and slope for each subject. The posterior probability threshold 0.90 was chosen to be consistent with the hypothesis testing of the primary endpoint. Posterior probability that the difference exceeds 0 is provided. Pooled and individual dose data for FVCpp was also compared to placebo using the frequentist approach as described above.

[0285] Efficacy results according to the primary and secondary endpoints are summarized in FIGS. 8 to 14 and Tables 5 to 8, noting that the primary endpoint was for pooled 550 mg TID and 825 mg TID arms, while Table 6 presents efficacy analyses for the individual dose arms. With reference to FIG. 8, the study achieved the primary endpoint for LYT-100 with the 550 mg and 825 mg pooled arms, demonstrating reduced lung function decline compared to placebo as measured by Forced Vital Capacity with a posterior probability value vs. placebo of 98.5%. With reference to FIG. 9A, 825 mg TID LYT-100 outperformed pirfenidone in change from baseline FVC by Bayesian analysis (99.7% posterior probability).

[0286] Based on historical development in IPF with single agents, a statistically significant effect was not anticipated between any individual arm vs placebo given the size of this Phase 2b trial; however, the magnitude of the efficacy demonstrated with deupirfenidone 825 mg TID was large enough to achieve a statistically significant p value in both the primary endpoint (efficacy, FVC) and the secondary endpoint (efficacy, FVCpp) as discussed below.

[0287] Preliminary pharmacokinetic results based on the foregoing extrapolations indicate that deupirfenidone 825 mg TID achieved -50% higher exposure (AUC) than pirfenidone 801 mg TID, corresponding with the greater efficacy results demonstrated with the 825 mg TID dose of deupirfenidone. Notably, the dramatically increased drug exposure did not result in an increase in tolerability challenges, suggesting that the deuterated structure of deupirfenidone may overcome the dose-limiting adverse events associated with pirfenidone.LYT100-IPF-2-WO

[0288] The study also achieved its key secondary endpoint, with the pooled deupirfenidone arms demonstrating a 99.7% posterior probability on the change in FVCpp based on a prespecified Bayesian analysis of forced vital capacity percent predicted (FVCpp) from baseline to week 26. While FVC (the primary endpoint) and FVCpp and are both measures of lung capacity, FVCpp accounts for key patient characteristics and therefore standardizes the results. Notably, this key secondary endpoint accounts for patient characteristics of height, age, and sex. With reference to FIGS. 10A and 10B, LYT-100 825 mg also outperformed pirfenidone on FVCpp. Although a statistically significant difference was not anticipated between any individual arms given the size of this Phase 2b trial, deupirfenidone 825 mg TID demonstrated a statistically significant benefit on this secondary endpoint compared to placebo (-0.43 vs. -3.43, respectively; p=0.01), reinforcing the robustness of the treatment's impact. With reference to Table 8, notably, the 825 mg TID LYT-100 arm had the greatest number of patients with advanced lung disease (FVCpp of 45-50%).

[0289] With reference to FIGS. 11A and 11B, LYT-100 demonstrated a clear dose-dependent effect with respect to change from baseline in FVC and FVCpp (Mixed Model Repeated Measure). With reference to FIG. 12, the 825 mg TID dose stabilized lung function. Specifically, the IPF patients in the LYT-100 825 mg TID arm had a 6-month FVC decline in line with that seen for healthy adults >60 years. See, e.g., Valenzuela, C. Poster 673, ERS Congress 2024) and Luoto et al., Eur Respir J. 53(3): 1701812 Mar 2019; 6-month decline in general population aged 60-102 years, estimated by taking reported 1-year decline and dividing by 2. Accordingly, FVC values for patients receiving the 825 mg TID LYT-100 dose for 26 weeks approached those expected for normal physiological decline in healthy older adults over the same time frame, suggesting the potential for this dose to stabilize lung function in IPF patients.

[0290] With reference to FIG. 13, a secondary endpoint of ELEVATE was time to IPF progression, as defined by time to an FVC decline of 5% or more or death. Deupirfenidone 825 mg TID was statistically significantly different from placebo with a hazards ratio (HR) of 0.439, with a log rank p value = 0.002. Deupirfenidone 825 mg delayed progression by such a degree that a median time to IPF progression was not evaluable (95% CI 26.14, not evaluable) since fewer than 50% of the arm had reached an IPF progression event by week 26. Pirfenidone 801 mg TID was statistically significantly different from placebo with a hazards ratio (HR) of 0.501, with a log rank p value = 0.008. With continued reference to FIG. 13, the 825 mg TID dose demonstrated an increase in the percentage of subjects with a positive change in FVC from baseline at week 26 relative to pirfenidone and placebo.LYT100-IPF-2-WOi Ai Blaesannassyy

[0291] With reference to Tables 5 to 7 and FIG 9B, the difference in the rate of FVC decline with deupirfenidone 825 mg TID compared to placebo was large enough to be statistically significant (-21.5 mL vs. -112.5 mL, respectively; p=0.02), which represents a robust treatment effect of 80.9% (Table 7 and FIG. 9C). In contrast, the pirfenidone 801 mg TID arm in this study showed a treatment effect of 54.1% compared to placebo (-51.6 mL vs. -112.5 mL; Table 7 and FIG. 9C). While the 550 mg TID dose did not demonstrate statistical significance in change from baseline for FVC or FVCpp versus placebo, efficacy comparable to that of 801 mg pirfenidone, the current standard of care was shown (FIGS. 9A, 9B, 10A, and 10B) and as described below, exhibited improved tolerability relative to pirfenidone. Accordingly, by various measures, LYT-100 distinguished over the current standard of care (801 mg TID pirfenidone). As described herein above, the 825 mg TID dose of LYT-100 provides an AUC of LYT-100 which is 143% that of the AUC of pirfenidone dosed at 801 mg TID. However, the efficacy of pirfenidone has not been explored above 2403 mg total daily dose in view of tolerability issues, and the dose-response effect has not been previously explored.Table 5. Efficacy Endpoints: Bayesian and Frequentist AnalysesDeupirfenidone Deupirfenidone Pirfenidone Placebo TIDEndpoint 550 mg TID 825 mg TID 801 mg TID (N=65)(N=65) (N=63) (N=61) Change from Baseline in FVC (mL) over 26 WeeksPosterior Mean-110.8 (19.63) -76.7 (28.60) -19.9 (28.29) -50.4 (28.33) (SE)Comparison vs.PlaceboPosterior MeanDifference (95% 34.1 90.9 60.4 Credible (-33.5, 100.0) (24.2, 159.1) (-8.6, 127.0) Interval)PosteriorProbability (%)84.1 99.7 95.7 of DifferenceOver Placebo>0Change from Baseline in FVCpp over 26 WeeksPosterior Mean-3.27 (0.57) -1.80 (0.88) -0.42 (0.88) -1.45 (0.89) (SE)Comparison vs.PlaceboLYT100-IPF-2-WOi Ai FlttreqensnassuyPosterior Mean1.47 2.85 1.81 (95% Credible(-0.58, 3.51) (0.82, 4.93) (-0.22, 3.91) Interval)PosteriorProbability (%)92.1 99.7 95.9 of DifferenceOver Placebo>0Change from Baseline in FVC (mL) over 26 WeeksAdjusted Mean-112.5 (27.84) -80.7 (29.32) -21.5 (28.86) -51.6 (29.13) (SE)Comparison vs.PlaceboAdjusted Mean60.9 Difference (95% 31.8 91.0(-18.3, Confidence (-47.6, 111.2) (12.2, 169.7)140.0) Interval)P- Value 0.43 0.02 0.13Change from Baseline in FVCpp over 26 WeeksAdjusted Mean-3.43 (0.842) -1.81 (0.886) -0.43 (0.872) -1.46 (0.881) (SE)Comparison vs.PlaceboAdjusted Mean(95% 1.62 3.00 1.97 Confidence (-0.78, 4.02) (0.62, 5.38) (-0.42, 4.37) Interval)P- Value 0.18 0.01 0.11Efficacy analyses used a random coefficient regression model with absolute FVC or FVCpp including baseline as response variable and week, treatment and interaction between week and treatment as fixed effect. The analyses were performed based on the predefined Full Analysis Set. N = number of participants in the specified analysis set under each treatment group; SE = standard error; TID = 3 times per day. Baseline is defined as the last available measurement performed before the first study drug administration in Part A. Adjusted mean is estimated based on a random coefficient regression model with absolute FVC over time, including baseline, as a response, and fixed effects for treatment, visit (week), and treatment by visit interaction, as well as participant-level random effects for the intercept and slope.Table 6. Effect size - Cohen’s DPirfenidone Deupirfenidone Deupirfenidone801 mg TID 550 mg TID 825 mg TID(N=63) n (%) (N=65) n (%) (N=64) n (%)FVC 0.27 0.14 0.40LYT100-IPF-2-WOFVCpp 0.29 0.23 0.44Table 7. Treatment effectPirfenidone Deupirfenidone Deupirfenidone 801 mg TID 550 mg TID 825 mg TID (N=63) n (%) (N=65) n (%) (N=64) n (%) FVC 54.1% 28.3% 80.9% FVCpp 57.4% 47.2% 87.5%LYT100-IPF-2-WOTable 8. Effect - Advanced Lung DiseasePlacebo Pirfenidone LYT-100550 LYT-100825 BaselineTID 801 mg TID mg TID mg TID FVCpp(N = 65) (N = 61) (N = 65) (N = 63) <50% 3 (4.6) 3 (4.9) 1 (1-5) 5 (7.9)>50% 62 (95.4) 58 (95.1) 64 (98.5) 58 (92.1)

[0292] When the efficacy data was analyzed by subgroups, it was found that a regional difference existed with respect to FVC for placebo versus LYT-100 825 mg TID and 550 mg TID. Forest plots of the change in baseline in FVC over 26 weeks for various subgroups, including by geographical region, is provided in FIGS. 17A and 17B (825 mg TID and 550 mg TID, respectively). With reference to FIGS. 17A and 17B, for subjects in Europe and South Africa, the placebo subjects had an adjusted mean change from baseline of -42.7 mL, which is far lower than the change in FVC for patients in the US and Central / South American placebo cohorts. Inclusion of these subjects therefore skewed the overall efficacy results downward for the 550 mg TID dose.

[0293] Accordingly, a Frequentist analysis of efficacy by FVC and FVCpp across the treatment arms was conducted with exclusion of patients in certain geographical locations (Georgia, Greece, Romania, and South Africa; G / G / R / SA; n=51 subjects). The data is provided in FIGS.18A and 18B and Table 8A. With respect to FIGS. 18A, 18B, and Table 8A, the change from baseline for 550 mg TID LYT-100 was comparable to that for 801 mg TID pirfenidone (-56.1 vs -44.2, respectively, for FVC; and -1.04 vs. -1.21, respectively, for FVCpp).LYT100-IPF-2-WOTable 8A. FVC and FVCpp - Excluding Georgia, Greece, Romania and South AfricaLYT-100550 mg LYT-100825 mg Pirfenidone Placebo TIDTID TID 801 mg TID Full -112.5 -80.7 -21.5 -51.6 FVC Analysis (N=65) (N=65) (N=63) (N=61) (mL) SetWithoutG / G / R / S -117.0 -56.1 -18.9 -44.2 A (N=55) (N=51) (N=44) (N=53) PatientsFull -3.43 -1.81 -0.43 -1.46 Analysis (N=65) (N=65) (N=63) (N=61) SetFVCppWithoutG / G / R / S -3.66 -1.04 -0.43 -1.21 A (N=55) (N=51) (N=44) (N=53) Patients

[0294] Efficacy data was further analyzed by subgroups with respect to age. Specifically, results from patients aged >75 (n=91) were compared to those aged <75 years (n=166) using frequentist statistical analyses with a mixed model for repeated measures (MMRM), treating time as a continuous variable. Results of these sub-group analyses are provided in Table 8B and Table 8C. With reference to Tables 8B and 8C, the data support continued clinical development of deupirfenidone in older patients.Table 8B. Completion Rate by AgeCompletion CompletionRate Rateage >75 age <75placebo 76.2% 81.8%pirfenidone 66.7% 69.4%deupirfenidone 71.4% 61.4%550 mg TIDdeupirfenidone 77.3% 78.6%825 mg TIDLYT100-IPF-2-WOTable 8C. Efficacy by AgeChange in Change in Change in Change in absolute FVC absolute FVC FVCpp over 26 FVCpp over 26 (mL) over 26 (mL) over 26 weeks for age weeks for age weeks for age weeks for age >75 <75 >75 <75placebo -122.2 -103.0 -4.64 -2.93 pirfenidone -58.7 -46.5 -1.82 -1.21 deupirfenidone -17.8 -113.6 -0.69 -2.37 550 mg TIDdeupirfenidone 13.6 -39.0 0.27 -0.79825 mg TID

[0295] Tolerability (secondary) endpoints included incidence and duration of dose modifications (dose reductions or interruptions), time to first dose modification, number of days on full assigned dose, time to treatment discontinuation due to an adverse event, and incidence and duration of adverse events of special interest (AESI; i.e., anorexia, decreased appetite, fatigue, diarrhea, nausea, vomiting, increase in aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) levels, photosensitivity reaction, rash of grade 3 severity or higher).

[0296] Both doses of LYT-100 were generally well-tolerated in the trial. The tolerability of study drug for each of the treatment arms for Part A is summarized in Tables 9 to 11 and FIG.15. This study evaluated in particular the tolerability based on prioritized gastrointestinal adverse events (GI AEs). Prioritized GI AEs reflect those with rates >5% overall in comparative drug arm, e.g., nausea / abdominal pain / decreased appetite / dyspepsia / diarrhea). Success was defined as meeting criteria for nausea (i.e., >25% improvement) with other prioritized AEs trending towards placebo rates. The desired endpoints were met for both LYT-100 doses (550 mg and 825 mg). Table 9 provides a summary of all treatment emergent adverse events in the study, while Table 10 summarizes AEs of special interest in specific patients. The 550 mg TID dose of LYT-100 also met the success criteria of >25% reduction in AEs vs. pirfenidone (combined GI SOC, nausea, dyspepsia, constipation).

[0297] The 825 mg TID dose of LYT-100 met the success criteria of less than 25% difference in AEs vs. pirfenidone (i.e., a similar tolerability profile). Specifically, this dose met the defined GI tolerability criteria, including improvement vs. PFD on nausea, dyspepsia, and diarrhea.

[0298] Table 11A provides a summary of treatment discontinuations, while FIG. 15 provides a graphical depiction of all dose modifications and discontinuations across treatment arms. As shown in Table 11A, discontinuation rates in the LYT-100 825 mg TID arm were similar toLYT100-IPF-2-WOplacebo (21.9% vs. 20.0%, respectively). Both doses of deupirfenidone were generally well- tolerated in the trial. The overall number of patients experiencing any gastrointestinal (GI)- related adverse events (AEs) was similar across the deupirfenidone 825 mg TID and pirfenidone 801 mg TID arms (53.1% vs. 52.4%, respectively) compared to 24.6% in the placebo arm. With reference to Table 11A and FIG. 15, 26% of patients on LYT-100550 mg and 19% of patients on 825 mg TID discontinued treatment due to AEs. LYT-100 825 mg TID demonstrated a favorable tolerability profile compared to pirfenidone 801 mg TID, with a lower percentage of patients reporting key GI AEs. The clinically meaningful GI AEs occurring in >5% of participants in at least one arm were: nausea (20.3% vs. 27.0%), dyspepsia (14.1% vs. 22.2%), diarrhea (7.8% vs. 11.1%), constipation (4.7% vs. 6.3%) and vomiting (1.6% vs. 3.2%). The only increase was observed in abdominal pain (14.1% vs. 7.9%).Table 9. Treatment-Emergent Adverse EventsPlacebo Pirfenidone Deupirfenidone Deupirfenidone TID 801 mg TID 550 mg TID 825 mg TID (N=65) (N=63) (N=65) (N=64) n (%) n (%) n (%) n (%)>=1 TEAE 48 (73.8%) 53 (84.1%) 47 (72.3%) 55 (85.9%) All TE SAE 10 (15.4%) 6 (9.5%) 12 (18.5%) 7 (10.9%) Study drug-related 2 (3.1%) 1 (1.6%) 0 (0%) 1 (1.6%) TE SAE AESI 1 (1.5%) 5 (7.9%) 2 (3.1%) 4 (6.3%) TEAE leading to 8 (12.3%) 11 (17.5%) 16 (24.6%) 12 (18.8%) study treatmentdiscontinuationTEAE leading to 20 (30.8%) 24 (38.1%) 27 (41.5%) 30 (46.9%) dose modificationsTEAE leading to 2 (3.1%) 5 (7.9%) 1 (1.5%) 1 (1.6%) deathAll-cause mortality 3 (4.6%) 5 (7.9%) 2 (3.1%) 1 (1.6%) SOC / PTGastrointestinal 16 (24.6%) 33 (52.4%) 23 (35.4%) 34 (53.1%) disordersNausea 5 (7.7%) 17 (27.0%) 11 (16.9%) 13 (20.3%) Dyspepsia 2 (3.1%) 14 (22.2%) 8 (12.3%) 9 (14.1%) Diarrhea 6 (9.2%) 7 (11.1%) 7 (10.8%) 5 (7.8%) Abdominal pain 3 (4.6% 5 (7.9%) 4 (6.2%) 9 (14.1%) Constipation 1 (1.5%) 4 (6.3%) 1 (1.5%) 3 (4.7) Vomiting 0 (0%) 2 (3.2%) 5 (7.7%) 1 (1.6%) Nervous system 7 (10.8%) 11 (17.5%) 12 (18.5%) 13 (20.3%) disordersDizziness 2 (3.1%) 5 (7.9%) 6 (9.2%) 8 (12.5%)Headache 3 (4.6%) 8 (12.7%) 5 (7.7%) 2 (3.1%)LYT100-IPF-2-WOPlacebo Pirfenidone Deupirfenidone Deupirfenidone TID 801 mg TID 550 mg TID 825 mg TID (N=65) (N=63) (N=65) (N=64) n (%) n (%) n (%) n (%)Skin disorders 3 (4.6%) 18 (28.6%) 12 (18.5%) 20 (31.3%) Photosensitivity 0 (0%) 5 (7.9%) 4 (6.2%) 5 (7.8%) reactionRash 1 (1.5%) 6 (9.5%) 3 (4.6%) 6 (9.4%) Pruritus 0 (0%) 3 (4.8%) 5 (7.7%) 5 (7.8%) Metabolism and 9 (13.8%) 12 (19.0%) 14 (21.5%) 17 (26.6%) nutrition disordersDecreased appetite 5 (7.7%) 9 (14.3%) 12 (18.5%) 13 (20.3%) General disorders 7 (10.8%) 11 (17.5%) 10 (15.4%) 11 (17.2%) Fatigue 1 (1.5%) 7 (11.1%) 5 (7.7%) 6 (9.4%) Respiratory 23 (35.4%) 12 (19.0%) 13 (20.0%) 15 (23.4%) disordersCough 7 (10.8%) 3 (4.8%) 1 (1.5%) 8 (12.5%) IPF 10 (15.4%) 2 (3.2%) 3 (4.6%) 4 (6.3%) Dyspnea 4 (6.2%) 3 (4.8%) 2 (3.1%) 1 (1.6%) Infections 20 (30.8%) 17 (27.0%) 17 (26.2%) 14 (21.9%) Upper respiratory 6 (9.2%) 9 (14.3%) 8 (12.3%) 6 (9.4%) infectionsUrinary tract 2 (3.1%) 5 (7.9%) 4 (6.2%) 3 (4.7%) infectionsPneumonia 3 (4.6%) 2 (3.2%) 4 (6.2%) 1 (1.6%) Psychiatric 1 (1.5%) 5 (7.9%) 3 (4.6%) 7 (10.9%) disordersInsomnia 0 (0%) 3 (4.8%) 1 (1.5%) 4 (6.3%)Table 10. Adverse Events of Special InterestYears Treatment Start Description Grade Action Outcome Related to from IPF arm day AESI Taken study diagnosis from for drug per random Study PI drug1.1 Deupirfenidone 64 Photo- 3 Interrupt Resolved Probably 550 mg TID sensitivityreaction0.5 Deupirfenidone 123 Fatigue 3 w / d Resolved Probably 825 mg TID4.0 Pirfenidone 801 26 Fatigue 3 w / d Resolved Not mg TID related 1.5 Pirfenidone 801 37 Diarrhea 3 w / d Resolved Probably mg TID0.5 Deupirfenidone 42 Elevated 3 w / d Resolved Possibly 825 mg TID liverenzymesLYT100-IPF-2-WOYears Treatment Start Description Grade Action Outcome Related to from IPF arm day AESI Taken study diagnosis from for drug per random Study PI drug2.4 Deupirfenidone 86 Nausea 3 w / d Resolved Possibly 825 mg TID2.1 Pirfenidone 801 34 Decreased 3 Interrupt Resolved Probably mg TID appetite,nausea0.6 Pirfenidone 801 117 Fatigue, 3 Dose not Resolved Possibly mg TID anorexia changed0.4 Placebo 66 Liver 3 Dose not Resolved Not function test changed related increased0.1 Pirfenidone 801 22 Vomiting 3 Dose not Resolved Probably mg TID changed0.1 Deupirfenidone 44 ALT 3 w / d Resolved Possibly 550 mg TID elevation3.5 Deupirfenidone 57 Liver 3 w / d Resolved Possibly 825 mg TID transaminase elevationTable 11A. Treatment DiscontinuationsParticipants Who Placebo Pirfenidone Deupirfenidone Deupirfenidone Discontinued 26- TID 801 mg TID 550 mg TID 825 mg TID Week Double-Blind (N=65) (N=63) (N=65) (N=64)Study Treatment n (%) n (%) n (%) n (%)Total 13 (20.0) 20 (31.7) 23 (35.4) 14 (21.9) Primary Reason forDiscontinuationWithdrew Consent 4 (6.2) 5 (7.9) 5 (7.7) 2 (3.1)Patient Discontinued 0 0 0Treatment 1 (1.5)Adverse Event 7 (10.8) 11 (17.5) 17 (26.2) 12 (18.8) Significant Protocol 0 0 0Deviation 1 (1-5)Investigator Decision 0 2 (3.2) 0 0Lack of Efficacy 0 0 0 0Lost to Follow-up 0 0 0 0Death 1 (1-5) 0 0 0Pregnancy 0 0 0 0Study Termination 0 0 0 0Other 0 2 (3.2) 0 0LYT100-IPF-2-WO

[0299] Studies suggest older patients with idiopathic pulmonary fibrosis (IPF) have gastrointestinal (GI) tolerability challenges with current antifibrotics and are less likely to be treated than younger patients. Accordingly, tolerability data in this study was further analyzed by subgroups with respect to age. Specifically, adverse events from patients aged >75 (n=91) were compared to those aged <75 years (n=166). Overall, treatment emergent adverse events, including gastrointestinal events, were similar for age >75 compared with <75 for each treatment arm. Results of the sub-group analysis with respect to nausea are provided in Table 11B. The tolerability data support continued clinical development of deupirfenidone in older patients.Table 11B. Nausea by Agenausea, age >75 nausea, age <75placebo 9.5% 6.8%pirfenidone 25.9% 27.8%deupirfenidone 14.3% 18.2%550 mg TIDdeupirfenidone 18.2% 21.4%825 mg TID

[0300] LYT-100 showed a small number of elevated liver enzymes as expected (Table 12). All liver enzyme elevation cases were transitory, with no instances of drug-induced liver injury or Hy’s Law.LYT100-IPF-2-WOTable 12. Liver ToxicityLYT- LYT- LYT- Placebo Pirfenidone 550 825100 TID Overall Parameter (unit) TID 801 mg TID mg mgPooled (N=257) Category (N=65) (N=63) TID TID(N=129) n (%) n (%) n (%) (N=63) (N=63)n (%)n (%) n (%)AlanineAminotransferase62 62 59 61 120 244 (U / L) at WorstPost-Baseline, N1Total (>3 ULN) 1 (1-6) 1 (1-6) 2 (3.4) 3 (4.9) 5 (4.2) 7 (2.9) 3-5 ULN 1 (1-6) 1 (1-6) 1 (1-7) 1 (1-6) 2 (1.7) 4 (1.6) 5-8 ULN 0 0 1 0 1 1 >8 ULN 0 0 0 2 2 2 AspartateAminotransferase62 62 59 61 120 244 (U / L) at WorstPost-Baseline, N1Total (>3 ULN) 0 0 1 (1-7) 3 (4.9) 4 (3.3) 4 (1.6) 3-5 ULN 0 0 1 (1-7) 1 (1-6) 2 (1.7) 2 5-8 ULN 0 0 0 0 0 0 >8 ULN 0 0 0 2 2 2 AlanineAminotransferaseor Aspartate62 62 59 61 120 244 Aminotransferase(U / L) at WorstPost-Baseline, N1Total (>3 ULN) 1 (1-6) 1 (1-6) 2 (3.4) 3 (4.9) 5 (4.2) 7 (2.9) 3-5 ULN 1 (1-6) 1 (1-6) 1 (1-7) 1 (1-6) 2 (1.7) 4 (1.6) 5-8 ULN 0 0 1 0 1 1 >8 ULN 0 0 0 2 2 2LYT100-IPF-2-WOSummary of Efficacy and Tolerability Results -Part A

[0301] LYT-100 550 mg TID (1650 mg total daily dose) provided efficacy (FVC) within one standard error of that of 801 mg TID pirfenidone (2403 total daily dose), while demonstrating a significant, i.e., a > 25%, reduction in adverse events (Tables 5 and 9).

[0302] LYT-100825 mg TID (2475 mg total daily dose) provided a significantly great efficacy (FVC) than that of pirfenidone at 801 mg TID (2403 total daily dose) (FIGS.9A and 9B), while meeting the GI tolerability criteria defined for 550 mg TID (Table 9), and an improvement compared to pirfenidone on nausea, dyspepsia, and diarrhea (Table 9). Notably, the LYT-100 825 mg TID patients included patients who were titrated down to a 1650 mg total daily dose of LYT-100 during the study, either temporarily or permanently.

[0303] LYT-100 825 mg TID provided an approximately a 150% greater effect size as compared to 801 mg TID pirfenidone for both FVC and FVCpp (Tables 6 and 7).

[0304] LYT-100 825 mg TID had a consistent benefit across age groups, gender, region, and diagnosis group (Table 5).

[0305] LYT-100 825 mg TID improved time to progression as compared to placebo (FIG. 13) and had the greatest percentage of patients with no decline (FIG. 11A).

[0306] LYT-100 825 mg TID (2475 mg total daily dose) stabilized lung function for IPF patients in-line with that seen for healthy older adults aged 60 or older over a six-month preiod (FIG. 12)

[0307] The pooled LYT-100 doses (1650 mg total daily and 2475 total daily) provided significantly better efficacy (FVC) than placebo using Bayesian statistical analysis (posterior probability > 98.5%) (FIG. 8).

[0308] The LYT-100825 mg TID dose provided significantly better change from baseline FVC than placebo (99.7% posterior probability and a p-value of 0.02) (FIG. 9B) and FVCpp (99.7% posterior probability and a p-value of 0.01) (FIGS. 10A and 10B).

[0309] LYT-100 demonstrated a favorable tolerability profile at both doses evaluated and -most importantly - has the potential to offer patients enhanced efficacy that approaches the stabilization of lung function at the higher dose.

[0310] Preliminary data support a durable treatment effect, and a consistently well-tolerated profile with deupirfenidone 825 mg.Pharmacokinetics Results -Part A

[0311] In accordance with the study protocol, a sparse PK sampling strategy was employed in which all patients provided pre-dose blood samples for determination of plasma concentrations of LYT-100 / pirfenidone and its metabolite(s). The generated PK data was based on pre-doseLYT100-IPF-2-WO(trough) samples drawn on three scheduled timepoints (i.e., Weeks 4, 12, and 26). Results were generated using a mixed-effects model for repeated measures on natural log transformed trough concentrations (or AUCs). The model used fixed effects for visit, treatment, and visit by treatment interaction and a repeated statement for visit. The following comparisons were assessed: LYT-100 825 mg vs. LYT-100 550 mg; LYT-100 550 mg vs. pirfenidone; LYT-100 825 mg vs. pirfenidone. Least square means of the natural log transformed treatment estimates were back transformed to derive the least square geometric means (LSGMs) for the treatments. Estimates of the natural log transformed treatment differences and corresponding 90% confidence intervals (Cis) were back transformed to derive the LSGM rations and corresponding 90% Cis for each comparison. AUC values were extrapolated from the measured trough concentrations using trough concentrations and AUCs measured for deupirfenidone and pirfenidone during a previous Phase 1 study in healthy older adults. Specifically, an exponential relationship between Ctrough and AUC was observed in the prior study, with a curve fitted to the data that allowed for extrapolation of the relationship beyond the measured data points. Accordingly, curves from the Phase 1 study were leveraged to estimate AUC levels in the ELEVATE trial based on the measured Ctrough levels. The PK population included all patients for whom PK samples were collected at any of the three scheduled visits (i.e., weeks 4, 12, and 26). Subjects were included in the >95% adherence subset if they took >95% of the capsules assigned to their regimen (i.e., patient took their medication as instructed each study day). The data is provided in Tables 13 to 18.Table 13. Estimated AUC for Deupirfenidone and Pirfenidone Deupirfenidone 825 Deupirfenidone 550 Deupirfenidone 825 mg mg TID vs. mg TID vs. TID vs. Pirfenidone Deupirfenidone 550 Pirfenidone 801 mg 801 mg TIDmg TID TIDAUC p-value AUC p-value AUC Ratio p-value Ratio RatioPK -69% < 0001 -14% 0.1493 -46% Greater 0.0002 Population Greater Lower(446 Samples)Subjects with -84% < 0001 -19% 0.0939 -50% Greater 0.0012 >95% Greater LowerAdherence(221 Samples)

[0312] With reference to Table 13 and Table 14, extrapolating concentration troughs to AUC suggests that deupirfenidone 825 mg has -50% greater exposure vs. pirfenidone, whileLYT100-IPF-2-WOdeupirfenidone 550 mg has approximately 15 to 20% lower exposure vs. pirfenidone. The exposure for deupirfenidone 825 mg TID was 70 to 85% higher vs. deupirfenidone 550 mg TID. The higher exposure for deupirfenidone 825 mg TID likely drove greater the efficacy compared to pirfenidone. In contrast, the slightly lower exposure for deupirfenidone 550 mg TID likely contributed to modestly lower efficacy compared to pirfenidone.Table 14. Overall Extrapolated AUCPopuEstimated AUC, Treatment Comparisonslation Least Square Deupirfenid Deupirfenidone 550 mg Deupirfenidone Geometric Mean (LSGM) one 825 mg TID vs. Pirfenidone 801 825 mg TID vs.TID vs. mg TID Pirfenidone 801 Deupirfenid mg TID one 550 mgTID DPF DPF Pfd 801 LSGM Ratio P- LSGM P- LSGM P- 550 mg 825 mg mg TID (90% CI) value Ratio value Ratio value TID TID (90% (90%CI) CI)PK 111,52 188,795 129,055 169.28 <.000 86.42 0.1493 146.29 0.0002 (n=446) 6 (N = 61) (N = 61) (143.76, 1 (73.15, (124.09(N = 199.33) 102.09)57) 172.46) >95% 119,46 220,392 146,737 184.48 <.000 81.42 0.0939 150.20 0.0002 Adherence 8 (N = 27) (N = 24) (151.50, 1 (66.54, (122.74 (n=221) (N = 224.64) 99.62)26) 183.79)Table 15. Least Square Geometric Mean Values for Trough Concentration Treatment Least Square Geometric Mean (LSGM) Deupirfenidone Deupirfenidone Pirfenidone 550 mg TID 825 mg TID 801 mg TID PK Population 1479.73 2528.61 1238.96 (446 Samples) (N= 57) (N = 61) (N = 61) Subjects with >95% 1722.79 3508.69 1679.08 Adherence (N = 26) (N = 27) (N = 24)(221 Samples)LYT100-IPF-2-WOTable 16. Deupirfenidone and Pirfenidone Trough Concentrations - Summary Deupirfenidone 825 mg Deupirfenidone 550 mg Deupirfenidone 825 mg TID vs. TID vs. Pirfenidone 801 TID vs. Pirfenidone Deupirfenidone 550 mg mg TID 801 mg TID TIDTrough p-value Trough p-value Trough p-value Concentration Concentration Concentration Ratio Ratio RatioPK ~71% Greater 0.0155 ~19% Greater 0.4282 ~104% 0.0015 Population Greater(446 Samples)Subjects with ~104% 0.0082 ~3% Greater 0.9240 ~109% 0.0076 >95% Greater GreaterAdherence(221 Samples)Table 17. Deupirfenidone (DPF) and Pirfenidone (Pfd) Trough Concentrations Treatment Least Square ComparisonsGeometric Mean (LSGM) DPF 825 mg TID DPF 825 mg DPF 825 mg TID vs. DPF 550 mg TID vs. Pfd 801 vs. Pfd 801 mg TID mg TID TIDDPF DPF Pfd 801 LSGM p-value LSGM P- LSGM p-value 550 mg 825 mg mg TID Ratio Ratio value Ratio TID TID (90% (90% (90%CI) CI) CI)PK 1479.73 2528.61 1238.96 170.88 0.0155 119.43 0.4282 204.09 0.0015 Population (N=57) (N=61) (N = 61) (118.91, (82.51, (141.66 (446 245.57) 172.88)Samples) 294.05) Subjects 1722.79 3508.69 1679.08 203.66 0.0082 102.60 0.9240 208.97 0.0076 with >95% (N=26) ( N=27) (N = 24) (131.65, (65.61, (133.61 Adherence 315.07 160.45)(221 326.81)Samples)

[0313] With reference to Tables 15 to 17, the deupirfenidone 825 mg TID trough concentration was 70 - 105% higher vs. deupirfenidone 550 mg TID, the deupirfenidone 550 mg TID trough concentration was 5 - 20% higher vs. pirfenidone 801 mg TID, and the deupirfenidone 825 mg TID trough concentration was 105 - 110% higher vs. pirfenidone 801 mg TID.LYT100-IPF-2-WOTable 18. Median Trough Concentration by Change in FVC at Week 26 Treatment Median Change in FVC mL Fisher’s Exact Concentration <0 (2-sided) >0 Test p- value Category n (%) n (%) <0 (2-sided) Deupirfenidone <2000 ng / mL 8 (33.3) 1 (4.2) 0.1907 550 mg TID <2000 ng / mL 9 (37.5) 6 (25.0)Deupirfenidone <2000 ng / mL 4 (21.1) 0 0.0090 825 mg TID <2000 ng / mL 3 (15.8) 12 (63.2)Pirfenidone 801 <2000 ng / mL 8 (36.4) 3 (13.6) 0.6594mg TID <2000 ng / mL 6 (27.3) 5 (22.7)

[0314] With reference to Table 18, deupirfenidone 825 mg TID had a statistically significant association between higher drug concentrations and improved efficacy, with the higher Ctrough for 825 mg TID deupirfenidone demonstrating better efficacy with respect to FVC. Notably, the dramatically increased drug exposure for 825 mg TID vs pirfenidone did not result in an increase in tolerability challenges. There was no apparent relationship between Ctrough and TEAEs or GI AEs (FIGS. 20A, 20B, 21A, 21B, 22A, and 22B). This data suggests that the deuterated structure of deupirfenidone may overcome the dose-limiting adverse events associated with pirfenidone.Efficacy and Tolerability Results - Part B

[0315] One hundred and seventy (170) patients (greater than 90%) enrolled in the Open Label Extension (Part B) of the study. Eighty-nine (89) received 550 mg TID LYT-100, and eighty-one (81) received 825 mg TID LYT-100. One hundred and forty (140) patients continued in the open label extension.

[0316] One hundred and one (101) of the one hundred and forty patients (more than 70%) have now received at least 52-weeks of treatment with deupirfenidone (the rest of the enrolled patients have not yet completed their 52-week administration). Preliminary data for these openlabel patents is provided in Table 19 and FIGS. 16, 19, and 23-26.

[0317] FIG. 23 provides a graphical depiction of adjusted mean change from baseline over time of Forced Vital Capacity for study parts A and B up to 52 weeks for the 550 mg TID and 825 mg TID dose groups, demonstrating the stabilization of FVC up to 52 weeks for the 825 mg TID dose. With reference to Table 19 and FIG. 23, findings based on this preliminary data show that the stabilization of lung function decline by FVC demonstrated with deupirfenidone 825 mg TID in Part A of the study is maintained out to 52 weeks. With continued reference toLYT100-IPF-2-WOTable 19 and FIG. 23, the change in FVC for the deupirfenidone 550 mg TID arm was -147.0 mL and for the deupirfenidone 825 mg arm was -32.8 mL over 52 weeks.

[0318] FIG. 24 provides a graphical depiction of adjusted mean change from OLE baseline Forced Vital Capacity over 26 weeks for Part B of the study for subjects who switched from placebo or pirfenidone to deupirfenidone 825 mg TID.

[0319] FIG. 25 provides a graphical depiction of adjusted mean change from OLE baseline Forced Vital Capacity over 26 weeks for Part B of the study for subjects who switched from placebo to deupirfenidone 550 mg TID or 825 mg TID.

[0320] FIG. 26 provides a graphical depiction of adjusted mean change from OLE baseline Forced Vital Capacity over 26 weeks for Part B of the study for subjects who switched from placebo to deupirfenidone 550 mg TID or 825 mg TID.

[0321] With reference to FIG. 24 and FIG. 25, for patients who switched from placebo to deupirfenidone 550 mg, the FVC change was -23.5 mL, while for patients who switched from placebo to deupirfenidone 825 mg TID, the FVC improvement was 20 mL at week 52 compared to week 26. With reference to FIG. 26, patients who switched from pirfenidone to deupirfenidone 550 mg TID, the FVC change was an improvement of 6.2 mL at week 52 compared to week 26, while for deupirfenidone 825 mg, the FVC change was was 20.0 mL. With reference to FIG. 26, notably, patients which switched from pirfenidone in Part A to deupirfenidone in Part B did better on deupirfenidone in Part B than on pirfenidone in Part A.Table 19. Change from Baseline in FVC over 52 Weeks by Frequentist Approach Part A and Part B Part A and Part BLYT-100 LYT-100550 mg TID 825 mg TIDEndpoint (N=65) (N=63)Change from Part A Baselinein FVC (mL) over 52 Weeksn 20 25Adjusted Mean (SE) -147.0 -32.895% Confidence Interval (-223.5, 70.4) (-107.4, 41.7)n = number of participants with data at the specified visit; N = number of participants in the specified analysis set under each treatment group; SE =standard error; TID = 3 times per day. Part A Baseline is defined as the lastavailable measurement performed before the first study drug administration inPart A. Adjusted means are estimated based on a random coefficient regressionmodel with absolute FVC over time, including baseline, as a response, and fixedeffects for treatment (LYT-100 550 mg or LYT-100 825 mg), visit (week), andLYT100-IPF-2-WOtreatment by visit interaction, as well as participant-level random effects for theintercept and slope.

[0322] FIG. 19 provides a graphical depiction of a) the expected decline of lung function in healthy older adults over 52 weeks (per Valenzuela, Boehringer Ingelheim, ERS 2024; and Luoto, Eur. Resp J 2019); b) the decline observed for the 101 patients in the study receiving 825 mg TID deupirfenidone for 52 weeks; and c) the decline observed in untreated IPF patients based on historical data (placebo arm decline over 48 weeks of Capacity 004 and Capacity 006 trials (Noble, Lancet 2011; and 52 week decline in placebo arm of INPULSIS- 1 and INPULSIS-2 nintedanib studies (Richeldi, N Eng J Med 2014). The deupirfenidone data is based on random coefficient regression model using integrated analysis of Part A and Part B data. With reference to FIG. 19, the expected decline in lung function occurring naturally over a period of 52 weeks for a healthy older adult is on the order of a 30 to 50 mL reduction of FVC, and the expected reduction in FVC over 52 weeks for an untreated IPF patient, based on historical data as described above, is on the order of 205 to 350 mL. In contrast, with continued reference to FIG.19, patients in the present study had an average FVC decline of only 32.8 mL, consistent with the expected natural decline in a healthy older adult.

[0323] These results suggest a durable response for 825 mg TID deupirfenidone and improvement for pirfenidone and placebo patients switched to deupirfenidone, reinforcing the potential for 825 mg TID deupirfenidone to stabilize lung function decline overtime.

[0324] An analysis of IPF progression was performed out to >52 weeks. In this analysis, IPF progression was defined as a decline in FVCpp of 10% or greater, or death. The results are summarized in FIG.27 and Table 20. With reference to FIG.27 and Table 20, the median time to IPF progression was 52.14 weeks for the LYT-100 550 mg TID group and 66.0 weeks for LYT-100 825 mg TID group.Table 20. Summary of IPF Time to ProgressionEndpoint Part A and Part B LYT- Part A and Part B LYT-100100550 mg TID (N=65) 825 mg TID (N=63) Time to IPF Progression (weeks)Kaplan-Meier Estimate [1]Number of Participants 65 63 AssessedNumber of Participants with 26 16EventsNumber of Participants 39 47CensoredLYT100-IPF-2-WO75th Percentile (95% CI) [2] NE (66.00, NE) NE (76.14, NE) Median (95% CI) [2] 52.14 (41.71, NE) 66.00 (64.29, NE) 25th Percentile (95% CI) [2] 29.43 (16.00, 42.14) 55.57 (36.00, 65.00)Min, Max [3] 0.4+, 93.0+ 0.1+, 92.3+CI = confidence interval; IPF = idiopathic pulmonary fibrosis; N = number of participants in the specified analysis set under each treatment group; NE = not evaluable; TID = 3 times per day. IPF Progression in LYT-100 Part A and Part B is defined as a decline for participants treated on LYT-100 in Both Part A and Part B from the start of Part A to the end of Part B in forced vital capacity % predicted (FVCpp) of 10% or greater, or death.[1] Based on Kaplan-Meier method.[2] 95% CI is computed by Brookmeyer and Crowley method (log log transformation).[3] + indicates censored observation. If a participant has no IPF progression in Part A and Part B, the participant will be censored at the earlier of (Part A end-of-treatment + 28 [for participants not enrolled into Part B], Part B end-of-treatment date + 28, end-of-study date, data extraction date, last FVCpp assessment date, last contact date for death).

[0325] Adverse event data obtained thus far (Tables 21 and 22) support the safety and tolerability conclusions from Part A. Overall, adverse events (AEs) were similar for patients in the deupirfenidone 550 mg TID and 825 mg TID arms in the open label extension.Table 21. Summary of Most Common (>5%) TEAEs for Part BPart A Part A Part A Part A Placebo Pirfenidone Placebo Pirfenidone System Organswitched to switched to switched to switched to Class / Preferred550 mg TID 550 mg TID 825 mg TID 825 mg TID TermDPF in Part B DPF in Part B DPF in Part B DPF in Part B (N=25) n(%) (N=19) n(%) (N=25) n(%) (N=20) n(%) Participants with at21 (84.0) 12 (63.2) 21 (84.0) 16 (80.0) least one TEAEGastrointestinal12 (48.0) 2 (10.5) 16 (64.0) 6 (30.0) disordersDyspepsia 5 (20.0) 0 8 (32.0) 1 (5.0) Nausea 4 (16.0) 1 (5.3) 5 (20.0) 2 (10.0) Abdominal Pain 1 (4.0) 0 2 (8.0) 1 (5.0) Vomiting 1 (4.0) 0 4 (16.0) 1 (5.0) Constipation 1 (4.0) 0 2 (8.0) 1 (5.0) Diarrhea 1 (4.0) 0 2 (8.0) 1 (5.0)LYT100-IPF-2-WOTable 22. Summary of Most Common (>10%) TEAEs for Part BDeupirfenidone Deupirfenidone System Organ550 mg TID (N=83) 825 mg TID Class / Preferred Termn(%) (N=87) n(%) Participants with at least58 (69.9) 65 (74.7)one TEAEStudy drug-related TEAE 2 (2.4) 1 (1.1)TEAE leading to study8 (9.6) 10 (11.5) treatment discontinuationNausea 7 (8.4) 10 (11.5) Dyspepsia 12 (14.5) 11 (12.6)Upper respiratory infection 14 (16.9) 15 (17.2)Cough 9 (10.8) 4 (4.6)

[0326] With reference to Table 21, incidences of abdominal pain, vomiting, constipation, and diarrhea were all less than 10%. With reference to Table 22, incidences of AEs >10% were dyspepsia (14% vs 13%), nausea (8% vs 12%), upper respiratory infection (17% vs 17%), and cough (11% vs 5%) for deupirfenidone 550 mg and 825 mg, respectively. The discontinuation rate due to adverse events during the open-label study was 9.6% for deupirfenidone 550 mg TID and 11.5% for deupirfenidone 825 mg TID.

[0327] Together, the efficacy, safety, and tolerability data support progression into a Phase 3 trial and highlight the potential for deupirfenidone to serve as a new standard-of-care treatment for IPF.

Claims

LYT100-IPF-2-WOCLAIMS1. A method of treating Idiopathic Pulmonary Fibrosis (IPF), the method comprising:administering to a subject in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:N(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, and wherein lung function is stabilized in the patient for at least 52 weeks.

2. The method of claim 1, wherein the lung function stabilization is determined by a decline in FVC (mL) over 52 weeks of less than about 50 mL.

3. The method of claim 2 or 3, wherein the lung function stabilization is determined by a decline in FVC over 52 weeks of less than about 40 mL.

4. The method of any one of claims 1-3, wherein the subject is 75 years of age or older.

5. A method of treating Idiopathic Pulmonary Fibrosis (IPF) in a subject over 75 years of age, the method comprising:administering to the subject a total daily dose between 1650 mg and 2500 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations, and wherein lung function is stabilized in the patient for at least 26 weeks.LYT100-IPF-2-WO6. The method of claim 5, wherein the subject is administered about 2500 mg deupirfenidone.

7. A dose escalation regimen method for providing deupirfenidone therapy to a subject in need thereof, the method comprising:providing deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at a third oral daily dosage of 2475 mg for at least day fifteen of the dose escalation regimen,wherein the subject is provided deupirfenidone therapy for the treatment of idiopathic pulmonary fibrosis.

8. The dose escalation regimen method of claim 7, the method comprising:providing deupirfenidone to the subject at the first oral daily dosage of 825 mg as one tablet comprising 275 mg of deupirfenidone three times a day for days one to seven of the dose escalation regimen;providing deupirfenidone to the subject at the second oral daily dosage of 1650 mg as two tablets comprising 275 mg of deupirfenidone three times a day for days eight to fourteen of the dose escalation regimen; andproviding deupirfenidone to the subject at the third oral daily dosage of 2475 mg as three tablets comprising 275 mg of deupirfenidone three times a day for at least day fifteen of the dose escalation regimen.

9. A starter pack for use in an initial dose escalation regimen which provides deupirfenidone to a subject at a first oral daily dosage of 825 mg for days one to seven of the initial dose escalation regimen; provides deupirfenidone to the subject at a second oral daily dosage of 1650 mg for days eight to fourteen of the initial dose escalation regimen; and provides deupirfenidone to the subject a third oral daily dosage of 2475 mg for at least day fifteen of the dose escalation regimen,the starter pack comprising a plurality of compartments for containing a dosage amount of deupirfenidone arranged within rows and columns,LYT100-IPF-2-WOwherein the starter pack comprises separate rows for Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 with three separate columns for three dosage amounts to be taken each day; andwherein each of the three compartments for Days 1, 2, 3, 4, 5, 6, and 7 separately contain one pill of 275 mg deupirfenidone and each of the three compartments for Days 8, 9, 10, 11, 12, 13, and 14 separately contain two pills of 275 mg deupirfenidone; andwherein the starter pack optionally further comprises at least one additional set of compartments for Days 15, 16, 17, 18, 19, 20 and 21 in separate rows and each compartment in the additional set of compartments separately contain three pills of 275 mg deupirfenidone.

10. A method for reducing the incidence of adverse events in a subject receiving oral deupirfenidone therapy for the treatment of a fibrotic disease or disorder, the method comprising a dose adjustment regimen comprising:administering deupirfenidone to the subject at an oral daily dosage of 2475 mg for a first period of time; andsubsequently administering deupirfenidone to the subject at an oral daily dosage of 1650 mg deupirfenidone for a second period of time.

11. The method of claim 10, wherein the oral daily dosage of 1650 mg deupirfenidone is administered as three equal daily doses of 550 mg each.

12. The method of claim 11, wherein the oral daily dosage of 1650 mg deupirfenidone is administered as two equal daily doses of 825 mg each.

13. The method of any one of claims 10-12, further comprising, after the second period of time, administering deupirfenidone to the subject as a 2475 mg total daily dose.

14. The method of claim 13, wherein the 2475 mg total daily dose is administered as three equal daily doses of 825 mg each.

15. A method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration thereof forLYT100-IPF-2-WOa period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprising administering to said subject deupirfenidone at a total daily dose of 1650 mg, administered as two daily administration of 825 mg each.

16. A method of administering deupirfenidone to treat a subject in need thereof, said patient having exhibited an intolerance to deupirfenidone after oral administration of deupirfenidone for a period of time at total daily dose of 2475 mg, administered as three daily doses of 825 mg, the method comprising administering deupirfenidone at a total daily dose of 1650 mg, administered as three daily doses of 550 mg each.

17. The method of claim 15 or 16, wherein the intolerance is one or more of nausea, vomiting, abdominal pain or distension, dyspepsia, diarrhea, decreased appetite, constipation, headache, dizziness, somnolence, fatigue, skin rash, photosensitivity, increased AST, increased ALT, increased GGT, and liver toxicity.

18. The method of any one of claims 1-17, wherein the subject has not received prior treatment for IPF.

19. The method of any one of claims 1-17, wherein the subject has received prior treatment for IPF with nintedanib.

20. The method of any one of claims 1-17, wherein the subject has received prior treatment for IPF with pirfenidone.

21. The method of claims 19 or 20, wherein the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

22. The method of any one of claims 1-17, wherein the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

23. The method of any one of claims 1-17, wherein the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.LYT100-IPF-2-WO24. A method of transitioning from pirfenidone to deupirfenidone for a subject in need thereof, the method comprising:a) discontinuing a daily amount of pirfenidone; andb) administering an initial daily amount of deupirfenidone the next day to the subject, wherein the daily amount of pirfenidone in a) is 801 mg and the initial total daily amount of deupirfenidone is 825 mg; orwherein the daily amount of pirfenidone in a) is 1602 mg and the initial total daily amount of deupirfenidone is 1650 mg; orwherein the daily amount of pirfenidone in a) is 2403 mg and the initial total daily amount of deupirfenidone is 2475 mg.

25. A method of treating Idiopathic Pulmonary Fibrosis (IPF) in a patient population, the method comprising administering to said patients in need thereof a total daily dose of 2475 mg of a deuterium-enriched pirfenidone having the structure:(deupirfenidone),wherein the total daily dose of deupirfenidone is administered as three equal administrations of 825 mg each, wherein the IPF is treated in the patient population, and wherein a rate of treatment discontinuation in the patient population is less than about 20% over 52 weeks.

26. The method of claim 25, wherein the rate of treatment discontinuation in the patient population is less than about 12%.

27. The method of claim 25, wherein the subject has not received prior treatment for IPF.

28. The method of claim 25, wherein the subject has received prior treatment for IPF with nintedanib.

29. The method of claim 25, wherein the subject has received prior treatment for IPF with pirfenidone.LYT100-IPF-2-WO30. The method of claim 28 or 29, wherein the prior treatment with nintedanib or pirfenidone was discontinued due to poor tolerability to the nintedanib or the pirfenidone.

31. The method of claim 25, wherein the subject is currently receiving treatment for IPF with pirfenidone, the method comprising switching the subject from pirfenidone to deupirfenidone.

32. The method of claim 25, wherein the subject is currently receiving treatment for IPF with nintedanib, the method comprising switching the subject from nintedanib to deupirfenidone.

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