Acute stress is a contributing factor to mood and anxiety disorders, but few treatments safely address physiological stress. Allopregnanolone is an endogenous neurosteroid GABAA positive allosteric modulator (PAM) with anti-depressant and anxiolytic activity but low oral bioavailability. LYT-300, an oral prodrug of allopregnanolone that uses the Glyph™ technology platform, has enhanced oral bioavailability. We tested the potential for LYT-300 to blunt stress reactivity in a randomized, double-blinded, placebo-controlled study of healthy participants using the Trier Social Stress Test (TSST), a validated clinical model of anxiety.

Allopregnanolone is an endogenous neurosteroid GABAA positive allosteric modulator (PAM) with validated anti-depressant and anxiolytic activity, but orally administered allopregnanolone is poorly bioavailable. LYT-300 is a lymphatically-absorbed oral triglyceride prodrug of allopregnanolone that uses the Glyph™ platform. Glyph enables preferential absorption through intestinal lymphatics, thus avoiding first-pass liver metabolism. LYT-300 was examined in a Phase 1 study to establish oral bioavailability, evaluate safety, tolerability, and pharmacokinetics (PK), and demonstrate GABAA target engagement.

PURPOSE: Pirfenidone (PIRF) is an approved antifibrotic that slows progression of lung function decline in IPF and in a realworld study improved 3-year survival.Current antifibrotics are poorly tolerated, leading to suboptimal dosing or discontinuation.Deupirfenidone (LYT-100) is a form of PIRF with deuterium substitution at sites of active metabolism.Previously presented pharmacokinetic (PK) study data demonstrated that LYT-100 has a differentiated PK profile and ~50% reduction in GI adverse events (AEs) compared to PIRF.LYT-100 doses for a Phase 2b IPF study were selected based on Phase 1 PK and safety data.METHODS: Double-blind Phase 1 PK studies in healthy older adults -First study: 2-period crossover design, LYT-100 550mg TID vs PIRF 801mg TID under fed day (D)3 and fasted D4 dosing conditions.Second study: subjects randomized 4:1 to LYT-100 550mg TID x 3D followed by LYT-100 824mg TID x 3D (n¼24) or placebo (PBO) TID x 6D (n¼6).PK analysis for parent and common primary metabolite, 5-carboxy-pirfenidone (5CP) assessed at steady-state fed D3 dosing and fasted D4.AEs incidence >5% reported.RESULTS: First study: D3 fed LYT-100 550mg TID had a 24% lower C max with similar AUC versus fed PIRF 801mg TID.D4 fasted dosing resulted in higher drug exposures, with a larger C max increase on PIRF.D3 fed 5CP C max was 46% lower for LYT-100 vs PIRF.AE rates trended with C max of parent and 5CP.Fasted PIRF, fed PIRF, fasted LYT-100, fed LYT-100, AEs respectively, were GI 28.3%, 10.6%, 11.1%, 6.5%; CNS 21.7%, 14.9%, 8.9%, 8.7%.Second study: D3 LYT-100 824mg TID C max 57% and AUC 0-24 43% higher than LYT-100 550mg.AEs were low and comparable between LYT-100 824mg TID and PBO (GI 0%, CNS 0%, Infection (COVID-19) 16.7%, for both arms).CONCLUSIONS: AE incidence rates were generally associated with C max of parent and/or 5CP metabolite for LYT-100 and PIRF.LYT-100 550mg TID fed had a similar AUC to PIRF 801mg TID with a lower C max and lower AE rates.However, PK differences did not fully explain the lower AE rates seen with 824mg TID LYT-100.Both doses of LYT-100 are currently being evaluated in a larger ongoing Phase 2b IPF study to further support dose selection.CLINICAL IMPLICATIONS: ELEVATE (NCT05321420) is an ongoing Phase 2b, double-blind, 4-arm IPF clinical study in which two doses of LYT-100 (550mg TID or 825mg TID) are being assessed versus PIRF 801mg TID and PBO.LYT-100 550mg TID was selected based on having a similar AUC as PIRF 801mg TID with a lower C max , while LYT-100 825mg TID was selected to assess whether a higher AUC will improve efficacy.This study will assess safety of LYT-100 550mg TID and 825mg TID and pulmonary function changes from baseline relative to PBO and PIRF.

LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone under development for the treatment of inflammatory and fibrotic diseases, including interstitial lung disease. Adverse events associated with antifibrotics can be a barrier to adoption and persistence in patients with interstitial lung diseases, most of whom are not on standard-of-care therapy. LYT-100 is designed to have a differentiated pharmacokinetic (PK) profile from pirfenidone and could offer a differentiated safety profile compared to current standard-of-care drugs while retaining the biochemical potency and specificity of pirfenidone. We conducted a phase 1b study to ascertain the safety, tolerability, steady-state PK profile, and food effect of LYT-100. This was a 2-part study. Part 1 assessed multiple ascending doses of LYT-100 from 100, 250, 500, 750, and 1000 mg twice daily given over 5 days without titration. Part 2 assessed the effects of fed vs fasting conditions on the PK profile of a single 500-mg dose of LYT-100. All doses up to 1000 mg were well tolerated, with adverse events being mild and transient. Exposure was slightly lower in the fed condition. LYT-100 was well tolerated and has a dose-proportional PK profile. The ratio of parent to major metabolite concentration was higher than reported with pirfenidone, which is consistent with an effect of deuteration on metabolism. No maximum tolerated dose was identified up to 1000 mg twice-daily dosing. These results support further clinical development of LYT-100, particularly considering the adverse event profile of current standard-of-care drugs.

Introduction: LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone designed to attenuate the rate of drug metabolism, resulting in a differentiated pharmacokinetic (PK) profile that retains the pharmacologic benefits of pirfenidone while potentially improving tolerability. Objective: Assess LYT-100 maximum tolerated dose and PK at steady-state as well as FE. Methods: The double-blind study (NCT04243837) had two parts. The MAD randomized LYT-100:placebo (6:2 healthy subjects) at doses of 100, 250, 500, 750, or 1000 mg twice-daily over 5 days. FE was assessed with a single dose crossover of LYT-100 500 mg. PK and safety, including adverse events (AE), were collected in each part. Results: The MAD enrolled 40 subjects. AEs were mild and transient with no dose limiting toxicities and no discontinuations. The most common AEs were headache (23.3% LYT-100 vs. 20.0% placebo), abdominal distension (10.0% LYT-100 vs. 0% placebo), nausea (10.0% LYT-100 vs. 0% placebo) and abdominal discomfort (6.7% LYT-100 vs. 10.0% placebo). The area under concentration curve (AUC) and maximum concentration (Cmax) at steady-state were dose proportional across doses. The FE enrolled 8 subjects and demonstrated 19% reduced AUC and 23% reduced Cmax under fed vs. fasting condition. Conclusions: LYT-100 was well-tolerated and has a dose-proportional PK profile. No maximum tolerated dose was identified through 1000mg twice-daily. These results support further clinical development of LYT-100 particularly considering the adverse event profile of pirfenidone.

BackgroundGalectin-9 (gal-9) acts as a pivotal immuno-suppressor that disables immune mediated activity through modulation of T cells, macrophages and other immune functions. As such it has emerged as a powerful biological target for cancer immunotherapy and a potential biomarker of response and/or prognosis. Patients exhibiting high gal-9 expression in tumors and blood often have poor prognosis and tumors with aggressive and immunosuppressed molecular features (Chen L. et al, AACR 2020-LB-350). LYT-200 is a fully human IgG4 monoclonal antibody targeting gal-9. LYT-200 has high affinity, high specificity, stability, and blocks galectin-9 interactions with its binding partners in biochemical and human cell-based assays. In murine models of melanoma and pancreatic cancer, LYT-200 significantly reduced tumor growth, extended survival and modulated the intra-tumoral immune microenvironment. LYT-200 treated patient derived tumor organoids showed an increase in T cell activation (Chen L. et al, SITC 2019-P765).MethodsLYT-200 is now being evaluated in the USA, in the first part of an adaptive Phase 1/2 trial (NCT04666688) in relapsed/refractory solid tumors. Patients with solid tumor malignancy that is metastatic or unresectable and refractory to prior therapy are included. Patients are treated with LYT-200 by IV infusion, every 2 weeks (Q2W), until disease progression or toxicity. Phase 1 of the study uses the continuous reassessment design (CRM), and entails recruiting two patients per dosing level. Starting dose level was 0.2mg/kg Q2W. Additionally, the protocol stipulates six patients must be treated at the dose level intended to be declared recommended phase 2 dose (RP2D), for more robust assessment of safety/tolerability. RP2D may be the maximum tolerated dose or the optimal biological dose. The primary objective of the ongoing Phase 1 is to assess the safety and tolerability of LYT-200 and to identify the RP2D. The Phase 1 is also assessing LYT-200’s pharmacokinetics, immunogenicity and pharmacodynamics (measuring circulating gal-9 and cytokine levels, immunophenotyping peripheral blood mononuclear cells and tumor tissue). Preliminary efficacy is captured as an exploratory endpoint in Phase 1. Phase 2 expansion cohorts would implement the Simon’s two-stage design to further assess LYT-200 as a single agent and/or in combination with chemotherapy and tislelizumab. Phase 2 is currently planned in pancreatic cancer and other/different tumor types for Phase 2 may be guided by results of the Phase 1.AcknowledgementsAll clinical trial sites participating in the LYT-200 study. Shohei Koide, Linxiao Chen and George Miller and their teams at New York University Langone Health & New York University School of Medicine, NY for all the preclinical work on LYT-200.Trial RegistrationNCT04666688