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BMS‐986263 is a retinoid‐conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen‐specific chaperone protein involved in fibrosis development. This is a phase I, open‐label, two‐part study evaluating pharmacokinetics and safety of BMS‐986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age‐ and body mass index (BMI)‐matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age‐ and BMI‐matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS‐986263 infusion. Compared with normal‐matched participants, geometric mean area under the plasma concentration‐time curve time zero to the time of the last quantifiable concentration (AUC(0‐T)) and AUC from zero to infinity (AUC(INF)) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal‐matched group. Overall, single‐dose BMS‐986263 was generally safe and well‐tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS‐986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure‐safety/efficacy relationship becomes available. [ABSTRACT FROM AUTHOR]

Objective: Obesity and type 2 diabetes mellitus (T2DM) are risk factors for nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. This study assessed pegbelfermin (BMS-986036), recombinant PEGylated human fibroblast growth factor 21 (FGF21), in patients with obesity and T2DM predisposed to fatty liver.Methods: In this randomized, double-blind, placebo-controlled study, patients with T2DM and BMI of 30 to 50 kg/m2 received subcutaneous pegbelfermin (1, 5, or 20 mg daily or 20 mg weekly; n = 96) or placebo (n = 24) for 12 weeks. Primary end points were safety, tolerability, and change in HbA1c. Additional end points included insulin sensitivity, lipids, adiponectin, and disease progression biomarkers.Results: There were no significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol (P = 0.015) and triglycerides (P = 0.037). All pegbelfermin regimens significantly increased adiponectin levels; 20-mg daily and weekly regimens decreased serum PRO-C3. Most adverse events were mild; the most frequent adverse events were injection-site bruising and diarrhea.Conclusions: Twelve-week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity-related metabolic diseases (e.g., nonalcoholic steatohepatitis). [ABSTRACT FROM AUTHOR]

Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity tbr mono-ester prodrugs having more than throe carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 ± 0.19 x 10[sup-1] cm sec[sup-1]) to its valerate ester prodrug (23.70 ± 1.36 x 10[sup-6] cm sec sup[-1]). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy. [ABSTRACT FROM AUTHOR]

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD); no approved therapies for NASH currently exist. Pegbelfermin (PGBF), a human fibroblast growth factor 21 analog, has metabolic effects that may provide benefit for patients with NASH. The FALCON 1 and 2 studies are phase 2b, multicenter, double-blind, placebo-controlled, randomized trials to assess safety and efficacy of PGBF treatment in patients who have histologically-confirmed NASH with stage 3 liver fibrosis (FALCON 1; NCT03486899) or compensated cirrhosis (FALCON 2; NCT03486912). In both studies, randomized patients receive once weekly subcutaneous injections of PGBF (10, 20, or 40 mg) or placebo during a 48-week treatment period and are then followed for an additional 4 weeks. The primary efficacy endpoint for FALCON 1 is the proportion of patients who achieve ≥1 stage improvement in fibrosis (by NASH CRN fibrosis score) without NASH worsening or NASH improvement (≥2 point decrease in NAFLD Activity Score) without fibrosis worsening at Week 24. For FALCON 2, the primary efficacy endpoint is ≥1 stage improvement in fibrosis without NASH worsening at Week 48. Key safety endpoints for both studies include incidence and frequency of adverse events, bone mineral density and immunogenicity. Previous clinical trial data show that PGBF can reduce hepatic fat and improve metabolic factors and biomarkers of hepatic injury and fibrosis. The FALCON studies aim to evaluate PGBF treatment specifically in patients with NASH and advanced fibrosis, who are at greatest risk of poor clinical outcomes over time. • FGF21, a non-mitogenic liver-secreted hormone, modulates glucose and lipid metabolism. • Pegbelfermin (PGBF) is a PEGylated, recombinant human FGF21 analog. • PGBF has a prolonged half-life that supports weekly dosing. • The phase 2b FALCON trials study PGBF in NASH and stage 3 fibrosis or cirrhosis. • Histology and noninvasive tests will assess key endpoints of steatohepatitis and fibrosis. [ABSTRACT FROM AUTHOR]

BMS-986263 is a retinoid-conjugated lipid nanoparticle delivering small interfering RNA designed to inhibit synthesis of HSP47 protein, a collagen-specific chaperone protein involved in fibrosis development. This is a phase I, open-label, two-part study evaluating pharmacokinetics and safety of BMS-986263 in participants with hepatic impairment (HI). Part 1 (n = 24) of this study enrolled two cohorts with mild and moderate HI and a separate cohort of age- and body mass index (BMI)-matched participants with normal hepatic function. Part 2 enrolled eight participants with severe HI and eight age- and BMI-matched participants with normal hepatic function. All participants received a single intravenous 90 mg BMS-986263 infusion. Compared with normal-matched participants, geometric mean area under the plasma concentration-time curve time zero to the time of the last quantifiable concentration (AUC (0-T) ) and AUC from zero to infinity (AUC (INF) ) of HSP47 siRNA were similar in participants with mild HI and 34% and 163% greater in those with moderate and severe HI, respectively, whereas the maximum plasma concentration was ~25% lower in mild and moderate HI groups but 58% higher in the severe HI group than in the normal group. Adverse events were reported by two of eight, four of eight, and three of eight participants with mild, moderate, or severe HI, respectively; none were reported in the normal-matched group. Overall, single-dose BMS-986263 was generally safe and well-tolerated and dose adjustment is not considered necessary for participants with mild or moderate HI. Although available data do not indicate that dose adjustment should be performed in patients with severe HI; the optimal posology of BMS-986263 in patients with severe HI may be determined later in its clinical development when additional data to establish exposure-safety/efficacy relationship becomes available., (© 2023 Bristol Myers Squibb. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA 1-6 ). Signalling via LPA 1 appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA 1 antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD., Methods and Analysis: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort., Ethics and Dissemination: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication., Trial Registration Number: NCT04308681., Competing Interests: Competing interests: TJC has served on advisory boards for Boehringer Ingelheim, Hoffman-LaRoche, Bristol Myers Squibb, Ad-Alta, Promedior and Prometic Life Sciences. Her institution has received grants or research fees from Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Galápagos and Hoffman-La Roche, outside the submitted work. LL has served on advisory boards for United Therapeutics, Bristol Myers Squibb, AstraZeneca, Galápagos, Genentech and DevPro Biopharma; and has received research funding from Biogen, Celgene, Novartis, Bellerophon Therapeutics, Galecto, Bristol Myers Squibb, Respivant Sciences, Galápagos, Boehringer Ingelheim, Roche and Pliant Therapeutics; and has provided disease-state education for Genentech, Boehringer Ingelheim, United Therapeutics and Veracyte. JJS receives honoraria from Genentech for giving unbranded, disease-state talks on IPF; he also receives grant support from Genentech and Boehringer Ingelheim. He is a paid consultant for Boehringer Ingelheim and an unpaid consultant for Bristol Myers Squibb. TMM has received personal fees from AstraZeneca, Bayer, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galápagos, GlaxoSmithKline, Indalo Therapeutics, Pliant Therapeutics, Roche, and UCB, outside the submitted work. His institution received grants or research fees from AstraZeneca, GlaxoSmithKline and UCB outside the submitted work. JGG is the founder of MedQIA, LLC. SMP has consulted or served on advisory boards for Boehringer Ingelheim, Bristol Myers Squibb and Altavant; and has received research funding to Duke from Boehringer Ingelheim, Bristol Myers Squibb and AstraZeneca. TS has served on advisory boards for Bristol Myers Squibb and has received an honorarium and research funding from Boehringer Ingelheim. TO has served on advisory boards for Bristol Myers Squibb and has received personal fees from Boehringer Ingelheim, Shionogi, Astellas Pharma and Toray industries. AM is a consultant for Bristol Myers Squibb. XZ, GST, BE, HX, HW, RAS, EDC and AF are all employees of Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms., Methods: Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses., Results: Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed., Conclusions: PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation., Lay Summary: Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver., Competing Interests: YL, EDC, DES, CM, PS, AA, and GST are employees of Bristol Myers Squibb and may own company stock. BED was an employee of Bristol Myers Squibb at the time of the study. AJS has been a consultant for and received grants from Allergan, AstraZeneca, Bristol Myers Squibb, Intercept Pharmaceuticals, and Viking Therapeutics; has consulted for AbbVie, Affyimmune Therapeutics, Ardelyx, Chemomab, Conatus Pharmaceuticals, Echosens, Fractyl, Galectin Therapeutics, Immuron, Nitto Denko, Nimbus Therapeutics, Nordic Bioscience, Novo Nordisk, and Synlogic Therapeutics; has received grants from Cumberland Pharmaceuticals, Gilead Sciences, Merck, Mallinckrodt Pharmaceuticals, Novartis, Salix Pharmaceuticals, and Shire; owns stock in Akarna Therapeutics, Durect, Genfit, and Tiziana Life Sciences; and is employed by Sanyal Bioscience. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)