pegbelfermin (BMS-986036) / BMS, J&J - LARVOL DELTA

FGF21 Signaling Exerts Anti-Fibrotic Properties During Pulmonary Fibrosis. (PubMed, Am J Respir Crit Care Med) - "Our data indicate a possible anti-fibrotic effect of FGF21 in the lung achieved through the inhibition of alveolar type 2 cells apoptosis."

Journal • Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • FGF21 • FGFR1 • KLB

Pegbelfermin for reducing transaminase levels in patients with non-alcoholic steatohepatitis: a dose-response meta-analysis of randomized controlled trials. (PubMed, Front Med (Lausanne)) - "PROSPERO, CRD42023448024. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=448024."

Retrospective data • Review • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

Therapeutic effect of long-acting FGF21 with controlled site-specific modification on nonalcoholic steatohepatitis. (PubMed, Int J Biol Macromol) - "However, the uneven distribution of PEGylation sites in FGF21 makes it difficult to purify PEG-FGF21, thereby affecting its yield, purity, and activity...Pharmacodynamic evaluation in mice with high-fat, high-cholesterol- and methionine and choline deficiency-induced NASH illustrated that PEG-mFGF21 exhibited long-term efficacy in improving liver steatosis and reducing liver cell damage, inflammation, and fibrosis. Taken together, PEG-mFGF21 could represent a potential therapeutic drug for the treatment of NASH."

Journal • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • FGF21

Anti-fibrotic effect of FGF21 in pulmonary fibrosis (ERS 2023) - "In human, PEGylated FGF21 analog (PEG-FGF21) was shown to reduce liver fibrosis in NASH. FGF21 overexpression prevented bleomycin-induced pulmonary fibrosis, whereas Fgf21 deletion was associated with an increased fibrosis. Our data indicate a possible antifibrotic effect of FGF21 in the lung.; Cell and molecular biology; Endoscopy and interventional pulmonology; Epidemiology; Respiratory intensive care"

Critical care • Fibrosis • Hepatology • Idiopathic Pulmonary Fibrosis • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Pulmonary Disease • Respiratory Diseases • COL14A1 • COL1A1 • COL3A1 • CTGF • FGF21 • FGFR1 • KLB • TGFB1

Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis. (PubMed, Aliment Pharmacol Ther) - P1/2 | "Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH."

Biopsy • Journal • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • FGF21

The Novel GlycoPEGylated FGF21 Analog Pegozafermin Activates Human FGF Receptors and Improves Metabolic and Liver Outcomes in Diabetic Monkeys and Healthy Human Volunteers. (PubMed, J Pharmacol Exp Ther) - "Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous-dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyderidemia."

Journal • Dyslipidemia • Hepatology • Hypertriglyceridemia • Metabolic Disorders • Non-alcoholic Steatohepatitis • FGF21 • FGFR1

"congrats! is the PEGylated FGF21 analog active in the brain?" (@CharlesMBrenner)

FGF21

Pegbelfermin (BMS-986036) reduces serum levels of secondary bile acids in patients with non-alcoholic steatohepatitis (EASL-ILC 2019) - P2; "Pegbelfermin tx in pts with NASH and fibrosis resulted in the reduction of serum 2° BAs and the 2° BAs:1° BAs ratio. 2° BAs are associated with elevated risk of hepatotoxicity and HCC. Further investigation is needed to understand the mechanisms mediating the effects of pegbelfermin on BAs, such as BA synthesis and absorption, and microbiome activities."

Clinical

Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study. (PubMed, Lancet Gastroenterol Hepatol) - P1/2 | "Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted."

Journal • P1/2 data • PK/PD data • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • FGF21

S3-E54.2 - Presentation on Efruxifermin in NASH with Fibrosis (YouTube) - "In this follow-up conversation, Stephen walks through his presentation on the efficacy and safety of Akero's lead product candidate EFX. After detailing the data, two important points emerge. First, Stephen and...share the idea that 'not all FGF-21's are created equal.' FGF-21's themselves need to be stabilized due to their two-hour half-lives. The first FGF-21, pegbelfermin, was PEGylated and revealed significant challenges in clinical development. EFX is a bivalent structure - two molecules stabilized by a fusion protein."

Video

ATTENUATIONS IN ADIPOSE ADIPONECTIN PRODUCTION OVER TIME RESTRICT SIMULATED EFFICACY FOR PEGBELFERMIN IN F3 NASH PATIENTS (AASLD 2022) - " Exposure of pegbelfermin was reproduced directly from publicly presented pharmacokinetic data and combined with a mechanistic representation of the actions of the peg-FGF21 on adipose... Simulations in NAFLDsym helped substantiate the hypothesis that pegbelfermin-driven increases in adiponectin mediate the observed effects on liver outputs in NASH patients. However, the attenuated increase in adiponectin over time may be associated with loss of durability over time."

Clinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • FGF21

Companion Protocol for ¹³C-Methacetin Breath Tests in BMS: NCT03486899, NCT03486912 Referenced Trials (clinicaltrials.gov) - P2b | N=124 | Completed | Sponsor: Exalenz Bioscience LTD. | Withheld ➔ Completed | Phase classification: PN/A ➔ P2b

Phase classification • Trial completion • Hepatology • Non-alcoholic Steatohepatitis

BIO89-100 Treatment Ameliorates a Subclinical Increase in Spleen Volume in Non-cirrhotic NASH in Correlation With Change in Liver Fat, HOMA-IR and Inflammatory Markers in a Phase 1b/2a, Placebo-Controlled, Double-Blind Proof of Concept Study (ENDO 2022) - "BIO89-100, a glycoPEGylated FGF21 analog, led to significant reductions in hepatic fat fraction and liver volume by MRI-PDFF, with concurrent metabolic benefits, in a Phase 1b/2a clinical trial in subjects with NASH. Learning Objective 1: - Understand that NASH may be associated with subclinical portal hypertension and higher spleen volume, within the normal range, in the absence of cirrhosis, and that spleen volume measurement by MRI may be a useful tool to assess subclinical portal hypertension Learning Objective 2: - Understand that subclinical portal hypertension may be ameliorated by effective treatment for NASH, and that spleen volume assessment by MRI may be a useful tool to assess change in subclinical portal hypertension. Science Topic(s) for Cardiovascular Endocrinology: Lipids (including fatty liver disease)"

Clinical • P1/2 data • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Portal Hypertension • FGF21

Pharmacokinetic (PK) and pharmacodynamics (PD) of BIO89-100, a novel glycoPEGylated FGF21, in nonalcoholic steatohepatitis (NASH) patients with compensated cirrhosis (EASL-ILC 2022) - "The interim PK/PD data indicate BIO89-100 elicits a robust PK/PD effect independent of NASH fibrosis stage. These findings highlight the feasibility of achieving favorable treatment outcomes in F4 patients with compensated hepatic function without requiring dose adjustment. Overall, these PK/PD properties warrant further investigation to allow assessments of effectiveness of BIO89- 100 in a larger F4 population."

Clinical • PK/PD data • Addiction (Opioid and Alcohol) • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Non-alcoholic Steatohepatitis • FGF21

Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis. (PubMed, Int J Mol Sci) - "A CCR2/5 inhibitor (BMS-687681-02-020) and a pegylated FGF21 agonist (BMS-986171) were tested in male C57BL/6J mice subjected to dietary models of NASH and fibrosis (choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) up to 12 weeks; short- (2w) or long-term (6w) treatment). (4) CCR2/5 inhibition blocks hepatic infiltration of inflammatory monocytes, FGF21 agonism improves obesity-related metabolic disorders. Combined therapy ameliorates steatohepatitis and fibrosis more potently than single drug treatment in rodent NASH, corroborating the therapeutic potential of combining these two approaches in NASH patients."

Journal • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • CCL2 • FGF21

A Study to Evaluate the Drug Levels, Safety, and Tolerability of BMS-986036 in Participants With Normal Liver Function and Participants With Moderate and Severe Liver Impairment (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed | N=24 ➔ 16

Enrollment change • Trial completion • Hepatology

A Study to Evaluate the Drug Levels and Safety of Pegbelfermin in Healthy Overweight and Obese Chinese and Korean Participants (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Bristol-Myers Squibb | N=48 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Obesity

A Study to Evaluate the Drug Levels, Safety, and Tolerability of BMS-986036 in Participants With Normal Liver Function and Participants With Moderate and Severe Liver Impairment (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Jul 2021 ➔ Apr 2022 | Trial primary completion date: Jul 2021 ➔ Apr 2022

Trial completion date • Trial primary completion date • Hepatology

A Study of Experimental Medication BMS-986036 in Adults With Nonalcoholic Steatohepatitis (NASH) and Stage 3 Liver Fibrosis (clinicaltrials.gov) - P2b | N=191 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Dec 2021 ➔ Sep 2021 | Trial primary completion date: Sep 2020 ➔ Aug 2021

Trial completion • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Relative Levels of BMS-986036 in Blood Plasma in Healthy, Overweight, and Obese Participants Following Subcutaneous Administration Via Auto-injector Versus Pre-filled Syringe (clinicaltrials.gov) - P1 | N=102 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed | Trial completion date: Sep 2020 ➔ Jun 2021 | Trial primary completion date: Sep 2020 ➔ Jun 2021

Trial completion • Trial completion date • Trial primary completion date • Obesity • FGF21

A Study of Experimental Medication BMS-986036 in Adults With Nonalcoholic Steatohepatitis (NASH) and Liver Cirrhosis (clinicaltrials.gov) - P2b | N=152 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Gastroenterology • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis. (PubMed, J Magn Reson Imaging) - "MRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data. 1 TECHNICAL EFFICACY STAGE: 2."

Journal • MRI • Preclinical • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • FGF21 • MRI

S2-E58.2 – Focus On NASH Cirrhosis: Reviewing FALCON 2 and the belapectin Post Hoc Analysis of Phase 2 Data (Surfing The NASH Tsunami Podcast) - "This episode follows S2 E43 in discussing the possible role of NASH cirrhosis clinical trials in the transition from biopsy as gold standard to a post-biopsy world. Stephen Harrison starts this conversation by reviewing a post hoc analysis of Phase 2 belapectin data from Galectin Therapeutics, followed by a review of the FALCON 2 stud of pegbelfermin in NASH cirrhosis, sponsored by Bristol Myers Squibb."

Audio

S2-E58 – What’s New In Clinical Trials for NASH Cirrhosis (Surfing The NASH Tsunami Podcast) - "Stephen Harrison leads the group in discussing recent results from NASH cirrhosis trials, including the REVERSE trial with obeticholic acid, the FALCON 2 trial with pegbelfermin and a post-hoc analysis of Galectin Therapeutics' Phase 2 trial for belapectin. The group also discussed ongoing trials including the FGF-21 efruxifermin, the FGF-19 aldafermin, the Galectin-3 inhibitor belapectin and the combination agent trial from Gilead Sciences."

Audio

[VIRTUAL] EFFICACY AND SAFETY OF PEGBELFERMIN IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND STAGE 3 FIBROSIS: RESULTS FROM THE PHASE 2b, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED FALCON 1 STUDY (AASLD 2021) - P2b | "Background : Pegbelfermin (PGBF) is a PEGylated fibroblast growth factor 21 analog... PGBF led to numerically higher rates of fibrosis improvement without NASH worsening or NASH improvement without fibrosis worsening at wk 24 compared with PBO. PGBF demonstrated evidence of improvements in steatosis, fibrosis, and inflammation based on noninvasive measures, and was generally safe and well tolerated in pts with NASH and stage 3 fibrosis."

Clinical • Late-breaking abstract • P2b data • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • FGF21