A Phase 2a, Randomized, Blinded, Placebo-controlled Study of BOS-580 in Obese Subjects At Risk For, or with Biopsy-confirmed, Nonalcoholic Steatohepatitis (NASH) with a Single Arm Open-label Extension

This is a randomized, blinded, placebo-controlled study of BOS-580 in obese participants at risk for, or with biopsy-confirmed, nonalcoholic steatohepatitis (NASH), with a single arm open-label extension. It includes Parts A, B, C and D.

Start Date30 Sep 2021

Sponsor / Collaborator

Boston Pharmaceuticals, Inc.Startup

NCT03466203 / CompletedPhase 1

A 12 Week Phase Ib Randomized Investigator and Subject Blinded Placebo Controlled Repeat-dose Study of LLF580

The purpose of the study is to evaluate the safety and tolerability of multiple doses of LLF580 administered subcutaneously over 3 months in obese subjects. In addition, the study will also determine early efficacy signals in various metabolic diseases associated with elevated triglycerides and/or obesity.

Start Date26 Feb 2018

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with Efimosfermin alfa

100 Translational Medicine associated with Efimosfermin alfa

100 Patents (Medical) associated with Efimosfermin alfa

Literatures (Medical) associated with Efimosfermin alfa

01 Jan 2022·The Journal of Clinical Endocrinology & MetabolismQ2 · MEDICINE

LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia

Q2 · MEDICINE

Article

Author: Ferriere, Michael ; Diener, John ; Wilson, Jessica ; Bajaj, Archna ; Hinder, Markus ; Maratos-Flier, Eleftheria ; Yowe, David ; Koren, Michael ; Escalon, Maricer ; Fein, Melanie ; Rader, Daniel J ; Nguyen, Amanda ; Hom, Doug ; Kompa, Jill ; Martic, Miljen ; Kankam, Martin K ; Li, Yifang ; Basson, Craig T ; Hunt, Allen ; Goldfine, Allison B

AbstractPurposeTo evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction.MethodsA multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses.ResultsOf 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects.ConclusionsIn obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted.ClinicalTrials.gov IdentifierNCT03466203

Therapeutics and Clinical Risk Management

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease

Review

Author: Mantzoros, Christos S ; Polyzos, Stergios A ; Raptis, Dimitrios D

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.

News (Medical) associated with Efimosfermin alfa

15 Nov 2024

·www.businesswire.com

Boston Pharmaceuticals to Announce Positive Phase 2 Data on Efimosfermin Alfa (BOS-580) in F2/F3 MASH During Late-Breaking Oral Presentation at AASLD 2024, The Liver Meeting®

CAMBRIDGE, Mass.--( BUSINESS WIRE )-- Boston Pharmaceuticals , a clinical-stage biopharmaceutical company developing differentiated molecules addressing serious liver diseases, today announced positive results from a Phase 2 study evaluating the safety and efficacy of once-monthly efimosfermin alfa (formerly known as BOS-580), a long-acting FGF21 analogue, in participants with stage F2/F3 fibrosis due to metabolic dysfunction-associated steatohepatitis (MASH). Treatment with efimosfermin led to significant improvements in fibrosis ≥1 stage without worsening of MASH, and MASH resolution without worsening of fibrosis over 24 weeks. In the study, efimosfermin demonstrated a favorable tolerability profile. These topline results will be presented on Nov. 19 in a late-breaking oral presentation at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting , ® Nov. 15-19, 2024, in San Diego. “These new data demonstrate that efimosfermin may rapidly and significantly reduce disease progression in people diagnosed with moderate-to-advanced-stage liver disease, is well-tolerated and offers the convenience of monthly dosing – all factors that are important to this patient population,” said Mazen Noureddin, M.D., M.H.Sc., lead investigator and professor of medicine at Houston Methodist Hospital, and director of the Houston Research Institute. “For patients with MASH, maintaining their treatment regimen is essential for the overall effective management of this debilitating disease.” The Phase 2 randomized, double-blind, placebo-controlled study (N=84) was designed to assess the efficacy and safety of once-monthly efimosfermin 300 mg dosed subcutaneously in participants with biopsy-confirmed F2 or F3 MASH over 24 weeks. The data provide a more comprehensive overview of the benefit-risk profile of the 300 mg dose and will inform future discussions with regulatory authorities. The company anticipates advancing the clinical program to late-stage development in 2025. Key treatment effects over 24 weeks with efimosfermin in biopsy-confirmed MASH patients with F2/F3 fibrosis showed: Histological Endpoints Efimosfermin alfa 300 mg (N=31) Placebo (N=34) p-value (vs. placebo) Fibrosis improvement ≥1 stage without worsening of MASH, n (%) 14 (45.2%) 7 (20.6%) 0.038 MASH resolution without worsening of fibrosis, n (%) 21 (67.7%) 10 (29.4%) 0.002 Fibrosis improvement ≥1 stage and MASH resolution, n (%) 12 (38.7%) 6 (17.6%) 0.066 In addition, study participants treated with efimosfermin showed rapid and significant improvement in fibrosis biomarkers and significant reductions in non-invasive markers of liver injury and liver fat over the study period. Participants with type 2 diabetes also had significant and clinically meaningful improvement in HbA1c values. Over 24 weeks of treatment, efimosfermin-treated study participants had low discontinuation rates due to adverse events, and an overall low incidence of gastrointestinal side effects and injection site reactions. “These data indicate that efimosfermin may effectively target the three main components of hepatic disease, thereby producing a meaningful impact on fibrosis improvement, which is a critical and often under-treated aspect of managing MASH,” stated Margaret Koziel, M.D., Chief Medical Officer at Boston Pharmaceuticals. “Furthermore, efimosfermin may offer important cardiometabolic benefits such as liver fat reduction and improved glycemic control in MASH patients who often struggle with co-morbidities such as obesity and diabetes.” The Phase 2 clinical development program of efimosfermin is continuing with an open-label extension in F2 and F3 patients, providing an additional 24 weeks of treatment to assess long-term safety and efficacy which should offer further information on the low immunogenicity of efimosfermin. “Efimosfermin has demonstrated significant efficacy across key liver and metabolic biomarkers, reinforcing its potential as a well-tolerated, once-monthly treatment for MASH,” said Sophie Kornowski, Chief Executive Officer, Boston Pharmaceuticals. “We believe these data, together with upcoming results from our extension study and our advanced fibrosis study, will enable us to build a comprehensive package for discussions with regulatory authorities ahead of our entry into pivotal studies.” Investor Webcast Boston Pharmaceuticals will host a conference call on Thursday, Nov. 21, 2024, at 4 p.m. ET. This virtual event will provide insights into the topline data including histology, changes from baseline in non-invasive markers, as well as safety and tolerability. Participants can register at the following link: https://events.q4inc.com/attendee/517931962 . An archived replay of the webcast will be available on the Boston Pharmaceuticals’ website. About efimosfermin alfa (BOS-580) Boston Pharmaceuticals’ lead investigational agent, efimosfermin alfa (BOS-580), is a once-monthly, subcutaneous injection of a long-acting variant of human fibroblast growth factor 21 (FGF21) that regulates metabolic pathways to decrease liver fat, ameliorate liver damage and inflammation, and reverse liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH). Efimosfermin is manufactured in mammalian cells, leading to human-like glycosylation. Efimosfermin is currently in Phase 2 clinical trials for the treatment of MASH. In clinical studies, efimosfermin has previously demonstrated statistically significant reductions in liver fat content, markers of liver injury and fibrosis, and improved metabolic biomarkers, with a favorable safety profile in a 12-week Phase 2a study. About MASH Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a growing global epidemic fueled by the increasing prevalence of obesity and type 2 diabetes. It is estimated that MASH affects 115 million people worldwide, including 17 million in the U.S., and is expected to increase by 63% by 2030. MASH is a progressive disease staged by the degree of fibrosis (scarring) in the liver and is closely associated with multiple cardiometabolic risk factors. Left untreated, MASH could lead to liver failure, liver cancer or death. In the U.S., MASH is now a leading cause of liver transplantation. About Boston Pharmaceuticals Boston Pharmaceuticals, a portfolio company of B-FLEXION , is a clinical-stage biopharmaceutical company that leverages an experienced and committed drug development team to advance a portfolio of highly differentiated therapies that may address important unmet medical needs in severe liver diseases, with MASH as the focus of its lead asset. The Company has significant expansion opportunities through its portfolio of promising drug development candidates that were acquired through partnerships with proven, innovative biotechnology and pharmaceutical companies. Boston Pharmaceuticals applies rigorous decision-making to advance programs to deliver differentiated medicines to patients in need of new options while creating value for all parties involved in the journey. For more information, please visit www.bostonpharmaceuticals.com and follow us on LinkedIn .

Phase 2Clinical Result

15 Nov 2024

·endpts.com

Boston Pharmaceuticals hits Phase 2 goals as it tries to keep up with MASH competitors

Boston Pharmaceuticals succeeded on two closely watched efficacy endpoints for its Phase 2 MASH study, putting the company in contention with other biotechs seeking to treat the liver disease. The company reported Friday that its FGF21 analog, called efimosfermin alfa, spurred a statistically significant improvement in both fibrosis without worsening of MASH, and resolution of MASH without worsening of fibrosis. The new data assessed the once-monthly shot over 24 weeks in 84 patients with advanced stages of MASH, also known as metabolic dysfunction-associated steatohepatitis. The company said it plans to discuss the data with regulators and advance the drug into late-stage development next year. As is frequently the case in MASH studies, efimosfermin was considerably better at resolving MASH than improving fibrosis, a type of liver scarring that’s a hallmark of the disease. In the group treated with efimosfermin, 67.7% had their MASH disease improve without their fibrosis worsening, compared with 29.4% of patients given placebo. For the fibrosis endpoint, which uses a scale to measure liver scarring, 45.2% of patients getting the drug had at least a one-stage improvement without worsening of MASH, compared to 20.6% of patients on placebo. Boston didn’t report a statistically significant number of treated patients who had both MASH resolution and fibrosis improvement compared to placebo, a higher bar than the other two endpoints. The trial’s primary endpoints were safety and tolerability, according to a government database of trials. Patients receiving efimosfermin had low discontinuation rates, according to the company, and “an overall low incidence of gastrointestinal side effects and injection site reactions.” The data bode well for Boston’s prospects in the larger FGF21 race , though it still trails two other biotechs that are slightly ahead: Akero Therapeutics’ efruxifermin is in the middle of two Phase 3 studies, as is 89bio. All three companies are looking to carve out a slice of the market that Madrigal Pharmaceuticals currently has to itself. Madrigal’s treatment, Rezdiffra, became the first to win FDA approval to treat the underlying biology of MASH earlier this year and recently impressed investors with more than $62 million in third-quarter revenue. Novo Nordisk could become a competitor, too, after posting positive Phase 3 data earlier this month with plans to file for regulatory approval in the US and EU in the first half of 2025.

Phase 2Clinical ResultPhase 3

05 Jun 2024

·www.biospace.com

Boston Pharmaceuticals Presents Data at EASL Congress 2024 Showing Treatment With Long-acting FGF21 Analogue, BOS-580, Improved Lipid Profiles in Patients with Phenotypic MASH

BOS-580 treatment over 12 weeks led to significant changes in the circulating lipidome, reduced MASEF scores and improved MASEF risk classification in patients with phenotypic MASH CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Boston Pharmaceuticals, a clinical-stage biopharmaceutical company developing differentiated molecules addressing serious liver diseases, today announced new Phase 2a data demonstrating the positive impact of BOS-580, an investigational, long-acting fibroblast growth factor 21 (FGF21) analogue, on the circulating lipidome and changes in the metabolomics advanced steatohepatitis fibrosis (MASEF) score in patients with phenotypic metabolic dysfunction-associated steatohepatitis (MASH). The data will be presented at the European Association for the Study of the Liver (EASL) Congress 2024, held from June 5-8 in Milan, Italy. “Our analysis demonstrated that the circulating lipidome in phenotypic MASH patients is distinct compared to that seen in obese but otherwise healthy adults. Treatment of these patients with BOS-580 over 12 weeks substantially improved patient lipid profiles and reduced MASEF scores, a novel composite biomarker to identify at-risk MASH patients,” said Sophie Kornowski, CEO of Boston Pharmaceuticals. “These data continue to highlight BOS-580’s potential as a powerful once-monthly treatment for MASH. They also support the relevance and potential use of diagnostic and predictive biomarkers in MASH for patient assessment and management. We look forward to sharing biopsy results from our ongoing study in patients with stage F2/F3 fibrosis due to MASH later this year.” Improvements in Circulating Lipidome and MASEF Scores in Phenotypic MASH Treated with BOS-580 Changes observed in the lipidome in MASH patients suggest that dysregulation in lipid metabolism may be fundamental to the disease's development, contributing to oxidative stress, inflammation and cell death. Understanding the role of lipid metabolism in healthy and disease states has the potential to drive the discovery of potential biomarkers for diagnosis and new therapeutic targets. The MASEF score is a metabolomics-driven score that offers a noninvasive way to identify patients with at-risk MASH who could benefit from medical therapies and intervention, making it a promising diagnostic tool.1 In this analysis, researchers evaluated variations in the comprehensive pro lipids present in the bloodstream after 12 weeks of treatment with BOS-580 in patients with phenotypic MASH who were enrolled in Part A of a randomized, double-blind, placebo-controlled Phase 2a study (N=102). Results show: BOS-580 treatment led to extensive changes in the circulating lipidome, including decreased levels of saturated fatty acids and triglycerides; notably, these samples also had significantly lower levels of lipotoxic molecules such as diglycerides and ceramides, suggesting that the potential beneficial effects of BOS-580 may be mediated in part by reducing lipotoxic molecules in MASH patients. Eighty-eight percent of patients treated with BOS-580 achieved reductions in their composite MASEF scores, compared to 33% in the placebo group. Treatment with BOS-580 also improved MASEF risk classification by decreasing the number of patients identified to be at-risk for MASH from 20% at baseline to 2% at 12 weeks, compared to an increase from 17% at baseline to 20% at 12 weeks in the placebo group. Details of Boston Pharmaceuticals’ presentation at EASL are as follows: Title: BOS-580, a long-acting FGF21 analogue, treatment shows beneficial changes in the circulating lipidome and improves MASEF score in patients with phenotypic metabolic dysfunction-associated steatohepatitis in a Phase 2a randomized, placebo-controlled, 12-week study (Poster Presentation) Abstract Number: 621 Poster Number: WED-220 Session Date, Time: June 5, 8:30 am CEST Presenter: Gerard Bain, Boston Pharmaceuticals For more information about BOS-580 and Boston Pharmaceuticals’ pipeline of highly engineered targeted therapies for patients with serious liver diseases, visit Booth #O1 at EASL Congress 2024. About Boston Pharmaceuticals Boston Pharmaceuticals is a clinical stage biopharmaceutical company that leverages an experienced and committed drug development team to advance a portfolio of highly differentiated therapies that may address important unmet medical needs in serious liver diseases, with MASH as the focus of its lead asset. The Company has significant expansion opportunities through its portfolio of promising drug development candidates that were acquired through partnerships with proven, innovative biotechnology and pharmaceutical companies. Boston Pharmaceuticals applies rigorous decision making to advance programs to deliver differentiated medicines to patients in need of new options, while creating value for all parties involved in the journey. For more information, please visit and follow us on LinkedIn. About B-Flexion Boston Pharmaceuticals is a portfolio company of B-Flexion, a private entrepreneurial investment firm that partners with sophisticated capital to deliver exceptional value over the generations, while also contributing positively to society. Chaired by Ernesto Bertarelli and with offices across Europe and the United States, B-Flexion seeds, acquires and builds investment partnerships, principally in the fields of Private Equity, Venture & Growth Capital, Real Assets, Hedge Funds, Credit, and Public Securities. As well as these partnerships, B-Flexion makes principal investments in operating businesses in transformative industries with a focus on Healthcare, Planet, Consumer and Technology. For more information, please visit . Reference: Noureddin M, Truong E, Mayo R, et al. Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF). Hepatology. 2024;79(1):135-148. doi:10.1097/HEP.0000000000000542.

Phase 2Clinical Result

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Phase 2	US	Boston Pharmaceuticals, Inc.Startup	30 Sep 2021
Obesity	Phase 1	US	Novartis Pharmaceuticals Corp.	26 Feb 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04880031 (BOS-580-201, Biospace) Manual	Phase 2	Nonalcoholic Steatohepatitis	84	Efimosfermin alfa 300 mg	vfkkstvkhc(lhvfneawef) = scmxfpsbqk yetgjtyaov (iojheurmdi ) View more	Positive	15 Nov 2024
				Placebo	vfkkstvkhc(lhvfneawef) = wpwdksdjhl yetgjtyaov (iojheurmdi ) View more
Phase 2a study (NASH_TAG2024)	Phase 2	-	102	BOS-580	(aaogttubdh) = wgyerukybf vyhmpebuom (kfokbxcjgd )	Positive	04 Jan 2024
				Placebo	(aaogttubdh) = hacwscrapo vyhmpebuom (kfokbxcjgd )
Biospace Manual	Phase 2	Nonalcoholic Steatohepatitis	102	BOS-580 (Once-monthly)	animovrtdf(vnqlctpwrq) = the % reduction in MRI-PDFF is similar whether a total monthly dose is given bi-weekly or once-a-month rjusepuxew (hetjdjqwki ) View more	Positive	10 Nov 2023
				BOS-580 (bi-weekly)
Biospace Manual	Phase 2	Nonalcoholic Steatohepatitis	102	overall	muxqrcllgk(otuatcwnnv) = No treatment emergent adverse events of hypoglycemia were reported in any patient enrolled in the study. shfiwvavmh (vlpjqevmgk ) View more	Positive	10 Nov 2023
				BOS-580 (HbA1c≥6.5%)
NCT03466203 (Pubmed \| J Clin Endocrinol Metab)	Phase 1	Hypertriglyceridemia \| Obesity	64	LLF580 300 mg	wikznhdffs(wrvqotmnan) = higher incidence of generally mild to moderate gastrointestinal adverse effects yptpkuprry (vtklsveput )	-	25 Aug 2021

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