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 and metabolismQ2 · MEDICINE

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

Q2 · MEDICINE

Article

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

Abstract:

Purpose:

To 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.

Methods:

A 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.

Results:

Of 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.

Conclusions:

In 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 Identifier:

NCT03466203

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

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

23 May 2024

·www.biospace.com

Boston Pharmaceuticals Announces Former NIH Director, Dr. Elias Zerhouni, As the New Chair of Its Board of Directors

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Boston Pharmaceuticals, a clinical-stage biopharmaceutical company developing differentiated molecules addressing serious liver diseases, has today named Dr. Elias Zerhouni as the new Chair of its Board of Directors, with Stefan Meister standing down from the Board after six years to focus on his ongoing roles elsewhere. Dr. Zerhouni has been a Board member and Scientific Advisor at Boston Pharmaceuticals since 2021. In assuming the position of Chair, he will now work even more closely with Sophie Kornowski, CEO of Boston Pharmaceuticals, her team, and the community of liver experts as the company’s promising drug candidates accelerate their development. In particular, over the past few years Boston Pharmaceuticals has emerged with two exciting candidates in liver diseases and is focused on accelerating BOS-580, the company’s investigational, long-acting, once-monthly fibroblast growth factor 21 (FGF21) analogue for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). “I am pleased to assume the chairmanship of Boston Pharmaceuticals after having been a board member since 2021 and seeing the impressive progress in addressing the growing burden of liver diseases worldwide made under the guidance of Stefan Meister and leadership of our CEO Sophie Kornowski through promising molecules now in clinical development,” says Dr. Zerhouni. Kornowski added: “I am delighted that Elias has taken on this additional leadership role. His vast experience and expertise will, I am sure, prove invaluable as we navigate the paths of our candidates through clinical development. I also want to thank Stefan for all of his many and sizeable contributions and accomplishments during his time as a colleague. I and the rest of the company are sincerely grateful to him for his role in helping Boston Pharmaceuticals get to this exciting stage in our journey.” Dr. Zerhouni is a Professor Emeritus in Radiology and Biomedical Engineering at Johns Hopkins University and was most recently the President, Global Research & Development, and a member of the Executive Committee for Sanofi. He also served as the Director of the National Institutes of Health from 2002 to 2008. He is, since 2020, a member of the Board at B-Flexion and is also President and Vice Chairman of OPKO Health. About BOS-580 BOS-580 is a once-monthly subcutaneous injectable of a long-acting, highly engineered variant of human fibroblast growth factor 21 (FGF21) that regulates various metabolic pathways to decrease liver fat and ameliorate liver inflammation and damage in patients with metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH). 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 .

Executive Change

05 Jan 2024

·www.biospace.com

Boston Pharmaceuticals Presents Data at NASH-TAG 2024 Demonstrating Low Immunogenicity Over Time With Long-acting FGF21 Analogue, BOS-580, for MASH

Low immunogenicity observed over time in patients with phenotypic MASH treated over 12 weeks with long-acting FGF21 analogue, BOS-580, in a Phase 2a study BOS-580 treatment also led to rapid and significant reductions in composite biomarkers associated with fibrosis CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Boston Pharmaceuticals, a clinical-stage biopharmaceutical company developing differentiated molecules addressing serious liver diseases, today announced additional Phase 2 data supporting the low risk of immunogenicity and positive clinical effects associated with BOS-580, the company’s investigational, long-acting fibroblast growth factor 21 (FGF21) analogue for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH). The data were presented at NASH-TAG 2024 (Jan. 4-6, 2024) in Park City, Utah. “These encouraging results indicate that BOS-580 is unlikely to generate anti-drug antibodies, which is a key feature for drug developers working on FGF21 analogues in the field of MASH, as patients need sustained powerful efficacy over time,” said Sophie Kornowski, CEO of Boston Pharmaceuticals. “This low immunogenicity distinguishes BOS-580 from other FGF21 analogues currently in development.” Another analysis of data from Boston Pharmaceuticals’ Phase 2a trial demonstrated the impact of BOS-580 treatment on several non-invasive indicators of fibrosis based on markers of liver injury and fibrosis in MASH patients. “Our latest data highlight that BOS-580 has great potential to become a backbone in the treatment of patients suffering from MASH. We are committed to advancing once-monthly BOS-580 to pivotal clinical trials in the near term. We believe BOS-580 may offer a compelling and convenient treatment option for people living with MASH,” said Juan Carlos Lopez-Talavera, M.D., Ph.D., CMO of Boston Pharmaceuticals. Low Immunogenicity Reported in Patients with Phenotypic MASH Treated with BOS-580 Protein-based therapeutics can trigger an immune response that can alter or reduce their efficacy and may be associated with adverse effects. Researchers assessed the impact of BOS-580 treatment (once-monthly and bi-weekly dosing regimens) on the formation of anti-drug antibodies (ADAs), a clinical measure of protein therapeutic immunogenicity, in patients with phenotypic MASH enrolled in Part A of a randomized, double-blind, placebo-controlled Phase 2a study (N=102). Results indicate: BOS-580 showed low and transient ADA responses, detected at one or two measurements Titers for anti–BOS-580 and anti–FGF-21 antibodies were low One out of 65 patients (1.5%) exposed to BOS-580 had consecutive increasing anti-FGF21 antibodies, which had no impact on the drug’s pharmacokinetic or pharmacodynamic parameters BOS-580 Treatment Resulted in Significant Reductions in Composite Biomarkers Associated with Fibrosis An analysis of data from Boston Pharmaceuticals’ Phase 2a trial demonstrated the efficacy of BOS-580 on biomarkers of liver injury and fibrosis in MASH patients. With the high prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), also known as non-alcoholic fatty liver disease (NAFLD), which can lead to MASH, there is an urgent need to identify non-invasive methods to avoid the use of biopsies. Results of this analysis show treatment with BOS-580 led to significant reductions across composite scores for Fibroscan-AST (FAST), Fibrosis-4 Index (FIB-4), Aspartate aminotransferase-to-platelet ratio index (APRI) and ADAPT. The responses observed were rapid, within one to two weeks, and were sustained over the 12-week study, suggesting BOS-580 treatment may lead to clinical benefit in MASH patients. Details of the NASH-TAG 2024 presentations are as follows: Title: Low Immunogenicity Rates in Phenotypic MASH Patients Treated for 12 Weeks With Once-Monthly and Bi-weekly Subcutaneous Dosing of BOS-580 (Poster Presentation) Abstract Number: 42 Session Date, Time: Saturday, Jan. 6, 2024 Presenter: Swapan K Chowdhury, Boston Pharmaceuticals Title: Improvement in FAST and FIB-4 Composite Biomarker Scores in Phenotypic MASH Patients Treated for 12 Weeks With Monthly and Bi-weekly Subcutaneous Dosing of BOS-580 (Oral Presentation) Abstract Number: 46 Session Date, Time: Saturday, Jan. 6, 2024 at 11:45 a.m. MST Presenter: Rohit Loomba, M.D., MHSc, Professor of Medicine, Chief in the Division of Gastroenterology and Hepatology, and Director of MASLD Research Center at University of California, San Diego About BOS-580 BOS-580 is a once-monthly subcutaneous injectable of a long-acting, highly engineered variant of human fibroblast growth factor 21 (FGF21) that regulates various metabolic pathways to decrease liver fat and ameliorate liver inflammation and damage in patients with metabolic dysfunction-associated steatohepatitis (MASH), also known as non-alcoholic steatohepatitis (NASH). 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 .

Phase 2Clinical Result

100 Deals associated with Efimosfermin alfa

R&D Status

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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

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Phase 2a study (NASH_TAG2024)	Phase 2	-	102	BOS-580	wxlnaajeeu(fefzshvqnp) = ulhystlbxd urvhksbzsu (tvyobwkyvv )	Positive	04 Jan 2024
				Placebo	wxlnaajeeu(fefzshvqnp) = ximjokyvvw urvhksbzsu (tvyobwkyvv )
Biospace Manual	Phase 2	Nonalcoholic Steatohepatitis	102	overall	aygdqxglgy(ysostsldbp) = No treatment emergent adverse events of hypoglycemia were reported in any patient enrolled in the study. tqkwnvibcr (ewuukveyut ) View more	Positive	10 Nov 2023
				BOS-580 (HbA1c≥6.5%)
Biospace Manual	Phase 2	Nonalcoholic Steatohepatitis	102	BOS-580 (Once-monthly)	ogdjcvhrmf(nknirsnroi) = the % reduction in MRI-PDFF is similar whether a total monthly dose is given bi-weekly or once-a-month jkjokjhszi (skyqnzupwk ) View more	Positive	10 Nov 2023
				BOS-580 (bi-weekly)
NCT03466203 (Pubmed \| J Clin Endocrinol Metab)	Phase 1	Hypertriglyceridemia \| Obesity	64	LLF580 300 mg	ygtgeclkei(wkxkdhvisb) = higher incidence of generally mild to moderate gastrointestinal adverse effects nmvjjwwcat (hzvnuxdfub )	-	25 Aug 2021

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