Efruxifermin for NASH
Recruiting in Palo Alto (17 mi)
+181 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Akero Therapeutics, Inc
Disqualifiers: Alcoholic liver disease, Autoimmune disorders, Type 1 diabetes, others
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This trial is testing a medication called efruxifermin (EFX) to see if it can help people with specific liver conditions. These conditions are hard to treat with current methods. EFX aims to improve liver health by reducing inflammation and fat buildup in the liver.
Do I need to stop my current medications for the Efruxifermin for NASH trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Efruxifermin for NASH?
How is the drug Efruxifermin unique for treating NASH?
Efruxifermin is unique because it is a fusion protein that combines a part of the human antibody with FGF21, a protein that helps regulate metabolism, and it specifically targets liver fibrosis in NASH, a condition with no approved treatments. Its mechanism involves binding to a specific receptor on cells to activate pathways that may reduce liver damage.56789
Eligibility Criteria
This trial is for adults aged 18-80 with a suspected or confirmed diagnosis of NASH/MASH or NAFLD/MASLD, and who have at least two components of metabolic syndrome or type 2 diabetes. It's not open to those with other liver diseases, type 1 diabetes, or unstable type 2 diabetes.Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive Efruxifermin or placebo for the assessment of safety and tolerability
52 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- Efruxifermin (Growth Factor)
Trial OverviewThe study tests Efruxifermin (EFX) against a placebo in a controlled setting where neither the participants nor the researchers know who receives the actual drug. The goal is to see if EFX can help people with certain types of fatty liver disease.
Participant Groups
3Treatment groups
Experimental Treatment
Placebo Group
Group I: EFX 50 mg (Open-Label Rollover)Experimental Treatment1 Intervention
Group II: EFX 50 mgExperimental Treatment1 Intervention
Group III: PlaceboPlacebo Group1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Akero Clinical Study SiteMorehead City, NC
Akero Clinical Study SiteSan Francisco, CA
Tandem Clinical Research, CovingtonCovington, LA
Tandem Clinical Research, New YorkNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Akero Therapeutics, IncLead Sponsor
References
Efruxifermin, a long-acting Fc-fusion FGF21 analogue, reduces body weight gain but does not increase sympathetic tone or urine volume in Sprague Dawley rats. [2022]Analogues of fibroblast growth factor 21 (FGF21) demonstrate diverse metabolic benefits in preclinical models of type 2 diabetes, dyslipidaemia and non-alcoholic steatohepatitis (NASH), but clinical responses with different analogues are inconsistent. Efruxifermin is an Fc-FGF21 fusion protein with prolonged half-life and enhanced receptor affinity compared with native human FGF21. Efruxifermin is in clinical trials for the treatment of non-alcoholic steatohepatitis.
Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. [2023]Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P
Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. [2023]Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis.
A randomized, double-blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis. [2023]Efruxifermin has shown clinical efficacy in patients with non-alcoholic steatohepatitis (NASH) and F1-F3 fibrosis. The primary objective of the BALANCED Cohort C was to assess the safety and tolerability of efruxifermin in patients with compensated NASH cirrhosis.
Noncompetitive immunoassay optimized for pharmacokinetic assessments of biologically active efruxifermin. [2023]Efruxifermin (EFX) is a homodimeric human IgG1 Fc-FGF21 fusion protein undergoing investigation for treatment of liver fibrosis due to nonalcoholic steatohepatitis (NASH), a prevalent and serious metabolic disease for which there is no approved treatment. Biological activity of FGF21 requires its intact C-terminus, which enables binding to its obligate co-receptor β-Klotho on the surface of target cells. This interaction is a prerequisite for FGF21 signal transduction through its canonical FGF receptors: FGFR1c, 2c, and 3c. Therefore, the C-terminus of each FGF21 polypeptide chain must be intact, with no proteolytic truncation, for EFX to exert its pharmacological activity in patients. A sensitive immunoassay for quantification of biologically active EFX in human serum was therefore needed to support pharmacokinetic assessments in patients with NASH. We present a validated noncompetitive electrochemiluminescent immunoassay (ECLIA) that employs a rat monoclonal antibody for specific capture of EFX via its intact C-terminus. Bound EFX is detected by a SULFO-TAG™-conjugated, affinity purified chicken anti-EFX antiserum. The ECLIA reported herein for quantification of EFX demonstrated suitable analytical performance, with a sensitivity (LLOQ) of 20.0 ng/mL, to support reliable pharmacokinetic assessments of EFX. The validated assay was used to quantify serum EFX concentrations in a phase 2a study of NASH patients (BALANCED) with either moderate-to-advanced fibrosis or compensated cirrhosis. The pharmacokinetic profile of EFX was dose-proportional and did not differ between patients with moderate-to-advanced fibrosis and those with compensated cirrhosis. This report presents the first example of a validated pharmacokinetic assay specific for a biologically active Fc-FGF21 fusion protein, as well as the first demonstration of use of a chicken antibody conjugate as a detection reagent specific for an FGF21 analog.
A TNFR2-Specific TNF Fusion Protein With Improved In Vivo Activity. [2022]Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.
Monoclonal antibodies directed against human FcRn and their applications. [2022]The MHC class I-like Fc receptor (FcRn) is an intracellular trafficking Fc receptor that is uniquely responsible for the extended serum half-life of antibodies of the IgG subclass and their ability to transport across cellular barriers. By performing these functions, FcRn affects numerous facets of antibody biology and pathobiology. Its critical role in controlling IgG pharmacokinetics has been leveraged for the design of therapeutic antibodies and related biologics. FcRn also traffics serum albumin and is responsible for the enhanced pharmacokinetic properties of albumin-conjugated therapeutics. The understanding of FcRn and its therapeutic applications has been limited by a paucity of reliable serological reagents against human FcRn. Here, we describe the properties of a new panel of highly specific monoclonal antibodies (mAbs) directed against human FcRn with diverse epitope specificities. We show that this antibody panel can be used to study the tissue expression pattern of human FcRn, to selectively block IgG and serum albumin binding to human FcRn in vitro and to inhibit FcRn function in vivo. This mAb panel provides a powerful resource for probing the biology of human FcRn and for the evaluation of therapeutic FcRn blockade strategies.
FcRn Antagonism Leads to a Decrease of Desmoglein-Specific B Cells: Secondary Analysis of a Phase 2 Study of Efgartigimod in Pemphigus Vulgaris and Pemphigus Foliaceus. [2023]Immunoglobulin G (IgG) levels are maintained by the IgG-recycling neonatal Fc-receptor (FcRn). Pemphigus vulgaris and pemphigus foliaceus are debilitating autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. Recently, a phase 2 clinical trial (NCT03334058; https://clinicaltrials.gov/NCT03334058) was completed in participants with pemphigus using efgartigimod, an FcRn inhibitor, in combination with prednisone. Efgartigimod demonstrated an early effect on diease activity and was well tolerated. In addition to the safety and efficacy assessment, clinical trials present an opportunity to gain more insights into the mechanism of disease, the mode of action of treatment, and potential for corticosteroid-sparing activity.
Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting the Effects of Anti-FcRn Therapy on the Disposition of Endogenous IgG in Humans. [2020]This work scaled up a previously developed physiologically based pharmacokinetic model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single- and multiple-dose administration of anti-FcRn monoclonal antibodies (1-256 mg/kg) and high-dose intravenous immune globulin (0.4-2 g/kg). The model was evaluated for prediction accuracy through comparison to the effects of rozanolixizumab, an anti-FcRn monoclonal antibodies under current clinical evaluation, on the disposition of endogenous IgG in healthy human subjects. The model provided reasonably accurate predictions of the effects of rozanolixizumab. Prediction errors for the maximum reduction in endogenous IgG concentrations were -8.50% (90% model prediction interval: -14.0% to 1.44%), 3.33% (90% model prediction interval: -13.9% to 21.2%), and 6.85% (90% model prediction interval: -35.2% to 10.5%) for rozanolixizumab doses of 1, 4, and 7 mg/kg, respectively. Model simulations predict that anti-FcRn therapies will exhibit greater dose potency in healthy volunteers than in patients with elevated IgG production rates (e.g., as typically found in autoimmune disease). The model appears to have potential for use in assessing and predicting novel dosing strategies for anti-FcRn therapies.