Elafibranor is currently being evaluated in the clinical Phase 3 study RESOLVE-IT. This pivotal study aims to achieve conditional marketing approval based on the interim analysis of the first 1 000 patients, after 72 weeks treatment, based on a single histological surrogate endpoint.
Its pleiotropic beneficial anti-NASH activities, combined with its anti-fibrotic properties, position elafibranor as an attractive new generation drug candidate for treating NASH and eliminating the underlying causes of fibrosis, thus avoiding evolution to cirrhosis and its complications.
Elafibranor (GFT505) is GENFIT’s lead pipeline product. It’s an oral once-daily treatment, positioned as a first-in-class drug to treat nonalcoholic steatohepatitis (NASH). Based on the beneficial activities that it demonstrates on the different features of the pathology, elafibranor represents the ideal drug for NASH patients, including those suffering from the most severe forms of the disease.
Phase 3 study RESOLVE-IT
In November 2015, GENFIT announced the design of the global Phase 3 trial RESOLVE-IT to evaluate the benefits of Elafibranor treatment on NASH patients.
RESOLVE-IT is a randomized pivotal trial, double-blind, placebo-controlled (2:1), conducted in approximately 2 000 patients, at 250 centers worldwide. The study population is NASH patients (NAS≥4) with F2 or F3 fibrosis. Elafibranor 120 mg or placebo are administered once daily.
An interim analysis, for initial market approval under Subpart H, will be performed after 72 weeks of treatment in order to evaluate the beneficial effect of Elafibranor on the liver histology of the first 1 000 patients. To support full approval, the trial will continue in order to demonstrate the impact of Elafibranor on the prevention of cirrhosis and other liver related outcomes on the full study population. A group of patients with F1 fibrosis and concomitant cardiometabolic comorbidities, which are associated with rapid progression of the disease, will also be enrolled.
Initial approval will be based on the interim analysis (72 weeks / 1 000 patients) of the following surrogate histological primary endpoint: NASH resolution without worsening of fibrosis, corresponding to ballooning=0, inflammation=0-1. This criteria defining disease activity, based on a centralized histological reading, is considered by the regulatory authorities as well as NASH experts as a surrogate endpoint for approval.
In order to confirm the long-term clinical benefits of NASH resolution induced by Elafibranor 120mg, the trial will continue post-marketing and remain blinded after the interim analysis. All patients will be followed until the occurrence of a pre-defined number of progressions to cirrhosis and other liver related events.
The trial will also evaluate key secondary histological endpoints, including an improvement on fibrosis, and non-invasive markers of steatohepatitis. In addition, the trial will assess the improvement of cardiometabolic profile, including plasma lipids, glucose homeostasis and inflammatory markers.
Results demonstrated on hundreds of patients
In March 2015, GENFIT announced topline results from the phase 2b GOLDEN-505 trial in NASH (GFT505-2127) in which elafibranor has been tested for clinical efficacy in NASH in a 1-year liver biopsy-based Phase 2b trial (GFT505-2127), one of the largest interventional studies ever conducted in NASH:
- Elafibranor demonstrated dose-dependent efficacy on the primary endpoint, after controlling for baseline severity and heterogeneity (p=0.027)
- Treatment with elafibranor lead to significant cardio-metabolic benefits
- Elafibranor was safe and well tolerated in this 1-year trial
A total of 56 centers of clinical excellence in the United States and in multiple European countries (France, Belgium, The Netherlands, Italy, United Kingdom, Germany, Spain, and Romania) actively participated in this study initiated in October 2012. 275 diabetic and non-diabetic patients were included in this study, divided into 3 groups treated with elafibranor at 80 or 120 mg/day, or with placebo.
In February 2014, the FDA granted Fast Track designation to elafibranor in NASH.
Administered to over 800 patients and healthy volunteers to date, elafibranor has demonstrated beneficial properties for NASH, including in particular:
- Improvement of markers of liver dysfunction, including ALAT, ASAT, γGT, ALP
- Improvement of insulin sensitivity and glucose homeostasis
- Favorable effects on plasma lipids, including decrease of plasma triglycerides and LDL-C, and increase of HDL-C levels.
- Anti-inflammatory properties
- Efficacy on histological NASH parameters (steatosis, inflammation, fibrosis) in animal disease models – anti-fibrotic activities
- The absence of safety concern has been confirmed in a full toxicological package up to 2-year carcinogenicity studies.