Elafibranor in NASH
Nonalcoholic steatohepatitis, or NASH, is a liver disease that affects millions of people and for which there are currently no approved therapies. In the light of the increasing number of patients worldwide, making therapies available to patients suffering from NASH has become a critical public health emergency. During its preliminary studies, elafibranor has shown positive effects on the two key markers of the disease (inflammation + ballooning), while maintaining a favorable safety and tolerability. Consequently the U.S. Food and Drug Administration, or FDA, has granted a fast-track designation to elafibranor for the treatment of NASH. We are currently evaluating our drug candidate in the Phase 3 clinical trial: “RESOLVE-IT”.
RESOLVE-IT: Our Pivotal Phase 3 Clinical-Trial in NASH
RESOLVE-IT is a global randomized, double-blind, placebo-controlled (2:1) Phase 3 clinical trial that began in the first quarter of 2016, and enrolls patients with NASH (NAS>=4) and fibrosis (F2 or F3; stages at which liver damage is already significant). Throughout the trial, patients will receive either elafibranor 120 mg or placebo once daily.
An interim analysis of the first 1,000 enrolled patients after 72 weeks of treatment is scheduled, with, as primary endpoint, the proportion of elafibranor-treated patients achieving NASH resolution without worsening of fibrosis as compared to placebo, and as key secondary histological endpoint, fibrosis improvement without worsening of NASH. The trial will evaluate alongside the improvement of cardio metabolic profiles in patients treated with elafibranor versus patients treated with placebo.
In April 2018, we achieved the enrollment of the first 1,000 patients required for the interim cohort analysis, and expect to report data by the end of 2019 which, if positive, will support accelerated approval from the U.S. Food and Drug Administration, or FDA, and conditional approval from the European Medicines Agency, or EMA, as early as 2020.
In May 2019, the Data Safety Monitoring Board (DSMB) issued a new positive recommendation for the continuation, without any modifications, of the RESOLVE-IT Phase 3 trial evaluating elafibranor in NASH. This sixth planned review by the DSMB reiterates previous positive guidance and saw no safety concerns. The 36-month positive DSMB safety review supports GENFIT’s positive momentum in continuing the RESOLVE-IT study.
Elafibranor: a unique mechanism of action
Elafibranor is a dual agonist of the PPARα and PPARδ. Meaning the drug candidate acts simultaneously on the two nuclear receptors, which both play an important role in numerous processes involved in the development of NASH and its co-morbidities.
An important distinction between elafibranor and some of the other programs targeting PPARs in NASH is that it does not have any pharmacological PPARγ activity.
Thus, elafibranor doesn’t show the unwanted side effects most commonly associated with PPARγ activation, such as weight gain, edema, and fluid retention, which are associated with increased risk of heart failure.
Confirmed in prior preclinical and clinical studies in NASH
The efficacy and safety of elafibranor have been evaluated in an extensive preclinical program which included multiple disease models.
0ur 5 Phase 2a included trials performed in different populations of metabolic disease patients, including patients with atherogenic dyslipidemia, pre-diabetes or type-2 diabetes. In these studies, we observed that treatment with elafibranor promoted:
- Cardio protective lipid profile;
- Glucose homeostasis;
- Increased insulin sensitivity;
- Anti-inflammatory properties;
- Decreased markers of liver injury;
- Decreased cardiovascular risk factors.
Our phase 2b trial, launched in 2012, was one of the largest interventional trials and first true international study ever conducted in NASH.
Elafibranor achieved the FDA-recommended endpoint of “NASH Resolution without Worsening of Fibrosis”, which is the primary endpoint of our ongoing global Phase 3 clinical trial. Patients treated with elafibranor experienced improvement in circulating markers of liver dysfunction such as ALT, GGT and ALP. In our evaluation of the secondary endpoints, we observed therapeutic activity of elafibranor 120 mg on cardiometabolic risk factors associated with NASH, such as:
- Improvement in levels of plasma lipids and lipoproteins;
- Improvement of insulin sensitivity and glucose metabolism in diabetic patients;
- Anti-inflammatory effects.
Complete results of the GOLDEN-505 trial were published in the peer-reviewed Gastroenterology journal in 2016.
Elafibranor for the treatment of pediatric NASH
As prevalence of obesity in children has increased, NAFLD has become a growing health concern in this population. A study published in 2016 estimates that NAFLD affects approximately 10-20% of the general pediatric population, with approximately 25% of these children progressing to NASH, and that within the next 10 years, pediatric NAFLD is expected to become the most prevalent cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescents in the Western world.1
After receiving an agreement from the EMA on our Pediatric Investigation Plan, or PIP, and from the FDA on our Pediatric Study Plan, or PSP, we announced in January 2018 the official launch of the NASH pediatric program with elafibranor as, to our knowledge, the only drug with proven efficacy in adults currently permitted to be developed for the treatment of children with NASH. In March 2019, we announced protocol clearance by the FDA for a Phase 2 trial evaluating elafibranor in children and adolescents with non-alcoholic steatohepatitis (NASH).
We plan to begin enrolling patients in a Phase 2 clinical trial as early as 2019.
Elafibranor’s activity on liver fat quantity and fat composition in NAFLD patients
We recently announced the launch of a P2 clinical trial evaluating elafibranor’s activity on liver fat quantity and – most importantly – fat composition in nonalcoholic fatty liver disease (NAFLD) patients. The objective is to determine the effect of elafibranor, a dual PPAR alpha/delta agonist, on fatty acid saturation. This trial will use state of the art non invasive techniques (H-MRS) to provide indications on both quantitative and qualitative evolution of liver fat.
Elafibranor in both monotherapy and backbone of combination regimens
We are confident in elafibranor’s potential to become a first-line treatment for NASH as a monotherapy. However NASH is a complex and multifaceted disease and combinations of several drug classes with complementary mechanisms of action may further improve clinical management of NASH, liver fibrosis and their co-morbidities. We are proactively evaluating combination therapy approaches with elafibranor as backbone and other molecules with:
Our own pipeline drug candidates:
In April 2018 at the International Liver Congress, we presented data from studies evaluating elafibranor in proprietary combination with nitazoxanide, or NTZ, that showed synergistic effect in primary human stellate cells revealing unsuspected anti-fibrotic properties in NASH models, and beneficial effects on multiple pathological mechanisms. Altogether, findings indicate that NTZ may be a good candidate for a NASH combination therapy with elafibranor.
Other third-party drug candidates:
In 2018 at The Liver Meeting, we also presented new data on anti-NASH treatment combinations, using elafibranor as backbone, in in vitro and in vivo NASH models, associating it with an ACC inhibitor. A complementary and synergistic action was observed on fatty acid catabolism accompanied by resolution of liver steatosis. In addition, Elafibranor counteracted the ACC inhibitor-induced hypertriglyceridemia.
Drugs approved in other indications:
In 2017 at the International Liver Congress, we presented data on the complementarity of elafibranor with an FXR agonist, illustrating the potential for new treatment combinations with elafibranor as backbone. The synergistic effect we have observed in disease models shows a decrease in fibrosis at sub maximal doses, which we believe supports this combination therapy approach.
A proof of concept study will be initiated in 2H19 to evaluate the safety, tolerability and exploratory markers of efficacy of a GLP-1 receptor agonist or an SGLT2 inhibitor (anti-diabetic drugs) in combination with elafibranor.
1Jonathan Temple et al., A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence, 2016