Clinical Trials

Date: 2016-02-11

Type of information: Publication of results in a medical journal

phase: 2b

Announcement: publication of results in Gastroenterology

Company: Genfit (France)

Product: elafibranor - GFT505

Action mechanism: PPAR agonist. Elafibranor (GFT505) is an oral once-daily treatment, and a first-in-class drug acting via dual peroxisome proliferator-activated alpha/delta pathways to treat nonalcoholic steatohepatitis (NASH).

Disease: NASH (non-alcoholic steatohepatitis)

Therapeutic area: Metabolic diseases - Liver diseases

Country: Belgium, France, Germany, Italy, The Netherlands, Romania, Spain, UK, USA

Trial details: GFT505-212-7 is an international multi-center Phase IIb trial study involving 75 clinical investigation centers, including 20 centers in the US (NCT01694849). This double-blind placebo-controlled study will include 270 patients with a histological diagnosis of NASH at recruitment and will evaluate the efficacy on NASH of GFT505 at two doses administered daily for one year, in particular on the improvement of histological parameters. All the clinical centers will be opened by the end of January 2013, and the last patient should be recruited by October 2013 at the latest. Based on the prior recommendations of the FDA and the EMA concerning the global development plan for GFT505 in NASH, the primary aim of this pivotal double-blind study is to demonstrate the efficacy of one year of treatment with GFT505 at two doses (80 mg and 120 mg) versus placebo (90 patients/group) on the reversion of NASH in diabetic and non-diabetic patients. Multiple secondary objectives, in particular the demonstration of the effects of GFT505 on steatosis, inflammation, liver cell damage, and histological fibrosis, will also be pursued. Moreover, a large panel of plasmatic efficacy markers will be measured, including lipid profile, glycemia, and markers of inflammation and liver function. Patient safety will be assured throughout the study by an independent committee (Data Safety Monitoring Board). Finally, a particular focus will be made on the validation of diagnostic markers that could be developed as companion tests.

Latest news:

• • On February 11, 2016,  Genfit announced that detailed results from the Phase 2b clinical trial evaluating GFT505 in NASH have been published online in Gastroenterology, in advance of appearing in print in the May isssue. Key elements of context and content below : - The GOLDEN-505 clinical trial was the first international trial on NASH, conducted in 56 centers spread across 9 countries, with the ambition to address the NASH burden using “resolution of NASH without worsening of fibrosis” as primary endpoint. - The detailed results of the GOLDEN-505 trial represent an essential contribution to the global effort to address this disease related to the obesity and diabetes epidemics (and for this reason considered a priority by the regulatory agencies, as confirmed by the fast-track designation granted to Elafibranor, as well as by the Subpart H process applied to its Phase 3 trial). - In the Phase 2b trial, GFT505/Elafibranor or a placebo was administered to patients with a histological diagnosis of NASH. The treatment was taken for 52 weeks. The inclusion and end-of-treatment biopsies were all read centrally in a blinded manner. At end of study, all slides (baseline and end-of-study) were read in scrambled order. -  The conclusions of the scientific publication take into account the new recommended definition of “NASH resolution”, which focuses on the necroinflammation, considered as the key driver of disease activity and progressive fibrosis towards cirrhosis (necroinflammation is defined as the combination of two important lesions in the liver : hepatocellular ballooning, and lobular inflammation). - A key conclusion of the work carried out by the large team of worldwide specialists in the field of hepatology is that 120mg Elafibranor achieved resolution of NASH without fibrosis  worsening, in both intention-to-treat population and subgroups of moderate/severe NASH patients, based on the recommended definition of “NASH resolution” now used for clinical trials. Key results can be summarized as follows :
• ? 120mg Elafibranor significantly increased resolution of NASH without fibrosis worsening (19% vs. 12%, OR=2.31, 95% CI [1.02,5.24], p=0.045) on the whole study population, in an analysis based on the new recommended definition for “NASH resolution”.
• ? In a subgroup of NASH4 patients (N=234), 120mg Elafibranor performed better than placebo, regardless of the definition used for “NASH resolution” (20% vs. 11%, OR=3.16, 95% CI [1.22-8.13], p=0.018 ; and 19% vs. 9%, OR=3.52, 95% CI [1.32-9.40], p=0.013; for the predefined protocol definition and for the new recommended definition, respectively).
• ? Patients with NASH resolution on 120mg Elafibranor improved liver fibrosis (mean reduction of the fibrosis score -0.65±0.61 in responders vs. increase 0.10±0.98 for non-responders, p<0.001).
• ? In the 120mg Elafibranor group, liver enzymes and inflammatory markers have been reduced significantly; lipid and glucose profiles have also been improved.
• ? Elafibranor was well tolerated, without weight gain, without cardiac events, and with a mild and reversible increase in serum creatinine. (click for the article).
• • On October 2, 2015, Genfit announced the presentation of elafibranor results during the annual meeting of the AASLD, “The Liver Meeting”, in San Francisco from November 13-17, 2015. The results of the GOLDEN-505 Phase 2b study have been selected by the scientific review committee for presentation in a Presidential Plenary session. Professor Vlad Ratziu, principal investigator and international coordinator of the GOLDEN-505 study, will describe the efficacy and safety results during a plenary session presentation: Monday, November 16 from 11am – 12:30pm “An international, phase 2 randomized controlled trial of the dual ppar alpha-delta agonist gft505 in adult patients with NASH”. Additionally, the AASLD has selected two other abstracts for presentation on the GOLDEN-505 study: - Professor Stephen Harrison will detail the beneficial effects of elafibranor (GFT505) on cardiometabolic risk markers of NASH patients: “beneficial effects of the dual ppar alpha-delta agonist, GFT505, on hepatic and cardiometabolic markers in adult nash patients” SA Harrison et al. (Abstract 162)
• ? Professor Arun Sanyal will analyze the hepatic and extra-hepatic responses linked to the treatment of NASH by elafibranor:“the hepatic and extra-hepatic profile of resolution of steatohepatitis induced by GFT-505” A Sanyal et al. (Abstract 2145)
• ? One additional poster will be presented illustrating the efficacy of elafibranor in a novel disease model of NASH that mirrors the histological effects observed in the GOLDEN-505 study. This model enables a better description of the mechanism of therapeutic action of elafibranor: “GFT505 (elafibranor) prevents nonalcoholic steatohepatitis (NASH), hepatic fibrosis and hepatocarcinoma in a new preclinical model” ” B Noel et al. (Abstract 974)
• • On March 26, 2015, Genfit announced topline results of the phase 2 GOLDEN-505 trial in NASH. Due to the unexpected rate of resolution of NASH in patients randomized to placebo who had early NASH (NAS of 3, placebo response rate>57%), along with the high number of sites for a limited sample size, the study as initially designed did not enable the trial to meet directly the primary endpoint. With correction for this baseline severity and site heterogeneity by a standardized statistical analysis, GFT505 120mg meets the primary endpoint: Reversal on NASH without worsening of fibrosis, as detailed below.
• Treatment with GFT505 provides a significant beneficial effect on the primary endpoint (GFT505 120mg vs placebo, p=0.016, RR=2.03) in the global randomized population (n=274, full analysis set), where patients without an end of treatment biopsy were considered as non-responders. The primary endpoint was also achieved in the evaluable population of patients who underwent both baseline and end of study liver biopsies (n=237, ITT; p=0.027 vs placebo; RR=1.94). In the evaluable patient population, GFT505 120mg also has a beneficial effect of a decrease of NAS-score 2 (p=0.04 vs placebo). Early NASH patients with NAS=3 were not included in other recent NASH trials. If the same is done in the GOLDEN-505 study, keeping patients with more severe disease defined by NAS 4 (n=202), GFT505 120mg demonstrates a doubling of responders on the primary endpoint (22.4% vs 12.7%, p=0.046, RR=1.9), thus providing evidence of a clinically meaningful benefit in patients with more advanced disease.
• This 52-week phase 2b trial evaluated the efficacy and safety of GFT505 in 274 subjects (double blind, placebo-controlled; three arms: placebo, 80mg, 120mg) with centrally-read, liver biopsy proven NASH across 56 centers in nine countries in North America and Europe. Study criteria required patients to have all three histological components of NASH. The patients’NAFLD Activity Score, or NAS, ranged from those with early disease with NAS=3 to severe disease of NAS=8. The primary endpoint was defined as “resolution of NASH without worsening of fibrosis” which requires reaching a NAS of zero on any one of the three histological components. This trial also assessed a comprehensive set of safety and secondary efficacy endpoints.
• The evaluation of various biomarkers confirms the beneficial biological activity of GFT505 120mg. Specifically, using the initial protocol analysis, statistically significant improvement of the following liver related biomarkers was noted: decrease of ALT, GGT, ALP, and improvement on various NAFLD composite scores (Steatotest, Fibrotest, Fatty Liver Index, NAFLD Fibrosis score). Even on top of various standard of care therapies, GFT505 provides additional improvements vs placebo on cardio-metabolic risk factors, commonly found in NASH patients: - lipid profile: TG, LDL-C, HDL-C - glycemic indices/insulin resistance in Diabetics: HbA1c, FPG, Fasting insulin - inflammatory markers: Haptoglobin, Fibrinogen, CRP Taken together, these beneficial effects on cardio-metabolic parameters are very important for the treatment and management of NASH patients, in whom cardiovascular disease is the leading cause of mortality. The safety assessment of this one-year study demonstrates a very favorable profile, which is consistent with the conclusions of the DSMB reviews throughout the study. There were no cardiac events, signal on cancer, nor death in the GFT505 treatment groups. Weight remained stable, and no signal for edema was observed. A mild dose dependent increase in creatinine was noted (< 5%; GFT505 120mg vs placebo), which is a known reversible effect of GFT505. The most common adverse events were of gastrointestinal nature of mild intensity. These data will be presented in the next weeks to the FDA and the EMA as a basis for phase 3 launch.
• • On June 27th, 2014, Genfit announced the recommendation of the independent Data and Safety Monitoring Board (DSMB) of international experts charged with ensuring the safety of use of GFT505 in the ongoing Phase 2b study. The experts of the Data and Safety Monitoring Board in charge of assuring the security of patients in the GFT505-212-7 trial, consulted all safety data of the patients included since the launch of the trial, notably 120 patients who have already terminated the one year treatment period with the dose of 80mg/d and more than half of the patients treated for at least 6 months with the dose of 120mg/d. Based on analysis performed after partial unblinding, the DMSB does not raise any safety concern which might jeopardize the security of the patients and provides its unrestricted approval to continue the Phase 2b clinical trial in NASH as planned in the inititial protocol.
• • On October 25, 2013, Genfit has announced the recommendation of the independent Data Safety and Monitoring Board (DSMB) of international experts charged with ensuring the safety of use of GFT505 in the current Phase IIb study. The DSMB gives its unrestricted approval to continue the Phase IIb clinical trial in NASH according to the planned protocol. Genfit has launched this study in September 2012, after obtaining FDA approval to perform the study in the United States. To date the study has recruited 139 diabetic and non-diabetic patients with a histological diagnosis of NASH by liver biopsy at the time of recruitment. The study is currently ongoing in Europe and the United States in 56 clinical investigation centers. The members of the DSMB, an independent committee set up to ensure patient safety within the Phase IIb study, analyzed the complete safety data for patients that have been treated for more than 6 months with GFT505 at 80 mg/day. The members of the DSMB unanimously concluded that, after more than 6 months of treatment at the dose of 80 mg/day, GFT505 shows no safety issue that compromises the continuation of the Phase IIb study.
• • On November 20, 2012,  Genfit has announced that the first patients have been recruited and are under treatment in the pivotal phase IIb GFT505-212-7 study that aims to demonstrate the therapeutic efficacy of GFT505 in non-alcoholic steatohepatitis (NASH). After obtaining the approval of the FDA, of national health authorities in Europe, and of local ethical committees, Genfit has entered the operational phase of the international study GFT505-212-7. The first clinical investigation centers have been opened in the United States and in Europe, and the first patients are already under treatment. The final results are expected in December 2014, when GFT505 should become the first dedicated drug candidate with proven therapeutic efficacy in NASH. Based on the prior recommendations of the FDA and the EMA concerning the global development plan for GFT505 in NASH, the primary aim of this pivotal double-blind study is to demonstrate the efficacy of one year of treatment with GFT505 at two doses (80 mg and 120 mg) versus placebo (90 patients/group) on the reversion of NASH in diabetic and non-diabetic patients. Multiple secondary objectives, in particular the demonstration of the effects of GFT505 on steatosis, inflammation, liver cell damage, and histological fibrosis, will also be pursued. Moreover, a large panel of plasmatic efficacy markers will be measured, including lipid profile, glycemia, and markers of inflammation and liver function. Patient safety will be assured throughout the study by an independent committee (Data Safety Monitoring Board). Finally, a particular focus will be made on the validation of diagnostic markers that could be developed as companion tests. Prof. Vlad Ratziu, Principal Investigator and International Coordinator of the GFT505-212-7 study, declared: « The large number of US and European clinical centers and internationally-recognized NASH experts involved in the GFT505-212-7 study illustrates the significant unmet medical needs in NASH and the hopes raised by GFT505 for this therapeutic indication. This is without a doubt one of the most complete NASH studies initiated in terms of patient number, length of treatment, and the number of associated clinical and biological analyses. As the principal investigator and international coordinator of the study, I am very pleased that the first patients have been recruited, and am confident as to the organization set up by GENFIT to successfully accomplish this study ».Dr. Rémy Hanf, EVP, Product Development, declared: «The initiation of this pivotal study is a key step in the vast development program that we have discussed with the health agencies. For example, during 2013, GENFIT will set up complementary clinical trials and will initiate the development of new formulations of GFT505 for Phase III studies. Moreover, studies to determine the mechanism of action of GFT505 on fibrosis have been launched, and the first results show a direct effect of the molecule on the cells that are responsible for fibrosis
• • On September 3, 2012, Genfit  has announced that the FDA has approved the continuing development of GFT505 in NASH*, and the initiation of a Phase IIb clinical study in the United States. The FDA approval follows an extensive review of the pre-clinical and clinical data obtained with GFT505 to date. The FDA experts thus confirm that GFT505 shows a favorable activity on the spectrum of biological markers associated with NASH, together with an excellent safety profile. They accepted the proposed Phase IIb protocol, and considered that it met the clinical objectives in NASH, while ensuring patient safety throughout the study. The FDA thus authorizes the immediate initation of this study on the entire US territory.FDA approval reinforces the positive opinion of the EMA, which had validated in February 2012 and confirmed in July the scientific basis and rationale for GFT505 in NASH by giving a favorable response to the submitted Phase IIb and III development plan.
• • On June 20, 2012, Genfit has announced that it will file an Investigational New Drug (IND) application with the FDA before the end of June 2012, to enable the conduct of a Phase IIb trial with GFT505 inNASH (non-alcoholic steatohepatitis)   in the United States.  This IND application follows a very positive consulting meeting with the FDA on the entire GFT505 dossier, on the Phase IIb study, and more generally on the development plan for GFT505 in NASH.  Last April, Genfit has received favorable responses of the European Medicines Agency (EMA) on the efficacy/safety ratio of GFT505, the design of the upcoming phase IIb study, and the clinical development plan for GFT505 in NASH (See below).
• • On April 4th, 2012, Genfit has announced that it has received the official scientific opinion of the European Medicines Agency (EMA) on the efficacy/safety ratio of GFT505, the design of the upcoming phase IIb study, and the clinical development plan for GFT505 in non-alcoholic steatohepatitis (NASH). The EMA gave a favorable response to all the questions related to GFT505 and its efficacy/safety ratio at the proposed therapeutic doses. The opinion of the EMA experts concerning the pivotal phase IIb study that aims to demonstrate the therapeutic activity of GFT505 on the histological regression of NASH is in agreement with the study protocol submitted by GENFIT. Finally, the EMA has given its recommendations for the phase III development plan of GFT505 in this new therapeutic indication. The positive opinion of the EMA opens the door to the initiation of the pivotal phase IIb study, pending regulatory authorization by national health agencies. At least 270 patients with NASH will be recruited for this international (Europe, US) multi-center study, one of the largest ever conducted for NASH. The objective is to provide the first proof of therapeutic efficacy for a product dedicated to the treatment of NASH (there is currently no existing treatment for NASH). The EMA judged satisfactory GENFIT’s comments on the questions raised, and opted for the ‘accelerated’ procedure to give its opinion.

 

Is general: Yes