Genfit SA used its recent R&D day to argue that its elafibranor is best suited to become the first-line treatment for non-alcoholic steatohepatitis (NASH) due to better tolerability than Intercept Pharmaceuticals Inc.'s obeticholic acid (OCA), and because of its work with biomarkers to determine which patients need to be treated.

Further taking aim at Intercept, which is the only other company to advance to Phase III in NASH, the French biotech also revealed that it plans to initiate a Phase IIa study of elafibranor in primary biliary cholangitis (PBC), the same indication for which Intercept expects to launch OCA. FDA's Gastrointestinal Drugs Advisory Committee voted 17-0 on April 7 that OCA should receive accelerated approval for PBC; the farnesoid X receptor agonist has a May 29 user fee date ([A#14160407004]).

Genfit, meanwhile, also said it plans to begin testing elafibranor, a selective peroxisome proliferator-activated receptor (PPAR) agonist of alpha and delta pathways, in pediatric non-alcoholic fatty liver disease (NAFLD) and in patients with cirrhosis. BioMedTracker gives Intercept's OCA (planned brand name Ocaliva) the greater likelihood of being the first approved therapy for NASH, with an 84% chance of approval, compared to 48% for elafibranor.

Intercept and Genfit currently are the leaders in a multi-company race to reach market in NASH, competing with firms like Tobira Therapeutics Inc., Conatus Pharmaceuticals Inc., MediciNova Inc. and Immuron Ltd. ([A#00151130011]). Intercept has been out front in part because it was first to get pivotal endpoints accepted by FDA ([A#00150525014]).

There's hesitation about elafibranor because of questionable results in the Phase IIb GOLDEN-505 study released in 2015. The drug failed to meet the primary endpoint of reversal of NASH without worsening of fibrosis in that study. However, Genfit contends the drug does show success using a new definition of "NASH resolution" focused on necroinflammation – a combination of hepatic necrosis and inflammation – presented in a peer-reviewed article published in the March 2016 issue of Gastroenterology.

"The revised endpoint – corresponding to a more stringent definition of 'NASH resolution without the worsening of fibrosis' – has been provided by regulators and is in alignment with NASH experts," Genfit Chief Operating Officer and Chief Scientific Officer Dean Hum explained in an email. "This new endpoint actually strengthens the demonstration that elafibranor hits the right targets: the main focus is now indeed on the two lesions that are considered as the real drivers of disease activity (ballooning and inflammation, aka 'necroinflammation'), which is precisely where elafibranor's effect is the most beneficial for patients."

Fat in the liver (steatosis) is not considered as a relevant target any longer in NASH, the exec added.

"This very same endpoint is expected to be used for all ongoing and future NASH trials: this means chances of success with elafibranor in Phase III can be considered as quite high, given what has been observed in Phase IIb," Hum said.

The previous definition of NASH resolution depended upon a score of zero for at least one of three NASH components, Manal Abdelmalek, a hepatologist with Duke University Health System, pointed out during the R&D presentation, but the revised definition is actually more stringent. It requires a score of zero for ballooning, of zero or one for inflammation, and either no progression of fibrosis or progression no worse than one stage. The revised definition does not set a score objective for steatosis.

The company was not questioned about the revised endpoint during the R&D presentation, in part because Vlad Ratziu, lead author of the Gastroenterology article on GOLDEN-505, had detailed the rationale behind the endpoint on behalf of Genfit at a plenary session during the American Association for the Study of Liver Disease conference last November, Hum stated.

The Gastroenterology article notes that 120 mg of elafibranor for 52 weeks, the higher of the two doses tested in Phase IIb, resulted in NASH resolution without worsening of fibrosis. "This result is confirmed both in intention-to-treat population as well as in subgroups of moderate/severe NASH patients, based on the recommended definition of 'NASH resolution' now used for clinical trials," Abdelmalek noted.

In the trial, NASH resolution was achieved in 19% of the total 274 patients tested, compared to 12% of the placebo group, which met statistical significance. For patients with a non-alcoholic fatty liver disease activity score (NAS) of up to four (n=234), 19% of treatment-arm patients had NASH resolution compared to 9% of placebo-arm participants. For patients with NAS scores up to 4 and any degree of fibrosis (n=204), the drug resolved NASH in 20% of patients, compared to 11% in the placebo group. The trial data also show that elafibranor improved patients' cardiometabolic risk profile and was safe and well tolerated, she said.

Drug Profile Advantages Compared To OCA

In an interview, Hum said these data indicate that elafibranor is better suited for first-line treatment of NASH than OCA.

"We considered the two leading programs, elafibranor and OCA, and they both have comparable efficacy but elafibranor provides a cardioprotective lipid profile," he said. "The leading cause of mortality in NASH patients is cardiovascular events. And there is no tolerability issue with elafibranor – it does not increase pruritis, for example, which is important for patients when you think about long-term or chronic treatment."

Hum asserted that with the new endpoint for NASH studies, Genfit may actually be better positioned for approval than Intercept. OCA's likelihood of success in Phase III should be questioned, he said, because in its Phase IIb FLINT study, the drug did not produce resolution of NASH, but did hit an easier target of reduction in NAS score by two points.

"Today, nobody knows how FLINT results look in the light of the new consensual definition of 'NASH resolution,'" Hum added.

In a Feb. 12 note, Kepler Chevreux analyst Arsene Guekam said the GOLDEN-505 data demonstrate that safety will not be an issue for elafibranor. "No safety issues were reported except a mild dose-dependent increase in creatinine (<5%), known="" as="" a="" reversible="" effect="" and="" without="" any="" consequence="" for="" patients,"="" guekam="" wrote.="" "besides,="" elafibranor="" provides="" additional="" improvements="" vs.="" placebo="" on="" cardiometabolic="" risk="" factors="" (lipid="" profile,="" glycemic="" indices="" and="" inflammatory="">

Genfit plans to investigate potential combination therapy in NASH using elafibranor with other drugs, the exec added, including other proprietary liver candidates in its pipeline as well as other sponsors' drugs. He would not specify what types of drugs or targets Genfit wanted to look at for combination therapy, however, but indicated the company is conducting partnering talks with other companies.

In Phase III, which recently began enrolling, Genfit will test the 120 mg dose against placebo in more than 1,000 NASH patients, with plans for an interim look at 72 weeks of treatment and an extension period. The company expects to have data by 2018 and to file for approval with FDA and the European Medicines Agency in 2019.

While Intercept hopes the PBC indication will enable it to bring OCA to market before approval in NASH, Genfit expects to file for approval in PBC in roughly the same timeframe as for NASH, Hum said. The Phase IIa study will begin enrolling before the end of this year in patients who can't tolerate or have not responded sufficiently to the current standard of care for PBC, ursodeoxycholic acid. Genfit estimates that as many as 70% of PBC patients may fit that profile.

Genfit hopes to move into Phase IIb in PBC in 2017, followed by Phase III in 2018. In pediatric NAFLD, the goal is to begin a pharmacokinetic/pharmacodynamic study in the second half of this year, followed by moving into Phase III in 2017. For NASH with cirrhosis, the plans call for launch of a pilot study during the second half of this year, followed by Phase III investigation in 2017 or 2018.

Genfit also is searching for biomarkers to help determine which NASH patients need to be treated. Longer-term, Hum said the company also plans to work on developing a companion diagnostic for NASH disease progression, but that is a lesser priority for now than prioritizing which patients need treatment.

The company plans to present its biomarker data later this month at the European Association for the Study of Liver Disease conference, April 13-17 in Barcelona. The data derive from blood samples taken from patients in the Phase IIb study at each month's follow-up visit, which was bracketed by a pre-treatment liver biopsy and a second biopsy after 12 months of treatment with elafibranor, Hum explained. Other companies have sought access to these samples to verify their own NASH biomarkers, he added.

Genfit's biomarker work seeks to develop an algorithm for determining which patients need treatment based on five measures: miR-200a, miR-34a, A2M, HbAIc and P3NP. The company plans to use data from a cohort of the Phase III trial to further validate its findings, Hum noted.

The need for biomarkers to better identify patients, especially those with early disease, and for markers to help guide treatment and serve as surrogate endpoints are a major undertaking in NASH research being pursued by many of the companies developing drug candidates for the condition, including Intercept ([A#00140324003]).

Genfit Positions To Battle Intercept On Both NASH And PBC Fronts

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