Genfit Assesses Optimal Elafibranor NASH Combo Therapy Opportunity
Executive Summary
As it nears the Phase III data readout for elafibranor in NASH, Genfit plans combo therapy studies to determine if a GLP-1 analog or SGLT2 inhibitor would offer the best therapeutic synergy, market potential and partnership opportunity.
Genfit SA is ready to begin combination therapy studies of its Phase III non-alcoholic steatohepatitis (NASH) candidate elafibranor with two classes of already marketed diabetes drugs, but that does not mean it has found a partner for a potential combo regimen. The Lille, France-based company wants to get proof-of-concept data first so that it then can choose the partner associated with the greatest opportunity.
Genfit research and development head Dean Hum explained that moving into combination trials is part of the launch strategy for elafibranor, an agonist of peroxisome proliferator-activated receptors (PPAR) alpha and delta for which Phase III data are expected before the end of 2019. (Also see "Genfit Hopes To Make Case For First-Line Treatment In NASH" - Scrip, 4 Apr, 2019.) The company believes getting combination data for elafibranor with a validated diabetes drug can improve uptake as the launch progresses.
Genfit will be the third company to report Phase III data in NASH, following Gilead Sciences Inc.’s unsuccessful trial with ASK1 inhibitor selonsertib in February and Intercept Pharmaceuticals Inc.’s success with FXR agonist obeticholic acid (OCA) a week later. (Also see "NASH Pipeline: Racing To The Finish" - Scrip, 21 Mar, 2019.)
In May, Genfit announced that it will initiate Phase II proof-of-concept (POC) studies this summer to assess the potential of combination therapy in NASH for elafibranor plus well-known diabetes drug mechanisms. The dual PPAR agonist will be tested with a GLP-1 analog, such as Eli Lilly & Co.’s Trulicity (dulaglutide), AstraZeneca PLC’s Byetta (exenatide) or Novo Nordisk AS’ Victoza (liraglutide). It also will be combined with an SGLT2 inhibitor, such as AstraZenec/Bristol-Myers Squibb Co.’s Farxiga (dapagliflozin), Lilly/Boehringer Ingelheim GmbH’s Jardiance (empagliflozin) or Janssen Biotech Inc.’s Invokana (canagliflozin).
However, Genfit is initiating the POC studies without a partnership, which led Bryan Garnier & Co. analyst Jean-Jacques Le Fur to speculate that the company might want to wait for Victoza’s patent to expire to create a relatively inexpensive combo regimen for NASH. (Also see "CymaBay Alters NASH Hypothesis After Phase IIb Failure In Hepatic Fat Reduction" - Scrip, 11 Jun, 2019.)
Separately, Genfit announced on 24 June that it is licensing development and commercial rights in greater China for elafibranor in NASH and primary biliary cholangitis to Terns Pharmaceuticals Inc., a liver disease- and cancer-focused company based in both the San Francisco area and Beijing. Genfit gets $35m up front and can earn up to $193m in clinical, regulatory and commercial milestones under an agreement that gives Terns rights to the drug in mainland China, Hong Kong, Macau and Taiwan.
If elafibranor is launched commercially for NASH in greater China, Genfit also would be eligible for sales royalties in the mid-teens in Terns’ territories. The companies also will jointly conduct liver disease R&D projects, including development of elafibranor in tandem with Terns’ proprietary drug candidates. These include FXR agonist TERN-101, in-licensed from Lilly in April 2018. [See Deal] Terns initiated a Phase I study of the compound on 13 June.
Getting Ready For Commercial Competition
Speaking with Scrip on 20 June, Hum conceded that Intercept’s OCA will reach market first, but asserted that elafibranor’s efficacy and safety profile will position it as both first-line monotherapy and the backbone of combination therapy in NASH. Intercept will seek approval in the US and Europe based on the ability of OCA to reduce fibrosis without worsening of NASH, while Genfit hopes its Phase III data will confirm earlier trials showing elafibranor can resolve NASH by eliminating ballooning of hepatocytes and eliminating or reducing inflammation. (Also see "Intercept Retakes The Lead In NASH" - Scrip, 19 Feb, 2019.)
“It’s important for us to get ahead of [the competition] and consider what kind of combinations make sense,” Hum explained. "If you consider some of the drugs and who NASH patients are, our understanding is … different combinations will be tried by different doctors. We think GLP-1 will be a good candidate for combination therapy. We have preclinical data in disease models, in vivo animal models, showing that that combination does provide synergy. And then, the other class of drugs which makes a lot of sense is SGLT2 inhibitors, and we also have results looking at in vivo animal models.”
Genfit will launch studies of two doublets – elafibranor with a GLP-1 analog and an SGLT2. It has not said yet whether it also plans to investigate triple combination therapy, Hum said. The goal is to demonstrate safety and tolerability with those combinations, while looking for signs of efficacy in both imaging data and circulating markers of liver health.
“This is all a part of our strategy to ensure a successful launch with elafibranor and make sure it has good market uptake,” the exec said. “And this, of course, is all for the benefit of the patients, to make sure that they will be optimally managed by the different physicians.”
Genfit’s expectation is that in the early days after NASH drugs hit the market, patients will be seen more often by general practitioners and endocrinologists than by hepatologists, making the availability of data for combination therapy extra important, Hum added.
Genfit already is building a commercial team, led by recent hire Pascal Prigent, most recently VP of marketing for GlaxoSmithKline PLC vaccines and before that a commercial executive with Lilly. The commercial team will be split between Genfit headquarters in Lille and its US offices in Boston, Hum said.
Doing its combination work independently leaves Genfit with ideal optionality, he asserted. “The objective for us is not to be tied down to any one drug at this point,” Hum said. “What’s important for us is that when the time comes, we can have a drop-in strategy for combination … with another drug which has the biggest market share. That is the long-term view.”
No Read-Through From CymaBay PPAR Agonist Data
But before Genfit obtains combo therapy data, SVB Leerink analyst Pasha Sarraf said in a 19 June note that the company's upcoming Phase III RESOLVE-IT data for elafibranor monotherapy is the most significant near-term catalyst in the NASH drug development space.
However, Genfit’s shares have been trending down slightly since a competitor reported disappointing interim Phase II data for a similar drug on 11 June. That's when CymaBay Therapeutics Inc. said its PPAR delta agonist did no better than placebo in reducing hepatic fat in NASH patients. CymaBay has contended that its candidate is more potent than Genfit’s elafibranor and offers advantages by only targeting the PPAR delta receptor. (Also see "CymaBay Following The Leaders, Pursues NASH, PBC Simultaneously" - Scrip, 16 Apr, 2019.)
CymaBay’s shares finished trading on 20 June down 3.6% to $6.77, as the company struggles to recover from the loss of more than half of its valuation following the Phase II data report. CymaBay closed at $11.09 a share on 10 June but was down to $5.80 in heavy trading on 11 June.
Meanwhile, although analysts including Leerink’s Sarraf and Garnier’s Le Fur cautioned that there should be no read-through from CymaBay’s poor data to elafibranor, Genfit’s stock has declined from $23.87 on 10 June to $20.14 on 20 June.
Hum also said there should be no read-through from CymaBay to Genfit, even though both drugs are in the same class, because Genfit’s drug offers different benefits as a dual PPAR agonist and because its thesis for Phase III is showing that elafibranor can resolve NASH by reducing or eliminating liver inflammation and eliminating ballooning hepatocytes, not by reducing liver fat.
Cutting Fat Vs. Reducing Inflammation
While quantity of liver fat – CymaBay's focus – is an upstream characteristic of NASH, it can be benign in pre-NASH patients, Hum noted, pointing out that the thesis that reducing hepatic fat can resolve NASH is not proven. Regardless, the liver-fat-reduction hypothesis is being pursued by several companies, including Madrigal Pharmaceuticals Inc., which recently entered Phase III with thyroid hormone receptor (THR) beta agonist MGL-3196. (Also see "NASH News & Notes From The European Liver Meeting" - Scrip, 16 Apr, 2019.)
Elafibranor addresses inflammation through two separate and independent but complementary pathways, Hum explained, with agonism of the PPAR alpha receptor targeting inflammation in hepatocytes, while PPAR delta agonism targets Kupffer cells, which clear bacteria and help break down red blood cells in the liver.
He added that CymaBay’s interim Phase II data was derived from magnetic resonance imaging – proton density fat fraction (MRI-PDFF) scans – while elafibranor’s benefits have been demonstrated with histological data from liver biopsies.
“Elafibranor has shown benefit on resolution of NASH without worsening of fibrosis independent of whatever happens on [hepatic] fat,” Hum noted. “It’s going to be the histology that is most important.”
Genfit also has Phase II data indicating that elafibranor can offer patients additional therapeutic benefit by increasing insulin sensitivity in the liver and peripheral tissue, the exec said.