Genfit bags FDA breakthrough tag en route to phase 3 in PBC

Genfit Chief Operating Officer Dean Hum (Genfit)

Genfit has secured FDA breakthrough designation for elafibranor in primary biliary cholangitis (PBC) on the back of midstage data. The breakthrough tag comes as Genfit gears up to start a phase 3 trial in the indication later in the year.

France’s Genfit published top-line data from a phase 2 trial of dual PPARα/δ agonist elafibranor in autoimmune disease PBC late last year and arrived at the recent European Association for the Study of the Liver meeting with additional results. The readout suggests elafibranor has positive effects on serum alkaline phosphatase, bilirubin and a host of other markers relevant to PBC patients.

As in nonalcoholic steatohepatitis (NASH), Genfit is up against Intercept Pharmaceuticals in PBC. Intercept won approval for Ocaliva in PBC in 2016, thereby providing an option for patients in whom ursodeoxycholic acid (UDCA) is ineffective or intolerable.

While Intercept has a healthy head start in PBC, Genfit thinks elafibranor has some advantages over Ocaliva. The phase 2 linked the two tested elafibranor doses to 67% and 79% responses rates against the composite endpoint used in the pivotal Ocaliva trial. Ocaliva came to market with a 47% response rate.

On other key endpoints, Genfit thinks the phase 2 may fail to capture the full efficacy of elafibranor. With levels of some biomarkers still trending downward as of the end of the phase 2, Genfit is talking up the prospect of delivering better results in the longer, possibly one year, phase 3.  

“This is ... a fairly short trial. We would expect to have even stronger effects in a longer trial. It's reasonable to be expecting higher efficacy in the longer [phase 3 trial],” Genfit Chief Operating Officer Dean Hum said.

The other area in which Genfit may have an edge is in pruritus, a symptom of PBC defined by itchy skin. Pruritus is one of the most common side effects of Ocaliva, meaning if anything the drug may make that symptom worse. 

In contrast, the phase 2 linked elafibranor to a reduction in itching, although the change fell short of statistical significance. Genfit can only speculate as to what mechanism underpins the trend, in part because the cause of pruritus in PBC is unclear, but Hum thinks the longer phase 3 trial may reveal a stronger link between elafibranor and reduced itching. 

Genfit plans to talk to FDA in June or July and start a phase 3 trial in PBC in the second half of 2019. That means Genfit could be starting the PBC trial around the time it gets results from its late-phase study in NASH, which is the bigger of the two opportunities for elafibranor.

Elafibranor entered phase 3 on the strength of a post hoc analysis that provided a more favorable impression of its efficacy in NASH than the main study. The phase 2 data wiped 30% off Genfit’s stock at the time and created skepticism about the prospects of its pivotal trial.

Hum thinks the PBC data provide evidence to counter the NASH skeptics.

“A lot of these different markers, whether they're lipid markers or inflammatory markers or things like gamma GT, these are going to be important for the NASH patient as well. So, I think this provides some readthrough as to what we can expect in the phase 3 in the NASH patients. It is hitting targets in the liver,” Hum said.