Shares in Enanta Pharmaceuticals fell 10% after the company posted phase 2a data on EDP-305 in nonalcoholic steatohepatitis (NASH) patients. The trial narrowly hit its primary endpoint, but tolerability concerns and doubts about whether EDP-305 is more effective than other FXR agonists overshadowed the readout.
EDP-305, like Intercept Pharmaceuticals’ Ocaliva, works by modulating FXR, a nuclear receptor that regulates bile acid levels in the liver. Intercept is set to file for FDA approval of Ocaliva in NASH soon.
With Intercept leading a large pack of NASH drug developers, Enanta may need to generate strong data to carve out a niche for EDP-305. The 132-patient phase 2a gave Enanta an opportunity to do just that. However, the readout left investors underwhelmed.
Enanta reported a statistically significant reduction in levels of the liver enzyme ALT in the high-dose arm, as compared to placebo. At week 12, the ALT reduction in subjects who received the high dose was 28 U/L, as compared to 15 U/L in the placebo arm. The difference resulted in a p-value of 0.049, meaning the trial just cleared the threshold for statistical significance.
However, it is questionable whether the improvement is big enough to differentiate EDP-305 from other FXR agonists. The placebo-adjusted change (PDF) from baseline in ALT in the high-dose EDP-305 arm was 12 U/L. In phase 2 and 3 trials, Intercept linked Ocaliva to placebo-adjusted 12-week reductions in ALT of 17 U/L and 21 U/L.
Such cross-trial comparisons can be unreliable, but there is little in the ALT data to suggest EDP-305 can come from behind to claim the NASH market. Enanta reported more comprehensive successes for the high dose against secondary endpoints including change in liver fat content, but the efficacy results were offset by the safety and tolerability data.
In the high-dose cohort, 51% of subjects experienced pruritus, the medical term for severe itching of the skin. More than one-fifth of participants dropped out of the high-dose arm after experiencing pruritus related to the study drug.
Ocaliva suffers from a similar tolerability profile. An interim analysis of a phase 3 trial of Intercept’s drug found 51% of people in the high-dose arm experienced pruritus. Almost 10% of subjects in that cohort stopped treatment.
The lower dose of EDP-305 was more tolerable—triggering pruritus in less than 10% of patients—but was also less efficacious. The low dose group performed numerically better than the placebo cohort against the primary endpoint, but the difference fell short of statistical significance.
Enanta thinks the data are strong enough to justify running a 72-week phase 2b trial. The plan is to test two doses of EDP-305. Enanta will set one dose level to maximize efficacy, accepting that some of the subjects who receive it will experience pruritus. The second dose will seek to balance efficacy and tolerability. Enanta may use that more balanced dose in combination with other NASH drugs.