With Gilead and rivals deep in phase 3, FDA unveils draft guidance on NASH drug development

Aspects of the guidance clash with the designs of active phase 2 trials.s (FDA)

The FDA has published draft guidance on developing NASH drugs that has implications for Gilead and the host of other companies targeting the indication. In the draft, the FDA sets out the endpoints and patient populations it wants companies to look at in phases 2 and 3.

NASH, the acronym for nonalcoholic steatohepatitis, has emerged as a key battleground for biopharma in recent years on the basis of a high level of unmet need and the range of promising drugs seeking to address it. Allergan, Genfit, Gilead and Intercept Pharmaceuticals are leading the pack and due to start delivering phase 3 data next year.

With a clutch of rivals coming up behind the frontrunners, the FDA has posted draft NASH guidance. The document runs through the features of NASH and their broad implications for drug development programs, before delving into the specific points companies should factor into phase 2 and 3 trials.


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The FDA is open to granting accelerated approval on the basis of phase 3 data showing drugs resolve steatohepatitis on overall histopathological reading while holding liver fibrosis steady. Alternatively, the agency will also grant accelerated approval if a drug improves liver fibrosis by a stage or more and prevents the worsening of steatohepatitis. 

As Jefferies analyst Michael Yee observed in a note to investors, the pivotal trial design and endpoints for accelerated approval detailed in the FDA guidance are in line with late-phase studies underway at Genfit, Gilead and Intercept. The endpoints proposed by the FDA also fit with that used by Allergan, which is aiming to show that cenicriviroc improves fibrosis and stops steatohepatitis from worsening.

The phase 2 section of the guidance could have a bigger effect on ongoing programs. Notably, the FDA wants companies to run “late” phase 2 trials—as opposed to earlier proof-of-concept phase 2 trials—that last at least 12-18 months and provide enough response information to support the selection of the phase 3 dose. 

“The latter two points are important as there are several companies pursuing phase 2b studies that are less than 12 months in duration and there remains questions as to what dose some companies will use in phase 3 following completion of phase 2 studies,” Yee wrote.

Bristol-Myers Squibb is running two phase 2b trials of BMS-986036 that will take primary endpoint readings at 24 and 48 weeks. And Inventiva Pharma is enrolling patients in a phase 2b trial of IVA337 that will dose patients for 24 weeks. 

The publication of the FDA document comes two weeks after its European counterpart released a draft reflection paper on the development of drugs to treat NASH and other noninfectious chronic liver diseases. The European document is open for comment until the end of August. The FDA text is open for a 60-day comment window.

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