In the bid to break the non-alcoholic steatohepatitis (NASH) market, a two-horse race to be first-to-market emerged between Gilead’s selonsertib and Intercept’s Ocaliva (obeticholic acid). On the 11th of February 2019, Gilead announced that in STELLAR-4, a Phase III trial of selonsertib missed a primary endpoint, seemingly a massive setback to hopes for its approval as the first NASH drug treatment.

Selonsertib failed to show it caused a 1-stage improvement in fibrosis after 48 weeks in NASH patients with compensated cirrhosis. The trial was designed to show selonsertib was approvable after a year of treatment, and then that it had a truly impactful benefit after 4 years, by late 2022. Failing the first hurdle is big problem. If it were to continue it could potentially still demonstrate improvements in NASH histology and/or patient outcomes but committing to complete the 240-week trial may now be too financially risky. Regulators might shut it down on ethical grounds after reviewing the data. Language in the press release hints that Gilead has already decided to terminate the trial: “Gilead will work with the Data Monitoring Committee and investigators to conclude the STELLAR-4 study in a manner consistent with the best interests of each patient.”

All is not yet lost though as STELLAR-3 is another ongoing Phase III trial of selonsertib with a very similar design to STELLAR-4 but in a less severe classification of NASH. It is feasible that selonsertib is more effective in an earlier state of disease progression; given the trial begun a month later than its failed predecessor we should expect top line results very soon. If STELLAR-3 also fails to demonstrate a 1-point improvement in fibrosis, FDA approval is highly unlikely given the FDA’s recently published document on approval requirements (see below).

In November 2018 the FDA published draft guidance specifying what it wants to see in Phase III clinical trials of NASH drug candidates:

  • Improvement in NASH without worsening fibrosis OR
  • Improvement in fibrosis without worsening NASH OR
  • Both the above

If Gilead discontinues development of selonsertib the company falls out of pole position but is still very much in the NASH game. It has other NASH pipeline assets, including a combination approach with selonsertib and two other agents (GS-0976, GS-9674) – a Phase II trial (ATLAS) investigating the approach is scheduled to complete in October 2019. Attention now turns to the new race leader, Intercept Pharmaceuticals’ obeticholic acid, for which top-line results from its Phase III trial REGENERATE should be announced soon.

Because NASH is a relatively new indication, and there are no approved therapies, defining exactly what is required from a safe and effective treatment is still evolving. None of the current Phase III candidates had convincing Phase II trials – to be frank, we are yet to see impressive clinical data in NASH trials. Gilead has lost ground to its competitors, including Intercept, Genfit, and Allergan that have the next Phase III trials to read out. Although these competitors now may have one less rival, STELLAR-4 is a stark reminder of the difficulty and pitfalls of targeting a disease without an established treatment. Before we start counting the billions of dollars the NASH market is likely to be worth, we need at least one drug to crawl over the finish line. NASH remains an exciting space to study.

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