It is probably fortunate for patients with non-alcoholic steatohepatitis that numerous drug developers have rushed in, because the past week might have seen two projects endangered. Allergan has disclosed that cenicriviroc is struggling to reduce liver fibrosis, while a growing safety scare has cast more doubt on Intercept’s Ocaliva.
This is not necessarily the end of the road for either project in Nash, and cenicriviroc's pivotal trials might be adjusted to account for the latest data. Yet the news does raise questions about their commercial promise, as it likely limits the population that will be eligible to use Ocaliva and cenicriviroc.
The announcements of the week were good news for Nash competitors like Genfit and Galectin, which saw their shares rise 8% and 1% respectively. Intercept suffered the most, its shares down 40% since news emerged last week that it had sent a letter to warn doctors about using a high Ocaliva dose in patients in its approved indication, primary biliary cholangitis. A new FDA warning has extended the worries into patients receiving appropriate doses, too.
Allergan announced two-year follow up from a phase II trial of cenicriviroc that found no difference between treatment and placebo on the composite primary endpoint, reduction in fibrosis by at least one stage with no worsening of Nash. The New Jersey-based company will be thankful for more positive data on other endpoints, including in patients who started treatment with a higher baseline score, as well as improvement by placebo patients who crossed over to active treatment.
Cenicriviroc’s previous owner, Tobira, had been able to show a fibrosis improvement at 12 months, so the latest data must come as a bit of a surprise to Allergan executives, who paid $534m up front for Tobira last year – however, at least they can congratulate themselves for structuring the deal with contingent value rights that kept the overall price down (Despite a deck stacked in its favour, Tobira fails in NASH, July 25, 2016).
A 2,000-patient phase III trial is now recruiting patients, with the same primary endpoint to be analysed after 12 months of treatment as part one, and long-term outcomes at part two. With two-year phase II data in hand, this could conceivably allow Allergan to alter the pivotal study design to make the higher-baseline patients a key part of the analysis.
In any case, regulators are likely only to consider these surrogate endpoints as part of a larger package that includes data on mortality and progression to liver complications like cirrhosis – as is the case with Intercept’s more advanced Regenerate trial.
Ocaliva safety stumble worsens
Meanwhile, Intercept’s safety worries with Ocaliva have gone from bad to worse – and have led to fears among some that a black box warning might be imminent.
While an earlier “dear doctor” letter suggested that the danger was limited to patients with moderate to severe primary biliary cholangitis (PBC) receiving excessive dosing, yesterday’s FDA warning letter said Ocaliva might also have led to liver injury in patients with mild disease receiving the correct dose.
Baird analysts went into firefighting mode, saying the 19 deaths and 11 cases of severe liver injury seen as of July 2017 were not surprising given the serious nature of PBC – but the development further dents Intercept’s chances of making Ocaliva a success in the bigger Nash indication, where higher doses are being tested (Intercept’s safety scare ramps up Nash pressure, September 13, 2017).
Nash is expected to account for $971m of Ocaliva’s total $1.5bn sales in 2022, according to EvaluatePharma. Of course, efficacy still needs to be proven here, with data from the phase III Regenerate trial due in 2019 – but now safety will be watched just as closely.
Competitors will today be breathing a sigh of relief, though the travails of Allergan and Intercept highlight yet again the difficultiues of developing therapies for Nash.