FDA flags 19 deaths in Ocaliva patients, putting Intercept's NASH bid in doubt

NASH, shown here in a liver biopsy, is one of the diseases targeted by multiple drugmakers, including Intercept, Gilead Sciences, Novo Nordisk and Allergan.

Intercept Pharmaceuticals has been the presumed leader in the race toward one of the hottest new markets in pharma, the liver disease NASH. But 19 as-yet-unexplained deaths in current Ocaliva patients have put that lead in doubt, and the med faces a threat in its now-approved indication, too.

Those 19 patients died after taking Ocaliva, which won an FDA nod last year to treat a rare liver disease, primary biliary cholangitis (PBC), as an add-on to ursodeoxycholic acid, the agency said Thursday in a drug safety dispatch. Seven of those patients had been taking the drug more often than its official labeling recommended.

But the agency said Ocaliva may be associated with liver damage even in patients with mild PBC who’d been taking the correct dose. Overall, the FDA turned up 11 cases of liver injury in addition to the deaths. Intercept's shares had lost almost a third of their value—down to $68—by Monday morning premarket trading.

The deaths and injuries could lead to a black-box warning, the FDA’s most severe, and that would likely affect Ocaliva’s current sales. That possibility “bears close watching, given the deleterious impact this could have on Intercept revenues now and in the future,” Leerink analyst Joseph Schwartz said in a note Thursday afternoon, adding, “This could significantly constrain the market opportunity for Ocaliva in PBC.”

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But the bigger hit would come from a denied approval in NASH—nonalcoholic steatohepatitis—which is also known as fatty liver disease. A hit worth up to $7 billion, in fact. Analysts have predicted up to $8.6 billion in Ocaliva sales if it moves into the NASH market, and predictions run to $1.6 billion with just PBC on the label.

The dosing issue could raise a red flag with the FDA when that approval decision rolls around, because higher doses of Ocaliva would be on tap for NASH treatment. Also, PBC is an orphan indication. NASH isn’t, and myriad other drugs are moving toward an approval in that disease, though some have reported setbacks of their own. Genfit, for instance, had said it expected its elafibranor to win approval in 2019, but earlier this year, it delayed enrollment in a phase 3 trial by six months.

Gilead Sciences recently reported phase 2 data on its candidate, GS-4997, and expects a trial on a combo cocktail to wrap up later this year. Shire’s NASH med volixibat won an FDA fast-track designation last October. Then there are Allergan’s cenicriviroc, which it acquired along with Tobira Therapeutics last year, and Novartis’ emricasan, which it licensed from Conatus, also last year.

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“Today's disclosure could add another layer of investor concern as Intercept continues to pursue NASH, which presents a larger market opportunity, but also requires a higher dose of the drug—10 mg and 25 mg dosing arms in the phase 3 Regenerate trial versus 5 mg and 10 mg in PBC,” Schwartz said..

“In turn,” he added, “investors may begin to assign more market opportunity to other drugs investigated in PBC even if earlier in development stage.”

Ocaliva is now the only drug approved for PBC patients who’ve responded poorly to ursodeoxycholic acid therapy alone. But the FDA’s disclosure “will likely add another layer of caution as physicians may find Ocaliva dosing more cumbersome and patients more reluctant to initiate therapy even if urso yields sub-optimal response.”

More data on many of these meds will be rolling out in late October at the American Association for the Study of Liver Diseases conference, and the safety numbers will likely get plenty of attention in light of the Ocaliva developments.

In the meantime, the FDA is advising doctors to assess their patients’ liver function and use only 5 mg weekly for those whose function is impaired, rather than the 5 mg daily for other PBC patients. All patients should be monitored frequently for disease progression or liver injury, the agency said, and should discontinue the med if they find problems.