Medical Innovation Exchange

Durect fails alcohol-associated hepatitis trial, plans phase 3 anyway as investors scorch stock

Durect and investors have reached radically different conclusions about its severe alcohol-associated hepatitis phase 2 data. The biotech hailed “remarkable” results—on a secondary goal, in a subpopulation—but failed to persuade investors to look past the failure of the primary endpoint, causing its stock to sink.

Investigators randomized around 300 patients to receive one of two doses of larsucosterol, an epigenetic modulator, or placebo. Durect had originally set out to show whether larsucosterol improved the 90-day mortality rate, before switching last year to a composite primary endpoint covering 90-day mortality and liver transplantation. Nothing good came from the change.

“We had some input from some thought leaders, and we made an adjustment midstream, changed horses in the middle of a stream, which one should never do,” Durect CEO James Brown said on a conference call with investors to discuss the data. 

“We learnt the hard way here, unfortunately,” Brown added. “But it doesn’t change … the outcome. The outcome here is we have really good mortality data.”  

Neither dose of larsucosterol met the primary endpoint, with the proportions of patients who were alive and transplant-free at 90 days ranging from 71.6% in the placebo group to 78.8% in the low-dose arm. Durect pinned the failure on the transplant rates and data generated outside the U.S. 

Narrowing the analysis to 90-day mortality at the U.S. sites, Durect linked the two larsucosterol doses to a relative risk reduction of 57% and 58% versus standard of care. The relative reduction in mortality in the entire study was 40.7% in the low-dose cohort and 34.9% in the high-dose arm, suggesting that the ex-U.S. sites, which enrolled around one-quarter of the patients, dragged on the results. 

“We don’t know for sure exactly what happened outside the United States. It could be just random bad luck, it could be something more than that,” Brown said. “We know some characteristics are slightly different—these patients had a higher level of cirrhosis, they were older, things like that. Is it enough to make a difference? We don’t know.” 

Durect is trying to figure out what happened while preparing to meet with the FDA in the first quarter of next year to discuss the results and the design of a planned phase 3 trial. The biotech plans to use 90-day mortality as the primary endpoint and may enroll all of the phase 3 patients in the U.S.

Shares in Durect fell 62% to below $1 in premarket trading.

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