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the blood, alkaline phosphatase, that is linked to PBC. The panel will consider whether it’s enough to use the alkaline phosphatase reduction as a predictor for a health benefit, which FDA described as fewer deaths or liver transplants.
The issue of surrogate endpoints, as such predictors are called, can loom large over a drug. The FDA approved two next-generation cholesterol drugs last year, known as PCSK9 inhibitors, based on their ability to reduce bad cholesterol.
But the drugs have not yet been shown to actually improve health outcomes, and insurers are proving extremely stingy in paying for their use. Instead, they are waiting for the drug makers, Regeneron Pharmaceuticals (NASDAQ: REGN), Sanofi (NYSE: SNY), and Amgen (NASDAQ: AMGN), to reveal results of those longer-term, expensive outcome trials in the next year or two.
Further clouding the outlook for OCA—especially if one is looking past the immediate discussion regarding PBC and toward the horizon of NASH—is that very few PBC patients received OCA on its own. Most were also taking the standard of care, ursodeoxycholic acid, which is only effective in early stages of the disease.
UCSF’s Rosenthal says drug trials for NASH, especially Intercept’s FLINT trial, have shown “pretty good” evidence that with treatment, damage from NASH in adults and children could be reversible. But there are no drugs approved to date. A host of companies are racing to develop them. Gilead just paid $400 million for a drug that’s only been through Phase 1, with $800 million more to come if Gilead can move it to market. Gilead has another NASH drug in its pipeline, simtuzumab, although it recently failed to show any benefit in patients with the lung scarring known as idiopathic pulmonary fibrosis.
The French firm Genfit, with a presence in Cambridge, MA, has a NASH drug that just began a 2,000-patient Phase 3 trial. The company hopes to show enough for a faster approval by reading data from roughly half the patients after 72 weeks of treatment.
And after shelving its lead drug in HIV in 2013, Tobira Therapeutics (NASDAQ: TBRA) of South San Francisco, CA, shook up management and pushed the same drug ahead instead in NASH, with a Phase 2b trial underway.
Intercept’s OCA has made the biggest splash. The FDA granted it a breakthrough designation for NASH in early 2015, which could help speed up the review process. A year before, the Phase 2 FLINT trial ended early because OCA was performing so well, sending its stock to all-time highs over $450 a share. But that glow faded after more data emerged that underscored the itching and cholesterol concerns, followed by gloomier results in a separate trial in Japan.
A worldwide Phase 3 trial is ongoing, with final data due in 2021, but Intercept, like Genfit, wants to stop roughly half way to see if the data warrant an early approval. Because those patients would only take the drug for 72 weeks before evaluation, the benefit would be based on surrogate endpoints—it’s not enough time to show actual health benefits.
That’s why NASH followers want to see how the FDA’s advisors, and ultimately the agency itself in a final decision, react to the data Intercept is presenting for PBC patients. Intercept itself highlighted the uncertainty in recent regulatory filings: “We will face these risks for OCA for the treatment of NASH because of our plan to seek accelerated approval based on the [Phase 3] trial which incorporates interim co-primary surrogate endpoints.”
The panel’s recommendation Thursday isn’t binding, but the FDA doesn’t often stray too far from the advice it gets at these hearings. The agency’s final approval decision is due May 29.
Photo “White Oak — FDA” courtesy of thisisbossi via a Creative Commons license.