|Intercept CMO David Shapiro|
FDA staffers reviewing Intercept's data on obeticholic acid (OCA) for rare cases of primary biliary cirrhosis (PBC) noted that the drug clearly hit a key goal in the study after finding the safest dose for patients. But the panel of outside experts scheduled to meet on Thursday will be charged with considering whether its impact on the single biomarker for the disease--a surrogate for transplant-free survival--is sufficient for an approval, with data lacking on another biomarker and lingering concerns about potential liver damage.
The internal review at the FDA paints a complex portrait of PBC and the experimental drug, which is being closely followed as a potential blockbuster with a future treating NASH. But after a three-month delay at the FDA triggered some jitters earlier, the market responded in an upbeat fashion after the agency's documents were released today, pushing shares of Intercept ($ICPT) up 17% in early trading.
Investigators in the studies concentrated heavily on whether OCA could significantly cut the level of alkaline phosphatase, ALP, from baseline compared to a placebo. The pivotal work also focused on total bilirubin, or TB, although the outcomes were hampered on that score by the low number of more advanced-stage patients with elevated TB enrolled in the pivotal study. And regulators also felt that the low number of patients intolerant to ursodeoxycholic acid (UDCA) included in the study--16--made it difficult to assess the drug's usefulness as a monotherapy.
Due to some severe problems with pruritus during the midstage studies using a 50-mg dose, with little added benefit over the 10-mg dose, the FDA and Intercept agreed to limit the Phase III dose to 10 mg, with an option to start patients at 5 mg and then move them up to 10.
And it clearly hit the primary endpoint on ALP, with about 46% of the patients in the drug arms achieving the endpoint, compared to a little less than 10% in the placebo arm.
"Treatment with OCA (titration or 10 mg) resulted in a reduction in ALP levels as early as 2 weeks after treatment initiation with steep early reductions continuing through Month 3," states the review. "In the OCA 10 mg group, the maximal effect on ALP reduction occurred at Month 6 and was sustained through Month 12."
The regulators also had to wrestle with the threat of pruritus in the titration arm as well as the 10-mg group, with the titration group doing better in terms of safety. Regulators refused to rule out a causal relationship between the drug and liver damage. There was an increase in LDL and a drop in HDL that will also get some attention during the discussion on safety. And on several instances in the review, the FDA insiders also focused on the limitations of the study, noting that the patients were mostly at an early stage of the disease, making it harder to understand the safety issues regarding potential liver damage among patients with more advanced disease.
None of the safety issues, though, were presented as deal killers in the FDA review. And that's likely going to keep the conversation about a near-term approval, and future trial demands, centered on the efficacy of the drug. Several analysts breathed a sigh of relief on the review.
"Though we admit being scared by FDA's three-month delay, today's briefing docs are, what's the word? Boring," writes Baird's Brian Skorney. "And that is a good thing. There seems to be some question still around validity of the surrogate endpoints, specifically ALP, but all in all, we think the FDA is leaning toward an approval here, and that safety issues that could have readthrough to NASH, didn't really seem to be an issue."
The bigger question for many, though, will focus on the implications in the data for OCA's future in NASH, a fatty liver disease that has been spreading around the globe. Intercept's Phase III for NASH includes a 10-mg as well as a 25-mg dose, and analysts will be looking closely to see what kind of safety and efficacy issues may be raised by a drug that has a dose-dependent adverse-event issue.
- here's the review