The FDA has rejected an Intercept Pharmaceuticals drug developed to treat the fatty liver disorder nonalcoholic steatohepatitis, more commonly referred to as “NASH.”
New York-based Intercept (NASDAQ: ICPT) said Monday that the agency’s complete response letter for obeticholic acid (OCA) stated that its review found that the investigational NASH drug’s benefit “remains uncertain” and does not sufficiently outweigh its potential risks. The agency recommended that the company submit more safety and efficacy data from an ongoing clinical study, and continue its long-term evaluation of the drug in NASH patients. Speaking on a conference call, Intercept CEO Mark Pruzanski said the FDA changed the agreed upon clinical trial goals that would support an approval decision.
“At no point during [the drug’s] review did FDA communicate that OCA was not approvable on an accelerated basis,”he said. “In fact, during the course of our ongoing program, FDA progressively increased the complexity of the histologic endpoints, creating a very high bar that only OCA has so far met in a pivotal Phase 3 study, which the FDA has acknowledged.”
NASH is a liver disease in which buildup of fat causes inflammation and scarring. Its rise has been driven by sugary diets and obesity. There are no FDA-approved drugs for the condition, which is a leading driver of liver transplants.
Intercept’s OCA, a once-daily pill, was designed to bind to a receptor that regulates the creation of bile acids. The company says activating this receptor can trigger activity that combats fibrosis, inflammation, and fat retention. In Phase 3 results, Intercept reported that its drug beat a placebo in reducing liver fibrosis—damage caused by the formation of scar tissue— one of the main goals of the pivotal study.
The drug fell short of the other main goal of resolving the other symptoms of NASH. But in 2017, the company and the FDA agreed on an amended clinical trial design in which meeting just one of the two clinical trial endpoints would be enough to support regulatory approval. Based on meeting the fibrosis reduction goal, Intercept last September submitted an application for OCA seeking accelerated approval. It’s a speedier pathway that grants an earlier regulatory decision based on a thinner body of evidence. In exchange, a company must submit additional data to keep the drug’s approval status.
The accelerated approval pathway is typically a six-month process. The FDA had scheduled an April meeting of an independent advisory panel to discuss the merits of OCA and vote on whether to recommend approval. But the COVID-19 pandemic led the FDA to push that meeting to June 9—just 17 days before the agency’s target date for a regulatory decision. In late May, Intercept announced that the advisory committee meeting had been postponed once more to allow the FDA to review more data that it requested from the company. The advisory committee never convened. Pruzanski said the requested data were submitted within one week and the company heard nothing until receiving the FDA letter, which the executive called “unexpected and disappointing.”
“We don’t have clarity, based on the letter we received, what exactly the agency is looking for,” Pruzanski said. “Again, we firmly believe the data already submitted to date should fully, fully and convincingly support benefit risk, positive benefit risk-assessment, and therefore, approval.”
OCA is already approved for primary biliary cholangitis (PBC), a disease that damages the liver’s bile ducts. For PBC, Intercept markets the drug as Ocaliva. Its known side effects include severe itching, fatigue, abdominal pain, and rash. Pruzanski said the NASH studies turned up no new additional safety concerns.
The FDA rejection of OCA follows the high-profile stumbles by several other NASH drug developers. A little more than a year ago, Cymabay Therapeutics (NASDAQ: CBAY) reported Phase 3 results showing its experimental drug, seldelpar, failed to beat a placebo in reducing liver fat—the main goal of the study. The placebo effect also stymied Genfit (NASDAQ: GNFT), whose drug elafibranor failed to beat a placebo in resolving NASH without a worsening of fibrosis. Gilead Sciences (NASDAQ: GILD) also fell short of beating a placebo with its NASH drug candidate.
But OCA, unlike the other NASH drug contenders, achieved the main goal of its pivotal study, Pruzanski emphasized. He added that the agency is not asking the company to conduct new clinical trials; it wants to see more data from the Phase 3 study that is underway. That study is fully enrolled.
Based on the FDA’s letter, Pruzanski said Intercept does not believe this Phase 3 study would need to finish in order for the company to resubmit its OCA application. That new filing would start a fresh six-month review countodown. But Pruzanski said the immediate next step is scheduling a meeting with the FDA to discuss the rejection letter.
Image: iStock/Rasi Bhadramani