When the FDA rejected Intercept Pharmaceuticals’ nonalcoholic steatohepatitis (NASH) drug candidate two years ago, the agency didn’t call for another clinical trial. It said it hoped to get more data from the ongoing Phase 3 study.The research has accumulated Additional Safety and Efficacy Data, and the Intercept now says these results support a second shot seeking FDA approval. A meeting with regulators is scheduled for later this month.
NASH is a fatty liver disease that causes inflammation and damage to organs. There is no FDA-approved treatment for this condition, which can lead to liver failure. Intercept’s drug obeticholic acid (OCA) is an analog of a naturally occurring human bile acid. It is designed to bind and activate receptors expressed in the liver and gut, regulating inflammatory, fibrotic and metabolic pathways.
The Phase 3 clinical trial, called REGENERATE, has two primary goals. One is showing reduced scarring of the liver, also known as fibrosis. The other was to show regression of NASH without worsening of liver fibrosis. The company had previously reached an agreement with the FDA that meeting just one of the two goals would be enough for the Phase 3 test to be successful.
High-dose OCA treatment resulted in improvement at 18 months in 22.4 percent of patients, compared with 9.6 percent of those receiving placebo, as assessed by liver biopsy, according to interim results of 931 patients released Thursday. On the study’s second main goal, more participants who received OCA met the goal, but not enough to distance the treatment from the placebo group.
Both results are the same as Original analysis that led to FDA rejection of Intercept drug in 2020The Morristown, N.J.-based company said Thursday that the same subjects and the same liver biopsies were read in the new interim analysis. The difference this time is that the latest results were generated by using a new liver biopsy assay that the FDA requires to support new drug applications. In this “consensus reading approach,” a panel of three board-certified pathologists demonstrated the accuracy and reproducibility of liver biopsy assessments. The new interim analysis reassessed liver biopsy at baseline and 18 months.
“Achieving a statistically significant histological endpoint in clinical trials in NASH has proven to be an extremely high bar,” Intercept President and CEO Jerry Durso said in a prepared statement. “We are pleased that OCA has demonstrated sustained improvement in fibrosis based on the second approach, and we now have two positive, statistically significant primary endpoint results from our pivotal REGENERATE trial.”
A blinded independent panel of experts reviewed liver, heart and kidney safety events, which Intercept says are safety measures specifically requested by the FDA. OCA has been evaluated in 2,477 people who took at least one daily dose of the oral medication, the company said. Nearly 1,000 study participants have been using the drug for nearly four years.
A preliminary analysis over four years of treatment showed a higher number of adjudicated liver safety events with high-dose obeticholic acid, Intercept said. Most of these events were classified as mild. For adjudicated cardiovascular and renal impairment, Intercept said the frequency of such events was low and balanced across treatment groups.
The most common side effect was severe pruritus or pruritus, which was reported by 24% of patients in the placebo group and 55% of those receiving the high-dose Intercept drug. Itching was the most common reason patients discontinued treatment. Severe itching is also a side effect of this drug to treat primary biliary cholangitis, a disease of the bile ducts. For this approved indication, the Intercept drug is marketed under the name Ocaliva.
The growing prevalence of NASH and the lack of approved treatments for the disease have sparked a lot of research and development. The FDA’s rejection of Intercept’s drug two years ago was one of several high-profile setbacks in the field. Genfit’s NASH drug candidate, elafibranor, failed a pivotal study in 2020, which led the company to turn its efforts toward a rare liver disease. last year end, Genfit sells rights to drug to Ipsen for 120 million euros.
Other R&D work continues. The partnership between Gilead Sciences and Novo Nordisk is testing various drug combinations in NASH. GlaxoSmithKline joined the ranks of NASH contenders last year, paying $120 million for the rights to an early-stage NASH candidate from Arrowhead Pharmaceuticals. Other NASH drug contenders include Madrigal Pharmaceuticals, Viking Therapeutics, Akero Therapeutics and 89bio.
Public domain images by Flickr users National Institutes of Health Photo Gallery
