On July 7, Intercept Pharmaceuticals released new results from the continuation of the REGENERATE trial and announced their intent to file a new NDA for obeticholic acid (OCA) in NASH fibrosis. In this conversation, Stephen Harrison leads Jörn Schattenberg, Louise Campbell and Roger Green in examining the new efficacy analysis and exploring what it means for obeticholic acid, both in terms of the drug’s performance and its revised prospects for FDA approval.
Obeticholic Acid (OCA) Efficacy
After Stephen lists the four major bullet points from Intercept’s press release, this conversation focuses on the first point: “The 25mg dose of obeticholic acid met the agreed primary endpoint of improvement in liver fibrosis without worsening of NASH at 18 months.” The data behind this bullet point stem from a new interim analysis of the original 931 cases. In the re-analysis, the treatment effect remained constant but the placebo effect dropped slightly. The different results from a different method of analyzing histopathology, one that relied on consensus panel reads instead of an individual histopathologist’s interpretation (as was done in the original analysis). Stephen goes on to note that there is a similar small change in the NASH resolution percentages, but, like the original analysis, these do not reach statistical significance. He notes that this submission relied on hitting one of the primary endpoints, not both of them. He then asks the group two questions: “Does this change our perception of OCA in NASH?” and “Does this change our perception of this drug as a driver of the field in drug development for NASH?”
Roger answers first. Taking a narrow focus on the question, he answers that we still see OCA as an effective anti-fibrotic at the same level we did three years ago. If there is a change, it is that if obeticholic acid had a three-year lead on the market, it would have focused a significant amount of research on FXR agonists — both in terms of developing more FXRs and in considering them the backbone in NASH pharmacotherapy. In 2022, with another very different agent appearing to be fairly close to market, he felt these results would not dramatically change the other directions in which research is heading.
Jörn Schattenberg goes back to the original 2019 paper, which he describes as “groundbreaking” and, quoting Zobair Younossi, “a watershed moment.” He notes that the reading method seems more consistent with what FDA wants and says that while others may comment on the small effect size (11%), his view is that this is a positive achievement as the first paper to demonstrate significant effect against fibrosis.
Louise Campbell echoes her colleagues’ comments about the successful efficacy results but notes that patients who could have benefitted from OCA’s approval two years ago have gone two more years without the benefit of medication.
Stephen concludes the conversation by agreeing with Jörn that this is a watershed moment. He notes how many observers have said that proving efficacy was essentially impossible due to the complexity of the disease and regulators “moving the goalposts.” This study, he says, proves that it can be done.