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S3-E36.3 – REGENERATE Redux: Safety and Tolerability With Obeticholic Acid

Stephen Harrison leads the rest of the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green), through a discussion of Intercept Pharmaceuticals' July 7 press release on re-analysis of the REGENERATE trial evaluating obeticholic acid (OCA) for treating of NASH fibrosis. This conversation focuses on safety and tolerability issues in this analysis. This is important because most observers believe it was the risk:benefit tradeoff analysis that led to the Complete Response Letter in 2020.

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 how the larger sample and longer time patients were on therapy changed the safety and tolerability profile from the initial analysis.

Safety and Tolerability With Obeticholic Acid

After reviewing the four key points from Intercept’s press release, Stephen Harrison kicks off this conversation by discussing the safety evaluation, which included a far larger population with significantly longer exposure to study drug. After describing the enriched population, he quotes from the press release, “Emergent adverse events treatment, emergent serious adverse events, and deaths were generally balanced across the OTC and placebo treatment groups.” He goes on to cite the considerable differences in pruritus across groups (22% in placebo, 33% in 10mg and 55% in 25mg), share the comment that most discontinuation stemmed from pruritus, note that gall bladder-related events occurred in less than 3% of patients and, finally, that OCA 25mg had a higher rate of biliary events. He then asked the rest of the group for comments.

Jörn commented first, noting that this was mostly “recapitulated” data, but with a much broader set of subjects. Because risk:benefit ratio was perceived as the pivotal issue around the time of the original Complete Response Letter (CRL), he describes the data as improved “by a lot.”

Louise describes as “reassuring” the idea that the NASH dose could be so much higher than the approved PBC dose (25mg vs. 5 or 10mg) but not demonstrate additional safety concerns. She goes on to declare that practices planning to use OCA should be “planning pathways into delivery” in anticipation that the high level of pruritus will lead to a significant set of discontinuation with a careful approach to patient orientation and management.

Roger shared his recollection that increases in LDL levels and the implicit associated cardiovascular risk were major issues in the negative risk:benefit assessment, but that this analysis appears to report that levels returned to normal within the first year of treatment. This might increase chances for approval.

At this point, Stephen reads the press release carefully to identify potential safety hazards that are not addressed directly in the document, although, as he notes, one can fit only so much into a press release. As the conversation ends, Stephen asks Jörn if he has “ongoing lingering questions”. Jörn notes that he wondered how the reads were done and that he also looked for LDL data. He makes a few other points, but suspects that they may have been covered in the 2019 paper.

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