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 episode, Stephen Harrison leads the Surfers through a discussion of the new REGENERATE results and the Surfers discuss what they find compelling in the new data, discuss the possibility of approval, and ask (and answer) what an approval might mean for the Fatty Liver community.
REGENERATE Redux – Can OCA Succeed With New Data?
The basic structure of this episode is: Stephen Harrison walks the group through issues, opportunities and considerations raised in the July 7 press release and the rest of the panel responds with comments and questions as appropriate.
He starts by noting that in a recent episode, the Surfers identified the release of updated REGENERATE data and subsequent OCA approval in NASH fibrosis as a potentially transformational event in the Fatty Liver community and proceeds to read the four bullet points that Intercept Pharmaceuticals highlighted:
- The 25mg dose of OCA met the agreed primary endpoint of improvement in liver fibrosis without worsening of NASH at 18 months.
- The 25mg dose of OCA doubled the fibrosis response rate vs. placebo.
- This data set includes larger and more robust safety database of 2477 patients with nearly 1000 on study drug for four years.
- Intercept will refile an NDA in liver fibrosis due to NASH, starting with a pre-submission meeting with the FDA later this month.
From there, Stephen dives into the data, starting with the efficacy results. He notes that the results for reduction of fibrosis without worsening of NASH are comparable to the initial REGENERATE results statistically: highly significant improvement in the 25mg dose vs. placebo, but not in the 10 mg dose. He also notes a small but statistically insignificant numerical difference in NASH resolution without worsening of fibrosis.
The 25mg score is roughly the same as in the earlier trial, but the placebo score dropped, possibly due to a change in the methodology for reading histology slides . In the previous analysis, two histopathologists each read half the slides independently. This time, two teams of three histopathologists read slides in a design that forced consensus on each slide included in the final data.
In discussing efficacy data, Jörn describes this study as “groundbreaking” and Louise notes the impact of a two-years-later approval in terms of patients who did not receive drug benefit over that time. In agreeing with Jörn, Stephen notes that this study proves that we can get a fibrosis drug “over the finish line” by meeting FDA efficacy criteria.
The group moves on to discuss safety criteria. Stephen notes that pruritus is still the most common side effect and reason for discontinuation, while Roger comments that LDL and cardiovascular issues, which were implicated as the major risk issue in the earlier data, appear to resolve over time and not present as much risk this time. Jörn and Louise both praise the increased robustness of safety data based on sample size and duration of therapy, after which Stephen notes the questions that the press release does not answer (but, presumably, the full data release will).
The rest of the discussion focuses on some decisions Intercept made about how to present data and the overall implications of this trial. Stephen and Roger praise Intercept for their continued commitment to OCA in the face of FDA’s 2019 Complete Response Letter and the group agrees that this data is more likely to gain approval. When Roger asks for a prediction of what the world might look like 1-2 years from now, the group considers that we might have two approved agents (with resmetirom) as early as the end of 2023.