- Intercept just announced that phase 3 NASH candidate obeticholic acid (OCA) achieved superiority to placebo on one of two co-primary endpoints in the REGENERATE study (n=2,370), in F1-F3 fibrosis due to NASH: The 25 mg dose of OCA improved liver fibrosis with no worsening of NASH, while trending positively but not reaching superiority on NASH resolution with no worsening of fibrosis. The 10 mg dose achieved nominal significance on fibrosis.
Intercept will file the FXR agonist with FDA and EMA in 2H19, setting OCA up to potentially become the first approved NASH therapy. Importantly, FDA has agreed that only one co-primary endpoint must be met for approval – and fibrosis is strongly regarded as the more important of the two.
Intercept Pharmaceuticals just announced the first-ever positive (interim) results for a phase 3 study in NASH – a true watershed moment for the field and FXR agonist obeticholic acid (OCA).
In REGENERATE (n=2,370), OCA 25 mg (once-daily) achieved superiority on one of its two co-primary endpoints in a 72-week interim analysis: OCA 25 mg met significance on the primary endpoint of fibrosis improvement of at least one stage with no worsening of NASH (p=0.0002 vs. placebo), while trending toward improvement without reaching significance on the endpoint of NASH resolution with no worsening of liver fibrosis. However, the 10 mg dose achieved nominal superiority, indicating a dose-dependent response.
Of those patients taking OCA 25mg (n= 308), 23% achieved fibrosis improvement of at least one stage with no worsening of NASH (p = 0.0002), compared to 12% on placebo (n = 311). The OCA 10mg cohort (n = 312) saw 18% of patients improve (p = 0.0446). For the missed secondary endpoint, NASH resolution with no worsening of fibrosis, the 25mg group was 12% (p = 0.1268) and the 10mg group was 11% (p = 0.1814). Importantly, (i) FDA previously agreed that only one of the two co-primary endpoints had to be met for FDA approval and (ii) fibrosis improvement is very strongly considered the more important endpoint of the two. See below for tables detailing results on both of these co-primary endpoints.
Intercept plans to file for approval with US and European regulatory agencies in 2H19, and it’s very possible (even likely) that OCA will become the first molecule to ever receive an indication in NASH. As outlined at JPM 2019, the company hopes a full-cohort 72-week readout will come after approval, which it hopes to achieve via this interim data from these first 931 participants. As the cohort with F1 fibrosis is exploratory, the F2/F3 data will primarily be considered for approval, and the study will continue blinded to completion.
Full results from REGENERATE will be presented at the European Association for the Study of the Liver (EASL): The International Liver Congress 2019 (April 10-14 in Vienna). The REVERSE trial in F4 fibrosis (compensated cirrhosis) is ongoing; Intercept hopes to fully enroll this 540-participant, 52-week trial in 2019.
Primary Endpoint Results for OCA in Phase 3 REGNERATE Trial:
Safety & Tolerability
As expected, the most common side effect with OCA was pruritus (severe itching of skin). Incidence of pruritus was 19% with placebo, 28% with OCA 10 mg, and 51% with OCA 25 mg. Importantly, OCA is already on the market as Ocaliva, a primary biliary cholangitis treatment – meaning HCPs may be more comfortable prescribing the therapy for NASH, compared to a novel agent. Additionally, we’ve heard anecdotally that pruritis doesn’t drive as much discontinuation of therapy as many HCPs expected, though there could be differences between the PBC and NASH populations. Overall study discontinuation rates were 16% for placebo, 17% for OCA 1o mg, and 15% for OCA 25 mg.
- OCA was also associated with an increase in LDL cholesterol (another known effect), peaking at +23 mg/dl after 4 weeks before dropping to +4 mg/dl at 18 months, compared to baseline. Rates of cardiovascular events were low and balanced between placebo and treatment groups (2%, 1%, 2%), though 72 weeks may be too short a duration to observe any negative CV impact. On balance, triglycerides “rapidly and continually” fell with OCA treatment – we’ll be interested to see how the scientific community balances the contrasting changes in LDL, triglycerides, and liver fibrosis.
This positive readout emerged mere days after Gilead’s phase 3 selonsertib missed its primary endpoint in the STELLAR 4 trial. However, it’s important to note that STELLAR 4 enrolled patients with F4 fibrosis (compensated cirrhosis) due to NASH – more advanced than the F2/F3 patients in REGENERATE. We’ll have to wait a bit longer to see how OCA fares in the F4 population, but a readout from STELLAR 3 (selonsertib in F3 fibrosis) is due in 1H19. Still, analysts have long been more bullish on OCA than selonsertib, which has much weaker phase 2 evidence than OCA and, based on topline p-values of p=1.00 and p=0.56 vs. placebo, had seemingly had no effect in phase 3. We also point toward a recent survey of NASH professionals conducted by Hanson Wade (which organizes the annual NASH summit that has been held the last two years) in which 26% of respondents felt OCA was the most likely phase 3 candidate to gain approval first, compared to 7% for selonsertib and 40% who felt it was too close to say.
Investor reaction was mildly bullish – shares of Intercept closed up 6% at $118 (it opened at $132). The difference of 11 percentage points in efficacy between OCA 25 mg and placebo, while significant, was not dramatic, particularly as the placebo showed 12% improvement. Shares of competitor Genfit, trading on European exchanges, rallied sharply on the Intecept news and closed up 12%, at the high of the day. Genfit’s dual PPAR agonist is in p3 and is due to have a preliminary readout in the second half of 2019. Genfit shareholders were likely encouraged by the relatively tight difference between OCA and placebo, and expect that Genfit’s elafibranor may improve on that margin. Shares of Allergan (in p3 with CCR2/CCR5 cenicriviroc) and Gilead (awaiting readout on its second p3 trial with selonsertib) both closed lower today. Please see our NASH competitive landscape. For additional analysis and commentary, we also point toward STAT’s Adam Feuerstein’s summary of these results.
--by Martin Kurian, Ann Carracher, and Kelly Close