Intercept can claim to have conducted the first ever positive Phase III trial in NASH. By showing obeticholic acid (Ocaliva, OCA) caused a ≥ 1 improvement in fibrosis stage, Intercept’s REGENERATE trial is a significant breakthrough. Amid the good news, there are several problems to consider.

  • Only a small proportion of patients benefited.
  • It caused a rise in cholesterol.
  • It caused adverse events, particularly severe itching.

It is possible for liver fibrosis to resolve with lifestyle modification and time, and this effect was observed in REGENERATE: 23.1% of 25mg obeticholic acid patients achieved fibrosis improvement by one or more stages, while 11.9% achieved this goal in the placebo group. Liver fibrosis is classified into only 4 stages, and improvement by 1 stage is a highly sought-after clinical result, but only working in 10-20% of patients isn’t going to transform treatment in this space.

One of the strongest, most familiar targets we have to reduce CV risk is LDL-cholesterol (LDL-C), and most patients eligible for obeticholic acid will have a LDL-C target of <70mg/dL. In REGENERATE, obeticholic acid showed a peak increase in LDL-C of 22.6 mg/dL at 4 weeks, that subsequently reversed. Although problematic, I think it can still get approved despite this effect; regulators will gain more certainty in its long-term CV-safety from the final years of the REGENERATE trial. However, if specifically called out on its FDA label, a rise in LDL-C is going to look bad to the eyes of many physicians.

The most common adverse event reported was dose-related pruritus (itching), occurring in 51% of patients treated with 25mg obeticholic acid. Given that 19% of the placebo group reported itching, it is perhaps more sensible to measure severe itching. Severe itching occurred in <1% of placebo, and 5% in 25mg obeticholic acid groups. Further, 3% of the 25mg obeticholic acid group experienced gallstones or cholecystitis compared to <1% on placebo. Severe side effects occurring in less than 5% of patients should not prevent obeticholic acid getting approved in NASH, but in the context of a, chronic disease that is not usually acutely dangerous, tolerability issues will likely hinder its prescription rates and persistence.

After the STELLAR-4 trial of rival drug, Gilead’s selonsertib, missed its primary endpoint earlier this month, obeticholic acid looks favourite to be first-to-market in NASH. All eyes are now on another critical trial read-out in this action-packed development space: selonsertib’s STELLAR-3, expected 1Q 2019.

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