Acasti blames phase 3 lipid-lowering flop on placebo response

A krill, the crustacean from which Acasti derives CaPre (Øystein Paulsen/CC BY-SA)

A phase 3 trial of Acasti Pharma’s omega-3 drug CaPre has missed its primary endpoint, denting its hopes of challenging Amarin’s Vascepa for the hypertriglyceridemia market. Yet, Acasti still thinks its drug has a chance, pointing to the reduction in triglyceride levels in the placebo group to explain the failure.

CaPre, like Vascepa, is an omega-3-based drug designed to reduce triglyceride levels in patients who are at increased risk of cardiovascular disease. Acasti moved CaPre into phase 3 in the belief that its use of krill oil as a starting material will result in more efficient transport of EPA and DHA omega-3s, leading to improved absorption and decreased synthesis of LDL cholesterol.

To test the idea, investigators enrolled 242 patients with severe hypertriglyceridemia and randomized them to take CaPre or placebo once a day for 26 weeks. 

After 12 weeks, triglyceride levels in the CaPre arm were down 30.5%. The figure compares favorably to the performance of Vascepa, which Amarin linked to a 27% reduction in triglycerides during its development. However, the reduction in triglycerides associated with CaPre was scarcely better than the performance of placebo, which Acasti’s study linked to a 27.5% drop in the lipids. 

Similarly small differences between the CaPre and placebo results were seen in related endpoints, which tracked subjects out to 26 weeks and looked at a subpopulation of patients on background statins. Acasti is still waiting on results for other secondary and exploratory endpoints due to a delay in data processing.

Acasti thinks the available data reveal an unusually strong placebo effect. Most of the omega-3 trials assessed by Acasti linked placebo to decreases in triglyceride levels of no more than 10%. The biggest decline across the assessed studies was 17%. In the Vascepa study discussed above, the triglyceride levels of people in the placebo arm increased by 10%. 

The search for an explanation for the 27.5% reduction seen in the CaPre placebo arm has led Acasti to zero in on five of the 54 sites that enrolled patients in the trial. Acasti found the five study sites “disproportionately contributed to the overall placebo response,” prompting it to start auditing the raw data and patient records gathered at those locations. 

Acasti expects to have the findings of the audit next month. The biotech may also look into whether patients continued or discontinued other lipid-lowering drugs during screening or the trial itself as it searches for an explanation for the placebo response.

If the investigation yields a plausible explanation, Acasti thinks it may still have a path to a filing for FDA approval of CaPre. The availability of that path depends on the successful outcome of a second phase 3 that is due to deliver top-line data later this month. Investors took a bleaker view of the situation, wiping two-thirds off Acasti’s market cap.

Acasti released the results on the same day AstraZeneca revealed it had stopped a phase 3 trial of its omega-3 drug, Epanova, as the independent data monitoring committee found it was unlikely to succeed. Shares in Amarin climbed slightly following the failures of two would-be rivals.