Shares in Acasti Pharma plunged as much as 67% on Monday after the company reported that a Phase III study of CaPre (omega-3 phospholipid) in severe hypertriglyceridaemia failed to meet its primary endpoint. CEO Jan D’Alvise remarked "while we are encouraged by the magnitude of reduction in triglyceride levels seen among patients receiving CaPre, the large placebo effect was completely unexpected, and was about double what was seen in all other therapeutic [omega-3] hypertriglyceridaemia trials."
The TRILOGY 1 trial involved 245 patients with triglyceride levels between 500 mg/dL and 1500 mg/dL who were randomised to receive four capsules of the krill-oil-derived drug administered once a day for 26 weeks, or placebo. The primary outcome measure was change in fasting triglyceride levels from baseline to week 12. Secondary goals looked at change from baseline in non-HDL, VLDL, HDL and LDL cholesterol levels at week 12, while the study also assessed several other outcome measures as well.
Top-line results showed that patients given CaPre had a 30.5% median reduction in triglyceride levels, compared to a 27.5% reduction for placebo at 12 weeks. Among patients receiving background statin therapy, the median reduction was 42.2% in the CaPre group versus 31.5% for placebo. At 26 weeks, the company reported a 36.7% median reduction in triglyceride levels among CaPre-treated patients, compared to 28% for those on placebo. Acasti noted that both the CaPre and placebo arms of the TRILOGY 1 trial achieved significant reductions in triglycerides within the first four weeks from baseline, and "even though the difference at 12 and 26 weeks was in favour of CaPre, due to the unexpectedly large placebo response, [the study] did not reach statistical significance."
Acasti is evaluating possible explanations for the discrepancy, noting that the simple cornstarch used as placebo in TRILOGY 1 is unlikely to be the root cause for the high placebo response, which was seen at five of a total of 54 enrolling sites and "contributed disproportionately" to the overall placebo response. Findings from the review are expected by the end of February. Acasti noted that "in similar previously conducted triglyceride lowering trials involving prescription omega-3 preparations," including GlaxoSmithKline's Lovaza, Amarin's Vascepa and AstraZeneca's Epanova, the placebo responses using corn oil, olive oil, or vegetable oil "ranged from a change of +16% to -17% across 18 interventions arms, with 14 of 18 arms ranging between +10% to -10%."
The company is now awaiting results from the ongoing TRILOGY 2 trial, which are expected by the end of the month. It added that "if one or more of these investigations provide a plausible explanation as to what may have influenced the placebo arm, and assuming the primary endpoint reaches statistical significance in TRILOGY 2, [we] may still have a path forward" to file a US marketing application for CaPre.
The CaPre news coincides with AstraZeneca announcing Monday that it is ending a cardiovascular outcomes study for Epanova due to a "low likelihood" of demonstrating a benefit in certain patients with mixed dyslipidaemia. Meanwhile, the FDA recently expanded approval of Vascepa to include lowering the risk of cardiovascular events in adults with triglyceride levels of 150 mg/dL or more.