Topline Results for TRILOGY 1 Phase 3 Trial of CaPre Reported by Acasti Pharma
Posted on January 14, 2020
Acasti Pharma Inc. (“Acasti or the “Company”), a biopharmaceutical innovator focused on the research, development and commercialization of its prescription drug candidate CaPre® (omega-3 phospholipid) for the treatment of severe hypertriglyceridemia (triglyceride blood levels from 500 mg/dL to 1500 mg/dL), today announced topline results for the Primary Endpoint (triglyceride reduction at 12 and 26 weeks) from its Phase 3 TRILOGY 1 trial for the Company’s lead product candidate, CaPre.
The Company reported a 30.5% median reduction in triglyceride levels among all patients receiving CaPre, compared to a 27.5% median reduction in triglyceride levels among patients receiving placebo at 12 weeks. The Company also reported a 42.2% median reduction in triglycerides among patients receiving CaPre while on background statin therapy at 12 weeks, compared to a 31.5% median reduction in triglyceride levels among patients receiving placebo and on background statin therapy. In addition, the Company reported a 36.7% median reduction in triglyceride levels among patients receiving CaPre at 26 weeks (end of the study), compared to a 28.0% median reduction in triglyceride levels among patients receiving placebo. Both the placebo and CaPre study groups experienced significant reductions in triglycerides within the first four weeks from baseline, and even though the difference at 12 and 26 weeks was in favor of CaPre, due to the unexpectedly large placebo response, TRILOGY 1 did not reach statistical significance. The safety profile of CaPre in TRILOGY 1 was similar to placebo, as there were no significant difference in treatment-related serious adverse events in the trial. Results for all of the secondary and exploratory endpoints were delayed as previously reported on December 23, 2019, and are expected to be available by the end of Q1, 2020.
The observed reductions in triglyceride levels in the placebo group were far greater than that seen in any previous triglyceride lowering trial with a prescription omega-3. The placebo used in the TRILOGY trials is simple cornstarch, which is a complex carbohydrate with a low glycemic index, and consequently would be expected to have a neutral effect on key biomarkers of patients in the placebo group. In similar previously conducted triglyceride lowering trials involving prescription omega-3 preparations, 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%.
Given that cornstarch is likely not the root cause for the significant placebo response in TRILOGY 1, the Company is carefully evaluating other possible explanations. The Company has noted that a high placebo response at 5 sites (out of a total of 54 enrolling sites) disproportionately contributed to the overall placebo response, and is being further investigated. A full audit of these sites, including review of all raw data and records from patients taking both CaPre and placebo, will be conducted to identify a possible root cause of the unprecedented placebo effect. This audit is likely to take at least several weeks, with an outcome expected by the end of February 2020. Additional avenues of investigation will include further assessment related to specific continuation or discontinuation of other lipid lowering drugs during screening, and changes in the use of other lipid-lowering medications during the trial. Furthermore, the results of the ongoing TRILOGY 2 trial with CaPre may provide additional important information and insight in this regard. 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, the Company may still have a path forward to file an NDA, and would seek a meeting with the FDA as soon as possible to discuss all of the TRILOGY data, investigational findings, and obtain their input and guidance on next steps.
Dariush Mozaffarian, M.D., Dr.P.H., principal investigator for the study, commented, “Compared with baseline, triglyceride levels in subjects receiving CaPre were substantially lower at 12 and 26 weeks in the CaPre arm, with 30.5% and 37.5% lower levels, respectively. However, these reductions were accompanied by larger than expected declines in triglyceride levels in the placebo group, which remain unexplained and highly unusual. Initial analyses suggest no protocol deviations in treatment allocation, capsule contents, laboratory quality control, or mismatched randomization that could explain these highly unusual placebo results. We are continuing to evaluate the data in detail to assess possible explanations. I am also hopeful that TRILOGY 2 topline data, expected in late January 2020, may provide more insight into this unprecedented placebo response seen in TRILOGY 1.”
Jan D’Alvise, president and CEO of Acasti Pharma, stated, “First, we wish to thank the physicians, study professionals, and of course the 242 patients who dedicated their time to participate in this trial. 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 OM3 hypertriglyceridemia trials. Several hypotheses are being investigated now by our clinical team, and by our CRO and Dr. Mozaffarian. These avenues of investigation are being carefully and rigorously pursued, and we are moving as quickly as possible to try to gain understanding and insight into the large and unexpected placebo response seen in TRILOGY 1. The Company will continue to provide updates on this investigation, as well as topline results for TRILOGY 2 as we get them, to be followed by all secondary and exploratory endpoints for TRILOGY 1 and 2 once the TRILOGY 2 study is completed and fully analyzed.”
Implementation of the TRILOGY 2 study remains on track, with the last patient having completed their final visit late last week. The Company remains blinded to the TRILOGY 2 data. Given the additional focus of critical resources now on TRILOGY 1, there could be a small delay of a couple weeks in reporting topline results for TRILOGY 2 to mid-February 2020. As previously disclosed, key secondary and exploratory endpoints from both studies, would be expected sometime later in the first quarter of 2020.
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