Clinical trials for two separate omega 3 products have encountered major obstacles in their search for conclusive results. Following the discontinuation of a trial for AstraZeneca’s omega 3 carboxylic acids – dubbed Epanova – the company anticipates a write-down of up to US$100 million relating to inventories, which could impact its core earnings in the fourth quarter of 2019. Meanwhile, Acasti Pharma’s TRILOGY 1 Phase 3 Trial of CaPre – an omega 3 phospholipid – found no statistical significance. This has been attributed to an unusually large placebo effect, with further analysis underway.

“Patients with mixed dyslipidaemia (MDL) frequently have multiple cardiovascular disease (CVD) risk factors. They are also at an enhanced risk of developing atherosclerotic disease and cardiovascular events. We wanted to explore whether Epanova would benefit these patients,” Rahul Agrawal, Vice-President, Global Medicines Leader, Cardiovascular at AstraZeneca, tells.

However, the Phase III STRENGTH trial was determined to have a low likelihood of demonstrating a benefit to patients with MDL who are at increased risk of CVD. This led an independent data monitoring committee to recommend the closure of the trial.

The large-scale global trial aimed to compare the safety and efficacy of 4 g daily Epanova to a placebo in the form of corn oil, both in combination with standard-of-care statin medicines. The trial commenced in 2014, with a total of 13,086 patients being enrolled at 675 sites in 22 countries.

Epanova is a fish oil-derived mixture of free fatty acids primarily composed of EPA and DHA. It is approved in the US and indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridaemia. The company highlights that indication is not impacted by the data from the STRENGTH trial.

“The data from the trial will be further analyzed to fully understand the findings and will be made available at a future medical meeting. We are continuing to evaluate the data to inform future decisions about Epanova,” notes Agrawal.

An unusual placebo effect
In another blow to the omega 3 sector, Acasti Pharma’s test of CaPre for the treatment of severe hypertriglyceridemia did not come to any statistically significant conclusions. The topline results for the primary endpoint reveal that at 12 weeks – although there was a 30.5 percent median reduction in triglyceride levels among all patients receiving CaPre – those receiving the cornstarch placebo had a 27.5 percent median reduction.

Additionally, there was a 42.2 percent median reduction in triglycerides among patients receiving CaPre while on background statin therapy at 12 weeks, compared to a 31.5 percent median reduction in triglyceride levels among patients receiving a placebo and on background statin therapy. Furthermore, the company reported a 36.7 percent median reduction in triglyceride levels among patients receiving CaPre at 26 weeks (the end of the study), compared to a 28.0 percent median reduction in triglyceride levels among patients receiving placebo.

Acasti Pharma says that cornstarch is not likely to be the root cause of the unexpectedly large placebo effect. Therefore, the company is now carefully evaluating other possible explanations. It has been observed that a high placebo response at five sites (out of a total of 54 enrolling sites) disproportionately contributed to the overall placebo response, and is being further investigated.

“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, may provide more insight into this unprecedented placebo response seen in TRILOGY 1,” says Dariush Mozaffarian, principal investigator for the study.

Jan D’Alvise, President and CEO of Acasti Pharma, adds that the company will continue to provide updates on this investigation, as well as topline results for TRILOGY 2. This will 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. Meanwhile, the results of all of the secondary and exploratory endpoints of TRILOGY 1 are expected to be available by the end of the first quarter this year.

Omega 3 has been the subject of controversy in recent months. Last November, a study found that omega 3 supplements improve attention among children with Attention Deficit Hyperactivity Disorder (ADHD), but only among those with pre-existing low levels of omega 3 in their blood. However, the study faced criticism. One researcher noted that it is important to recognize that this study did not find any benefit of fish oil supplementation over placebo on ADHD symptom levels or emotional problems among participants, while another critiqued the study’s operationalization.

Last month, experts also warned that omega supplementation is not a universal health solution, while advocating for more product transparency and greater consumer education.