麻豆传媒

Pooled analysis of two failed parallel trials of the investigational omega-3 fatty acid formulation derived from krill (dubbed CaPre) succeeded in showing reduced triglycerides among patients with severely elevated levels.

Among the two trials' combined 520 patients, triglycerides dropped 26.0% compared with 15.1% among placebo-treated patients from baseline to 12 weeks (mean treatment difference -10.9%, 95% CI -20.4% to -1.5%, P=0.02).

For the key secondary endpoint, this change at 26 weeks was 33.5% versus 20.8% (mean treatment difference -12.7%, P=0.02), Dariush Mozaffarian, MD, DrPH, of Tufts Friedman School of Nutrition Science and Policy in Boston, and colleagues reported in .

The two trials -- TRILOGY 1 and 2 (Study of CaPre in Lowering Very High Triglycerides) -- had both missed on the primary analysis for the 12-week primary endpoint.

"As reported by the sponsor, although TG [triglyceride] levels were lowered in the active treatment group in both trials, these differences did not achieve statistical significance compared with placebo in either individual trial owing to larger than expected reductions in TG levels in the placebo groups," the researchers noted.

Acasti Pharma, which is developing the drug, was not planning to do further trials or file for regulatory review after the disappointing news from the second trial, the company had stated in a in mid-2020.

"Based on what we have seen in the preliminary topline data, we believe TRILOGY 2 was likely not affected by the same 'Pre-Randomization Triglyceride Normalization' effect that we saw in TRILOGY," Acasti CEO Jan D'Alvise, had said at the time in the release. "While the triglyceride reduction observed in the control arm was less than what was observed in the Trilogy 1 Study, it still remains one of the highest seen amongst the previously conducted triglyceride reduction studies, and may be explained by the excellent background standard of care that is being provided to these patients today."

In the pooled analysis, the researchers pointed to potential evidence of the same.

"We found that participants in the placebo group who experienced larger TG level reductions after randomization were also more likely to show a large increase in TG after the initial screening visit but before randomization," the team wrote. "This suggests that the placebo-group reduction in TG levels may in part be associated with regression toward the mean among patients who had less stable or less severe hypertriglyceridemia at baseline."

The exploratory pooled analysis was planned after both trials finished but before any of their data had been pooled.

The phase III trials had an identical design with double-blind randomization to 4 g per day of krill oil (including 1.24 g/d of eicosapentaenoic acid and docosahexaenoic acid or matched placebo in patients ages 18 years or older with fasting triglycerides levels at 500 to 1500 mg/dL at baseline). TRILOGY 1 enrolled only at U.S. centers; while TRILOGY 2 enrolled patients in Canada and Mexico as well.

Use of fibrates, statins, PCSK9 inhibitor, ezetimibe (Zetia), or any combination thereof was allowed as long as the dose was stable.

After concerns about the mineral oil placebo in the REDUCE-IT trial of icosapent ethyl (Vascepa), the TRILOGY trials used cornstarch, "selected to be relatively inert compared with lipid-based or mineral oil placebos," Mozaffarian's group wrote.

The pooled analysis didn't turn up any subgroups with differential effects of the krill oil pill, nor were there any safety concerns noted by the researchers, who called the safety profile similar to that of placebo. The treatment didn't significantly raise LDL cholesterol or ApoB levels compared with placebo.

Among the secondary endpoints, the investigators noted: "At both 12 and 26 weeks, approximately 1 in 9 patients in the omega-3–PL/FFA [phospholipid esters and free fatty acids] group achieved TG levels of less than 500 mg/dL, providing a number needed to treat 11 patients for 1 more patient to achieve this goal."

Comment