Amarin’s Vascepa cuts heart risks in key trial, but placebo noise fuels controversy

Neon heart
Amarin's purified fish-oil drug Vascepa significantly cut major cardiovascular events in key outcomes trial. (Connor Wells/Unsplash)

Some expecting a home-run win from Amarin’s heart drug Vascepa in cardiovascular benefits might leave the American Heart Association annual meeting feeling less excited. The drug did cut heart risks significantly, but the choice of placebo and the effect on results also stirred up debate.

After revealing positive top-line results in late September, Amarin rolled out detailed results on Saturday from the REDUCE-IT trial, showing Vascepa reduced the risks of three major CV events—death, heart attack and stroke—by 26% over placebo.

Calling the results “the most significant breakthrough in preventative cardiovascular care since the introduction of statin,” Harvard Medical School professor Deepak Bhatt, M.D., the study’s principal investigator, said the study could represent a shift in treatment paradigm.

Just as management touted the “robustness and consistency” of the data, though, some saw a problem with the study’s design: The placebo might have caused harm and in turn inflated Vascepa’s effectiveness profile.

RELATED: Believe it: Just as Amarin promised, Vascepa delivers big win in heart-risk study

In the 8,179-subject trial, patients in the control arm received a mineral oil-filled pill to look like Amarin’s purified fish-oil drug. Critics seized upon the fact that these patients saw some key CV biomarkers trending in a bad way that should not be observed with normal placebos, Jefferies analyst Michael Yee noted in a Sunday memo to investors.

Patients who got the dummy pill saw their levels of bad cholesterol—usually associated with higher heart risks—increase around 10% in the first year versus less than 3% changes in the Vascepa group. Level of high-sensitivity C-reactive protein (hsCRP)—an indication of inflammation—also increased 30% in the placebo group.

All these data fueled the debate that the placebo might have added noise to the study results, which couldn’t be fully understood with the current trial design. But in Yee’s view, the controversy “[is] not likely to drive the overall view [Vascepa] is beneficial.”

Investigators did a post-hoc analysis, management noted, according to Yee. It showed that the magnitude of effect on major adverse cardiac events was the same between those whose low-density lipoprotein level increased and those who experienced a decline. That means, “change in LDL had no impact on results,” said Yee, adding that LDL also goes up in many CV outcomes studies, including Sanofi and Regeneron PCSK9 drug Praluent’s Odyssey trial.

As for hsCRP, the 30% could be considered an outlier according to those on the bull case side because the baseline levels are so low that even “a 30% change doesn’t really change the risk profile of the patient,” wrote Yee.

RELATED: Sanofi, Regeneron's Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients

The debate aside, Amarin might be able to count on the data to drive some new growth after all. A survey at AHA after the presentation showed 87% of doctors in the session plan to prescribe “exclusively” Vascepa to all high-risk patients with moderately elevated triglyceride (TG). But as another Jefferies analyst, Biren Amin, noted, that the survey didn’t mention LDL levels.

“We note a key enrollment criterion in REDUCE-IT was LDL >40 and ≤100 mg/dL on stable statin therapy for ≥4 weeks … which represents patients with better controlled LDL,” he wrote in a Monday note to clients. In contrast, Praluent’s benefits, as shown in the Odyssey trial, “were clustered in patients with LDL ≥100 mg/dL.” In this highest LDL group, Praluent cut all-cause mortality by a whopping 29%. Those results led Amin to project that PCSK9s would still be the “go-to agents” for high LDL patients, while Vascepa could capture some of the patients with better LDL.

Amarin is now looking to submit the CV data to the FDA in early 2019 for inclusion on Vascepa’s label. Prior to the AHA meeting, Yee predicated the drug could enjoy peak sales of $2 billion to $3 billion, significantly up from its current $250 million a year.