Latest REDUCE-IT Results Bolster Case For Amarin's Vascepa Fish Oil Pill

Data may pave way for inclusion in heart disease treatment guidelines, ACC spokesperson says.

Amarin Corp. PLC's latest results for the prescription-grade fish-oil product Vascepa in the REDUCE-IT cardiovascular outcomes trial presented at the American College of Cardiology (ACC) annual meeting boost the case for the drug's efficacy ahead of a supplemental US filing in a broader patient population.

Vascepa is a proprietary formulation of the omega-3 acid eicosapentaenoic acid (EPA).

Data released on March 18 at the ACC meeting in New Orleans suggest that the drug used on top of statins provides a significant 30% reduction in risk compared with placebo for a composite of first, subsequent and total ischemic events. Investigators also reported a significant 20% reduction in risk for CV death and a 13% numerical risk reduction in total mortality (p-value of 0.09)

An early unedited copy of an article with the data was published the same day by Deepak Bhatt, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, and colleagues in the Journal of the American College of Cardiology (JACC).

The primary composite endpoint included cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization or hospitalization for chest pain related to blockages.

The key secondary endpoint, which is considered more robust, included cardiovascular death, nonfatal MI or nonfatal stroke. And on this measure, the drug was associated with a significant 26% reduction in risk. Vascepa was well-tolerated, with a risk profile in line with the what has been previously reported.

Vascepa is US FDA approved for use as an adjunctive treatment of patients with severe hypertriglyceridemia, defined as 500 mg/dL or above. Amarin plans to submit a supplemental NDA with results from the REDUCE-IT outcomes study, which was designed through a special protocol assessment with the agency, by the end of March in a bid to broaden the patient population.

REDUCE-IT included about 8,000 patients with triglyceride levels between 135 mg/dL and 500 mg/dL. The median triglyceride level at baseline was 216 mg/dL, but the study also included some patients with triglyceride levels as low as 81 mg/dL at baseline. The patients were well-controlled on statins, as evidenced by the median baseline LDL cholesterol (LDL-C) of 75 mg/dL.

Building On Prior Release, Tackling Placebo Question

The company released data for Vascepa at the American Heart Association (AHA) annual meeting in November. (Also see "Amarin's REDUCE-IT Data For Vascepa May Be Game-Changing, But Not Without Controversy" - Scrip, 12 Nov, 2018.) On the primary efficacy endpoint of the study – the first occurrence of a composite of major adverse cardiovascular events (MACE) – the drug was associated with a significant, 25% reduction in risk compared with placebo.

As the first major study of a fish oil product to show a CV outcomes benefit, the study was groundbreaking, though there was controversy about the use of mineral oil as a comparator for placebo as this increased LDL-C, raising questions about whether this was a true placebo.

The JACC paper by Bhatt and colleagues acknowledged that some biomarkers in the placebo arm increased from baseline – median LDL was 5 mg/DL higher in the placebo group versus the Vascepa group – but added that "such changes are common in statin-treated patients within cardiovascular outcome studies."

It's unclear whether that statement along with the consistency of the latest results will be enough to reassure the cardiology community regarding a potentially negative effect in the mineral oil placebo arm that benefited the Vascepa arm of the trial.

Cedars-Sinai cardiologist Sanjay Kaul noted in emailed responses to questions from Scrip that the placebo/mineral oil issue has been brought up twice at the FDA with this compound and was not deemed to be a major issue.

The fact that a benefit was consistently observed in patients with an LDL increase and in those with no LDL increase in the placebo group "suggests this is not a major issue," said Kaul, who has participated as a panelist in agency reviews of cardiovascular drugs.

Consistent Reductions In Risk

In the latest release at the ACC meeting, investigators noted that first events were reduced by 25%, second events by 32%, third events by 31%, and fourth or more events by 48%.

The analysis of recurrent events was pre-specified, but a limitation of the study was that it was an exploratory analysis and one method used to evaluate the data was done on a post hoc basis, the authors acknowledged in the JACC paper.

A total of 159 primary endpoint events were prevented in the course of the five-year study, including 12 cardiovascular deaths and 42 heart attacks.

"The times to first occurrence, second occurrence, third occurrence, or fourth occurrence of the primary composite endpoint were consistently reduced with icosapent ethyl," Bhatt and colleagues wrote.

"Patients don’t care just about the first event, they care about the second event especially if that one happens to be a fatal one, but even otherwise," Bhatt said during an ACC press briefing, adding that from an insurance, health economics and public health perspective the intervention would have a "very large impact."

The wholesale acquisition cost (WAC) for Vascepa in 2019 is $303.65 per month and Amarin stressed there are "numerous discounts and rebates" negotiated in the supply chain as well as coupon programs to help patients with out-of-pocket costs. Amarin reported $228m in product sales for 2018.

Bhatt also highlighted results for people in the study with a baseline triglyceride level as low as 81 mg/dL, which is lower than what might be considered the target treatment population for the drug. Study participants with a baseline triglyceride between 81 mg/dL and 190 mg/dL had a 26% reduction in risk for the primary endpoint. That compares with 23% risk reduction for those with baseline between 190 mg/dL to 250 mg/dL, and 40% risk reduction where the baseline was between 250 mg/dL and 1,401 mg/dL.

Bhatt and two other clinicians – Duke Clinical Research Institute's Ann Marie Navar and Boston University's William Boden – questioned whether the threshold for what is considered a high level of triglycerides needs to be lowered during an investor call held by Amarin on March 18 after the market closed.

Discussing the study during the press briefing, University of Florida Research Professor Eileen Handberg said that patients with cardiovascular disease have multiple events and continuing to reduce that risk over time is extremely important.

These analyses are not that commonly done, but should be done in all trials with MACE outcomes, Handberg said, noting that REDUCE-IT represents a kind of paradigm shift for clinical trial reporting.

JACC authors credited the efficacy benefit to high EPA levels, in contrast with other fish oil products, which are composed of EPA and docosahexaenoic acid (DHA). (Also see "Amarin Says REDUCE-IT Results Are Off Limits To Omega-3 Supplement Claims" - Pink Sheet, 5 Nov, 2018.)

"EPA has unique lipid and lipoprotein, anti-inflammatory, anti-platelet, anti-thrombotic, and cellular modifying effects, all of which may contribute to benefits in atherosclerotic processes such as reduced development, slowed progression, and increased stabilization of atherosclerotic plaque," the JACC paper noted.

Kaul described the time-to-first events of REDUCE-IT as "quite impressive" given that they came on top of optimal medical therapy with pre-treatment LDL levels (75 mg/dL) among the lowest recorded in LDL trials; he said the recurrent event results were "along expected lines."

"The results of this recurrent event analysis show that the benefits are preserved (for the more robust secondary endpoint of CV death, MI or stroke), and to some degree amplified (for the less robust primary endpoint), when all events are accounted for, thereby capturing the totality of treatment benefit," Kaul said.

He added that regulatory agencies appear to be "increasingly supportive of an analysis strategy based on recurrent events." For example, the primary endpoint of the PARAGON-HF study of Novartis AG's Entresto (sacubitril/valstartan) in heart failure was the cumulative number of primary composite events of cardiovascular death (first and recurrent) and total heart failure hospitalizations, he noted.

Hadley Wilson, an interventional cardiologist at the Sanger Heart and Vascular Institute and a member of the ACC Board of Trustees, said that the study provides evidence for another agent that can be used in people with hypertriglyceridemia and lipid problems. It may also pave the way for inclusion in treatment guidelines, he said.

The ACC/AHA released new guidelines for primary prevention of heart disease and Vascepa was not included. The next version is may be released in a year or more.

Joint ACC/AHA guidelines for managing cholesterol released last November also left Vascepa out and it is unclear when they will be revised. (Also see "New US Cholesterol Guidelines Hit PCSK9s Hard On Pricing, Value" - Scrip, 19 Nov, 2018.)