Amarin says detailed REDUCE-IT results bolster CV risk reduction claims for Vascepa, but some question whether placebo used may have exaggerated benefit

Detailed data from the REDUCE-IT cardiovascular (CV) outcomes study of Amarin's Vascepa (icosapent ethyl) presented at the American Heart Association (AHA) meeting confirmed top-line results showing a relative risk reduction of 25 percent in first occurrence of major adverse CV events (MACE) on a five-point primary composite endpoint. The company also said the fish-oil-derived drug met a key secondary goal of a 26-percent relative risk reduction in three-point MACE in the intent-to-treat population, including a 20-percent reduction in the risk of dying of heart disease. 

"The robustness and consistency of these clinical results are exciting," said Steven Ketchum, president of R&D and chief scientific officer at Amarin, continuing "extensive scientific evaluation led to the design and conduct of this study, but the degree of benefit shown with Vascepa nevertheless exceeded our expectation." The company stated that it plans to seek expanded FDA approval for Vascepa in early 2019 "based on the cardioprotective effect of Vascepa demonstrated in the REDUCE-IT study," with potential approval anticipated late next year.  

The study involved 8179 statin-treated adults with established CV disease or with diabetes and other risk factors, including persistent elevated triglyceride levels of between 135 mg/dL and 499 mg/dL and a median baseline low-density lipoprotein (LDL) cholesterol level of 75 mg/dL. Patients were randomly assigned to treatment with Vascepa twice daily or a placebo containing mineral oil, and were followed for a median of 4.9 years. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularisation or unstable angina. The key secondary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, with additional secondary goals including cardiovascular death, among others. 

Results from the study, which were also published in the NEJM, showed that 17.2 percent of patients in the Vascepa arm experienced a primary endpoint event, versus 22 percent for placebo, translating to a 25-percent risk reduction. Additionally, the rates of three-point MACE in these two groups were 11.2 percent and 14.8 percent, respectively, reflecting a 26-percent reduction in risk.  

Further, in addition to the 20-percent relative risk reduction in cardiovascular death, other secondary endpoint results showed that Vascepa cut the relative risk of cardiovascular death or nonfatal heart attack by 25 percent. The drug was also associated with a 31-percent reduced relative risk of fatal or nonfatal heart attack, as well as a 35-percent lower relative risk of urgent or emergent revascularisation.

However, results from the trial also indicated that LDL levels rose by 10 percent to 84 mg/dL in the placebo group, 6 percent more than for the Vascepa arm. Moreover, patients in the placebo group also saw their C-reactive protein levels jump from 2.1 mg/L to 2.8 mg/L, reflecting an increase of 30 percent. Steven Nissen, chairman of cardiology at the Cleveland Clinic, remarked that the blood test changes observed in the placebo arm could be "a potential factor for driving the results that may result in an exaggeration of the benefits compared to what would be seen if there was a [true] placebo." He suggested "it's about the magnitude of the result…not that the result would completely disappear." 

The researchers commented that "if mineral oil in the placebo affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups." However, they said "the relatively small differences in LDL cholesterol levels between the groups would not be likely to explain the 25-percent lower risk observed with [Vascepa], and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL cholesterol level among the patients in the placebo group." The authors also pointed to a study, dubbed JELIS, of a similar medicine conducted in Japan, noting that "although JELIS was designed as an open-label study that did not use a mineral oil placebo, it showed a 19-percent lower risk of ischaemic events with statin therapy plus EPA [eicosapentaenoic acid, the active ingredient in Vascepa] than with statin therapy alone."

Vascepa was initially approved by the FDA in 2012 to reduce triglyceride levels in adults with severe hypertriglyceridaemia. The company later reached a settlement with the FDA permitting it to promote the treatment for off-label uses. 

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