The next prespecified secondary endpoint in the hierarchy, and the only such endpoint that did not achieve statistical significance, is as follows:
| | • | | Total mortality, which includes mortality fromnon-cardiovascular and cardiovascular events: 13% RRR (HR, 0.87; 95% CI,0.74-1.02; p=0.09) |
Baseline demographics: Patients qualified to enroll inREDUCE-IT hadLDL-C between41-100 mg/dL (median baselineLDL-C 75 mg/dL) controlled by statin therapy and various cardiovascular risk factors including persistent elevated triglycerides (TGs) between135-499 mg/dL (median baseline 216 mg/dL) and either established cardiovascular disease (secondary prevention cohort) or age 50 or more with diabetes mellitus and at least one other CV risk factor (primary prevention cohort). Approximately 59% of the patients had diabetes at baseline and approximately 71% of the patients had established cardiovascular disease at time of enrollment.
Safety: Excluding the major adverse CV events (MACE) results described above, overall adverse event rates inREDUCE-IT were similar across the statin plus Vascepa and the statin plus placebo treatment groups. There were no significant differences between treatments in the overall rate of treatment emergent adverse events or serious adverse events leading to withdrawal of study drug. The one serious adverse event occurring at a frequency of >2% was pneumonia which occurred at a numerically higher rate in the statin plus placebo treatment group (2.9%) than in the statin plus Vascepa treatment group (2.6%). Adverse events occurring in 5% or greater of patients and more frequently with Vascepa than placebo were peripheral edema (6.5% Vascepa patients versus 5.0% placebo patients), constipation (5.4% Vascepa patients versus 3.6% placebo patients), and atrial fibrillation (5.3% Vascepa patients versus 3.9% placebo patients). There were numerically more serious adverse events related to bleeding in the statin plus Vascepa treatment group although overall rates were low with no fatal bleeding observed in either group and no significant difference in adjudicated hemorrhagic stroke or serious central nervous system or gastrointestinal bleeding events between treatments. In summary, Vascepa was well tolerated with a safety profile generally consistent with clinical experience associated withomega-3 fatty acids and currentFDA-approved labeling of such products.
Subgroups and otherREDUCE-IT information: PositiveREDUCE-IT results were consistent across various patient subgroups, including female/male,diabetic/non-diabetic and secondary/primary prevention. At baseline, approximately 59% and 71% of the patients had diabetes and established cardiovascular disease, respectively. Approximately 71% of the patients studied were classified as Westernized with the largest cohort from the United States. Vital status was obtained for 99.8% of the patients randomized supporting robust trial results.
Differentiated result and mechanism of action: The success ofREDUCE-IT is distinct from past failures to show significant benefit of other agents that lower triglyceride levels when studied on top of statin therapy, including mixtures ofomega-3 fatty acids, fenofibrates, niacin and CETP inhibitors. InREDUCE-IT, the median change in triglyceride levels from baseline to year one was-18.3%(-39 mg/dL) for Vascepa and +2.2% (4.5 mg/dL) for placebo; placebo-corrected median change from baseline of-19.7%(-44.5 mg/dL; p=<0.001). As expressed inThe New England Journal of Medicine publication, at least some of the reduction in MACE demonstrated by Vascepa inREDUCE-IT is likely explained by metabolic effects other than triglyceride lowering.3
The active pharmaceutical ingredient in Vascepa has a unique molecular structure. Vascepa has demonstrated clinical effects that have not been shown for any other product. The clinical effects of Vascepa demonstrated inREDUCE-IT cannot be generalized to any other product.
Mechanisms responsible for Vascepa’s effects in theREDUCE-IT study were not directly evaluated in the outcomes study. Independent ofREDUCE-IT, Amarin has worked to further support theREDUCE-IT hypothesis with published scientific findings based on various degrees of evidence that show that icosapent ethyl may interrupt the atherosclerotic process (e.g., plaque formation and instability) by beneficially affecting cellular functions thought to contribute to atherosclerosis and cardiovascular events and by beneficially affecting lipid, lipoprotein and inflammation biomarkers.4, 5, 6, 7, 8
Scientific presentation: Presentation of theREDUCE-IT results at AHA were made by the Global Principal Investigator and Steering Committee Chair for the study, Deepak L. Bhatt, MD, MPH, Professor of Medicine at Harvard Medical School, Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital Heart and Vascular Center.
Dr. Bhatt stated,“REDUCE-IT establishes a new paradigm for the prevention of important cardiovascular events in statin-treated patients at elevated risk with increased triglycerides. I believe that the results of this study may represent the most significant breakthrough in preventative cardiovascular care since the introduction of statin therapy decades ago.”
Amarin perspective: Commenting on these results from Amarin:
“The robustness and consistency of these clinical results are exciting. Extensive scientific evaluation led to the design and conduct of this study; but the degree of benefit shown with Vascepa nevertheless exceeded our expectation,” stated Steven Ketchum, president of research and development and chief scientific officer of Amarin. “We believe that these positive results identify an important new treatment option to help lower cardiovascular risk in appropriate patients. Cholesterol management lowers cardiovascular risk by25-35%.REDUCE-IT suggests that the residual65-75% cardiovascular risk beyond cholesterol management can be significantly lowered with Vascepa in studied patients. We again thank all of the patients, investigators and others involved in this landmark study.”
“Amarin has spent over $500 million developing Vascepa. We are intently focused on improving patient care. Our priorities are now shifting to educate the world regarding these results so that the pain, loss of productivity and high costs of cardiovascular events can be reduced,” stated John F. Thero, president and CEO of Amarin.
Regulatory Pathway
TheREDUCE-IT study was designed under a special protocol assessment agreement with the U.S. Food and Drug Administration (FDA). Amarin intends to submit an sNDA to the FDA in early 2019 seeking approval to expand the label for Vascepa based on the cardioprotective effect of Vascepa demonstrated in theREDUCE-IT study. FDA’s determination of standard or priority review will be made when the sNDA is submitted. At this time, Amarin is planning for a standard review with potential approval anticipated in late 2019.
Vascepa is Affordably Priced
Vascepa is alow-cost drug. The majority of patients covered by insurance who obtain prescriptions for Vascepa pay a monthlyco-pay charge of $9.99 or less. A patient with commercial insurance can pay as little as $9.00 for a90-day supply prescription of Vascepa.
