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REDUCE-IT® EPA Encore Presentation reinforces Eicosapentaenoic Acid (EPA) levels from VASCEPA® (icosapent ethyl) strongly correlated to cardiovascular outcomes, more so than other biomarkers
VASCEPA COVID-19 CardioLink-9 Randomized Trial suggests improvement in outpatient-reported COVID-19 symptoms while achieving its primary endpoint by demonstrating a 25% reduction in high-sensitivity C-reactive protein (hsCRP) with encouraging short-term safety and tolerability data using VASCEPA loading dose
Amarin to Webcast Discussion of Presented Data Today, Monday, December 14, 2020 at 8:00 a.m., Eastern Standard Time
DUBLIN, Ireland and BRIDGEWATER, N.J., Dec. 14, 2020 (GLOBE NEWSWIRE) -- Amarin Corporation plc (NASDAQ:AMRN) today announced the presentation of important VASCEPA® (icosapent ethyl)-related scientific findings during the National Lipid Association (NLA) Scientific Sessions 2020, held virtually from December 10 – 12, 2020, from a variety of academic collaborators and based on research or analyses supported by Amarin.
“We are privileged to have supported several important presentations at NLA Scientific Sessions 2020, including two Late Breakers,” said Steven Ketchum, Ph.D., senior vice president and president, research & development, and chief scientific officer, Amarin. “We continue to forge ahead with scientifically-driven evidence of the uniqueness of VASCEPA in cardiovascular risk reduction while providing support to investigators exploring other ways in which VASCEPA can potentially improve public health while potentially lowering the cost of patient care.”
These presentations were on the following topics:
1. Late Breakers
Highlights: Following administration of VASCEPA, a pure, stable, unique prescription eicosapentaenoic acid (EPA)-based therapy at 4 g/day in the successful REDUCE-IT cardiovascular outcomes study, analysis shows that median serum EPA levels increased in year 1 to well over 100 ug/mL (144 μg/mL; p=1x10-30) and increased approximately 400% across the study from baseline (26.1 μg/mL) versus placebo. Docosahexaenoic acid (DHA) levels were measured and showed a decrease of 2.9% (p=0.002).
On-treatment EPA levels in the VASCEPA group were found in these analyses to be associated strongly with reduced cardiovascular events, including benefits observed in the primary (5-point MACE, consisting of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina) and key secondary (3-point MACE, consisting of cardiovascular death, myocardial infarction, and stroke) endpoints.
“These analyses suggest that achieved EPA levels with 4 g/day of icosapent ethyl is a marker for the majority of the relative risk reduction observed in REDUCE-IT,” said Michael Miller M.D., University of Maryland Medical System, Baltimore, MD. “The EPA levels achieved in REDUCE-IT were well above levels that can be achieved with diet or with dietary supplements and the clinical results have not been demonstrated by any other agent, reflecting the uniqueness of this FDA-approved prescription therapy.”
Highlights: The VASCEPA COVID-19 CardioLink-9 Trial was a randomized, open-label trial enrolling 100 SARS-CoV-2 positive and symptomatic outpatients displaying at least one of the following: fever, cough, sore throat, shortness of breath, myalgia. Patients in the VASCEPA arm received a loading dose of 8 g/day for 3 days followed by 4 g/day for 11 days on top of usual care. Patients randomized to the non-active arm received usual care. Baseline characteristics were comparable between groups.
The primary biomarker endpoint of the study was within-group changes in high-sensitivity C-reactive protein (hsCRP), a measure of inflammation. Within-group changes in D-dimer were also examined. VASCEPA administration resulted in a 25% reduction in hsCRP (p=0.011) as well as a reduction in D-dimer (p=0.048).
In addition to these biomarker changes, assessment was made of COVID-19 symptom changes from baseline to 14 days in the influenza patient-reported outcome (FLU-PRO) score, a validated patient-reported outcome measure designed to evaluate the presence, severity and duration of flu symptoms in clinical trials. VASCEPA administration resulted in a significant 52% reduction of the total FLU-PRO prevalence score as compared to a 24% reduction in the usual care group (p=0.003 between groups), with reductions across individual score domains, including a significantly larger reduction compared to usual care in the body/systemic domain (54% vs. 26%; p=0.003). Significant reductions in the FLU-PRO symptom score compared to usual care were also observed in the total symptom score (p=0.003), as well as in the body/systemic (p=0.0007) and chest/respiratory (p=0.01) domains.
Limitations of this study include the modest sample size, the unblinded nature of this randomized trial, and that the trial was not powered for clinical events. These results have not yet been published or reviewed by regulatory authorities. Additional study is needed.
This randomized trial represents the first human experience with an 8 g/day loading dose of icosapent ethyl and has suggested short-term safety and tolerability in a modest sample size. Regarding COVID-19, this study provides the first evidence of potential early anti-inflammatory effect of icosapent ethyl in symptomatic, COVID-19 positive outpatients.
Amarin added that the VASCEPA COVID-19 CardioLink-9 trial is the first in a series of ongoing investigator-sponsored studies into the potential role of VASCEPA therapy in COVID-19 settings. Other ongoing trials include PREPARE-IT: Prevention of COVID19 With EPA in Healthcare Providers at Risk - Intervention Trial sponsored by Estudios Clínicos Latino América, and A Pragmatic Randomized Trial of Icosapent Ethyl for High-Cardiovascular Risk Adults (MITIGATE) sponsored by Kaiser Permanente.
“This randomized trial represents the first human experience with a loading dose of icosapent ethyl and has demonstrated short-term safety and tolerability in a modest sample size,” commented Deepak L. Bhatt, M.D., M.P.H., Executive Director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School, principal investigator of VASCEPA COVID-19 CardioLink-9 and REDUCE-IT. “Regarding COVID-19, this study provides the first evidence of an early anti-inflammatory effect of icosapent ethyl in symptomatic, COVID-19 positive outpatients. The large and significant improvement in patient-reported symptoms may provide a safe, well-tolerated, and relatively inexpensive option to impact upon COVID-19-related morbidity, though these results should be confirmed in a bigger trial.”
Amarin thanks the patients, investigators, support staff, and all others involved in the VASCEPA COVID-19 CardioLink-9 study.
2. Other Amarin-supported REDUCE-IT abstracts presented include:
Highlights: In the REDUCE-IT USA subgroup, 3,146 patients (38.5% of the full trial cohort) were randomized and followed for a median of 4.9 years. This prespecified REDUCE-IT subgroup analysis showed robust risk reductions in the USA patients treated with icosapent ethyl 4 g/day versus placebo across all prespecified composite and individual primary and secondary endpoints, including 31% relative risk reduction and 6.5% absolute risk reduction in first occurrence of 5-point major adverse cardiovascular events (MACE), corresponding to a number needed to treat of 15 (NNT=15), and a significant 30% relative and 2.6% absolute risk reduction (NNT=38) in all-cause mortality in the USA subgroup. Safety and tolerability findings in the USA subgroup were consistent with the full study cohort.
Additional prespecified cardiovascular endpoints in which the REDUCE-IT USA subgroup showed significant relative risk reduction included myocardial infarction, cardiovascular death, and stroke, similar to the full cohort in the overall REDUCE-IT global results. These results were incremental to the cardiovascular risk reduction achieved by conventional therapy administered to the high-risk patients studied, including incremental to statin therapy.
3. Other Amarin-supported abstracts providing mechanism of action insights include:
Highlights: This study compared the effects of EPA and mixed omega-3 fatty acid (O3FA) supplement on membrane structure and cholesterol crystalline domain formation under conditions of hyperglycemia and oxidative stress. Membranes containing either EPA or the mixed O3FA supplement had a structure characterized by normal cholesterol distribution prior to oxidation. EPA preserved normal membrane structure and cholesterol distribution while reducing lipid oxidation under conditions of hyperglycemia in a manner that was not reproduced with a DHA-containing mixed O3FA supplement. These data indicate a unique hydrocarbon chain length and number of unsaturated fatty acids for EPA that preserves membrane structure and cholesterol distribution under conditions of hyperglycemia and oxidative stress.
Highlights: This study compared the treatment effects of EPA, DHA and the omega-6 fatty acid arachidonic acid (AA) on endothelial cell (EC) functions and fatty acid composition. ECs treated with EPA, but not DHA or AA, had significantly greater nitric oxide/peroxynitrite (NO/ONOO−) release ratio at all time points with an average increase of 37%, and only EPA treatment also increased NO levels at all time points compared with vehicle. These findings support a preferential benefit of EPA on an index of EC function that correlates with its rapid metabolism without increases in AA levels. While DHA and AA levels increased with treatment, there was no correlation of either with improved EC function.
Highlights: This study tested the effects of EPA on protein expression in human pulmonary endothelial cells (ECs) under conditions of inflammation using the cytokine interleukin-6 (IL-6). Human lung microvascular ECs pretreated with EPA and then challenged with IL-6 showed down-regulation of >60 proteins compared with untreated controls. Among the proteins significantly down-regulated by EPA was angiotensin-converting enzyme (ACE) by 3-fold (p
