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American Heart Journal Plus: Cardiology Research and Practice
Volume 17, May 2022, 100148
American Heart Journal Plus: Cardiology Research and Practice
Review article
Differentiating EPA from EPA/DHA in cardiovascular risk reduction
Author links open overlay panelPeter P.TothabM. JohnChapmancKlaus G.ParhoferdJohn R.Nelsone
https://doi.org/10.1016/j.ahjo.2022.100148Get rights and content
Under a Creative Commons licenseOpen access
Highlights
•
Mixed EPA + DHA therapies failed to demonstrate consistent reduction in CV events.
•
Only EPA alone plus statin reduced major CV events, as shown in REDUCE-IT and JELIS.
•
Plasma EPA levels may help explain CV benefit seen with EPA-only therapies.
•
EPA and DHA are distinct biochemically and exert different pharmacologic effects.
•
Future research should evaluate DHA monotherapy in patients with CV disease.
Abstract
None of the clinical trials of omega-3 fatty acids using combinations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were able to show any effect on cardiovascular outcomes, despite reductions in triglyceride levels. In contrast, the Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial (REDUCE-IT), which employed high-dose (4 g) purified EPA, demonstrated a 25% reduction in atherosclerotic cardiovascular disease–related events compared with placebo (hazard ratio 0.75; 95% confidence interval 0.68–0.83; P < 0.001). Moreover, REDUCE-IT is the first clinical trial using a lipid-lowering agent as adjuvant therapy to a statin to show a significant reduction in cardiovascular mortality. Significant reductions in stroke, need for revascularization, and myocardial infarction were also observed. The pharmacology of EPA is distinct from that of DHA, with a differential effect on membrane structure, lipoprotein oxidation, and the production of downstream metabolites that promote the resolution of inflammation. Attained plasma levels of EPA may be an important determinant of efficacy, with a substudy of REDUCE-IT suggesting that the threshold for clinical benefit of EPA is approximately 100 µg/mL, a level achieved in only a minority of patients in other studies. No similar clinical trials of DHA monotherapy have been conducted, so no such threshold has been established. The results of the REDUCE-IT and the Japan EPA Lipid Intervention Study (JELIS) together affirm the efficacy of EPA therapy for cardiovascular disease risk reduction in certain patient populations.
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Keywords
Eicosapentaenoic acidDocosahexaenoic acidOmega-3 fatty acidIcosapent ethylTriglycerideCardiovascular diseases
1. Introduction
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide, and resulted in approximately 1.7 million deaths in the European Union (EU) in 2016 [1]. Although high levels of low-density lipoprotein cholesterol (LDL-C) are recognized as one of the most readily modifiable risk factors for ASCVD, hypertriglyceridemia is also associated with increased risk independent of LDL-C [2], [3], [4]. Statins are central to the management of cardiovascular (CV) disease through lowering of LDL-C levels, but have a relatively modest impact on triglyceride (TG) levels in patients with TG levels <250 mg/dL [5]. Recent longitudinal studies have re-emphasized the need for effective TG lowering, with many patients having residual CV risk despite control of LDL-C levels with statins [6]. However, TG-lowering therapies such as niacin and fibrates have also failed to show any meaningful reduction in the risk of ASCVD events when added to statins [7], [8].
Epidemiologic studies have suggested that populations with even a low to moderate intake of omega-3 fatty acids from fish in their diet have an unexpectedly low rate of CV disease and mortality [9], [10]. As a result, the potential for omega-3 fatty acids to reduce CV risk has long been of interest [11], and a number of omega-3 fatty acid products have been approved and are available (Table 1) [12], [13], [14], [15]. However, mixed omega-3 fatty acid products are not indicated to reduce CV events, with many high-profile trials of mixed omega-3 fatty acid products (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]) failing to show a reduction in ASCVD [16]. In the recent REDUCE-IT trial (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a highly purified formulation of EPA demonstrated a significant risk reduction of ASCVD events in statin-treated patients ≥45 years of age with established CV disease, or ≥ 50 years of age with diabetes mellitus and at least one additional risk factor [17], leading to regulatory approvals for CV event risk reduction [12], [14].
Table 1. Prescription omega-3 fatty acids.
Formulation Product EPA/DHA composition Dose Indication
Icosapent ethyl (ethyl ester of EPA) Vascepaa (US) [14] 1-g capsules containing 998 mg icosapent ethyl 2 × 1-g capsules twice daily with or following a meal To reduce the risk of CV events in adult statin-treated patients with elevated TG (≥150 mg/dL) and established CV disease, or diabetes and at least two other CV risk factors
Vazkepa (EU) [12] To reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated TG (≥150 mg/dL) and established CV disease, or diabetes and at least one other CV risk factor
Omega-3-ethyl esters Lovaza (US) [15]b 1-g capsules containing ≥900 mg PUFA, including EPA 460 mg and DHA 380 mg 4 capsules daily To reduce TG levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia in adjunct to diet
Omacor (EU) [13]c 2–4 capsules daily Treatment of endogenous hypertriglyceridemia as a supplement to diet when dietary measures alone are insufficient to produce an adequate response: as monotherapy or in combination with statins when control of TG is insufficient
CV, cardiovascular; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; EU, European Union; PUFA, polyunsaturated fatty acid; TG, triglycerides; US, United States.
a
Generic versions of Vascepa are available in the US; these generic versions are approved for treatment of severe hypertriglyceridemia (≥500 mg/dL) only.
b
Generic versions of Lovaza are available in the US.
c
Generic versions of Omacor are available in the EU.
2. Early evidence for omega-3 fatty acids and cv risk
It is well established that prescription omega-3 fatty acids can reduce TG levels by ˜20% to 30% in patients with TG levels 200 to 499 mg/dL and by ≥30% in patients with TG levels ≥500 mg/dL [18]. However, early CV outcomes trials failed to show a consistent benefit in CV risk reduction. A likely reason for this is that the dose of omega-3 fatty acids studied was too low. In a recent meta-analysis of 13 trials of omega-3 fatty acids (11 trials of DHA + EPA and 2 trials of EPA monotherapy), including some of the more recent trials reviewed below, the median dose of omega-3 fatty acids was 1000 mg (median EPA, 500 mg; median DHA, 380 mg) [19]. The same meta-analysis found that 1 g/day DHA, taken from combination DHA + EPA products, was associated with a nonsignificant 4% (95% confidence interval [CI] 0.89–1.03; P = 0.27) reduction in major CV events. A statistically significant 7% (95% confidence interval [CI] 0.91–0.95; P < 0.001) reduction in major CV events was observed for a 1 g/day dose of EPA, but more than half of studies did not employ a dose that high [19]. Given the apparent lack of benefit of combination DHA + EPA products in preventing CV disease and death, in 2019 the European Medicines Agency took steps that led to the removal of their indications for secondary prevention of CV disease [20].
Although most of the trials in the meta-analysis failed to demonstrate any CV benefit, the presumed health benefits of EPA and DHA, including supporting the health of the skin, eyes, and CV and central nervous systems, as well as reduced inflammation have led to a proliferation of fish oil dietary supplements. Because the regulation of dietary supplements is less stringent than that required for pharmaceutical products, such as prescription and over-the-counter medications [21], the quality and EPA content of these products can be quite variable. Contaminants such as saturated fats and oxidized lipids, including peroxides and secondary oxidation products, may counter the purported beneficial effects of omega-3 fatty acids by exerting atherogenic and proinflammatory effects within the arterial wall [22], [23].
There continues to be great interest in the use of omega-3 fatty acids for reducing CV risk, including prescription medications and dietary supplements. Here we review recent clinical trial data that shed new light on the best approach for use of omega-3 fatty acids to reduce ASCVD, and offer potential explanations as to why early trials failed, while more recent ones have finally shown promise.
3. Contemporary omega-3 fatty acid outcomes trials
Contemporary CV outcomes trials using omega-3 fatty acids are summarized in Table 2 [17], [24], [25], [26], [27]. Findings from ASCEND (A Study of Cardiovascular Events in Diabetes) and VITAL (Vitamin D and Omega-3 Trial), which used low-dose (≤1 g) formulations, were consistent with earlier studies [26], [27]. ASCEND was conducted in patients with diabetes mellitus, while VITAL was a primary prevention study. Neither trial prospectively included patients with established CV disease or dyslipidemia, and only 75.2% and 34.9% were taking a statin, respectively. Both ASCEND and VITAL failed to show any reduction in CV endpoints (Table 2).
Table 2. Overview of contemporary cardiovascular outcomes trials with omega-3 fatty acids.a, b, c, d
Empty Cell REDUCE-IT [17] STRENGTH [24] OMEMI [25] ASCEND [26] VITAL [27]
Intervention 2?g icosapent ethyl twice daily vs 2?g twice daily mineral oil placebo 4?g/day omega-3 carboxylic acids or 4?g/day corn oil placebo 1.8?g/day (930?mg EPA?+?660?mg DHA) vs 1.8?g/day corn oil placebo 1?g/day (460?mg EPA?+?380?mg DHA) or 1?g/day olive oil placebo 1?g/day (460?mg EPA?+?380?mg DHA) or 1?g/day olive oil placebo
Total number of patients 8179 13,078 1027 15,480 25,871
Entry criteria
•
TG 150–499?mg/dL
•
LDL-C 41–100?mg/dL
•
≥45 years of age with established CV disease
OR
≥50 years of age with diabetes mellitus and ≥1 additional CV disease risk factor
•
Stable statin
•
TG 180–499?mg/dL
•
LDL-C <100?mg/dL or on maximally tolerated statin
•
HDL-C <42?mg/dL for men and <47?mg/dL for women
•
Adult patients with established ASCVD
OR
Type 1 or 2 diabetes (≥40 years of age for men and ≥50 years of age for women) with ≥1 additional CV risk factor
OR
High-risk primary prevention patients (≥50 years of age for men and ≥60 years of age for women) with ≥1 additional CV risk factor
•
Stable statin
•
Patients hospitalized due to acute MI, 70–82 years of age
•
Diabetes mellitus without evidence of CV disease
•
≥40 years of age
•
Men ≥50 years of age and women ≥55 years of age
Patients with established CVD, % 70.7 55.9 100 – –
Concomitant statin, % 100 100 95.2 75.2 34.9
Median baseline metabolic parameters
TG, mg/dL 216 240 111.4a – –
LDL-C, mg/dL 75 75 76.1a – –
Median follow-up 4.9 years 42 months 24 months 7.4 years 5.3 years
Primary endpoint Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina First major CV event, consisting of nonfatal MI, unscheduled revascularization, stroke, or all-cause deathb First serious vascular event (composite of nonfatal MI or stroke, transient ischemic attack, or vascular death excluding intracranial hemorrhage) Major CV events (composite of MI, stroke, and death from any CV cause)
Primary endpoint result, HR (95% CI) 0.75 (0.68–0.83; P?<?0.001) 0.99 (0.90–1.09; P?=?0.84) 1.07 (0.82–1.40; P?=?0.62) 0.97 (0.87-1.08; P?=?0.55)c 0.92 (0.80-1.06)
Components of the primary endpoint, HR (95% CI)
All-cause mortality – – 1.01 (0.54–1.88; P?=?0.98) – –
CV death 0.80 (0.66–0.98) 1.09 (0.90–1.31; P?=?0.37) – 0.81 (0.67-0.99)d 0.96 (0.76-1.21)
MI – – – – 0.72 (0.59-0.90)
Nonfatal MI 0.70 (0.59–0.82) 0.97 (0.81–1.17; P?=?0.77) 1.14 (0.72–1.80; P?=?0.57) 0.93 (0.76-1.14) –
Stroke – – 1.37 (0.65–2.88; P?=?0.41) – 1.04 (0.83-1.31)
Nonfatal stroke 0.71 (0.54–0.94) 1.14 (0.90–1.45; P?=?0.28) – 1.01 (0.84-1.22) –
Transient ischemic attack – – – 1.03 (0.84–1.26) –
Coronary revascularization 0.66 (0.58–0.76) 0.94 (0.83–1.08; P?=?0.41) 0.66 (0.34–1.30; P?=?0.23) – –
Hospitalization for unstable angina 0.68 (0.53–0.87) 0.84 (0.63–1.12; P?=?0.23) – – –
Hospitalization for heart failure – – 1.19 (0.62–2.26; P?=?0.61) – –
Secondary endpoint Composite of CV death, nonfatal MI, or nonfatal stroke Composite of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina in patients with established CV disease at baseline New-onset atrial fibrillation Serious vascular event or revascularization Major CV events plus coronary revascularization
Secondary endpoint result, HR (95% CI) 0.74 (0.65–0.83; P?<?0.001) 0.94 (0.84–1.05; P?=?0.27) 1.84 (0.98–3.44; P?=?0.056) 1.00 (0.91-1.09) 0.93 (0.82-1.04)
Median placebo-corrected percent change in metabolic parameters after 1 year
TG, mg/dL -20.1 -18 -13.2% – –
LDL-C, mg/dL -6.6 +3 -0.7% – –
ASCEND, A Study of Cardiovascular Events in Diabetes; ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; OMEMI, Omega-3 Fatty acids in Elderly with Myocardial Infarction; qd, daily; REDUCE-IT, Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial; STRENGTH, Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia; TG, triglyceride; VITAL, Vitamin D and Omega-3 Trial.
a
Mean.
b
Hospitalization for heart failure was added to the definition of major cardiovascular events.
c
Rate ratio.
d
Vascular death.
The OMEMI (Omega-3 Fatty acids in Elderly with Myocardial Infarction) and STRENGTH (Statin Residual Risk Reduction With Epanova in High CV Risk Patients With Hypertriglyceridemia) trials investigated higher doses of mixed EPA + DHA formulations (1.8 g/day and 4 g/day, respectively), while REDUCE-IT employed a higher dose of pure EPA (icosapent ethyl 4 g/day) [17], [24], [25]. Results from RESPECT-EPA (Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy–Statin and Eicosapentaenoic Acid), which is investigating EPA 1.8 g/day in 3900 statin-treated patients with stable coronary artery disease, are expected in 2022 [28]. Of note, all CV outcomes trials conducted to date have investigated EPA alone or EPA + DHA formulations; there have been no studies of purified DHA, so it is not possible to effectively evaluate its role in prevention of CV disease.
3.1. OMEMI
OMEMI was a multicenter, placebo-controlled, double-blind trial conducted in Norway [25]. A total of 1027 patients, aged between 70 and 82 years with baseline TG approximately 110 mg/dL, and who had been admitted for acute myocardial infarction (MI) were randomized to EPA + DHA 1.8 g/day or placebo; almost all patients were taking a statin at baseline. In the EPA + DHA group, 108 patients (21.0%) experienced a composite primary endpoint consisting of nonfatal MI, unscheduled revascularization, stroke, or all-cause death compared with 102 patients (19.8%) in the placebo group (hazard ratio [HR] 1.07; 95% confidence interval [CI] 0.82–1.40; P = 0.62). There was also no difference between groups for the various components of the primary endpoint. Elderly patients with a recent acute MI who were treated with EPA + DHA 1.8 g/day, therefore, did not have a lower incidence of major adverse CV events or death than those treated with placebo.
3.2. STRENGTH
The double-blind, randomized, multicenter STRENGTH trial randomized 13,078 statin-treated patients at high CV risk to receive EPA + DHA 4 g/day or placebo [24]. High CV risk was defined as either the presence of established ASCVD or type 1 or 2 diabetes (age ≥ 40 years for men and age ≥ 50 for women) with at least one additional risk factor (chronic smoking, hypertension, high sensitivity C-reactive protein [hsCRP] ≥2 mg/L, or moderately high albuminuria). The trial also included high-risk primary prevention patients (age ≥ 50 years for men and age ≥ 60 for women) with at least one additional risk factor (including a family history of premature coronary artery disease, chronic smoking, hsCRP ≥2 mg/L, impaired kidney function, or coronary calcium score > 300 Agatston units). Median baseline TG level was 240 mg/dL. After 54 months of follow-up, there was no difference in the primary composite endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, and hospitalization for unstable angina; overall, 785 patients (12.0%) treated with EPA + DHA and 795 (12.2%) treated with corn oil placebo experienced the primary endpoint (HR 0.99; 95% CI 0.90–1.09; P = 0.84). Therefore, the mixed EPA + DHA formulation had no statistically significant effect on the incidence of major CV events in patients at increased CV risk compared with placebo. Furthermore, patients treated with the mixed EPA + DHA compound had an increased rate of investigator-reported atrial fibrillation compared with those treated with corn oil placebo (2.2% vs 1.3%; HR 1.69; 95% CI 1.29–2.21; P < 0.001).
3.3. JELIS
Thus far, our discussion of clinical trials involving omega-3 fatty acids has largely focused on mixed formulations of EPA plus DHA, which predominantly failed to demonstrate benefit in CV outcomes. Conversely, JELIS (Japan EPA Lipid Intervention Study) emerged as the first prospective randomized clinical trial of a highly purified, EPA-only omega-3 fatty acid to show significant reduction in risk of CV events [29]. The open-label trial included 18,645 Japanese patients with mean TG levels of 1.7 mmol/L who were randomized to receive 1800 mg EPA plus statin or statin alone. The primary endpoint was occurrence of any major coronary event, including sudden cardiac death, fatal and nonfatal MI, and other nonfatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting [30]. The 5-year cumulative rate of major coronary events was 2.8% in the EPA-plus-statin group versus 3.5% in the statin-only group, translating to a 19% (95% CI 0.69–0.95; P = 0.011) reduction in CV events, including a 24% (95% CI 0.62–0.95; P = 0.014) reduction in unstable angina and a 19% (95% CI 0.68–0.96; P = 0.015) reduction in nonfatal coronary events. Overall, reduction in CV events was not significant in the primary prevention group; however, there was a significant 19% (95% CI 0.66–1.00; P = 0.048) reduction in CV events in the secondary prevention group [30].
It is important to note several unique aspects of JELIS, which subsequently helped to inform the design of REDUCE-IT. First, the dose of EPA was relatively low [31], and was administered to patients whose dietary intake of EPA is comparatively higher than in those in other countries. In addition, JELIS was an open-label design without a placebo group. Furthermore, the trial used a low-intensity statin. Finally, the trial was conducted in a single country, which limits generalizability to a wider patient population [30].
3.4. REDUCE-IT
REDUCE-IT was a randomized, double-blind, placebo-controlled trial in 8179 statin-treated patients ≥45 years of age with established CV disease or ≥ 50 years of age with diabetes mellitus and at least one additional risk factor [17]. This study built on the earlier JELIS study that established the potential role of a higher 4 g dose of EPA [30]. Enrolled patients had a fasting LDL-C level of 41–100 mg/dL and the initial fasting TG level inclusion range was 150–499 mg/dL, while the protocol allowed for a 10% lower TG level from the target lower limit to account for intraindividual variability of TG levels, which permitted patients to be enrolled if they had a TG level of at least 135 mg/dL. The first protocol amendment changed the lower limit of the acceptable TG level from 150 mg/dL to 200 mg/dL, with no allowance for variability. Median baseline TG level was 216 mg/dL and median baseline LDL-C level was 75 mg/dL. After a median 4.9 years of follow-up, pharmaceutical-grade, stable EPA (icosapent ethyl) at 4 g/day reduced ASCVD events by 25% compared with placebo (HR 0.75; 95% CI 0.68–0.83; P < 0.001) and reduced total (first and recurrent) events by 30% (HR 0.70; 95% CI 0.62-0.78; P < 0.0001) [32]. In addition, icosapent ethyl was associated with reductions in a number of components of the composite primary endpoint, including death due to CV causes (20% reduction; 95% CI 0.66–0.98; P = 0.03), nonfatal MI (30% reduction; 95% CI 0.59–0.82), and nonfatal stroke (29% reduction; 95% CI 0.54–0.94).
In contrast to ASCEND, patients with diabetes in REDUCE-IT derived significant clinical benefit from icosapent ethyl, with the risk of first and total occurrence of the primary composite endpoint decreased by 23% (95% CI 0.68–0.87; P < 0.001) and 24% (95% CI 0.66–0.88; P < 0.001), respectively, compared with placebo [33]. This result is particularly important because patients with diabetes in the placebo arm had a 1.5-fold greater rate of the primary endpoint than those without diabetes. Patients with established CV disease also had a significant clinical benefit with icosapent ethyl. For those with established CV disease and diabetes, there was a 30% (95% CI 0.59–0.84; P < 0.001) and 28% (95% CI 0.62–0.84; P < 0.001) reduction in the risk of first and total primary events, respectively. Among patients with established CV disease without diabetes, the risk of first composite primary endpoint was reduced by 41% (95% CI 0.49–0.70; P < 0.001), and the risk of total endpoints by 27% (95% CI 0.62–0.85; P < 0.001). Patients with diabetes and/or established CV disease should therefore be considered good candidates for treatment with icosapent ethyl 4 g/day. Further subgroup analyses have been published; a REDUCE-IT analysis in patients with a history of coronary artery bypass grafting (n = 1837) found that icosapent ethyl was associated with a significant reduction in the primary endpoint (HR 0.76; 95% CI 0.63–0.92; P = 0.004) and key secondary endpoint (HR 0.69; 95% CI 0.56–0.87; P = 0.001) [34]. Among patients in REDUCE-IT with prior MI, a similar relative reduction was found for the primary endpoint (HR 0.74; 95% CI 0.65–0.85; P < 0.001) as well as the key secondary endpoint (HR 0.71; 95% CI 0.61–0.84; P < 0.001) [35]. An analysis comparing the treatment effect of icosapent ethyl across the range of kidney function encountered in REDUCE-IT found benefit on the primary endpoint and key secondary endpoint in all estimated glomerular filtration rate (eGFR) groups (eGFR <60 mL/min/1.73m2, 60 to <90 mL/min/1.73m2, ≥90 mL/min/1.73m2), with patients in the <60 mL/min/1.73m2 group having the largest risk reduction in the primary (HR 0.71; 95% CI 0.59–0.85; P = 0.0002) and secondary endpoint (HR 0.71; 95% CI 0.57–0.88; P = 0.001) [36].
The use of a mineral oil placebo in REDUCE-IT has generated controversy, with some commentators suggesting that mineral oil may reduce absorption of certain drugs and raise levels of atherogenic lipoproteins and inflammatory markers such as hsCRP [16], [37]. However, a comprehensive review of 281 papers, including 80 in which mineral oil was used as a placebo, concluded that mineral oil is biologically inert, except when taken in high doses as a lubricant laxative [38]. Critically, mineral oil was found to have no systemic effects. In trials reporting changes in blood lipids and inflammatory markers, changes were mixed and inconsistent, ranging from -16% to +18.5% for TGs and - 6.1% to +9.2% for LDL-C when taken orally. Concerns about the effect of mineral oil on drug absorption are theoretical, with no clinically important drug–drug interactions with statins reported, particularly if the statin and mineral oil are administered separately. An analysis of REDUCE-IT data comparing the primary and key secondary endpoint in subgroups based on lipophilic versus lipophobic statin category found no difference in terms of benefit from icosapent ethyl between groups as evidenced by similar event rates and treatment with statin-type group interaction P values of 0.67 for the primary endpoint and 0.74 for the key secondary endpoint [39]. Findings in mice showed that coadministration of mineral oil (10 or 30 µL) with a single dose of atorvastatin (5 or 10 mg/kg) was associated with a reduction in statin plasma exposure (AUC0-8 ratio 0.81-0.87), whereas repeated dosing of atorvastatin 10 mg/kg with 30 µL of mineral oil resulted in increased statin exposure (AUC0-8 ratio 1.5); the lack of consistent effects suggest mineral oil does not affect the absorption of atorvastatin [40]. Independent regulatory reviews and approvals by the US Food and Drug Administration (FDA), European Medicines Agency, Medicines Healthcare Products Regulatory Agency, and Health Canada support that any effect of mineral oil placebo on the outcomes in REDUCE-IT were clinically insignificant [38], [41], [42].
Based on the results of REDUCE-IT, icosapent ethyl has been approved in the US to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated TG levels (≥150 mg/dL) and established CV disease or diabetes and at least two other CV risk factors [14]. In the EU, icosapent ethyl has been approved to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated TG levels (≥150 mg/dL) and established CV disease or diabetes and at least one other CV risk factor [12], [43]. Icosapent ethyl has also been adopted globally in major medical society guidelines as a recommended treatment for patients with persistent CV risk despite statin treatment, including the American Diabetes Association (ADA), the National Lipid Association (NLA), the European Society of Cardiology (ESC)/European Association for the Study of Diabetes, and the ESC/European Atherosclerosis Society [44], [45], [46], [47], [48].
An exploration of the difference in outcomes between REDUCE-IT and other CV outcomes trials is warranted. There were some differences in baseline TG levels and the observed reductions in TG levels across trials. Baseline TG levels were low in OMEMI (111 mg/dL) but were higher in STRENGTH (239 mg/dL) than in REDUCE-IT (216 mg/dL); the percent reduction in TG levels was similar in REDUCE-IT and STRENGTH. Furthermore, REDUCE-IT investigators demonstrated that the difference in clinical benefit likely cannot be attributed to reductions in TG levels alone [49], [50]. The biggest apparent difference among these trials that may help to explain the positive result observed in REDUCE-IT is that a highly purified ethyl ester of EPA (icosapent ethyl) was used as opposed to the mixed EPA + DHA formulations of different structural forms in OMEMI and STRENGTH. The high dose of pure EPA resulted in a substantial increase in blood EPA levels, which correlated with the CV benefits seen in REDUCE-IT [49]. Additionally, potential antiplatelet/antithrombotic effects may also play a potential beneficial mechanistic role for CV risk reduction as noted by a nonsignificant trend in increased bleeding events that was not seen in STRENGTH or OMEMI [51].
4. Pharmacology of omega-3 fatty acids
Both EPA and DHA (and mixed EPA + DHA combinations) have been shown to reduce circulating TG levels, explaining why many trials have focused on mixed combinations [52], [53]. However, the two omega-3 fatty acids have different pharmacologic effects (Fig. 1, Fig. 2), including effects on other circulating lipoproteins, formation of cholesterol domains, cell membrane structure, and as precursors for bioactive compounds involved in platelet function and inflammation [54], [55]. EPA is associated with reduced circulating very-low-density lipoprotein cholesterol (VLDL-C) and TGs, as well as apolipoprotein (apo) B, apo-CIII, and remnant-like particle cholesterol [53]. EPA may also inhibit phosphatidic acid phosphatase/phosphohydrolase and diacylglycerol transferase to reduce TG synthesis [56], increase clearance of TG-rich lipoproteins via lipoprotein lipase activity, and reduce expression of platelet endothelial cell adhesion molecule-1 on endothelial cells [57], [58]. Furthermore EPA, but not DHA, induces expression of heme oxygenase-1 and increases nitric oxide levels in endothelial cells under inflammatory conditions; this may help to preserve vascular endothelial cell function [59]. Endothelial nitric oxide synthase coupling efficiency, as measured by the nitric oxide to peroxynitrite ratio, was greater in endothelial cells pretreated with EPA than in cells pretreated with DHA, further supporting a preferential benefit of EPA on endothelial function [60].
Fig. 1
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Fig. 1. Molecular membrane interactions of omega-3 fatty acids. Schematic illustration of the proposed location and contrasting effects of EPA and DHA on membrane structure. The insertion of EPA and DHA affects distinct regions of the membrane lipid bilayer due to differences in their hydrocarbon length and number of double bonds. The longer hydrocarbon length of DHA leads to more rapid isomerization and conformational changes that result in increased membrane fluidity and promotion of cholesterol domains. EPA has a more stable and extended structure that contributes to membrane stability as well as inhibition of lipid oxidation and cholesterol domain formation. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid. Reprinted with permission from Mason RP, Libby P, Bhatt DL. Emerging mechanisms of cardiovascular protection for the omega-3 fatty acid eicosapentaenoic acid. Arterioscler Thromb Vasc Biol 2020;40(5):1135–1147; www.ahajournals.org/journal/atvb [54].
Fig. 2
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Fig. 2. Specialized pro-resolving mediator biosynthetic pathways [65]. (A) Biosynthesis of the D series resolvins, protectins, and maresins from docosahexaenoic acid (DHA) and the E series resolvins from eicosapentaenoic acid (EPA). (B) Biosynthesis of lipoxins and aspirin-triggered (AT)-lipoxins from arachidonic acid (AA), the T series resolvins AT-RvDs and AT-PD1 from DHA, and the resolvin, protectin, and maresin conjugates in tissue regeneration (RCTRs, PCTRs, MCTRs) from their epoxy precursors. 15-LOX, 15-lipoxygenase; 5-LOX, 5-lipoxygenase; 12-LOX, 12-lipoxygenase; COX2-ASA, aspirin-acetylated cyclooxygenase-2; P450, cytochrome P450; RvD1, resolvin D1; RvD2, resolvin D2; RvD3, resolvin D3; RvD4, resolvin D4; PD1/NPD1, protectin D1/neuroprotectin D1; MaR1, maresin 1; RvE1, resolvin E1; RvE2, resolvin E2; RvE3, resolvin E3; LXA4, lipoxin A4; LXB4, lipoxin B4; AT-LXA4, aspirin-triggered lipoxin A4. Reprinted with permission from Panigrahy D, Gilligan MM, Serhan CN, Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharmacol Ther 2021;227:107879. Copyright 2021, with permission from Elsevier.
EPA has a minimal or neutral effect on LDL-C; DHA, by contrast is associated with increases in LDL-C levels. For example, in a study comparing treatment with purified EPA versus DHA, DHA was associated with a significant 8% increase in serum LDL-C levels, while there was a nonsignificant decrease of 3.5% with EPA; both omega-3 fatty acids reduced TG levels by approximately 20% [61].
Omega-3 fatty acids have a role in maintaining membrane fluidity and preventing development of atherosclerotic plaque, with both EPA and DHA being incorporated into the cholesterol domain of cell membranes (Fig. 1) [54]. However, EPA and DHA have different effects on membrane structure [54], [62]. When omega-3 fatty acids are in low supply, membrane structure can facilitate formation of extracellular cholesterol crystals, which are associated with atherogenesis and plaque rupture. EPA preserves membrane structure and promotes normal distribution of cholesterol, inhibits lipid oxidation and cholesterol crystal formation, and influences signal transduction pathways related to inflammation and vasodilation. Compared to DHA, EPA has a more stable extended molecular structure that allows it to scavenge reactive oxygen species, hence promoting membrane stability [54]. In fact, EPA inhibits oxidation of apo-B–containing lipoprotein particles of different sizes, an effect that has been attributed to quenching of reactive oxygen species in the lipid membrane [63]. DHA, on the other hand, increases membrane fluidity and promotes lipid domain changes, has reduced antioxidant activity due to lipid-disordering effects, and is concentrated in brain and retinal membranes [54], [62]. Interestingly, when EPA and DHA are combined, the resulting effects on membrane structure are attenuated compared to their separate actions, providing a potential mechanistic explanation for contrasting results between EPA-only and EPA + DHA clinical trials [64].
Another key difference between EPA and DHA is in how they are metabolized by cyclooxygenase and lipoxygenase and other downstream enzymes to produce anti-inflammatory and antithrombotic compounds (Fig. 2) [55], [65]. Metabolism of EPA leads to production of 3-series prostaglandins, thromboxane A3, 5-series leukotrienes, and E-series resolvins RvE1 and RvE2. DHA by contrast is converted to D-series resolvins, protectins, and maresins. EPA competes with arachidonic acid (AA) for cyclooxygenase and lipoxygenase, leading to production of less inflammatory and less prothrombotic bioactive lipid metabolites, whereas AA results in the predominantly proinflammatory 2-series prostaglandins, thromboxane A2, and 4-series leukotrienes [66]. As a result, increased serum EPA, resulting in a higher EPA:AA ratio, shifts the balance toward a less inflammatory milieu; a higher EPA:AA ratio is associated with lower CV disease risk [66]. The downstream effects of this less inflammatory state have been demonstrated in mouse models. Administration of EPA resulted in attenuated chronic post-MI cardiac modeling related to modulation of proinflammatory M1 macrophage activity [67]. Compared with the EPA:AA ratio, the DHA:AA ratio has a much weaker association with CV disease risk [66]. Increasing the EPA:AA ratio has anti-aggregatory effects through increased production of antithrombotic thromboxane A3 and prostacyclin I3 versus the prothrombotic thromboxane A2 and prostacyclin I2 [68], [69]. The production of resolvin RvE1 may also reduce platelet activation and thrombosis [68], [70].
EPA demonstrated consistent antiatherosclerotic effects in imaging studies; in combination with a statin, EPA has been associated with a decrease in features associated with vulnerable plaque [71]. Recent evidence for a role for icosapent ethyl comes from the randomized, double-blind, placebo-controlled EVAPORATE study (Effect of Vascepa on Progression of Coronary Atherosclerosis in Persons With Elevated Triglycerides [200–499] on Statin Therapy) [72]. Patients with coronary atherosclerosis involving at least one angiographic stenosis with ≥20% narrowing and on stable statin therapy with LDL-C levels 40–115 mg/dL and TG levels 135–499 mg/dL underwent multidetector computed tomography during 18 months of follow-up. After 18 months, there were significant decreases versus placebo in low-attenuation plaque (P = 0.006), total noncalcified plaque (P = 0.0005), and total plaque (P = 0.0002) in icosapent ethyl–treated patients. In the CHERRY trial (Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography), addition of EPA 1800 mg/day to pitavastatin 4 mg/day led to significant reductions in normalized total atheroma volume over ˜8 months in patients with stable angina pectoris and acute coronary syndrome. Moreover, reductions were significantly greater than in patients receiving pitavastatin alone [73], providing further evidence that observed effects from EPA are not driven by changes due to a placebo. By contrast, there was no significant difference in the volume of noncalcified plaque—the most sensitive measure of plaque volume—after a longer follow-up of 30 months in the randomized, controlled, parallel-design HEARTS trial (Slowing Heart Disease with Lifestyle and Omega-3 Fatty Acids) of EPA + DHA (1.86 g and 1.5 g, respectively) versus control (no EPA + DHA) in 285 subjects with coronary artery disease and ≥ 50% stenosis in at least one coronary artery at cardiac catheterization, prior MI or percutaneous coronary intervention (both ≥6 months previously), coronary bypass surgery (≥12 months previously), abnormal exercise treadmill test or reversible ischemia on nuclear imaging, and/or pharmacologic stress or stress echocardiography with subsequent revascularization [74]. Although this study was negative overall, a substudy of HEARTS further demonstrated the importance of EPA [75]. Higher plasma levels of EPA and DHA were associated with an increased ratio of resolvin E1 plus 18-hydroxy-EPA (both derived from EPA) to leukotriene B4 and significant plaque regression. Similar to the HEARTS trial, the AQUAMARINE study assessed the effect of 2 g of mixed EPA/DHA, 4 g of mixed EPA/DHA, or no treatment for 12 months in addition to statin treatment in 84 patients with coronary artery disease and found no difference in plaque-to-myocardial ratio changes among the groups [76].
5. EPA plasma levels
These differences in the pharmacology of EPA and DHA may therefore help to explain differences in clinical outcomes between patients taking EPA versus EPA+DHA. JELIS provided the first data in a cardiovascular outcomes trial with EPA that the on-treatment EPA plasma level was related to the risk of a major coronary event [29]. Compared to an EPA level of <150 µg/mL, patients with plasma EPA ≥150 µg/mL had an 18% reduction in major coronary events (95% CI 0.68–0.98; P = 0.032). In REDUCE-IT, the crucial relationship between higher levels of on-treatment EPA and reduced CV disease events rate were again seen. The on-treatment EPA levels in patients taking icosapent ethyl correlated strongly with the primary endpoint, the key secondary endpoint, CV death, MI, stroke, coronary revascularization, unstable angina, sudden cardiac death, new heart failure, and all-cause mortality [49]. Time-varying covariate analyses revealed that changes in other biomarkers such as TGs, LDL-C, and high-density lipoprotein cholesterol levels had only a limited impact on the primary and secondary endpoint. In fact, on-treatment EPA levels accounted for essentially all of the 25% (95% CI 0.68–0.83; P < 0.001) relative risk reduction in the primary endpoint and 26% (95% CI 0.65–0.83; P < 0.001) relative risk reduction in the secondary endpoint. Furthermore, dose-response analyses showed that the higher the on-treatment serum EPA level, the greater the ASCVD event risk reduction; therefore, some ASCVD events may require higher EPA thresholds to observe beneficial effects. Further evidence comes from a comparison of achieved EPA levels between REDUCE-IT and STRENGTH. In REDUCE-IT, median EPA levels increased by almost 400% to 144 µg/mL after 1 year of treatment with icosapent ethyl compared with a 269% increase to only 90 µg/mL in STRENGTH (DHA levels increased by 40%) [24], [49].
6. Conclusions
Dyslipidemia management has evolved to utilize a range of drugs beyond statins that target LDL-C. These include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, and bempedoic acid, which also target LDL-C, and omega-3 fatty acids, niacin, and fibrates, which target TGs [18], [46]. As reviewed here, there is now clear, strong evidence-based data to support use of EPA 4 g/day for reduction of CV disease risk beyond its effect on TGs alone, and it has now been included in a number of national and international guidelines [44], [45], [46]. Based on REDUCE-IT, EPA is currently the only lipid-modifying agent available that has been shown to reduce CV mortality over and above statin therapy in high-risk patients.
It is important to note that there is an apparent need to differentiate omega-3 fatty acids and drug formulations and their roles in conferring CV benefit. EPA and DHA have distinct biochemical properties and exert different pharmacologic effects, so it cannot be assumed that both will have the same effects on CV outcomes. Although products containing mixed EPA + DHA and EPA alone have been approved to reduce TGs in patients with hypertriglyceridemia, only EPA-alone formulations have demonstrated clinical benefit in reducing major CV disease events and death when added to contemporary medical therapy, including statins. The ongoing RESPECT-EPA trial, which is assessing the effect of 1.8 g EPA per day versus no EPA on CV outcomes in 3900 patients with established ASCVD and on statin therapy will provide further insight into EPA-only treatment [77], [78]. While EPA may have pleiotropic pharmacologic effects, it is not clear which of these are clinically relevant. A current limitation is the lack of available data on use of DHA monotherapy, including at higher doses. Future research should evaluate the impact of DHA alone in patients with CV disease. Further evaluation of the importance of plasma EPA levels both as a tool for measuring adherence as well as efficacy is also warranted. This would include further establishing a threshold above which maximum clinical benefit can be achieved.
Role of the funding source
Medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by Amarin Pharma Inc.
CRediT authorship contribution statement
Peter P. Toth: Writing – original draft, Writing – review & editing. M. John Chapman: Writing – original draft, Writing – review & editing. Klaus G. Parhofer: Validation, Writing – review & editing. John R. Nelson: Validation, Writing – review & editing.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
PP Toth serves on the speaker's bureaus of Amarin, Amgen, Esperion, and Novo-Nordisk and serves as a consultant to Amarin, Amgen, Merck, Novartis, Resverlogix, and Theravance.
MJ Chapman has received research funding from CSL, Kowa, Merck, and Pfizer and has participated in advisory boards and/or speaker's bureaus for Akcea, Alexion, Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Kowa, Medscape, Novartis, Pfizer, Sanofi, Regeneron, and Servier.
KG Parhofer has received research funding and/or honoraria for consultancy and/or speaker's bureaus and/or DMC activity from Akcea, Amarin, Amgen, Boehringer-Ingelheim, Dr. Schär, Daiichi-Sankyo, Ionis, MSD, Novartis, Pfizer, Regeneron, Sanofi, and Silence Therapeutics.
JR Nelson is on the speaker's bureau and/or advisory board of Amarin, Amgen, Esperion, and Regeneron. He is a stockholder of Amgen.
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Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin And Eicosapentaenoic Acid UMIN000012069
UMIN Clinical Trials Registry (2018)
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https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R00001
UMIN-CTR Clinical Trial
BACK TOP
UMIN-CTR English Home Glossary (Simple) FAQ Inquiry Search clinical trials
Name
UMIN ID
Recruitment status No longer recruiting
Unique ID issued by UMIN UMIN000012069
Receipt No. R000014051
Scientific Title Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid
Date of disclosure of the study information 2013/10/21
Last modified on 2022/05/11
* This page includes information on clinical trials registered in UMIN clinical trial registed system.
* We don't aim to advertise certain products or treatments
Basic information
Public title Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid
Acronym RESPECT-EPA
Scientific Title Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and Eicosapentaenoic Acid
Scientific Title:Acronym RESPECT-EPA
Region
Japan
Condition
Condition Coronary artery disease
Classification by specialty
Cardiology
Classification by malignancy Others
Genomic information NO
Objectives
Narrative objectives1 Patients with chronic coronary artery disease receiving LDL-C lowering treatment by statin will be randomized to either a control group (standard treatment) or EPA group (standard treatment plus eicosapentaenoic acid), to examine the effects of eicosapentaenoic acid on the incidence of cardiovascular events. Relationship between EPA/AA ratio and incidence of event will be also examined.
Basic objectives2 Safety,Efficacy
Basic objectives -Others
Trial characteristics_1 Confirmatory
Trial characteristics_2 Pragmatic
Developmental phase Phase IV
Assessment
Primary outcomes Primary endpoints are the first occurrence of any of the following cardiovascular events.
Cardiovascular death, non-fatal myocardial infarction (MI)*, non-fatal cerebral infarction, unstable angina requiring emergent hospitalization and coronary revascularization, and coronary revascularization based on clinical findings. * indicates not including percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) related MI.
Key secondary outcomes (1) Composite endpoint.
1) Composite event of coronary artery disease
Endpoints are the first occurrence of any of the following events.
Cardiac sudden death, fatal/non-fatal MI*, unstable angina requiring emergent hospitalization and coronary revascularization, and coronary revascularization based on clinical findings.
2) Composite event of cerebrovascular disorders
Endpoints are the first occurrence of any of the following events.
2-1) Fatal/non-fatal stroke, hospitalization due to transient ischemic attack.
2-2) Fatal/non-fatal stroke
(2) Event relating to death
Occurrence of each following event;
1) All-cause death
2) Cardiovascular death
3) Cardiac death
(3) Event relating to cardiac disease
Occurrence of each following event;
1) Fatal/non-fatal MI*
2) PCI related MI
3) CABG related MI
4) Stent thrombosis associated with MI
5) Cardiac sudden death
6) Unstable angina requiring emergent hospitalization and coronary revascularization
7) Resuscitation from cardiac arrest
8) Hospitalization due to heart failure
9) New-onset of atrial fibrillation
10) Coronary revascularization (PCI or CABG)
10-1) All coronary revascularization
(a) TLR (b) TVR (c) TVR-Remote (d) Non-TVR
10-2) Coronary revascularization based on clinical findings
(a) TLR (b) TVR (c) TVR-Remote (d) Non-TVR
(4) Events relating to cerebrovascular disorders
Occurrence of each following event;
1) Fatal/non-fatal cerebral hemorrhage
2) Fatal/non-fatal stroke
3) TIA requiring hospitalization
(5) Other events
Occurrence of each following event;
1) Revascularization to peripheral artery disease (PAD)
2) Carotid artery stenting (CAS) or carotid endarterectomy (CEA)
3) Deep vein thrombosis (DVT) or pulmonary thromboembolism (PTE)
4) New occurrence of malignant tumor
5) Progression to dialysis
6) Hemorrhagic event
(6) Biomarkers
Base
Study type Interventional
Study design
Basic design Parallel
Randomization Randomized
Randomization unit Individual
Blinding Open -no one is blinded
Control Active
Stratification YES
Dynamic allocation NO
Institution consideration Institution is considered as a block.
Blocking YES
Concealment Central registration
Intervention
No. of arms 2
Purpose of intervention Treatment
Type of intervention
Medicine
Interventions/Control_1 Continuous administration of statin + EPA 1800mg/day
Interventions/Control_2 Continuous administration of statin
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10
Eligibility
Age-lower limit
20 years-old <=
Age-upper limit
80 years-old >
Gender Male and Female
Key inclusion criteria Patients with CAD who took statin over one month and met all following criteria;
(1) Patients aged 20 years to 79 years at the time of informed consent
(2) Patients given written informed consent
CAD is defined as having at least one of the following criteria (1) to (3);
(1) History of acute coronary syndrome (acute myocardial infarction or unstable angina)
(2) History of coronary revascularization (PCI or CABG)
(3) Clinically diagnosed ischemic heart disease and severe coronary artery stenosis (75% or higher according to AHA classification) demonstrated in coronary angiography
Key exclusion criteria Patients who meet one of the following criteria;
(1) Patients on dialysis
(2) Patients with serious hepatic disease
(3) Patients with active malignant tumor
(4) Patients for whom coronary angiography or coronary revascularization is scheduled but not yet conducted
(5) Patients with severe heart failure (LVEF<30% or NYHA class 3 or 4 according to NYHA classification)
(6) Patients who experienced acute coronary syndrome (acute myocardial infarction or unstable angina) within three month at the time of informed consent
(7) Patients who received coronary revascularization (PCI or CABG) within three month at the time of informed consent
(8) Patients with inadequately controlled diabetes mellitus[HbA1c (JDS): 8.0% or more, HbA1c (NGSP): 8.4% or more]
(9) Patients with secondary dyslipidemia associated with (a) nephrotic syndrome, (b) hypothyroidism, (c) Cushing syndrome and (d) other diseases, patients with drug-induced dyslipidemia such as that caused by steroid hormone, or patients receiving EPA (including OTC drugs) or EPA/DHA, or having received such drug within previous 1 month at the time of informed consent
(10) Patients having active bleeding or bleeding tendency
(11) Patients with a history of adverse reaction to EPA
(12) Patients participating in other clinical trial
(13) Pregnant women, possibly pregnant women, or women during lactation
(14) Other patients who, in the opinion of the participating physician, are not eligible
Target sample size 3900
Research contact person
Name of lead principal investigator
1st name Hiroyuki
Middle name
Last name Daida
Organization Juntendo University Graduate School of Medicine
Division name Department of Cardiology
Zip code 113-8421
Address 2-1-1, Hongo, Bunkyo-ku, Tokyo, Japan
TEL 03-3813-3111
Email daida@juntendo.ac.jp
Public contact
Name of contact person
1st name Kumiko
Middle name
Last name Kitagawa
Organization Research Institute for Production Development
Division name Secretariat of RESPECT-EPA
Zip code 606-0805
Address 15, Shimogamo Morimoto-cho, Sakyo-ku, Kyoto, 606-0805
TEL 075-781-1107
Homepage URL
Email jimu-epa@world.odn.ne.jp
Sponsor
Institute Study group on treatment of coronary artery disease
Institute
Department
Funding Source
Organization Japan Heart Foundation
Organization
Division
Category of Funding Organization Non profit foundation
Nationality of Funding Organization
Other related organizations
Co-sponsor
Name of secondary funder(s)
IRB Contact (For public release)
Organization Juntendo University
Address 2-1-1, Hongo, Bunkyo-ku, Tokyo, Japan
Tel 03-5802-1589
Email chiken@juntendo.ac.jp
Secondary IDs
Secondary IDs NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW
Institutions
Institutions
Other administrative information
Date of disclosure of the study information
2013 Year 10 Month 21 Day
Related information
URL releasing protocol
Publication of results Unpublished
Result
URL related to results and publications
Number of participants that the trial has enrolled
Results
Results date posted
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics
Participant flow
Adverse events
Outcome measures
Plan to share IPD
IPD sharing Plan description
Progress
Recruitment status No longer recruiting
Date of protocol fixation
2013 Year 09 Month 20 Day
Date of IRB
2013 Year 05 Month 24 Day
Anticipated trial start date
2013 Year 11 Month 01 Day
Last follow-up date
2021 Year 10 Month 31 Day
Date of closure to data entry
2022 Year 03 Month 31 Day
Date trial data considered complete
2022 Year 09 Month 15 Day
Date analysis concluded
Other
Other related information
Management information
Registered date
2013 Year 10 Month 18 Day
Last modified on
2022 Year 05 Month 11 Day
Link to view the page
URL(English) https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014051
Research Plan
Registered date File name
Research case data specifications
Registered date File name
Research case data
Registered date File name
Building IP: AMRN Patent Grant re "Methods of reducing the risk of cardiovascular events in a subject"
United States Patent 11,369,582
Soni June 28, 2022
Methods of reducing the risk of cardiovascular events in a subject
Abstract
In various embodiments, the present disclosure provides methods reducing the risk of cardiovascular events in a subject on statin therapy by administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester or a derivative thereof.
Inventors: Soni; Paresh (Mystic, CT)
Applicant:
Name City State Country Type
Amarin Pharmaceuticals Ireland Limited
Dublin
N/A
IE
Assignee: Amarin Pharmaceuticals Ireland Limited (Dublin, IE)
Family ID: 1000006398218
Appl. No.: 17/469,051
Filed: September 8, 2021
Prior Publication Data
Document Identifier Publication Date
US 20220000829 A1 Jan 6, 2022
Related U.S. Patent Documents
Application Number Filing Date Patent Number Issue Date
17165688 Feb 2, 2021 11116743
17153606 Jan 20, 2021 11116742
17126619 Dec 18, 2020
16927224 Jul 13, 2020 11000499
16736936 Sep 29, 2020 10786478
16574415 Sep 18, 2019
16391128 Jun 2, 2020 10668042
62818514 Mar 14, 2019
62813888 Mar 5, 2019
62758387 Nov 9, 2018
62735680 Sep 24, 2018
62735670 Sep 24, 2018
Current U.S. Class: 1/1
Current CPC Class: A61K 31/232 (20130101); A61K 9/0053 (20130101); A61P 9/10 (20180101); A61K 31/505 (20130101); A61K 31/40 (20130101)
Current International Class: A61K 31/232 (20060101); A61K 9/00 (20060101); A61P 9/10 (20060101); A61K 31/505 (20060101); A61K 31/40 (20060101)
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Primary Examiner: Rao; Savitha M
Attorney, Agent or Firm: Perkins Coie LLP
Parent Case Text
PRIORITY CLAIM
This application is a continuation of U.S. patent application Ser. No. 17/165,688 filed Feb. 2, 2021, which is a continuation of U.S. patent application Ser. No. 17/153,606 filed Jan. 20, 2021, which is a continuation of U.S. patent application Ser. No. 17/126,619 filed Dec. 18, 2020, which is a continuation of U.S. patent application Ser. No. 16/927,224 filed Jul. 13, 2020, which is a continuation of U.S. patent application Ser. No. 16/736,936 filed Jan. 8, 2020 (now U.S. Pat. No. 10,786,478), which is a continuation of U.S. patent application Ser. No. 16/574,415 filed Sep. 18, 2019, which is a continuation of U.S. patent application Ser. No. 16/391,128 filed Apr. 22, 2019 (now U.S. Pat. No. 10,668,042), which claims priority to U.S. Provisional Application No. 62/735,670 filed on Sep. 24, 2018, U.S. Provisional Application No. 62/735,680 filed on Sep. 24, 2018, U.S. Provisional Application No. 62/758,387 filed on Nov. 9, 2018, U.S. Provisional Application No. 62/813,888 filed on Mar. 5, 2019, and U.S. Provisional Application No. 62/818,514 filed on Mar. 14, 2019, the entire contents of each of which are incorporated herein by reference and relied upon.
Claims
The invention claimed is:
1. A method of reducing a cardiovascular event in a subject, the method comprising administering daily 4 g of ethyl icosapentate to the subject, wherein the subject is receiving a high intensity statin regimen, has elevated triglyceride levels and (1) established cardiovascular disease, or (2) diabetes and at least two additional risk factors for cardiovascular disease, wherein the high intensity statin regimen comprises about 40 mg to about 80 mg per day of atorvastatin or about 20 mg to about 40 mg per day of rosuvastatin.
2. The method of claim 1, wherein the cardiovascular event is one or more of: myocardial infarction, stroke, cardiovascular death, unstable angina, coronary revascularization procedures and/or hospitalizations for unstable angina.
3. The method of claim 1, wherein the subject has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL.
4. The method of claim 1, wherein the subject has a fasting baseline triglyceride level of at least about 135 mg/dL.
5. The method of claim 1, wherein the administering occurs for at least about 2 years.
6. The method of claim 1, wherein the subject exhibits at least about a 30% reduction in risk for the cardiovascular event.
7. The method of claim 1, wherein the ethyl icosapentate is present in a pharmaceutical composition and the ethyl icosapentate comprises at least about 90 wt. % of all omega-3 fatty acids in the pharmaceutical composition.
8. The method of claim 7, wherein the ethyl icosapentate comprises at least about 96 wt. % of all omega-3 fatty acids in the pharmaceutical composition.
9. The method of claim 1, wherein the at least two additional risk factors for cardiovascular disease are selected from the group consisting of a subject (a) of male gender of at least 55 years of age or of female gender of at least 65 years of age, (b) who smokes cigarettes or has stopped smoking cigarettes within three months before administration of the ethyl icosapentate, (c) with blood pressure of at least 140 mmHg systolic or at least 90 mmHg diastolic, (d) on antihypertension medication, (e) of male gender with HDL-cholesterol level 40 mg/dL or less or of female gender with HDL-cholesterol level 40 mg/dL or less, (f) who has an hsCRP level of greater than 3 mg/L, (g) who has a creatine clearance between 30 mL/min and 60 mL/min, (h) who has non-proliferative retinopathy, (i) who has pre-proliferative retinopathy, (j) who has proliferative retinopathy, (k) who has maculopathy, (1) who has advanced diabetic eye disease or a history of photocoagulation, (m) who has micro- or macro-albuminuria, and (n) who has an asymptomatic ankle-brachial index of less than 0.9.
Description
BACKGROUND
Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dyslipidemia, congestive heart failure and stroke.
Lovaza.RTM., a lipid regulating agent, is indicated as an adjunct to diet to reduce triglyceride levels in adult patients with very high triglyceride levels. Unfortunately, Lovaza.RTM. can significantly increase LDL-C and/or non-HDL-C levels in some patients. A need exists for improved treatments for cardiovascular diseases and disorders.
SUMMARY
In various embodiments, the present disclosure provides methods of treating and preventing cardiovascular diseases and disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic of the study design according to an embodiment of the present disclosure.
FIG. 2 is a schematic showing disposition of patients according to an embodiment of the present disclosure.
FIGS. 3A and 3B are representative Kaplan-Meier event curves for the cumulative incidence of the primary composite endpoints. FIGS. 3A and 3B indicate a 25% relative risk reduction for the primary composite endpoint over the course of 5 years.
FIG. 4 is a representative forest plot of individual components of primary endpoints analyzed as time to first event of each individual endpoint and indicates that each component, individually, was reduced.
FIGS. 5A and 5B are representative Kaplan-Meier event curves for the cumulative incidence of the key secondary composite endpoints. FIGS. 5A and 5B indicate that there was a 26% RRR for the key secondary composite endpoint over the course of 5 years.
FIGS. 6 and 7 are representative forest plots of primary efficacy outcomes in select prespecified subgroups. FIGS. 6 and 7 indicate that a subject's baseline triglyceride levels (e.g., .gtoreq.150 vs. <150 mg/dL or .gtoreq.200 or <200 mg/dL) did not influence the primary endpoint outcomes.
FIGS. 8 and 9 are representative forest plots of secondary efficacy outcomes in select prespecified subgroups. FIGS. 8 and 9 indicate that a subject's baseline triglyceride levels (e.g., .gtoreq.150 vs. <150 mg/dL or .gtoreq.200 or <200 mg/dL) did not influence the key secondary endpoint outcomes.
FIGS. 10A and 10B are representative Kaplan-Meier curves of primary and key secondary endpoints by achieved triglyceride level at 1 year. FIGS. 10A and 10B indicate that patient's triglyceride levels had no influence on the efficacy of icosapent ethyl as compared with placebo with respect to the primary or key secondary efficacy endpoint outcomes.
FIG. 11 is a representative forest plot of prespecified hierarchical testing of endpoints and indicates that all individual and composite ischemic endpoints were significantly reduced by icosapent ethyl (AMR101).
FIG. 12 is a schematic of the study design according to an embodiment of the present disclosure.
FIG. 13 is a representative bar graph depicting the distribution of first, second, and recurrent ischemic events in patients. FIG. 13 indicates that the first, second, and recurrent ischemic events were reduced in patients randomized to icosapent ethyl (IPE) compared to placebo.
FIG. 14 is a representative overall cumulative event Kaplan-Meier event curve for the primary endpoint indicating that overall cumulative primary endpoints were reduced in patients randomized to icosapent ethyl.
FIG. 15 is a representative cumulative event Kaplan-Meier event curve for the primary endpoint for patients in the secondary prevention cohort, which, similar to FIG. 14, indicates that cumulative primary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
FIG. 16 is a representative cumulative event Kaplan-Meier event curve for the primary endpoint for patients in the primary prevention cohort, which, similar to FIGS. 14 and 15, indicates that cumulative primary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
FIG. 17 is a representative forest plot of the total event for each occurrence of the primary endpoint. FIG. 17 indicates that the times to first, second, third, or fourth occurrences of the primary composite endpoint were consistently reduced in the icosapent ethyl group as compared to placebo.
FIG. 18 includes representative pie charts for the proportion of first and subsequent primary endpoint events, overall and by component.
FIG. 19 is a representative graph depicting the risk difference in 100 patients treated for five years with icosapent ethyl versus placebo of the composite primary endpoint.
FIG. 20 is a representative forest plot of the total event for each occurrence of the primary and key secondary efficacy endpoints. FIG. 20 indicates that the total events for each component of the primary endpoint events were significantly reduced.
FIG. 21 is a representative overall cumulative event Kaplan-Meier curve for the key secondary endpoint indicating that overall cumulative key secondary endpoints were reduced in patients randomized to icosapent ethyl.
FIG. 22 is a representative cumulative event Kaplan-Meier curve for the key secondary endpoint for patients in the secondary prevention cohort, which similar to FIG. 21 indicates that cumulative key secondary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
FIG. 23 is representative cumulative event Kaplan-Meier curve for the key secondary endpoint for patients in the primary prevention cohort, which, similar to FIGS. 21 and 22, indicates that cumulative secondary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
FIG. 24 is a representative overall cumulative Kaplan-Meier event curve as a function of years since randomization for the primary endpoint indicating that overall cumulative primary endpoints were reduced in patients randomized to icosapent ethyl.
FIG. 25 is a representative overall cumulative event Kaplan-Meier curve as a function of years since randomization for the key secondary endpoint indicating that overall cumulative key secondary endpoints were reduced in patients randomized to icosapent ethyl.
FIG. 26 is a representative Kaplan-Meier curve for recurrent events as a function of years since randomization of the primary endpoint for patients in the secondary prevention cohort indicating that cumulative primary endpoints were reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
FIG. 27 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the key secondary endpoint for patients in the secondary prevention cohort indicating that cumulative key secondary endpoints were also reduced in patients in the secondary prevention cohort randomized to icosapent ethyl.
FIG. 28 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the primary endpoint for patients in the primary prevention cohort indicating that cumulative primary endpoints were also reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
FIG. 29 is a representative Kaplan-Meier curve as a function of years since randomization for recurrent events of the key secondary endpoint for patients in the primary prevention cohort indicating that cumulative key secondary endpoints were reduced in patients in the primary prevention cohort randomized to icosapent ethyl.
FIG. 30 are representative plots of the total events by number of events per patient for the primary composite endpoints and for each individual component for patients randomized to icosapent ethyl and placebo.
FIGS. 31A and 31B are representative flow charts of the total primary and secondary composite endpoint events for patients randomized to AMR101 and placebo, respectively.
FIG. 32 includes representative pie charts for a proportion of first and subsequent primary endpoint events, overall and by component.
FIG. 33 is a representative bar graph depicting a distribution of total (i.e., first and subsequent) primary composite endpoint events in patients. FIG. 33 indicates that there was a 30% relative risk reduction in total events for the primary composition endpoint in patients randomized to icosapent ethyl.
FIGS. 34A and 34B are representative Kaplan-Meier curves over time for total (i.e., first and subsequent) and time to first primary composite events and secondary composite endpoint events, respectively. FIGS. 34A and 34B indicate that both primary and key secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compare to placebo.
FIG. 35 is a representative forest plot of total primary and key secondary composite endpoint events and indicates that times to first, second, and third occurrence of the primary and secondary endpoints were significantly reduced in patients randomized to icosapent ethyl compared placebo.
FIG. 36 is a representative forest plot of total primary and key secondary composite endpoints and each individual component or endpoint for patients randomized to icosapent ethyl and placebo indicating that not only was there a significant reduction in the composite of the primary and key secondary endpoints, but also, each individual component was also significantly reduced.
FIGS. 37A and 37B are representative forest plots of total primary and secondary composite endpoints in selected subgroups by the negative binomial model, respectively, for patients randomized to icosapent ethyl and placebo.
FIG. 38 is a representative graph depicting the risk difference in patients treated for five years with icosapent ethyl versus placebo for total components of the composite primary endpoint and indicates that approximately 159 total primary endpoint events could be prevented within that time frame to include 12 cardiovascular deaths, 42 myocardial infarctions, 14 strokes, 76 coronary revascularizations, and 16 episodes of hospitalization for unstable angina.
FIGS. 39 and 40 show the forest plot for total primary and key secondary composite endpoint events and first second, and third occurrences for the reduced dataset with unadjusted and adjusted values, respectively.
FIGS. 41 and 42 show the forest plots for the total primary composite endpoint events and total key secondary composite endpoint events and first, second, and third occurrences for the reduced data with unadjusted values, respectively.
FIGS. 43 and 44 show the total primary composite endpoint events and key secondary composite endpoint events and first, second, and third occurrences for the reduced data set with adjusted values, respectively.
FIGS. 45 and 46 show the total primary and key secondary composite endpoint events and first, second, and third occurrences for the full data set for the unadjusted and adjusted values, respectively.
FIG. 47 is a representative forest plot depicting the reduction of total primary composite endpoint events in subjects as a function of triglyceride level. FIG. 47 indicates that total primary composite endpoints were reduced in all patients across the entire triglyceride range and within each of the defined triglyceride tertiles.
FIG. 48 is a representative forest plot depicting time to first event of primary composite endpoint events in subjects as a function of triglyceride level. FIG. 48 demonstrates that the time to first event of the primary composite endpoint was reduced across the entire triglyceride range.
FIG. 49 is a representative bar graph for a placebo-corrected reduction in blood pressure in patients administered icosapent ethyl 4 g per day.
FIG. 50 is a representative bar graph for the study drug adherence over time for each of the first, second, third, and fourth events.
ACC2022 Vascepa/Icosapent Ethyl Abstract Titles 2-4Apr2022 in Washington, DC
Session 405 - Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials
405-08 - A Pragmatic Randomized Trial Of Icosapent Ethyl For High Cardiovascular Risk Adults (mitigate) In An Era Of Coronavirus Disease 2019
Add to My Itinerary
April 3, 2022, 8:00 AM - 8:10 AM Main Tent, Hall D
Authors
Andrew P. Ambrosy, Thida Tan, Rachel Thomas, Rishi Parikh, Daniel Stevens, Ryan Wi, Harshith Avula, Matthew Solomon, Van Selby, Jesse Fitzpatrick, Choon Goh, Jacek Skarbinski, Sephy Philip, Deepak Bhatt, Alan Go, Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA, Kaiser Permanente Northern California - Division of Research, Oakland, CA, USA
Abstract
Abstract is embargoed at this time.
Session 1188 - Prevention and Health Promotion: Lipids Digital Presentations
1188-004 / 4 - ICOSAPENT ETHYL REDUCES CARDIOVASCULAR RISK SUBSTANTIALLY AND CONSISTENTLY REGARDLESS OF WAIST CIRCUMFERENCE
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April 2, 2022, 8:30 AM - 8:30 AM eAbstract site
Authors
Deepak L. Bhatt, Eliot A. Brinton, Michael Miller, Philippe Gabriel Steg, Terry A. Jacobson, Steven Ketchum, Lixia Jiao, Ralph T. Doyle, Jr, Jean Claude Tardif, Christie M. Ballantyne, on behalf of the REDUCE-IT Investigators, Brigham and Women’s Hospital, Boston, MA, USA
Abstract
Abstract is embargoed at this time.
Session 1276 - Vascular Medicine: Pharmacology 2
1276-082 / 82 - EICOSAPENTAENOIC ACID (EPA) COMBINED WITH HIGH INTENSITY STATINS REDUCE LIPID OXIDATION IN MODEL MEMBRANES
Add to My Itinerary
April 2, 2022, 10:45 AM - 11:30 AM Poster Hall, Hall C
Authors
Samuel R. Sherratt, Peter Libby, Deepak L. Bhatt, R. Preston Mason, University of New Hampshire, Durham, NH, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Abstract is embargoed at this time.
Session 1453 - Vascular Medicine: Basic and Translational Science 11
1453-077 / 77 - EICOSAPENTAENOIC ACID (EPA) INCREASES HEME OXYGENASE-1 EXPRESSION IN MACROPHAGES AND ENDOTHELIAL CELLS DURING INFLAMMATION
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April 3, 2022, 2:45 PM - 3:30 PM Poster Hall, Hall C
Authors
Samuel CR R. Sherratt, Peter Libby, Deepak L. Bhatt, Hazem Dawoud, Tadeusz Malinski, R. Preston Mason, University of New Hampshire, Durham, NH, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Abstract is embargoed at this time.
Session 1453 - Vascular Medicine: Basic and Translational Science 11
1453-078 / 78 - EICOSAPENTAENOIC ACID (EPA) DECREASES ANGIOTENSIN CONVERTING ENZYME (ACE) EXPRESSION IN VASCULAR AND PULMONARY ENDOTHELIUM FOLLOWING CYTOKINE CHALLENGE
Add to My Itinerary
April 3, 2022, 2:45 PM - 3:30 PM Poster Hall, Hall C
Authors
Samuel CR R. Sherratt, Peter Libby, Deepak L. Bhatt, Hazem Dawoud, Tadeusz Malinski, R. Preston Mason, University of New Hampshire, Durham, MA, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Abstract is embargoed at this time.
Session 1453 - Vascular Medicine: Basic and Translational Science 11
1453-079 / 79 - EICOSAPENTAENOIC ACID (EPA) REDUCES INFLAMMATION AND IMPROVES NITRIC OXIDE BIOAVAILABILITY IN PULMONARY ENDOTHELIAL CELLS FOLLOWING EXPOSURE TO AIR POLLUTION PARTICLES
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April 3, 2022, 2:45 PM - 3:30 PM Poster Hall, Hall C
Authors
Samuel CR R. Sherratt, Hazem Dawoud, Peter Libby, Deepak L. Bhatt, Tadeusz Malinski, R. Preston Mason, University of New Hampshire, Durham, NH, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Abstract is embargoed at this time.
Session 1108 - Vascular Medicine Basic/Translational Science: Moderated Poster Contributions
1108-03 - EICOSAPENTAENOIC ACID (EPA) REDUCES J774 MACROPHAGE ACTIVATION AND CYCLOOXYGENASE (COX-1) EXPRESSION
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April 4, 2022, 10:00 AM - 10:10 AM Special Topics Moderated Poster Theater 5_Hall C
Authors
Samuel CR R. Sherratt, Peter Libby, Deepak L. Bhatt, Hazem Dawoud, Tadeusz Malinski, R. Preston Mason, University of New Hampshire, Durham, NH, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Abstract is embargoed at this time.
https://endpts.com/waking-up-from-some-big-blockbuster-dreams-pfizer-scraps-a-250m-drug-deal-as-data-sours-safety-fears-rise/
January 31, 2022 07:30 AM ESTUpdated 07:51 AM R&D
Waking up from some big blockbuster dreams, Pfizer scraps a $250M drug deal as data sour, safety fears rise
John Carroll
Editor & Founder
A little over 2 years after Pfizer paid Ionis $250 million cash to in-license rights to vupanorsen (AKCEA-ANGPTL3-LRx) – immediately vaulting the drug onto its list of top prospects — the pharma giant has decided to ax its ambitious late-stage work on the drug and hand it all back to Ionis, which has had more than its share of setbacks recently.
Pfizer had at one time been extremely bullish on this drug’s mid-stage data, grabbing exclusive worldwide rights, but researchers say they took a cold, hard look at the data from their Phase IIb and found the therapy wanting on efficacy as well as safety.
Pfizer noted that the trial achieved “a statistically significant reduction in non-high density lipoprotein cholesterol (non-HDL-C), as well as statistically significant reductions in triglycerides (TG) and angiopoietin-like 3 (ANGPTL3). However, the magnitude of non-HDL-C and TG reduction observed did not support continuation of the clinical development program for CV risk reduction or severe hypertriglyceridemia, a condition where patients have three times the normal level of triglycerides. Vupanorsen was also associated with dose-dependent increases in liver fat, and higher doses were associated with elevations in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).”
Pfizer CEO Albert Bourla had tapped the drug as one of its top 3 prospects in late 2020, outlining a $3 billion-plus future in annual revenue. In a small mid-stage study, investigators did see a significant reduction in ANGPTL3, offering a shot at a first-in-class antisense drug. But as I noted at the time, how often do those kinds of trials prove a misfire under closer scrutiny.
The road is open, but how often do you see these big Phase III studies scuttled by weak efficacy or bad safety? And Pfizer still has to run a Phase IIb to determine the late-stage dose — so plenty of places for this to go wrong. Pfizer, though, bet big early and remains the biggest cheerleader for the drug.
None of the majors maintains a perfect batting score in the big leagues of R&D. And this setback follows last week’s CRL for Pfizer’s FDA application for the growth hormone therapy somatrogon.
Bourla, though, can comfort himself with the Covid-19 numbers, which will excuse many clinical mishaps.
Building IP: AMRN Patent Grant re "Stable pharmaceutical composition and methods of using same"
United States Patent 11,147,787
Manku , et al. October 19, 2021
Stable pharmaceutical composition and methods of using same
Abstract
The present invention relates to, inter alia, pharmaceutical compositions comprising a polyunsaturated fatty acid and to methods of using the same to treat or prevent cardiovascular-related diseases.
Inventors: Manku; Mehar (Birmingham, GB), Osterloh; Ian (Kent, GB), Wicker; Pierre (Mystic, CT), Braeckman; Rene (Richboro, PA), Soni; Paresh (Mystic, CT)
Applicant:
Name City State Country Type
Amarin Pharmaceuticals Ireland Limited
Dublin
N/A
IE
Assignee: Amarin Pharmaceuticals Ireland Limited (Dublin, IE)
Family ID: 1000005873577
Appl. No.: 16/562,294
Filed: September 5, 2019
Prior Publication Data
Document Identifier Publication Date
US 20200000759 A1 Jan 2, 2020
Related U.S. Patent Documents
Application Number Filing Date Patent Number Issue Date
15996901 Jun 4, 2018 10449172
15415468 Jul 3, 2018 10010517
15092391 Mar 7, 2017 9585856
14709937 May 12, 2015
14259724 Jul 7, 2015 9072715
14084887 Jun 23, 2015 9060982
13685291 Dec 24, 2013 8613945
13614111 Jun 4, 2013 8454994
13458496 May 21, 2013 8445003
12769885 Oct 30, 2012 8298554
61173763 Apr 29, 2009
Current U.S. Class: 1/1
Current CPC Class: A61K 9/48 (20130101); A61P 9/00 (20180101); A61P 9/10 (20180101); A61P 9/06 (20180101); A61P 9/04 (20180101); A61K 31/202 (20130101); A61K 9/4858 (20130101); A61K 31/232 (20130101); A61P 3/06 (20180101); A61K 9/4825 (20130101); A61K 45/06 (20130101)
Current International Class: A61K 31/202 (20060101); A61K 31/232 (20060101); A61K 45/06 (20060101); A61K 9/48 (20060101); A61P 3/06 (20060101); A61P 9/04 (20060101); A61P 9/06 (20060101); A61P 9/10 (20060101); A61P 9/00 (20060101)
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Primary Examiner: Sasan; Aradhana
Attorney, Agent or Firm: Perkins Coie LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 15/996,901 filed Jun. 4, 2018 (now allowed), which is a continuation of U.S. application Ser. No. 15/415,468 filed Jan. 25, 2017 (now U.S. Pat. No. 10,010,517), which is a continuation of U.S. application Ser. No. 15/092,391 filed Apr. 6, 2016 (now U.S. Pat. No. 9,585,856), which is a continuation of U.S. application Ser. No. 14/709,937 filed May 12, 2015, which is a continuation of Ser. No. 14/259,724 filed Apr. 23, 2014 (now U.S. Pat. No. 9,072,715), which is a continuation of U.S. application Ser. No. 14/084,887 filed Nov. 20, 2013 (now U.S. Pat. No. 9,060,982), which is a continuation of U.S. application Ser. No. 13/685,291 filed Nov. 26, 2012 (now U.S. Pat. No. 8,613,945), which is a continuation of U.S. application Ser. No. 13/614,111 filed Sep. 13, 2012 (now U.S. Pat. No. 8,454,994), which is a continuation of U.S. application Ser. No. 13/458,496 filed Apr. 27, 2012 (now U.S. Pat. No. 8,445,003), which is a continuation of U.S. application Ser. No. 12/769,885 filed Apr. 29, 2010 (now U.S. Pat. No. 8,298,554), which claims priority to U.S. Provisional Application No. 61/173,763, filed Apr. 29, 2009, the entireties of each of which are incorporated herein by reference and relied upon.
Claims
We claim:
1. A pharmaceutical composition, comprising: omega-3 fatty acids in free acid form including (a) eicosapentaenoic acid in an amount selected from about 925 mg, about 950 mg, and about 975 mg; and (b) docosapentaenoic acid in an amount of about 5%, by weight, of total fatty acids in the pharmaceutical composition.
2. The pharmaceutical composition of claim 1, wherein the eicosapentaenoic acid is present in an amount of about 925 mg.
3. The pharmaceutical composition of claim 1, wherein the eicosapentaenoic acid is present in an amount of about 950 mg.
4. The pharmaceutical composition of claim 1, wherein the eicosapentaenoic acid is present in an amount of about 975 mg.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is present in one or more dosage units.
6. The pharmaceutical composition of claim 5, wherein the one or more dosage units comprise capsules.
7. A method of reducing triglycerides in a subject in need thereof comprising, administering to the subject daily the pharmaceutical composition of claim 1.
8. The method of claim 7, wherein the subject has very high serum triglycerides.
Description
BACKGROUND
Mixed omega-3 fatty acid esters are typically encapsulated in type 2a gelatin capsules containing gelatin (.about.43.4%), glycerol (.about.20%) and water (.about.36.6%) and do not experience stability problems throughout their shelf life. While chemically modified gelatins such as succinated/succinylated gelatin have been used to encapsulate reactive fill ingredients, such gelatin is not approved for use in the U.S. and other markets.
SUMMARY
We have unexpectedly found that high purity eicosapentaenoic acid (EPA) is more susceptible to oxidative degradation than mixed omega-3-acid ethyl esters. In various embodiments, the invention provides pharmaceutical compositions comprising a fatty acid or a derivative thereof in a capsule shell that resists, hinders, attenuates, or prevents oxidation of the fatty acid or fatty acid derivative, for example to a greater extent than is provided by a standard type IIa capsule shell. In a related embodiment, the fatty acid comprises eicosapentaenoic acid (EPA) or a derivative of EPA, for example ethyl eicosapentaenoate (ethyl-EPA or E-EPA). In another embodiment, the fatty acid comprises ultra-pure EPA.
In one embodiment, the invention provides a pharmaceutical composition comprising ultra-pure EPA encapsulated in a capsule shell, where the ultra-pure EPA has a baseline peroxide value not greater than about 5 meq/mg and upon storage of the composition at 23.degree. C. and 50% RH for a period of time, that ultra-pure EPA has a second peroxide value not greater than about 20 meq/mg.
In other embodiments, the invention provides a pharmaceutical composition comprising EPA (e.g. E-EPA or ultra-pure E-EPA) encapsulated in a capsule shell comprising a film forming material and a hygroscopic plasticizer, wherein the weight ratio of film-forming material to hygroscopic plasticizer is not less than about 2.5:1. Further, the capsule shell can optionally comprise a non-hygroscopic plasticizer. In one embodiment, the capsule contains no chemically modified gelatin, for example succinated or succinylated gelatin.
In still other embodiments, the present invention provides methods of treating or preventing a cardiovascular-related disease using compositions as described herein.
These and other embodiments of the present invention will be disclosed in further detail herein below.
Building IP: AMRN Patent Grant re "Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis"
United States Patent 11,141,399
Manku , et al. October 12, 2021
Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
Abstract
In various embodiments, the present invention provides methods of treating and/or preventing NASH and/or PBC comprising administering to a subject in need thereof a pharmaceutical composition comprising eicosapentaenoic acid or a derivative thereof.
Inventors: Manku; Mehar (Birmingham, GB), Wicker; Pierre (Mystic, CT), Braeckman; Rene (Richboro, PA), Soni; Paresh (Mystic, CT), Zakrzewski; Joseph S. (Bedminster, NJ)
Applicant:
Name City State Country Type
Amarin Pharmaceuticals Ireland Limited
Dublin
N/A
IE
Assignee: Amarin Pharmaceuticals Ireland Limited (Dublin, IE)
Appl. No.: 17/106,741
Filed: November 30, 2020
Prior Publication Data
Document Identifier Publication Date
US 20210128582 A1 May 6, 2021
Related U.S. Patent Documents
Application Number Filing Date Patent Number Issue Date
14145106 Dec 31, 2013
61747667 Dec 31, 2012
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Primary Examiner: Azpuru; Carlos A
Attorney, Agent or Firm: Perkins Coie LLP
Parent Case Text
PRIORITY CLAIM
This application is a continuation of U.S. patent application Ser. No. 14/145,106 filed Dec. 31, 2013, which claims the benefit of U.S. Provisional Patent Application No. 61/747,667, filed on Dec. 31, 2012, the entire contents of which are incorporated herein by reference and relied upon.
Claims
The invention claimed is:
1. A method of inhibiting Farnesoid X receptors ("FXR") in a subject having triglyceride levels of at least about 500 mg/dL, the method comprising administering orally to the subject about 4 g of ethyl eicosapentaenoate per day.
2. The method of claim 1, wherein the method comprises administering orally to the subject about 4 capsules per day, each capsule comprising about 900 mg to about 1.1 g of ethyl eicosapentaenoate and not more than about 20%, by weight, of total fatty acids present in the capsule, docosahexaenoic acid or its esters.
3. The method of claim 1, wherein prior to administration of ethyl eicosapentaenoate, the subject has one or more of: an elevated baseline alanine aminotransferase ("ALT") level, an elevated baseline aspartate aminotransferase ("AST") level, liver fibrosis, an elevated baseline gamma-glutamyl transferase level, an elevated baseline alkaline phosphatase level, an elevated baseline antimitochondrial antibody level, an elevated baseline antinuclear antibody level, an elevated total serum bilirubin level, and/or an elevated transaminase level.
4. The method of claim 1, wherein after administration of the ethyl eicosapentaenoate, the subject has one or more of: a reduced ALT level, a reduced AST level, reduced liver fibrosis, a reduced gamma-glutamyl transferase level, a reduced alkaline phosphatase level, a reduced antimitochondrial antibody level, a reduced antinuclear antibody level, a reduced total serum bilirubin level, and a reduced transaminase level.
5. The method of claim 4, wherein a triglyceride level, an IgM level, and/or a C-reactive protein level is reduced in the subject.
6. The method of claim 5, wherein the subject exhibits one or more of: a reduction in an IgM level of at least about 0.5 g/L and a reduction in C-reactive protein level of at least about 30%.
7. The method of claim 1, wherein the ethyl eicosapentaenoate is present in a composition and represents at least about 90%, by weight, of total fatty acids present in the composition.
8. The method of claim 7, wherein the ethyl eicosapentaenoate represents at least about 96%, by weight, of total fatty acids present in the composition.
9. The method of claim 7, wherein the composition comprises less than about 10%, by weight, of total fatty acids present in the composition, docosahexaenoic acid or its esters.
10. The method of claim 9, wherein the composition comprises less than about 3%, by weight, of total fatty acids present in the composition, docosahexaenoic acid or its esters.
11. The method of claim 10, wherein the composition comprises substantially no docosahexaenoic acid or its esters.
Description
BACKGROUND
Nonalcoholic steatohepatitis ("NASH") is characterized by fat, inflammation and damage in the liver in people who consume little or no alcohol. NASH can lead to liver cirrhosis. NASH tends to be diagnosed in overweight or obese middle-aged people who often have elevated blood lipid levels and diabetes or prediabetes. Primary biliary cirrhosis ("PBC") is characterized by inflammation and damage to the bile ducts. PBC is believed to be an autoimmune condition, but is more common in people who have been exposed to chemicals or who have had an infection. However, the causes of NASH and PBC are not well understood. There are no specific approved therapies for NASH, and only one approved drug for treatment of PBC. A need exists for improved treatments for NASH and PBC.
SUMMARY
In various embodiments, the present invention provides methods of treating and/or preventing NASH and/or PBC in a subject and, in particular, a method of treating and/or preventing NASH and/or PBC in a subject comprising administering to a subject in need thereof a pharmaceutical composition comprising eicosapentaenoic acid ("EPA") or a derivative thereof. In one embodiment, a pharmaceutical composition comprising about 1 to about 6 g of EPA or derivative thereof is administered to the subject daily. In one embodiment, the composition contains not more than 20% or not more than 10%, by weight, docosahexaenoic acid or derivative thereof, substantially no docosahexaenoic acid or derivative thereof, or no docosahexaenoic acid or derivative thereof. In another embodiment, eicosapentaenoic acid ethyl ester comprises at least 96%, by weight, of all fatty acids present in the composition; the composition contains not more than 4%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; and/or the composition contains about 0.1% to about 0.6% of at least one fatty acid other than eicosapentaenoic acid ethyl ester and docosahexaenoic acid (or derivative thereof).
In one embodiment, a pharmaceutical composition useful in accordance with the invention comprises, consists of or consists essentially of at least 95% by weight ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight ethyl nonadecapentaenoate (NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E). In another embodiment, the composition is present in a capsule shell. In another embodiment, the composition contains substantially no or no amount of docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA (DHA-E).
In another embodiment, the invention provides a method of treating moderate to severe hypertriglyceridemia comprising administering a composition as described herein to a subject in need thereof one to about four times per day.
These and other embodiments of the present invention will be disclosed in further detail herein below.
This is the full list of Late-Breaking Science sessions:
Sep 21st, 2021
Late-Breaking Science lineup this November
Seven late-breaking science sessions are on tap for Nov. 13-15.
(Abstracts have been accepted, but are pending confirmation by authors)
LBS.01 | Valves, Veins and New Viewpoints in Cardiothoracic Surgery
Aortic Valve Replacement Versus Watchful Waiting in Asymptomatic Severe Aortic Stenosis: The Avatar Trial (AVATAR)
Evaluating the Benefit of Concomitant Tricuspid Repair During Mitral Valve Surgery
A Randomized Study of Early Versus Standard Coronary Artery Bypass Surgery Among Patients Presenting With Acute Coronary Syndromes Treated With Ticagrelor (RAPID CABG)
Efficacy and Safety of an External Support Device for Saphenous Vein Coronary Bypass Grafts: The VEST Trial (VEST)
LBS.02 | Hypertension: Local, Global and Pandemic Impacts
A Remotely Delivered Hypertension and Lipid Program in 10,000 Patients Across a Diverse Health Care Network
Disruption in Blood Pressure Control With the Covid-19 Pandemic: A Study of 24 U.S. Health Systems in the PCORnet Blood Pressure Control Laboratory (BP Track)
A Cluster Randomized Trial of a Village Doctor-Led Intervention on Blood Pressure Control: China Rural Hypertension Control Project (CRHCP)
LBS.03 | Prevention to Intervention in Atrial Arrhythmias
The Coffee and Real-Time Atrial and Ventricular Ectopy (CRAVE) Trial (CRAVE)
Dabigatran Versus Warfarin on Cognitive Outcomes in Nonvalvular Atrial Fibrillation: Results of the GIRAF Trial. (GIRAF)
Posterior Left Pericardiotomy Reduces Postoperative Atrial Fibrillation After Cardiac Surgery (PALACS)
Outcomes of Adjunctive Left Atrial Appendage Ligation Utilizing the LARIAT Compared to Pulmonary Vein Antral Isolation Alone: The AMAZE Trial (AMAZE)
LBS.04 | Information Overload? Striving to Improve Care Delivery Through Digital Health and Automated Data
Risk Evaluation and its Impact on Clinical Decision-Making and Outcomes in Heart Failure: The REVeAL-HF Trial (REVeAL-HF)
Detection of Atrial Fibrillation in a Large Population Using Wearable Devices: The Fitbit Heart Study
Testing Individualized Triggers of Atrial Fibrillation: A Randomized Controlled Trial (I-STOP-AFib)
LBS.05 | Building on the Foundations of Treatment: Advances in Heart Failure Therapy
Heart Failure With a Preserved Ejection Fraction ≥50% - Results From the EMPEROR-Preserved Clinical Trial (EMPEROR-Preserved)
The Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure (CHIEF-HF) Clinical Trial (CHIEF-HF)
Efficacy and Safety of Empagliflozin in Hospitalized Heart Failure Patients: Main Results From the EMPULSE Trial (EMPULSE)
Randomized Trial of Targeted Transendocardial Delivery of Mesenchymal Precursor Cells in High-Risk Chronic Heart Failure Patients With Reduced Ejection Fraction (DREAM-HF)
LBS.06 | Fish Oil, Cocoa and Cholesterol: Recipes for CVD Prevention?
Icosapent Ethyl Versus Placebo in Outpatients With Covid-19: The Main Results of PREPARE-IT 2 (PREPARE-IT 2)
Primary Findings From the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) on the Prevention of Cardiovascular Disease (COSMOS)
The Clinical Safety, Pharmacokinetics and LDL-Cholesterol Lowering Efficacy of MK-0616, an Oral PCSK9 Inhibitor
LBS.07 | New Drugs and New Drug Indications in Cardiovascular Disease
Effects of Aspirin on Dementia and Cognitive Impairment in the ASCEND Trial (ASCEND)
P2y12 Inhibitors in Noncritically Ill Hospitalized Patients With Covid-19 (ACTIV-4A)
Effect Of Bentracimab on Platelet Inhibition and Hemostasis in Ticagrelor Patients With Uncontrolled Hemorrhage or Requiring Urgent Surgery in the REVERSE-IT (REVERSE-IT)
Milvexian for Prevention of Venous Thromboembolism After Elective Knee Arthroplasty: The AXIOMATIC-TKR Study (AXIOMATIC-TKR)
AHA2021 Late-Breaking Session "LBS.06 | Fish Oil, Cocoa and Cholesterol: Recipes for CVD Prevention" (includes PREPARE-IT Main Results) 13-15Nov2021
LBS.06 | Fish Oil, Cocoa and Cholesterol: Recipes for CVD Prevention?
Icosapent Ethyl Versus Placebo in Outpatients With Covid-19: The Main Results of PREPARE-IT 2 (PREPARE-IT 2)[color=red][/color]
Primary Findings From the Cocoa Supplement and Multivitamin Outcomes Study (COSMOS) on the Prevention of Cardiovascular Disease (COSMOS)
The Clinical Safety, Pharmacokinetics and LDL-Cholesterol Lowering Efficacy of MK-0616, an Oral PCSK9 Inhibitor
Besides BMY's 11.5% ownership of XLRN, BMY has 75-80% of Reblozyl economics, 20% royalty of XLRN's eventual potential multi-blockbuster Sotatercept in PAH,
The potential size of PAH could atrract multiple large biopharma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301027/
J Med Virol. 2020 Jun 9 : 10.1002/jmv.26097.
doi: 10.1002/jmv.26097 [Epub ahead of print]
PMCID: PMC7301027
PMID: 32516845
Elevated level of C-reactive protein may be an early marker to predict risk for severity of COVID-19
Nurshad Alicorresponding author 1
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
To the Editor,
The outbreak of coronavirus disease-2019 (COVID-19) is an emerging global health threat. The healthcare workers are facing challenges in reducing the severity and mortality of COVID-19 across the world. Severe patients with COVID-19 are generally treated in the intensive care unit, while mild or non-severe patients treated in the usual isolation ward of the hospital. However, there is an emerging challenge that a small subset of mild or non-severe COVID-19 patients develops into a severe disease course. Therefore, it is important to early identify and give the treatment of this subset of patients to reduce the disease severity and improve the outcomes of COVID-19. Clinical studies demonstrated that altered levels of some blood markers might be linked with the degree of severity and mortality of patients with COVID-19. 1 , 2 , 3 , 4 , 5 Of these clinical parameter, serum C-reactive protein (CRP) has been found as an important marker that changes significantly in severe patients with COVID-19. 3 CRP is a type of protein produced by the liver that serves as an early marker of infection and inflammation. 6 In blood, the normal concentration of CRP is less than 10?mg/L; however, it rises rapidly within 6 to 8?hours and gives the highest peak in 48?hours from the disease onset. 7 Its half-life is about 19 hours 8 and its concentration decreases when the inflammatory stages end and the patient is healing. CRP preferably binds to phosphocholine expressed highly on the surface of damaged cells. 9 This binding makes active the classical complement pathway of the immune system and modulates the phagocytic activity to clear microbes and damaged cells from the organism. 7 When the inflammation or tissue damage is resolved, CRP concentration falls, making it a useful marker for monitoring disease severity. 7
The available studies that have determined serum concentration of CRP in patients with COVID-19 are presented in Table 1. A significant increase of CRP was found with levels on average 20 to 50?mg/L in patients with COVID-19. 10 , 12 , 21 Elevated levels of CRP were observed up to 86% in severe COVID-19 patients. 10 , 11 , 13 Patients with severe disease courses had a far elevated level of CRP than mild or non-severe patients. For example, a study reported that patients with more severe symptoms had on average CRP concentration of 39.4?mg/L and patients with mild symptoms CRP concentration of 18.8?mg/L. 12 CRP was found at increased levels in the severe group at the initial stage than those in the mild group. 1 In another study, the mean concentration of CRP was significantly higher in severe patients (46?mg/L) than non-severe patients (23?mg/L). 21 The patients who died from COVID-19 had about 10 fold higher levels of CRP than the recovered patients (median 100 vs 9.6?mg/L). 16 A recent study showed that about 7.7% of non-severe COVID-19 patients were progressed to severe disease courses after hospitalization, 3 and compared to non-severe cases, the aggravated patients had significantly higher concentrations of CRP (median 43.8 vs 12.1?mg/L). A significant association was observed between CRP concentrations and the aggravation of non-severe patients with COVID-19 [1], and the authors proposed CRP as a suitable marker for anticipating the aggravation probability of non-severe COVID-19 patients, with an optimal threshold value of 26.9?mg/L. 3 The authors also noted that the risk of developing severe events is increased by 5% for every one-unit increase in CRP concentration in patients with COVID-19.
Table 1
Levels of C-reactive protein (CRP) in patients with COVID-19
Reference Group Patients (n) CRP, mg/L P value N and % of patients with elevated CRP
Chen et al 10 Hospitalized 99 51.4 (41.8) NA 63/73 (86)
Chen et al 11 Death 113 113 (69.1-168.4) NA 59/68 (60)
Recovered 161 26.2 (8.7-55.4) 21/45 (14)
Gao et al 12 Severe 15 39.4 (27.7) .011 NA
Mild 28 18.8 (22.2)
Guan et al 13 Severe 173 NA NA 110/135 (81.5)
Non-severe 926 NA 371/658 (56.4)
Jin et al 14 Severe (GI symptoms) 74 15.7 (4.8-23.9) .003 NA
Non-severe (no-GI symptoms) 577 7.9 (2.6-19.6)
Liu et al 15 Severe 13 62.9 (42.4-86.6) NA NA
Mild 27 7.6 (3.1-57.3)
Luo et al 16 Died 84 100 (60.7-179.4) .000 NA
Recovered 214 9.6 (5-37.9)
Mo et al 17 Severe 85 46 (22-106) .001 NA
Mild 70 23 (10-47)
Shang et al 18 Severe 139 43.1 (9.8-97.3) <.001 NA
Non-severe 304 10 (2.9-27.1)
Shi et al 19 Hospitalized 81 47.6 (41.8) NA NA
Wang et al 3 Severe 16 43.8 (12.3-101.9) .000 NA
Non-severe 193 12.1 (0.1-91.4)
Young et al 20 Severe 6 65.6 (47.5-97.5) NA NA
Non-severe 18 11.1 (0.9-19.1)
Open in a separate window
Note: Data are presented as mean (SD) or median (IQR). Severe: patients admitted to the ICU. P value indicates the mean or median difference of CRP levels between the severe and non-severe group.
Abbreviations: GI, gastrointestinal; ICU, intensive care unit; IQR, interquartile range; NA, not available.
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
Furthermore, it was observed that patients with low oxygen saturation (SpO2?≤?90%) had significantly higher levels of CRP (median 76.5?mg/L) compared with patients with high oxygen saturation (SpO2?>?90%) (median 12.7?mg/L), 22 indicating that more severe patients with lung damage have elevated levels of CRP. So, higher levels of CRP indicate more severe disease course-linked to lung injury and worse prognosis. CRP levels are correlated well with the severity of symptoms of patients with COVID-19; therefore, it may be a suitable marker in assessing a patient's conditions together with other clinical findings.
The elevated levels of CRP might be linked to the overproduction of inflammatory cytokines in severe patients with COVID-19. Cytokines fight against the microbes but when the immune system becomes hyperactive, it can damage lung tissue. Thus, CRP production is induced by inflammatory cytokines and by tissue destruction in patients with COVID-19. In conclusion, elevated level of CRP may be a valuable early marker in predicting the possibility of disease progression in non-severe patients with COVID-19, which can help health workers to identify those patients an early stage for early treatment. Besides, COVID-19 patients with elevated levels of CRP need close monitoring and treatment even though they did not develop symptoms to meet the criteria for the severe disease course. However, CRP levels in patients with COVID-19 who may progress from non-severe to severe cases need to be further studied in large-scale multicenter studies.
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CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
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AUTHOR CONTRIBUTION
NA wrote and revised the manuscript.
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REFERENCES
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AMRN CEO Karim Mikhail did not set expectations for the PREPARE-IT-1 late-breaking science presentation during the 2Q2021 earnings call. In fact, there was no reference to it.
Here is the only relevant excerpt re Life Cycle Management (LCM):
We plan not to waste any opportunity that will allow us to leverage the investment in our global commercial infrastructure. The first work stream we are prioritizing is our own lifecycle planning for VASCEPA. Icosapent ethyl has proven to be a beneficial molecule in a number of clinical settings. And we are actively evaluating other potential research settings in which to further explore and characterize the drugs activity. And these efforts will align with clinical and commercial needs across individual and global markets for the brand.
The ESC2021 Schedule Overview invited confusion, as it suggested a 02:00 (2 in the morning CEST) start time for the Late Breaking Trials - Covid-19 session on Channel 1 with later times in the usual European time format without am/pm. However, there are no live sessions now, which suggests the interpretation as 2 pm or 1400.
Rafa is correct re timing:
Late Breaking Trials - COVID-19
Topic: Other
Session type: Late-Breaking Science
Date: 29 August
Start time: 02:00
End time: 02:45
Channel: Channel 1 - COVID-19
Chairpersons
Susanna Price (Royal Brompton Hospital - London, United Kingdom of Great Britain & Northern Ireland) susannaprice
Jean-Claude Tardif (Montreal Heart Institute - Montreal, Canada)
Presentations
Colchicine in Patients Hospitalized with COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)
The Michelle trial: Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy
Speaker: Eduardo Ramacciotti (Science Valley Research Institute - Santo Andre, Brazil) Ramacciotti_MD
Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial
Speaker: Michael Zile ( Medical University of South Carolina & VA Med Ctr - Charleston, S C, United States of America)
PREPARE-IT: Icosapent Ethyl Versus Placebo in People Exposed to COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)
Pfizer bought into Eliquis/Apixaban in 2007:
https://www.fiercebiotech.com/biotech/pfizer-partners-bms-1b-deal
BMY and PFE alliance
https://www.businesswire.com/news/home/20201026005265/en/Decreases-in-Americans-Primary-Care-Visits-May-Lead-to-Late-Diagnoses-of-Potentially-Serious-Conditions1
Decreases in Americans' Primary Care Visits May Lead to Late Diagnoses of Potentially Serious Conditions1
‘No Time to Wait’ campaign launches to educate about symptoms of Atrial Fibrillation (AFib), Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
October 26, 2020 08:00 AM Eastern Daylight Time
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--The Bristol Myers Squibb–Pfizer Alliance, with the support of leading advocacy organizations and medical societies, announces the launch of the No Time to Wait campaign. No Time to Wait aims to raise awareness of the symptoms of three conditions – atrial fibrillation (AFib), deep vein thrombosis (DVT) and pulmonary embolism (PE). AFib is the most common type of irregular heartbeat and increases the risk for stroke.2 DVT is a condition where a blood clot forms in a deep vein, which can travel to the lungs and lead to a PE—and a PE can be deadly.3,4,5 Seeking medical attention early – by phone, online or in person – may help reduce the chance of these conditions becoming something more serious.6,7
Unfortunately, many Americans have not been getting their standard healthcare this year, as indicated by IQVIA’s National Disease and Therapeutic Index of nationally representative, outpatient data. The data show a decrease in office-based primary care visits by approximately 50 percent in April through June 2020 when compared to the same timeframe the previous two years.1 While telehealth visits increased by approximately 35 percent during the same time frame, there was still about a 20 percent decrease of all types of primary care visits – showing that many people skipped their primary care appointments.1
AFib is the most common type of irregular heartbeat and increases risk for stroke by approximately five times.2,8,9 The symptoms may include, but are not limited to, irregular heartbeat, heart palpitations, chest pain, shortness of breath, fatigue and/or light headedness.2,6 It is estimated that 8.4 million people in the U.S. are projected to have AFib in 2020.10
“My colleagues and I are deeply concerned about the impact that delaying medical care may have on patient health,” said Andrea Russo, M.D., cardiologist, immediate past-president, Heart Rhythm Society and director of electrophysiology and arrhythmia services at Cooper University Hospital in Camden, NJ. “Atrial fibrillation may increase stroke risk approximately five-fold, so it is critical to consult with a doctor if experiencing symptoms.”
DVT is a condition where a blood clot forms in a deep vein, occurring usually in the legs, thigh, or pelvis.5 DVT symptoms may include swelling, pain, tenderness, or redness of the skin.5 DVT related blood clots, or parts of them, can break off and travel through the bloodstream to the lungs, reducing or cutting off blood supply.3 A PE is a blood clot in the lungs and is a serious condition that can be caused by DVT.3 PE may cause chest pain, discomfort or difficulty breathing – and can be deadly.5 According to CDC data from 2010, approximately 900,000 Americans are affected by DVT/PE each year.5
“It’s understandable why patients may feel compelled to avoid visiting hospitals and healthcare facilities right now. But it’s integral for them to know that not addressing symptoms may have serious consequences,” said Jenice Baker, M.D., associate emergency medicine director in Camden, NJ. “For people with symptoms that may be associated with deep vein thrombosis or pulmonary embolism, talking to a doctor is imperative.”
Individuals are encouraged to visit www.NoTimetoWait.com, where they can find additional information about AFib and DVT/PE. Through the No Time to Wait campaign, the Alliance is hoping to prompt those experiencing symptoms to reach out to a healthcare provider by phone, online, or in person. Symptoms could be representative of many conditions, so only a healthcare provider is able to make the proper diagnosis.
“The Bristol Myers Squibb-Pfizer Alliance is committed to educating Americans about the most common symptoms of AFib and DVT/PE, which are potentially serious conditions that may require time sensitive care,” said Rory O’Connor, M.D., Chief Medical Officer, Internal Medicine Medical Affairs at Pfizer. “We’re proud to introduce the No Time to Wait campaign in response to the current environment, encouraging people to speak to a doctor if they feel symptoms.”
About the No Time to Wait Campaign
The Bristol Myers Squibb-Pfizer Alliance, with support of leading advocacy organizations, launched the No Time to Wait campaign to raise awareness of symptoms of atrial fibrillation (AFib) and deep vein thrombosis (DVT)/pulmonary embolism (PE). Seeking medical attention early may help reduce the chance of AFib leading to, or DVT/PE becoming, something more serious. AFib, the most common irregular heartbeat, increases the risk for stroke by approximately five times.2 DVT is a condition where the blood forms clots, which could travel to your lungs and lead to a PE — and be deadly.3,4,5 To learn more about AFib and DVT/PE, including the associated symptoms and how to prepare for a healthcare appointment, visit www.NoTimetoWait.com. Visit the following resources for more information: Heart Rhythm Society, Association of Black Cardiologists, StopAfib.org, Anticoagulation Forum, National Blood Clot Alliance, International Society on Thrombosis and Haemostasis: World Thrombosis Day Campaign, Preventive Cardiovascular Nurses Association, American Academy of Family Physicians, Mended Hearts, WomenHeart, North American Thrombosis Forum, Atrial Fibrillation Association, Arrythmia Alliance and Pulmonary Embolism Response Team Consortium
About the Bristol Myers Squibb-Pfizer Collaboration
The Bristol Myers Squibb-Pfizer Alliance (the Alliance) is committed to driving education and awareness about atrial fibrillation and deep vein thrombosis (DVT) and/or pulmonary embolism (PE). With long-standing cardiovascular leadership, global scale and expertise in this field, the Alliance strives to implement global, research-driven approaches to illuminate and address the unmet needs around strokes related to non-valvular atrial fibrillation, which are often fatal or debilitating.9,11 Through collaborations with non-profit organizations, the Alliance aims to provide patients, physicians and decision makers with the information they need to understand and take appropriate action on risk factors associated with stroke and other cardiovascular conditions.
About Bristol Myers Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.
About Pfizer Inc.: Breakthroughs that change patients’ lives
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer.
Session: Late-Breaking Trials-COVID-19
“Icosapent Ethyl Versus Placebo in People Exposed to COVID-19: The Main Results of PREPARE-IT-1” – presented on behalf of all authors by Rafael Diaz, M.D., Estudios Cardiologicos Latinoamerica (ECLA), Rosario, Argentina – August 29, 2:00 p.m. CEST
Based on the BMY acquisition of CELG, the tax treatment is a bit more onerous unless the stock represents 80% of the deal value to the best of my recollection based on changes made in the most recent change in US tax code.
In the BMY-CELG deal, all components, 50 in cash, 1 share of BMY worth 56.41 at closing and 2.30 allocation for the CVR were all taxable. It was not an ideal structure unless shares were in a tax-exempt account, e.g. IRA.
BMY and PFE alliance
https://www.businesswire.com/news/home/20201026005265/en/Decreases-in-Americans-Primary-Care-Visits-May-Lead-to-Late-Diagnoses-of-Potentially-Serious-Conditions1
Decreases in Americans' Primary Care Visits May Lead to Late Diagnoses of Potentially Serious Conditions1
‘No Time to Wait’ campaign launches to educate about symptoms of Atrial Fibrillation (AFib), Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)
October 26, 2020 08:00 AM Eastern Daylight Time
PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--The Bristol Myers Squibb–Pfizer Alliance, with the support of leading advocacy organizations and medical societies, announces the launch of the No Time to Wait campaign. No Time to Wait aims to raise awareness of the symptoms of three conditions – atrial fibrillation (AFib), deep vein thrombosis (DVT) and pulmonary embolism (PE). AFib is the most common type of irregular heartbeat and increases the risk for stroke.2 DVT is a condition where a blood clot forms in a deep vein, which can travel to the lungs and lead to a PE—and a PE can be deadly.3,4,5 Seeking medical attention early – by phone, online or in person – may help reduce the chance of these conditions becoming something more serious.6,7
Unfortunately, many Americans have not been getting their standard healthcare this year, as indicated by IQVIA’s National Disease and Therapeutic Index of nationally representative, outpatient data. The data show a decrease in office-based primary care visits by approximately 50 percent in April through June 2020 when compared to the same timeframe the previous two years.1 While telehealth visits increased by approximately 35 percent during the same time frame, there was still about a 20 percent decrease of all types of primary care visits – showing that many people skipped their primary care appointments.1
AFib is the most common type of irregular heartbeat and increases risk for stroke by approximately five times.2,8,9 The symptoms may include, but are not limited to, irregular heartbeat, heart palpitations, chest pain, shortness of breath, fatigue and/or light headedness.2,6 It is estimated that 8.4 million people in the U.S. are projected to have AFib in 2020.10
“My colleagues and I are deeply concerned about the impact that delaying medical care may have on patient health,” said Andrea Russo, M.D., cardiologist, immediate past-president, Heart Rhythm Society and director of electrophysiology and arrhythmia services at Cooper University Hospital in Camden, NJ. “Atrial fibrillation may increase stroke risk approximately five-fold, so it is critical to consult with a doctor if experiencing symptoms.”
DVT is a condition where a blood clot forms in a deep vein, occurring usually in the legs, thigh, or pelvis.5 DVT symptoms may include swelling, pain, tenderness, or redness of the skin.5 DVT related blood clots, or parts of them, can break off and travel through the bloodstream to the lungs, reducing or cutting off blood supply.3 A PE is a blood clot in the lungs and is a serious condition that can be caused by DVT.3 PE may cause chest pain, discomfort or difficulty breathing – and can be deadly.5 According to CDC data from 2010, approximately 900,000 Americans are affected by DVT/PE each year.5
“It’s understandable why patients may feel compelled to avoid visiting hospitals and healthcare facilities right now. But it’s integral for them to know that not addressing symptoms may have serious consequences,” said Jenice Baker, M.D., associate emergency medicine director in Camden, NJ. “For people with symptoms that may be associated with deep vein thrombosis or pulmonary embolism, talking to a doctor is imperative.”
Individuals are encouraged to visit www.NoTimetoWait.com, where they can find additional information about AFib and DVT/PE. Through the No Time to Wait campaign, the Alliance is hoping to prompt those experiencing symptoms to reach out to a healthcare provider by phone, online, or in person. Symptoms could be representative of many conditions, so only a healthcare provider is able to make the proper diagnosis.
“The Bristol Myers Squibb-Pfizer Alliance is committed to educating Americans about the most common symptoms of AFib and DVT/PE, which are potentially serious conditions that may require time sensitive care,” said Rory O’Connor, M.D., Chief Medical Officer, Internal Medicine Medical Affairs at Pfizer. “We’re proud to introduce the No Time to Wait campaign in response to the current environment, encouraging people to speak to a doctor if they feel symptoms.”
About the No Time to Wait Campaign
The Bristol Myers Squibb-Pfizer Alliance, with support of leading advocacy organizations, launched the No Time to Wait campaign to raise awareness of symptoms of atrial fibrillation (AFib) and deep vein thrombosis (DVT)/pulmonary embolism (PE). Seeking medical attention early may help reduce the chance of AFib leading to, or DVT/PE becoming, something more serious. AFib, the most common irregular heartbeat, increases the risk for stroke by approximately five times.2 DVT is a condition where the blood forms clots, which could travel to your lungs and lead to a PE — and be deadly.3,4,5 To learn more about AFib and DVT/PE, including the associated symptoms and how to prepare for a healthcare appointment, visit www.NoTimetoWait.com. Visit the following resources for more information: Heart Rhythm Society, Association of Black Cardiologists, StopAfib.org, Anticoagulation Forum, National Blood Clot Alliance, International Society on Thrombosis and Haemostasis: World Thrombosis Day Campaign, Preventive Cardiovascular Nurses Association, American Academy of Family Physicians, Mended Hearts, WomenHeart, North American Thrombosis Forum, Atrial Fibrillation Association, Arrythmia Alliance and Pulmonary Embolism Response Team Consortium
About the Bristol Myers Squibb-Pfizer Collaboration
The Bristol Myers Squibb-Pfizer Alliance (the Alliance) is committed to driving education and awareness about atrial fibrillation and deep vein thrombosis (DVT) and/or pulmonary embolism (PE). With long-standing cardiovascular leadership, global scale and expertise in this field, the Alliance strives to implement global, research-driven approaches to illuminate and address the unmet needs around strokes related to non-valvular atrial fibrillation, which are often fatal or debilitating.9,11 Through collaborations with non-profit organizations, the Alliance aims to provide patients, physicians and decision makers with the information they need to understand and take appropriate action on risk factors associated with stroke and other cardiovascular conditions.
PREPARE-IT in Late-Breaking Covid-19 Trials Session at ESC Congress 2021on 29Aug2021
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Late Breaking Trials - COVID-19
Topic: Other
Session type: Late-Breaking Science
Date: 29 August
Start time: 02:00
End time: 02:45
Channel: Channel 1 - COVID-19
Chairpersons
Susanna Price (Royal Brompton Hospital - London, United Kingdom of Great Britain & Northern Ireland) susannaprice
Jean-Claude Tardif (Montreal Heart Institute - Montreal, Canada)
Presentations
Colchicine in Patients Hospitalized with COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)
The Michelle trial: Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy
Speaker: Eduardo Ramacciotti (Science Valley Research Institute - Santo Andre, Brazil) Ramacciotti_MD
Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial
Speaker: Michael Zile ( Medical University of South Carolina & VA Med Ctr - Charleston, S C, United States of America)
PREPARE-IT: Icosapent Ethyl Versus Placebo in People Exposed to COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)
PREPARE-IT in Late-Breaking Covid-19 Trials Session at ESC Congress 2021on 29Aug2021
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Schedule overview
Search in the programme
My Programme
Late Breaking Trials - COVID-19
Topic: Other
Session type: Late-Breaking Science
Date: 29 August
Start time: 02:00
End time: 02:45
Channel: Channel 1 - COVID-19
Chairpersons
Susanna Price (Royal Brompton Hospital - London, United Kingdom of Great Britain & Northern Ireland) susannaprice
Jean-Claude Tardif (Montreal Heart Institute - Montreal, Canada)
Presentations
Colchicine in Patients Hospitalized with COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)
The Michelle trial: Medically Ill hospitalized Patients for COVID-19 THrombosis Extended ProphyLaxis with rivaroxaban ThErapy
Speaker: Eduardo Ramacciotti (Science Valley Research Institute - Santo Andre, Brazil) Ramacciotti_MD
Insights into the Effects of the COVID-19 Pandemic: Comprehensive Analysis from the GUIDE-HF Trial
Speaker: Michael Zile ( Medical University of South Carolina & VA Med Ctr - Charleston, S C, United States of America)
PREPARE-IT: Icosapent Ethyl Versus Placebo in People Exposed to COVID-19
Speaker: Rafael Diaz (Estudios Cardiologicos Latinoamerica (ECLA) - Rosario, Argentina)[color=red][/color]
Endpoints 13Apr2021 AMRN Article
April 13, 2021 07:45 AM EDTUpdated 07:56 AM People
Amarin CEO John Thero passes baton to Europe commercial chief as M&A hopes continue to deflate
Amber Tong
Senior Editor
Karim Mikhail
As Amarin breaks into the European market, John Thero is heading out.
After steering the ship for 7 years, Thero is handing the CEO job to Karim Mikhail, who came on board earlier this year to head the commercialization of Amarin’s fish oil pill in Europe. Mikhail’s appointment is effective Aug. 1, when Thero will officially retire and transition to an advisor role until the end of 2021.
Since joining Amarin in 2009, Thero has been credited for a slate of achievements that gave investors lots to be excited about. Under his watch, Vascepa — the pharmaceutical grade omega-3 fatty acid product first approved in 2012 — was cruised to a positive Phase III data readout despite some controversy, spurring an impressive reduction in risk of cardiovascular events that led to a quick FDA add-on approval.
The one thing he is leaving without is a multibillion-dollar buyout — and, with the doors apparently closed to a patent extension, the hopes are dimming by the day.
All of that signals a “tough road ahead,” according to Jefferies analyst Michael Yee, who’s been a big cheerleader for Thero:
Thus, investors may be disappointed in the transition and that it may signal no near term M&A on the table (which is the clear and primary bull case to the stock). That said – one might argue perhaps a change means new mgmt may position AMRN in a way to be easier to sell via M&A and/or that this opens the co up to more options, but we don’t think that is likely and the most logical scenario is AMRN will go forward with a Q3 EU launch which will take time.
In a statement, Amarin praised Mikhail’s credentials in launching new drugs — topped by a stint as global commercial leader for Merck’s $4 billion lipid franchise. In that role, the company highlighted, “he was responsible for reversing the business’ decline in the US market and globally, accelerating revenue by an additional $380 million through the launch of ATOZET and driving EBITDA growth through international expansion.”
Amarin will need it. Yee expects the US sales for Q1 to come in just shy of consensus, even as its generic competitors at Hikma and Dr. Reddy’s are having issues with manufacturing and scaling up.
“(It) looks like Amarin should be okay in the near term and maintain 80-90% share, but uncertainty remains around eventual durability of US sales (i.e., what percent tail value is retained over 2-5+ years),” he wrote.
Freshly approved as Vazkepa in Europe just days ago, the drug is set for a near-term launch and should score another OK in China later this year, Mikhail added.
HCW - AMRN: Europe Can Present Second Wind for Vascepa, Despite Program’s Infancy (Buy PT 10)
European Vazkepa on verge of launch; approval expected April 2021. With domestic Vascepa’s European counterpart Vazkepa on the heels of a positive CHMP opinion, we note formal approval from the European Commission is expected in April 2021. Specifically informed by: (1) Amarin’s displayed domestic launch aptitude from Vascepa’s expanded label in cardiovascular (CV) risk reduction; (2) preliminary market access discussions in preparation for commercial launch and (3) the company’s actively growing European commercial team, we believe that pending approval, Vazkepa is well positioned to enter the European market comprised of upwards of millions of patients at high risk for CV events, despite potential statin therapy. While we believe education remains a top priority in terms of Vazkepa awareness and understanding of its CV risk reduction profile, we believe key strategic strengths of the prospective European launch are driven by: (1) Amarin conducting commercial launch without a strategic partner, with the potential to in turn reap the progressive country-by-country commercial benefits based on coverage market access negotiations; and (2) design of its intended label to focus on Vazkepa’s evidenced CV risk reduction benefit and not targeted to triglyceride (TG) reduction, which we note had presented the Achilles’ heel for the threat of generic entry within the U.S. market. A key point to appreciate about prospective European launch is that Vazkepa would be entering a CV market where there are no immediate competitors in the space and with established IP protection from generic entry. While we note Vascepa has continued to perform from a revenue standpoint domestically, reporting 43% year-over-year growth in net total revenue for 2020, we believe that the European presence of Vazkepa can directly drive both CV risk reduction awareness and top-line growth looking into the near-term horizon.
You thought that was it? China approval potentially near end of 2021. We emphasize opportunity for global expansion continues with strategic partner Edding (private) for the potential approval of Vascepa in China, further broadening the reach of its preventative CV risk benefits. We note approval is anticipated near the end of 2021, with: (1) the Chinese National Medical Products Administration (NMPA) reviewing icosapent ethyl for Mainland China approval; and (2) the Hong Kong Department of Health reviewing icosapent ethyl for approval in Hong Kong. Further informed from Edding’s positive topline from its pivotal Phase 3 trial, we believe that a potential approval in the region could be well received among high TG patients at risk for CV events. Lastly, as we turn our sights back to domestic positioning of Vascepa, we believe commercial progress continues to benefit specifically from: (1) Hikma Pharmaceuticals’ (HIK.L; not rated) launch of generic icosapent ethyl comprised of a skinny label targeted to treat severe hypertriglyceridemia (SHTG) patients, which Amarin notes is limited to approximately 7% of current Vascepa usage; (2) continued question of generic manufacturing capacity, product purity and stability; and (3) the prospect of Vascepa being able to potentially compete with regard to pricing informed from co-pays and rebates, as Amarin continues to determine the overall cadence of educational marketing.
4Q in numbers. The company recorded total revenues of $167.3M for 4Q20 compared to consensus of $164.4M, representing 17% YoY growth despite limitations posed by the ongoing pandemic. Total revenues of $614.1M were reported for full-year 2020, and represented 43% YoY growth. The company reported net income of $4.9M, or $0.01/share for 4Q20, and reported net loss of $18.0M, or $0.05/share for full-year 2020. Reported R&D expenses were $39.0M, and SG&A expenses were $463.3M for full-year 2020. As of December 31, 2020, the company reported $563.4M in cash and investments.
Valuation and risks. We reiterate our Buy rating and $10 price target. Our price target of $10 is based on equally weighted average of: (a) $9.23/ share, as a 30x multiple of taxed and diluted FY29 GAAP EPS of $0.95 discounted back to FY21 at 15%; and (b) an NPV of $10.16/share (discount rate 10%, growth rate 2%). Risks to our investment thesis include: (1) Vascepa commercial ramp-up and/or peak sales not meeting our projections; and (2) further competitive disruption of the omega-3 market by branded drugs or generics and/ or OTC supplements beyond our model.
Conference Calls
Symbol
Date
Number
Code
Comments
AMRN
Web Cast Available 2/25/21, 07:30 AM 877-545-0320 635842 Conference Call to discuss earnings for the Q4.
AMRN 7Jan2021 PR "AMARIN PROVIDES PRELIMINARY 2020 RESULTS AND 2021 OUTLOOK"
Unaudited 2020 Total Net Revenue Estimated to Be Approximately $610 Million, an Increase of Approximately 42% Compared with 2019
Completion of European Regulatory Review and Submission of China Regulatory Application for VASCEPA® (icosapent ethyl) Expected in Late January or February 2021
DUBLIN, Ireland and BRIDGEWATER, N.J., Jan. 07, 2021 (GLOBE NEWSWIRE) -- Amarin Corporation plc (NASDAQ:AMRN) today provided a business update, including preliminary unaudited full-year 2020 revenue results. Amarin plans to discuss these results and expectations with investors in connection with the 39th Annual J.P. Morgan Healthcare Conference at which Amarin is scheduled to present on Tuesday, January 12, 2020, at 2:00 pm Eastern time.
Preliminary (unaudited) 2020 Financial Results
Record Revenue Levels: Full-year 2020 total net revenue, subject to audit, are expected to be approximately $610 million. Despite the impact of COVID-19, this estimated 2020 net revenue expectation represents an increase of approximately 42% compared with full-year 2019 results. This growth was primarily driven by increased prescription levels of VASCEPA® in the United States.
Liquid Assets: Amarin ended 2020 with more than $550 million in cash and investments, approximately $150 million in net accounts receivable and approximately $180 million in inventory.
No Debt: At year-end 2020, Amarin had no debt, having fully repaid its prior royalty-like debt instrument in the fourth quarter of 2020, which from 2013 through most of 2020 required approximately 10% of net revenue to be paid against this prior obligation.
Management Commentary
“Amarin has the people, product and resources to expand globally starting with anticipated 2021 VASCEPA regulatory approval and commercial launch in Europe. Our expected growth in Europe and elsewhere overseas will build on our growth and experience in the United States,” commented John F. Thero, president and chief executive officer. “We intend to build on our strong scientific foundation and medical experience. As patients begin to return for medical care beyond the COVID-19 era, we aim to ensure that VASCEPA is increasingly prescribed to help at-risk patients. While 2020 was a challenging year, I am thankful to our employees for the progress they made in countless areas. Their hard work and passion provide a strong foundation from which we will further launch VASCEPA to reduce persistent cardiovascular risk in appropriate patients, or P-CVR, in the United States, Europe and around the world.”
Highlights from 2020 and Outlook
U.S. Commercial
Amarin achieved a number of important commercial milestones in 2020, despite the challenges Amarin faced with COVID-19 and the November launch of generic icosapent ethyl in the United States.
U.S. commercial highlights from 2020 include:
Record levels of VASCEPA revenues, prescriptions, prescribers and patients
Faster prescription growth for VASCEPA as compared to most other cardiovascular drugs that reported positive outcomes studies in recent years, despite VASCEPA having a lower level of promotional spend than many such drugs
VASCEPA growth in 2020 due to COVID-19 was slower than initially expected but compares well with the growth in 2020 of peer drugs
The P-CVR indication has quickly garnered the largest part of the market as approximately 93% of VASCEPA prescriptions based on the most recent data reported to us by IQVIA were for patients with triglyceride (TG) levels below 500 mg/dL
Further expanded managed care coverage for VASCEPA during 2020 with additional improvements agreed for 2021
Such increases are consistent with third-party analysis, which found VASCEPA to be cost effective, and with medical guidelines or recommendations from six leading U.S. medical societies
Doubled size of sales force (training for this expanded group was completed in March 2020 just before Amarin’s customer-facing team was temporarily prohibited from conducting in-person meetings due to COVID-19)
Adapted to COVID-19 protocols with various tele-sales, tele-marketing and virtual education initiatives as well as training representatives to safely interact with healthcare professionals where possible
U.S. commercial outlook includes:
Confidence that millions of at-risk patients remain untreated for P-CVR and could benefit from VASCEPA
Recognition that many at-risk patients ceased doctor visits for ordinary care in 2020 but are likely to return to their doctors for needed care as COVID-19 risk recedes
According to IQVIA, patient visits to medical offices for non-emergency medical care were down approximately 70% in April 2020 during the height of COVID-19, with visits steadily increasing thereafter. In December 2020, as a result of a spike in COVID-19 cases, patient visits have decreased approximately 50% compared to pre-COVID levels
Following a resurgence of COVID-19 in recent months, Amarin intends to reduce spending levels for certain forms of promotion (e.g., television advertisements) in early 2021
U.S. promotional spending likely to be variable with adjustments upward or downward in response to the changing impact from COVID-19 and generic competition
As COVID-19 vaccine progress is made, along with other mitigating approaches, Amarin plans to increasingly resume its promotion of VASCEPA for P-CVR while continuing to adapt to market changes
Generic competition launched in November 2020 only for the original indication (TG >500 mg/dL) and is expected to continue to face supply limits, despite stockpiles of generic product likely created prior to launch
Variability is expected as patients, pharmacies and payers adjust to the availability, pricing and label of this generic competition
Due to the uncertainties regarding COVID-19 and potential generic supply, Amarin will continue to withhold 2021 revenue guidance for VASCEPA in the U.S. until there is greater clarity on the impact of these issues
Amarin intends to continue to manage its U.S. commercial operations to expand patient care and enhance profits from U.S. operations
Europe
Europe highlights from 2020 include:
Reached Day 180 of the European Medicines Agency, or EMA, centralized regulatory review of VASCEPA assuring that the United Kingdom is grandfathered into a facilitated review process despite its withdrawal from the European Union
An expanded recommendation was issued by the European Society of Cardiology regarding use of icosapent ethyl (U.S. brand name VASCEPA)
Increased the size of the Amarin team in Europe to approximately 50 experienced professionals to support pre-approval and pre-launch preparations for VASCEPA in select countries
Commenced interactions with authorities in select countries regarding VASCEPA market access assuming approval, noting that more formal proceedings cannot progress until after the product is approved and the label is established
Made major advances in expanding company-wide systems to support expected commercial launch of VASCEPA in Europe in 2021
Europe outlook includes:
Millions of at-risk patients could benefit from VASCEPA in Europe
There are more patients on statins in Europe in aggregate compared to the U.S. and the rate of death from cardiovascular disease is higher
Regulatory approval expected in early 2021
CHMP opinion expected in late January or February 2021
EMA approval decision expected within 67 days of CHMP decision
Market access negotiations anticipated on a country-by-country basis promptly after approval
Seeking net pricing that equals or exceeds U.S. net pricing with focus on P-CVR indication based on outcomes data in Europe, whereas pricing in the U.S was based on original TG lowering indication
Launch timing by country dependent on market access (i.e., insurance coverage)
At a minimum, launch expected in Germany in 2021 after initial product awareness campaign
Launch in Germany and other countries is anticipated to give priority to specialists (e.g., cardiologists) and to also include substantial digital educational and promotional initiatives
Target of approximately 200 employees (or contractors) in the European commercial team by end of 2021
Rest of World
Rest of world, or ROW, highlights from 2020 include:
China positive clinical study results reported
Canada commercial launch of VASCEPA initiated (just prior to slowdown from COVID-19)
Canada reimbursement levels for VASCEPA established within six months of product regulatory approval to facilitate treating patients with established cardiovascular disease
ROW outlook includes:
Large at-risk patient opportunities
In China 290 million people are reported to have cardiovascular disease, a number which has been increasing rapidly in recent years, including approximately 52 million reported to have high TG levels, a substantial portion of whom might be able to benefit from VASCEPA
Plans to submit application for regulatory approval through Amarin’s commercial partner in the People's Republic of China
Anticipate inclusion of VASCEPA in the treatment guidelines in Chinese medical societies
Pursue opportunities for VASCEPA in untapped countries after approval and market access in Europe is secured, with such approval and market access expected to enhance ROW positioning
R&D and Medical Advancement
R&D and medical advancement highlights from 2020 include:
EVAPORATE exploratory study results, as previously reported, reported 17% reduction in plaque volume in patients with coronary atherosclerosis treated with VASCEPA
Numerous other studies presented in support of the potential unique mechanism of action of VASCEPA
In aggregate, Amarin supported over 40 scientific publications and presentations in 2020
CardioLink-19 exploratory study results, as previously reported, evaluated a higher initial dose of VASCEPA and suggested VASCEPA could potentially have utility as a therapeutic option for mitigating COVID-19 effects in an out-patient setting
This pilot study was rapidly commenced and completed with results that exceeded expectations
Additional COVID-19 investigational studies of VASCEPA were also commenced in 2020
Witnessed an increase to twelve (12) the number of medical societies globally that now include icosapent ethyl in their guidelines or have otherwise recommended its use
R&D and medical outlook includes:
Supporting approval of VASCEPA in Europe and regulatory review processes initiated by Amarin’s commercial partner in the People's Republic of China
Supporting cost-effectiveness studies and market access for VASCEPA wherever it is approved
Support completion of COVID-19 investigational studies and, based on the results, decide on appropriate next steps
Continue to study and differentiate the unique clinical and biological effects of VASCEPA
In concert with Amarin’s business development and other efforts, prioritize and execute on potential opportunities to expand indications for VASCEPA or develop new products
Financial Resources
Amarin reiterates that it believes its current cash resources are adequate to support the European launch and its planned operations and priorities in the United States and globally. Such guidance included anticipated resources likely needed to further expand its VASCEPA supply capacity in anticipation of launches of VASCEPA in Europe, China and other countries as well as the opportunity to continue to grow prescription levels in the United States after COVID-19 recedes, continuing the launch of VASCEPA for P-CVR as commenced in 2020.
Currently, Amarin anticipates 2021 operating expenses of approximately $550 million to $600 million which represents an increase of approximately 10% to 20%, compared with 2020 levels. Included in these anticipated expenses are increased costs associated with Amarin’s commercial launch preparations and initial launch in Europe as well as continued U.S. promotional activities, including increased face to face interactions between Amarin’s sales professionals and health care providers and direct-to-consumer advertising in the U.S. after the impact of COVID-19 becomes less pronounced and at-risk patients begin returning to their doctors for non-urgent medical care. With continued investment in consumer and in-person marketing, Amarin expects VASCEPA revenue growth in the U.S. As described above, these spending levels may vary from quarter to quarter. Further these operating expense levels assume substantial societal recovery in 2021 from COVID-19 and the continued limited availability of supply to the generic companies. Amarin will re-evaluate its planned spend in 2021 if any of these assumptions change.
More Information to Follow
Amarin expects to provide further details regarding its 2020 results and perspective regarding its future outlook in the company's annual report on Form 10-K.