Amarin Corp Plc (AMRN)

[FesteringPus]

Letter to Members of Congress/Senate

Here is a slightly improved version of the letter I have sent to my representatives in Congress. I would suggest that anyone interested in giving Anchor a fair shot of approval do the same. Please feel free to modify this letter.


Dear Congress/Senate Member,

I’m writing to inform of a rather urgent matter of public policy related directly to cardiovascular disease, one of the most pressing issues of American public health. There is a pending decision for Anchor, a treatment indication for the drug Vascepa, on December 20th, 2013, by the FDA’s Office of New Drugs. Vascepa has been demonstrated to be highly safe and well-tolerated in clinical trials. Moreover, there is an abundance of good scientific evidence implicating Vascepa’s role in reducing mechanisms, primarily related to lipids and inflammation, involved in the pathogenesis of and improving outcomes in cardiovascular disease (CVD).

Overview and Introduction of Issue:
The FDA has taken a very negative view, as evidenced in a recent advisory committee meeting, on approving Vascepa for use in a patient population that is estimated to range from 35 to 84 million Americans. This is despite Anchor having met agreed upon endpoints in a prior special protocol assessment (SPA) with the FDA. SPAs are used to mitigate risks and costs associated with new drug development and have been historically honored at a 100% rate given that the drug in question does not pose a risk to public health.

Vascepa, known chemically as Eicosapentaenoic acid (EPA), is an omega-3 fatty acid derivative protected by over 16 patents in the United States. In a surrogate trial conducted in Japan known as JELIS, EPA has been shown to lower the risk of adverse cardiovascular outcomes by 19%. Post-hoc analysis showed a 53% reduction in adverse outcomes among the treatment population being targeted with Anchor. It is expected that outcomes in American populations will be even better due to the lower baseline levels and higher dosing of EPA that will be used in the Anchor indication. GISSI-P was an Italian study using EPA and DHA at lower dosages that demonstrated a 20% reduction in risk of CV death, nonfatal myocardial infarction, and nonfatal stroke.

Another very recent study in a leading journal recognized as the authority on CVD has detailed the good scientific connection between Vascepa (EPA) and improved CVD outcomes. These studies are presented as supplemental information at the end.

The following are the most recent statistics on CVD released by the American Heart Association:
• Approximately 84 million people in this country suffer from some form of cardiovascular disease, causing about 2,200 deaths a day, averaging one death every 40 seconds.
• Almost one out of every three deaths results from cardiovascular disease.
• The direct and indirect costs of cardiovascular disease and stroke are about $300 billion. This figure is increasing every year.
• On average, someone in the U.S. suffers a stroke every 40 seconds.
• Stroke is a leading cause of serious, long-term disability that accounts for more than half of all patients hospitalized for a neurological disease.
• Cardiovascular disease is the cause of more deaths than cancer, chronic lower respiratory diseases, and accidents combined.

Rationale of Approval for the Anchor Indication:
The FDA reviewer formulated the panel question in a highly unusual manner for the indication being sought in Anchor, which is to lower triglycerides. The FDA’s stance seems to be that Vascepa should be rejected for Anchor until an outcome study known as REDUCE-IT is finished sometime after 2016. Despite protests from panel members as to the unusual wording of the voting question, they voted 9-2 against approval for Anchor. There are, however, several very serious problems with a decision to wait three-to- four years for the results of REDUCE-IT.

1) There is good evidence of a reduction in mortality and morbidity associated with CVD through the use of Vascepa. There is also a body of scientific knowledge implicating the role of inflammation and lipids in the pathogenesis of CVD. EPA has been demonstrated in clinical trials to lower some aspects of the inflammatory process and to definitively lower triglycerides.

2) Given that the side effect profile of EPA in the Marine and Anchor trials has been demonstrated as equivalent to placebo, there is no harm in offering Vascepa as a treatment option to patients.

3) Current treatment options for lowering triglycerides includes niacin, fibrates, and EPA + DHA, all of which have comparable efficacy to EPA, but much more serious side effects. Some of these risks include raising other markers known to be associated with worse CVD outcomes. This limits their usage in certain patients. Vascepa has none of these risks. By rejecting Vascepa as a treatment option, the FDA is effectively lowering the current standard of care.

4) The reduction in adverse events demonstrated in JELIS and other studies, if shown to occur in American populations, would lead to non-trivial reductions in the rates of death and morbidity in patients with CVD. Good scientific evidence points to the benefit of EPA in CVD outcomes in American populations and even more so than those shown in JELIS.

5) There already is an SPA in place for Vascepa for REDUCE-IT and that is scheduled to finish sometime after 2016. There is a risk that this study will be unable to continue if the FDA takes the unprecedented move to reject Anchor as the company which has developed Vascepa may be unable to continue to fund the study.

This brings us to the risk/benefit analysis of approving Anchor versus rejection. There are really two scenarios of interest with respect to the consequences of approving Anchor which are examined below:
1) Vascepa is approved for Anchor and is shown, against current scientific evidence, that it does not have a beneficial effect on CVD outcomes. The implication of this scenario is that no harm is done to the health of the general public as Vascepa has been shown to be essentially equivalent to placebo with respect to side effects.

2) Vascepa is rejected for use in Anchor and is shown, consistent with current evidence, to be effective in reducing the pathogenesis and improving outcomes of CVD. Two of the implications of this scenario are that even with small reductions in risk, many tens of thousands of people are spared from adverse CV outcomes including death and tens of billions of dollars are saved.

Conclusion:
This discussion centers on a treatment option that is safe and well-tolerated and presents little to no risk to the health of the general public; therefore, the analysis shifts to one of discussion of likely benefits to public health. Any treatment which is likely to show benefits and will not harm public health should be approved as an OPTION to patients. By not approving Anchor as an option to patients, the FDA will be effectively making patients jump through hoops as they will have to pay out of pocket and deal with the hassle of locating a physician willing to prescribe off-label for them. This would be particularly insidious of the FDA to allow tens of millions of patients to go unaware of a treatment option which is better tolerated and as efficacious as the current standard of care.

In summary, the FDA is poised to lower the standard of medical care, stifle innovation in therapeutics development, and likely put the American public at unnecessary increased risk of death and morbidity. Rejection of the Anchor indication would be an unprecedented commentary on safe and effective therapeutic development and would likely cause irreparable harm to the health of the general public. If the FDA is concerned about potential misuse or side effects, there are ways to more than adequately address this through labeling restrictions. Approval of Anchor would be the path of least risk to public health, and not the other way around.

This decision deserves full public scrutiny as I do not believe the FDA officials involved are adequately representing the public interest in this matter. I will include contact information of the committee chairperson on the FDA advisory panel that voted affirmatively to approve the Anchor indication. I believe that he has correctly assessed the risk/benefit profile of Anchor despite the unreasonable tone, cherry picking of evidence, and leading questions posed by the FDA. He should be able to provide the necessary perspective on this important issue of public health. I am also including contact information for management at Amarin, the firm that has been developing Vascepa.

Thank you for your time and patience in this matter.

Sincerely,
The committee chair, along with another, who voted “Yes” to approval of Vascepa for the Anchor Indication is;
Robert J. Smith, MD
(Acting Chairperson)
Professor of Medicine (Endocrinology)
Alpert Medical School of Brown University
Ocean State Research Institute
Providence Veterans Administration Medical
Center
Providence, Rhode Island
Phone: [phone]
E-mail: [e-mail]

US Office:
Amarin Pharma Inc.
1430 Route 206, Suite 200
Bedminster, NJ 07921
USA
Tel: [phone]
Fax: [phone]
Joseph S. Zakrzewski – CEO
John Thero – President
Steven Ketchum, PhD – President of Research and Development, SVP
Joseph T. Kennedy – SVP, General Counsel and Secretary, Chief Compliance Officer

It is important to note that in all outcome studies done so far, the dosing of omega-3s has been significantly less than that in the ongoing REDUCE-IT and already completed Anchor trials. It is expected that this higher level of dosing will magnify the cardioprotective effects of EPA supplementation. FDA materials relating to the advisory committee meeting can be found here under the October 11th, 2013 updates.

http://www.fda.gov/advisorycommittees/whatsnew/default.htm

Some Studies on EPA:
Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio.
Ohnishi H, Saito Y.
J Atheroscler Thromb. 2013 Sep 18. [Epub ahead of print]

Abstract
The clinical efficacy of fish oil and high-purity eicosapentaenoic acid ethyl ester (hp-EPA-E) for treating cardiovascular disease (CVD) has been reported. Fish oil contains saturated and monounsaturated fatty acids that have pharmacological effects opposite to those of ?3 fatty acids (?3). Moreover, ?3, such as EPA and docosahexaenoic acid (DHA), do not necessarily have the same metabolic and biological actions. This has obscured the clinical efficacy of ?3. Recently, the Japan EPA Lipid Intervention Study (JELIS) of hp-EPA-E established the clinical efficacy of EPA for CVD, and higher levels of blood EPA, not DHA, were found to be associated with a lower incidence of major coronary events. A significant reduction in the risk of coronary events was observed when the ratio of EPA to arachidonic acid (AA) (EPA/AA) was >0.75. Furthermore,the ratio of prostaglandin (PG) I3andPGI2 to
thromboxane A2 (TXA2) ([PGI2+PGI3]/TXA2) was determined to have a linear relationship with the EPA/AA ratio as follows: (PGI2+PGI3)/TXA2=?+p* (EPA/AA). Like PGI2, PGI3 not only inhibits platelet aggregation and vasoconstriction, but also is assumed to reduce cardiac ischemic injury and arteriosclerosis and promote angiogenesis.

Thus, the effects of EPA in reducing the risk of CVD could be mediated by biological action of PGI3 in addition to hypotriglyceridemic action of EPA. Compared with DHA, EPA administration increases the EPA/AA ratio and the (PGI2+PGI3)/TXA2 balance to a state that inhibits the onset and/or progression of CVD.

PMID:
24047614
[PubMed - as supplied by publisher]
https://www.jstage.jst.go.jp/article/jat/advpub/0/advpub_18002/_pdf

JELIS - Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study
The JELIS trial, reported in 2007, suggested that treatment with 1.8 g/day of EPA reduced cardiovascular adverse outcomes in Japanese hypercholesterolemic patients on low-dose statins.30 In this open-label trial, 18,645 Japanese men and postmenopausal women with or without a history of coronary artery disease, with total cholesterol levels =6.5 mmol/L (>250 mg/dL), were randomized to either statin (pravastatin 10 mg or simvastatin 5 mg) + 1.8 g/day EPA or statin alone with a planned 5-year follow-up.

The primary endpoint was a cardiovascular composite, which included sudden cardiac death, fatal and non-fatal myocardial infarction, unstable angina pectoris including hospitalization, angioplasty, stenting, or coronary bypass grafting.

Mean baseline lipid values after a 4-8-week washout of any lipid-lowering drugs, included TC 7.1 mmol/L (~275 mg/dL), LDL-C 4.7 mmol/L (~182 mg/dL), TG 1.7 mmol/L (~150 mg/dL), and HDL-C 1.5 mmol/L (~58 mg/dL). During a mean follow-up of 4.6 years, a 19% relative reduction in the primary CV composite endpoint was observed (p=0.011). Among the components of the primary composite, only unstable angina including hospitalization for documented ischemic episodes, achieved nominal statistical significance (p=0.014). Lipid changes in the EPA + statin and statin alone group were similar, with the exception of triglycerides. As expected with the introduction of statin therapy, both groups exhibited decreases in LDL-C and small increases in HDL-C. Triglycerides decreased 9% in the EPA + statin group and decreased 4% in the statin-alone group (p<0.0001 between groups).

Although underpowered to evaluate subgroups, there were no apparent differences in the treatment effect on the primary endpoint across various subgroups defined using baseline characteristics, including whether baseline TG was below or above 1.7 mmol/L (150 mg/dL). A post-hoc analysis of the primary prevention cohort of JELIS suggested that EPA reduced the incidence of major coronary events by 53% (95% CI, 2% to 77%, p=0.043) in 957 patients with high TG (=150 mg/dL) and low HDL-C (<40 mg/dL)

Long chain omega-3 fatty acids and cardiovascular disease: a systematic review.
Delgado-Lista J, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F.

Source
Lipids and Atherosclerosis Unit, Department of Medicine, IMIBIC/Hospital Universitario Reina Sofía/
Universidad de Cordoba, Cordoba, Spain.

Abstract
Introduction: Cardiovascular disease remains the commonest health problem in developed countries, and residual risk after implementing all current therapies is still high. The use of marine omega-3 fatty acids (DHA and EPA) has been recommended to reduce cardiovascular risk by multiple mechanisms. Objectives: To update the current evidence on the influence of omega-3 on the rate of cardiovascular events. Review Methods: We used the MEDLINE and EMBASE databases to identify clinical trials and randomized controlled trials of omega-3 fatty acids (with quantified quantities) either in capsules or in dietary intake, compared to placebo or usual diet, equal to or longer than 6 months, and written in English. The primary outcome was a cardiovascular event of any kind and secondary outcomes were all-cause mortality, cardiac death and coronary events. We used RevMan 5•1 (Mantel-Haenszel method). Heterogeneity was assessed by the I2 and Chi2 tests. We included 21 of the 452 pre-selected studies. Results: We found an overall decrease of risk of suffering a cardiovascular event of any kind of 10 % (OR 0•90; [0•85-0•96], p = 0•001), a 9 % decrease of risk of cardiac death (OR 0•91; [0•83-0•99]; p = 0•03), a decrease of coronary events (fatal and non-fatal) of 18 % (OR 0•82; [0•75-0•90]; p < 1 × 10?4), and a trend to lower total mortality (5 % reduction of risk; OR 0•95; [0•89-1•02]; p = 0•15. Most of the studies analyzed included persons with high cardiovascular risk. Conclusions: marine omega-3 fatty acids are effective in preventing cardiovascular events, cardiac death and coronary events, especially in persons with high cardiovascular risk.

GISSI-P Study
In 1999, the open-label Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Prevenzione (GISSI-P) trial was one of the first randomized clinical trials to evaluate the effect of omega-3 FA on CV outcomes.29 GISSI-P randomized 11,324 patients with a recent history (3 months or less) of MI to 1 g/day of EPA/DHA (n=2836), vitamin E (n=2830), both (n=2830), or no treatment (the control group; n=2828). Mean baseline lipid values included TC 211 mg/dL, LDL-C 137 mg/dL, TG 162 mg/dL, and HDL-C 42 mg/dL. Five percent of patients were on cholesterol-lowering drugs (authors did not provide percentage on statin therapy) at baseline. After an average follow-up of 3.5 years, a 20% reduction in the primary endpoint of CV death, nonfatal MI, and nonfatal stroke was observed in the EPA/DHA treated group compared with the no treatment group (RR 0.80, 95% CI 0.68-0.95).

Voting Question for the FDA Advisory Panel Meeting on October 16th, 2013
FOOD AND DRUG ADMINISTRATION (FDA)
Center for Drug Evaluation and Research (CDER) Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC)
FDA White Oak Campus, Building 31, the Great Room, White Oak Conference Center (Rm. 1503), Silver Spring, MD
October 16, 2013

1. DISCUSSION:
In ANCHOR, 12 weeks of treatment with Vascepa 4 g/day led to an estimated median -21.5% (95% CI, -26.7% to -16.2%; P<0.0001) change in fasting triglycerides, compared with the mineral oil placebo, among statin-treated patients with mixed dyslipidemia at high cardiovascular risk. Changes in other lipid/lipoprotein parameters (selected secondary and exploratory endpoints) are summarized in the table below.
Median % Change from Baseline to Week 12
Median % Change (95% CI)
Placebo Vascepa 4g/day Treatment Difference
Fasting TG +5.9 -17.5 -21.5 (-26.7, -16.2)
Direct LDL-C +8.8 +1.5 -6.2 (-10.5, -1.7)
Non-HDL-C +9.8 -5.0 -13.6 (-17.2, -9.9)
VLDL-C +15.0 -12.1 -24.4 (-31.9, -17.0)
Apo B +7.1 -2.2 -9.3 (-12.3, -6.1)
Tot. Chol. +9.1 -3.2 -12.0 (-14.9, -9.2)
HDL-C +4.8 -1.0 -4.5 (-7.4, -1.8)
Apo A-I +3.6 -2.9 -6.9 (-8.9, -4.9)
Please discuss the efficacy results from the ANCHOR trial, including the clinical significance of the observed changes in lipid/lipoprotein parameters and your level of confidence that these changes will translate into a meaningful reduction in cardiovascular risk among the target population.

2. VOTE:
Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dyslipidemia and CHD or CHD risk equivalent prior to the completion of REDUCE-IT? Please provide the rationale underlying your recommendation.