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Why the FDA Got It Wrong and Why the FDA Will Approve Vascepa for ANCHOR sNDA Submission

By Clinician Scientist • MD, PhD • Professor of Medicine, Cell Biology & Physiology

Disclosure: I am an academic physician and a clinician scientist with an on-going clinical and research interest in obesity, lipid and inflammatory disorders, and health outcomes. I have served as both member and chair of NIH and VA grant review study sections and have reviewed over 1,000 research grants during my academic career.

I. Overview:

In this article, I examine the merits of FDA’s controversial decision to rescind Amarin’s ANCHOR special protocols assessment agreement (SPA). On October 23, 2013, FDA unilaterally decided to rescind the ANCHOR SPA by declaring that a “substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began”. The FDA specifically cited that the results of the three recently completed outcome trials, ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE, “fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL)”.

A primary purpose of this article is to provide an in-depth review and analysis of the three clinical outcome trials cited by the FDA as the reason for rescinding the ANCHOR SPA and is intended to educate the readers as to the adequacy and fairness of FDA’s review/analysis and whether FDA’s decision to rescind ANCHOR SPA was justified based on the “substantial scientific issue” argument.

The major conclusion of this analysis is that the FDA erred in its review and its interpretation of the results of the trials. There were important omissions of data and leap-of-faith extrapolation of trials’ findings, well-beyond the accepted standards of evidence-based medicine, that lead to the FDA’s unsubstantiated and faulty conclusion that lowering TG in patients with high TG levels (≥ 200 mg/dl) will not lead to clinical benefit. As most of the patients enrolled in the 3 trials had either normal (< 150 mg/dl) or borderline high (≥ 150 and < 200 mg/dl) TG levels, these trials were not designed nor powered to detect clinical benefits of TG lowering therapy in patients that have high TG levels (≥ 200 mg/dl), the ANCHOR study population. The fundamental flaw in the FDA’s analysis was the assumption that failure of TG lowering therapy in trials that enrolled mostly patients with low or borderline TG levels (< 200 mg/dl) somehow demonstrates that TG lowering therapy in patients with high TG levels (≥ 200 mg/dl) will not be beneficial. This conclusion is simply wrong and cannot be derived from the outcome trials that enrolled patients with low TG levels (< 200 mg/dl). Thus, the FDA reason for rescinding the SPA has no scientific base.

Highly relevant findings of these trials, as it relates the ANCHOR SPA, are the information obtained based on patients’ TG levels. The post-hoc sub-group analysis based on TG levels indicated that patients with normal of borderline TG levels did not benefit from TG lowering therapy in these trials; however, sub-group of patients covered by the ANCHOR SPA, those patients having high TG level (≥ 200 mg/dl) and low HDL-cholesterol, had a marked reduction in CVD complications of 28 and 38 % in ACCORD-Lipid and AIM-HIGH trials, respectively, indicating that TG lowering therapy was highly beneficial in these patients with high TG levels (≥ 200 mg/dl).

The final conclusion of this analysis is that the FDA decision to rescind the ANCHOR SPA was not justified and not supported by the three clinical trials. On the contrary, the sub-group analysis of these trials provide compelling evidence that the patients covered by the ANCHOR SPA, those with high TG and low HDL-cholesterol level, had the greatest clinical benefit with an impressive reduction (up to 37 % reduction) in CVD complications.

As a clinician scientist who has dedicated his life to advancing medical science and discovering new medical therapies to save lives, I am deeply concerned with this inappropriate and unjustified action taken by the FDA. The FDA action, if it stands, is likely to be harmful to the public’s interest and may lead to thousands of lives being lost that could have been saved by this highly efficacious and safe therapy for lowering TG. I am optimistic believe that on closer inspection FDA will reverse its decision to rescind the ANCHOR SPA and approve Vascepa for use in patients with high TG levels ≥ 200 mg/dl. The scientific evidence from the outcome trials cited by the FDA clearly show that TG lowering in ANCHOR sub-population with high TG and low HDL-cholesterol leads to a reduction in CVD complications.

II. Background

A. The Company

Amarin Corporation, with global headquarters in Dublin, Ireland, and United States Headquarters in Bedminster, New Jersey, is an advanced clinical stage pharmaceutical company with an emphasis on treating lipid disorders and a long-term objective to is to extend its expertise to being recognized for reducing cardiovascular risk. A public company, it is listed on NASDAQ as “AMRN”.

In July of 2012, the United States Food and Drug Administration (FDA) approved the company’s leading product, Vascepa for the treatment of high triglycerides (serum triglycerides > 500 mg/dl), or otherwise known as the “MARINE” indication. This is an indication for which major pharmaceutical companies such as GlaxoSmithKline (GSK) have approved products such as Lovaza. At present, it is estimated that up to four million Americans are afflicted by this health condition and treatment costs are also in the billions of dollars.

As noted above, the long-term plans of the company are to be able to serve the mixed dyslipidemia (serum triglycerides ≥ 200 and < 500 mg/dL) market, which is a market of up to 40 million Americans and as high as 120 million individuals world-wide. To this end, the company submitted its sNDA for “ANCHOR in February of 2013 for “approval for the use of Vascepa® (icosapent ethyl) capsules as an adjunct to diet in the treatment of adult patients with high triglycerides (TG ≥ 200 mg/dL and < 500 mg/dL) with mixed dyslipidemia”.

B. The ANCHOR Clinical Trial

The ANCHOR trial is a “multicenter, placebo-controlled, randomized, double-blind, 12-week study,” which investigated the efficacy of ultra-pure eicosapentaenoic acid (EPA) (AMR101) at doses of 2 gm and 4 gm for the treatment of “high triglycerides (≥ 200 and < 500 mg/dL) in 702 patients with mixed dyslipidemia (two or more lipid disorders) on background statin therapy who were at high risk of cardiovascular disease” (Amarin Corp. press release, 2013).

“The ANCHOR trial met its primary endpoint, which was defined as the median placebo-adjusted percentage change in triglyceride (TG) levels from baseline after 12 weeks of treatment. This endpoint was achieved at doses of 4 grams and 2 grams per day with median placebo-adjusted reductions in triglyceride levels of 21.5% (P<0.0001 value) for 4 grams and 10.1% (P=0.0005) for 2 grams.” These data indicated that efficacy of pure EPA (Vascepa) was dose dependent and that the dose of 4 gm/day had significantly greater efficacy than the 2 gm/day. These studies suggested that higher dose of EPA (4 gm/day) was necessary to achieve optimal TG lowering.

The Vascepa treatment also resulted in a “statistically significant 6.2% reduction in LDL-cholesterol for patients who were optimally treated with statins”. The reduction in LDL-cholesterol was an important beneficial effect of Vascepa as other TG lowering drugs, including fenofibrates (ABT) and Lovaza (GSK) cause an increase in LDL-cholesterol, an important risk factor for cardiovascular disease. Vascepa “appeared to be safe and well tolerated, with incidence of treatment-emergent adverse events similar to placebo”.

C. FDA Justification for Rescinding ANCHOR SPA

In an unprecedented move, on October 29, 2013, FDA rescinded the ANCHOR study special protocol assessment agreement (SPA) with Amarin Corporation. Per FDA regulations, SPAs are binding agreements and can only be broken when a company fails to comply with the provisions of the agreement or “if the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after the testing has begun”. In the case of sNDA submission for ANCHOR indication, Amarin (AMRN) fulfilled all aspects of ANCHOR SPA including the pre-defined primary endpoint (i.e. lowering TG level in patients with high TG level ≥ 200 and < 500 mg/dl) (Amarin Corp FDA Briefing Document, 2013).

However, FDA unilaterally decided that

“a substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began. Specifically, the FDA cited results from the ACCORD-Lipid and AIM-HIGH outcome trials, as well as the publicly presented results from the HPS2-THRIVE outcome trial, which the FDA stated in its notice to Amarin, fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). Thus, the FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dL.” (Amarin Corp. Form 8-K announcement, 2013)

This surprising and controversial action by the FDA has created a great deal of confusion and concern, and question as to whether such action was justified. The FDA unilateral dissolving of a binding SPA sets a troubling precedence and could have important negative consequences for both the FDA and the pharmaceutical industry.

III. What We “Do” Know About Hypertriglyceridemia and Risk of Cardiovascular Disease

Following summarizes the current science supporting the role of hypertriglyceridemia in CVD.

IV. Analysis of the Clinical Trials Cited by the FDA

In this section, I review the results of three clinical trials cited by the FDA (ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE trials) and whether the outcomes of these trials provide “substantial” new scientific evidence to support FDA justification for rescinding the ANCHOR SPA. The key question is whether the outcomes of these clinical trials provide substantial new scientific evidence to demonstrate that lowering TG in patients with high TG level (≥ 200 and < 500 mg/dl), the ANCHOR sNDA population, would not be beneficial.

Following is the summary statement from the “Executive Summary” of FDA Briefing Document referring to the three outcome trials that the FDA cited as supporting “substantial scientific issue” argument.

“During a pre-IND meeting with the applicant in July 2008, however, the Division noted that there was a lack of prospective, controlled clinical trial data demonstrating that pharmacological reduction of non-HDL-C (or TG) with a second drug, in patients with elevated TG levels at LDL goal on statin therapy, significantly reduces residual cardiovascular risk. The Division referenced trials ongoing at the time (e.g., AIM-HIGH, ACCORD-Lipid) that, while not able to assess the effect of specifically lowering non-HDL-C (or TG) on clinical outcomes, would be expected to provide important information on the incremental benefit of adding a second lipid-active drug to statin therapy. It was stated that before an indication would be entertained for Ethyl-EPA as add-on to statin therapy in patients with elevated TG levels, the applicant at a minimum would have to provide results from a 12-week study with lipid endpoints as well as initiate an appropriately designed cardiovascular outcomes study. This outcomes study, known as REDUCE-IT, is ongoing and is investigating whether the addition of AMR101 4 g daily ameliorates residual cardiovascular risk among patients at high CV risk who have moderate hypertriglyceridemia at LDL-C goal on statin therapy. The study designs for both ANCHOR and REDUCE-IT were agreed to by the Division under special protocol assessments.

Several cardiovascular outcome trials of non-statin lipid-modulating therapy, such as those referenced by the Division in 2008, have since been completed. ACCORD-Lipid, AIMHIGH, and HPS2-THRIVE, which were designed to target residual cardiovascular risk by improving lipid parameters other than LDL-C (e.g., HDL-C and/or TG) in patients optimally treated with statin therapy, failed to demonstrate unequivocally additional cardiovascular benefit from non-statin lipid-modulating drugs. Several hypotheses could be put forward regarding the failures of these large, carefully designed trials to demonstrate benefit on their primary endpoints, but the evidence to date certainly challenges the hypothesis that adding lipid-modulating therapies to patients optimally treated with statins will reduce residual cardiovascular risk. Although it can be argued that lipid and/or lipoprotein parameters can be used to define subpopulations of statin treated patients who would be expected to benefit from various non-statin lipid modulating agents, contemporary trials have not yet prospectively tested this hypothesis. Members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) are asked to consider the results of the ANCHOR trial in the context of the available science when recommending whether to approve the proposed treatment indication for 4 grams AMR101 daily to be co-administered with statin therapy for the treatment of patients with mixed dyslipidemia and coronary heart disease (CHD) or its risk equivalent.”

The specific questions that will be addressed in the review for each of the three clinical trials are:

  1. What specifically did the clinical trial investigate and what was the primary endpoint of the clinical trial;
  2. Did the study examine whether lowering of TG in the ANCHOR population (TG ≥ 200 and < 500 mg/dl) leads to a reduction in CVD risks;
  3. Does the trial outcome support the FDA assertion that the results of the clinical trial provide substantial new scientific evidence to indicate that Vascepa (ultra-pure EPA) treatment of patients with high TG levels (≥ 200 mg/dl) would not improve clinical outcome.

A. ACCORD-Lipid Clinical Trial:

What specifically did the clinical trial investigate and what was the primary endpoint of the clinical trial?

To determine whether “addition of fibrate to statin therapy compared with statin monotherapy alone reduces the risk of cardiovascular disease in patients with type 2 diabetes mellitus who are at high risk for cardiovascular disease” (Ginsberg HN, NEJM, 2010). The primary outcome of the study was whether fibrate therapy reduces the risk of CVD in diabetic patients. The risk of CVD was pre-specified as “nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes in diabetic patients”. The final outcome of the study showed that fibrate therapy did not reduce the risk of CVD in type 2 diabetic patients.

Did the study examine whether lowering of TG in the ANCHOR population (TG ≥ 200 and < 500 mg/dl) leads to a reduction in CVD risks?

No. This clinical trial was not designed or pre-specified to investigate the TG lowering effects on patients with high TG levels (≥ 200 mg/dl). It’s critical to note that, in this trial, patients were enrolled without consideration of their TG levels. The study population included those with normal (< 150 mg/dl), borderline high (≥ 150 to < 200 mg/dl), or high (≥ 200 mg/dl) triglycerides and the median TG level in the study was 162 mg/dl, indicating that the majority of patients in the study had TG levels that were either normal (≤ 150 mg/dl) or borderline levels (≤ 200 mg/dl). Thus, the study was not designed nor powered to determine whether fibrate therapy reduces CVD risk in patients with high TG levels (≥ 200 mg/dl); and, as such, the primary endpoints of this study do not inform whether fibrates reduce CVD risk in the high TG population. To determine whether a specific sub-group benefitted from the fibrate therapy, a post-hoc sub-group analysis was performed. The sub-group analysis showed that fibrates did not reduce CVD complication in patients that had normal or borderline high TG levels. However, a sub-group of patients that had high TG (>204 mg/dl) and low HDL (< 34 mg/dl) levels had a 28% reduction in CVD risks, prompting the investigators to conclude that the patients with high TG level (> 204 mg/dl) and low HDL level “appeared to benefit from fenofibrate” therapy.

Does the trial outcome support the FDA assertion that the results of the clinical trial provide substantial new scientific evidence to indicate that Vascepa (ultra-pure EPA) treatment of patients with high TG levels (≥ 200 mg/dl) would not improve clinical outcome?

No. The ACCORD-Lipid clinical trial was not designed to inform whether TG lowering in high TG patients would lead to a reduction in risk of CVD. As the study population included patients with normal and high TG levels, no conclusion can be derived as to whether fibrate therapy would not benefit patients with high TG level without a sub-group analysis. Directly relevant to the ANCHOR SPA, the sub-group analysis showed that fibrates did not reduce CVD risk in patients with normal or borderline high TG levels (< 200 mg/dl); however, fibrate therapy produced a 28% reduction in CVD risk in patients with high TG (>204 mg/dl) and low HDL-cholesterol. As it relates to the ANCHOR population, ACCORD-Lipid trial informs us that patients with high TG (>204 mg/dl) and low HDL-cholesterol would likely benefit from fibrate therapy.

B. AIM-HIGH Clinical Trial

What specifically did the clinical trial investigate and what was the primary endpoint of the clinical trial?

The primary objective of the AIM-HIGH clinical trial was to examine whether treatment with extended-release niacin leads to a reduction in CVD complications in high risk patients with CVD (The AIM-HIGH investigators, NEJM, 2011). The CVD complication was defined as “death from coronary heart disease, nonfatal myocardial infarction, and ischemic stroke, hospitalization for an acute coronary syndrome or symptom-driven coronary or cerebral revascularization”. The rationale for the study is as follows:

“In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk.”

Thus, the primary intent of the study was to examine whether raising HDL-cholesterol leads to a reduction in CVD related complications in patients with an established CVD. A total of 3,414 patients were randomly assigned to receive niacin (1,718) or placebo (1,696). The study was stopped prematurely after 3 years of follow-up as patients on niacin therapy had an unexpected increase in ischemic strokes. At the time of the trial termination, niacin therapy did not reduce CVD complications in the study population.

Did the study examine whether lowering of TG in the ANCHOR population (TG ≥ 200 and < 500 mg/dl) leads to a reduction in CVD risks?

No. It is critical to note that the study was not designed nor pre-specified to assess whether TG lowering would reduce CVD risk in patients with high TG patients. The failure of niacin to reduce CVD risk in the AIM-HIGH trial does not inform us as to whether TG lowering in high TG patients is clinically beneficial. The patients were enrolled without consideration of their TG levels and most of the enrolled patients had either normal (< 150 mg/dl) or borderline (< 200 mg/dl) levels and only small proportion (12.9%) of patients had high TG (≥ 200 mg/dl) levels that the ANCHOR SPA is addressing. The median baseline TG level of patients in the study was 166 mg/dl. The failure of niacin therapy to reduce CVD risk in the AIM-HIGH trial does not inform us as to whether TG lowering in high TG patients (≥ 200 mg/dl could be clinically beneficial or not. Similar to ACCORD-Lipid trial, a post-hoc sub-group analysis was performed to identify sub-groups that may have benefitted from niacin therapy (Guyton JR, Journal of the American College of Cardiology, 2013). The sub-group analysis showed that niacin did not reduce CVD complication in patients with normal or borderline high TG levels. However, as relates to the ANCHOR population, niacin significantly reduced CVD risk in patients that had high TG (≥ 200 mg/dl) and low HDL-cholesterol levels by 37% (p=.017). These findings are consistent with the findings of ACCORD-lipid trial, which also showed that the sub-group of patients with high TG (≥ 200 mg/dl) also had a reduction in CVD risk.

Does the trial outcome support the FDA assertion that the results of the clinical trial provide substantial new scientific evidence to indicate that Vascepa (ultra-pure EPA) treatment of patients with high TG levels (≥ 200 mg/dl) would not improve clinical outcome?

No. AIM-HIGH trial was not designed to investigate the TG lowering effects in patients with high TG levels. The failure of niacin to reduce CVD risk in patients with pre-existing CVD does not provide insight as to whether TG lowering in the high TG (≥ 200 mg/dl) patients would not be clinically beneficial. As in the ACCORD-Lipid trial, sub-group analysis based on TG levels indicated that niacin does not reduce CVD risk in patients with normal or borderline TG levels (< 200 mg/dl). However, niacin therapy produced an impressive 37% reduction in CVD risk in patients with high TG (≥ 200 mg/dl) and low HDL-cholesterol levels. Thus, the results of AIM-HIGH trial inform us that niacin treatment of patients with high TG (≥ 200 mg/dl) and low HDL-cholesterol greatly reduces the CVD risk.

C. HPS2-THRIVE Clinical Trial:

What specifically did the clinical trial investigate and what was the primary endpoint of the clinical trial?

The purpose of the study was to assess the effects of niacin (2 g) in reducing CVD risk in patients with occlusive arterial disease (HPS2-THRIVE Collaborative Group, European Heart Journal, 2013). The occlusive vascular disease was defined as “history of myocardial infarction, cerebral vascular disease, peripheral artery disease, and diabetes mellitus with any of the above three vascular conditions”. CVD risk was defined as “coronary death, nonfatal MI, stroke, or coronary revascularization.” A total of 25,673 patients were randomized to receive either niacin or placebo. All patients also received simvastatin. The final results of this study indicated that niacin did not reduce CVD risk in patients with occlusive arterial disease.

Did the study examine whether lowering of TG in the ANCHOR population (TG ≥ 200 and < 500 mg/dl) leads to a reduction in CVD risks?

No. As in the above clinical trials, this trial was not designed to examine the effects of TG lowering in ANCHOR population (TG ≥ 200 and < 500 mg/dl). The patients were enrolled based on the presence of occlusive arterial disease without regard to their TG level. The median baseline TG was 125 mg/dl and, thus, most of the patients in the study had normal TG levels. Since most of the population in this study had normal TG levels, the study was not powered to inform whether TG lowering in the high TG (≥ 200 mg/dl) population can lead to a reduction in CVD risk. The sub-group analysis of patients with high TG levels has yet to be published for this trial, and is probably unlikely to occur as most of the patients in the study had low TG levels.

Does the trial outcome support the FDA assertion that the results of the clinical trial provide substantial new scientific evidence to indicate that Vascepa (ultra-pure EPA) treatment of patients with high TG levels (≥ 200 mg/dl) would not improve clinical outcome?

No. Most of the patients in this trial had normal or borderline TG levels, with a median TG level of 125 mg/dl. Thus, the trial was not designed nor powered to assess the beneficial effects of TG lowering in the high TG population.

V. Final Analysis

After an in-depth review and analysis of the three clinical trials referenced by the FDA, my conclusion is that FDA erred in their review of the three clinical trials (ACCORD-Lipid, AIMHIGH, and HPS2-THRIVE) and in extrapolating that the failure of these three clinical trials to achieve their primary endpoints equates to a “substantial scientific issue” suggesting that TG lowering in the ANCHOR population (≥ 200 mg/dl) will not lead to a clinical benefit. This appears to be a huge leap-of-faith by the FDA and not supported by the results of the trials. Contrary to FDA’s conclusion and as discussed above in the review of the trials, these trials were not designed nor powered to inform whether TG lowering in the ANCHOR population (TG ≥ 200 and < 500 mg/dl) would have clinical benefit. As most of the patients enrolled in the trial had either normal or borderline TG levels (< 200 mg/dl), the trials were not designed nor intended to assess the risks of CVD in the high TG patients (≥ 200 and < 500 mg/dl). The FDA’s decision to rescind the ANCHOR SPA based on “substantial scientific issue” from these trials simply has no merit and is not supported by the results of the trials. Over the next month, there will be numerous discussions between Amarin and FDA regarding the merits of FDA action and approval of ANCHOR sNDA and Amarin will have an opportunity to refute FDA’s flawed argument and convince the FDA to come to an agreement that will be lead to ANCHOR approval. Based on the review of the clinical trials, I can only conclude that the FDA’s assertion is baseless and that FDA must acknowledge their error if they are to maintain their credibility and fairness. I am optimistic, that in the end, a compromise will be reached that will lead to the approval of Vascepa for ANCHOR indication.

Another important factor that will impact ANCHOR SPA discussions is the sub-group analysis from these trials showing clinical benefit in sub-population of patients with high TG levels ≥ 200 mg/dl. The post-hoc sub-group analysis indicated that a sub-group of patients with high TG levels ≥ 200 mg/dl having low HDL cholesterol had a reduction in CVD complications of 28 and 37 % in ACCORD-Lipid and AIM-HIGH trials, respectively, indicating that TG lowering therapy benefitted these patients. These data are also consistent with the published findings from the only large prospective clinical trial with pure EPA, which examined the efficacy of purified EPA in preventing CVD risks in hypercholesterolemic Japanese patients, referred to as the JELIS trial (Yokoyama, Lancet, 2007). In the JELIS trial, 18,645 patients were randomized to receive either EPA (1.8 gm) and statin or statin alone, and followed for a 5 year period. At the end of the study, the patients treated with EPA had a significant 19% reduction in CVD complications. A sub-group analysis also showed that the patients with elevated TG (≥ 150 mg/dl) and low HDL-cholesterol (< 40 mg/dl) levels had the greatest benefit with an impressive 53 % reduction in CVD risks (Saito, Atherosclerosis, 2008). Together, sub-group analyses of ACCORD-Lipid, AIM-HIGH, and JELIS trials provide compelling evidence that TG lowering therapy in patients with high TG level (≥ 200 mg/dl) and low HDL level (< 40 mg/dl) leads to a reduction in CVD complications. If Amarin and FDA cannot come to an agreement on ANCHOR SPA, an obvious compromise that would clearly benefit patients with high TG and one that FDA should not object to (since the sub-group analysis of their cited trials support this) would be to narrow the Vascepa approval to patients with high TG levels (TG ≥ 200) and low HDL cholesterol (< 40 mg/dl). Ultimately, I believe this may be the final outcome that all can agree on. As FDA cited outcome studies show a reduction CVD risk in patients with high TG and low HDL cholesterol, it would be hypocritical of FDA to not approve Vascepa for this sub-group of patients. Money lost may be recovered eventually, but human life lost is lost forever.

Financial Impact and Collateral Damage

The financial impact of FDA’s decision to rescind the ANCHOR SPA has been staggering to Amarin. Amarin has lost over 80% of its market value from market capitalization of $1.5 billion prior to the FDA briefing document release to market capitalization of $270 million following the 8-K announcement of FDA decision to rescind the ANCHOR SPA. Almost overnight, Amarin went from being one of the most promising biotech companies with the best-in-class drug for TG therapy to one that is facing questions about its future viability and financial solvency. There is also a concern that Amarin may not be able to complete the all-important Reduce-It outcome trial due to funding issues. The recent decision to reduce the work force by 50 % was a direct consequence of FDA’s decision to rescind the ANCHOR SPA. The financial future of Amarin is intricately linked to FDA’s decision on ANCHOR SPA. Ultimately, I believe that a compromise will be reached and ANCHOR sNDA will be approved in some form.

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