URGE THE FDA TO APPROVE VASCEPA FOR MIXED DYSLIPIDEMIA!

Citizens for VASCEPA www.care2.com Search Vascepa October 18, 2013 Dear Concerned Citizen, The present letter summarizes the specific arguments the FDA Advisory Committee (ADCOM) made against the approval of Vascepa given on October 16th, 2013, and the following monograph directly refutes these arguments with scientific evidence. 

On or before December 20, 2013, the Food and Drug Administration will decide if Vascepa should be approved for marketing and sale of Vascepa(R) (icosapent ethyl) capsules for use 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. It is our sincere hope that with the support of other concerned citizens, we can bring to light the misinterpretations and misrepresentations witnessed during the Advisory Committee review on the 16th of October. Regarding the discussion segment of the AdCom meeting, it appeared to many observers and interested parties that the purpose of the meeting seemed to become unclear to both observers as well as several members of the committee as much of the discussion veered off of the parameters set forth in the SPA and thus became generally inappropriate with respect to the relevant indication that is pending approval. It should be noted that the question provided by the FDA for the ADCOM board panelists to vote on was unclear AND INCORRECT, at best. In fact, Ellen W. Seely, MD, said, "I'm still kind of stuck. I just don't know if it's going to lower CVD risk. We could approve it for lowering triglycerides, if that's the way the question is raised." This statement clearly illustrates the confusion among the panelists on what the ultimate question was for the panelists to vote on. Wasn't this ADCOM meeting scheduled by the FDA to review the ANCHOR indication? This is what the Special Protocol Assessment (SPA) was based on, for the ANCHOR indication, correct? The SPA is a binding contract between the FDA and Amarin. If the FDA had any issue(s) with the Anchor sNDA filing they should have communicated this to Amarin. They did NOT! There are many opportunities leading up to the ADCOM for both sides to communicate any concerns. Again, NOTHING occured! So, Amarin was blindsided when they went into the ADCOM meeting. It is clear that these panelists were confused or uncertain what the voting question was, and therefore voted no, to NOT recommend Vascepa to be approved for the more broad based population indication, not based on the ANCHOR indication but rather on the uncertainity of whether Vascepa added to a statin to lower triglycerides actually lowers the risk of CHD/CVD risk. Isn't this what the REDUCE-IT Trial will determine? In addition to communicating with the FDA throughout the drug development and approval processes, Amarin has further shown that they want to fully adhere to the FDA's wishes by choosing to enter into a SPA agreement with the FDA. The purpose of this was obviously to make sure that nothing would jeopardize the future of their drug that may very well improve and/or save millions of lives. In order to receive a positive vote, Amarin would have been essentially forced to provide outcomes data from REDUCE-IT, or otherwise prove that their drug lowers the risk of CVD or MACE with complete certainty. Not only was this discussed, but, further, it seemed to quickly become the sole focus of the ADCOM. It would seem that this should appear to even the most casual of observers as a classic example of "moving the goalpost when the ball is already in the air." Obviously, these should not have been realistic expectations, as both are impossible at this time. The sole requirement agreed upon in the SPA between Amarin and the FDA before the Anchor sNDA could be filed, which were met was that Amarin have the REDUCE-IT substantially enrolled (50% of patients). Representatives from Amarin have also stated during past conference calls that the FDA had never implied to them that actual outcomes data from REDUCE-IT were necessary for ANCHOR approval. Secondly, under the terms of the SPA, it is not reasonable whatsoever for Amarin to have been required to prove that their drug lowers the risk of CVD. Aside from Vascepa lowering TG's in the Anchor study, Vascepa lowered LDL-C, Non-HDL, and Apo B. All of these are either primary or secondary markers for CVD. There are no side effects with Vascepa like some of the other TG lowering products currently on the market. Doesn't it make sense to have Vascepa available for physicians to prescribe for this population? Statistics show that America is only getting fatter...more diabetics as a result who have more risk for comorbidities like CVD. Even the AACE Guidelines for 2013 state lowering TG's, Non-HDL, and APO B should be measured after a person is at goal for LDL-C. If there is no risk to the patient to take Vascepa and could possibly save them from readmittance to the hospital or possible from a heart attack isn't this what we want in the medical community? A body of evidence from AACE, AHA, ATP III and NCEP, to name a few, support the benefits of lowering Triglycerides and other independent biomarkers. NCEP states, Fish oil may have a future place in therapy regardless of baseline cholesterol levels AACE states, Amarin has developed Vascepa to improve lipid markers and inflammatory markers that have been deemed as independent risk factors of a myriad pathologies Again, the FDA panel members at the AdCom delved far beyond the scope of examining the objective efficacy of Vascepa and blatantly questioned the actual benefits of lowering these lipid parameters. Clearly, this was outside of the scope of both sNDA and the parameters agreed upon in the SPA. This not only led to the seemingly subjective discreditation of Amarin, but also unfairly discredited the testimony of numerous leaders in this field who have dedicated their lives to collecting and analyzing data and drawing reasonable conclusions to improve lives. It was very obvious from the beginning the FDA had their own agenda at the ADCOM meeting unbeknownst to Amarin. Is this fair? A great analogy...you are in college and you have a test...your teacher gives you a review sheet of what will be on the test, however, when you get to class the next morning and begin taking the test, you realize that none of the questions are related to the review sheet from the teacher. Is this fair? Are you prepared? Will you do well on this test? Are you frustrated? YES! his is what happened to Amarin...The FDA is the teacher and Amarin is you, the student. Many patients retain a high cardiovascular (CV) risk despite achieving their recommended LDL-C targets. Based on a series of large statin trials, optimal statin treatment reduces CVD events by 30-40% over five years (Cannon 2007, Cholesterol Treatment Trialists' 2008), meaning many patients treated to LDL-C goal still have residual CVD risk. An important independent contributor to this residual risk is elevated non-high density lipoprotein cholesterol (non-HDL-C), which is often driven by elevated hepatic TG. A growing body of evidence supports TG as an important biomarker of CV risk (Austin 2000, Austin 1998, Assmann 1996, Sarwar 2007). After diet and lifestyle modification, and after reaching LDL-C goal, if a patient has persistently elevated TG (200 mg/dL), ATP III and AACE recommends a secondary treatment goal for non-HDL-C and ApoB. TG-lowering therapies are key therapeutic options for the reduction of non-HDL-C in this hypertriglyceridemic patient population. Current TG-lowering therapies, including fibrates, niacin, and omega acid mixtures either have serious side effects and/or increase LDL-C. These limitations contribute to a high rate of treatment discontinuation within the first year of therapy, as well as, a costly burden on the medical community. In fact, more recently in 2013 consensus from AHA states 32% of adults have total cholesterol levels above 240mg/dL, with a prevalence of 14%. If you consider that 19.7 million Americans have diabetes in 2010 and this number is drastically increasing the urge to have a product like Vascepa available to this population is critical. Take into consideration the changing Medical World with the ACO's and Medical Homes, Procedure Utilization and Costs, second and third readmittance to hospitals for same disease like diabetes, stroke and/or heart attack, and the cardiovascular procedure use and costs. Did you know that almost 35% of Americans are overweight or obese? This number is increasing...among children 2 to 19 years of age, 32% are overweight or obese. Fibrates, the prescription omega acid mixture (Lovaza), Omega 3 supplements containing DHA, and other marine oils, can all increase LDL-C (Jacobson 2012). Myopathy and Contraindications in Liver Disease Fibrates and niacin may increase the risk for myopathy as monotherapy and this risk is increased when combined with statins. Fibrates and niacin also include contraindications in liver disease. Contraindications in Gallbladder and Renal Disease Fibrates additionally include contraindications in gallbladder and renal disease. Worsening Glycemic Control and Flushing Niacin may worsen glycemic control in diabetic patients and causes flushing in many patients, which may interfere with compliance and lead to premature discontinuation of treatment (Niaspan PI 2013). *A new treatment for patients with high TG (200 to 499 mg/dL) that can safely and effectively be added on to a statin to lower TG, VLDL-C, LDL-C, Apo B, Lp-PLA2, and non-HDL-C is needed. Vascepa has been shown to be a safe and effective therapy when added to statin therapy to significantly reduce TG, while meeting the FDA-agreed pre-specified non-inferiority assessment for LDL-C. In ANCHOR, the placebo adjusted change in fasting TG from baseline at Week 12 with Vascepa 4 g/day was -21.5 percentage points . The data support the conclusion that Vascepa provides benefits to patients when taken as an adjunct to diet and in combination with a statin for the reduction of TG, non-HDL-C, Lp-PLA2, Apo B, LDL-C, TC, and VLDL-C in patients with mixed dyslipidemia and high risk for CVD. Within the clinical studies, Vascepa was well tolerated with a low incidence of reported AEs. Overall, AE incidence was similar to placebo. There were no clinically meaningful changes in laboratory parameters. No statistically significant differences were seen in the efficacy or safety profile in diabetic patients compared to non-diabetic patients. Prior studies using omega acid mixtures have reported adverse events such as bleeding and hepatic disorders. These AEs were reviewed for Vascepa. Within the clinical program, Vascepa demonstrated no clinically meaningful effect on hepatic function. The incidence of bleeding-related AEs in ANCHOR was low in all treatment groups, but occurred more often on Vascepa (2.4%) than on placebo (1.3%). Even though the incidence is greater, it remains substantially low. Currently approved labeling for Vascepa advises physicians that omega-3s may be associated with an increased risk for bleeding. Since approval of the original NDA for severe hypertriglyceridemia, no new safety concerns have emerged. Vascepa offers advantages over existing TG-lowering therapies. One of key benefits of Vascepa therapy is the absence of a significant increase of LDL-C, since fibrates and omega acid complex mixtures that contain EPA+DHA are known to increase LDL-C levels in hypertriglyceridemic patients (Goldberg 1989, Bays 2008). A further benefit of Vascepa therapy is that it does not interfere with glucose control. While small numerical elevations were see in FPG, they were not statistically significant or clinically meaningful. The more accurate markers of glucose control (insulin, HbA1c, HOMA-IR) were similar between active and placebo arms. Patients who are at high risk for CVD who are taking statin therapy and have persistently high TGs are at-risk and need a safe and effective therapy that can be added to their statin therapy for more aggressive and comprehensive lipid control. If approved, Vascepa would fill an important unmet medical need for these patients. It was also suggested during the ADCOM Meeting by one of the voting panelists that since Vascepa is currently available and marketed for the very high TG market, that if doctors want to prescribe, they can just prescribe off label. If this were the case then why did the FDA require the ANCHOR trial? Isn't that exactly why we have a regulatory system to avoid such actions by the medical community? We find this statement to be preposterous and quite frankly an inherently flawed way of thinking. Not only do doctors rarely have adequate time to keep current with all of the new drugs available, it is even more difficult when sales representatives are not allowed to promote/mention Vascepa for off label usage. Due to this, most doctors will not immediately realize the advantages of Vascepa compared to current off label alternatives, including LDL-C neutrality(1)/reduction(2) and safety profile. With the popularity of statins being largely due to their LDL-C lowering effects, it makes no sense that Vascepa's favorable LDL-C profile has been belittled with regards to their competition. Whatever happened to rewarding a company for innovation and dedication, especially with a product that could potentially save and extend millions of lives that would otherwise be cut short by the #1 cause of death in the United States? If nothing else, the timeless question of, "What's the worst that could happen?" needs to be asked. If Vascepa is denied for the ANCHOR indication until outcomes from REDUCE-IT are available, and outcomes meet or exceed endpoints millions of lives could have been saved between now and ~2016 when REDUCE-IT results can be expected at the earliest. If Vascepa is accepted for the ANCHOR indication and REDUCE-IT endpoints are not met, then patients on Vascepa may have unnecessarily spent money for ~3 years to lower their lipid parameters, without much actual benefit. In this circumstance, it is nothing less than completely obvious that the potential reward far outweighs the risk involved. With the undeniable safety profile, there is no downside to approving ANCHOR before REDUCE-IT is complete. Even if the label reads, "Vascepa has not been proven to reduce CVD or major adverse cardiac events," which is common for drugs lacking outcomes data, the patients and their doctors are more than capable of deciding for themselves whether their health and financial situations constitute taking Vascepa with the chance that it will not actually reduce their risk of CVD or MACE. By not approving Vascepa for the ANCHOR indication, you are forcing the hand of the medical doctor to prescribe other Triglyceride lowering products with far worse side effects and with NO proven outcomes data. We ask of you the following With almost a perfect safety profile, make it available for the mixed dyslipidemia patient population and let the doctors decide how and when it should be prescribed. We have the privilege and right in our country to stand together and protest when we feel the needs of the commons are not being supported by our government officials. We believe the data show that Vascepa is a safe and efficacious drug for the ANCHOR indication of Vascepa. The facts are as follows: #1 The FDA has breached the SPA agreement with Amarin by asking the ADCOM panel to vote on a different indication other than the SPA-ANCHOR agreement. #2 Dr. Hiatt asked the chairman if Vascepa was recommended for approval by the ADCOM panel and REDUCE-IT failed what recourse did the FDA have against Amarin. The chairman responded by stating the FDA would remove the sNDA for ANCHOR and if Amarin protested lawyers would be involved. This is misleading to say the least. If this were the case then why hasn't Niaspan and the Fenofibrates removed from the market? #3 We believe that the issue brought up by the FDA in the briefing documents regarding the mineral oil inertness against a statin was a smoke screen. If the FDA approved the in the SPA the use of mineral oil for MARINE, ANCHOR and REDUCE-IT then why would this issue be questioned at the ADCOM meeting? If you are in agreement with our position, and would like to show your support, please sign the online petition. Sincerely, 

Citizens for VASCEPA GO TO: www.care2.com and search Vascepa to sign the petition 

Please note that the citizens who have signed this letter represent broad diversity professionally, geographically and politically. We are, however, strongly united in our desire to defend a just and balanced evaluation in the matter of VASCEPA. PLEASE ADD YOUR NAME TO THE GROWING LIST OF SUPPORTERS BY SIGNING THIS PETITION.