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A practicing physician with expertise in understanding what medications and devices will have mass application in the most common disease processes which account for the largest markets
  • AMRN: Does The FDA Need To Be Investigated  29 comments
    Oct 21, 2013 8:11 AM | about stocks: AMRN

    AMRN - Does the FDA Need to be Investigated?

    Recently, the FDA rejected AMRN's bid for the utilization of Vascepa in treatment of triglycerides less than 500 mg/dl. This rejection is groundbreaking in that the only possible explanation appears to be that the FDA is seeking to rewrite the entire understanding of factors causing the development of CAD. This ground breaking information needs to be immediately transferred to primary care physicians who are currently spending billions of dollars to treat a number that in the FDA's understanding must not matter.

    Background:

    I am a family physician with 25 years of clinical experience. I have minimal financial analysis skills and I am not a basic research scientist, however, I can speak specifically to what most physicians in the United States do in their day-to-day practice with respect to the prevention and treatment Coronary Artery Disease.

    History and Physiology :

    Approximately 70 years ago medical science begin to focus on the number one killer of individuals above age 40 in the US. It rapidly became apparent that coronary artery disease was number one followed by cancers. The war on cancer has been very slow and difficult. Fortunately developments for the treatment of CAD have been more successful. It became apparent that arteries become clogged by substances known as plaque. When arteries are blocked tissue dies and this results in heart attacks (NYSE:MI) and brain attacks (CVA or strokes). Identification of risk factors, which cause individuals to develop plaque, includes: genetics, cigarette smoking, hypertension, diabetes and lipids. The medical community began to address each one of these. Obviously genetics cannot be corrected. Other risk factors fortunately could be and are currently being aggressively addressed both from a pharmaceutical and behavioral modification standpoint of view. The risk factor, which of course concerns AMRN, is the lipid profile. The term lipids encompass a very broad spectrum. Suffice it to say that lipids consist of a series of various sized (density) fatty particles. It became apparent that some of these particles conferred atherogenic risk (plugging of arteries with plaque) while others were protective. LDL was identified as being the major atherogenic particle. HDL was identified as being protective.

    The chemistry and physiology of lipids is rather complex. Basically, lipids are various particles containing fat. Scientists have chosen to classify these by density. The largest and least compact particle is known as a Chylomicron followed by VLDL then LDL and finally HDL. High-density lipoproteins (HDL) are very small and very compact (highly dense). These are felt to be beneficial. Lipids that are low density (large and light) are more atherogenic (causing formation of plaque blocking arteries causing MI's - heart attacks), these include LDL and VLDL

    Note that triglycerides are not a specific particle but rather are contained as a percentage in each one of the above mentioned particles. Triglycerides are a higher percentage of the least dense particles and then decrease their percentage as particles become denser.

    Since triglycerides constitute a larger portion of the lightest least dense (most atherogenic particles) they have therefore been implicated in the development of coronary artery disease. These particles are sometimes referred to as triglyceride rich lipoproteins

    As a side note Patient's LDL levels are mainly dependent upon their genetics. Reducing LDL by dietary manipulation alone is usually not feasible. The liver manufactures Eighty percent of LDL and only 20% comes from dietary consumption. Therefore if an individual can reduce 50% of their fat intake they will only reduce their LDL by approximately 10%. This is usually not considered to be sufficient to reduce the risk factor. As a result pharmaceutical firms investigated and developed statins for the reduction of LDL. Statins have been markedly successful in reducing CAD.

    Current Standards:

    If you enter a doctor's office for a physical examination most will be applying ATP III standards with respect to your lipids. It is important to note that the standards focus on cholesterol levels. Practitioners will first treat your cholesterol. The only time the practitioner will first address your triglycerides, according to the standards, is if you're triglyceride levels are greater than 500. This is why medications have been approved for that level and above.

    This is not to say that if your triglycerides are less than 500 they will not be treated. The practitioner will simply first concentrate on your cholesterol level and then your triglycerides. Triglycerides levels greater than 200 are considered to be high and worthy of treatment.

    Studies regarding reduction of coronary artery disease by reducing triglycerides give varying results however, it is important to note the NCEP considers hypertriglyceridemia to be an independent risk factor for CHD and calls for medical treatment in cases where lifestyle changes are not adequate to reduce levels.

    This is very important because this is the mindset of the majority of medical practitioners throughout the United States. They will first focus on your LDL if your triglycerides are less than 500 and then we'll treat triglycerides if they are greater than 200.

    Thus it is an accepted standard that the vast majority of practitioners will consider treating triglycerides greater than 200. The question, which should then be posed to the FDA, is how does Vascepa compare to currently accepted treatments for triglycerides.

    There are several treatments available these include but are not limited to:

    Lopid, fenofibrates (Tricor), Lovaza and now Vascepa

    Lopid is fraught with issues including a large study showing that it may cause a higher rate of some cancers in humans.

    Tricor side effects are not nearly as serious. Lovaza amazingly increases LDL the most atherogenic particle by 45%. The point of the, matter is that Vascepa side effects are nowhere as serious as other treatment currently available.

    So now we come to the guts of the issue. The FDA may have not approved Vascepa for trigs less than 500 for several reasons. However, in my view the rejection demands certain actions :

    Possible reasons for lack of approval would include:

    1.) Side effects

    As explained above Vascepas side effects are minimal and therefore this argument seems to hold little weight.

    2.) Lack of efficacy

    Since Vascepa has been approved for triglycerides greater than 500 it would be illogical not to approve it for triglycerides less than 500 based on efficacy

    3.) Issues of the placebo oil altering triglyceride levels

    If researchers filled capsules with a substance other than oil (say water) then the FDA would have proposed that should one of these capsules have broken in a patients mouth they would have immediately known they were on a placebo. However, to fill the capsule with any form of "oily" substance that the average individual would identify as such immediately allows the FDA to pose a concern regarding the oil and its effect. Thus it would appear the researchers are damned if they do and damned if they dont

    4.) An entire new understanding of lipid physiology

    This would appear to be the only reasonable answer as to why the FDA rejected AMRN's bid for the utilization of Vascepa to treat trigs between 200 and 500 as none of the above stand up to close scrutiny .

    The FDA may have an entire new understanding of lipid physiology. Indeed, lipid physiology as noted previously is complex and studies are not entirely clear. As previously explained it is believed that larger less dense lipid particles are responsible for the induction of plaque formation resulting in coronary artery disease. Triglycerides constitute a percentage of all lipid particles however they form a greater percentage of lighter larger (more atherogenic) particles ie LDL than more dense less atherogenic particles ie HDL

    Many researchers now believe that other particles as well as inflammation may be more responsible for the development of plaque. However, even if that is the case Vascepa (EPA) has been shown to reduce most of these other particles as well as reducing inflammatory markers. If the FDA is focusing on inflammatory markers or particle count, Vascepa improves these parameters and therefore rejection based on a new understanding of lipid physiology does not appear to be reasonable.

    If the FDA is indeed rejecting the current understanding of triglycerides role in the development of CAD they have a responsibility to inform primary care physicians who are currently prescribing billions of dollars of medications to treat triglycerides that are between 200 and 500. If the FDA is certain of this new insight, ie treatment of triglycerides between 200 and 500 has no effect on the development of CAD, their failure in informing primary care physicians is costing a tremendous amount of resources and would be unconscionable.

    Summary:

    Throughout a physicians day they are constantly mentally applying risk-benefit scenarios, Weighing the risk of certain actions vs. the benefits .

    The issue of treating triglycerides and whether this will reduce CAD is still not entirely clear. Indeed, new theories and new understandings are developing. However, there remains good evidence that triglycerides do indeed seem to play a role in the development of CAD. Therefore one has to ask what is the risk of utilizing Vascepa versus the potential benefit. There appears to be very little risk in the utilization of this medication however there does appear to be potential benefit for the reduction of CAD. Therefore under risk-benefit ratio it makes absolutely no sense not to have approved the medication for Triglycerides > 200 mg /dl.

    If the FDA is certain that trigs between 200 - 500 have no role in the development of CAD they have a responsibility to inform primary care practitioners immediately to save billions of dollars in unnecessary pharmaceutical treatments that are currently being prescribed.

    However, since this data does not exist and since current theory implicates triglycerides in the development of CAD and since Vascepa not only improves triglyceride levels but also other markers that may be part of our newer understanding of particles and inflammatory markers associated with CAD and since Vascepa's side effect profile is absolutely minimal not to have approved VASCEPA for triglycerides between 200 - 500 in my opinion is bureaucratic malpractice

    Disclosure: I am long AMRN.

    Stocks: AMRN
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Comments (29)
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  • regnilsek
    , contributor
    Comments (5) | Send Message
     
    Thank you for your perspective. I'm an AMRN long and still believe there is hope for the upcoming PDUFA decision for many of the same reasons that you mention in your article. I just wanted to point out that the decision last week was an ADCOM recommendation, not an FDA rejection.
    21 Oct 2013, 09:37 AM Reply Like
  • drrc1949
    , contributor
    Comments (8) | Send Message
     
    ralphie, just wanted to let you know I read your article in its entirety and really enjoyed hearing your perspective, that of a practicing clinician. I too am long AMRN and have immersed myself in the science behind Vascepa, to the full extent of my ability to grasp it. It certainly does appear that from the point of view of the FDA, something went seriously awry with the Anchor AdComm. They definitely conveyed the message that there is no longer a reason to treat high triglycerides and that they will not approve any new treatments for that purpose unless there is evidence of a reduction in CVD attached. It makes no sense to me because there is no new science on which to base these conclusions. So there must be some other motivation at play here and it seems we'll need to wait until the FDA decides to reveal exactly what that may be.
    21 Oct 2013, 10:20 PM Reply Like
  • Takiko
    , contributor
    Comments (31) | Send Message
     
    I have posted a link on Ihub's AMRN message board to a letter I have written to my local congressional representatives with arguments similar to those in the above. I would suggest that anyone interested in contacting their representatives for oversight on the Anchor decision use my letter as a template and make any changes they feel is necessary. The post with the link to my letter is post number 18600.
    22 Oct 2013, 04:57 AM Reply Like
  • Takiko
    , contributor
    Comments (31) | Send Message
     
    Below is a link to a slightly revised version of a letter that I have sent to my local members of Congress to petition for the oversight of the Anchor decision in December. Please feel free to use this letter or any modifications of it to contact your own representatives.

     

    http://bit.ly/1bUrz2z
    22 Oct 2013, 08:14 PM Reply Like
  • ranjo
    , contributor
    Comments (42) | Send Message
     
    When is someone going to talk about the EPA/AA ratio
    21 Oct 2013, 07:25 PM Reply Like
  • ranjo
    , contributor
    Comments (42) | Send Message
     
    and i might add ... great read! it may be possible that statins used in combination with EPA my minimize some of the anti inflammatory qualities of EPA
    21 Oct 2013, 07:28 PM Reply Like
  • Pirateescapee
    , contributor
    Comments (111) | Send Message
     
    Ralphy - Quick question. What sort of dialogue is going on between doctors in your circle concerning the Amarin/FDA situation and Vascepa in general ? I guess I'm trying to gauge whether or not there will be any effective or substantial support to reverse this situation from doctors/medical professionals.
    21 Oct 2013, 08:35 PM Reply Like
  • ralphey
    , contributor
    Comments (382) | Send Message
     
    Author’s reply » Unfortunately , not a lot. Although for us as investors AMRN and Vascepa are on our radar for most primary care docs this is just one of 1000's of drugs and they dont have the time to look at the nuances many are just vaguely aware of its existence
    22 Oct 2013, 03:35 PM Reply Like
  • pointtrader
    , contributor
    Comments (18) | Send Message
     
    What is your opinion do you think this is a valid substantial meta analysis of EPA & CV event reduction ? by Haruo Onish and Yasushi Saito. http://bit.ly/16v2J4m
    21 Oct 2013, 08:43 PM Reply Like
  • ralphey
    , contributor
    Comments (382) | Send Message
     
    Author’s reply » I am not a statistician or research scientist so I cannot really comment although I think its one more arrow in the quiver
    7 Nov 2013, 09:35 AM Reply Like
  • Jorylu
    , contributor
    Comments (3) | Send Message
     
    To be clear, the FDA hasn't rejected the use of Vascepa. An FDA advisory panel has voted in favor or rejecting the approval of Vascepa in treatment of triglycerides less than 500 mg/dl. A physician should realize the importance in this distinction .
    21 Oct 2013, 10:13 PM Reply Like
  • chris2468
    , contributor
    Comments (358) | Send Message
     
    Although the FDA doesn't have to follow the Adcomm's votes, the briefing document's questionnaires provide a guidance to FDA's stance. If the FDA plan to welcome Adcomm's opinion, they would have questioned such as "Given the current result from Anchor trial (efficacy & safety), is that enough to grant approval for expansion?"... But instead they targeted Reduce-IT and bypassed Anchor's result altogether.

     

    The only thing could possibly sway the outcome is some sort of internal audit as to why they came up with such skew stance just against AMRN. As suggested in the article, to be fair, the FDA must treat other Lipid drugs same if they plan to implement the new stance. Given latest incident at the IRS corruption, anything is possible.
    22 Oct 2013, 12:01 AM Reply Like
  • Logic Man
    , contributor
    Comments (225) | Send Message
     
    Chris, what IRS corruption do you speak of? You mean the hundreds of politically motivated groups that recieved hundreds of millions in tax deductible donations because they claimed on their tax forms that they were a charity when in fact they were simply a PAC used to funnel millions from Koch and friends in an attempt to buy elections....all tax free and all while abusing the IRS status of a claimed charity?.....That corruption? The corruption is that the IRS let them all get away with it when in reality non of those groups should be approved as a tax free charity.
    22 Oct 2013, 01:32 PM Reply Like
  • ralphey
    , contributor
    Comments (382) | Send Message
     
    Author’s reply » Please reread the first line of the article

     

    "Recently, the FDA rejected AMRN's bid for the utilization of Vascepa in treatment of triglycerides less than 500 mg/dl"

     

    which part of less than 500 mg/dl didnt you understand ?
    22 Oct 2013, 03:37 PM Reply Like
  • bunny2005
    , contributor
    Comments (12) | Send Message
     
    Excellent article. Many thanks for posting. I hope you intend on forwarding to the FDA.
    21 Oct 2013, 10:33 PM Reply Like
  • butters301
    , contributor
    Comments (12) | Send Message
     
    Thank you for your analysis. Insightful. As a healthcare provider, consumer, and an investor in Amarin (because I truly believe in their best-in-class product for a greater cause), I would like to add that if those panel experts have decided to change our conventional understanding of omega-3 benefits, the FDA perhaps should consider removing the heart logo on foods containing omega-3. The label reads, "Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease..." In my opinion that is misleading to the general public. So which is it, FDA?
    22 Oct 2013, 02:36 AM Reply Like
  • ralphey
    , contributor
    Comments (382) | Send Message
     
    Author’s reply » Excellent point !
    22 Oct 2013, 03:38 PM Reply Like
  • ajbrzoz
    , contributor
    Comments (65) | Send Message
     
    The Vascepa AdCom Panel ties to industry should be investigated as it appears that Amarin was led to the gallows without a fair trial.
    22 Oct 2013, 02:45 AM Reply Like
  • Steve Rosenman
    , contributor
    Comments (765) | Send Message
     
    FDA did not reject...yet. Panel voted against. I'm sure you know, but wanted to clarify as your post did not.
    22 Oct 2013, 02:45 AM Reply Like
  • 5967241
    , contributor
    Comments (109) | Send Message
     
    Ok, FDA did REJECT now. Just to clarify it further if you are still doubtful about this outcome.
    5 Nov 2013, 02:15 AM Reply Like
  • Shopboy
    , contributor
    Comments (12) | Send Message
     
    Again lets be clear! FDA did not reject... yet.

     

    Panel voted against the extension to an even broader population with the usage of statins (a way of covering their rear-end in case they wanted to "fast track" the REDUCE acceptance during the ANCHOR PDUFA maybe?), as they can not be sure there is favorable CV outcome tied to the utilisation the combo V+statins.

     

    Due to the rewording from the FDA at the end of the ADCOM, the committee didn't get the chance to vote on the safety and the effective lowering of TG.

     

    But I am pretty sure that the FDA will vote "yes" on dec 20th on those last parameters (which where in the ANCHOR SPA tied to the sNDA and that neither the FDA or AMRN broke... yet).
    22 Oct 2013, 03:54 AM Reply Like
  • Life-Science
    , contributor
    Comments (50) | Send Message
     
    So in your opinion would you say there is a chance that Dec 20th is a "YES" with a controlled label? (Only approval for NON-Statin Patients)

     

    That is the way I see it possibly! If the FDA was trying to protect their rear so to say, and still stick to the legal side of SPA, and what was outlined in the sNDA and clean 74 Day letter..

     

    Your thoughts?
    22 Oct 2013, 09:15 AM Reply Like
  • Shopboy
    , contributor
    Comments (12) | Send Message
     
    Spot on! This is exactly what I think...
    22 Oct 2013, 09:35 AM Reply Like
  • metazeph
    , contributor
    Comments (2) | Send Message
     
    I am quoting your article here: "Since Vascepa has been approved for triglycerides greater than 500 it would be illogical not to approve it for triglycerides less than 500 based on efficacy" .... agree.
    22 Oct 2013, 08:56 AM Reply Like
  • seawolfssn21
    , contributor
    Comments (25) | Send Message
     
    Seems to me the FDA set the stage to get the ADCOM to endorse a position that right now treating triglycerides between 200 and 500 has no demonstrated improvement in CVD outcomes. That to me is a de-facto message to the industry to not bring any new drugs to the FDA to lower triglycerides without having a CVD outcomes study to support the efficacy of the treatment. IMHO this has an effect on GSK's recent move to buy an other omega-3 drug candidate as well as the future of BASF's recent omega-3 manufacturers. By extension, the fact that the FDA got the answer to the issue it explictly poised , it sends a non-official notice to currently approved triglyceride lower drug manufacturers that their products are at risk of being declared worthless by extension. It will be interesting to see if the drug insurance providers react to the ADCOM's "expert" statement as a license to minimize the costs associated with condoning the triglyceride lowering treatments. Without a "Reduce-it" type study the entire segment of this market is threatened if not locked out. The FDA must be required to
    provide some substantial rationale for having approved drugs currently on the market and not approving a new treatment that has lesser side effects due to a change in their opinion of the ultimate desired outcome.
    22 Oct 2013, 08:58 AM Reply Like
  • INVESTOR KING
    , contributor
    Comments (4) | Send Message
     
    The FDA Review Panel tasks were to review and approve the drug on efficiency and safety. The Panel kept asking question about what happen if Vascepa is approved for the expanded lable and reduced it trial failed. Can the FDA remove it immediately. FDA responded "No" without a lawsuit, then the Panelists voted against the recommendation.
    Why are FDA outside Panelists feel they have to do the job of the FDA regulators. This is a joke.
    22 Oct 2013, 09:06 AM Reply Like
  • ralphey
    , contributor
    Comments (382) | Send Message
     
    Author’s reply » Sorry for my misunderstanding of lack of approval vs rejection. Still learning the intricacies of this bureaucracy
    22 Oct 2013, 03:46 PM Reply Like
  • sts66
    , contributor
    Comments (3285) | Send Message
     
    It's not "lack of approval" either - the ADVISORY Committee voted to not recommend SOMETHING be approved by the FDA on Dec 20, the PDUFA date, but is sure as hell wasn't a vote on the proposed ANCHOR indication! But that's really all it means - the panel said "we don't think this should be approved". FDA has gone against two highly negative panel votes this year, but seeing as they apparently have it in for AMRN, doubtful they reverse course here unless significant political pressure is put on them and Congress starts poking their noses into things, as in investigations and hearings into this debacle. As you so eloquently described, this absurd panel question and vote goes against everything in the book, from both a drug/patient health basis and multiple violations of the FDAs own rules.

     

    Looks like AMRN finally believes the game is rigged and they won't be able to convince the FDA to approve ANCHOR, seeing as they just fired half of their sales force. Now it's more than some retail investors losing money and complaining about the unfair treatment AMRN has received, it's resulting in several hundred people losing their jobs too. Expect to see lawsuites coming out of the woodwork now, if we're lucky some ex-employees will attempt to sue the FDA instead of AMRN.
    22 Oct 2013, 05:50 PM Reply Like
  • Jolk
    , contributor
    Comments (306) | Send Message
     
    The panel wanted to approve ANCHOR based on its fulfillment of its objectives, the FDA reneged and made them vote on whether they should wait for REDUCE-IT.

     

    Some were mislead to think that off-label scripts would be fine and dandy. So yeah, just wait for REDUCE-IT since it is approved already, certainly some members were not the sharpest tools in the shed.

     

    The logic involved in this massive bungling, it is hard to think that there isn't something nefarious behind the lynching of ANCHOR.
    2 Aug 2014, 12:41 PM Reply Like
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