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Todays case
64 yo male prexisitng hx of dm2, hyperlipidemia and sleep apnea
Non compliant diabetic hgbaic at 10.4 – refuses injectables
Vascepa initiated 4/14 trigs 442
5/14 trigs 271
trigs 8/17 449
taking meds as prescribed
again isolated case - trigs have increased back to original levels as if med has become ineffective (odd it mimics last one ??) – could it just be worsening of diabetes which is out of control ? Certainly – yet other trig lowering meds dont seem to lose their capability in the face of escalating loss of glucose control ?
What does this mean ?
I dont know - its an observation of an existing reality in my daily practice ....
How does it make me feel ?
It give me an uneasiness about vascepa – because as stated - with other trig lowering meds I dont see this loss of control.
What did I do ?
This is a bit of a quandary as a diabetic hes on a statin - FDA says no to statin and fibrates (ineffective) using gemfiobrozil with statins – risks of side effects
My guidance?
Concentrate on controlling diabetes – stop vascepa, increase statin concentrate on diet and recheck lipids in 8 weeks
Unfortunately many of the patients that I had prescribed vascepa for were denied by insurance - ultimately about 50% or less got it -
you question asks ? DO I have a study that would replace REDUCE IT - no - no scientific study to replace REDUCE IT - I hardly think if I had 80 million odd dollars laying around I would spend it on such - but I have isolated cases - One person with MI -
One person with artificial heart valve - numerous strokes despite being on coumadin, despite being at therapeutic levels at time of stroke - extensive w/u for hypercoag state ( ie antithrombin III, lupus anticoagulant factor V leydig etc etc - all negative) w/u for structural abnormality in cerebral vasculature negative) no cause found ... remember FDA concerns about clotting ? - yea - was that the cause - I dont know ....
and then the odd cases where it seem to have lost its effect on trig levels over time as I revealed yesterday. In general I see about a 25% reduction - however, that level of reduction can easily be obtained with dietary change ( as opposed to ldl where dietary manipulation has little benefit).
Of course the easy answer to your ? is what have you seen that is positive - ie how would anyone know that they were going to have a heart attack and vascepa stopped it ? You do see how illogical such a statement would appear to an outside observer?
Thats my whole point - we cant know until the study is completed - thus to have unbridled enthusiasm that it will work is illogical to me - I am simply saying there is a possibility that this is not going to be as successful as we think.
Again my position is I believe it will have limited success mainly in subsets ie diabetics with high trigs and low HDL
I found the article very fascinating it opens up one more of the trillion puzzles we need to decipher to understand the workings of the human body. From what I recall there was a Danish study that revealed genetic defects which caused either a lower or higher ( cant recall which one ) trig level which resulted in a higher or lower rate of CAD - suggesting direct correlation of Trigs and CAD.
Does this mean that Vascepa will be an automatic success in lowering CAD - hardly - from what I recall a recent study on PCSK9-s revealed that the reduction of atherosclerosis was not what was expected for the reduction in LDL . Look at NIacin it raises HDL and HDL was touted as being one of the strongest markers for CAD - no effect on CAD - Zetia initially shown to have no effect on CAD after reducing LDL - repeat study suggested mild benefit .... which of course gets into the whole issue of outcomes studies vs just looking at markers the role of inflammation in CAD etc etc
After practicing medicine for many years one point becomes clear - biological systems are immensely complex - controlling and isolating factors to determine cause and effect is extremely difficult. Whereas , in the electronic, mechanical perhaps even chemical world this is rather easy.
Absence or variation of a gene, resulting in variation in a marker chemical, may not necessarily be the direct correlation we believe it is for disease induction. That gene alteration may be having countless other effects that we are unable to identify - IN many ways we are the blind man who can only feel one part of the elephant - then run out insisting that the elephant is a snake because the only part we felt was the trunk. (Unfortunately, the guy upstairs who made us - never gave us the blueprints).
So this study is great news and perhaps it will lead to the development of a med that has success in lowering the incidence of CAD. However, let me perhaps reflect onto your own experience. WHen you hear about a great breakthrough for cancer - what do you think ?
Currently , I am very jaundiced about such claims - I have heard them for over 30 years. Perhaps there are great breakthroughs in our knowledge and understanding - yet the reality is - cancer has become the #1 killer and our progress is painfully slow as compared to CAD. ( OF course CAD was mainly a plumbing problem - open the pipes - Cancer is so much more complex)
The proof is in the pudding ...and the pudding is still in the oven .......
(dictated with Dragon Dictate excuse errors)
Sorry .... he was fasting .... like I said there are many many reasons this could happen and its just one case - and one case does not a science make ... but the problem is, its not the first time I have seen this ... I have seen it multiple times ... now do I have the time and resources to do an extended scientific study on this ...hardly ( if that is what is required to advance science than I am afraid most observations would be relegated to the useless pile and we would have stagnated in out advancement of such )... none the less that does not make the observation false - the observation is what it is - but - what amazes me is that people who believe they are scientific become so upset when someone makes an observation that does not fit their hopes ... they would much prefer if we all kept saying 'yes the KING IS wearing clothes' - maybe he is maybe he isnt all I am saying is from what I can see ....the clothes are falling off ......
keep getting upset at the canary that is dying and dont pay attention - why its the canaries fault! - get MAD at THAT canary - he should have never died !
(for those of you who dont know - the canary was what miners carried into the mines to alert them of dangerous gas - when the canary dies its a warning system to get out
the king is a fable about a king who wore no clothes but everyone was afraid to say so and they all kept saying he had clothes on when he didnt - I guess they dont teach these moral fables and stories anymore ...too bad )
Hilarious - A doctor is going to call every patient to see if they fill the rx, to see if they take it, to make sure the pharmacy has not purchased a foreign substitute, to make sure the baby sitter has not opened the capsules and changed the med, maybe martians got in there ..... I now understand why you cannot believe your own personal experiences in the world ...
OK I am going to start posting some actual real world info - obviously no names - to explain why I am changing my views - todays case
patient age 45 started vascepa 2013 trigs 409 - fu readings 294 284 reading today 411 yes they are taking med as prescribed - just an isolated case - many possibilities why this occurred ...problem is I am running into more and more such "ISOLATED " cases.
SO now you can all get upset at the canary who just died in the coal mine - its the canaries fault - get mad at the canary ....
Once again I am just making observations about the reality that I am experiencing - I am sorry that this reality does not match your dreams
This reminds me of specialists who will see a patient and say 'they cant be having those symptoms - they don't fit in "
I often have to explain to them that the patient is experiencing what they are experiencing - just because it doesnt match our model of the disease does not mean its not occurring - you cant deny the patients reality because of your theoretical model - perhaps the model of the disease is wrong or there is another disease present etc etc
Personal experience is false ..... wow it must be an amazing world you live in then - you dont believe anything you experience ?
AS I clearly stated I am only reacting to my own real life experience. This is no different then when I bought underarmour years ago when I noted all the young people wearing it - it is my methodology of investing - examining the reality that lies about me.
Such investing may not work for you and that is fine - use your own methodology
AS to Rx's going up - well that means little - a lot of thalidomide was sold years ago as well - the rx's are rising on an unproven assumption - this means little other than good marketing - a lot of pet rocks were sold as well
Hmmm... somebody better tell my 8000 patients. I have written for vascepa over 300 times ... but you dont want to hear my reality ... go ahead believe all you want ... that's your choice. I do wish you the best of luck - my experience however, which is what I use to guide me in most investments has not been one of great results .
One point that you may wish to remember in life - to seek truth you must be willing to examine an issue from 360 degrees - even the side you dont want to see or disagree with - if you cant do that you wont find truth. I can clearly say that I have looked at this from all sides - from being a great supporter to one of doubt as my experience continues to accumulate.
I find it odd that people who believe they are rational get so upset when someone says - I dont think the way you do. You are still welcome to think and invest any way you want - if your belief in this 'medication' is so strong why would you let let my statements alarm you so much ?
Like I said I wish you the best of luck and hope that REDUCE IT does come through - I too am being a realist - speaking from first hand experience of over 300 patient experiences .... would you have me ignore my experience and continue to cheer on the sinking ship or would you prefer to have someone that says - I'm not certain this ship is going to stay afloat much longer you might want to take a look - if you were confident in your position my statements woudl not have bothered you - the fact that they have suggests to me you too are rather uncertain but perhaps afraid to admit it perhaps. Once again I wish you the best of luck
This is true and my experience has revealed that this med is not the game changer I had originally believed it would be - (learning from experience is a valuable tool - on the other hand one can simply keep repeating the same mantra over and over and convince yourself that you have made a good investment)
Vascepa does not lower trigs very well - actually its rather dismal and insurance coverage is ridiculous and if OTC provides the same benefit - why not use it - as a matter of fact that is what most of the cardiologists are saying to patients - get OTC Omega 3
There remains a possibility that REDUCE IT does have some modest success ... and for all the poor chumps who invested in this hope I do wish them the best of luck - in the meantime I will continue to buy low on reality and sell high on hopes - (I must say I have made some profits off this debacle.)
AMRN has a lot of issues it has to get by to be a success. AS a Family Doc I used the drug a fair amount. Its trig lowering capacity is not significant. However, as you have said that may be irrelevant if the outcomes study reveals great results.
The current issues I see are;
If the drug were a booming success study probably would have already been stopped. That leaves us with the ff possibilities:
1.) Moderate success in general population ( best choice)
2.) Success only in subsets ( ie diabetics with high trigs low hdl - personally I think this is what we will see )
3.) No success
Lets look at all three
no success - then it reverts to the trigs >500 market where it doesnt do a very good job - and the company fails
success only in subsets - currently docs are prescribing the med based on an understanding that it is reducing CAD risk in people with trigs 200-500. If it proves only successful in subsets then the potential market actually shrinks from current usage - rx numbers will decline - as will the stock
Thus REDUCE IT must be a success in the general population - but wait - even if it is the last hurdle is that about 60- 70% of my Rx's for vascepa get returned from the insurance company indicating that the patient should use OTC omega 3. So if the study does show moderate success the insurance companies just substitute OTC omega 3 - and believe me no docs are going to spend any time fighting that battle - The study may ultimately have been named ...for the stocks value
VAscepa ... the statin of Triglycerides -
Vascepa ... Your statins best friend
over one year ago I posted the ff on SA (http://seekingalpha.com/instablog/1077258-ralphey/3082365-amrn-sitting-on-a-gold-mine)
heres the issue:
The new standard for treatment and reduction of CAD will not just be statins - it will be a combo pill of a statin and EPA. Doctors will no longer just prescribe Lipitor or Crestor etc - they will prescribe them with EPA - AMRN captures nearly the entire statin market as an add on to every statin ! This is monstrous . The statin market can be estimated to be 35 billion worldwide. Lets say VASCEPA only captures ¼ of the new combo market - roughly 9 billion dollars of it. The company is currently burning 80 million per year . Quadruple or quintuple those expenses , that still leaves a potential of 8.5 billion per year on 180 million shares - of course that makes the stock invaluable.
HI:
just posted a letter that anyone can send to their insurance company and if you need me to argue the point with them just let me know
Response to INsurance companies
Hello: I was asked for a response to insurers who deny vascepa here it is. Denial will be based on one of two suppositions -
a.) Substitution of substandard treatment
b.) Belief that trigs in the 200- 500mg / dl range need not be treated
this letter covers both - feel free to copy and use
***************************
I am writing to request the medication Vascepa for patient …... .
You have either denied the treatment of offered substitution of niacin, fenofibrate, lovaza or over-the-counter FISH OIL
1.) Offer of Substitution:
If you have offered a substitute for Vascepa then you have automatically negated the FDA supposition that trigs in the 200- 500 mg/dl range need not be treated . Therefore the question becomes which medication is best for this issue:
a.) Niacin
Outcomes studies with Niacin reveled it to be useless to lower CAD associated with elevated Triglycerides. Do you really want me to prescribe a medication that was shown to be useless ?
b.) Fenofibrates
With respect to fenofibrates :
1. Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. This risk is increased when taken in combination with a statin
2. Tricor can increase serum transaminase. Requiring Monitor liver tests, ALT periodically
3. Tricor can reversibly increase serum creatanine levels. Monitor renal function with renal impairment
4. Fenofibrates have mixed outcomes studies
a. FIELD STUDY
Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer NFMI and revascularizations.
Do you really want me to prescribe a medication that has this many side effects when it is unkown whether it works or not ?
c.) Lovaza
Lovaza increases the highly atherogenic particle LDL by 49%.! You cant seriously expect me to substitute Lovaza to reduce triglyceride in the hopes of reducing CAD when it increases LDL by 49% - it may very well be inducing the very disease I am trying to prevent
d.) OTC Fish Oil
To match the efficacy of Vascepa the patient would have to take over 18 capsules of otc fish oil per day – do you really seriously want them to do that ? Also OTC fish oil may be both DHA and EPA. DHA has been shown to elevated LDL significantly thereby actually inducing the very disease we are trying to prevent.
EPA (Vascepa) the medication I have chosen has an outcomes study in Japan – JELIS which revealed 50% reduction in CAD. Vascepa has almost no side effects
In summary , (ins company ) agrees contrary to FDA findings that trigs in the 200 – 500 range should be treated. The medications they offer either have no outcomes studies or negative outcomes studies and have very serious side effects. The medication I have chosen has positive outcome studies and no side effects. I therefore ask to allow vascepa utilization for those patients with trigs in the 200- 500 range giving them the best medication in this class .
2.) Coverage of Vascepa decline based on the highly controversial belief that TRIG in the 200- 500 mg/ dl need not be treated
Newest guidelines (ATP IV) have simply ignored the triglyceride issue. They have neither said treat or do not treat. Since triglycerides were not addressed it is entirely logical to continue with the existing standard – ie if there is no change this DOES NOT mean cease treating – It means no changes are warranted.
You are well aware that recently , NEJM published groundbreaking studies showing an almost definitive link between high triglycerides and extremely high risk of heart attacks (study showed 40pct reduction in heart attacks for those w normal triglycerides versus high levels.) This clearly reveals the need to treat triglyceride elevations . In addition, you are well aware of the JELIS study involving 18,000 individuals in Japan that showed almost a 50% reduction on coronary events for individuals already taking statin to which EPA (Vascepa) was added . There are a plethora of studies revealing EPA’s benefits in lowering inflammatory markers associated with CAD. Most recently The Journal of Cardiology published research that revealed pre-treatment with EPA in addition to statins significantly reduced the incidence of type IVa MI compared to statin therapy only.
Therefore, in either situation – offer of substitution or denial of treatment for trigs in the 200- 500 mg/dl range you are offering your customer substandard treatment. If you prevent your customer access to Vascepa you are potential contributing to the development of CAD and their early demise. All substitutions are of substandard efficacy and lack of treatment is contrary to the existing mounting scientific evidence. Your failure to cover this medication will require me, as my patients advocate, to ask for a State Insurance Commissioner investigation of such
Sincerely,
The FDA ombudsman is as useless as teats on a boar / a screen door in a submarine /
PDUFA Limbo for all intents and purposes yes BIO B - however, the official PDUFA has not yet occurred - meaning that the FDA is still obligated ( sorry such terms have no meaning with gov officials ) to render a decision - it is still possible they will right the ship and do their own evaluation of the science independent of the ADCOM recommendation - it rarely has happened
Thnxs The PDUFA is in limbo FDA has head in sand no one can force them to do anything- unless AMRN takes legal action which I suspect they will soon do if FDA does not align its ship
AMRN - Sitting on a Gold Mine
Amarin (AMRN - NASDAQ) corporation is biopharmaceutical firm located in Ireland with expertise in lipid science to improve cardiovascular health. AMRN's product Vascepa® (icosapent ethyl) capsules is approved by the U.S. Food and Drug Administration for the use as an adjunct to diet to reduce triglyceride levels in adult patients with severe (TG>500mg/dL).
Amarin currently has 172 million outstanding shares with 31% Institutional ownership.
Cash collections for the sale of Vascepa in the first quarter of 2014 were approximately $11.6 million. Gross margin during the quarter ended March 31, 2014 was 61% as compared to 45% in Q1 2013 reflecting declining expenses. At the end of the first quarter of 2014 the company had $164 million cash. The company estimates cash outflows of 80 million dollars for 2014 and has reserves to make it until the year 2016
Alphabet Soup
To those of you who are new to the alphabet soup of governmental bureaucracy that surrounds the FDA let me try to give an explanation of the events that have placed AMARIN into its current situation .
AMARIN developed a refined fish oil called EPA - the medication is known as Vascepa. EPA has distinct benefits over its nearest exiting competitor Lovaza . Lovaza consists of both DHA and EPA. The DHA component of Lovaza raises LDL (Low density lipoprotein - which happens to be the major atherogenic (causing heart attacks - MI's) particle by 49% . Lovaza has only been approved for triglycerides over 500 mg dl to prevent pancreatitis which can be caused by highly elevated triglycerides.
Vascepa has also received approval from the FDA for the treatment of triglycerides > 500 mg / dl to prevent pancreatitis.
After receiving the above endorsement AMARIN petitioned the FDA to also obtain approval for the treatment of triglycerides in the 200- 500 mg/dl range as well. Note that the treatment of trigs in this range is NOT for pancreatitis but rather for the prevention of CAD ( coronary artery disease ie heart attacks). Most important is the fact that LOVAZA (Produced by GSK) could not apply for this indication since, as previously mentioned they raise the very atherogenic particle LDL by 49% . Many physicians , however, have been and continue to prescribe Lovaza for elevated triglycerides (>200 mg/dl) to prevent CAD and appear to be unaware of its effect on LDL , unknowingly perhaps contributing to the very disease they wish to prevent.
AMARIN petitioned the FDA for this new application of the drug in what is called an sNDA (Supplemental New Drug Approval). The FDA agreed to this new application with several stipulations - these stipulations are called a SPA (Special Protocol Agreement). These included that AMARIN :
1.) Perform a study called ANCHOR - this study was simply to show that the medication did lower triglycerides in patients with levels between 200- 500 mg/dl and was neutral or better on the LDL question
2.) Initiate a study called REDUCE -IT - this is an actual outcomes study to reveal that lowering triglycerides actually will prevent deaths due to CAD
AMARIN complied with these requirements and had a successful ANCHOR study proving what the FDA requested. In the meantime the REDUCE-IT trial was initiated as per FDA request. AMRN thus successfully complied with the SPA (Special Protocal Agreement) contract that they held with the FDA and which was constructed by the FDA .
The actual decision to approve VASCEPA for the treatment of trigs in the 200- 500 mg /dl range is called PDUFA . This stands for Prescription Drug User Fee Act - basically this is a law that was initiated to allow pharmaceutical firms to pay a fee to the FDA to have their medications reviewed in a timely manner.
AMRN shelled out over 1.7 million believe it or not for what has turned into a kangaroo court as described below.
Before actually deciding on the PDUFA the FDA holds an ADCOM (Advisory Committee Meeting). This is a meeting of various specialist in the fields as well as the pharmaceutical firm which is supposedly allowed to present their side of the issue.
Since AMRN had met all the requirements of the FDA's SPA successfully there appeared no reason why the ADCOM would not vote in favor of the sNDA. As a matter of fact as we review the science as outlined below , for an investor to have predicted that the ADCOM would fail to support the medication would leave one with the ff conclusions:
1.0) They totally misunderstood the science as did the FDA
2.0) Outside sources clued them in
Either one speaks poorly - yet I digress
The ADCOM voted NO Approval 9-2 and here is where the highly irregular leaps of faulty and bizarre logic begin as explained below. As of this writing the FDA has not finalized the PDUFA one way or the other. However, in what appears to be an illegal action the FDA has pulled the SPA agreement. Ie the FDA had a contract with AMRN in which both parties agreed that if the endpoints of the ANCHOR protocol were reached the company would receive the sNDA. The FDA can only renege on a SPA if there is proven danger to patients . There are no such dangers since the drugs side effect profile is almost equivalent to placebo.
IN summary ;
1.) FDA approves Vascepa for the treatment of trigs >500 mg/dl for the prevention of pancreatitis
2.) AMRN applies for sNDA for the treatment of trigs in the 200- 500 mg /dl range for the prevention of CAD
3.) FDA agrees to consider sNDA provided AMRN fulfills SPA via ANCHOR study which proves that Vascepa indeed lowers trigs in the 200- 500 mg /dl range and is at least neutral on LDL
4.) ANCHOR study is completed and meets all endpoints
5.) ADCOM committee votes 9-2 against recommending Vascepa for the sNDA (see below)
6.) FDA pulls SPA agreement despite the fact that all endpoints of SPA were met and the medication has no significant side effects
7.) PDUFA remains in limbo at this time despite the fact that the law guarantees a decision within a set time
The ADCOM Fiasco
As noted above since AMRN met all endpoints it appeared that approval of the sNDA by the ADCOM was guaranteed. The FDA however, had something else in mind for AMRN.
It is unclear what was the impetus for the FDA to not approve of Vascepa for the treatment of triglycerides in the 200- 500 mg / dl range, however, an understanding of the greater picture for the treatments of lipids to prevent CAD at the time of the meeting sheds light onto the matter.
Prior to the ADCOM meeting the standard of treatment for lipids was known as ATP (Adult Treatment Panel )III guidelines . Most practitioners were and many still are utilizing these guidelines. These guidelines indicate that first the practitioner should address the patients LDL level - unless triglycerides are greater than 500. However, after addressing LDL that practitioner then examines the triglyceride level. Triglyceride >200 mg/dl are considered to be elevated and are to be treated.
At the time of the ADCOM meeting the FDA was apparently aware that new guidelines were surfacing . The new guidelines focused entirely on risk factors and the use of statins. They simply did not address the issue of triglycerides - they neither supported nor refuted whether trigs should be treated they simply did not mention them . Of course this left many practitioners in a quandary and indeed many organizations especially those that deal with diabetes emphasized the need to continue treating triglycerides. Most practicing physicians took the stand that since there was no mention of triglycerides - the old standards regarding their treatment remained in effect and continue to treat them when >200 mg/dl . Indeed there was no mention to cease treating them and indeed the, major medical societies recognize the importance of TG elevation as a risk factor in CVD including but not limited to: The American Heart Association (AHA), American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), and American College of Cardiology (ACC) who recommend treatment of patients whose TG > 200 mg/dL. .
.
The FDA however, in a meeting that became nothing short of a kangaroo court took the stance that triglycerides need not be treated. The irony of the situation was that instead of coming forth and stating that the new guidelines neither endorse or refute treatment of triglycerides they attempted to present studies to indicate that trigs in the 200- 500 mg/dl need not be treated. Apparently the FDA understood that if they indicated new guidelines make no mention of trigs it would be logical to assume that the old guideline with respect to triglycerides remain standing. So instead, for reasons which remain entirely unclear, the FDA did rather instantaneous retrospective research, and incorrectly analyzed previous studies, in an attempt to prove that trigs in the 200- 500 mg /dl need not be treated.
Of course this begs the question - why all of a sudden did the FDA become interested in proving that trigs in the 200 - 500 mg /dl range not be treated when new guidelines make no mention one way or the other ? ie since when did the FDA become a research organization ?
The FDA presented three studies which I will review, however, before doing so I will prove that no matter the results of these studies the FDA's logic in extrapolating from one medication to the next is clearly flawed.
Lets examine the medication Zetia which reduces LDL. Outcomes studies for ZETIA initially revealed it has no effect on reducing CAD (Another study is being conducted) . Consider if Zetia presented to the FDA prior to statins. The FDA would have concluded that lowering LDL has no effect on CAD. Utilizing this logic if statins then presented to the FDA they would have been rejected as the FDA concluded that lowering ldl has no effect on CAD.
Clearly it is contorted thought to conclude that because two medications have the same effect on one marker that the outcome studies of these medication will be the same . The FDA applied this reasoning to Vascepa in a glaring example of faulty logic - concluding that since other medications that lower trigs must not reduce CAD mortality.
Ironically the logical ineptitude ran even deeper as the conclusion were based on studies in which the patients triglyceride levels were not elevated in the 200- 500 mg / dl range ! (see below)
Can it get even worse? Most unfortunately for US citizens - YES! The FDA prevented a study (JELIS) which used the exact compound in question (EPA) and revealed a nearly 20 % reduction in CAD mortality from being utilized as evidence. So on one hand the FDA extrapolates information from different molecules equilibrating similar effects on markers as having similar outcomes, equilibrated lower levels of trigs as being the same risk as higher levels of trigs ( a logical dichotomy when juxtaposed against reason to perform the study) and then on the other hand indicated that a study with a compound of the exact same chemical structure is irrelevant. Lets look closer at the studies presented or rejected
1.) AIM-HIGH study - Presented by FDA
This study examined whether the combination of statin-niacin would provide a greater cardiovascular risk reduction in patients with coronary heart disease and atherogenic dyslipidemia vs statin alone .
The results concluded that Niacin had no effect on the rate of CAD. Of course since Niacin is not EPA this information is useless. (As noted above with Zetia it is scientifically flawed to assume that medications with different mechanisms but the same effects on markers will have the same outcomes studies) However, most amazingly the average triglyceride levels of the patients in this study was 162 mg/dl . This is not even in the range that AMRN requested Vascepa be considered for in the sNDA ( ie > 200 mg /dl) . This is equivalent to saying that since treating people with normal blood sugars or normal blood pressures had no effect on mortality therefore treating people with high BP or high BS will also have no effect on mortality - this is truly embarrassing for the FDA and the ADCOM panel, calling into question credibility or honesty. However, even more embarrassing is that a subgroup analysis revealed that individuals who do have triglyceride elevations in the range that AMRN sought their sNDA DID have a reduction of CAD risk by an amazing 37% !
2.) ACCORD study - Presented by the FDA
ACCORD was to determine Combination therapy with fenofibrate and simvastatin would reduce the risk of fatal cardiovascular events. The answer is it did not however, once again Vascepa is NOT a fibrate and equilibration of drugs with different mechanism is flawed. Ironically the average triglyceride level was once again 162 mg / dl - irrelevant to the group in question with respect to Vascepa's sNDA as outlined above. The same two identical logical flaws
More importantly , however as closer look at the data reveals that in a subgroup analysis, patients with higher baseline triglycerides 284 mg / dl and lower HDL-cholesterol levels benefited with a reduction of CAD risk by 28% This is within the range that AMRN requested for their sNDA!
Of course this is extremely embarrassing for the FDA when they propose that medication for the treatment of Triglycerides in the 200- 500 mg / dl range should be denied because another medication gave no benefit for patients with an average triglyceride level of 162 - but then conveniently ignore the fact that patients with a triglyceride level of 264 mg / dl did have benefit.
3.) HP2S Thrive - Presented by the FDA
This study was to determine if adding niacin to a statin would reduce CAD mortality . It did not . However, once again niacin is not EPA. Ironically the average triglyceride level in this study was 125+ 74. Once again not even in the range that AMRN requested.
Thus in all three studies that the FDA cited we see two consistent logical flaws
· Equilibrating drugs with different mechanism but the same effects on makers as having the same effect on mortality . Blatantly untrue as we revealed with Zetia
· Indicating that since lowering markers that are considered to be in a normal range had no effect on mortality lowering levels that are elevated would have no effect on disease mortality - begging the question as to why then do we then have any definitions of what elevated Blood sugar - blood pressure etc are? Apparently, since treating normal blood pressure has no benefit then neither does treating elevated blood pressure
But wait in a final Grand finale the FDA prevents JELIS study from being cited
4.) JELIS study - FDA Prevented this study from being presented
Performed in Japan to determine if EPA (The active ingredient in Vascepa) would reduce the incidence of CAD when added to a statin. Results revealed a 20% reduction in non fatal coronary artery events despite the fact that the triglyceride levels in question were beneath proposed study values and the recipients were given only half the proposed US dosage of the medication
Ironically this was the only study that utilized the compound in question (EPA) and
and thus was promptly rejected by the FDA. Most unbelievable one of the issues that the FDA presented was the fact that Japanese were already consuming a fair amount of EPA in their diets. This of course is another logical breakdown involving basic pharmacology, as it is generally true that compound naïve patients will have a greater benefit than those with compound already present - ie by doubling a drug dosage you rarely ever double efficacy - most efficacy is obtained in the first amount of compound ingested. Thus the FDA true to form initiates another logical fallacy . If anything, because Japanese already consumed EPA, one would have expected the benefit to be lessened
During the ADCOM meeting at about 22 minute the panelist are given four parameters to consider - one of them being the effect of EPA on CAD. However, one minute later when asked to vote are told to disregard that parameter. Not one panelist questioned this dichotomy
Summation of the Logical Fallacies :
SO lets summarize the broken reasoning and logical fallacies of the FDA;
1.) The FDA agreed to a contract (the SPA previously indicated) giving AMRN an approval of Vascepa for the treatment of trigs in 200- 500 mg/dl range if the guidelines constructed by the FDA (not AMRN ) were met.. AMRN met the guidelines and the FDA then rescinded the SPA contrary to existing law which states they could only do so if there were a medical threat or danger to patients from the medication
2.) The FDA analyzed three studies and in each inappropriately equilibrated drugs with different mechanism of actions as having the same end results. (The real question is are we disregarding the statin of triglycerides because of this fallacy ? think if zetia had come first and this logic was applied ! )
3.) The FDA analyzed three studies in which triglycerides levels were lower than the proposed range of treatment of Vascepa and then unbelievable indicated that if there was no benefit for treating normal levels there would be no benefit for treating elevated levels - which I guess makes it nearly impossible now to define most any 'disease'.
4.) The FDA rejected the only study that actually analyzed the compound being analyzed
5.) The FDA indicates that preexisting levels of compounds in the human body would increase effectiveness - when we know the opposite is usually true
Newest Studies:
The above information in itself clearly reveals severe deficiencies in the FDA's analysis of data - the reasons remain unclear - we either have an organization that is incompetent or malevolent - however, neither case is beneficial for the American public. However, if you are still not convinced that the treatment of triglycerides is warranted, the science has produced a continuous stream of article revealing the benefits of EPA. A few of these are as follows (If not interested please skip to next section)
Effect of purified eicosapentaenoic acid on red cell distribution width in patients with ischemic heart disease - Heart Vessels DOI 10.1007/s00380-014-0526-3 Feb 2014
Conclusion, highly purified EPA may reduce RDW a known risk factor for CAD) in IHD patients. This effect was particularly strong in diabetic patients with high levels of hs-CRP. IHD patients with high levels of RDW may be targeted for treatment with highly purified EPA.
Stabilizing effect of combined eicosapentaenoic acid and statin
therapy on coronary thin-cap fibroatheroma Atherosclerosis 234 (2014) 114e119
Conclusion : Although detailed mechanisms remain unclear, our results
suggest that EPA stabilizes TCFAs better than the statin alone
therapy through greater suppression of vascular inflammation.
Fish oil constituent eicosapentaenoic acid inhibits endothelin-induced 2 cardiomyocyte hypertrophy via PPAR-a Life Sciences xxx (2014)
In conclusion, the present study shows that ET-1 induces significant 380
cardiomyocyte hypertrophy, and that pretreatmentwith EPA attenuated 381
these remodeling events by up regulating levels of PPAR-a pathway
Effects of Eicosapentaenoic Acid Treatment on Epicardial and Abdominal Visceral Adipose Tissue Volumes in Patients with Coronary Artery Disease.
Conclusions: Oral intake of purified EPA appears to be associated with reductions in EAT (Epicardial Adipose tissue ) and AVAT (abdominal visceral adipose tissue) volumes. (both associated with higher incidences of CAD)
Inverse relationship between long chain n-3 fatty acids and risk of sudden cardiac death in patients starting hemodialysis Kidney Int. Jun 2013; 83(6): 1130-1135
In summary, long chain n-3 fatty acids are strongly associated with a lower risk of sudden cardiac death in incident hemodialysis patients during the entire first year of dialysis
Combination Eicosapentaenoic Acid and Statin Treatment Reversed Endothelial Dysfunction in HUVECs Exposed to Oxidized LDL
Poster presentation 1Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; 2Elucida Research LLC, Beverly, MA, USA; 3Ohio University, Athens, OH, USA
The results of this study indicate that both EPA and statins have a beneficial effect on endothelial NO production while reducing cytotoxic ONOO- levels. Both EPA and statins improve endothelial function using complimentary pathways, including their ability to
(1) interfere with sources of reactive oxygen species (eNOS and NADPH) or (2) enhance eNOS coupling efficiency due to restored levels of essential co-factors. These data suggest that EPA and statin combination treatment may provide atheroprotective benefits by reducing oxidative stress and reversing endothelial dysfunction.
And many others which for the sake of time I will not post .
The Hammer Falls :
The aforementioned studies are interesting but certainly are not groundbreaking. However, the gavel fell several weeks ago when a landmark study revealed that individuals with a genetic defect that results in lower triglyceride levels have a 40 % reduction in CAD . For those in the know the trail of bread crumbs did indeed lead to what they knew all along - lowering triglycerides will reduce CAD.
Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A
N Engl J Med. 2014 Jun 18.
This study analyzed data from over 75.000 participants in two Danish prospective studies. The participants with the specific genetic defect that reduced triglycerides had substantially lower rates of CAD in proportion to the reduction of triglycerides.
Conclusion : Life-long low levels of non-fasting TGs due to one of three loss-of-function mutations in APOC3 are associated with lower risk of ischemic vascular disease and ischemic heart disease in the general population.
It may be argues that perhaps these genetic defest also effec other inflammatory markers which are no w considered by any to play a role int eh development of CAD . That may be the case ans therefore it is very important to note that unlike NIACIN , Fibrates and Lovaza) EPA ( Vascepa) has studies revealing reductions in VLDL, LDL, APO C-II, Lp-PLA2 and hsCRP. EPA (Vascepa) also reveals reduction of inflammatory markers similar to the mechanism of statins. (Once again explaining why it is a logical fallacy for the FDA to equilibrate drugs with different mechanism but the same effect on one marker as having the same outcomes .)
Where is the FDA ?
The FDA has been left in an extremely embarrassing position . Numerous logical flaws and misinterpretation of the science led to a ADCOM recommendation that made little sense to those with an understanding of the science at hand. With respect to those non FDA members who predicted that the FDA ADCOM would not support the recommendation for the sNDA they are left with a perhaps even more embarrassing scenario which I will let those with more nefarious minds examine
Suffice it to say that failure of the FDA to approve AMRN's PDUFA will only lead to a flurry of law suits which will be most difficult to defend. The science supported the PDUFA prior to the above landmark study - this study has only proven what JELIS suggested .
To argue the other side of the equation - is it possible that the REDUCE -IT study will fail to show results? Yes it certainly is however, at this time the overwhelming burden of evidence supports approval of AMRN sNDA until such time that REDUCE-IT proves the issue one way or the other.
For the FDA not to approve the PDUFA at this point would be a most egregious error.
THE GOLD MINE :
What does this mean to you the investor. The value of AMRN stock has been artificially deflated compared to its potential. The company continues to sell product for its niche of trig> 500 however, many physicians who understand the data continue prescribing off label to treat trigs in the 200- 500 mg / dl range .
Rx growth has been slow but steady and as KOWA co promotes numbers will continue to grow.
Basically there is not much more downside for AMRN - perhaps, further stock dilution of 20% due to recent financing but it appears that most investors have weighed that into the current price. However, the potential here is vast. The newest studies as mentioned above clearly show a link between lowering trigs and reducing mortality from CAD. It certainly may be argued that individuals with this genetic defect have other alteration in other markers which have not been measured that account for the benefit. However, that does not explain the benefit revealed in JELIS. Also remember EPA has a very favorable profile on these other markers The pieces of the puzzle are slipping together rather well suggesting that they do indeed fit. It is entirely reasonable at this time to argue that a reduction in trig by EPA will reduce CAD until such time that REDUCE -IT offers results. The risks of Vascepa are negligible. Therefore at this time the FDA has a duty to the American Public to allow this lifesaving medication to be utilized in the above arena. The potential for benefit has clearly been developed - the risks are negligible - not to approve the medication would again be an egregious failure and allows insurance companies to rationalize denying payment for the medication
What this means is that the new standard for treatment and reduction of CAD will not just be statins - it will be a combo of a statin and EPA. Doctors will no longer just prescribe Lipitor or Crestor etc - they will prescribe them with EPA - AMRN captures nearly the entire statin market! This is monstrous . The statin market can be estimated to be 35 billion worldwide. Lets say the VASCEPA only captures ¼ of that market used in combo with statins roughly 9 billion dollars of it. The company is currently burning 80 million per year . Quadruple or quintuple those expenses , that still leaves a potential of 8.5 billion per year on 180 million shares - of course that makes the stock invaluable.
As an investor looking at risk benefit ratio - I see very little downside left for AMRN. The science is strongly in support of EPA and statins becoming the new standard of care for the treatment of CAD. What happens if RECDUE-IT fails? AMRN continues to sell product for trigs > 500 mg /dl - the stock price may decrease some but again there is still intrinsic value in the company and the product - and if REDUCE-IT succeeds - a multibillion dollar market.
The issue has never been treating triglycerides - the issue is a new standard, statins and EPA for reducing CAD.
I am sorry that I do not have time to answer individual comments and questions , however (as opposed to the FDA) I do encourage a lively discussion by all interested parties