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.
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.
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.
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.