Amarin's Mineral Menace
Nov. 15, 2018 1:58 AM ET|7 comments | About: Amarin Corporation PLC (AMRN)
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Summary
Dr. Chowdhury with the FDA determined that mineral oil was an acceptable placebo during the original drafting of the NDA for Vascepa in 2011.
This same exact issue has been brought up by critics with the Marine Trial, the Anchor Trial, and now the REDUCE-IT Trial.
Each time it is brought up, the market overreacts and sells for a short period of time, followed by a significant increase in stock price.
The stock should once again rebound and recover its losses once the mineral oil drama dies down again.
It is this article's proposal that the mineral oil debate will soon once again be recognized as a non-issue and the entirety of the extremely positive REDUCE-IT results will be recognized by the scientific minds of the investing community.
It is extremely important to note that this "mineral oil" menace has been popping its head up after each significant achievement that Amarin (NASDAQ:AMRN) has hit. It came about during the Marine Trial, during the Anchor Trial, during the ADCOM, and now again after the REDUCE-IT results were announced. It is also important to note that Amarin has consistently hit its primary endpoints on each of these mile markers. Lovaza is a world recognized drug and at its peak was bringing in revenues of over $1 billion a year. Would it shock you to know that Lovaza had similar placebo effects without using mineral oil as its placebo?
This alone should dispel any and all doubt that mineral oil was the reason behind the LDL rise in the placebo arm. If Lovaza did not even use mineral oil as its placebo, and had the same effect as Amarin did, then how could it be the fault of mineral oil? Simple answer: it is not because of the placebo used.
The fact is that when a company is doing a trial with a placebo, that placebo has to resemble the real drug's consistency. The FDA approved mineral oil to be used as placebo during the MARINE Phase 3 trial and therefore should not have even discussed its relevance during the ANCHOR sNDA Briefing Document. It is an approved placebo, with minimal effects on the efficacy of Vascepa and does not damage the positive effects of the trial result according to Dr. Sek Kathiresan shown below.
Marine Trial:
The Marine Trial tested Vascepa 2g and 4g in the hypertriglyceridemia population, or triglyceride levels over 500 mg/dL in the blood. This trial was given guidance by Dr. Choudhury from the FDA. The primary efficacy analysis demonstrated that Vascepa decreased triglyceride levels by 26.6% without increasing LDL levels. The data is shown in the bar graph in Figure 1.
Figure 1
MARINE NDA Submission Review
Even back in 2011/2012, the issue of mineral oil Placebo was being brought up as a potential "disaster" for Amarin, according to the short market. Of course, hind-sight being 20/20 we now know that the mineral oil placebo issue was not of any significance then, due to the fact that it received FDA approval, and is insignificant today as well. FDA stated:
Given the increase in median TG levels in the placebo group from baseline to Week 12, Dr. Iffat Chowdhury requested that the applicant submit information about the composition of the placebo capsule used in the clinical study. The placebo was composed of light mineral oil or paraffin light liquid. Data submitted by the applicant support the assertion that light mineral oil does not increase serum TG levels. Dr. Chowdhury notes in her review that similar increases in TG levels were observed in the placebo groups from the Lovaza clinical trials of hypertriglyceridemic patients. -FDA Review Summary
Dr. Choudhury correctly stated back in 2012 that similar triglyceride increases were seen in the Lovaza placebo groups, which did NOT use mineral oil as placebo. This indicates that it is not the placebo being used if both companies saw similar results with different placebos. Amarin's Vascepa has the potential to be a new and improved Lovaza, with a larger market base and a higher revenue potential.
This larger market comes from the Mixed Dyslipidemia market, or in other words, people that have between 200-500 mg/dL of triglycerides in the blood. This market is roughly ten times the size of the hypertriglyceridemia market in the USA alone. Worldwide, there is a market of 570 million people suffering from dyslipidemia as of 2013. At $300 a monthly prescription that equates to $17 billion a year if AMRN only gets 10 percent of the worldwide dyslipidemia market. In America, patients are expected to spend $23.4 billion a year on triglyceride treatment pharmaceuticals by the year 2023. If Amarin gains just 10 percent of the American market alone, it will still be a $2.3-billion drug, bigger than Lovaza which did a little over $1 billion a year in revenue.
Anchor Trial:
After receiving FDA approval for the Marine indication, Amarin went on to seek an expanded label for the successful Anchor Trial indication. The company submitted its sNDA and prior to the ADCOM, Amarin received the FDA's Briefing Document.
The FDA briefing documents raised questions about the mineral oil placebo used in the ANCHOR clinical trial intended to support the expanded approval, thereby potentially negatively impacting the control group data, and suggesting that 'the treatment effects observed with [Vascepa] may be overestimated.' EPA Drug Initiative
As you can see, the issue was once again brought up in 2013 with the Anchor NDA. However, closer studies showed that there was no evidence of the type of effect the naysayers were claiming mineral oil had on the placebo arm.
Evidence:
Lovaza saw similar signals in its trial which did not include mineral oil, as noted on page 15/155 from the FDA briefing document.
Dr. Roberts mentioned that the mineral oil theory is just theory and not known to be true from existing science.
Several times Dr. Roberts pointed out that no conclusive studies exist suggesting mineral oil would have this type of effect. The fact that Lovaza presented similar anomalies with baseline TG levels in the absence of mineral oil placebo completely negates the Vascepa mineral oil theory. Analysis of FDA's Briefing Documents
Given the absence of any evidence that mineral oil was the cause of the placebo arm TG and LDL increases, the FDA concluded that the likely culprits were unknown factors that were likely evenly randomly distributed among all treatment arms. Such factors could be that some patients changed their diet, physical activity, statin therapy, or independently noted lacking benefit from treatment, etc. Mineral Oil Should Not Concern AMRN Investors
However, the FDA issued a CRL to Amarin on the expansion request.
In the Complete Response Letter to Amarin, FDA indicated the need for data showing a reduction in CV events (i.e., data from the REDUCE-IT trial) prior to approval for persistently high TG. Thus, the FDA stated that it no longer considered a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce CV risk in subjects with serum triglyceride levels below 500 mg/dL. -Examining the Amarin Vascepa Saga
So even though Amarin succeeded in significantly lowering triglyceride levels in the Anchor indication without increasing LDL levels, the FDA said Amarin had to show a reduction in major cardiovascular events in the REDUCE-IT study prior to gaining the label expansion. Amarin withdrew its NDA and began to get to work on REDUCE-IT.
REDUCE-IT STUDY:
It is now 2018 and Amarin finally just released the results of the REDUCE-IT trial as requested by the FDA prior to granting Amarin access into the larger expanded label. Amarin announced its full results at the American Heart Association on November 10, 2018. The company hit every goal it had set for itself.
Dr. Bhatt stated, “REDUCE-IT establishes a new paradigm for the prevention of important cardiovascular events in statin-treated patients at elevated risk with increased triglycerides. I believe that the results of this study may represent the most significant breakthrough in preventative cardiovascular care since the introduction of statin therapy decades ago.” See More Here
See Figure 2 for a visual representation of end point success. A decrease of cardiovascular death of 20%, fatal/nonfatal myocardial infarction reduction of 31%, urgent or emergency revascularization reduction of 35%, and reduction of fatal/nonfatal stroke events of 28%!
Figure 2
NEJM Publication
Once again, however, investors are selling in fear due to the same shadow of doubt that critics have been using since 2012, blaming the mineral oil placebo effect.
The data consistently show that triglycerides for all subjects are rising steadily when all other secondary therapies are stopped. If the mineral oil had interaction with the effectiveness of statin, triglycerides at 4 weeks in the placebo arm should have elevated the level of triglycerides. The rate of change in triglycerides as a function of time should have been accelerated. However, the plot of triglycerides against a 6-week period prior to taking oil and 12 weeks with the mineral oil shows a linear function.
Triglyceride levels are increasing linearly as a function of time until the trial ends. This should tell anyone with a background in science or medicine that it is not the mineral oil affecting the rise in placebo arm. The rising levels are already there before taking 4 grams of mineral oil. Subjects in the placebo arm show continuously increasing triglycerides and LDL levels over 18 weeks. This observation clearly indicates that stable dose statin therapy alone is not powerful enough to control triglycerides in this population group (TG>200 mg/dL to <500 mg/dL).
The effectiveness of Vascepa for reducing triglycerides is truly dose-dependent. The group taking 4 gms of Vascepa has shown full effect on triglyceride levels within a 4-week period by reaching a pseudo equilibrium zone (a stable state) during the next 8 weeks.
The increase in triglycerides for the placebo arm during the 12 weeks trial period is not related to interference of mineral oil in statin therapy. It is related to the ineffectiveness of statin therapy and its inability to control triglyceride levels upon removing secondary treatment taken by the placebo arm prior to being admitted into the Phase 3 Trial.
This indicates that the population group (TG>200 mg/mL to <500 mg/mL) needs effective additional secondary treatment in addition to statin therapy to control TG. A daily dose of 4 grams of Vascepa in addition to statin therapy is recommended to control triglyceride levels and reduce the risks of cardiovascular events in patients. EPA Drug Initiative
Conclusion
Amarin has seen its fair share of ups and downs, like most bio-tech companies. However, to continually bring up the same mineral oil fear over and over again when there is no evidence that mineral oil skews the data one way or the other is just plain bad due diligence. The facts remain that Amarin succeeded in hitting its endpoint goal in the Marine trial, in the Anchor trial, and now again in the REDUCE-IT trial. REDUCE-IT results were so phenomenal, in fact, that investors and some doctors can't believe the results are this great. This is why the stock has been selling off. Again, I repeat, the results are a “game changer” according to Dr. Bhatt. It is going to completely alter the way doctors practice.
According to Amarin,
The REDUCE-IT study was designed under a special protocol assessment agreement with the U.S. Food and Drug Administration (FDA). Amarin intends to submit an sNDA to the FDA in early 2019 seeking approval to expand the label for Vascepa based on the cardioprotective effect of Vascepa demonstrated in the REDUCE-IT study. FDA's determination of standard or priority review will be made when the sNDA is submitted. At this time, Amarin is planning for a standard review with potential approval anticipated in late 2019. -See More Here
Investors should recognize that this same critical point of mineral oil having an impact on results is being pushed since 2012. It was an approved placebo by the FDA, and the doctors and scientists involved in the study agree that its effect does not change the results Amarin achieved through REDUCE-IT. At this point, AMRN is a discounted stock if we look at the average $34.80 price target set by the five analysts covering the stock. I project a price target of $55 due to the fact that during the conference call after the AHA conference, the diabetes doctor said he would be prescribing Vascepa to his diabetic and pre-diabetic patients. This is a very large market in conjunction with the hypertriglyceridemia and mixed dislipidemia market. I project annual revenue to reach $5 billion over the next 3 years due to the stellar REDUCE-IT results being promoted to doctors by an expanded sales team. The only downside risk Amarin faces is if the FDA decides not to grant a priority review for the expanded label and investors have to wait until the end of 2019 for the approval of the expanded label. I am confident in the results of REDUCE-IT and look forward to Amarin helping millions of new patients across the world.
Disclosure: I am/we are long AMRN.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
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