Having taken some time off from article writing, I recently made the decision to write a new Amarin (AMRN) article prior to the company's upcoming FDA Advisory Panel meeting on October 16. This panel is meeting to consider the company's SNDA filed for the 'ANCHOR indication', which seeks to expand Amarin's Vascepa patient population indication to treat patients on statin therapy with multiple lipid disorders, including triglycerides levels greater than 200 mg/DL. Currently, Vascepa is only indicated as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (triglycerides greater than or equal to 500 mg/dL), also known as the MARINE indication.
I announced that I would be writing the new article via Twitter, and in that tweet I jokingly made a reference to The Street Senior Columnist Adam Feuerstein, whom has been very bearish on Amarin's prospects. Amarin bulls have been at odds with Adam for over a year, as his extremely bearish sentiments raised hackles of many leading into the company's FDA approval for Vascepa's so-called MARINE indication in 2012. His response to me was a bit cynical, but on point when he asked me what I was going to write that had not already been written or said thousands of times by Amarin bulls:
He had a valid point, and so I decided to review all of my diligence for the past two years and come up with an article that addresses something that has been largely overlooked or perhaps a valuable key piece of information that has been ignored when crunching the data for ANCHOR. Fortunately, I believe that I was able to uncover some specifics regarding GlaxoSmithKline's (GSK) Lovaza's (formerly Reliant Pharmaceutical's Omacor) attempt to receive a similar approval as the one that Amarin is seeking with ANCHOR, and I believe these have received little direct attention by commentators (or have not been explored thoroughly). My hope is that this article provides some additional food for thought for both Amarin bulls and bears.
Most of the bearish talk by Feuerstein and others about whether or not Amarin will receive a favorable panel recommendation for ANCHOR has centered on whether the FDA will required the REDUCE-IT trial to be completed before giving the company the thumbs up. This in itself is quite strange, given that the company is not seeking an indication for the reduction of cardiovascular events (which is what REDUCE-IT is examining) yet. Instead, they are merely seeking to expand Vascepa's indication to include the high triglyceride patient population, including those who are also taking statins. The only FDA requirement I am aware of regarding ANCHOR and REDUCE-IT was that the latter be substantially underway, and this was a stated requirement for the submission of the ANCHOR SNDA.
Beyond the misleading chatter around REDUCE-IT, there are reasons that Vascepa will not face the same hurdles as Lovaza/Omacor in gaining an indication for this new patient population. These reasons are centered around the fact that the ANCHOR study has already addressed FDA concerns that were expressed previously when Reliant Pharmaceuticals attempted to gain approval for the same indication for Omacor. Although Reliant was unable to address these concerns to the satisfaction of the FDA, Amarin already has, and this has been overlooked by Wall Street, bloggers, and many retail investors. In order to explain why this is true, we first need to take an in-depth look at what happened with Omacor.
Lovaza/Omacor and the COMBOS/OM6 study
(NOTE: GSK acquired Reliant Pharmaceuticals in 2007, Lovaza was formerly known as Omacor, and references to the OM6 study may also be referred to by the acronym COMBOS.)
Questions as to why Reliant did not receive approval for the high triglyceride patient population can be found by reviewing the Statistical Reviews published by the FDA after Reliant's drug application was submitted for that indication. "In the original application decreases in triglycerides... were associated with increases in LDL, HDL and Apo-B in patients treated with omacor. The FDA expressed concern that these changes may increase cardiovascular risk and that these changes may attenuate the effects of a statin given in combination." The publication goes on to state that "Based on the original submission, it was concluded that additional data was needed to show that the increases in LDL seen in Type IIb and IV patients using omacor would not increase the risk of atherosclerosis or that the addition of omacor to a statin would not attenuate the effects of the statin while providing a clinical benefit regarding TG."
Reliant Pharmaceuticals attempted to address those concerns in a study known as Study OM6 (also called COMBOS), conducted from May 2005 to June 2006, and submitted a response to the approvable letter (previously issued by the FDA) on December 11, 2006. Of note, in regards to the FDA's concerns regarding the increase in the risk of atherosclerosis, Reliant was silent, providing only data supporting that the addition of omacor to a statin would not attenuate the effects of the statin, while still providing a clinical triglyceride benefit ("The applicant has submitted the results of one study to demonstrate the latter.") Additionally, as part of the complete response, Reliant submitted "the results of one clinical trial (OM6) to support an indication for combination use of omacor with a statin to reduce non-HDL, TG, TC, Apo-B and VLDL and to increase HDL in patients with TG between 200 and 500 mg/dL."
The OM6 study appears to have been successful on the surface in terms of using Lovaza/Omacor with a statin, except for the fact that there were some additional recommendations made: "In a letter from FDA dated February 15, 2005, the Division of Metabolic and Endocrine made the following recommendations for the protocol of OM6:
-Patients treated with simvastatin 40 mg should be at NCEP AT III goal levels for LDL at randomization to placebo or omacor.
-Non-HDL should be the primary endpoint.
-The study should be adequately powered to rule out a treatment difference of 4% to 6% on LDL. (emphasis added)
This is where Reliant ran into another problem. Beyond not addressing the risk of atherosclerosis, they also failed to address the concerns of the Division of Metabolic and Endocrine regarding LDL issues. The FDA summed up the issue nicely: "Regarding LDL, the trial results did not meet the criterion of ruling out a 4-6% treatment difference…" (emphasis added). In my opinion, this was a major problem and part of the reason the indication was ultimately not approved in the for the population. However, I think a piece of information has been overlooked that the FDA may have also taken note of.
Dr. William S. Harris argued subsequently that "If the study had enrolled perhaps 20 less people… It would not have reached statistical significance and the investigators could have concluded that they did not get a significant change in LDL-C. Here is an example where statistical significance and clinical significance diverge." In essence, he thought that the clinical significance of the LDL-C numbers in the OM6 study was not clinically significant, and he expressed surprise that after "the results of the study were submitted to the FDA in June, the FDA issued an Approval Letter permitting the addition of select study data within the clinical studies section of the label for Lovaza, but it did not approve the additional indication," referencing Lovaza/Omacor not being approved for use in patients with high triglycerides (≥200 mg/dL and <500 mg/dL) who were also on statin therapy.
There is a hole in his hypothesis, and this is where I believe that the FDA might have focused on the results of another study published in 2003 to support not granting an approval for the high triglyceride patient population. The STELLAR Study indicates that simvastatin alone could reduce LDL-C (although not as effectively as rosuvastatin), without the addition of a triglyceride lowering medication. If this is fact the case, one may perhaps deduce that Lovaza/Omacor did in fact attenuate the effects of simvastatin, at least so far as the reduction of LDL-C goes. If Lovaza/Omacor did not clinically increase LDL-C as Dr. Harris suggested, why then did we not see the decrease reported previously in the STELLAR study? I think this point has been previously overlooked, and I think it is important to consider, especially when compared with Vascepa's ANCHOR results.
The underlying point is this - if Omacor/Lovaza did not raise LDL-C in a clinically significant manner, as Dr. Harris argued - then it either negated the LDL-C lowering effects of the statin, or worse, it's propensity to raise LDL-C was mitigated by the use of a statin. Either way, this was in my opinion, the clinically significant reason that it did not receive the indication.
Amarin's Vascepa and ANCHOR
Amarin does not have the same issues with raising LDL-C as Lovaza, has better efficacy in terms of triglyceride lowering, and has supporting evidence that it may help prevent atherosclerosis, addressing all of the issues that Reliant was unable to effectively deal with when attempting to gain the indication being sought via the ANCHOR indication.
As reported in The American Journal of Cardiology, Vascepa (formerly known as AMR101) "4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A2 (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons)" in the ANCHOR study. Further, the trial's non-inferiority criterion for LDL-C was met, and for the 4 grams per day Vascepa group, LDL-C decreased significantly (-6.2%, P=0.0067) from baseline versus placebo, demonstrating superiority over placebo. It is also possible that the FDA has seen new information regarding something that was not addressed in the reported OM6 results, regarding whether the use of Vascepa would increase the risk of atherosclerosis. In fact, according to one study, the oral ingestion of eicosapentaenoic acid may actually induce the rapid regression of atherosclerosis (Vascepa is an ethyl eicosapentaenoic acid).
Further, Amarin has already published the result of a Phase I study that indicates that the bioavailability of one statin was not inhibited in a fixed-dose combination study with Vascepa (AMR-102), further paving the way for a successful future with patients on statin therapy.
As you can see, all the evidence points in a positive direction for Amarin in regards to all of the FDA concerns, and it would seem that the road is clear of obstacles moving forward. Concerns about REDUCE-IT have been dramatically overstated, and even if they are mentioned in the briefing documents, will not be an obstacle.
When you look at exactly what the FDA addressed previously in considering Lovaza/Omacor for what many are now calling the ANCHOR indication, it becomes clear why the FDA allowed the information to be included in the package insert, but did not approve the indication. Atherosclerosis was not addressed, LDL-C goals were not met, and there was perhaps some indication that Lovaza did attenuate the effects of statins, although not in the manner many may have considered previously. Vascepa does not have these same issues, in fact having significant data indicating the polar opposite, and I expect the FDA Advisory Committee to give Amarin the thumbs up and recommend approval for the ANCHOR indication at the advisory committee.