BEDMINSTER, NJ (TheStreet) -- The FDA advisory panel convening Wednesday will focus on whether or not to recommend the expanded use of Amarin's ( (AMRN)) prescription fish-oil pill Vascepa. There's also a larger and more important issue at stake: Should the FDA approve cardiovascular drugs based solely on surrogate endpoints, or hold off approval until these drugs are proven to reduce the risk of heart attacks, strokes and death?
Let's preview Amarin's all-important Vascepa FDA panel:
Adam, clear something up for me before we get into the meat of the Vascepa debate. What the hell is "mixed dyslipidemia" and why is it so important to Amarin?
With respect to Amarin, a person with mixed dyslipidemia is taking a cholesterol-lowering statin to lower LDL or "bad" cholesterol but still has moderately elevated levels of triglycerides, a fatty substance found in blood. People with mixed dyslipidemia are believed to be at higher risk for cardiovascular disease.
Last year, FDA approved Vascepa to lower triglycerides in patients with severe hypertriglyceridemia, defined as super high triglyceride blood levels greater than 500 mg/dl. Now, Amarin wants FDA to approve an expanded use of Vascepa to treat these mixed dyslipidemia patients.
Expanding the FDA-approved use of Vascepa is important to Amarin because approximately 21% of Americans have mixed dyslipidemia. Amarin has not done a very good job selling Vascepa today so it hopes to turn the drug's fortunes around by broadening its FDA-approved label.
Amarin and its supporters talk about the "Anchor" patient population? What do they mean?
"Anchor" was the acronym used by Amarin to describe the phase III clinical trial of Vascepa in patients with mixed dyslipidemia. When you hear someone talk about "Anchor" think mixed dyslipidemia.
Amarin apparently likes nautical imagery because the company's first phase III study used for the initial Vascepa approval was dubbed "Marine."
Was the "Anchor" study positive?
Yes it was, and for the most part, the efficacy and safety of Vascepa, as defined in the "Anchor" study, are not going to be a point of contention or debate during at Wednesday's FDA advisory panel.
In the "Anchor" study, 12 weeks of Vascepa dosed at 4 mg/day lowered triglycerides levels by a median 17.5% compared to a median 5.9% increase for patients treated with a placebo. This Vascepa reduction in triglyceride levels, relative to placebo, met the primary endpoint of the "Anchor" study. Beneficial changes in other lipids levels also favored Vascepa, and no significant adverse events or toxicities associated with the drug were reported.
Ha! Adam, you're such a trickster. This is where you tell me about the red flags in the "Anchor" study and why Amarin is hiding reams of negative Vascepa data. C'mon, stop playing games.
Nope. Amarin isn't hiding any negative data. Vascepa is prescription-grade fish oil designed to lower triglyceride levels. That's what the drug did in the "Anchor" study. FDA isn't disputing Vascepa's ability to lower triglycerides. Well, FDA does bring up an issue with the mineral oil used as a placebo in the "Anchor" study, but let's not go there quite yet.
I'm confused. If the "Anchor" study results aren't up for debate, why is FDA holding this advisory panel on Wednesday?
Ah! Time to dig into the meat of the Vascepa debate. The FDA explains the issue best in the review of Vascepa posted to the agency's web site on Friday afternoon:
With rare exception, FDA has historically considered granting approval for lipid-altering drugs based on favorable changes in the lipid profile, with the assumption that these changes would translate into a benefit on clinical outcomes. Both epidemiological studies and controlled interventional trials of lipid-lowering agents, including omega-3 FA, supported the hypothesis that pharmacologically-induced improvements in the lipid profile are cardioprotective. These studies also informed professional society guidelines that promoted the consumption of EPA and DHA [fish oil] with the goal to reduce cardiovascular risk. Recent clinical trials and meta-analyses have failed to confirm definitive cardiovascular benefit with EPA and DHA [fish oil] supplementation, however.
Let me see if I understand. FDA is saying Vascepa may not benefit patients with mixed dyslipidemia even if the drug lowers triglycerides?
Right. Think of it another way, in simpler, starker terms. A doctor prescribes Vascepa to a patient with mixed dyslipidemia. After a few months, the patient's triglyceride levels fall. But one month later, the patient has a heart attack and dies. Did Vascepa help this patient?
Exactly. Vascepa lowers triglyceride levels in the blood, but this is just a laboratory measurement or surrogate marker for improved cardiovascular health. Doctors -- and the FDA -- used to believe strongly that improving lipid measurements would lead to fewer heart attacks or strokes and a reduced risk of death from heart disease. But in recent years, this assumption has proven false, based on negative results from large clinical trials in which certain cardiovascular drugs were added to a background of statin therapy.
For example, the ACCORD-Lipid study found that adding a fenofibrate to statins cut triglycerides in diabetic patients but didn't lower the rate of cardiovascular events. In the AIM-High study, the addition of niacin to statin therapy failed to improve cardiovascular outcomes in patients with a history of heart disease. The HPS2-Thrive study produced similar, disappointing results.
The new thinking is that reducing triglycerides doesn't necessarily correlate with real cardiovascular benefit.
But doesn't Amarin have any clinical data proving Vascepa reduces the number of heart attacks or strokes?
Not yet. Amarin wants FDA to expand the use of Vascepa based on the "Anchor" trial, which as I described above, only examined changes in lipid levels like triglycerides. The study was not designed to determine if patients treated with Vascepa derive "real" cardiovascular benefit i.e. fewer heart attacks, strokes or a reduced risk of death.
Amarin is conducting another large study known as "Reduce-It" which will answer the question of whether or not Vascepa provides mixed dyslipidemia patients with cardiovascular benefit. The "Reduce-It" study is expected to finish in 2016.
So, you're saying the experts on the advisory panel Wednesday will spend most of their time debating whether or not to approve Vascepa now based on lower triglycerides, or wait until 2016 when cardiovascular outcomes data from the "Reduce-It" study is available
Yup. Here's how FDA frames the debate for the panel experts:
Please discuss the efficacy results from the ANCHOR trial, including the clinical significance of the observed changes in lipid/lipoprotein parameters and your level of confidence that these changes will translate into a meaningful reduction in cardiovascular risk among the target population.
And here's the voting question, drawn up by FDA, for Wednesday's panel experts:
Taking into account the described efficacy and safety data for Vascepa, do you believe that its effects on the described lipid/lipoprotein parameters are sufficient to grant approval for co-administration with statin therapy for the treatment of patients with mixed dyslipidemia and CHD or CHD risk equivalent prior to the completion of REDUCE-IT? Please provide the rationale underlying your recommendation. [CHD means coronary heart disease.]
None of the large but negative cardiovascular outcomes studies you mentioned above were designed to treat patients with prescription-grade fish oil. Vascepa is not only prescription-grade fish oil but it consists of almost pure EPA. Doesn't this distinguish Vascepa from other fish oils that are less pure, containing EPA and DHA like GlaxoSmithKline's ( (GSK)) Lovaza? Won't this make a positive difference with the panel experts?
Maybe, but FDA also spends a lot of time in its review of Vascepa discussing issues and concerns with previously conducted cardiovascular outcomes studies involving fish oil which are relevant to the Vascepa debate -- and not necessarily in a good way. You can read the extensive discussion yourself on pages 63-87 of FDA's Vascepa review.
And yes, FDA even has issues with the so-called "Jelis" study of EPA conducted in Japan. Amarin bulls point to the "Jelis" study as proof that Amarin's Reduce-IT study will be successful. It doesn't sound as if FDA shares that optimism, necessarily.
Adam, you're a looser and an Amarin basher! FDA will approve Vascepa because the company has an SPA. Amarin will sue FDA if Vascepa is rejected, so shut up and just buy the stock.
Wow, who let Steve Rosenman into the room? It's true, Amarin and FDA did reach an agreement on a Special Protocol Assessment (SPA) which allowed the company to seek expanded use of Vascepa in mixed dyslipidemia based on 1) positive data from the "Anchor" trial; and 2) the start -- but not completion -- of the Reduce-It study.
However, the Vascepa "Anchor" SPA was reached in 2008 before FDA became aware of the numerous negative studies of add-on statin therapy failing to improve cardiovascular outcomes. SPA agreements are fungible and do not lock FDA into approving a drug when circumstances -- or scientific knowledge -- changes.
Again, FDA is convening Wednesday's panel precisely because the cardiovascular benefit of lipid-lowering drugs is now in doubt. This doubt didn't exist when Amarin and the agency drew up the Vascepa SPA agreement.
Adam, you've been bearish on Amarin for more than a year, starting right before Vascepa was approved in July 2012. Can I assume you believe Wednesday's panel meeting won't end well for the company?
I'm on the record predicting a negative vote at the Vascepa FDA panel, meaning I believe the experts will recommend FDA reject an expansion of Vascepa to treat mixed dyslipidemia patients until positive proof of cardiovascular benefit is demonstrated from the "Reduce-It" study in 2016.
Two more factors work against Amarin. First, mixed dyslipidemia patients aren't at imminent risk of sudden death. A delay in expanding Vascepa's approval isn't going to kill these patients. There is no urgent unmet medical need here. Second, Vascepa is already approved, so if doctors really want to treat mixed dyslipidemia patients with Vascepa, they can do prescribe the drug off label.
What's the biggest risk to your bear thesis for the FDA panel?
The relatively clean safety profile of Vascepa. Experts on the FDA panel may decide adding Vascepa to statin therapy might not help but couldn't really hurt mixed dyslipidemia patients, so just approve the drug now. The expanded Vascepa approval could be affirmed or rescinded in two years based on the results from the Reduce-It study.
Earlier, you mentioned a problem with mineral oil used as a placebo in the "Anchor" study. Is this a big deal?
I don't think so. In its review, FDA raises a concern that the mineral oil placebo may have interfered with the efficacy of statin therapy, thereby causing Vascepa's lipid-lowering profile to appear stronger than it actually is. I expect FDA to discuss these concerns during Wednesday's panel but the risk doesn't appear to be a game changer.
If I'm wrong, however, the mineral oil issue is another negative for Amarin and increases the likelihood of a negative panel decision.
I hear you're planning a live blog of Wednesday's Vascepa panel?
You're so kind, allowing me to shamelessly plug my big event tomorrow. Yes, I'll be live-blogging the Amarin panel, starting around 7:45 am ET. It should be an interesting debate and I hope you'll log in.
-- Reported by Adam Feuerstein in Boston.
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