Is Amarin's FDA Panel Important for Other Cardiovascular Drugmakers?

If for some reason you had nothing to do on a random Wednesday and opted to follow along as a Food and Drug Administration panel debated expanding the label for Amarin's (NASDAQ: AMRN  ) Vascepa... join the club! Some incredibly interesting twists and turns took place, and you can find detailed analysis of the effect on Amarin's future all over the web. What I found interesting, though, was the potential implications it had on other companies developing drugs that lower triglycerides -- fish-oil-based or otherwise.

For once, the debate over the efficacy of fish oils to reduce triglyceride levels was not the main topic (though there was some discussion of the safety profile and placebo). Instead, the issue was over a more philosophical question: Do we approve a drug that lowers triglycerides if it's still unclear that lowering triglycerides actually reduces cardiovascular risk? That question was left in doubt when several clinical trials showed no additional clinical benefit to lowering triglycerides in patients already treated with cholesterol-lowering statins. The answer was a resounding "no."

Amarin is currently conducting the REDUCE-IT trial to get a better picture of the long-term benefits of triglyceride reduction on cardiovascular risk. While FDA approval is still possible despite the panel's recommendation, will this decision set a precedent that longitudinal outcome studies will be requisite for all triglyceride-lowering drugs in the future?

Unfortunate timing
The real issue that caught Amarin in a sticky situation was timing. The design of its short-term ANCHOR trial to assess triglyceride reduction in moderate hypertriglyceridemia was formulated in correspondence with FDA, and Amarin really did everything they were asked to do. Only after the trial was initiated did doubts surrounding triglyceride reduction surface, and by then Amarin's strategy was set. Moving forward, any company testing drugs with the goal of triglyceride reduction will be aware of the concerns of its use as a surrogate marker for cardiovascular health, and can plan accordingly. So which companies might that affect?

Another fish in the sea
New competition in the fish oil market is on the way from AstraZeneca (NYSE: AZN  ) after its purchase of Omthera and its fish oil derivative Epanova. Like Amarin, Omthera received a thumbs-up on Epanova's development program without a trial designed to test clinically relevant cardiovascular outcomes. Their NDA was accepted last month for the treatment of severe hypertriglyceridemia, but I'd count on more red tape should they attempt to expand its label to the lesser moderate hypertriglyceridemia or mixed dyslipidemia. I'd consider this a serious blow to AstraZeneca's thesis in the Omthera acquisition at a time when the struggling company could really use a win. The stock was up on Thursday as investors watched competition from Amarin fall away.

The big PCSK9 question
In the wake of the Amarin FDA panel, many journalists have pondered the implications on the up-and-coming PCSK9 inhibitor market. PCSK9 inhibitors mimic the effects of a naturally occurring genetic mutation that causes remarkably low levels of LDL "bad" cholesterol, and also have a substantial effect on triglyceride levels. While statins have demonstrated clinically relevant reductions in cardiovascular risk by reducing cholesterol, companies like Amgen  (NASDAQ: AMGN  ) and Regeneron  (NASDAQ: REGN  )  have not yet shown that their method of lowering LDL cholesterol is efficacious. 

While the relevance of triglyceride reduction is in question, the abundance of historical evidence in support of cholesterol reduction should support PCSK9 inhibition's clinical use. Both Amgen's AMG145 and Regeneron's alirocumab have shown LDL-reducing effects as a monthotherapy and as an add-on therapy to statins, and both are conducting long-term cardiovascular outcomes studies should the FDA request them.

The bottom line
The FDA panel decision not to recommend label expansion for Vascepa without clinical outcomes data could shake up the market for drugs that treat hypertriglyceridemia. AstraZeneca should be prepared to face similar resistance should they attempt to expand Epanova's label to only moderate hypertriglyceridemia. By contrast, I think the backlash will be minimal in the PCSK9 field because of the established connection between LDL reduction and improvements in cardiovascular outcomes.

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  • Report this Comment On October 17, 2013, at 6:21 PM, jabel5 wrote:

    If the FDA fails to approve AMRN's application, then aren't the global implications even bigger than you stated? I don't know of any similar situation where the FDA has telegraphed its intent to ignore a SPA where there was not some significant failure in safety or efficacy measures as defined in the SPA. With the Advisory Committee briefing documents and the form of the question voted on, the FDA has moved the goalpost a long distance from the target contained in the SPA. Did drug discovery and approval suddenly become massively more uncertain with this event? Will it now be the norm that completing all SPA requirements means little or nothing?

  • Report this Comment On October 17, 2013, at 7:46 PM, PharmTeam wrote:

    @jabel5 Thanks for reading and commenting. I chose in this article to focus on the cardiovascular implications because, frankly, they're a little easier to talk about. The global implications of the FDA reneging on an SPA should be very disease specific - dependent on both previous studies validating the surrogate marker and the degree of unmet medical need. I'm not sure this case suggests that SPAs are worthless, but rather that moving forward we might see SPAs more explicitly call for clinical outcomes studies.

  • Report this Comment On October 18, 2013, at 8:31 AM, clyderon wrote:

    Since it is understood that high TG'S contribute to cv events why wouldn't lowering TG'S automatically be seen as lowering cases of cv events?

  • Report this Comment On October 18, 2013, at 9:51 AM, PharmTeam wrote:

    @clyderon Correlation vs causation. TGs are considered a risk factor for cv events, but the FDA is concerned that reducing them doesn't provide any additional benefit over cholesterol reduction. For more information on the FDAs concerns, check out the ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE studies that the FDA cited as their main concerns.

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