Cordaptive Was a Red Rag to FDA Bull

In an article in this month's IN VIVO, we suggested that Merck’s presenting Cordaptive to FDA might be likened to waving a red rag at a bull.

Admittedly, we added a few mitigating statements, and the overall tone of the article was positive, reflecting a number of analysts' bullish outlook for the drug. Cordaptive is, after all, a seemingly uncontroversial combination of extended-release niacin (an age-old product with plenty of safety data) with the anti-flushing agent laropiprant, whose effects are, we're told, restricted to just that--minimizing the nasty (but non-fatal) side-effect that has limited niacin's uptake.

In the event, though, the bull/rag analogy was right on: FDA yesterday issued a not-approvable letter for Cordaptive. (And, adding insult to injury, it said it didn't like the name, either.)

Ok, so given recent events, we probably all should have seen this coming. FDA also late last week rejected Merck’s application for a fixed-dose combination of Singulair and Claritin, as we reported here (and updated here.) Notwithstanding FDA’s rather stringent requirements for all combination drugs (sponsors must prove each component’s safety and efficacy as a standalone and show that the combination affects neither), one might be forgiven for suspecting that the red rag is actually a combination drug application on Merck headed paper.

Merck is after all one of the ENHANCE sponsors (alongside Schering-Plough); that saga called into question the clinical effectiveness of yet another combo, Vytorin. It probably didn't help that Merck also recently halted enrolment in one Cordaptive trial that was designed similarly to ENHANCE.

Still, ENHANCE’s effects have rippled—and will continue to ripple—far beyond Whitehouse Station. FDA this month poured cold water over Isis’ cholesterol-lowering hopeful, mipomersen—yes, the one that Genzyme in January agreed was worth $325 million up front and up to $825 million in development and regulatory milestones. The partners need outcomes studies, the Agency says, for all indications other than the highly specialist, and life-threatening, familial hypercholesterolemia. (Luckily for Genzyme, the deal terms aren’t confirmed, so watch out for lower-value Version B of the deal--and, we'll venture to suggest, a tonne more regulatory contingencies and conditional language in tomorrow's term-sheets.)

Now Merck’s doing outcomes studies with Cordaptive, but results from their 20,000-patient THRIVE trial won’t be out until 2012 or so. Small wonder, then, that some analysts have already removed four years’ worth of revenues for the drug, and its follow-on, MK-0524b.

This is the last thing Merck needs. From 2010, $4.2 billion worth of its products start to lose patent protection—Cozaar/Hyzaar that year, and Singulair two years later. Cordaptive and its follow-on could have helped fill about a third of that hole, according to analyst Catherine Arnold at Credit Suisse; now they’ll barely have any impact at all.

Nor does FDA’s harsh stance on safety requirements and outcomes studies bode well for two further Merck late-stage candidates. Can CETP inhibitor anacetrapib survive the aftermath of Pfizer’s torcetrapib blow-out? And does taranabant (a cannabinoid receptor inverse agonist) really have a chance, given FDA’s unswerving rejection of Sanofi-Aventis’ rimonabant (Zimulti)?

Maybe we’re being too cynical. Maybe it’s just a question of time: time for THRIVE results to pour in, and/or for Merck to sort out whatever the actual problem is with its Cordaptive NDA. “We plan to meet with FDA as soon as possible and submit additional information to enable the agency to further evaluate the benefit/risk profile of MK-524A,” was all a Merck spokesman would reveal to IN VIVO Blog. (The European regulators this month approved the combo--albeit as Tredaptive--though as we saw with rimonabant, a green light across the Atlantic is irrelevant to FDA.)

So nobody knows what’s wrong, and we’ll only spend one paragraph speculating. It’s tempting to assume that laropiprant is the culprit, since this is the only NCE component of the cocktail (and a couple of journal papers point to elevated liver enzymes associated with the compound). Merck’s Senior Director for Cardiovascular Clinical Research, John Paolini, MD, PhD, told us in March that since laropiprant--a selective prostaglandin D2 receptor-1 antagonist--acts on the final step in the flushing pathway, the chances of any unwanted additional effects are reduced, at least in theory. The company also boldly ventured that Cordaptive’s safety profile is “similar to that of extended release Niaspan.” But “similar” may well not be good enough (assuming this theory is right). Particularly when you’re tampering with a side-effect that, if uncomfortable, is hardly fatal.

What we know for sure is what my quicker-off-the-mark colleagues have already said: there’s no such thing as a low-risk drug. Certainly, combination products don’t any longer represent no-brainer life-cycle extension tools. When it comes to getting past the FDA bull, it seems they’re up there with even the newest of NCEs.

photo by flickr user pmorgan used under a creative commons license