Although Merck's cholesterol combination Cordaptive failed to clear FDA on the first pass, the company is clear that FDA's decision does not signal the end of development for the cholesterol drug.

Merck announced that the combination product candidate drew a "not approvable" letter from FDA April 28. The company declined to say where the application ran afoul of FDA standards, but at the Morgan Stanley Global Healthcare Unplugged Conference May 1 Merck CEO Richard Clark reiterated his support.

"We believe there is a pathway forward. We support the product and believe from a safety and efficacy standpoint that it is a good product," he said.

Cordaptive, or MK-0524A, represents Merck's attempt to capitalize on the established cardiovascular benefit of niacin, including its ability to boost HDL cholesterol. Niacin, while free of serious safety issues, causes flushing, an uncomfortable side effect that can impede compliance.

MK-0524A pairs extended-release niacin - a product with a clear efficacy pedigree - with laropiprant, an anti-flushing agent to improve tolerability. The combination was approved by European regulators April 24.

At a recent American College of Cardiology meeting, Merck presented Phase III data that showed significantly fewer flushing events for Cordaptive patients than those taking Niaspan . Merck also reported that Cordaptive's safety profile is similar to that of extended-release Niaspan.

In addition, Merck has initiated a large cardiovascular outcomes study that could have served as a post-market commitment to provide confirmatory evidence. The 20,000-patient THRIVE trial is comparing Cordaptive to simvastatin in patients with coronary artery disease (¹ Also see "Merck To Await Additional Torcetrapib Data Before Advancing CETP Agent" - Pink Sheet, 18 December, 2006., p. 6).

Given niacin's reputation as a safe product, a "not approvable" action letter rather than the less discouraging "approvable" response comes as a surprise - and raises a lot of questions that remain unanswered for now.

There are cases, such as with Pfizer's atypical antipsychotic Geodon (ziprasidone), where products that received "not approvable" letters were subsequently approved, but they are certainly rare.

Nonetheless, Merck plans to resubmit the product pending a meeting with FDA to discuss Cordaptive's benefit/risk profile, Clark said, although there is no timeline for this.

"At this point, we're not at all pessimistic or concerned," Merck CFO Peter Kellog added during the Unplugged conference.

Merck will also move forward with MK-0524B, a Cordaptive/simvastatin combination, Clark said. The product ran into formulation problems in 2006, but those seem to have been resolved, as the combination is currently in Phase III and Merck plans to file the application this year.

According to Merck, future MK-0524 submissions will be made with the proposed trade name Tredaptive ; FDA rejected the Cordaptive brand.

Merck Sailing Into Choppy Waters

Merck has experienced a series of R&D setbacks as of late. The firm halted enrollment of its ACHIEVE trial evaluating Cordaptive for patients with familial hypercholesteremia to review the trial design. The study is similar to the ENHANCE study that was unable to demonstrate improvement in stopping the progression of atherosclerosis for Merck/Schering- Plough's Vytorin (simvastatin/ezetimibe) compared to simvastatin alone (² Also see "No Surprises From ENHANCE At ACC Mean Vytorin Hopes Hang On IMPROVE-IT" - Pink Sheet, 7 April, 2008., p. 4).

Merck and Schering-Plough also received a "not approvable" letter for their Claritin / Singulair combination allergy product April 25. The rejection could be related to an early communication in March from an ongoing safety review of Singulair (montelukast) noting that adverse event reports suggest an association with suicide attempts.

Merck's pipeline is replete with risky ventures - several of its leading projects are progressing in the shadow of recent class failures.

Beyond niacin, Merck is also pursuing an HDL cholesterol-boosting agent through development of its CETP inhibitor. Despite the high-profile failure of Pfizer's torcetrapib, Merck is cautiously proceeding into Phase III with anacetrapib (³ Also see "Merck Hopes To Make A Success Story of CETP Inhibitors And Obesity Drugs" - Pink Sheet, 17 December, 2007., p. 3).

Merck is also in Phase III with a selective cannabinoid-1 receptor inverse agonist for obesity, taranabant. Sanofi-Aventis was forced to withdraw its application for rimonabant for a weight loss indication due to psychiatric and neurological effects (⁴ Also see "Sanofi Seeks Further FDA Input Following Zimulti NDA Withdrawal" - Pink Sheet, 2 July, 2007., p. 19). Merck is hoping that changes in its dosing strategy will help it avoid the same kind of side effects.

"There's some signals to that effect. ... At least early on, we think that there's such an unmet medical need and there's a chance for a different profile that it's worth the risk to be able to take a look at it," Clark said at the Morgan Stanley conference.

Abbott Benefiting From Failures

Of all the companies in the cholesterol playing field, the one that seems best poised to steal a base while other companies strike out is Abbott.

Starting with its acquisition of Kos in 2006, Abbott has developed a substantial cardiovascular portfolio. In 2007, Abbott introduced a new formulation of its extended-release niacin product Niaspan that reduced incidence of flushing (⁵ Also see "Abbott Cardiovascular Franchise Swells; Combo Waves Will Crest in 2009" - Pink Sheet, 23 July, 2007., p. 11). Its other approved cardiovascular products include fenofibrate Tricor and the Niaspan/lovastatin combination Advicor .

In February, FDA also approved Abbott's Simcor , a combination of Niaspan and simvastatin, even though a study to determine whether the combination product is better than either component will not be completed until 2011.

Abbott also has an application pending for its next-generation fenofibrate TriLipix . Embracing the combination approach, Abbott has paired fenofibric acid in Phase III combination studies with Pfizer's Lipitor , AstraZeneca's Crestor (rosuvastatin) and simvastatin (⁶ [A#00700150012], p. 22).

With its assortment of improved versions of older non-statin cholesterol agents, Abbott has benefited from the industry interest in using combination approaches to cholesterol therapy. The firm also benefited from other companies trying to invigorate alternate modes of cholesterol treatment (i.e., raising HDL).

Given the doubts raised over Vytorin in the last few months, Abbott has an attractive alternative simvastatin combination therapy in Simcor. And the hold-up with Cordaptive gives Abbott more time to build the base for its own reduced-flushing niacin.

FDA's approval of Simcor may seem to offer a parallel in that both combination products include niacin. But the difference between Simcor and Cordaptive is that both elements of Simcor are time-tested, stand-alone agents, whereas Cordaptive is introducing a new molecular entity element.

Why Cordaptive Is A Hard Sell

Further complicating the combination, the NME laropiprant does not offer an efficacy advantage - the selective prostaglandin D2 receptor-1 antagonist is aimed at reducing the flushing side effect, which does not pose a significant health risk.

So from the start Merck was approaching FDA with a difficult case to make in terms of risk/benefit ratio: an unknown agent that could offer risk but definitely does not offer an outcome advantage, unless FDA were to take a kind view toward improved compliance.

What FDA's denial of the Cordaptive approval most clearly shows is what big pharma has been complaining about for years: the agency is taking a tougher stance on drug approvals.

And with Cordaptive, as well as Claritin/Singulair, FDA's rejection underscores the complications of combination products and the risks involved in utilizing combinations as a line-extension strategy.

- Brian Marson (b.marson@elsevier.com)

Merck’s Cordaptive “Not Approvable,” But Clark Not Giving Up On Combo

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