Preliminary results from Merck's pivotal Phase III study of rolofylline - its investigational agent for acute heart failure - did not meet the primary or secondary efficacy endpoints, adding another notch onto Merck's already lengthy tally of Phase III failures.

While Merck will continue to analyze the data with outside experts, the firm said it will not file an application for regulatory approval of the drug this year, as it initially planned. "These results are disappointing because we had been hopeful that blocking the adenosine A1 receptor with rolofylline would prove to be a useful new approach for patients," Merck Executive Director of Cardiovascular Research Dan Bloomfield said in a press release, adding that advances in the therapeutic area have "long been elusive."

Merck highlighted the drug at its 2008 business review in December, noting that rolofylline had the potential to be the first major acute heart failure therapy that preserves renal function and improves outcomes (¹ Also see "NovaCardia & Domain: New-Model Spec Pharma Investing" - Scrip, 1 September, 2007.). A pilot study showed an overall trend toward efficacy.

The setback represents a "psychological negative for Merck," Sanford F. Bernstein analyst Tim Bernstein said in a note to investors. His comment was telling in that he said he had not forecast sales for rolofylline despite the late-stage status of the drug, reflecting the uncertainty about the clinical profile of the product. Nor did the news cause him to change his forecasts for Merck's stock price or product sales .

Rolofylline wasn't expected to be a big seller, but the loss of yet another Phase III compound is a blow for Merck, which historically has seen cardiovascular as one of its key strengths. In October 2008, Merck dropped its Phase III obesity candidate taranabant (² Also see "Taranabant Loss No Surprise For Obesity Field, But Shock To Merck’s Pipeline" - Pink Sheet, 6 October, 2008., p. 22). It has also experienced delays with MK-0524A and B, formerly known as Cordaptive (niacin/laropiprant), in the form of a "not approvable" letter in April 2008 (³ Also see "Merck’s Cordaptive “Not Approvable,” But Clark Not Giving Up On Combo" - Pink Sheet, 5 May, 2008., p. 13). FDA requested an outcomes study, and refiling is pushed back until at least 2013 (⁴ Also see "FDA Seeks Outcomes Data For Merck’s MK-0524A" - Pink Sheet, 20 June, 2008.). Its Phase III hepatitis B vaccine Heplisav is also on clinical hold.

The thinning Merck pipeline was one impetus for Merck's decision to buy Schering-Plough for $41.1 billion, announced in March. That merger, which is expected to be completed in the fourth quarter of this year, will bring a much-needed infusion for the late-stage pipeline. Schering's offerings will double the number of potential medicines that Merck has in Phase III development, bringing the total to 17 candidates (⁵ Also see "Schering Helps Merck Where It’s Needed Most: The Pipeline" - Pink Sheet, 16 March, 2009., p. 18). Schering's thrombin receptor antagonist, TRA, now in Phase III, is an anti-platelet agent, which analysts say could be a blockbuster.

The primary endpoint of the 2,033-patient study, PROTECT, was that rolofylline 30 mg would improve symptoms of acute heart failure compared to placebo. The secondary endpoints were that the drug would reduce the risk of death or cardiovascular or renal re-hospitalization 60 days after treatment and that it would reduce the incidence of persistent kidney impairment. The company did not say where the drug fell short, but the full results will be presented at a meeting later this year.

Rolofylline was developed by NovaCardia, which Merck acquired for $350 million in 2007.

Merck's late-stage pipeline of investigational agents for cardiovascular disease also includes MK-524A (approved in some markets outside the U.S.), MK-524B, ezetimibe/atorvastatin, and anacetrapib (MK-0859) for atherosclerosis, and vernakalant for atrial fibrillation.

-Lauren Smith (lauren.smith@elsevier.com)

Merck’s Heart Failure Drug Flunks Phase III

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