Washington Editor

Even though the angina drug Ranexa (ranolazine) missed its primary endpoint in a study designed to broaden its label, its maker, CV Therapeutics Inc., believes positive safety data still could support at least part of that plan.

The top-line findings should endorse its use as a front-line angina treatment, expanding Ranexa's reach in that indication, but the Palo Alto, Calif.-based company no longer plans to seek approval for acute coronary syndrome, or ACS. Of note, the American Heart Association estimates the angina market to be measurably larger than ACS. There are about 8.9 million angina patients in the U.S. compared to 1.5 million hospital discharges for ACS.

Nevertheless, fickle investors dropped CVT's stock (NASDAQ:CVTX) by 23.6 percent Wednesday, or $2.90, with the shares closing at $9.40 on heavy volume.

The positive takeaway from the data, according to John Bluth, the company's senior director of corporate communications and investor relations, relates to the drug's safety profile. He pointed out that there were no adverse trends in death or arrhythmias in Ranexa-treated patients in the study, known as MERLIN TIMI-36, satisfying one component of a special protocol assessment agreement with the FDA.

The trial's "primary purpose," Bluth told BioWorld Today, "was to generate safety data that could specifically address the perceived concern" about the drug's 6-millisecond prolongation of patients' QT interval, an electrocardiogram measure of the time between the start of ventricular depolarization and the end of ventricular repolarization. "So based on our agreement with the FDA, that's what will lead, we believe, to the first-line angina indication."

The drug was first approved early last year for second-line use in combination with the calcium channel blocker amlodipine, beta-blockers or nitrates, and to date has been prescribed to about 33,000 patients. But that's just a small fraction of the total angina patients in the U.S., owing somewhat to the second-line restriction but also to cautious prescribing habits, Bluth said.

"Cardiologists have been conservative with the product," he said, but the MERLIN study's safety data "should address" their concerns. "That added information, we hope, will provide additional comfort to doctors in prescribing Ranexa to appropriate angina patients."

If indeed such thinking holds true, the drug's usage should increase more immediately than the time frame in which the FDA clears a broader label. CVT plans to file a supplemental new drug application later this year.

Ranexa generated $9 million in sales last quarter.

Despite his positive outlook regarding broader angina use, Bluth conceded CVT's disappointment that the study missed its primary endpoint, a composite measure of cardiovascular death, myocardial infarction and recurrent ischemia in ACS patients. "That would have been nice icing on the cake," he said, noting that details on whether or not Ranexa-treated patients trended toward efficacy would "likely be included" in a full data presentation in three weeks during the American College of Cardiology meeting in New Orleans. Such complete findings that will not only include numbers related to the primary endpoint, but also secondary measures that evaluated ischemia on Holter monitoring, hospitalization for new or worsening heart failure, quality of life measures and exercise performance.

The international, double-blind trial included about 6,500 patients with non-ST elevation ACS. Within 48 hours of the onset of angina due to ACS, eligible hospitalized patients were randomized to receive intravenous Ranexa or placebo, followed by long-term outpatient treatment with Ranexa extended-release tablets or placebo. All patients also received standard therapy during both hospital-based and outpatient treatment.

The drug, which remains under review in Europe, acts by inhibiting the late sodium current to prevent calcium overload in the heart.

Beyond Ranexa, the company soon plans to file a new drug application for regadenoson, a product being developed as a pharmacologic stress agent in myocardial perfusion imaging studies. It successfully completed a pair of Phase III studies, with late-breaking data also scheduled for presentation in New Orleans, and its regulatory submission is expected by midyear.

Regadenoson is partnered in the U.S. with Astellas Pharma US Inc., a subsidiary of Tokyo-based Astellas Pharma Inc. CVT holds its rights in all other territories.

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