At last, the FDA cleared Ranexa (ranolazine extended-release tablets), the first new angina drug approved in the U.S. in more than 20 years.
Developed by CV Therapeutics Inc., Ranexa is specifically indicated for treating chronic angina, essentially for second-line use, to be combined with the calcium channel blocker amlodipine, beta-blockers or nitrates. An antiangina drug that does not slow heart rates or reduce blood pressures, Ranexa acts by inhibiting the late sodium current, which as a result prevents calcium overload in the heart.
"It's been decades since there's been a new pharmaceutical approach," said John Bluth, CV Therapeutics' senior director of corporate communications. "Patients will be the big winners here."
But the label is somewhat restrictive, as the drug prolongs the QT interval, an electrocardiogram measure of the time between the start of ventricular depolarization and the end of ventricular repolarization, by about 6 milliseconds.
An extended QT interval theoretically could lead to other problems, Bluth told BioWorld Today, "but those are problems we have not seen with Ranexa, and with its underlying mechanism of action, it is not something we would expect."
The drug's label said it should be reserved for patients who have not achieved an adequate response with other anti-anginal drugs. The effect on angina rate or exercise tolerance appeared to be smaller in women than men. Still, CV Therapeutics, of Palo Alto, Calif., expected that restriction, and Bluth said the label "provides an excellent platform for the successful launch of Ranexa."
Speaking during a conference call, Chairman and CEO Louis Lange said the label would reflect about 10 percent to 25 percent of the 6.5 million patients in the angina market.
The indication, which could be expanded should an ongoing study generate what Lange termed an "acceptable" safety database, is based on an amended new drug application submitted to the FDA last year. That amendment followed positive results of a Phase III study called ERICA (Evaluation of Ranolazine In Chronic Angina), which was conducted under the FDA's special protocol assessment process. In the 565-patient trial, Ranexa met its primary endpoint of reducing weekly angina frequency compared to placebo (p=0.028). (See BioWorld Today, April 19, 2005.)
Two earlier Phase III studies, CARISA and MARISA, formed the basis of the drug's original NDA. Another Phase III trial, called MERLIN, is under way to evaluate the drug's safety and efficacy during acute and long-term treatment in about 5,500 patients with non-ST elevation acute coronary syndromes treated with standard therapy.
That trial could open the door for a broader label, Bluth said, calling it "the pathway to expand the label into first-line use." (See BioWorld Today, Aug. 2, 2004.)
MERLIN's enrollment should close next quarter, and positive safety findings could lead to a front-line angina indication. Secondly, the indication could be expanded based on the study's primary endpoint that is measuring Ranexa's use for the intravenous treatment of patients presenting at the hospital with acute coronary syndrome.
The trial should finish by the end of the year, with top-line data to follow shortly.
CV Therapeutics, which has yet to determine pricing, expects to make Ranexa available in pharmacies in late March. Its prescribing information calls for physicians to initially dose their patients at 500 mg twice daily, and increase them to 1,000 mg twice daily if needed. Ranexa's promotional materials continue to be developed, and its manufacturing and packaging is nearing completion.
While still developing new products, including the pharmacologic stress agent regadenoson that should complete a second Phase III study later this year, CV Therapeutics has built a sales team of about 400 employees by way of a co-promotional arrangement with Solvay Pharmaceuticals Inc., of Marietta, Ga.
As a result, CV Therapeutics' sales representatives already have been getting to know cardiovascular doctors through sales of the ACE inhibitor Aceon (perindopril erbumine) for the past two quarters, as Lange said "there is a significant overlap there."
For Europe, Bluth said CV Therapeutics would need to complete some additional pharmacokinetic evaluations before resubmitting for Ranexa's approval in that territory. The company, which owns the drug's rights throughout most of the world, voluntarily withdrew a previous application.
"The approved label allows us to execute the marketing plan we have been developing all along," Lange said.
On Monday, the company's shares (NASDAQ:CVTX) fell $1.15 to close at $24.93.