Ranolazine Roche Bioscience

Ranolazine is a metabolic modulator developed by Syntex (Roche) and is in phase III clinical trials as an anti-anginal agent and for the treatment of peripheral arterial disease, particularly intermittent claudication. It allows maintenance of energy output by muscle cells under hypoxic conditions. Ranolazine may be especially useful in angina patients in whom other therapies are ineffective. The licensee, CV Therapeutics (CVT), began a pivotal placebo-controlled, phase III clinical trial of ranolazine in October 1997 enrolling 150 angina patients [265551]. CVT plans to begin a second phase III trial in 350 to 400 angina patients receiving other anti-anginal medications during 1998 [279177]. Clinical studies suggest that ranolazine lowers the heart's demand for oxygen by increasing its ability to use carbohydrate, rather than fat, as a fuel. This is thought to be due to activation of pyruvate dehydrogenase and modulation of the activities of L-type calcium channels. This is achieved without reducing heart rate or blood pressure, or impairing pumping ability [253375,247228]. Ranolazine has been tested in more than 1300 US and European patients in phase I and phase II clinical trials, and is now being evaluated in a placebo-controlled, double-blind multicenter study to determine its effectiveness in treating stable angina. Phase II trials, in over 1200 patients with ischemic heart disease, were completed by Syntex. They demonstrated increased exercise times to onset of angina or electrocardiographic change associated with insufficient blood flow to the heart with three times daily dosing of ranolazine [224364]. Roche Bioscience claims that in the US and Western Europe approximately 1.4 million angina patients are not adequately treated with existing therapies and some 5 million patients suffer from intermittent claudication [166817]. In August 1998, CV Therapeutics signed an agreement with Catalytica Pharmaceuticals, which will manufacture specified quantities of ranolazine for use in clinical trials [293333].