Though still waiting for an action letter from the FDA, CV Therapeutics Inc.'s news Thursday that an advisory panel has slated for Dec. 9 a review of Ranexa (ranolazine) for chronic angina was enough to boost the company's stock.
David Webber, analyst with First Albany Corp. in New York, said the FDA might ask for more information in the meantime, but Ranexa "has good odds of being approved."
The latest development, disclosed Thursday, brought a 23.2 percent rise in the shares, which jumped $4.23 to close at $22.45. In August, the FDA and CV Therapeutics mutually agreed to cancel the panel hearing that had been scheduled for September, causing the stock to lose $7.31, or 20.8 percent, closing at $27.87. The shares (NASDAQ:CVTX) rose 97 cents on Friday to close at $23.42. (See BioWorld Today, Aug. 5, 2003.)
Canceling and then re-scheduling the appearance in front of the Cardiovascular and Renal Drugs Advisory Committee did not change the FDA action date of Oct. 30 for Ranexa - which could still be pushed into late January if the FDA takes a 90-day extension. The action date is "not intrinsically tied" to the panel date, Webber noted.
"It seems to me that the likeliest action would be to send the company an approvable letter [by Oct. 30], with approval contingent on some additional information," he told BioWorld Today.
That information could be in the form of a post-marketing risk-management program, "or it could be something quite negative for the company, such as having to do another clinical trial," Webber said.
Ranexa, the first new class of drug candidates for angina in two decades, is a partial fatty acid oxidation inhibitor, which works by letting the heart use glucose rather than fat for energy, thereby lowering its demand for oxygen without reducing heart rate, blood pressure or pumping ability.
One potential glitch in the drug's advance has been the possible side effect of prolonged QT interval, a heart abnormality, which "has been the focus of the bulk of Wall Street's debate [on Ranexa] for nearly two years," Webber said.
"The FDA has been working for some time to develop a comprehensive approach to regulating QT-prolonging drugs," he said. "A significant percentage of drugs that the FDA has had to withdraw post-approval in the last half-dozen years or so have been drugs that both prolong the QT interval and caused deaths from cardiac arrhythmias."
Other drugs with similar profiles have survived FDA scrutiny, such as the erectile-dysfunction treatment Levitra (vardenafil), developed by Bayer AG, of Leverkusen, Germany, and GlaxoSmithKline plc, of London, and Alfuzosin, an alpha-1 blocker for benign prostatic hyperplasia from Sanofi-Synthelabo Inc., of New York, and London-based SkyePharma plc, of London.
"In general, the FDA has certainly not said it's never going to approve a QT-prolonging drug," Webber said, but the agency wants to get enough data to compare Ranexa with existing treatments. "The side-effect profile of Ranexa appears benign compared to that of existing anti-anginal drugs," he added.
One angina drug therapy known to prolong the QT interval, the calcium channel blocker Vascor (bepridil hydrochloride) from New Brunswick, N.J.-based Johnson & Johnson, has chalked up mediocre sales.
Ortho-McNeil Pharmaceutical Inc., the J&J unit handling Vascor, recently sent a letter to physicians informing them that the company is withdrawing the drug because of lack of demand. Not only does the compound cause QT prolongation, but also in clinical trials it had been shown to cause torsades de pointes ("twisting of the points," or atypical ventricular tachycardia) - and physicians have plenty of other choices in the calcium-channel blocker class.
Mark Monane, analyst with Needham & Co. Inc. in New York, acknowledged that the QT problem is "one of the issues" in Vascor's low sales, but the problem is much more pronounced with Vascor than with Ranexa.
"The single most important question to ask is, are the benefits of the drug greater than the risks," Monane said. "For ranolazine, the [main] risk has to be the risk of arrhythmia. QT prolongation doesn't kill people; arrhythmias kill people. It is true that all the drugs that cause arrhythmia seem to have QT prolongation, but the reverse is not true."
He told BioWorld Today there is "even some data to suggest [Ranexa] is anti-arrhythmic, but that's speculation at this point." CV Therapeutics, he said, has "done a lot of homework to address this issue, but we won't really know until it's out there in the real world" and follow-up studies are done.
Angina patients in the U.S. total about 6.5 million people. Ranexa has been tested in 3,300 patients, and "it's hard to extrapolate from such a group," said Monane, a physician with experience in internal medicine and geriatrics.