Washington Editor

Despite reassuring words from chairman and CEO Louis Lange, CV Therapeutics Inc.'s stock tumbled 20.8 percent on news that the company and FDA had mutually agreed to cancel a September advisory panel meeting for the chronic angina candidate Ranexa.

CV Therapeutics stock (NASDAQ:CVTX) fell $7.31 Monday to close at $27.87.

"Two things have changed," Lange told BioWorld Today. "The panel was canceled, but the review is still very active, and the stock went down. Not much else has changed. This is probably an unintended consequence of PDUFA III."

The FDA has a series of deadlines and requirements it must adhere to under PDUFA III, also called the Prescription Drug User Fee Act, a federal law requiring the agency to take action on drugs and biologics applications within a certain time period. Canceling CV Therapeutics' panel appearance does not change Ranexa's action date of Oct. 30.

The company was scheduled to appear before the Cardiovascular and Renal Drugs Advisory Committee at the Sept. 15-16 meeting. Thirty days prior to the meeting, the agency and the company had to have all documentation and questions surrounding the NDA prepared for the panel's "briefing document," the package of information distributed to members in advance of the meeting.

Lange said Monday morning that neither side could meet the Aug. 15 deadline.

"Everybody thought on both sides that all the work would get done that would be preparatory for the meeting, but it just didn't for one reason or another," Lange said. "It's nobody's fault; the FDA has been good and productive with us, but when we talked to them [Aug. 1], we said we're not ready to write the package, which is essentially the panel presentation. They're not ready and we're not ready."

CV Therapeutics, of Palo Alto, Calif., submitted the Ranexa new drug application in December. Ranexa (ranolazine), which is in the class of partial fatty acid oxidation inhibitors, lets the heart burn glucose rather than fat for energy, thus lowering its demand for oxygen without reducing heart rate, blood pressure or pumping ability to stable, or chronic, angina, which is the regular pain associated with heart disease.

In other news last month, CV Therapeutics regained all rights associated with Ranexa from partner, Innovex Inc., a subsidiary of Research Triangle Park, N.C.-based Quintiles Transnational Corp. At the time, CV said it had better resources to take the product forward than when it signed the deal in 1999. In exchange for commercialization rights and the opportunity to hire and train a sales force, CV Therapeutics agreed to issue Innovex warrants for 200,000 shares at $32.93 apiece. (See BioWorld Today, July 14, 2003.)

Meanwhile, the FDA could decide about Ranexa at any time, said Lange, who believes there are two likely scenarios: Either the FDA will review the application and make a decision by Oct. 30, or the agency will seek an extension, pushing the PDUFA date into 2004. In the case of the latter, CV Therapeutics could be asked to present at a later panel date, possibly in December.

After Sept. 1 (60 days prior to the PDUFA date), the FDA has a "one time" opportunity to push the action date back 90 days to Jan. 30 if additional time is needed to review an amendment to the NDA.

Either way, CV Therapeutics is ready. "We have anticipated uncertainty," Lange said. CV Therapeutics is poised to hire between 100 and 200 employees to sell the company's first marketed product.

Of a possible delay, Lange said, "We were planning an '04 launch, but we were never planning a Jan. 1, 2004, launch. We're in good shape."

Among the data submitted as part of the NDA, CV Therapeutics included two successful Phase III trials called CARISA and MARISA.

MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) was a randomized, double-blind, placebo-controlled study of 191 patients not receiving any other anti-anginal products. Compared to placebo, Ranexa taken twice a day was statistically significant (p<0.005) in increased exercise duration at trough plasma concentrations.

The CARISA trial (Combination Assessment of Ranolazine in Stable Angina) was a multinational, randomized, double-blind, placebo-controlled, parallel group trial demonstrating that for patients on a background anti-anginal therapy, Ranexa significantly (p=0.012) increased symptom-limited exercise duration at trough drug concentrations, compared to placebo.