CV Therapeutics Inc. received a mixed bag of news related to Ranexa, its lead compound for chronic angina, and investors took the news badly as the company's stock slipped 21.7 percent Friday.

After the market closed Thursday, CV Therapeutics disclosed that the FDA issued conditional approval for the drug, which could delay its time to market. On Friday, its stock (NASDAQ:CVTX) fell quickly and stayed down - it lost $4.89 to close at $17.63.

The agency delivered the approvable letter for Ranexa (ranolazine) a week after the Palo Alto, Calif.-based company learned that an FDA advisory committee would review the drug Dec. 9. The company submitted its new drug application last December.

Regardless of what the Cardiovascular and Renal Drugs Advisory Committee finds in December, CV Therapeutics acknowledged that the FDA is not required to follow the committee's recommendations. In the approvable letter, the agency indicated that "additional clinical information is needed prior to approval," though CV Therapeutics said the FDA could reevaluate its position based on the advisory review.

"This is an approvable letter, so it tells us that there are multiple paths to an approval," John Bluth, CV Therapeutics' director of corporate communications, told BioWorld Today. "The outcome of the panel meeting should provide much more clarity on what the path to approval for Ranexa looks like."

The FDA's concerns center around the product's risk-benefit profile relative to QTc prolongation that occurs in patients using the therapeutic. CV Therapeutics has long kept watch on Ranexa's effect on the lengthened interval, which can be viewed as an indicator of torsades arrhythmia. But Bluth said no cases of that arrhythmia have been seen in clinical trials of Ranexa, and that preclinical evidence suggests that the drug does not possess underlying properties causative of torsades.

He added that the company has expected for some time that the drug's path to approval would include a risk-benefit discussion at an advisory meeting.

"The agency has asked for the advisory committee to provide an opinion on the issues they feel are important regarding Ranexa," Bluth said. "Clearly they want the input of the advisory committee in their decision-making process."

CV Therapeutics took a number of other positives from the FDA's communiqué, which was issued on the product's PDUFA date. In the letter, the FDA pointed to evidence of Ranexa's efficacy as an anti-anginal product. There has not been a new class of angina therapies in more than 20 years in the U.S.

"Ranexa acts differently than existing classes of anti-anginal therapy, which exert their [effects] through reductions in heart rate and blood pressure," Bluth said. "In clinical trials, Ranexa did not do that. It exerted anti-anginal effects without clinically significant compromises in heart rate and blood pressure."

Eric Schmidt, an analyst with SG Cowen Securities Corp. in New York, expects the panel to focus primarily on QTc prolongation.

"We understand the FDA review team for Ranexa did not include a cardiologist," he wrote in a research note. "Thus we are somewhat optimistic the advisory panel will be more sympathetic to CVT's data, expert electrophysiologist consultant and arguments than the FDA. Nonetheless, with CVT and the FDA apparently entering the panel from different vantage points, the panel could be tumultuous."

But he added that should the FDA require an additional study, which could add two to three years to getting the drug to the market, CV Therapeutics' $462 million in cash reserves would be sufficient to support such a program.

The company must wait a little more than a month to get its message to the advisory panel, though. In fact, it was just over a week ago that CV Therapeutics was able to circle Dec. 9 on its calendar when the FDA advised the company of the schedule. That news boosted the company's stock by about 23 percent. (See BioWorld Today, Oct. 27, 2003.)

More than two months earlier, the stock value had slipped by nearly 21 percent when the FDA and CV Therapeutics mutually agreed to cancel a September panel meeting. (See BioWorld Today, Aug. 5, 2003.)

Schmidt said the drug could have $500 million in sales potential for angina alone. CV Therapeutics, which does not yet sell any drugs, owns full U.S. marketing rights to Ranexa.

Beyond Ranexa, its pipeline includes another late-stage candidate, CVT-3146, for which a pivotal Phase III trial began last week to evaluate the selective A2A-adenosine receptor agonist's use as a pharmacologic stress agent in cardiac perfusion imaging studies. (See BioWorld Today, Oct. 30, 2003.)

A third late-stage candidate, an adenosine A1 agonist called tecadenoson, is in a Phase III program for the treatment of atrial arrhythmias.