GAITHERSBURG, Md. - An FDA panel generally agreed that Ranexa, CV Therapeutics Inc.'s candidate for chronic angina, is approvable if the company is willing to conduct another clinical trial in a broader population that includes patients who are not resistant to traditional drugs.
While panel members were mostly split on whether Ranexa should be approved in a restricted or unrestricted population, the consensus seemed to lean toward an additional clinical trial to include blacks, women, Hispanics and people taking other anti-arrhythmia drugs. (The pivotal trials were 98 percent Caucasian and largely male.)
The Cardiovascular and Renal Drugs Advisory Committee did not take a formal vote on whether Ranexa should go to market, despite negative speculation a day in advance of the meeting when Wall Street took about 27.2 percent of the company's value after an FDA briefing document questioned a number of issues including dosing response and the risk-benefit profile.
CV Therapeutics' stock (NASDAQ:CVTX) Monday closed at $12.21, down $4.55. Trading was suspended during the meeting.
Near the end of Tuesday's meeting, several panel members complimented the company on its "eloquent" presentation and trial data, which is something of a turnaround after the FDA in late October issued an "approval letter with conditions" for Ranexa, which included criticism of dosing, the lack of QT prolongation data and safety data in general. (See BioWorld Today, Nov. 3, 2003.)
Following receipt of the letter, it was believed that CV Therapeutics would be required to conduct additional trials. The company, however, declined to state whether it was moving in that direction. Instead, the company said the panel would help clarify its next steps, noting that the FDA is not bound by any decision or recommendation made by the panel.
Speaking after the hearing, Louis Lange, company chairman and CEO, said it's too early to make statements about future trials or steps the company will take to win approval before taking a meeting with the FDA.
CV Therapeutics' journey through the final stages of the regulatory process is slightly backward because its Prescription Drug User Fee Action (PDUFA) date fell before its panel date. Initially the two were to meet for a September panel meeting, but both sides agreed to postpone as neither could complete the "briefing document" 30 days prior to the meeting. (See BioWorld Today, Aug. 5, 2003.)
CV Therapeutics submitted data on 2,783 trial participants but was criticized for its "slim" safety data that included only about 800 patients. The FDA said in chronic illnesses it is customary to submit safety data on 1,500 people, including 100 people followed for a year.
The company also was hurt prior to the meeting by failing to provide data on Ranexa's impact on repolarization that clinically manifested as prolongation of the QT interval. Lange said the QT prolongation issues looked like Mount Everest before going into the hearing, but afterward it appeared as if the company did an adequate job explaining that there's no evidence of QT prolongation for Ranexa users.
Speaking on behalf of the company, Jeremy Ruskin, associate professor of medicine at Harvard University Medical School and director, cardiac arrhythmia service at Massachusetts General in Boston, said there could be a small theoretical risk associated with QTc (corrected) prolongation that could be handled with risk-management strategies such as dose-titration labeling, education and post-marketing studies.
He added that the company was committed to conducting required post-marketing trials.
Steven Nissen, a panel member and medical director, Cleveland Clinic Cardiovascular Coordinating Center, said he's "on the border" as to whether Ranexa should be released to an unrestricted population because of the QT effect. "The real question is does the QT prolongation warrant restricting it to a resistant population," he said. "We could release it to everyone and find out real fast [about QT prolongation] - I'm not sure if the regulators would like that."
Generally, panel members agreed that safety problems would crop up if Ranexa is introduced into a larger population, and the real question, according to Nissen, is whether it causes Torsades de Pointes (TdP, a malignant polymorphic ventricular tachyarrhythmia that can be caused by drugs that induce electrophysiological changes).
The trials produced no evidence of TdP in the clinical trials, a fact that panel members found encouraging.
In clinical trials, Ranexa was dosed at different levels, and the company said adverse events (such as dizziness) were more likely to appear as the dose increased to 1,000 mg or 1,500 mg twice daily. The FDA had previously said the company had not provided adequate information for dose labeling.
Ranexa (ranolazine), 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.
If and when approved, Ranexa would be CV Therapeutics' first marketed product. CV Therapeutics had been developing Ranexa in conjunction with partner Innovex Inc., a subsidiary of Research Triangle Park, N.C.-based Quintiles Transnational Corp. But in July CV Therapeutics regained all rights from Innovex, saying it had better resources to develop it than it did at the time of signing the deal in May 1999. The company agreed to issue Innovex warrants for 200,000 shares at $32.93 apiece for the rights. (See BioWorld Today, May 12, 1999, and July 14, 2003.)
The new drug application was comprised of data from two Phase III studies (CVT 3031 and CVT 3033, also called the Marisa and Carisa trials, respectively), which used the sustained-release formulation of Ranexa, and three controlled trials using the immediate-release formulation. In total, the studies randomized about 1,596 angina patients. Another six studies randomized a total of 157 patients to gather data supporting the mechanism of action.