CV Therapeutics Inc. and the FDA agreed to the design of another trial that could support approval of Ranexa.
It sets up the potential for approval in the broad indication of a first-line therapy for chronic angina, whereas prior discussions between the company and the agency considered authorization in chronic angina in a restricted patient population. The most recent agreement, which was reached under the agency's special protocol assessment (SPA) process, also could result in approval for treating acute coronary syndromes and its long-term prevention.
"We're very excited to have two SPA agreements in place to conduct these studies," John Bluth, the company's senior director of corporate communications, told BioWorld Today. "What they do is significantly mitigate the regulatory risk associated with Ranexa. We need to execute the studies, but there is very clear agreement now between the company and the FDA in the form of written SPA agreements that outline the protocol for these studies."
The newest study, called MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes), will evaluate the drug's safety and efficacy during acute and long-term treatment in about 5,500 patients with non-ST elevation acute coronary syndromes treated with standard therapy. Its primary efficacy endpoint will measure the time to first occurrence of any element of the composite of cardiovascular death, myocardial infarction or recurrent ischemia.
The SPA agreement notes that if treatment with Ranexa is not associated with an adverse trend in death or arrhythmia compared to placebo, the resulting safety database could support the drug's approval as first-line chronic angina therapy. To that end, the Palo Alto, Calif.-based company said it would conduct a separate clinical evaluation of higher doses of Ranexa to support its use in that indication.
"And that is regardless of how we do on the primary endpoint," Bluth said, noting that if approved, Ranexa would represent the first new class of anti-anginal drugs in the U.S. in more than 25 years. "But we hope that we achieve statistical significance on the primary endpoint, as well."
In that case, the SPA stipulates that Ranexa could gain approval for hospital-based treatment of acute coronary syndrome and for its long-term prevention in patients that present symptoms at the hospital and are treated and discharged.
That study, which will be event-driven, will continue until a pre-specified number of cases of cardiovascular death, myocardial infarction or severe recurrent ischemia have been observed, and a pre-determined number of deaths from any cause have occurred. CV Therapeutics expects enrollment to begin next quarter, with preliminary data potentially available by the end of 2006.
About 600 sites are expected to be involved in the study, which will enroll eligible hospitalized patients who, within 48 hours of the onset of angina due to acute coronary syndrome, will be randomized to receive intravenous Ranexa or placebo, followed by long-term outpatient treatment with oral Ranexa or placebo. All patients also will receive standard therapy during both hospital-based and outpatient treatment. The oral doses have been studied in previous Phase III trials.
In addition to performing periodic safety assessments, an independent Data Safety Monitoring Board overseeing MERLIN will conduct a blinded interim efficacy analysis, based on the endpoint of cardiovascular death, which is anticipated to occur after about half the specified cardiovascular events have been observed. A p' value of 0.001 would be required to stop the study early at the time of the interim efficacy analysis, though the company admitted such a scenario is unlikely.
The trial also will include a blinded interim assessment of sample size to permit the overall study size to expand to about 6,500 patients, if the overall mortality rate needed to complete the study is significantly lower than anticipated. It will be conducted by the Thrombolysis in Myocardial Infarction research network in Boston.
The study agreed upon two months ago will test Ranexa in about 500 patients with chronic angina who remain symptomatic despite daily treatment with the maximum labeled dose of amlodipine, an approved calcium channel blocker. Bluth said the company expects to begin the trial this quarter. (See BioWorld Today, June 4, 2004.)
That study's protocol follows a recommendation late last year by the FDA's Cardiovascular Renal Drugs Advisory Committee, which said that Ranexa would be approvable if CV Therapeutics completed another clinical trial in a population that would include patients who did not respond to maximal therapy. (See BioWorld Today, Dec. 10, 2003.)
The committee's review followed an approval letter issued a month earlier by the FDA that sought additional clinical information. (See BioWorld Today, Nov. 3, 2003.)
CV Therapeutics first submitted Ranexa's new drug application about a year and a half ago. Data in the submission included findings from two prior Phase III studies, labeled MARISA and CARISA. The product remains under review in Europe, where the company also has submitted an application for its approval in treating chronic angina. (See BioWorld Today, Dec. 31, 2002.)
The company also reported its second-quarter earnings last week, showing a net loss of $37.2 million, compared to a net loss of $22.9 million a year earlier. It had about $415.7 million in cash, cash equivalents and marketable securities.
Beyond Ranexa, CV Therapeutics' pipeline includes three other clinical-stage drug candidates. Regadenoson, a selective A2A adenosine receptor agonist, is in two Phase III trials testing its use as a pharmacologic stress agent in cardiac-perfusion imaging studies. Three-quarters of the pivotal studies' costs are covered by Deerfield, Ill.-based Fujisawa Healthcare Inc., which would sell the product in North America if approved.
Tecadenoson, an A1 adenosine receptor agonist, also is in Phase III development for the reduction of rapid heart rate during atrial arrhythmias. CV Therapeutics owns all rights to that drug. Adentri, an A1 adenosine receptor antagonist for heart failure, has completed Phase II studies under the watch of Biogen Idec Inc., of Cambridge, Mass.
On Friday, CV Therapeutics' stock (NASDAQ:CVTX) fell 47 cents to close at $13.39.