Last week's FDA panel nod for Cardiome Pharma Corp.'s intravenous atrial fibrillation/flutter drug vernakalant - lately branded Kynapid - came with the expected provisos, and put the company in strong position as the race to market continues for I.V. and oral versions of AF drugs.
Briefing papers posted by the agency's Cardiovascular and Renal Drugs Advisory Committee presaged a positive vote, pointing to "persuasive demonstration of efficacy" that was "consistent across subgroups" - even in patients with congestive heart failure - and was "robust to exploration."
Last summer Cardiome reported results from the ACT 2 trial, testing Kynapid in patients with atrial fibrillation (AF) or atrial flutter after coronary artery bypass graft (CABG) surgery - data that could pave the way for off-label use in new-onset AF, and helped grease the regulatory path for the atrial-selective blocker of potassium and sodium channels. (See BioWorld Financial Watch, Aug. 27, 2007.)
ACT 2 used the same dosing regimen as ACT1 and ACT3 pivotal trials in new-onset AF. Positive top-line results from ACT 1 and ACT 3, were released in December 2004 and September 2005, respectively, and Astellas submitted a new drug application at the end of last year.
The FDA's advisory panel voted 6 to 2 in favor of recommending approval of Kynapid for the rapid conversion of acute AF to sinus rhythm. Kynapid caused two cases of ventricular fibrillation, one of them fatal, in the course of testing, but panel reviewers found the death "very likely" caused by the patient's aortic stenosis and heart failure, though there was not enough evidence to know for certain. If approved, it will be the first new drug for AF conversion in eight years.
Safety data from the IV trials could mean the oral version of vernakalant will be used to maintain normal rhythm in patients after surgery. Not only post-CABG but also patients undergoing valve surgeries and thoracic operations risk AF, and might be treated with Kynapid, partnered with Astellas Pharma Canada Inc., an affiliate of Astellas Pharma US Inc., which also has filed a new drug submission with Health Canada for acute conversion of AF.
Astellas, a subsidiary of Astellas Pharma Inc., holds North American rights to the I.V. formulation, while Cardiome retains rights outside the U.S. and holds worldwide rights on the oral version.
Kynapid faces competition in Sanofi-Aventis Group's Multaq (dronedarone) for AF, the oral follow-on product to the pharma giant's Cordarone (amiodarone), which lost patent protection in the U.S. in 2002. Multaq got a non-approvable letter last year. Also in the queue is Procter & Gamble's late-stage Stedicor (azimilide), and Datamonitor expects five new AF products to reach the $1 billion market by 2010, forecasting that Kynapid, Stedicor and Multaq probably will generate sales of more than $500 million each.
Solvay Pharmaceuticals BV has filed for approval here and overseas of I.V. Pulzium (tedisamil), a multiple potassium-channel blocker for conversion of recent onset AF or atrial flutter. The FDA panel took up Solvay's drug the day after dealing with Kynapid - and voted unanimously to recommend against approval, which might have given Kynapid a leg up, since the drug avoided any safety pall that might be left over from Pulzium debates.
Pulzium would be administered in a two-part dosing schedule, and panel members worried that higher amounts of the drug put patients at risk of torsades de pointes, a dangerous side effect of some anti-arrhythmics. (The French phrase means "twisting of the points," and refers to the look of the electrocardiogram.)
CV Therapeutics Inc. has Phase II-stage tecadenoson, a selective A2A-adenosine receptor agonist for atrial arrhythmia, though CV said in the spring that it would reduce research and development costs by 20 percent, and not kick off AF trials with chronic angina drug Ranexa (ranolazine) until the compound is partnered.
Kynapid, the panel warned, shouldn't be used at all in patients with recent myocardial infarctions, or for those with Class 3 or Class 4 heart failure, a combined group that comprises 10 percent and 20 percent of patients, estimated analyst Michael King of Rodman & Renshaw. Based on the restriction, King reduced his peak sales forecast for I.V. Kynapid by about $100 million, to a range between $500 million and $600 million, but noted the advisory group's recommendation of a three-hour to seven-day treatment window, long enough to get "adequate" use in the acute setting.
Advisors, while not asking for randomized trials in patients with impaired livers, called for post-marketing surveillance and recommended observational studies in 2,000 patients (as suggested by Astellas) in order to get a better idea of Kynapid's safety in a broad range of potential users.
All in all, the panel outcome proved a victory for Cardiome and Astellas, and makes approval likely by the PDUFA date in mid-January. Meanwhile, interim Phase IIb data with the oral version are expected in late February, as Cardiome seeks a partner next year - and, importantly, the advisory committee on the I.V. version cited no apparent safety problems that could imperil the oral program.
In late November, Cardiome disclosed a delay of the oral interim data, deciding to wait until about 360 patients have been treated for three months, which means results will not be available until March 2008. (Originally the firm had planned to offer numbers in the fourth quarter of this year, but this would only have included 30-day to 60-day results.)
The holdup means a better likelihood of statistically significant results, which could draw a partner sooner - or even inspire a buyout - and extending the trial might let Cardiome include its results, along with those from another study, in the registration package.
Kynapid's history is not unmarred. In the summer of 2006, the FDA issued a refusal to file letter for the compound, then known as RSD1235, though company officials said the data had nothing to do with the letter. (See BioWorld Financial Watch, July 17, 2006.)