After a testing last year for Multaq (Sanofi's dronedarone) in 2011, its major PALLAS study was terminated and safety alerts were issued by the FDA and European Medicines Agency 2012 offers a ray of hope for the antiarrhythmic drug. In January 2012, at the Boston Atrial Fibrillation Symposium, plans for a new clinical trial, testing a combination of Multaq and Ranexa (Gilead's ranolazine) in AF patients were unveiled a development strategy that Decision Resources had predicted over a year ago. Combination antiarrhythmic therapy for AF is a novel treatment approach that could deliver key benefits to patients, but developing such an agent poses a series of unique challenges. Given these factors, and the competitive landscape for antiarrhythmic drugs, what are the prospects for success of a Multaq and Ranexa combination therapy?
The HARMONY trial will investigate the effects of Multaq in combination with Ranexa in approximately 150 patients with non-permanent AF and implanted pacemakers the enrollment of these patients will allow for investigators to quantify the therapy's effects on AF burden. Although a small study, the results from HARMONY could lead to a paradigm shift in the treatment of AF.
Based on preclinical data, we believe that a Multaq and Ranolazine combination therapy could be well positioned to offer important benefits over current agents, which suffer from limited efficacy and/or safety concerns. Multaq and Ranexa have different modes of action and research in an animal model of AF showed that treatment with both agents yields synergistic antiarrhythmic effects. We expect that this finding prompted the choice of lower drug doses in the HARMONY trial (for example, only 150-225 mg of dronedarone will be tested vs. its current label of 400 mg twice daily). Additionally, Ranexa benefits from a strong safety profile; previous, intensive safety testing and Phase III research have shown that it poses no risk of major adverse events, particularly cardiac toxicity. Furthermore, although Multaq's hepatic and cardiac safety profiles have been recently scrutinized, lower doses of the drug may reduce the risk of encountering these adverse events.
Despite the potential therapeutic benefits afforded by a Multaq and Ranexa combination therapy, it may face a number of regulatory and commercial challenges during its late-stage development and following its launch. For example, given the risk of developing QT prolongation with both drugs, and Multaq's prior history in the ANDROMEDA and PALLAS trials, the FDA is likely to demand a broad range of safety data in the form of dedicated studies (e.g., a thorough QT test) and at least one large outcomes-based trial. Selecting the optimal suite of safety studies and patient populations to enroll will prove crucial in demonstrating and reinforcing the combination's safety to regulatory agencies and the medical community. The design of a subsequent Phase III program will also be pivotal in shaping physicians and payers perceptions of the combination's efficacy and merits over existing agents; however, overcoming current perceptions of Multaq's profile could prove challenging. Based on primary research conducted by Decision Resources, we believe that Multaq's Phase III data from its ATHENA trial, which used an unconventional efficacy end point for AF (cardiovascular hospitalization), failed to resonate with prescribers and contributed to its modest uptake. Surveying cardiologists in the major markets to gauge the importance assigned to different efficacy end points in prescribing decisions could provide key insight into designing a Phase III study to fuel post launch uptake.
According to thought leaders interviewed by Decision Resources, the availability of safer and more effective antiarrhythmic drugs is a pressing unmet medical need in AF and, based on our current knowledge of the Multaq and Ranexa combination, we believe that it has the potential to offer important advantages over current agents. Nonetheless the combination therapy may face competition from key emerging drugs, such as oral vernakalant (Merck/Cardiome) and NTC-801 (Bristol-Myers Squibb/Teijin). The launch of Multaq, and the challenges it faced, provides the developers of new agents, including the combination therapy, with important learning opportunities regarding the design of late-stage AF trials, optimal end points to use, key patient subpopulations to target, and the best approaches to addressing regulators concerns. At this early stage in the combination's development, harnessing this new insight to inform its future clinical pathway could play a major role in shaping its commercial success.