The Lankenau Institute for Medical Research
Excerpted from The Lancet article by Asher Mullard [Volume 379, Issue 9816, Page 601, 18 February 2012]
FEBRUARY 18, 2012 - Sanofi's dronedarone was approved for the treatment of paroxysmal and persistent atrial fibrillation (AF) in both the USA and Europe in 2009, largely on the basis of positive ATHENA trial results. When a post-hoc analysis of the same trial unexpectedly raised the possibility that the drug might also provide a benefit to patients with permanent AF, the cardiology community thought it might for the first time have a safe and easy-to-use antiarrhythmic that could be prescribed across the AF board. This hope evaporated last year when Sanofi prematurely halted the PALLAS trial because treatment was associated with an increased risk of death, forcing the field instead to re-evaluate the position of the multiple ion channel blocker.
“It was not an outcome that I think anyone expected,” says Peter Kowey, a cardiologist at the Main Line Health Heart Center based in [Wynnewood], PA, USA, who has been involved in the development of dronedarone. “It was disappointing.” Detailed PALLAS results, published in the New England Journal of Medicine in December, 2011, showed that twice as many high-risk patients with permanent AF who received dronedarone died due to cardiovascular causes compared with those who received placebo.
Although there is as yet no definitive resolution of the contradictory PALLAS and ATHENA results, a few possibilities have been raised. Kowey, for instance, points out the promise of efficacy in patients with permanent AF in ATHENA only emerged in a post-hoc test, emphasizing the hazards of this type of analysis. The subpopulation that benefited in ATHENA was also at lower risk for major vascular events than those who were enrolled in PALLAS. Yet the implications, which have been spelled out by regulators in both Europe and the USA, are nevertheless clear: dronedarone should not be used by patients with permanent AF.
Yet, even as dronedarone's promise as an easy-to-use antiarrhythmic fades, some researchers hope the drug will achieve renewal in a combination form. Gilead, a relative newcomer to the cardiovascular arena but an accomplished combination developer, recently announced its plans to launch a Phase 2 AF trial of dronedarone plus the sodium channel blocker ranolazine, which is currently approved for the treatment of angina.
So far, says trial investigator Kowey, preclinical studies “suggest that a combination of these drugs will suppress AF much more efficiently than either drug alone.” The team also thinks that each agent may be able to be used at lower doses than are currently available, possibly reducing their toxicity and increasing tolerability as well.
The proof of concept HARMONY trial could be launched in 150-200 patients with periodic AF as early as April, with results anticipated within a year from initiation. Because both dronedarone and ranolazine are reasonably safe drugs in their approved patient populations, says Kowey, one hope is that the combination will emerge as the much needed simple, safe, and effective therapeutic option.