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Second chance for dronedarone after recent setback?
World Report
Second chance for dronedarone after recent setback?
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 easyto-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 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, emphasising the hazards of this type of analysis. The subpopulation that benefited in ATHENA were 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 www.thelancet.com Vol 379 February 18, 2012
Europe and the USA, are nevertheless clear: dronedarone should not be used by patients with permanent AF.
“‘We are still on the quest to find a good, effective and safe antiarrhythmic...’” Because the drug is also contraindicated in patients with heart failure and carries warnings about possible liver damage and more, the spectre of toxicity has raised some concerns about its use in periodic AF as well. “Now, as opposed to being a drug that was considered to be very clean and nice and safe in everybody, it is a drug with bullet points stating ‘be careful in the following...’”, says Gregory Lip, from the Centre for Cardiovascular Sciences at the University of Birmingham, UK. As a result, instead of finding a place in internists’ and family physicians’ medicine cabinets, dronedarone is only likely to be prescribed by specialists who can ensure its use in the proper patient population. The European Medicines Agency and others have also argued that as a result of the safety findings the drug should only be used as a later line antiarrhythmic after alternative treatments have been considered. 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. HARMONY may also pave the way as one of the first randomised clinical trials to test a combination of agents for AF control, adds Stanley Nattel, a cardiologist at the Montreal Heart Institute in Canada who is not involved in the study. “I think combinations are probably not used enough in this setting”, says Nattel, adding that to date part of the problem has been that because many antiarrhythmics are available as generics, few sponsors have been willing to fund the required randomised controlled studies. Beyond the new combination, another possible antiarrhythmic on the horizon is an oral formulation of Merck’s potassium channel blocker vernakalant, which may enter into phase 3 trials soon (an intravenous formulation of the drug has already been approved in Europe, but not in the USA, for acute conversion of AF). Ongoing research into surgical interventions and new devices could also help some subpopulations. “We are still on the quest to find a good, effective and safe antiarrhythmic”, sums up Lip.
Science Photo Library
Sanofi’s dronedarone is not the simple and safe antiarrhythmic some had once hoped it would be, but a combination study could restore its promise as an easy-to-use option. Asher Mullard reports.
For the ATHENA trial results see N Engl J Med 2009; 360: 668–78
For the PALLAS results see N Engl J Med 2011; 365: 2268–76
Asher Mullard 601
Second chance for dronedarone after recent setback?
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 easyto-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 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, emphasising the hazards of this type of analysis. The subpopulation that benefited in ATHENA were 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 www.thelancet.com Vol 379 February 18, 2012
Europe and the USA, are nevertheless clear: dronedarone should not be used by patients with permanent AF.
“‘We are still on the quest to find a good, effective and safe antiarrhythmic...’” Because the drug is also contraindicated in patients with heart failure and carries warnings about possible liver damage and more, the spectre of toxicity has raised some concerns about its use in periodic AF as well. “Now, as opposed to being a drug that was considered to be very clean and nice and safe in everybody, it is a drug with bullet points stating ‘be careful in the following...’”, says Gregory Lip, from the Centre for Cardiovascular Sciences at the University of Birmingham, UK. As a result, instead of finding a place in internists’ and family physicians’ medicine cabinets, dronedarone is only likely to be prescribed by specialists who can ensure its use in the proper patient population. The European Medicines Agency and others have also argued that as a result of the safety findings the drug should only be used as a later line antiarrhythmic after alternative treatments have been considered. 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. HARMONY may also pave the way as one of the first randomised clinical trials to test a combination of agents for AF control, adds Stanley Nattel, a cardiologist at the Montreal Heart Institute in Canada who is not involved in the study. “I think combinations are probably not used enough in this setting”, says Nattel, adding that to date part of the problem has been that because many antiarrhythmics are available as generics, few sponsors have been willing to fund the required randomised controlled studies. Beyond the new combination, another possible antiarrhythmic on the horizon is an oral formulation of Merck’s potassium channel blocker vernakalant, which may enter into phase 3 trials soon (an intravenous formulation of the drug has already been approved in Europe, but not in the USA, for acute conversion of AF). Ongoing research into surgical interventions and new devices could also help some subpopulations. “We are still on the quest to find a good, effective and safe antiarrhythmic”, sums up Lip.
Science Photo Library
Sanofi’s dronedarone is not the simple and safe antiarrhythmic some had once hoped it would be, but a combination study could restore its promise as an easy-to-use option. Asher Mullard reports.
For the ATHENA trial results see N Engl J Med 2009; 360: 668–78
For the PALLAS results see N Engl J Med 2011; 365: 2268–76
Asher Mullard 601