Dronedarone, a new anti-arrhythmic drug in development, may fill unmet need in atrial fibrillation

Dronedarone, a new Class III multi-channel blocking anti-arrhythmic drug currently in Phase III development by Sanofi-Aventis for the prevention of atrial fibrillation (AF) and atrial flutter (AFL) may help fill the unmet need for a safe pharmacologic treatment that effectively controls atrial fibrillation, cardiologists said this month. Sanofi-Aventis presented new data on dronedarone at the American Heart Association’s (AHA) annual scientific sessions held in Dallas.

 “Effective new treatments for AF are urgently needed,” commented Professor Peter Kowey of Jefferson Medical College, Philadelphia. “The condition is sweeping through the population of ageing baby-boomers in developed countries, increasing the incidence of stroke five-fold.”  AF affects 2.5 million people in the US alone. In the UK the condition affects 1 in 25 adults over age 60 and 1 in 10 of the over 80s. It is estimated that uncontrolled AF accounts for between 15 and 20 per cent of all strokes. By reducing the heart’s pumping ability, AF also predisposes patients over time to develop heart failure.

Dronedarone is a structurally modified version of amiodarone, currently the acknowledged gold standard anti-arrhythmic, and has been designed to match amiodarone’s efficacy whilst offering a much improved safety profile.  Dronedarone contains no iodine radical whilst this makes up over a third of amiodarone’s molecular structure.  Amiodarone is associated with significant thyroid problems and with cumulative, potentially fatal, lung and liver toxicity. To date, dronedarone’s adverse event profile appears comparable to placebo.   In pivotal trials it showed no evidence of generating pro-arrhythmia (tachy- or bradyarrythmia), no episodes of torsade de pointes and no signs of amiodarone-related organ toxicity affecting thyroid, liver or lungs.

Previously, data presented in 2004 from two pivotal trials, EURIDIS and ADONIS, involving over 1,200 patients, showed dronedarone 400mg produced a significantly greater reduction in AF recurrence following electrical cardioversion compared with placebo. Overall, treatment with dronedarone significantly reduced the risk of a first recurrence by between 22% (ADONIS) and 27.5% (EURIDIS).

At the AHA meeting in Dallas, researchers showed the versatility of the drug’s effect; the lowered risk of first recurrence was consistent across three patient subgroups.  A highly significant 25 per cent (p<0.0001) risk reduction for first recurrence was seen in patients previously treated with amiodarone, in patients with structural heart disease and among those with a recent need for cardioversion therapy.  “In each subgroup, dronedarone was consistently and uniformly more effective than placebo,” said lead ADONIS investigator Professor Bramah Singh of UCLA Medical School.

A further study presented at AHA by Professor Stefan Hohnlose from Goethe University, Frankfurt showed dronedarone significantly reduced all-cause hospitalisations or deaths by 27 per cent compared to placebo in patients with paroxysmal and persistent AF.

“Dronedarone was able to maintain a consistent sinus rhythm in patients with AF,” commented Professor Hohnlose, lead investigator of the EURIDIS study.  “The potential clinical benefits of dronedarone may provide an important new treatment approach for AF.”  A large prospective study ATHENA which will enrol 37,000 subjects is currently assessing morbidity and mortality outcomes of AF patients treated with the drug.

Data from an additional Phase III study, ERATO, also presented at AHA, showed dronedarone was able to control heart rate in patients inadequately controlled by concomitant standard therapies including beta-blockers, digitalis and calcium channel blockers.  Compared against baseline measures, placebo-treated patients showed no significant change whilst the dronedarone-treated group significantly reduced their mean 24-hour heart rate by 11.7 beats per minute (bpm) and maximal exercise ventricular rate by 24.5 bpm at day 14 (p<0.0001). 

Drugs with a class III mechanism of action are seen as the most promising area of research for improved pharmacotherapy of AF, with several new agents in addition to dronedarone in development.  

Dronedarone was filed with the US FDA and the European Regulatory Authority, EMEA, in June 2005.

To see more features by Olwen Glynn Owen follow this link to his first feature article and scroll to the end for a list:
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