Dronedarone - Investigational Agent for the Treatment of Cardiac Arrhythmia

Multaq (dronedarone) is a new Class III antiarrhythmic drug under development by Sanofi-Aventis (formerly Sanofi-Synthlelabo) for the prevention of cardiac arrhythmias. The drug is currently in advanced-stage development for prevention and treatment of atrial fibrillation (AF), its initial indication.

Promising outcome data from its European EURIDIS and American / Australian / African ADONIS phase III trials suggest dronedarone may become a worthy successor to amiodarone, the current reference treatment for AF. In June 2005, Sanofi-Aventis filed for regulatory approval with both the US FDA and European EMEA.

However, in September 2006, the company decided to withdraw its European application, citing too tight a timeframe in which to provide the additional clinical data requested by the regulators. Meanwhile, in the US, the FDA rejected Multaq as a treatment for AF. Re-filing is scheduled for 2008 when new trial data become available.

THE BURDEN OF ATRIAL FIBRILLATION

AF, a condition characterised by an irregular heart beat, is the most common sustained disorder of cardiac rhythm. AF occurs when the atria (the upper chambers of the heart) contract very rapidly. This causes the lower chambers of the heart, the ventricles, to contract chaotically so that blood is inefficiently pumped to the body.

Primarily affecting the elderly, AF is not thought a benign consequence of ageing, but rather a serious condition with adverse clinical sequelae. These can include:

• Increased risk of transient ischaemic attack (TIA) and stroke
• Worsening of congestive heart failure
• Thromboembolic disease
• Impaired quality of life
• Increased risk of hospitalisation
• Increased mortality - sudden cardiac death and stroke

Affecting almost 10% of the very elderly (80–89 years), AF is already a major public health problem and projected to increase as the population of the industrialised countries ages. In the US alone it is estimated to affect 2.5 million Americans, while across the European Union the figure is believed to be around 10 million. Men are at greater risk of developing AF than women. Many patients with AF have underlying cardiovascular conditions such as hypertension, coronary heart disease, heart failure and valvular heart disease.

IN SEARCH OF THE IDEAL ANTIARRHYTHMIC DRUG

Several classes of drugs are currently used in the management of patients with AF and include:

• Calcium antagonists
• Beta-blockers and cardiac glycosides
• Anticoagulants (used in conjunction with rate-controlling drugs)
• Class III antiarryhthmics

The aim of therapy is to control ventricular rate and restore and maintain the heart's normal sinus rhythm (NSM). Maintenance of NSR is seen as the ultimate goal of therapy for patients with AF. Although pacemakers, defibrillators, radiofrequency ablation and surgery increasingly have a place in treatment of cardiac arrhythmias, drug therapy remains an important first-line therapy, for which improved antiarrhythmic agents are needed.

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. Ideally, any new agent should have:

• Superior efficacy to current class III antiarrhythmics
• Low risk of proarrhythymia
• Superior safety and tolerability to current class III antiarrhythmics
• Low propensity for drug interactions

MULTAQ – A POTENTIAL SUCCESSOR TO AMIODARONE

Sanofi-Aventis' Multaq (dronedarone) is chemically related to its class III agent amiodarone the current gold standard. The company hopes that dronedarone will match the efficacy of amiodarone but offer improved safety and tolerability; currently the major drawback with class III drugs. Recent pooled safety data from two pivotal phase III studies suggest it has a similar adverse event profile to placebo.

Evidence of efficacy was first demonstrated in the DAFNE trial, a phase IIb study that compared dronedarone with placebo for the maintenance of sinus rhythm after cardioversion for AF. These promising results have since been confirmed with data from the two pivotal phase III EURIDIS and ADONIS trials. Involving over 1,200 patients, these studies were designed to investigate the effect of dronedarone on prevention of recurrence in patients with AF.

First-year data from these trials, in which patients received treatment with dronedarone 400mg, showed that active treatment produced a significantly greater reduction in AF recurrence. Compared with placebo, AF recurrence was 2.3 to 2.7 times longer following treatment with dronedarone. Dronedarone proved effective on all recurrences of AF including those that were symptomatic. Overall, treatment with dronedarone significantly reduced the risk of a first recurrence by between 22% (ADONIS) and 27.5% (EURIDIS).

Given the safety issues raised by the earlier ANDROMEDA trial, which led to its premature discontinuation on safety grounds, the EURIDIS and ADONIS trial safety data were encouraging. There was no evidence of proarrhythmia and no cases of the potentially fatal condition Torsade de Pointes during the 12-month follow-up.

MARKETING COMMENTARY

Increasing recognition that AF constitutes a growing health problem among elderly patients has stimulated the search for improved agents to treat this cardiac rhythm disorder. Current therapies are limited by their tendency to cause pro-arrhythmic (tachy- or bradyarrythmia) and toxic side effects and so there is a need for safer drugs to treat this condition.

The potential to combine drugs with implantable devices, so called hybrid therapy, is also being pursued and together with new drug therapy may help to bridge current treatment gaps for AF.

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