Multaq - Investigational Agent for the Treatment of Cardiac Arrhythmia

Multaq (dronedarone) is a new Class III antiarrhythmic drug developed by Sanofi-Aventis (formerly Sanofi-Synthlelabo) for the prevention of cardiac arrhythmias. The drug has been developed for prevention and treatment of atrial fibrillation (AF), its initial indication.

On 2 July 2009, the company received approval for Multaq 400mg tablets from the US Food and Drug Administration (FDA). Commercial launch of the tablets in the US is expected in late 2009.

Multaq is claimed to be the first FDA-approved drug that can bring down the instances of cardiovascular hospitalisation in AF/AFL patients. Despite a series of regulatory setbacks that followed filing in 2005, including FDA rejection, the company was poised to resubmit a registration dossier with the EMEA and FDA before the end of 2008.

This followed the release of data from the ATHENA trial, the largest randomised, double-blind outcome trial in AF. Results of the trial were also published in the New England Journal of Medicine in February 2009.

On 12 August 2009 the drug was approved by Health Canada. On 25 September 2009 Sanofi-Aventis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) gave a positive response to sanction marketing authorisation for Multaq in the EU.

Multaq was approved for use in adults who are suffering from non-permanent AF at present or in the past, to prevent AF recurrence or to slow down the ventricular rate.

The positive opinion is based on the comprehensive data submitted from clinical trials that involved 7,000 patients and from the ATHENA trial.

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 EU the figure is believed to be around 4.5 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 (NSR). 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.

The drug's action is similar to amiodarone but lacks an iodine moiety, which means the drug shows less pulmonary and thyroid toxicity.

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 proarrhythmia
• superior safety and tolerability to current Class III antiarrhythmics
• low propensity for drug interactions.

Significant data from ATHENA trial

Sanofi-Aventis' Multaq (dronedarone) is chemically related to its Class III agent amiodarone, the current gold standard. Prior to the publication of ATHENA trial results in 2009, the company hoped that dronedarone would match the efficacy of amiodarone but offer improved safety and tolerability; the major drawback with Class III drugs. The pooled safety data in 2008 from two pivotal Phase III studies suggested that it had a similar adverse event profile to placebo.

In addition, data from the ATHENA trial showed significant reductions in rates of cardiovascular hospitalisation and death following treatment with dronedarone. The landmark trial on 4,628 patients was the first in the Multaq (dronedarone) Phase III programme to look at the impact of treatment on morbidity and mortality.

Results showed a highly significant 24% reduction in all-cause mortality and cardiovascular hospitalisations (primary endpoint), as well as a 30% reduction in risk of cardiovascular death on top of standard therapy and a 45% reduction in the risk of arrhythmic death. First cardiovascular hospitalisation was also reduced by 26% in the dronedarone group. In relation to drug safety, Multaq (dronedarone) was comparable to placebo in the rate of pro-arrhythmia. No excess hospitalisations for CHF were seen in the dronedarone-treatment arm.

In September 2008, further additional data were released from a post-hoc analysis that suggested that Multaq (dronedarone) also had a significant effect on incidence of stroke in AF patients. Over a follow-up period of about 21 months, patients in the dronedarone-treatment arm had a 34% fall in adjusted risk of stroke compared with placebo recipients (p=0.027).

Study investigators believe no other antiarrhythmic therapy has achieved such reductions. Importantly, the reduction was achieved in patients who were in most cases receiving appropriate antithrombotic therapy.

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.