Multaq (dronedarone) is a Class III antiarrhythmic drug developed by Sanofi-Aventis (formerly Sanofi-Synthlelabo) for the prevention of cardiac arrhythmias. Its initial indcation is for the prevention and treatment of atrial fibrillation.
On 2 July 2009, the company received approval for Multaq 400mg tablets from the US Food and Drug Administration (FDA) for use in adults who currently have or previously had non-permanent atrial fibrillation, as a means to prevent atrial fibrillation reccurence or slow down the ventricular rate. The tablets were commercially launched in the US in the same month.
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Multaq is claimed to be the first FDA-approved drug that can reduce instances of cardiovascular hospitalisation in patients with atrial fibrillation or atrial flutter. Despite a series of regulatory setbacks that followed filing in 2005, including FDA rejection, the company resubmitted a registration dossier with the European Medicines Agency (EMEA)and FDA by the end of 2008.
This followed the release of data from the ATHENA trial, the largest randomised, double-blind outcome trial in atrial fibrillation. Results of the trial were also published in the New England Journal of Medicine in February 2009.
with atrial fibrillation or atrial flutter.”
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, part of the EMEA, gave a positive response to sanction marketing authorisation for Multaq in the EU, based on the comprehensive data submitted from the ATHENA trial, and other clinical trials that involved 7,000 patients. In December 2009, the EMEA approved Multaq, and granted Sanofi-Aventis rights to market the drug in all 27 EU countries. The positive opinion was based on the comprehensive data submitted from clinical trials that involved 7,000 patients and from the ATHENA trial.
As projected, sales of Multaq picked up before its approval. In March 2010, Sanofi-Aventis received a boost when the UK’s National Institute for Health and Clinical Excellence (NICE) recommended the use of Multaq as the first therapeutic option in treating atrial fibrillation. Multaq also became commercially available in the UK in March 2010.
The burden of atrial fibrillation
Atrial fibrillation, a condition characterised by an irregular heartbeat, is the most common sustained disorder of cardiac rhythm. It 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.
Although it primarily affects the elderly, the condition is not thought of as 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.
Atrial fibrillation affects almost 10% of the very elderly (80–89 years), and is already a major public health issue. It is projected to increase as the population of industrialised countries ages. In the US alone, it is estimated to affect 2.5 million people, while across the EU the figure is believed to be around 4.5 million.
Men are at greater risk of developing the atrial fibrillation than women, and many patients with the condition 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 atrial fibrillation. They 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 atrial fibrillation. Although pacemakers, defibrillators, radiofrequency ablation and surgery increasingly have a place in the 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 atrial fibrillation, with several new agents in development in addition to dronedarone. 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 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 Multaq 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 Multaq. The landmark trial, which involved 4,628 patients, was the first in the 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 hospitalisations were also reduced by 26% in the Multaq group.
In relation to drug safety, Multaq was comparable to placebo in the rate of pro-arrhythmia. No excess hospitalisations for congestive heart failure were seen in the Multaq-treatment arm.
In September 2008, further additional data were released from a post-hoc analysis that suggested that Multaq also had a significant effect on the incidence of stroke in atrial fibrillation patients.
Over a follow-up period of about 21 months, patients in the Multaq-treatment arm had a 34% (adjusted) lower risk of stroke compared with placebo recipients (p=0.027).
Study investigators believe no other antiarrhythmic therapy has achieved such reductions. Importantly, the reductions were seen in patients who were, in most cases, receiving appropriate antithrombotic therapy.
Marketing commentary
Increasing recognition that atrial fibrillation constitutes a growing health problem among elderly patients has stimulated the search for improved agents to treat it. 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 atrial fibrillation.
