Dronedarone gets cautious nod from FDA advisory panel

The FDA’s Cardiovascular and Renal Advisory Committee voted 10 to 3 in favor of approval for Sanofi’s dronedarone. By all accounts it was a difficult decision for the committee.

CardioBrief has received statements from panel members Sanjay Kaul (yes, he did make it to the meeting) and Darren McGuire.

Here is Darren McGuire‘s comment on the meeting:

Bulk of discussion centered around placing the ATHENA results, which demonstrated a trend favoring overall mortality and a statistically significant reduction in CV mortality as secondary endpoint analyses of components of the primary outcome (CV hospitalization and total mortality), in context of the ANDROMEDA trial of advanced, recently unstable HF that was stopped early due to excess  mortality. Whether the ANDROMEDA findings were related to the instability of HF, or the underlying severity of Class III/IV HF with low EF remains uncertain, and therefore consensus was that this group of patients, stable or unstable, should not be candidates for dronedarone, at least until further data are available. The vote to approve was driven primarily by the robust and highly significant redcution in CV hospitalization, and while granular detail about those hospitalizations, which were investigator-reported and not adjudicated, most agreed that this observation represented an important increment in the evidence for clinically relevant outcome improvement for patients with Afib/Aflutter.

Many voiced an imperative to conduct longer-term post-approval trial(s) against amiodarone to further estimate efficacy and long-term safety, especially in the context of often latent non-cardiac toxicities of amiodarone that was the impetus to develop this compound in the first place.

Here is Sanjay Kaul‘s comment on the meeting:

Overall assessment
The whole premise behind ATHENA was to overcome the adverse mortality observed with dronedarone in ANDROMEDA. When one combines all the placebo-comparison studies conducted with dronedarone so far, I am not sure a clinically unacceptable increase in mortality has been excluded. The only reason the results of the ATHENA trial provide some reassurance about the long-term use of dronedarone (especially in light of the concerns raised by the results of the ANDROMEDA trial) is that a much lower risk population was studied.

The efficacy appears to be very modest with respect to NSR maintenance and rate control. Although these differences were statistically significant, the clinical significance is debatable.  The patient population enrolled does not reflect the spectrum of atrial fibrillation (AF) patients typically observed in clinical practice (permanent AF patients excluded, only 25% of pts had AF/AFL (atrial flutter) on randomization, only 21% patients had CHF Class II, III; etc.). Coupled with the lack of improvement in patient’s symptoms and/or quality of life status (which was not systematically evaluated) and the lingering controversy about the primacy of rhythm vs rate control strategy, a proper role for this drug in clinical practice requires careful consideration.

Finally, the drug was ostensibly designed to offset the adverse and extra-cardiac toxic outcomes associated with amiodarone. Even for this objective, I am not sure if superior tolerability was demonstrated with some degree of confidence. It was shown to be 50% less effective compared to amiodarone with only a modest, but nonsignificant, tolerability advantage.

On the other hand, ATHENA is the largest outcome trial in patients with history of or current AF/AFL with demonstrated benefits in reducing CV hospitalization, admittedly not the most robust of endpoints. However, this endpoint is somewhat clinically relevant (especially the reductions in ICU admissions), and might have the potential for cost savings.

What role do I see for this drug in clinical practice if approved?
For reducing CV hospitalizations related to atrial fibrillation/atrial flutter in low-intermediate risk patients with current or previous history of non-permanent AF/AFL and who do not have any contraindications including, in addition to the obvious ones, Class III heart failure and/or patients with low ejection fraction (<35%). For patients with Class III CHF or LVEF <35% (regardless of NYHA functional class) and patients with LVH, amiodarone should remain the first-line rhythm control strategy (as per ACC/AHA/ESC guidelines). Dronedarone could be considered in these patients if they become intolerable to amiodarone. No claim for superior tolerability against amiodarone should be allowed. I would like to see a larger comparative study, if feasible, with longer follow-up to demonstrate superior tolerability without unacceptable loss of efficacy before allowing that claim.

Bottomline, the data are sufficient to support a restricted label with a boxed warning for patients with advanced heart failure, but insufficient to support superior tolerability claim compared to amiodarone.

Here is Sanofi’s press release:

FDA Advisory Committee Recommends Approval of Multaq(R) (dronedarone)

PARIS, March 18 /PRNewswire-FirstCall/ — Sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced today that the Cardiovascular and Renal Drugs Advisory Committee voted 10 to 3 in favor of the approval of Multaq(R) by the U.S. Food and Drug Administration (FDA) to treat patients with non-permanent atrial fibrillation (AF).

As demonstrated in the ATHENA trial, Multaq is the only anti-arrhythmic drug to have shown in a clinical study a significant reduction in morbidity and mortality in patients with atrial fibrillation/atrial flutter (AFL) or a recent history of these conditions.

Sanofi-aventis is pleased with the outcome of today’s discussions and positive recommendation,” said Jean-Pierre Lehner, Chief Medical Officer, sanofi-aventis. “The panel’s insightful feedback which concluded with a positive vote, is an important step in gaining FDA approval of Multaq.”

The FDA is not bound by the Committee’s recommendation, but it takes its advice into consideration when reviewing new drug applications.

Atrial fibrillation is the leading cause of hospitalization for arrhythmia in the U.S. and represents one-third of hospitalizations for arrhythmia in Europe. Hospitalization due to AF has increased dramatically (two-to-three fold) in recent years in the U.S. Atrial fibrillation is a complex disease that increases the risk of stroke up to five-fold, worsens the prognosis of patients with cardiovascular risk factors, and doubles the risk of mortality. There are approximately 2.5 million Americans and 4.5 million people in the European Union with atrial fibrillation and it is emerging as a growing public health concern due to an aging population.

About dronedarone (Multaq(R))

Multaq(R), an investigational treatment discovered and developed by sanofi-aventis, has been studied in a clinical development program including more than 6,700 patients. Multaq(R) is one of the major therapeutic innovations in atrial fibrillation for the last twenty years. Multaq(R) has been granted a priority review by the U.S. Food and Drug Administration (FDA) and a registration dossier is also under regulatory review by the European Medicines Agency (EMEA).

About sanofi-aventis

Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone. Sanofi-aventis is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY). For more information, visit: www.sanofi-aventis.us or www.sanofi-aventis.com.

Forward Looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include product development, product potential projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future events, operations, products and services, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects,” “anticipates,” “believes,” “intends,” “estimates,” “plans” and similar expressions. Although sanofi-aventis’ management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of sanofi-aventis, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMEA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such products candidates, the absence of guarantee that the products candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives as well as those discussed or identified in the public filings with the SEC and the AMF made by sanofi-aventis, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in sanofi-aventis’ annual report on Form 20-F for the year ended December 31, 2008. Other than as required by applicable law, sanofi-aventis does not undertake any obligation to update or revise any forward-looking information or statements.

Media Contact: Marisol Peron, 908.981.6565, mobile: 908-672-9051, [email protected]

SOURCE sanofi-aventis


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