Development of post-dronedarone agents slow, but progress being made

16th Annual Boston Atrial Fibrillation Symposium

Following dronedarone has proved to be difficult for new anti-arrhythmic agents and their respective manufacturers. Despite this, research in the field has continued to explore the potential of other drugs in reducing the recurrence of atrial fibrillation.

Peter Kowey, MD, professor of medicine and pharmacology at Jefferson Medical College, Philadelphia, addressed this topic in his presentation at the Boston Atrial Fibrillation Symposium, providing an update on the progress of several newer agents.

Celivarone

The first of the new anti-arrhythmic agents that Kowey highlighted was celivarone (Sanofi-Aventis), the “daughter” of dronedarone (Multaq, Sanofi-Aventis). “This is a drug that has a very similar, although not identical, ion channel profile [to dronedarone],” Kowey, a Cardiology Today Editorial Board member, said in his presentation. “But it is a drug that can be used once a day rather than twice a day, and it’s been studied for both atrial as well as ventricular indication.”

In the ICARIOS trial, which featured patients with implantable cardioverter defibrillators, two doses of celivarone (100 mg and 300 mg) lowered the primary endpoint of the mean number of ICD therapies compared with placebo, although that extent did not attain statistical significance because of a small sample size.

The MAIA trial tested several doses of celivarone, as well as amiodarone and placebo, for the maintenance of sinus rhythm in patients with AF and found that 50-mg celivarone led to the lowest recurrence of AF and atrial flutter (RR=28%; P=.055), a reverse dose response similar to that seen with dronedarone. None of the doses proved effective enough to take forward in a larger AF trial.

Currently, Kowey and colleagues are conducting a trial that will combine elements of both studies, comparing the efficacy and safety of celivarone at 50 mg, 100 mg and 300 mg once-daily with an amiodarone calibrator arm for the prevention of ICD intervention or death. The trial, called ALPHEE, is scheduled for completion in July.

Other candidate therapies

Kowey discussed additional anti-arrhythmic agents include budiodarone (Aryx), a structural analogue to amiodarone with similar electrophysiological effects, and vernakalant (Cardiome Pharma), an amino-cyclohexyl ether.

“[Vernakalant] is a drug that’s further along in clinical development. It has a unique ion channel blocking profile, affecting not just potassium but also some sodium currents that are expressed in the atrium, with a fairly good degree of specificity,” he said.

The AVRO trial, in fact, indicated superior results for vernakalant in achieving cardioversion from AF to sinus rhythm when compared with amiodarone (P<.0001).

Kowey said there are “upstream therapy” candidates for use before a patient develops disease. “The one that I think most of us have been most enamored with is the idea of renin-angiotensin-aldosterone system (RAAS) modulation … because there appears to be a signal that patients who receive RAAS modulators may have a lower incidence of incident AF than patients who receive a placebo,” Kowey said.

However, two of the upstream therapies he presented data for, angiotensin II receptor blockers from the GISSI-AF trial, and fish oil from the OM-8 study, showed that neither reduced the recurrence of AF in a population of patients who had prior AF.

Challenges should not stop progress

“We have some preliminary data on a number of new concepts, and that’s always hopeful. But we have not seen proof of safety and efficacy from any large phase 3 trials after dronedarone,” Kowey said.

As a result, many pharmaceutical companies have made public comments that they are not interested in continuing the exploration for new chemical entities for this indication.

“That’s a bit short-sighted,” Kowey said. “Although our non-pharmacologic approach has improved by the year, many of our patients do need better drug treatment, and hopefully, we’ll see more movement on this front as time goes by.” – by Brian Ellis

For more information:

• Kowey P. Presented at: 16th Annual Boston Atrial Fibrillation Symposium; Jan. 13-15, 2011; Boston.

Disclosure: Dr. Kowey has served as a consultant, speaker and grantee for several companies of interest, including Aryx, Cardiome, Astellas, Merck and Sanofi-Aventis.

Follow CardiologyToday.com on Twitter.