Early clinical data with budiodarone (ARYx Therapeutics, Fremont, CA), a novel
antiarrhythmic medication that is a chemical analog of amiodarone, showed that
the drug significantly reduced atrial-fibrillation burden in a dose-dependent
manner and was safe and well tolerated at even the highest doses studied.

Presenting the results of the study here at the Heart Rhythm Society 2009
Scientific Sessions, lead investigator Dr Michael Ezekowitz (Lankenau Institute
for Medical Research, Wynnewood, PA) told heartwire that budiodarone appears "to
be a very user-friendly drug, at least as part of this initial evaluation, but
naturally we will need do perform a larger, more definitive phase 3 clinical
trial."

During the late-breaking clinical-trials session, Ezekowitz explained that
budiodarone shares similar mechanisms of action with amiodarone, in that it
works as calcium-, potassium-, beta-, and alpha-receptor blocker, as well as a
sodium-channel antagonist. However, it has a much more positive side-effect
profile because it has a short half-life, just seven hours, and is cleared by
the body in 48 hours. Moreover, it is metabolized by tissue esterases and has a
reduced dependence on CYPP450 for clearance, which is subject to considerable
variability in patients.

"Amiodarone, at least long term, is associated with high complication rates
involving the lungs, kidneys, liver, skin, and neurologic complications, and the
presumed mechanism is that it remains in the body for a very long time, often
greater than three or four months after the last oral administration," Ezekowitz
told heartwire . "So what budiodarone does is capitalize on the mechanism of
action of amiodarone--it's practically identical--but it's rapidly removed from
the body and has a rapid onset of action. In all likelihood, the side-effect
profile is going to be much less."

Data From the PASCAL Study

In this phase 2 study, known as the Paroxysmal Atrial Fibrillation Study with
Continuous Atrial Fibrillation Logging (PASCAL), researchers tested safety and
efficacy in 72 patients randomized to placebo or to 200-mg, 400-mg, or 600-mg
doses of budiodarone. They included patients with dual-chamber pacemakers to
detect and log atrial-fibrillation data and excluded patients with NYHA class 3
and 4 congestive heart failure.

After 12 weeks of treatment, budiodarone significantly reduced
atrial-fibrillation burden, doing so in a dose-dependent manner. From baseline,
there was a significant 54% and 75% reduction in disease burden with the 400-mg
and 600-mg doses, respectively. With the 200-mg dose, there was a nonsignificant
10% reduction in atrial-fibrillation burden.

In an analysis of patients treated with the 600-mg dose, the number and duration
of atrial-tachycardia/atrial-fibrillation episodes decreased by at least 50%
over the 12 weeks, while the time spent in normal sinus rhythm increased. In an
assessment of patient impressions, most were satisfied with the medication, and
nearly 50% reported "a lot of improvement or complete relief."

During his presentation, Ezekowitz noted there were observed side effects, but
none of these progressed and all were reversible. Creatinine elevations were
observed, similar to what was reported with amiodarone and dronedarone, although
there was no evidence of renal toxicity. Also, there were minor changes in
thyroid function, and two cases of elevated liver enzymes without an increase in
total bilirubin levels.

"I think that if the drug is shown to be efficacious in larger studies, without
major side effects, then the competitor will be dronedarone, which I think will
be approved," said Ezekowitz. "The only negative of that drug is in patients
with heart failure; otherwise it's a very safe drug. The problem with
dronedarone is that it doesn't appear to be as effective as amiodarone. The
advantage of budiodarone is that we're seeing a dose response. At the lowest
dose, it doesn't work. You can increase the dose, which you can't do with
dronedarone and which you can't really do with amiodarone, because the side
effects are really dose related."

This past March, a Food and Drug Administration advisory panel voted 10 to 3 to
recommend approval of dronedarone for the treatment of atrial fibrillation. The
yes vote, however, was tempered with cautions against using the drug in patients
with severe systolic heart failure, based in large part on the ANDROMEDA trial.

Ezekowitz reported consulting fees and grant support from Boehringer Ingelheim,
ARYx Therapeutics, Portola, Wyeth, Sanofi-Aventis, Bristol Myers-Squibb,
AstraZeneca, Daiichi Sankyo, and Medtronic.