Gilead announces results from phase 2 study showing reduction in AF burden with the investigational combination of ranolazine and low-dose dronedarone


Gilead Sciences has announced results from HARMONY, a randomized, double-blind, placebo-controlled phase 2 study evaluating the effect of ranolazine and low-dose dronedarone, each given alone and in combination, on atrial fibrillation burden (AFB) in patients with paroxysmal atrial fibrillation (AF).

In HARMONY, the combination of ranolazine and low-dose dronedarone provided greater reductions in AFB from baseline than either therapy used alone. Detailed results from the study were presented during a late-breaking clinical trials session at the annual meeting of the Heart Rhythm Society in San Francisco, USA.

Ranolazine is approved in the United States under the tradename Ranexa for the treatment of chronic angina at marketed doses of 500mg and 1,000mg twice daily. Ranexa with or without dronedarone is not approved for the treatment of AF.

In the study, patients in the ranolazine 750mg / dronedarone 150mg (RD150) and ranolazine 750mg / dronedarone 225mg (RD225) arms experienced respective reductions of 45% and 59% in AFB from baseline over 12 weeks (p=0.072 and p=0.008, respectively, versus placebo). Among patients receiving RD225, 45% achieved AFB reductions from baseline of ≥70% over 12 weeks. Neither ranolazine 750mg (p=0.49) nor dronedarone 225mg (p=0.78) alone caused statistically significant reductions in AFB from baseline compared to placebo. These results are consistent with pre-clinical findings of a synergistic effect when these therapies are used in combination.

“There currently are a limited number of safe and effective anti-arrhythmic therapies for AF patients, underscoring the need to evaluate new treatment strategies,” says Peter R Kowey, William Wikoff Smith chair in Cardiovascular Research, Lankenau Medical Center and of Medicine and Clinical Pharmacology, Jefferson Medical College, Thomas Jefferson University. “HARMONY suggests that a new therapeutic approach of combining ranolazine and low-dose dronedarone is more effective than either therapy alone in lowering AF burden. Pending larger phase 3 evaluation, a combination of ranolazine and low-dose dronedarone has the potential to help address a significant and growing unmet need for additional treatment options for people living with this serious disease.”

In HARMONY, 134 patients were randomised to one of five treatment arms: placebo (n=26); ranolazine 750mg tablet twice daily (n=26); dronedarone 225mg capsule twice daily (n=26); RD150 twice daily (n=26); or RD225 twice daily (n=27).

There was no clinically significant difference between active treatment groups in the overall incidence of adverse events or adverse events leading to discontinuations. Among the most frequent adverse events leading to discontinuation within each treatment group were: atrial fibrillation (placebo, two patients), vertigo and dizziness (ranolazine 750mg, two patients each), dyspnea and pruritus (dronedarone 225mg, two patients each), hypotension (RD225, two patients) and no adverse events leading to discontinuation were reported for more than one patient in the RD150 group (e.g. dizziness and constipation).

The primary endpoint was change in AFB over 12 weeks. AFB was defined as the total time a patient was in atrial tachycardia/atrial fibrillation expressed as percentage of total recording time continuously from 0 to 12 weeks.