ARCA biopharma, Inc. (Nasdaq: ABIO), a biopharmaceutical company developing genetically-targeted therapies for atrial fibrillation and other cardiovascular diseases, today announced results of analyses of atrial fibrillation (AF) data from the BEST trial, a previously conducted Phase 3 heart failure (HF) trial involving Gencaro (bucindolol hydrochloride), in 2,708 advanced heart failure patients. Researchers believe increasing plasma norepinephrine (NE) levels as a measure of adrenergic activity herald worsening of HF in patients with reduced left ventricular ejection fractions (HFREF). In this new analysis, researchers, including Dr. Michael R. Bristow, ARCA’s CEO, found that patients who developed new onset AF during the BEST trial had higher baseline NE levels than patients who did not develop AF. NE levels at three months decreased in the Gencaro subgroups compared to placebo subgroups. Researchers believe this sympatholytic effect likely contributed to an associated 41% reduction in the risk of developing AF for the 1,202 Gencaro patient cohort without AF at baseline. As previously reported at the American Heart Association’s Scientific Sessions 2011, Gencaro reduced the risk of developing AF by 74% in the genetic subgroup that was homozygous for the 389 arginine version of the beta-1 adrenergic receptor, which has high affinity for norepinephrine. Researchers found that Gencaro's norepinephrine lowering properties appear to contribute to its effects in all HFREF patients, but in particular those who have only beta-1 389 arginine receptors.
The data were selected for moderated poster presentation at the American College of Cardiology 61 st Annual Scientific Sessions & Expo, being held March 24-27, 2012 in Chicago, Illinois. Dr. Ryan Aleong, Assistant Professor of Medicine, Cardiology, Director of Implanted Cardiac Device Clinic, University of Colorado Hospital, and Interim Director of Arrhythmia Services at Denver Health Medical Center, presented “Bucindolol's Sympatholytic Properties Contribute to Reduction in the Risk of Developing New Onset Atrial Fibrillation in Patients with Advanced Heart Failure” during the session “Arrhythmias: AF/SVT: Continuing Role of Pharmacologic Therapy for Atrial Arrhythmias,” Monday, March 26, 2012, 11:00am – 12:00pm Central.
Researchers assessed the role of NE in contributing to new onset AF and that of Gencaro in preventing new onset atrial fibrillation (NAF) in patients with advanced HF in the BEST trial. Baseline NE levels measured by high performance liquid chromatography (HPLC)/electrochemical detection (ECD) were available in 1,868 of the 2,392 enrolled patients who did not have AF at baseline. New onset AF, which was not a pre-specified endpoint in the BEST trial, was assessed from adverse event (AE)/serious adverse event (SAE) case report forms as well as routinely measured electrocardiograms (ECGs) in patients not in AF on study entry. In the 2,392 patient cohort without AF at baseline, there were 115/1190 (9.7%) new onset AF episodes in patients in the placebo group, and 75/1202 (6.2%) in the Gencaro group (hazard ratio +/- (95% confidence intervals) = 0.59 (0.44, 0.79), p =0.0004). Baseline NE was higher among patients with new onset AF compared to patients who did not develop AF (NAF 530+/-281 vs. no AF 498+/-328 pg/ml, p = 0.015). NE at three months decreased in the Gencaro subgroups as compared to placebo subgroups. NE reduction by bucindolol was similar in patients with beta-1 389 arginine/arginine and glycine carrier genotypes, suggesting that the high binding affinity of the 389 arginine receptor for NE contributes to differential pharmacogenetic efficacy, not differences in NE lowering between genotypes.