Norepinephrine responses to bucindolol influenced by alpha-2C adrenergic receptor genotype

ARCA biopharma, Inc. (Nasdaq: ABIO), a biopharmaceutical company developing genetically targeted therapies for heart failure and other cardiovascular disease, today announced that the paper “An alpha-2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine Lowering Effects and Therapeutic Response of the Beta Blocker Bucindolol in Chronic Heart Failure” was published in the January 2010 edition of the peer-reviewed journal Circulation: Heart Failure (http://circheartfailure.ahajournals.org). The paper concludes that in the Beta-Blocker Evaluation of Survival Trial (BEST) adrenergic polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by the alpha-2C adrenergic receptor genotype.

“Furthermore, we believe alpha-2C-receptor genetic biomarkers may be combined with the already reported beta1 receptor position 389 genetic biomarkers to define which patients are most likely to respond to this pharmacologically unique beta-blocking agent.”

“These data indicate that in heart failure patients in the study, the norepinephrine lowering effects of bucindolol are under genetic control, and that the degree of lowering may be kept in a therapeutic range by baseline screening using alpha-2C-adrenergic receptor genetic biomarkers,” said Michael R. Bristow, President and Chief Executive Officer of ARCA. “Furthermore, we believe alpha-2C-receptor genetic biomarkers may be combined with the already reported beta1 receptor position 389 genetic biomarkers to define which patients are most likely to respond to this pharmacologically unique beta-blocking agent."

Adrenergic activation, as most commonly measured by systemic venous norepinephrine levels, is an important determinant of outcomes in chronic heart failure. Adrenergic activity is generally thought to be regulated in part by cardiac prejunctional alpha-2C-adrenergic receptors, which exhibit genetic variation in humans. Bucindolol is a novel beta-adrenergic receptor blocking agent that lowers systemic norepinephrine in heart failure patients and thus is also a sympatholytic agent. This BEST substudy investigated whether alpha-2C-adrenergic receptor polymorphisms affected sympatholytic effects of bucindolol in patients with heart failure. In this study, patients who were homozygous for, or carried only, the wild type ("Ins") alpha-2C- receptor gene (87% of the total) had mild reductions in norepinephrine, which were associated with clinical therapeutic responses that were enhanced compared to the entire cohort investigated in the substudy. In contrast, the 13% of patients who carried a deletion ("Del") polymorphism in the alpha-2C-receptor gene had much greater degrees of norepinephrine lowering, which compromised clinical efficacy.