Gencaro™ [bucindolol hydrochloride]

ARCA is currently developing Gencaro™ (tradename pending FDA approval) (bucindolol hydrochloride) for the prevention of atrial fibrillation and the treatment of chronic heart failure. Gencaro™ is a pharmacologically unique beta-blocker and mild vasodilator. Gencaro™ is considered part of the beta-blocker class because of its property of blocking beta-1 as well as beta-2 receptors in the heart, preventing these receptors from binding with other molecules that would otherwise activate the receptor. Because of its mild vasodilator effects, the Company believes Gencaro™ is well-tolerated in patients with advanced HF. ARCA has identified common genetic variations, or genetic markers, which it believes predict patient response to Gencaro™. These are 1) a polymorphism (ADRB1 Arg389Gly) in the primary target of the drug, the cardiac myocyte beta-1 adrenergic receptor (1-AR, and 2) a polymorphism (ADRA2C Ins322-325Del) that affects response in a secondary target of Gencaro, the release of norepinephrine from adrenergic (sympathetic) nerve terminals. For ADRB1 Arg389Gly the Arg (arginine) variant has much higher functional activity (Liggett SB et al, PNAS 2006) and affinity for norepinephrine (O’Connor CM et al, PLoS One, 2012); compared to the Gly (glycine) Gencaro produces selectively greater responses for lowering of heart failure clinical event rates (Liggett SB et al, PNAS 2006, O’Connor et al PLoS one, 2012), arrhythmic events including prevention of atrial fibrillation (Aleong RG et al, JACC-Heart Fail 2013) and serious ventricular arrhythmias (Aleong RG et al, Circ Arrhythm Electrophysiol 2013). The mechanistic basis for Gencaro’s selectively beneficial effects in patients who are homozygous for the ADRB1 389Arg (and can therefore only express 389 Arg 1-AR receptors) appears to be its ability to facilitate inactivation of constitutively active 389 Arg 1-ARs through an inverse agonist effect (Liggett SB al, PNAS 2006) and norepinephrine lowering (O’Connor CM et al, PLoS One 2012). For the ADRA2C Ins322-325Del polymorphism, the DEL variant predisposes heart failure with reduced LV ejection fraction (HFrEF) patients to a greater degree of norepinephrine lowering from GencaroTM (Bristow MR et al, Circ Heart Fail 2011), which can obviate favorable therapeutic effects of blocking 1-ARs (Bristow MR et al, Circulation, 2004). However, in patients who express only the 389 Arg version of the 1-AR (ADRB1 389Arg homozygous genotype), enhanced norepinephrine lowering in patients with ADRA2C 322-325Del genotypes (heterozygotes or homozygotes) is not accompanied by loss of GencaroTM effectiveness (O’Connor CM et al, PLoS One 2012. These interactive features of the two AR polymorphisms mean that if a patient is homozygous for ADRB1 389Arg the ADRA2C Ins322-325Del is irrelevant in terms of prediction of effectiveness. For this reason clinical trials with GencaroTM are focused on treating patients who are ADRB1 389Arg homozygotes, where heart event rates are reduced 30-50% (Liggett et al, PNAS 2006; O’Connor et al PLoS One 2012), and arrhythmia endpoints are lowered by approximately 75% (Aleong et al JACC Heart Fail 2013; Aleong et al, Circ Arrhythm Electrophysiol 2013).

Target and Drug Discovery

ARCA’s approach to identifying and characterizing functionally important genetic variation that may interact selectively with a modifying drug as typified by GencaroTM, is to 1) analyze or in some cases de novo sequence the various regions of drug targets of interest; 2) identify functionally important genetic variation through the use of human tissue or cell screens; 3) screen variants for selective drug action, and 4) license-in or synthesize/screen new chemical entities that favorably interact with a variant that has a gene frequency consistent with commercialization (typically >5%). Using this approach ARCA has identified and has IP for multiple drug targets and drugs, in addition to GencaroTM.


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