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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.

References

355. O’Connor CM, Fiuzat M, Caron MF, Davis G, Karl Swedberg K, Peter E. Carson PE, Koch B, Bristow MR. Influence of global region on outcomes in large heart failure β-Blocker trials. J Am Coll Cardiol 58:915-922, 2011.
356. Patterson SD, Cohen N, Karnoub M, Truter SL, Emison E, Khambata-Ford S, Spear B, Okony IE, Sproule R, Barnes D, Bhathena A, Bristow MR, Russell C, Wang D, Warner A, Westelinck A, Brian W, Snapir A, Franc MA, Wong P, Shaw PM. Prospective retrospective biomarker analysis for regulatory consideration: A White Paper from the Industry Pharmacogenomics Working Group (I-PWG). Pharmacogenomics 12:939-939, 2011.
357. Fiuzat M, Bristow MR. Pharmacogenetics in heart failure trials. Heart Fail Clin 7:553-559, 2011.
358. Bristow MR. Treatment of chronic heart failure with -adrenergic receptor antagonists: A convergence of receptor pharmacology and clinical cardiology. Translational Success Stories, Circ Res 109:1176-1194, 2011.
361. Bristow MR. Pharmacogenetic targeting of drugs for heart failure. Pharmacology and Therapeutics, 134:107-115, 2012.
362. O’Connor CM, Fiuzat M, Carson PE, Anand I, Plehn JF, Gottlieb SS, Silver MA, Lindenfeld J, Miller AB, White M, Walsh R, Nelson PB, Medway AM, Davis G, Robertson AD, Port JD, Carr J, Murphy GA, Lazzeroni LC, Abraham WT, Liggett SB, Bristow MR. Combinatorial pharmacogenetic interactions of bucindolol and 1, 2C adrenergic receptor polymorphisms. PLOS ONE 7:e44324 epub Oct 10, 2012.
366. Musunuru D, Roden D, Boineau R, Bristow MR, McCaffrey TA, Newton-Cheh C, Paltoo DN, Rosenberg Y, Wohlgemuth JG, Zineh I, Hasan AK. Cardiovascular pharmacogenomics: Current status and future directions  Report of a National Heart, Lung, and Blood Institute Working Group. J Am Heart Assoc Apr;1(2):e000554. doi: 10.1161/JAHA.111.000554. Epub 2012 Apr 24.
367. Kao DP, Davis G, MS, Aleong R, O’Connor CM, Mona Fiuzat M, Carson PE, Anand IS, Plehn JF, Gottlieb SS, Silver MA, Lindenfeld J, Miller AB, White M, Murphy GA, Sauer W, MD, Bristow MR. Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation. Eur J Heart Fail 15:324-33, 2013.
368. Kao DP, Wagner BD, Robertson AD, Bristow MR, Lowes BD. A Personalized BEST: Characterization of latent clinical classes of nonischemic heart failure that predict outcomes and response to bucindolol. PLOS ONE 7: e48184, 2012.
369. Aleong RG, Sauer WH, Robertson AD, Liggett SB, Bristow MR. Adrenergic receptor polymorphisms and prevention of ventricular arrhythmias with bucindolol in patients with chronic heart failure. Circ Arrhythm Electrophysiol 6:137-143, 2013.
370. Aleong RG, Sauer WH, Davis G, Murphy GA, PhD, Port JD, PhD, Abraham WT, Liggett SB, Bristow MR. Prevention of atrial fibrillation by bucindolol is dependent on the beta-1 389 Arg/Gly adrenergic receptor polymorphism. JACC Heart Fail 1(4):338-344, 2013.
371. Fiuzat M, O’Connor CM, Guyffier F, Mascette AM, Geller NL, Mebazaa A, Voors AA, Adams KF, Pina IL, Neyses L, Muntendam P, Felker GM, Pitt B, Zannad F, Bristow MR. Biomarker-guided therapies in heart failure: A forum for unified strategies. J Cardiac Fail 19:592-599, 2013.
374. Aleong RG, Sauer WH, MD, Davis G, Bristow MR. New onset atrial fibrillation predicts heart failure progression. Am J Med 127(10):963-71, 2014.
376. Taylor MR, Sun AY, Davis G, Fiuzat M, Liggett SB, Bristow MR. Race, genetic variation, and therapeutic response disparities in heart failure. JACC Heart Fail 2(6):561-572, 2014.
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