EX-99.2 3 abio-ex992_30.htm EX-99.2 abio-ex992_30.pptx.htm

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GENETIC-AF Phase II Trial of Pharmacogenetic Guided Beta-Blocker Therapy with Bucindolol vs. Metoprolol for the Prevention of Atrial Fibrillation/Flutter in Heart Failure William T. Abraham, MD Professor of Medicine, Physiology and Cell Biology and Director, Division of Cardiovascular Medicine at the Ohio State University Exhibit 99.2

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β1 Adrenergic Receptor Polymorphism-Dependent Differences Mason DA et al. JBC 1999; Taylor et al. Cong Heart Fail 2004; Liggett et al. PNAS 2006; Walsh et al. J Card Fail 2008; O'Connor et al. PLOS ONE, 2012. b1389Arg >>> b1389Gly Binding affinity for norepinephrine Signal transduction capacity Constitutively active receptors C ® G nt 1165 Arg ® Gly 389 Frequency = EA 0.52, AA 0.32 Bucindolol has two unique properties that are specific for 389Arg b1-ARs: − Sympatholysis Inverse Agonism

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Interaction p = 0.008 Kaplan-Meier curves for prevention of atrial fibrillation in BEST: DNA substudy (Aleong et al, JACC Heart Fail; 1:338-44, 2013) BEST DNA Substudy: Prevention of Atrial Fibrillation by Bucindolol b1389 Arg/Arg (n = 441; 36 events) HzR = 0.26 (0.12 – 0.57) P-value = 0.0003 BUC PLB HzR = 1.01 (0.56 – 1.84) P-value = 0.97 b1389 Gly Carriers (n = 484; 44 events) BUC PLB Aleong et al, JACC Heart Fail; 1:338-44, 2013

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W8 W4 S W12 W0 W20 24-Week Follow-Up Period Start/ECV R Drug Lead-in Period Treatment Extension Period Clinic Visit every 12 weeks EOS W16 W24 Stop/1EP Bucindolol Metoprolol W2 8-week Screening Period Medtronic device (if needed) inserted any time between Randomization and Week 0 Genotype GENETIC-AF Study Design Phase 2B ® 3 Seamless Design Phase 2 interim analysis (230 pts) Bayesian predicted probability of success (PPoS) PPoS < 0.10 (Futility, stop study) 0.10 ≤ PPoS < 0.40 (Complete Phase 2) PPoS ≥ 0.40 (Seamless transition to Phase 3) Rand

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Key Eligibility Criteria History of HF with reduced left ventricle ejection fraction (HFrEF + HFmrEF) LVEF < 0.50 within 12 months of the Screening Visit Excluded: NYHA class IV Excluded: Significant fluid overload at Randomization Symptomatic paroxysmal or persistent AF episode ≤ 180 days of Screening Visit Excluded: Permanent AF > 1 year Possess the β1389Arg/Arg (ADRB1 Arg389Arg) genotype Receiving appropriate anticoagulation therapy prior to randomization for stroke Clinically appropriate for ECV if AF/AFL is present at the Week 0 Visit Excluded: More than 2 ECVs within 6 months of Randomization Excluded: Most recent ECV failed to produce sinus rhythm Systolic BP > 90 mmHg and < 150 mmHg at Randomization Heart rate ≥ 60 bpm (if BB naïve) and < 180 bpm (all) at Randomization

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Baseline Characteristics (± SD; *p <0.05 vs. MET) Parameter MET n = 133 BUC N = 134 Age 65.5 ± 10.0 65.8 ± 10.3 Gender M/F (%) 81 / 19 83 / 17 LVEF 0.36 ± 0.10 0.36 ± 0.10 NYHA I / II / III (%) 26 / 54 /20 30 / 60 / 10 Hx Ischemic / Non-Ischemic HF (%) 33 / 67 31 / 69 Randomized in AF / Not in AF (%) 52 / 48 49 / 51 Hx Persistent/Paroxysmal AF (%) 51 / 49 51 / 49 AF Dx to Randomization, days 1180 ± 2209 1431 ± 2271 HF Dx to randomization, days 1054 ± 1733 1252 ± 2070 sBP (mm Hg) 122 ± 15.7 125 ± 14.9 Heart Rate, bpm 76.0 ± 17.7 76.5 ± 17.9 Previous ECV / AF ablation / Class III AADs (%) 50 / 20 / 46 49 / 21 / 50 Device Type: ILR / CRT / ICD / PM (%) 15 / 10 / 12 / 10 17 / 6 / 18 / 9 HF Rx: b-bl / ACEI or ARB / Dig / Diuretic / MRA / Scbtl-Val (%) 92 / 78 / 17 / 61 / 32 / 5 94 / 75 / 15 / 57 / 32/ 4 NT-proBNP (pg/ml) 1343 ± 1846 1159 ± 1306 Norepinephrine (NE) (pg/ml) 664 ± 359 682 ± 348 Change in NE at Week 4, median (Q1, Q3) -10 (198, 121) -101 (-241, 43)*

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Primary Endpoint: Time to First AF/AFL/ACM Event Unadjusted HR: Entire Cohort = 0.96 (95% CI: 0.69, 1.33); U.S. Cohort = 0.77 (95% CI: 0.48, 1.22) BUC MET Entire Cohort USA

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Time to First AF/AFL/ACM Event: AF Burden Substudy AF Event = AFB ≥ 6 hours/day Probability of No AF/AFL/ACM Entire Cohort USA Adjusted HR: Entire Cohort = 0.74 (95% CI: 0.38, 1.45); U.S. Cohort = 0.50 (95% CI: 0.17, 1.42)

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AEs, Hospitalization, Stroke or Death Endpoint Metoprolol (N=133) Bucindolol (N=134) AEs leading to permanent study drug discontinuation 8.3% 8.2% AEs leading to study withdrawal (excluding death) 1.5% 1.5% AEs: Bradycardia 12.0% 3.7% AEs: Stroke (99% on OACs) 0.0% 0.0% SAEs: Any cardiovascular event 9.8% 9.0% All-cause hospitalization 15.0% 20.1% Cardiovascular hospitalization 10.5% 12.7% Heart failure hospitalization 7.5% 6.7% All-cause mortality 2.3% 2.3% Cardiovascular mortality 1.5% 0.7% Heart failure mortality 0.7% 0.0%

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USA (N=127) Canada (N=59) Hungary (N=33) Time to First AF/AFL/ACM Event by Region BUC MET BUC MET BUC MET BUC MET NED/POL/SRB (N=48) Probability of No AF/AFL/ACM Probability of No AF/AFL/ACM Probability of No AF/AFL/ACM Probability of No AF/AFL/ACM USA/NED/POL/SRB (N=175) Canada/Hungary (N=92)

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Time to First AF/AFL/ACM Event LVEF < 0.39 (median) or LVEF 0.39-0.49 with HF Dx to Rand - AF Dx to Rand (DTRI) >-30 days Unadjusted HR: Entire Cohort = 0.84 (95% CI: 0.58, 1.22) Country Included (%) All 77% USA 85% Canada 78% Hungary 39% Poland 78% Serbia 81% Netherlands 75%

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GENETIC-AF Conclusions Pharmacogenetic guided bucindolol did not reduce AF/AFL/ACM recurrence compared to the active comparator metoprolol in the overall population Trends for bucindolol benefit were observed in several large subpopulations Bucindolol appears to have a similar safety profile compared to metoprolol These Phase 2 results merit further investigation in a redefined population HFmrEF (LVEF ≥0.40 and <0.50) if DTRI > -30 days HFrEF (LVEF < 0.40) Symptomatic paroxysmal/persistent AF ≤ 180 days of randomization β1389Arg/Arg genotype