Th The GENETIC-AF Tri rial Jeff S. Healey, MD, 1 Jonathan P. - PowerPoint PPT Presentation

Im Impact of f Phar armacogenetic ic-guid ided Bu Bucin indolo lol l versus Metoprolo lol l Su Succin inate on th the Overall ll Bu Burden of f Clin Clinic ical l Events in in Pati tients with ith AF and Heart Fail ilure: Th The GENETIC-AF Tri rial Jeff S. Healey, MD, 1 Jonathan P. Piccini, MD, 2 William T. Abraham, MD, 3 Dirk J. Van Veldhuisen, MD, 4 Inder S. Anand, MD, PhD, 5 Michel White, MD, 6 Stephen B. Wilton, MD, 7 Michiel Rienstra, MD, PhD, 4 William H. Sauer, MD, 8 A. John Camm, MD, 9 Ian A. Carroll, PhD, 10 Christopher Dufton, PhD, 10 Michael R. Bristow, MD, 10,11 , and Stuart J. Connolly, MD, 1 on behalf of the GENETIC-AF Trial Investigators. 1 McMaster University; 2 Duke University Medical Center; 3 Ohio State University Medical Center; 4 University of Groningen; 5 US Department of Veterans Affairs; 6 Montreal Heart Institute; 7 University of Calgary; 8 Brigham and Women's Hospital and Harvard Medical; 9 St . George’s University of London; 10 ARCA biopharma, Inc.; 11 University of Colorado.

2 Bucindolol for the Treatment of AF in HF Patients Background • Bucindolol is a genetically-targeted  -blocker/mild vasodilator • Bucindolol has two unique pharmacologic properties • Sympatholysis and ADRB1 Arg389 inverse agonism 1,2 • BEST DNA substudy: 441 HF patents ADRB1 Arg389Arg genotype 3 • Time to first event of AF/AFL or ACM ( vs. placebo) • HR = 0.26 (95% CI: 0.12, 0.57); p < 0.001 • GENETIC-AF trial: 267 HF patients with ADRB1 Arg389Arg genotype 2 • Time to first event of AF/AFL or ACM ( vs. metoprolol succinate) • HR = 1.01 (95% CI: 0.71, 1.42); p = 0.961 1 O'Connor et al. PLOS ONE 2012; 7:e44324; 2 Piccini et al. JACC Heart Fail. 2019 Jul;7(7):586-598; 3 Aleong RG et al, JACC-HF 2013.

3 GENETIC-AF Precision Therapeutic Phenotyping (PTP) • Two variables strongly associated with an attenuation of bucindolol response • Interval of time from the initial diagnosis of HF and AF to randomization • Onset of AF relative to initial HF diagnosis • Large subgroup (N=196) identified with significant bucindolol 1EP response • PTP cohort: AF/HF onset < 12 years and AF onset not >2 years prior to HF 2 • Primary Endpoint: HR = 0.54 (95% CI: 0.33, 0.87); p = 0.011 • Current analysis examines cumulative clinical events for 24 weeks of follow-up • In GENETIC- AF population, PTP cohort, and PTP cohort with LVEF ≥ 40% 1 O'Connor et al. PLOS ONE 2012; 7:e44324; 2 Piccini et al. JACC Heart Fail. 2019 Jul;7(7):586-598.

4 GENETIC-AF Cumulative Events Methodology • Analyses includes all patients entering efficacy follow-up (N=259) • 8 patients (6 MET/2 BUC) withdrew prior to start of efficacy follow-up • ITT analysis for all events during 24 weeks of efficacy follow-up • On treatment analysis also reported • Prevalence rates (PR; events/pt) generated for a composite endpoint of: • AF interventions: ECV, catheter ablation, start of Class III AADs • CV adverse events: All AEs in MedDRA SOC of “Cardiac Disorders” • Deaths included as events in all analyses to account for competing risk (3 MET/0 BUC). • Comparisons between treatment groups expressed by PR Ratio (PRR = PR BUC /PR MET ) • Poisson regression test for significance

5 GENETIC-AF Baseline Characteristics All Patients PTP Cohort Bucindolol Metoprolol Bucindolol Metoprolol Parameter N = 134 N = 133 N = 98 N = 98 Age, years 65.8 ± 10.3 65.5 ± 10.0 65.6 ± 10.1 64.9 ± 9.7 Male/Female, % 83 / 17 81 / 19 80 / 20 81 / 19 Race: W / B / A / O, % 96 / 1 / 1 / 2 96 / 2 / 1 / 1 98 / 1 / 1 / 0 95 / 3 / 1 / 1 LVEF 0.36 ± 0.10 0.36 ± 0.10 0.37 ± 0.10 0.36 ± 0.09 NYHA: I / II / III, % 30 / 60 / 10 26 / 54 / 20 31 / 57 / 12 26 / 56 / 18 Ischemic / Non-Ischemic HF, % 31 / 69 33 / 67 34 / 66 31 / 69 Randomized in AF / Not in AF, % 49 / 51 52 / 48 48 / 52 48 / 52 Persistent / Paroxysmal AF, % 51 / 49 51 / 49 54 / 46 50 / 50 HF DxT Duration, days 1252 ± 2070 1054 ± 1733 810 ± 1071 749 ± 1060 AF DxT Duration, days 1431 ± 2271 1180 ± 2209 583 ± 831 495 ± 742 Systolic blood pressure, mm Hg 124.7 ± 14.9 121.8 ± 15.7 125.2 ± 15.2 122.6 ± 15.5 Diastolic blood pressure, mmHg 75.8 ± 11.0 74.8 ± 10.6 76.1 ± 10.7 74.6 ± 10.0 Heart Rate, bpm 76.5 ± 17.9 76.0 ± 17.7 75.8 ± 19.2 75.5 ± 17.8 Previous ECV / AF Ablation / Type III AAD, % 49 / 21 / 50 50 / 20 / 46 47 / 15 / 42 50 / 14 / 42 Device Type: ICM / PM / ICD, % 17 / 15 / 18 15 / 20 / 12 3 / 8 /19 8 / 7 / 10 Norepinephrine, pg/ml 682 ± 348 664 ± 359 681 ± 355 630 ± 268 NT-proBNP, pg/ml, median (IQR) 777 (355, 1326) 861 (420, 1607) 777 (329, 1309) 812 (436, 1463) W/B/A/O=White/Black/Asian/Other. HF DxT Duration=time from HF diagnosis to randomization. AF DxT Duration=time from AF diagnosis to randomization. ECV=electrical cardioversion. AAD=antiarrhythmic drug. ICM=insertable cardiac monitor. ICD=implanted cardiac defibrillator. PM=pacemaker. IQR=interquartile range. Note: mean ± standard deviations are presented unless otherwise specified.

6 GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up Composite of AF Interventions and CV Adverse Events GENETIC-AF PTP Cohort MET MET 30% Reduction 46% Reduction p = 0.008 p = 0.001 Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient) BUC BUC Total Incidence Rate Incidence Rate Ratio Total Incidence Rate Incidence Rate Ratio Group N Group N # Events (events/pt) (95% CI) # Events (events/pt) (95% CI) BUC 132 96 0.73 BUC 96 50 0.52 0.70 (0.54, 0.91) 0.54 (0.38, 0.76) p = 0.008 p = 0.001 MET 127 132 1.04 MET 94 90 0.96 PTP cohort: AF/HF onset < 12 years and AF onset not >2 years prior to HF onset. Per protocol analysis: GAF = 0.72 (95% CI: 0.54, 0.95), p = 0.021; PTP = 0.56 (95% CI: 0.38, 0.81), p = 0.002.

7 GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up Composite of AF Interventions and CV Adverse Events for LVEF ≥ 40% and ≤ 55% GENETIC-AF PTP Cohort MET 49% Reduction 55% Reduction MET p = 0.001 p = 0.005 Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient) BUC BUC Total Incidence Rate Incidence Rate Total Incidence Rate Incidence Rate Group N Group N # Events (events/pt) Ratio (95% CI) # Events (events/pt) Ratio (95% CI) BUC 63 35 0.56 BUC 50 20 0.40 0.51 (0.33, 0.77) 0.45 (0.25, 0.77) p = 0.001 p = 0.005 MET 60 65 1.08 MET 37 33 0.89 PTP cohort: AF/HF onset < 12 years and AF onset not >2 years prior to HF onset. Per protocol analysis: GAF = 0.51 (95% CI: 0.33, 0.77), p = 0.002; PTP = 0.46 (95% CI: 0.25, 0.82), p = 0.010.

8 GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up AF Interventions Only (ECV, Ablation, Class 3 AAD) GENETIC-AF PTP Cohort MET MET 33% Reduction 51% Reduction p = 0.009 p < 0.001 Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient) BUC BUC Total Incidence Rate Incidence Rate Ratio Total Incidence Rate Incidence Rate Ratio Group N Group N # Events (events/pt) (95% CI) # Events (events/pt) (95% CI) BUC 132 74 0.56 MET 94 72 0.77 0.67 (0.50, 0.90) 0.49 (0.32, 0.72) p = 0.009 p < 0.001 MET 127 106 0.83 BUC 96 36 0.37 PTP cohort: AF/HF onset < 12 years and AF onset not >2 years prior to HF onset. Per protocol analysis: GAF = 0.75 (95% CI: 0.55, 1.02), p = 0.070; PTP = 0.59 (95% CI: 0.38, 0.89), p = 0.014

9 GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up AF Interventions Only (ECV, Ablation, Class 3 AAD) for LVEF ≥ 40% and ≤ 55% GENETIC-AF PTP Cohort MET MET 48% Reduction 58% Reduction p = 0.005 p = 0.006 Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient) BUC BUC Total Incidence Rate Incidence Rate Ratio Total Incidence Rate Incidence Rate Ratio Group N Group N # Events (events/pt) (95% CI) # Events (events/pt) (95% CI) BUC 63 29 0.46 BUC 50 16 0.32 0.52 (0.33, 0.81) 0.42 (0.22, 0.77) p = 0.005 p = 0.006 MET 60 53 0.88 MET 37 28 0.76 PTP cohort: AF/HF onset < 12 years and AF onset not >2 years prior to HF onset. Per protocol analysis: GAF 0.54 (95% CI: 0.33, 0.85), p = 0.009; PTP = 0.46 (95% CI: 0.24, 0.87), p = 0.019.

10 GENETIC-AF: Cumulative Clinical Events during 24-week Efficacy Follow-up Summary and Conclusions • Bucindolol decreased AF interventions and CV adverse events compared to metoprolol succinate in a pharmacogenetically-defined HF population • Bucindolol decreased AF interventions (i.e., ECVs, ablations, and Class 3 AADs) compared to metoprolol succinate • Significant and numerically greater results were observed in the PTP cohort • Similar significant results observed for PTP cohort with LVEF ≥ 40% and ≤ 55%