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

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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.

1McMaster University; 2Duke University Medical Center; 3Ohio State University Medical Center; 4University of Groningen; 5US Department of Veterans Affairs; 6Montreal Heart

Institute; 7University of Calgary; 8Brigham and Women's Hospital and Harvard Medical; 9St. George’s University of London; 10ARCA biopharma, Inc.; 11University of Colorado.

• Bucindolol is a genetically-targeted -blocker/mild vasodilator
• Bucindolol has two unique pharmacologic properties
• Sympatholysis and ADRB1 Arg389 inverse agonism1,2
• BEST DNA substudy: 441 HF patents ADRB1 Arg389Arg genotype3
• 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 genotype2
• Time to first event of AF/AFL or ACM ( vs. metoprolol succinate)
• HR = 1.01 (95% CI: 0.71, 1.42); p = 0.961

Bucindolol for the Treatment of AF in HF Patients Background

1O'Connor et al. PLOS ONE 2012; 7:e44324; 2Piccini et al. JACC Heart Fail. 2019 Jul;7(7):586-598; 3Aleong RG et al, JACC-HF 2013.

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• 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 HF2
• 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%

GENETIC-AF Precision Therapeutic Phenotyping (PTP)

1O'Connor et al. PLOS ONE 2012; 7:e44324; 2Piccini et al. JACC Heart Fail. 2019 Jul;7(7):586-598.

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• 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 = PRBUC/PRMET)
• Poisson regression test for significance

GENETIC-AF Cumulative Events Methodology

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All Patients PTP Cohort

Parameter Bucindolol N = 134 Metoprolol N = 133 Bucindolol N = 98 Metoprolol 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)

GENETIC-AF Baseline Characteristics

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.

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GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up Composite of AF Interventions and CV Adverse Events

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.

Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient)

GENETIC-AF PTP Cohort MET BUC MET BUC 30% Reduction p = 0.008 46% Reduction p = 0.001

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Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 96 50 0.52 0.54 (0.38, 0.76) p = 0.001 MET 94 90 0.96 Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 132 96 0.73 0.70 (0.54, 0.91) p = 0.008 MET 127 132 1.04

GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up Composite of AF Interventions and CV Adverse Events for LVEF ≥ 40% and ≤ 55%

Incidence Rate (Cumulative Events/Patient)

MET BUC 49% Reduction p = 0.001

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Incidence Rate (Cumulative Events/Patient)

MET BUC GENETIC-AF PTP Cohort 55% Reduction p = 0.005

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 63 35 0.56 0.51 (0.33, 0.77) p = 0.001 MET 60 65 1.08

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.

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 50 20 0.40 0.45 (0.25, 0.77) p = 0.005 MET 37 33 0.89

GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up AF Interventions Only (ECV, Ablation, Class 3 AAD)

Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Events/Patient)

MET BUC MET BUC

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GENETIC-AF PTP Cohort

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) MET 94 72 0.77 0.49 (0.32, 0.72) p < 0.001 BUC 96 36 0.37

33% Reduction p = 0.009 51% Reduction p < 0.001

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 132 74 0.56 0.67 (0.50, 0.90) p = 0.009 MET 127 106 0.83

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

Incidence Rate (Cumulative Events/Patient)

MET BUC

GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up AF Interventions Only (ECV, Ablation, Class 3 AAD) for LVEF ≥ 40% and ≤ 55%

Incidence Rate (Cumulative Events/Patient)

MET BUC

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GENETIC-AF PTP Cohort

Incidence Rate (Cumulative Events/Patient)

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 50 16 0.32 0.42 (0.22, 0.77) p = 0.006 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.

Group N Total # Events Incidence Rate (events/pt) Incidence Rate Ratio (95% CI) BUC 63 29 0.46 0.52 (0.33, 0.81) p = 0.005 MET 60 53 0.88

48% Reduction p = 0.005 58% Reduction p = 0.006

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%

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