Bucindolol is Associated with a Lower Incidence of Dose Limiting - PowerPoint PPT Presentation

Bucindolol is Associated with a Lower Incidence of Dose Limiting Bradycardia in Heart Failure Patients with Atrial Fibrillation: The GENETIC-AF Trial Abraham WT, Bristow MR, Piccini JP, Healey JS, van Veldhuisen DJ, Anand IS, White M, Wilton SB, Rienstra M, Sauer WH, Camm AJ, Carroll IA, Dufton C, Connolly, SJ

Disclosures ● Bristow, Dufton and Carroll are employees of ARCA biopharma, sponsor of bucindolol ● All other authors are members of the GENETIC-AF Steering Committee or are ARCA consultants

Background (1), Heart Rate in HFrEF and AF/HFrEF ● Heart rate is a major determinant of outcomes in heart failure with reduced LV ejection fraction (HFrEF) − In SR lowering HR to <70 bpm is associated with improved clinical outcomes (e.g. SHIFT Trial, Ivabradine vs. placebo) − In AF HR/VRR is more complicated; HRs <70 bpm may be associated with worse outcomes in patients treated with beta-blocking agents, while VRR >100 bpm may be associated with tachycardia cardiomyopathy ● Patients in/out of AF are more prone to bradycardia because of associated sinus node or conduction system disease − Tachy -brady syndrome − Nocturnal pauses − Higher prevalence of pacemaker implantation − Drugs used to treat AF (rate & rhythm control) often exacerbate sinus node dysfunction and/or affect AV nodal function

Background (2), Beta-blockers and AF/HF ● Beta-blockers are GDMT indicated for HFrEF, in AF/HF are used off label for: − Modest AF prevention effects − Rate control − Most commonly used beta -blocker in AF/HF is metoprolol ● Beta-blockers are pharmacologically diverse beyond class effect of beta 1 -AR blockade Metoprolol succinate Bucindolol HCl ● Sustained release formulation of metoprolol; q.d. dosing ● Immediate release, b.i.d. dosing ● Selective b 1 -AR antagonist (Classed as 2 nd generation) ● High affinity b 1 / b 2 -AR antagonist, mild b 3 -AR agonist ● Mild vasodilation (weak a 1A -AR blockade), no ISA ● No vasodilation, no ISA ● No pharmacogenetic differentiation for ADRB1 389Arg vs. ● Marked pharmacogenetic differentiation for ADRB1 389Arg vs. Gly (Classed as 4 th generation (pharmacogenetic) compound) Gly

GENETIC-AF Trial: Seamless Ph 2b/Phase 3 Design Bucindolol vs. Toprol-XL, Prevention of Recurrent Atrial Fibrillation in HFREF Patients with the β 1 389 Arg/Arg Genotype post Electrical Cardioversion (ECV) or with recent (≤ 180d) AF History Hx HF, LVEF <0.50 last 12 mos, Hx AF Sx (HF or Arrhy) last 180d; At randomization NYHA I-III, No contra-indications to b -blockers; b 1 389 Arg/Arg ( ADRB1 Arg389Arg) genotype 94% were on b -blockers, 66% on metoprolol or bisoprolol Interim analysis after  200 pts  180 d Sx* Sample Size Estimates randomized, ≥150 evaluable; AF, now SR; Bayesian predictive probability Power (%) or current Effect (Ph 2 1EP) Finish as Ph2 n persistent / a = a = size paroxysmal 0.05 0.01 n = n = Sx* AF 71 134 133 200 25% – (1-T) Time 0: ECV @ 3 wks 98 90 Bucindolol Toprol-XL (spontaneous conversion 620 25% (2-T) (2-T) to SR counted as if ECV, Event rate M group 60%, ITT from time i.e. f/u clock starts @ of randomization 3wks if SR ECV @ 3 wks if in AF AF free/event: from 1 hr after ECV *Either classic arrhythmia or HF Sx Phase 2b: 1° Endpoint = Recurrent AF/AFL or ACM, 24 weeks 5

6 GENETIC-AF: Phase se 2B Genetic ically ly-Targeted Tri rial Pri rimary ry Endpoint: : Tim ime to AF/AFL/ACM Entire Cohort U.S. Cohort 1.00 1.00 0.90 0.90 HR = 0.70 (0.41, 1.19) HR = 1.01 (0.71, 1.42) Probability of No AF/AFL/ACM Probability of No AF/AFL/ACM 0.80 0.80 0.70 0.70 0.60 0.60 BUC 0.50 0.50 BUC MET 0.40 0.40 MET 0.30 0.30 0.20 0.20 Gencaro: 73/134 (54%) Gencaro: 33/60 (55%) 0.10 0.10 Toprol-XL: 70/133 (53%) Toprol-XL: 40/67 (60%) 0.00 0.00 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Weeks of Efficacy FU Weeks of Efficacy FU Cox proportional hazards model adjusted for the 4 randomization strata: 1) HF etiology, 2) LVEF, 3) rhythm at randomization 4) device type. Piccini et al. JACC Heart Fail. 2019 Jul;7(7):586-598 .

7 GENETIC-AF: Cumulative Days in AF during 24-week Efficacy Follow-up Days in AF by Continuous Monitoring in Device Substudy; AF interventions in Entire Cohort AFB substudy Cumulative {ECV, catheter ablation, Class III AADs} MET 33% Reduction 50 22% Reduction MET Incidence Rate (Cumulative Events/Patient) Incidence Rate (Cumulative Days in AF/Patient) Incidence rate Cumulative Days in AF/Pt 40 BUC BUC BUC 30 20 IRR CIL CIU P.Vale Total Incidence Rate Incidence Rate Ratio Group N 10 # Events (events/pt) (95% CI) 0.78 0.727 0.837 <0.000 Total Incidence Rate Incidence Rate Ratio Group N MET 127 106 0.83 # Days (Days/pt) (95% CI) 0.67 (0.50, 0.90) Subjects.with.Events Treatment N Events Incidence.Rate IRR p = 0.009 BUC 132 74 0.56 MET 33 1731 52.5 Bucindolol 35 1432 25 40.914 0.78 0.78 (0.73, 0.84) p < 0.001 Metoprolol 0 33 1731 24 52.455 0.78 BUC 35 1432 40.9 0 30 60 90 120 150 180 Days of Efficacy F/U Time in AF determined by continuous monitoring with implanted cardiac monitors in patients Incidence Rate Ratio = Incidence Rate BUC / Incidence Rate MET. 7 participating in the device substudy. Includes all patients entering the efficacy follow-up period.

Mean ECG HR±SD, on Study Medication at each clinic visit, GENETIC-AF Entire Cohort Metoprolol (71.0±17.8.)* Metoprolol (87.4±17.0)* Metoprolol (62.9±12.2)* Bucindolol (76.7±17.6)* Bucindolol (90.4±17.1)* Bucindolol (68.4±11.4)* Poly. (Metoprolol) Poly. (Metoprolol) (62.9±1.2) AF SR All Rhythms P <0.0001 P <0.0001 P = 0.015 Poly. (Bucindolol) (68.4±1.4) 85 100.0 110.0 95.0 105.0 80 90.0 100.0 75 HR, bpm 85.0 95.0 HR, bpm HR, bpm 70 80.0 90.0 85.0 75.0 65 80.0 70.0 60 75.0 65.0 55 70.0 60.0 65.0 50 55.0 60.0 50.0 45 2 4 8 12 16 20 24 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 2 4 8 12 16 20 24 2 4 8 12 16 20 24 0 1 2 3 4 5 6 7 Week post randomization Week post randomization Week post randomization (*Mean ± SD HR for entire 24 wk study period)

Bradycardia AEs and Study Medication dose, % Achieving Target GENETIC AF Entire Cohort Dose: (M 200 mg/d; B 187 mg/d) 100 P = 0.007 50 90 P = 0.019 Metoprolol Bucindolol 45 80 40 82.8 % Achieving Target dose 70 35 70.7 60 # of Patients 30 50 P = 0.003 25 P = 0.003 40 20 30 15 20 10 5 10 0 0 Brady AEs Brady AEs AND dose ↓ Brady AEs OR <Target dose

Bucindolol Metoprolol HR <60 Mean ± SD, (N) M 52.0 ± 5.4 (200) B 51.6 ± 5.8 (80) (N) P = <0.0001 % at target: M, 72.9%; B, 76.8%; P = 0.010 HR 60 − 100 Mean ± SD, (N) M 76.0 ± 10.6 (495) B 74.6 ± 11.0 (632) (N) P = <0.0001 % at target: M, 79.7%; B, 78.0%; P = 0.29 Mean ± SD, (N) M 115 ± 12 (70) HR >100 B 115 ± 13( 86) (N) P = 0.20 % at target: M, 73.0%; B, 74.2%; P = 0.85

11 GENETIC-AF: Cumulative Events during 24-week Efficacy Follow-up Bradycardia (Investigator ECG interpretation) & Study Drug Dose Reductions Population GENETIC-AF Event Type Bradycardia Dose Reductions Group BUC MET Brady No Brady Total # Patients 132 127 71 188 Total # Events 71 151 22 14 Incidence Rate 0.54 1.19 0.31 0.07 (events/pt) Incidence Rate Ratio 0.45 (0.34, 0.60) 4.16 (2.15, 8.32) (95% CI) p < 0.001 p < 0.001 • 49-55% reduction in treatment-limiting bradycardia • 61- 65% reduction in cohorts with LVEF ≥ 40% GENETIC-AF (G-AF) Cohort = randomized cohort of GENETIC-AF that entered efficacy follow-up. Incidence Rate Ratio by Bradycardia = Incidence Rate Brady / Incidence Rate NoBrady. 11 Bradycardia = bradycardia on ECG as assessed by the investigator. Includes all patients entering the efficacy follow-up period. Incidence Rate Ratio by Treatment = Incidence Rate BUC / Incidence Rate MET Deaths included as events due to competing risk.

Bucindolol is Associated with a Lower Incidence of Dose Limiting Bradycardia than Metoprolol in HFrEF Patients with Atrial Fibrillation, Summary : ● In GENETIC-AF both AF and SR patients had lower HRs on metoprolol vs. bucindolol − The AF difference was smaller − Mechanism for difference in HRs uncertain, ? beta 3 agonism in bucindolol ● The lower HRs in metoprolol treated patients were associated with − Lower doses relative to target − A greater number of bradycardia AEs and ECG reads, both associated with dose reduction − Failure to achieve target on M vs. B was largely confined to patients in the <60 HR range; patients in higher HR ranges achieved target doses for the two beta-blockers equally ● Bradycardia may limit the dosing of conventional beta-blockers in AF/HFrEF − Beta -blocker efficacy for HF event reduction in HFrEF is very dose-related − Failure to achieve target doses may be at least part of the explanation for why conventional beta-blockers lack efficacy in AF/HFrEF (Reinstra et al JHF 2013, Kotecha et al, Lancet 2014), and why bucindolol has substantial efficacy for lowering HF events in ADRB1 389 Arg homozygous HFrEF patients in AF (Kao et al, EJHF 2013)