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GENETIC-AF: A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL
for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure
Debra Marshall, MD5; Michelle Heidenreich5; Jonathan P. Piccini, MD1; Jeff S. Healey, MD2; Stuart J. Connolly, MD2; William T Abraham, MD3; Gordon Davis, MSPH5; and Michael R. Bristow, MD, PhD4,5.
1Duke University Medical Center- Duke Clinical Research Institute, 2Population Health Research Institute, McMaster University, 3The Ohio State University, 4University of Colorado School of Medicine, 5ARCA biopharma, Inc.
Background
Most anti-arrhythmic agents currently approved for the treatment of
atrial fibrillation (AF) and atrial flutter (AFL) are either
contraindicated or have label warnings for use in heart failure (HF)
patients due to an increased risk of mortality in this patient
population.
Bucindolol hydrochloride (bucindolol) is a nonselective β-adrenergic
receptor (AR) blocking agent with mild vasodilator properties, which
was previously studied in the BEST Phase 3 HF trial.1 In a large
pharmacogenomic substudy of the BEST trial, two unique
pharmacologic properties of bucindolol, sympatholysis and inverse
agonism, were shown to interact with AR polymorphisms in such a
way that targeting specific genotypes of these variants could improve
therapeutic index.3
Metoprolol (Toprol-XL), which is approved for the treatment of HF,
has demonstrated mild efficacy for the prevention of new onset AF in
a HF patient population and is often used off-label in this setting. In
contrast to bucindolol, metoprolol does not appear to confer added
clinical benefits in HF with reduced left ventricle ejection fraction
(HFREF) patients that possess the β1389Arg/Arg AR variant. In
addition, limited data from the MERIT-HF DNA substudy did not
indicate any evidence of a β1389 Arg/Gly polymorphism differential
effect for preventing AF.
β1-AR Polymorphisms
• The B1389 Arg AR provides substantially greater adrenergic drive
compared to the B1389 Gly form of the receptor.
 3-4X higher signal transduction capacity
 Higher binding affinity for NE
 More active state receptors
Atrial Fibrillation Rationale
• Meta-analysis of new onset AF in 7 large β-blocker HF trials (N = 11,951).4
 β-blockers: Relative Risk = 0.73 (27% risk reduction).
 Bucindolol: Relative Risk = 0.69 (31% risk reduction, all genotypes).
• Bucindolol’ s benefits are enhanced in β1389 Arg/Arg patients (below)5
 But no benefit was observed in β1389 Gly carriers (HR=1.01, p=0.569).
• Bucindolol also has two unique pharmacologic properties:
 Sympatholysis: ↓ adrenergic drive/norepinephrine release.
 Inverse agonism: inhibition of constitutively active β1ARs.
• GENETIC-AF is a seamless Phase 2B/Phase 3 adaptive trial.
• An independent DSMB will review unblinded data after at least 150
patients have AF endpoint data and will use pre-specified benchmarks to
determine if the trial should proceed to Phase 3.
• If the trial proceeds to Phase 3, a total of 620 patients (Phase 2B and
Phase 3) will be enrolled at ~150 sites worldwide.
• Data from Phase 2B & Phase 3 combined for the final analysis.
Study Endpoints
References
Heart Failure Rationale
• BEST was a double-blind, placebo-controlled, Phase 3 trial of
bucindolol in 2,708 CHF patients.1
 Primary Endpoint: all-cause mortality (p = 0.053).
 Improvements in 11 of 14 secondary endpoints (p < 0.05).
• The BEST genetic substudy of 1040 patients demonstrated
genotype-dependent enhancements for several HF endpoints.3
Endpoint
ACM
CVM
HF Progression
HF Hospitalization
CV Hospitalization
β1389 Arg/Arg
(n = 493)
0.62 (0.39, 0.99)
p = 0.042
0.52 (0.31, 0.88)
p = 0.014
0.66 (0.49, 0.88)
p = 0.005
0.64 (0.46, 0.89)
p = 0.007
0.64 (0.48, 0.86)
p = 0.002
β1389 Gly carrier
(n = 547)
0.92 (0.63, 1.35)
p = 0.661
0.78 (0.51, 1.18)
p = 0.233
0.85 (0.66, 1.11)
p = 0.233
0.85 (0.63, 1.15)
p = 0.303
0.93 (0.72, 1.21)
p = 0.588
All endpoints presented as time to event analyses, with hazard ratios and 95% confidence
intervals from a COX model and p-values generated using the logrank statistic.
• In BEST, β1389 Arg/Arg patients in AF at baseline who were receiving bucindolol had:
─ Greater heart rate reductions compared to β1389 Gly carriers (-14.7 vs -8.7 bpm) 6
─ Reduction in ACM/HFH (HR=0.23, p<0.05) and CVM/CVH (HR=28, p<0.05).6
• Not observed for β1389 Gly carriers (not shown) 6 or other β-blockers (below).7
Study Population
Key Inclusion Criteria
• Age ≥ 18 years and ≤ 85 years at screening.
• History of HF with reduced left ventricle ejection fraction.
 LVEF < 0.50 at any time within 12 months of screening.
• At least one symptomatic paroxysmal or persistent AF episode
≤ 180 days of screening.
 Patient may be in SR at time of enrollment.
• Possess the β1389 Arg/Arg genotype.
• Clinical euvolemia at randomization.
• Receiving appropriate anticoagulation therapy prior to
randomization which is considered optimal for stroke prevention.
• Systolic BP > 90 mmHg and < 150 mmHg at randomization.
Bucindolol hydrochloride
(Gencaro™)
The goal of the GENETIC-AF trial is to demonstrate the superiority of
pharmacogenetically targeted bucindolol compared to metoprolol for
the prevention of symptomatic AF/AFL in a genotype-defined
β1389Arg/Arg HFREF population at high risk of AF/AFL recurrence.
1. Beta-Blocker Evaluation of Survival Trial. A trial of the beta-blocker
bucindolol in patients with advanced chronic heart failure. NEJM
2001.
2. Liggett SB, et al. A polymorphism within a conserved beta(1)adrenergic receptor motif alters cardiac function and beta-blocker
response in human heart failure. PNAS 2006.
3. O'Connor CM, et al. Combinatorial pharmacogenetic interactions
of bucindolol and beta1, alpha2C adrenergic receptor
polymorphisms. PLoS One 2012.
4. Nasr IA, et al. Prevention of atrial fibrillation onset by beta-blocker
treatment in heart failure: a meta-analysis. Eur Heart J 2007.
5. Aleong RG, et al. Prevention of Atrial Fibrillation by Bucindolol Is
Dependent on the Beta1389 Arg/Gly Adrenergic Receptor
Polymorphism. JACC: Heart Failure 2013.
6. Kao DP, et al. 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 2013.
7. Kotecha D, et al. Efficacy of β blockers in patients with heart failure
plus atrial fibrillation: an individual-patient data meta-analysis.
Lancet 2014.
8. Nergardh AK, et al. Maintenance of sinus rhythm with metoprolol
CR initiated before cardioversion and repeated cardioversion of
atrial fibrillation: a randomized double-blind placebo-controlled
study. Eur Heart J 2007.
Study Design
Primary Endpoint
• Time to first event of symptomatic AF/AFL or ACM assessed after
establishment of stable SR on study drug.
Other Study Endpoints
• Time to first event of AF/AFL (Sx/aSx) or ACM.
• Proportion of patients with VT, VF, or symptomatic SVT.
• Total number of hospitalization (all-cause) days per patient.
• Time to first event of AF/AFL (Sx/aSx), HF hospitalization or ACM.
• Proportion of patients who have AF/AFL at the end of study
who demonstrate ventricular response rate control.
• AF burden assessed via continuous monitoring with new/pre-existing
Medtronic implanted devices (substudy).
Study Status
• The Phase 2B stage of the trial is currently recruiting 250 patients from
approximately 70 centers in the US and Canada.
• Approximately 30 centers in Europe are being opened in Q4 2016.
• Phase 2B enrollment began in June 2014. More than 100 patients enrolled.
• The DSMB decision to proceed to Phase 3 is targeted for 1H 2017.
• Currently recruiting clinical sites in US, Canada, and Europe for Phase 3
expansion (~150 total sites).
• Phase 3 follow-up will continue until a total of at least 330 primary
endpoint events have been observed.
Key Exclusion Criteria
• NYHA Class IV symptoms at randomization.
• Permanent AF at screening.
• >2 ECV procedures ≤ 6 months of screening or if the most
recent ECV ≤ 6 months of screening failed to produce SR.
• History of a successful atrioventricular node ablation.
• History of an AF ablation ≤ 30 days of randomization.
• Untreated 2nd degree Mobitz II or 3rd degree heart block.
• MI, unstable angina, ACS, cardiac surgery (including PTCA or stent
placement), or evidence of new ischemic changes ≤ 90 days of
randomization.
• Appropriate firing of ICD for VT/VF ≤ 90 days of randomization.
Prohibited Medications
• Previous β-blockers must be discontinued at randomization.
• The following are prohibited < 7 days prior to randomization:
 Antiarrhythmic drugs, non-dihydropyridine CCBs, daily NSAIDs,
thiazolidinediones, frequent use of sublingual nitroglycerin.
• The following interventions are allowed during the trial
after AF/AFL recurrence.
 Use of amiodarone or dofetilide.
 Non-investigational procedures (e.g., ablation, ECV).
Study Collaborators