IP Library Granted Patent US 12,491,177
Granted Patent B2
US 12,491,177 · App. 18/150,993 · Granted Dec 9, 2025

Methods and compositions involving bucindolol for the treatment of atrial fibrillation

Inventors: Michael Bristow (Englewood, CO); Christopher Dufton (Englewood, CO)
Assignee: GENVARA BIOPHARMA, INC.
A61K31/4045A61P9/06
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,491,177
App. No.
18/150,993
Granted
Dec 9, 2025
Kind
B2
Abstract

The current methods and compositions relate to treatment of atrial fibrillation with bucindolol in patients, including patients with heart failure, after being determined to be homozygous Arg389 in the β 1 adrenergic receptor gene.

Claims (27)

1 . A method for treating atrial fibrillation, the method comprising administering an effective amount of bucindolol to an atrial fibrillation or atrial flutter patient who has been identified as having at least one atrial fibrillation event within six months of the administering, (a) has been tested and found to have a left ventricle ejection fraction of greater than 0.35 and no more than 0.6; and (b) has been genotyped and found to be homozygous for Arg389 in the ADRB1 gene.

2 . The method of claim 1 , wherein the patient has been diagnosed with atrial fibrillation less than 2 years before or after being diagnosed with heart failure.

3 . The method of claim 1 , wherein the patient is continually monitored for atrial fibrillation burden.

4 . The method of claim 1 , wherein the patient has had one or more clinical interventions of electrical cardioversion, administration of a Class III anti-arrhythmic drug, and/or catheter ablation.

5 . A method of treating atrial fibrillation, the method comprising administering an effective amount of bucindolol to a patient who:

(a) has been diagnosed with heart failure;

(b) has been tested and found to have a left ventricle ejection fraction of greater than 0.35 and no more than 0.6;

(c) has been genotyped and found to be homozygous for Arg389 in the ADRB1 gene; and

(d) was initially diagnosed with heart failure less than 12 years before the administering.

6 . The method of claim 5 , wherein the patient has been diagnosed with new onset, recurrent, or ongoing atrial fibrillation, atrial flutter, tachycardia, or cardiac arrhythmia.

7 . The method of claim 5 , wherein the patient has been diagnosed with is symptomatic atrial fibrillation or atrial flutter (AF/AFL).

8 . The method of claim 5 , wherein the patient has been diagnosed with new onset, recurrent, or ongoing atrial fibrillation or atrial flutter (AF/AFL).

9 . The method of claim 8 , wherein the recurrent atrial fibrillation is symptomatic and/or paroxysmal atrial fibrillation.

10 . The method of claim 5 , wherein the patient was initially diagnosed with atrial fibrillation less than 2 years before or after being diagnosed with heart failure.

11 . The method of claim 5 , wherein the patient was characterized as a class I or II heart failure patient.

12 . The method of claim 5 , wherein the patient was characterized as a class III heart failure patient.

13 . The method of claim 5 , wherein the patient has been tested and found to have a left ventricle ejection fraction of less than 0.6.

14 . A method of reducing atrial fibrillation burden, the method comprising administering an effective amount of bucindolol to a patient who:

(a) has been diagnosed with heart failure;

(b) has been tested and found to have a left ventricle ejection fraction of at least greater than 0.35 and no more than 0.6;

(c) has been genotyped and found to be homozygous for Arg389 in the ADRB1 gene; and

(d) was initially diagnosed with atrial fibrillation less than 2 years before or after being diagnosed with heart failure.

15 . The method of claim 14 , wherein the patient has had at least one episode of atrial fibrillation burden of more than 6 hours in a 24 hour period.

16 . The method of claim 14 , wherein atrial fibrillation burden is determined by electrocardiogram.

17 . The method of claim 14 , wherein the patient has symptomatic atrial fibrillation or atrial flutter (AF/AFL).

18 . The method of claim 14 , wherein the patient has recurrent, or ongoing atrial fibrillation or atrial flutter (AF/AFL).

19 . The method of claim 18 , wherein recurrent atrial fibrillation is symptomatic and/or paroxysmal atrial fibrillation.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 6, 2024
From: ARCA BIOPHARMA, INC.
To: GENVARA BIOPHARMA, INC.
Reel/Frame 069506/0568 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2023
From: BRISTOW, MICHAEL; DUFTON, CHRISTOPHER
To: ARCA BIOPHARMA, INC.
Reel/Frame 064612/0240 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 16, 2023
From: BRISTOW, MICHAEL; DUFTON, CHRIS
To: ARCA BIOPHARMA, INC.
Reel/Frame 064615/0814 →
Continuity (6)
Continuation 17170528 · Feb 8, 2021
Continuation 16867394 · May 5, 2020
Continuation PCTUS2019034019 · May 24, 2019
Provisional Application 62839531 · Apr 26, 2019
Provisional Application 62676788 · May 25, 2018
Related Publication 20230149354A1 · May 18, 2023
References Cited (66)
US 8946284B2 · Bristow et al. · 2015 [cited by applicant]
US 9446023B2 · Bristow et al. · 2016 [cited by applicant]
US 9763916B2 · Bristow et al. · 2017 [cited by applicant]
US 20090192128A1 · Worcel et al. · 2009 [cited by applicant]
US 20150276717A1 · Liggett et al. · 2015 [cited by applicant]
JP 2008513019 · 2008 [cited by applicant]
WO WO2006031955 · 2006 [cited by applicant]
Hanley et al. ((Circ Arrhythm Electrophysiol. 2016, pp. 1-8). (Year: 2016). [cited by examiner]
Medical News, 2023 (https://www.medicalnews today.com/articles/237191#types, 2024) (Year: 2023). [cited by examiner]
Medical News, 2024 (https://www.medicalnews today.com/articles/257484#types) (Year: 2024). [cited by examiner]
AHA (https://www.heart.org/en/health-topics/consumer-healthcare/what-is-cardiovascular-disease) (Year: 2024). [cited by examiner]
“Ejectlon Fractlon. What the Numbers Mean” [cited by applicant]
Aleong, et al., “Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias with Bucindolol in Patients with Chronic Heart Failure,” [cited by applicant]
Aleong, et al., “New Onset Atrial Fibrillation Predicts Heart Failure Progression,” [cited by applicant]
Aleong, et al., Prevention of Atrial Fibrillation by Bucindolol is Dependent on the Beta-1 389 Arg/Gly Adrenergic Receptor Polymorphism, [cited by applicant]
Aleong, et al., “Ventricular Myocardial Gene Expression in HFrEF Patients with Atrial Fibrillation (AF) vs. No AF, and Changes in Response to Beta-Blockade,” [cited by applicant]
Anderson, et al. “Long-Term (2 year) Beneficial Effects of Beta-Adrenergic Blockade with Bucindolol in Patients with Idiopathic Dilated Cardiomyopathy,” [cited by applicant]
Becquemont, “Pharmacogenomics of Adverse Drug Reactions: Practical Applications and Perspectives,” [cited by applicant]
Black-Maier et al., “Bucindolol hydrochloride in atrial fibrillation and concomitant heart failure” [cited by applicant]
Bradford, “CYP2D6 Allele Frequency in European Caucasians, Asians, Africans and Their Descendants,” [cited by applicant]
Bristow, et al., “An Alpha2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the Beta-Blocker Bucindolol in Chronic Heart Failure,” [cited by applicant]
Bristow, et al., “Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the Beta-Blocker Evaluation of Survival Trial (BEST),” [cited by applicant]
Bristow, et al., “Structural and Functional Phenotyping of the Failing Heart: Is the Left Ventricular Ejection Fraction Obsolete?” [cited by applicant]
Bunch, et al., “Increasing Time Between First Diagnosis of Atrial Fibrillation and Catheter Ablation Adversely Affects Long-Term Outcomes,” [cited by applicant]
Butler, et al. “Developing Therapies for Heart Failure with Preserved Ejection Fraction: Current State and Future Directions,” [cited by applicant]
Butler, et al., Exploring New Endpoints for Patients with Heart Failure with Preserved Ejection Fraction. [cited by applicant]
Chen-Scarabelli, et al., “Device-Detected Atrial Fibrillation: What To Do With Asymptomatic Patients,” Journal of the American College of Cadiology, 65(3):281-294, 2015. [cited by applicant]
Cresci, et al., “Clinical and Genetic Modifiers of Long-Term Survival in Heart Failure,” [cited by applicant]
Davis, “Collaborative Research Group. Heart failure with Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial,” [cited by applicant]
Dean, L. (2020). Tramadol Therapy and CYP2D6 Genotype. Medical Genetic Summaries (Internet). Retrieved Jul. 14, 2020, from: https://www.ncbi.nlm.nih.gov/books/NBK3159850. [cited by applicant]
Extended European Search Report issued in Corresponding European Application No. 19808220.8, dated Jun. 4, 2021. [cited by applicant]
Fanarow G. “Refining classification of heart failure based on ejection fraction”, [cited by applicant]
Gaedigk, et al., “CYP2D6 Poor Metabolizer Status Can be Ruled Out by a Single Genotyping Assay for the-1584G Promoter Polymorphism,” [cited by applicant]
Gupta, “Heart Failure with Preserved Ejection Fraction in African Americans: The ARIC (Atherosclerosis Risk In Communities) Study,” [cited by applicant]
Healey, et al., “Subclinical Atrial Fibrillation and the Risk of Stroke,” [cited by applicant]
Hussein, et al., “Radiofrequency Ablation of Persistent Atrial Fibrillation: Diagnosis-to-Ablation Time, Markers of Pathways of Atrial Remodeling, and Outcomes,” [cited by applicant]
International Search Report and Written Opinion Issued in Corresponding PCT Patent Application No. PCT/US2019/034019, dated Nov. 8, 2019. [cited by applicant]
Kao, et al., “Effect of Bucindolol on Heart Failure Outcomes and Heart Rate Response in Patients with Reduced Ejection Fraction Heart Failure and Atrial Fibrillation,” [cited by applicant]
Kotecha & Piccini, “Atrial Fibrillation in Heart Failure: What Should We Do?” [cited by applicant]
Kotecha, et al., “Efficacy of Beta Blockers in Patients with Heart Failure Plus Atrial Fibrillation: An Individual-Patient Data Meta Analysis,” [cited by applicant]
Kotecha, et al., “Increased Stroke Risk in Atrial Fibrillation Patients with Heart Failure: Does Ejection Fraction Matter?” [cited by applicant]
Kotecha,, et al., “Heart Failure With Preserved Ejection Fraction and Atrial Fibrillation: Vicious Twins,” [cited by applicant]
Liggett, et al., “A Polymorphism Within a Highly Conserved Beta1-Adrenergic Receptor Motif Alters Beta-Blocker Response in Multiple Models and Human Heart Failure,” [cited by applicant]
Mason, et al., “A Gain-Of-Function Polymorphism in a G-Protein Coupling Domain of the Human Beta1-Adrenergic Receptor,” [cited by applicant]
Nasr, et al., “Prevention of Atrial Fibrillation Onset By Beta-Blocker Treatment in Heart Failure: A Meta-Analysis,” [cited by applicant]
Nergardh, 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,” [cited by applicant]
O'Connor, et al., “Combinatorial Pharmacogenetic Interactions of Bucindolol and Beta1, a2c Adrenergic Receptor Polymorphisms,” PLoS One, 7(10): e44324, 2012. [cited by applicant]
Office Action issued in Corresponding Japanese Application No. 2021-516549, dated Jun. 21, 2021 (English Translation provided). [cited by applicant]
Parikh et al., “Pharmacogenomics of Bucindolol in Atrial Fibrillation and Heart Failure” [cited by applicant]
Perez, et al., “Beta 1-Adrenergic Receptor Polymorphisms Confer Differential Function and Predisposition to Heart Failure,” [cited by applicant]
Piccini, et al., “A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure: Rationale and Design of… [cited by applicant]
Ponikowski, et al., “2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of C… [cited by applicant]
Rienstra, et al., “Beta-blockers and Outcome in Heart Failure and Atrial Fibrillation: A Meta-Analysis,” [cited by applicant]
Sandilands, et al., “Greater Inotropic and Cyclic AMP Responses Evoked by Noradrenaline Through Arg389 Beta1-Adrenoceptors versus Gly389 Beta1-Adrenoceptors in Isolated Human Atrial Myocardium,” [cited by applicant]
Sarkar, et al., “Burden of Atrial Fibrillation and Poor Rate Control Detected by Continuous Monitoring and the Risk for Heart Failure Hospitalization,” [cited by applicant]
Taylor, et al., “Race, Genetic Variation, and Therapeutic Response Disparities in Heart Failure,” [cited by applicant]
The Beta-Blocker Evaluation of Survival Trial Investigators, “A Trial of the Beta-Adrenergic Blocker Bucindolol in Patients with Advanced Heart Failure,” [cited by applicant]
Trulock, et al., “Rhythm Control in Heart Failure Patients with Atrial Fibrillation: Contemporary Challenges Including the Role of Ablation,” [cited by applicant]
Turagam, et al., “Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure: A Meta-analysis of Randomized Controlled Trials,” [cited by applicant]
Van Veldhuisen, et al., “Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study,” [cited by applicant]
Wennerholm, et al., “Characterization of the CYP2D6*29 Allele Commonly Present in a Black Tanzanian Population Causing Reduced Catalytic Activity,” [cited by applicant]
White, et al., “An Evaluation of the Beta-1 Adrenergic Receptor Arg389Gly Polymorphism in Individuals with Heart Failure: a MERIT-HF Sub-Study,” [cited by applicant]
Yancy, et al., 2013 ACCF/AHA Guideline for the Management of Heart Failure, [cited by applicant]
Extended European Search Report issued in corresponding European Application No. 23177989.3 mailed Oct. 16, 2023. [cited by applicant]
Hernandez, “Clinical effectiveness of beta-blockers in heart failure findings from the IPTIMIZE-HF (Organized program to initiate lifesaving treatment in hospitalized patients with heart failure), Registry”, [cited by applicant]
Mazurek et al. “Understanding heart failure”, [cited by applicant]