Gencaro (bucindolol) / Oruka Therapeutics - LARVOL DELTA

Predicting compounds that interact with the 2 known agonist-induced conformations of the human β1-adrenoceptor. (PubMed, Mol Pharmacol) - "Using a structure-activity hypothesis built on the predicted poses CGP12177 and 3 biphasic agonists (alprenolol, oxprenolol, and bucindolol), predictions based on ligand similarity and structural compatibility reasoning were made about 11 other β1-ligands not yet tested for secondary conformation interaction and examined in radioligand binding and functional assays using human β1- and β2-adrenoceptors...Carteolol (related to CGP12177) and bunitrolol (similar to alprenolol) activated both conformations with biphasic concentration responses...In a β1-adrenoceptor mutant (β1-V189T-L195Q-W199Y) where secondary site CGP12177 and pindolol interaction is lost, the 3 novel secondary-site compounds were also no longer able to stimulate secondary conformation responses, suggesting that there is a common TM4 secondary conformation-inducing interaction site. SIGNIFICANCE STATEMENT: The β1-adrenoceptor exists in 2 agonist-stabilized, pharmacologically distinguishable conformations...."

Journal

β 1 - and β 2 -adrenergic Receptor Haplotypes Regulate Therapeutic Responses to Placebo and the Biased Ligand β-blocker Bucindolol. (PubMed, medRxiv) - "1) Both β 1 - and β 2 -AR haplotypes regulate therapeutic responses in HF; internalizing species confer protection against clinical events in placebo-treated subjects, while in internalization-resistant haplotypes the biased ligand β-blocker bucindolol but not the non-biased ligand metoprolol is associated with favorable effects. 2) The biased ligand cardioprotective effect may be related to internalization-dependent or -independent ERK1/2 activation."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • ADRB2 • EGFR

Assessing Patient-Reported Outcomes in Heart Failure and Atrial Fibrillation: To Split or to Lump? (PubMed, JACC Heart Fail) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Symptoms Burden as a Clinical Outcomes Assessment in Heart Failure Patients With Atrial Fibrillation. (PubMed, JACC Heart Fail) - P2 | "Measurement of symptoms burden throughout clinical trial follow-up is feasible in AF/HF and should be useful for evaluating patient-centered outcomes in AF prevention trials. (Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure [GENETIC-AF]; NCT01970501)."

Clinical data • Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Comparative Efficacy of Different Drugs for the Treatment of Dilated Cardiomyopathy: A Systematic Review and Network Meta-analysis. (PubMed, Drugs R D) - "A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings."

Journal • Retrospective data • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure

Dose-limiting, adverse event-associated bradycardia with β-blocker treatment of atrial fibrillation in the GENETIC-AF trial. (PubMed, Heart Rhythm O2) - "On multivariate analysis of 21 candidate bradycardia predictors including presence of a device with pacing capability, bucindolol treatment was associated with the greatest degree of prevention (Z -4.24, P < .0001). In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent."

Adverse events • Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Right Ventricular Ejection Fraction and Beta-Blocker Effect in Heart Failure with Reduced Ejection Fraction: Beta-Blocker and outcomes in HFrEF by RVEF. (PubMed, J Card Fail) - "The effect of bucindolol on mortality in patients with HFrEF was modified by baseline RVEF. If these hypothesis-generating findings can be replicated using approved beta-blockers in contemporary patients with HFrEF, then RVEF may help risk-stratify patients with HFrEF for optimization of beta-blocker therapy."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

"$ABIO Gencaro Atrial Fibrillation Phase 2B Results Selected for Publication in Circulation: Arrhythmia and Electrophysiology https://t.co/4S7DPS7e8b" (@stock_titan)

Atrial Fibrillation • Cardiovascular

Bucindolol Decreases Atrial Fibrillation Burden in Patients with Heart Failure and the ADRB1 Arg389Arg Genotype. (PubMed, Circ Arrhythm Electrophysiol) - "In the GENETIC-AF trial conducted in a genetically defined heart failure (HF) population at high risk for recurrent atrial fibrillation (AF), similar results were observed for bucindolol and metoprolol succinate for the primary endpoint of time to first atrial fibrillation (AF) event; however, AF burden and other rhythm control measures were not analyzed. Reductions in plasma norepinephrine (p = 0.038) and NT-proBNP (p = 0.009) were also observed with bucindolol compared to metoprolol. Conclusions - Compared with metoprolol, bucindolol reduced AF burden, improved maintenance of sinus rhythm, and lowered the need for additional rhythm control interventions in patients with HF and the ADRB1 Arg389Arg genotype."

Clinical • Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Model-based meta-analysis of changes in circulatory system physiology in patients with chronic heart failure: MBMA of circulatory system physiology in CHF. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The clinical data from 61 studies mostly in HFrEF patients, reporting changes in heart rate, blood pressure, or ventricular volumes after treatment with carvedilol, metoprolol, bisoprolol, bucindolol, enalapril, aliskiren, or felodipine, were analyzed. The analysis based on the present models were reasonably consistent with the hypothesis that the treatment of HFrEF with various medications is due to effectively reducing the cardiac load. Assessment of circulatory physiological parameters by using MBMA would be insightful for quantitative understanding of CHF treatment."

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure

[VIRTUAL] Gender, Race, and Age Specific Baseline Predictors of All-Cause Mortality in BEST Identified by Machine Learning (AHA 2020) - P3 | "Background NHLBI supported Beta-Blocker Evaluation in Survival Trial (BEST) (NCT00000560) was designed to determine if bucindolol hydrochloride would reduce the death rate in patients with moderate to severe heart failure and a left ventricular ejection fraction ≤ 35 percent...Conclusion Using ML, we found in an unbiased fashion, novel unanticipated predictors of ACM in BEST trial. This underscores the value of gender, race and age groups specific predictors of hard associated with CV disease and efficacy of therapeutic interventions in advancing precision medicine."

Cardiovascular • Congestive Heart Failure • Heart Failure

GENETIC-AF: Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined Heart Failure Population. (PubMed, JACC Heart Fail) - "Pharmacogenetic-guided bucindolol therapy did not reduce the recurrence of AF/AFL/ACM compared to metoprolol in HFrEF patients, but populations were identified that merit further investigation in future Phase 3 trials."

Clinical • Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Ex Ante Economic Evaluation of Arg389 Genetically Targeted Treatment with Bucindolol versus Empirical Treatment with Carvedilol in NYHA III/IV Heart Failure. (PubMed, Am J Cardiovasc Drugs) - "This independent ex ante economic evaluation suggests that genetically targeted treatment with bucindolol is unlikely to yield clinicoeconomic benefits over empirical treatment with carvedilol in NYHA III/IV HF."

HEOR • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

GENETIC-AF: Digging Deeper Into Genotype-Phenotype and Heart Failure-Atrial Fibrillation Interactions. (PubMed, JACC Heart Fail) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Pharmacogenomic Guided Beta-blocker Therapy Withbucindolol Reduces Atrial Fibrillation Burden Compared To Metoprolol Succinate: The Genetic-af Trial (RHYTHM 2020) - "In a pharmacogenetically-defined HF population at risk for AF recurrence, bucindolol significantly decreased the cumulative AF burden compared to the active control metoprolol succinate."

Biomarker • Atrial Fibrillation • Cardiovascular

Impact Of Pharmacogenetic-guided Bucindolol Versus Metoprolol Succinate On The Overall Burden Of Clinical Events In Patients With Atrial Fibrillation And Heart Failure: The Genetic-af Trial (RHYTHM 2020) - "In a pharmacogenetically-defined HF population at risk for AF recurrence, bucindolol was associated with fewer AF interventions and CV AEs compared to the active control metoprolol succinate."

Biomarker • Clinical • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

Bucindolol Is Associated With A Lower Incidence Of Dose Limiting Bradycardia In Heart Failure Patients With Atrial Fibrillation: The Genetic-AF Trial (RHYTHM 2020) - "In a pharmacogenetically-defined HF population at risk for AF, bucindolol was associated with a lower incidence of dose limiting bradycardia compared to metoprolol succinate."

Clinical • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Heart Failure

ARCA Biopharma announces first quarter 2018 financial results and provides corporate update (GlobeNewswire) - P=2B, N=NA; "'The first quarter of this year saw an important milestone for the Gencaro development program with the reporting of top-line Phase 2B results for the GENETIC-AF clinical trial evaluating Gencaro as potentially the first genetically-targeted treatment for atrial fibrillation,' commented Dr. Michael Bristow...'Our End-of-Phase 2 meeting with the U.S. FDA is scheduled for the last week of June when we will review the data and potential future development plans for Gencaro.'"

Media quote

Bucindolol improves right ventricle function in rats with pulmonary arterial hypertension through the reversal of autonomic imbalance. (PubMed) - Eur J Pharmacol - "An improvement in RV systolic function was also observed in the monocrotaline+bucindolol group compared to the monocrotaline.In addition, bucindolol promoted a decrease in the cardiac sympathovagal balance (93%) by reducing sympathetic drive (70%) and increasing parasympathetic drive (142%). Bucindolol also reduced blood pressure variability (75%).Our results show thatthe beneficial effects from bucindolol treatment appeared to be a consequence of the reversal of monocrotaline-induced autonomic imbalance."

Journal • Biosimilar • Cardiovascular • Fibrosis • Heart Failure • Immunology

Bucindolol Modulates Cardiac Remodeling by Attenuating Oxidative Stress in H9c2 Cardiac Cells Exposed to Norepinephrine. (PubMed, Oxid Med Cell Longev) - "The protein kinase B/mammalian target of the rapamycin (Akt/mTOR) pathway which is involved in cardiac remodeling process was activated in response to norepinephrine and was mitigated by bucindolol. In conclusion, bucindolol was able to modulate cardiac remodeling which is mediated by oxidative stress."

Journal

Dose Response of β-Blockers in Adrenergic Receptor Polymorphism Genotypes. (PubMed, Circ Genom Precis Med) - "BB dose was defined as either no/low dose or high dose, according to total daily dose of either bucindolol (BEST subjects) or other BB (HF-ACTION subjects) standardized to carvedilol equivalents. Other BBs taken at low dose have reduced efficacy for Arg389Arg genotype subjects compared with 389Gly carriers, suggesting a greater relative treatment effect at high dose. These data support guideline recommendations to use high, clinical trial target doses of all BBs to treat HF with reduced ejection fraction."

Journal

Ppharmacogenetic Guided Beta-blocker Therapy with Bucindolol for the Prevention of Atrial Fibrillation/flutter in Heart Failure: Relationship of Left Ventricular Ejection Fraction to Treatment Effect (HFSA 2019) - No abstract available.

Biomarker • Late-breaking abstract

Arca Biopharma announces Gencaro atrial fibrillation clinical data selected for presentation at HFSA 2019 Scientific Meeting (GlobeNewswire) - P2b, N=267; GENETIC-AF (NCT01970501); Sponsor: ARCA Biopharma; "ARCA biopharma...today announced that Gencaro atrial fibrillation clinical data from the GENETIC-AF Phase 2B trial have been selected for presentation at the Heart Failure Society of America (HFSA) 2019 Annual Scientific Meeting being held September 13-16 in Philadelphia. William T. Abraham, MD...will present the data. 'Bucindolol response appears to be greater in heart failure patients with less severe left ventricular dysfunction, a patient population with few therapeutic options for AF prevention or heart failure,' commented Dr. Abraham..."

Media quote • P2b data

GENETIC-AF Phase 2B Trial Results Published in the Journal of American College of Cardiology: Heart Failure (GlobeNewswire, ARCA biopharma, Inc.) - "ARCA biopharma, Inc....today announced that the paper “GENETIC-AF: Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined Heart Failure Population” was published in JACC: Heart Failure, a journal of the American College of Cardiology....Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients who have the beta-one adrenergic receptor (ADRB1) Arg389Arg genotype. GENETIC-AF compared the effectiveness of bucindolol and metoprolol succinate for the maintenance of sinus rhythm in a genetically-defined HF population with AF."

Clinical data • P2b data