Inhibition of the K_Ca2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

"Competing interests A.G.H., B.V., U.S.S., J.G.D., M.G. and B.H.B. are employees of Acesion Pharma and hold shares or warrants in the company. N.E. is a consultant to Acesion Pharma. P.D. received consulting fees and honoraria from Acesion Pharma. D.L.B. has served on the Advisory Boards of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys. He has served on the Board of Directors of Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), the Society of Cardiovascular Patient Care and TobeSoft. He has been the Inaugural Chair of the American Heart Association Quality Oversight Committee. He has been a consultant for Broadview Ventures and Hims. He has served on the Data Monitoring Committees of Acesion Pharma, Assistance Publique-Hôpitaux de Paris, the Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), the Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), the Duke Clinical Research Institute, the Mayo Clinic, the Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo, and for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute and Rutgers University (for the National Institutes of Health-funded MINT trial). He has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi and Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly the Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committee), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary and Treasurer), WebMD (CME steering committee), Wiley (steering committee), Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair) and VA CART Research and Publications Committee (Chair). He is named on a patent for sotagliflozin (assigned to the Brigham and Women’s Hospital who assigned it to Lexicon; neither P.D. nor the Brigham and Women’s Hospital receive any income from this patent). He has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, the Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio. He has received royalties from Elsevier (Editor, Braunwald’s Heart Disease). He has been a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions. He is a trustee of the American College of Cardiology. He has carried out unfunded research for FlowCo. S.H.H. and J.T. declare no competing interests."

"We thank the patients who participated in the trial and the site investigators and staff. Grant funding for the present study was received from Wellcome Trust (Translational Award, 200450/Z/16/Z) and Innovation Fund Denmark (8064-00074B)."

"Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385."