Abstract 11495: HBI-3000: A Novel Drug for Conversion of Atrial Fibrillation - Phase 1 Study Results

BackgroundHBI-3000 is a multi-ion channel blocker with in vitro inhibitory effects on INa-Peak, INa-Late, ICa,L and IKr being developed by HUYA Bioscience International for the conversion of recent onset atrial fibrillation (AF).ObjectiveWe report the safety, tolerability, pharmacokinetics and electrocardiogram (ECG) results of a Phase 1 single ascending dose trial of intravenous (iv) HBI-3000 in healthy subjects.MethodsForty-seven subjects were randomized to 6 cohorts of 8 subjects to receive 1 of 5 single ascending iv doses (Table 1) of HBI-3000 or placebo (6:2), with 2 cohorts receiving the 600 mg dose. Continuous 12-lead Holter ECG data were recorded at baseline and 11 time points thereafter. Mean baseline and placebo subtracted (dd) ECG intervals (QTcF, HR, PR, QRS, and P-wave duration [PDur]) and T-wave segments (J to T peak [JTp] and T peak to T end [TpTe]) were calculated at Cmax for each dose.ResultsHBI-3000 was well tolerated with no dose limiting adverse events or arrhythmias observed. Table 1 summarizes ECG data at Cmax for each dose, as predicted by mixed-effects modeling. HBI-3000 induced dose-proportional changes in all ECG parameters. The increases in QRS and PDur are consistent with block of INa-Peak. The increase in the PR interval is consistent with the increase in PDur, and with both INa-Peak and ICa,L inhibition. Prolongation of TpTe is consistent with IKr block, which would be expected, in isolation, to lengthen JTp as well. The observed dose-related reduction of JTp is likely due to counteraction of the effect of HBI-3000 on IKr through its inhibition of both INa-Late, and ICa,L.ConclusionsThese data demonstrate that HBI-3000 is a potent inhibitor of multiple cardiac ion channels that play a role in onset and maintenance of AF. Its strong reduction of JTp may predict freedom from arrhythmias associated with IKr block. Based on these results and preclinical data indicating low proarrhythmic risk, the drug is now entering Phase 2 in recent onset AF.