Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

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 .

A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

A Phase 3, Randomized Trial Demonstrating the Improved Efficacy and Patient Acceptability of Fixed Dose Calcipotriene and Betamethasone Dipropionate Cream.

BACKGROUND: The fixed dose combination of calcipotriene and betamethasone dipropionate (CAL/BDP) is a well-established, efficacious, and safe topical treatment of psoriasis. METHOD: A Phase 3, multicenter, randomized, investigator-blind, active, and vehicle-controlled trial enrolling 796 patients with moderate to severe psoriasis according to the Physician Global Assessment (PGA) scale. Products were applied once daily for 8 weeks. RESULTS: The proportion of patients achieving PGA treatment success after 8 weeks was statistically significantly greater for CAL/BDP cream (37.4%) compared to CAL/BDP TS (22.8%, P<0.0001), and vehicle (3.7%, P<0.0001). A similar statistically significant difference in favor of CAL/BDP cream at week 8 was demonstrated for the percentage change in mPASI from baseline and the proportion of patients obtaining mPASI75. Patient reported treatment convenience for CAL/BDP cream was rated superior to CAL/BDP TS. Safety assessments during the trial demonstrated that CAL/BDP cream was well-tolerated with no adverse reactions with a frequency greater than 1%. CONCLUSION: CAL/BDP cream is a novel topical treatment of psoriasis, which in a single product, offers a unique combination of high efficacy combined with favorable safety and excellent treatment convenience. For these reasons, CAL/BDP cream offers a distinctive advantage for the topical treatment of plaque psoriasis. ClinicalTrials.gov: NCT03308799J Drugs Dermatol. 20(4):420-425. doi:10.36849/JDD.5653.