Lack of Electrocardiographic Effects of Deucravacitinib in Healthy Subjects.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion. The placebo-corrected change from baseline for the QT interval corrected for heart rate using the Fridericia method (QTcF), ECG parameters, and safety measures were evaluated. A clinically meaningful QTcF prolongation of >10 milliseconds was not found for deucravacitinib at tested doses. Assay sensitivity was demonstrated by the observation of known QT effects of moxifloxacin in the study. Deucravacitinib had no clinically relevant effect on other parameters and was generally well tolerated. The majority of adverse events (AEs) were mild, and all AEs resolved by study's end. Three treatment-related serious AEs of pharyngitis, cellulitis, and lymphadenopathy occurred in 1 subject following administration of deucravacitinib 12 mg, but resolved by end of study. This study demonstrated that a single oral dose of deucravacitinib 12 or 36 mg did not produce a clinically relevant effect on the corrected QT interval or other measured ECG parameters in healthy adults.

Effects of elotuzumab on QT interval and cardiac safety in patients with multiple myeloma.

PURPOSE: To assess the effect of elotuzumab on corrected QT (QTc) intervals and cardiac safety. METHODS: Patients with high-risk smoldering multiple myeloma who had been treated with elotuzumab monotherapy (10 or 20 mg/kg) in Study CA204011 (NCT01441973) underwent electrocardiogram (ECG) examination over 8-10 weeks (treatment cycles 1-3). ECG intervals and changes relative to baseline were assessed. The key ECG endpoint was change from baseline in QT interval corrected with Fridericia's method (ΔQTcF). The relationship between elotuzumab concentration and ΔQTcF was assessed using time-matched ΔQTcF data and linear regression. Adverse events (AEs) potentially related to abnormal ECG findings were summarized. RESULTS: There was no trend of change from baseline in QTcF, PR and QRS intervals among all 31 evaluable patients from Study CA204011, and no patient assessed had a QTcF interval >480 ms or a ΔQTcF >60 ms. Concentration-response modeling indicated that there was no significant relationship between ΔQTcF and elotuzumab serum concentration: Upper limits of 90% confidence intervals for mean change in QTcF were <10 ms over the range of observed elotuzumab concentrations. No ECG-assessed patient had an AE associated with abnormal ECG findings potentially related to proarrhythmia. CONCLUSIONS: Study CA204011 ECG data indicate that elotuzumab treatment was not associated with QT/QTc prolongation. Concentration-response modeling demonstrated that baseline-adjusted QTcF changes did not cross thresholds for clinical or regulatory concern.

Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab.

PURPOSE: The fully human monoclonal antibody nivolumab binds to the programmed death-1 (PD-1) receptor, blocking interactions between PD-1 and its ligands on tumor cells and preventing T cell exhaustion in patients with cancer. The potential for corrected QT interval (QTc) prolongation was assessed in a subset of patients enrolled in a phase 2 dose-ranging study of nivolumab. METHODS: Triplicate 12-lead electrocardiograms (ECGs) obtained predose and post-dose were assessed by an independent ECG core laboratory. QTc derived from Fridericia's formula (QTcF) was evaluated by central tendency, categorical, and concentration-response analyses. RESULTS: No patients had QTcF intervals or changes from baseline in QTcF (ΔQTcF) exceeding prespecified thresholds indicating borderline or prolonged QTcF (>480 ms) or ΔQTcF (>60 ms). Among 146 patients randomized to nivolumab 0.3, 2.0, or 10.0 mg/kg every 3 weeks, the maximum increases in mean (± SD) ∆QTcF at any time point were 4.9 (± 13.4), 1.2 (± 10.1), and 2.0 (± 8.9) ms, respectively. There was no relationship between ∆QTcF and nivolumab serum concentration and no association between predicted maximum ∆QTcF and mean maximum nivolumab concentration in any dosage group. CONCLUSION: Results of these intensive ECG analyses indicate that nivolumab has no clinically meaningful effect on QTc interval when administered at doses up to 10.0 mg/kg.

In vivo characterization of the mitochondrial selective K(ATP) opener (3R)-trans-4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095): cardioprotective, hemodynamic, and electrophysiological effects.

Recent studies have shown the importance of mitochondrial ATP-sensitive potassium channels (K(ATP)) in cardioprotection, and studies in vitro have shown that the benzopyran analog (3R)-trans- 4-((4-chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril monohydrochloride (BMS-191095) is a selective mitochondrial K(ATP) opener with cardioprotective activity. The goal of this study was to show selective cardioprotection for BMS-191095 in vivo without hemodynamic or cardiac electrophysiological effects expected for nonselective K(ATP) openers. BMS-191095 reduced infarct size in anesthetized dogs (90-min ischemia + 5-h reperfusion) in a dose-dependent manner (ED(25) = 0.4 mg/kg i.v.) with efficacious plasma concentrations of 0.3 to 1.0 microM, which were consistent with potency in vitro. None of the doses of BMS-191095 tested caused any effect on peripheral or coronary hemodynamic status. Further studies in dogs showed no effects of BMS-191095 on cardiac conduction or action potential configuration within the cardioprotective dose range. In a programmed electrical stimulation model, BMS-191095 showed no proarrhythmic effects, which is consistent with its lack of effects on cardiac electrophysiological status. BMS-191095 is a potent and efficacious cardioprotectant that is devoid of hemodynamic and cardiac electrophysiological side effects of first generation K(ATP) openers, which open both sarcolemmal and mitochondrial K(ATP). Selective opening or activation of mitochondrial K(ATP) seems to be a potentially effective strategy for developing well tolerated and efficacious K(ATP) openers.