Effects of NEPA (novel combination of netupitant and palonosetron) on ECG of healthy volunteers: A randomized, controlled, thorough ECG trial.

Abstract

e20538 Background: Despite advances in supportive cancer care, chemotherapy-induced nausea and vomiting (CINV) is ranked by patients among the worst side effects of chemotherapy. NEPA is a new antiemetic under development composed of a unique fixed-dose combination of netupitant (NETU, 300 mg), a new, highly selective NK1 receptor antagonist (RA), and palonosetron (PALO, 0.5 mg), a pharmacologically and clinically distinct 5-HT3RA. NEPA targets the 2 most important emetic pathways with a single oral dose. Although PALO is not associated with cardiovascular issues, this study aimed to evaluate the tolerability and cardiovascular safety of different doses of NETU + PALO. Methods: This randomized, double-blind, parallel-group, placebo- and open-label positive-controlled study in 197 volunteers (106 men) included 4 treatment groups: placebo, 200 mg NETU + 0.5 mg PALO (NEPA 200/0.5), 600 mg NETU + 1.5 mg PALO (NEPA 600/1.5), and 400 mg moxifloxacin. Assessments, based on ICH E14 Guidelines, included a 24-h baseline ECG after which volunteers received a single dose of treatment, followed by ECG measurements for 2 days. The primary objective was to determine the individual heart rate-corrected QT interval (QTcI) (n=196). Safety and tolerability of NEPA groups were also assessed (n=197). Results: Mean placebo-corrected QTcI change from baseline was +5 and +4 ms for NEPA200/0.5 and NEPA600/1.5, respectively. Mean placebo-corrected change from baseline for heart rate (HR) was -3 bpm for the 2 NEPA groups. Placebo-corrected changes in pulse rate (PR) and QRS durations were similar in both NEPA groups (0 to 1 ms) and not clinically different from placebo. These data show no signs of an effect of NEPA groups on QTcI. In comparison, the moxifloxacin showed the expected increase in QTcI vs placebo (+8/9 ms). The frequency of all treatment-related AEs (TRAEs) for NEPA200/0.5 was lower than placebo but slightly higher in volunteers treated with NEPA600/1.5. The most commonly reported TRAEs in the NEPA groups were constipation, upper abdominal pain, and headache. Conclusions: NEPA treatments produced no significant effects on QTcI, HR, PR, QRS interval, or cardiac morphology relative to placebo.