Abstracts

This is a Late Breaking abstract

Rationale: Evaluate pharmacokinetics (PK) and short-term safety and tolerability of lacosamide (LCM) in neonates with repeated electroencephalographic neonatal seizures (ENS) inadequately controlled with previous antiseizure medications (ASMs).

Methods: Ongoing Phase 2/3, multicenter, open-label, randomized, active comparator (AC) trial (SP0968/NCT04519645) enrolling neonates (≥ 34 and < 46 weeks of corrected gestational age and < 28 days of postnatal age [PNA]) with video-electroencephalogram confirmation of ≥ 2 minutes of cumulative ENS or ≥ 3 identifiable ENS before entering the Treatment Period, despite previous ASM treatment. A Screening Period (≤ 36 hours) was followed by a 96-hour Treatment Period. Patients were randomized 1:1 (stratified by seizure severity) to LCM 15 mg/kg/day (30-minute intravenous infusion) or an AC (chosen and dosed based on standard of care per local practice and treatment guidelines). Rescue medication, if needed, could be administered. Patients could continue randomized treatment in the Extension Period (up to 28 days of PNA). Patients who discontinued (in the Treatment or Extension Period) entered a Safety Follow-up Period. PK profiles for neonates were derived from an existing LCM population PK model (CL0447-Part IV; data from participants aged 1 month–16 years and adults). Short-term safety was assessed with treatment-emergent adverse events (TEAEs) and treatment-emergent marked abnormalities in 12-lead ECG, hematology and chemistry parameters, and vital signs.

Results: In this database snapshot of Aprril 27, 2022 (data cut: March 28, 2022), 9 patients had been randomized (mean PNA: 4.1 days; 55.6% female), 6 received LCM and 3 AC. Mean exposure duration was 217.6 and 28.8 hours in the LCM and AC groups, respectively. LCM plasma concentration data were obtained from 5 patients. Individual PK profiles (Figure) showed the population PK model under predicted LCM exposure in neonates. Simulations to estimate LCM exposure in steady state provided geometric mean PK parameters: average concentration, 15.3 µg/mL; maximum concentration, 18.9 µg/mL; area under the curve (AUC), 367 µg•h/mL; half-life, 12.2 hours (Table). AUC was 1.4- and 1.8- fold higher in neonates vs adults in the presence and absence of inducing ASMs, respectively. In the LCM group, 4 (66.7%) patients had TEAEs, 1 (16.7%) had serious TEAEs, and 1 (16.7%) had drug-related TEAEs. In the AC group, no patients had TEAEs. No patients discontinued due to TEAEs or deaths. No safety signals were identified from review of ECG, laboratory and vital sign data.

Conclusions: In this snapshot of the first randomized clinical trial of LCM in neonates, PK modeling showed that LCM treatment at 15 mg/kg/day resulted in higher estimated exposures vs adults. Despite the higher estimated exposure, no general safety concerns were identified. An external Data Monitoring Committee recommended the trial continue without modification. The trial is expected to complete enrollment in 2023.

Funding: Sponsored by UCB Pharma