Authors :
Presenting Author: Brian Moseley, MD – UCB
Jody M Cleveland, MS – UCB, Morrisville, NC, United States
Walter Krauwinkel, PharmD – UCB, Braine-l'Alleud, Belgium
Carrie McClung, MS – UCB, Morrisville, NC, United States
Robert Roebling, MD – UCB, Monheim am Rhein, Germany
Frank Weinsberg, PhD – UCB, Monheim am Rhein, Germany
Nicole H Cobo, MD – MemorialCare Miller Children's & Women's Hospital Long Beach, Long Beach, CA, United States
Jeffrey Gold, MD PhD – UC San Diego
Kristen C Heinan, MD – Pediatric Neurology and Epilepsy Clinic, University of Virginia Medical Center, Charlottesville, VA, United States
Anuj Jayakar, MD – Nicklaus Children's Hospital, Miami, FL, United States
Steven M Wolf, MD – Westchester Medical Center, Hawthorne, NY, United States
Rationale:
To evaluate the efficacy, safety, and pharmacokinetics of lacosamide (LCM) in neonates with repeated electroencephalographic neonatal seizures (ENS).
Methods:
SP0968 (NCT04519645) was a phase 2/3, multicenter, open-label, randomized, active comparator (AC) trial in neonates (≥ 34 and < 46 weeks of corrected gestational age; < 28 days of postnatal age [PNA]; ≥ 2.3 kg) with video-electroencephalogram (vEEG) confirmation of ≥ 2 min of cumulative ENS or ≥ 3 identifiable ENS despite previous antiseizure medication treatment. Screening (≤ 36 h) was followed by a 96-h treatment period. Patients were randomized 1:1 (stratified by seizure severity) to LCM 15 mg/kg/day (5 mg/kg q8h via 30-min intravenous infusions) or an AC (chosen and dosed based on standard of care per local practice and treatment guidelines). Rescue medication (RM) could be administered if needed; however, patients were excluded from the primary efficacy analysis if this occurred within 3 h after first dose and were treated as non-responders for responder outcomes. Patients who benefited from randomized treatment could continue in an extension period (up to 28 days PNA). Patients who discontinued at any time entered a 14-day safety follow-up. The primary outcome was reduction in seizure burden (defined as total minutes of ENS per hour) from baseline (BL) vEEG (−2 to 0 h before treatment initiation) to evaluation period vEEG (1 to 3 h after treatment initiation). Secondary outcomes included incidence of treatment-emergent adverse events (TEAEs) and mean serum concentrations of LCM.Results:
Of 26 patients who received ≥ 1 dose of treatment, 14 received LCM and 12 AC (mean PNA 3.7 days; 53.8% female; Safety Set [SS]). The AC treatments received were phenobarbital (5 [41.7%]), fosphenytoin (5 [41.7%]), and levetiracetam (2 [16.7%]). Although 15 patients were randomized to LCM, 1 ultimately received AC rather than LCM and was included in the LCM Full Analysis Set (FAS; patients in SS with interpretable vEEG data from both BL and evaluation period) as per randomized treatment (LCM n=15; AC n=9). Among patients without RM use (LCM n=11; AC n=9), the median reduction of seizure burden from BL to evaluation period was 4.74 min/h (range: −0.9, 22.0) with LCM and 2.51 min/h (range: −32.4, 19.6) with AC (Figure 1). In the LCM and AC groups, 9/15 (60.0%) and 6/9 (66.7%) patients were responders, 9/15 (60.0%) and 4/9 (44.4%) were ≥ 80% responders, and 9/14 (64.3%) and 6/8 (75.0%) were seizure free at 24 h, respectively (Figure 1). In the LCM group, 9 (64.3%) patients had 21 TEAEs, 1 (7.1%) had 2 drug-related TEAEs, and 2 (14.3%) had a single serious TEAE each; in the AC group, 5 (41.7%) patients had 21 TEAEs (Table 1). The geometric mean serum concentration of LCM was 7.003 μg/mL at 30–90 min (n=11) and 5.949 μg/mL at 6–8 h (n=12) after start of first infusion (Pharmacokinetic Per-Protocol Set).Conclusions:
In this first randomized clinical trial of LCM in neonates, LCM treatment reduced seizure burden and was well tolerated. Although LCM exposure tended to be higher in neonates, serum concentrations were generally in agreement with exposure in adults at a dose of 400 mg/day LCM (without use of inducers).Funding: UCB-sponsored