Authors :
Presenting Author: Anthony Fine, MD – Mayo Clinic
Alexandre Datta, MD – University Children’s Hospital Basel UKBB
Muhammad Zafar, MD – Duke University School of Medicine
Elia Pestana Knight, MD – Cleveland Clinic
Deborah Lee, MD, PhD – Neurocrine Biosciences, Inc.
Donald Phillips, MD, MPH – Children's Hospital of Orange County; UC Irvine School of Medicine
Nicole Wedick, ScD – Neurocrine Biosciences, Inc.
Carolyn McMicken, PsyD – Neurocrine Biosciences, Inc.
Grace Liang, MD – Neurocrine Biosciences, Inc.
Dietrich Haubenberger, MD, MHSc, FAAN – Neurocrine Biosciences, Inc.
Svetlana Shore, PhD – Neurocrine Biosciences, Inc.
Rationale:
Epileptic encephalopathy with continuous spike-and-wave during sleep (EE-CSWS) is a rare childhood epilepsy associated with spike-wave electroencephalogram (EEG) discharges during non-rapid eye movement (NREM) sleep. NBI-827104 is a novel, selective T-type calcium channel blocker that demonstrated antiseizure activity in preclinical studies. A double-blind, placebo-controlled (DBPC) Phase 2 trial (NCT04625101) was conducted to investigate the efficacy, safety, tolerability, and pharmacokinetics of NBI-827104 in EE-CSWS, followed by an open-label extension (OLE; NCT05301894) to evaluate long-term safety and tolerability.
Methods:
Participants aged 4–12 years with EE-CSWS were randomized 2:1 to once-daily NBI-827104 or placebo (PBO). The DBPC study included screening (4 weeks), titration to the highest tolerated of 3 dose levels (3 weeks), maintenance (9 weeks), taper (1 week), and safety follow-up (4 weeks). Participants could enroll in the OLE either de novo or after completing the DBPC. OLE participants received up to 229 weeks of maintenance treatment with the highest tolerated of 5 NBI-827104 dose levels. The primary endpoint in the DBPC study was ratio of spike-wave index (SWI) at Wk6 to baseline (BL), as measured by video EEG during the first hour of NREM sleep. SWI ratio at Wk12 to BL was a secondary endpoint. Log-transformed SWI ratios were analyzed using analysis of covariance with treatment group as a fixed factor and log-transformed BL SWI as a covariate (2-sided α=0.10). Global impression instruments were included as secondary outcomes and analyzed using Jonckheere Terpstra and Fisher’s exact tests. P-values were not adjusted for multiplicity. Safety assessments included treatment-emergent adverse events (TEAEs). The OLE evaluated long-term safety and the ratio of SWI compared to BL.Results:
Of 24 randomized participants (NBI-827104, n=16; PBO, n=8), 22 completed the DBPC study (n=15; n=7). No statistically significant difference between groups was found for SWI ratio at Wk6 to BL (least-squared mean difference [SEM], -0.04 [0.04], P=0.43). A nominally significant difference was found in SWI ratio at Wk12 to BL (-0.08 [0.04], P=0.06). No statistically significant differences were observed for global impression instrument endpoints at Wk6 or Wk12 (all P>0.10). All TEAEs were mild-to-moderate, with 1 serious TEAE in the NBI-827104 group (unrelated to study drug) and no TEAEs leading to study discontinuation. In the OLE, 19 participants were treated for a mean (SD) duration of 649.7 (217.6) days. Change from BL in SWI was highly variable between participants, likely driven by age-related disease course. NBI-827104 continued to be well tolerated, with 2 participants reporting serious TEAEs and no severe TEAEs. The OLE was terminated early due to limited efficacy during the DBPC study.Conclusions:
NBI-827104 did not meet the primary endpoint in the DBPC Phase 2 study. NBI-827104 was generally well tolerated.Funding:
Neurocrine Biosciences, Inc.