Authors :
Presenting Author: Piero Perucca, MD, PhD – Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional de Madrid
Jacqueline French, MD – Department of Neurology and Comprehensive Epilepsy Center, New York University Grossman School of Medicine, NYU Langone Health
Michal Bajacek, PhD – Central Military Teaching Hospital
Nicole Wedick, ScD – Neurocrine Biosciences, Inc.
Grace Liang, MD – Neurocrine Biosciences, Inc.
Dietrich Haubenberger, MD, MHSc, FAAN – Neurocrine Biosciences, Inc.
Svetlana Shore, PhD – Neurocrine Biosciences, Inc.
Rationale:
NBI-921352 is a potent, selective, small molecule inhibitor of NaV1.6, a predominant sodium-channel subtype of excitatory neurons in the brain. A double-blind, randomized, controlled, dose-finding Phase 2 study (RCT [NCT05159908]) and open-label extension (OLE [NCT05493293]) evaluated the safety, pharmacokinetics (PK), and efficacy of NBI-921352 as adjunctive therapy in adults with focal-onset seizures (FOS).Methods:
Adults with FOS were randomized 1:1:1:1 to oral NBI-921352 25 mg, 50 mg, or 75 mg, or placebo (PBO) 3x per day for 11 weeks (3 weeks titration, 8 weeks maintenance), followed by either a 2-week dose taper and a 2-week follow-up period, or enrollment into OLE. Participants who entered OLE received up to 105 weeks of treatment (1-week blinded dose conversion or OL titration, 104 weeks OL), followed by dose taper and a 4-week follow-up period. The RCT primary endpoints were safety, and the exposure-response relationship between NBI-921352 PK and percent change from baseline (PCFB) in 28-day FOS frequency during the treatment period. Both studies evaluated PCFB in 28-day FOS frequency.Results:
101 participants were randomized. At RCT baseline, participants had a mean (SD) age of 42.1 (11.1) years, median (range) 28-day FOS frequency of 11 (3.5-227.5), were taking 3 (1-4) concomitant antiseizure medications (ASMs), and had failed 6 (0-15) prior ASMs. NBI-921352 was generally well-tolerated with most adverse events (AEs) of mild or moderate intensity. AEs led to study discontinuation in 12% of the NBI-921352 groups and 8% of the PBO group. Few serious AE (SAEs) occurred with NBI-921352 (3%) or PBO (4%), and there were no deaths. Steady-state PK parameters were dose proportional to NBI-921352 but had no apparent association with PCFB in 28-day FOS frequency during the treatment period (β2 coefficient range: 0.0005-0.0050). The least-squares mean difference (95% CI) in PCFB in 28-day FOS frequency during the treatment period for the 25 mg, 50 mg, and 75 mg groups versus PBO were, respectively, -17.2% (-45.1, 10.7), -15.9% (-43.9, 12.2), and -4.1% (-32.3, 24.1). The median PCFBs for the same groups were -8.6, -18.1, -25.0 versus 1.1 for PBO. Of 82 participants who enrolled in OLE (64 directly from the RCT, 18 after a gap between studies), 34 (41.5%) were treated for over 6 months. The OLE was terminated early by the Sponsor due to lack of efficacy observed in the RCT; most participants discontinued OLE early for this reason. 11% discontinued study treatment due to AEs, 9% had an SAE, and there was 1 death. A mean (SD) reduction from baseline in 28-day FOS frequency was observed by Day 14 (N=78, -33.9% [51.0]) and ranged from -27.2% (84.3) to -41.0% (31.2) at each 2-month analysis visit through Month 14 (N=12). The mean (SD) PCFB in 28-day FOS frequency was -37.9% (29.6) during the OLE.
Conclusions:
Although NBI-921352 was not associated with meaningful reductions in FOS frequency in Phase 2 trials, these findings provide valuable data regarding safety and tolerability of adjunctive NBI-921352 in adults with FOS.Funding:
Neurocrine Biosciences, Inc.