NBI-827104’s Phase 2 Disappointment Highlight Therapeutic Needs for Epileptic Encephalopathy With Continuous Spike-and-Wave During Sleep

A poster from the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, provided more detail on the failed efficacy of NBI-827104 (NeuroCrine Biosciences), a calcium channel blocker, as a treatment for patients with epileptic encephalopathy who have continuous spike-and-wave during sleep (EE-CSWS). While the agent did not meet its primary end point, the findings also point to the complexities in treating EE-CSWS, a condition with no FDA-approved medications.¹

The results, which were originally disclosed in 2022, were from a double-blind, placebo-controlled phase 2 trial (NCT04625101) that featured 24 participants who were randomly assigned 2:1 to either NBI-827104 (n = 16) or placebo (n = 8).² After 6 weeks of treatment, investigators reported no statistically significant difference between the cohorts on the primary end point of spike-wave index (SWI; least-squared [LS] mean difference, –0.04 [SEM, 0.04]; P = .43).

EE-CSWS is a childhood-onset epileptic encephalopathy characterized by cognitive, language, or behavioral regression that coincides with near-continuous spike-wave discharges during non-REM sleep. NBI-827104, which also had a registered trial in essential tremor, is a potent, selective, and orally active brain-penetrating T-type calcium channel blocker.

In the phase 2 study, also known as STEAMBOAT, log-transformed SWI ratios were evaluated using an analysis of covariance model, with treatment group as the fixed factor and log-transformed baseline SWI as the covariate (two-sided α=0.10). Secondary outcomes based on global impression measures were analyzed using the Jonckheere–Terpstra test and Fisher’s exact test.

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The trial was led by a group at NeuroCrine, as well as several other prominent clinicians, including Anthony Fine, MD, a pediatric neurologist and epileptologist at Mayo Clinic. At week 12, there was a nominally significant difference between the investigational group and placebo on the primary end point of SWI ratio (LS mean difference, –0.08 [SEM, 0.04]; P = .06). In addition, there was no between-group difference on any of the global impression instrument end points at both week 6 and 12 (all P >.10).

In terms of safety, all treatment-emergent adverse events (TEAEs) were mild to moderate, with one serious event in the NBI-827104 group deemed unrelated to the study drug and no discontinuations due to adverse events. In the OLE, 19 participants received treatment for a mean (SD) duration of 649.7 (217.6) days, during which changes from baseline in SWI were highly variable, likely reflecting the age-related course of the disorder. NBI-827104 remained well tolerated, with two participants reporting serious TEAEs and no severe adverse events observed.

There are currently no late-stage drug trials for EE-CSWS at this time. Management for the disease relies entirely on off-label use of antiseizure medications, immunomodulation, and in select cases, surgery. Some of the most common high-dose benzodiazepines used include diazepam, clobazam, and clonazepam, while other therapies like valproate, levetiracetam, and lamotrigine have had variable success.

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REFERENCES
1. Fine A, Datta A, Zafar M, et al. NBI-827104 for the Treatment of Epileptic Encephalopathy With Continuous Spike-and-Wave During Sleep (EE-CSWS): Results of Phase 2 Trials. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, GA. ABSTRACT 1.374.
2. Neurocrine Biosciences Provides Update on Phase 2 Study of NBI-827104 in Pediatric Patients with Epileptic Encephalopathy with Continuous Spike-and-Wave During Sleep. News release. NeuroCrine Biosciences. December 6, 2025. Accessed December 4, 2025. https://www.prnewswire.com/news-releases/neurocrine-biosciences-provides-update-on-phase-2-study-of-nbi-827104-in-pediatric-patients-with-epileptic-encephalopathy-with-continuous-spike-and-wave-during-sleep-301696306.html