Key takeaways:
The BeeLine phase 3 trial will evaluate radiprodil, a selective NMDA GluN2B receptor modulator, for safety and efficacy in children with GRIN-related neurodevelopmental disorder (GRIN-NDD), focusing on both seizure and non-seizure symptoms.
The study includes two cohorts: a randomized qualifying seizure group (n ≤ 60) and an auxiliary cohort for behavioral or other non-seizure symptoms (n ≤ 40), using a newly developed GRIN-specific Clinical Global Impression scale (GRIN-CGI) to measure treatment outcomes.
Phase 1b Honeycomb data showed radiprodil was generally well tolerated and substantially reduced seizure frequency, supporting its progression to the registrational BeeLine trial for this rare disorder with no approved therapies.
Research on the design of a phase 3 clinical trial investigating radiprodil, an investigational therapy for GRIN-related neurodevelopmental disorder (GRIN-NDD), was presented at the 2025 Child Neurology Society Annual Meeting in Charlotte, North Carolina. The trial, named BeeLine, will evaluate the safety and efficacy of radiprodil, a selective negative allosteric modulator of NMDA GluN2B receptors, in children with GRIN-NDD.1
Background on GRIN-related neurodevelopmental disorder
GRIN-NDD is caused by genetic variants that affect NMDA receptor subunits, leading to a range of developmental, behavioral, and seizure-related symptoms. There are currently no FDA-approved treatments for this disorder. Previous data from the phase 1b Honeycomb study (NCT05818943) showed that radiprodil was generally well tolerated and substantially reduced seizure frequency, supporting advancement into a registrational phase 3 study.2
The BeeLine trial is a placebo-controlled study designed to evaluate radiprodil’s impact on both seizure frequency and non-seizure symptoms associated with GRIN-NDD. It includes 2 cohorts:
- a randomized qualifying seizure cohort (RQS) with at least 4 baseline countable motor seizures during a 4-week observation period (n ≤ 60)
- a randomized auxiliary cohort (RA) for participants with behavioral or other non-seizure symptoms who do not meet seizure frequency criteria (n ≤ 40).1
As part of the BeeLine study, researchers developed a GRIN-specific Clinical Global Impression scale (GRIN-CGI) to assess the severity and change of GRIN-NDD symptoms. This adapted scale is derived from a conceptual model based on data from caregiver surveys (n = 57) and interviews (n = 20). The model identified key symptom domains and treatment priorities for inclusion, focusing on receptive and expressive communication, gross and fine motor function, and behavioral regulation. The GRIN-CGI will be validated by clinical experts for use as a primary tool to measure patient outcomes in the BeeLine trial.
According to the CNS abstract, the GRIN-CGI is intended to capture clinically meaningful changes across diverse GRIN-NDD phenotypes and to measure treatment-related effects not limited to seizure control. Researchers noted that the BeeLine study will further evaluate radiprodil’s potential to target underlying disease mechanisms associated with NMDA receptor dysfunction in this rare neurodevelopmental disorder.
Previous phase 1 data for radiprodil
Radiprodil’s advancement to phase 3 follows promising results from the earlier Honeycomb study, which evaluated 15 patients with GRIN-related disorders who carried gain-of-function variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D. In Honeycomb, treatment with radiprodil resulted in a median reduction of 86% in seizure frequency relative to baseline, with 71% of patients achieving at least a 50% reduction in countable motor seizures. One patient achieved seizure freedom during the maintenance phase. The therapy was well tolerated, with no treatment-related serious adverse events reported.2
Together, the Honeycomb and BeeLine studies represent a continued effort to establish a therapeutic approach for GRIN-NDD, a condition with significant unmet medical need and currently no approved therapies.1,2
References:
1. Chin R, Whyte J, Ventola P, et al. Design of a Phase 3 Radiprodil Trial in GRIN-Related Neurodevelopmental Disorder and Development of an Adapted Clinical Global Impression Scale. Abstract. Presented at: Child Neurology Society Annual Meeting. October 8-11, 2025. Charlotte, North Carolina.
2. Meglio M. Radiprodil Significantly Reduces Seizure Frequency in Phase 1b Honeycomb Study of GRIN-Related Neurodevelopmental Disorder. NeurologyLive. Published September 10, 2024. Accessed October 8, 2025. https://www.neurologylive.com/view/radiprodil-significantly-reduces-seizure-frequency-phase-1b-honeycomb-study-grin-related-neurodevelopmental-disorder
