Key takeaways:
- The global Phase 3 Beeline trial has dosed its first patient, marking the most advanced evaluation to date of radiprodil for GRIN-related neurodevelopmental disorder with gain-of-function variants.
- Radiprodil is designed to directly target NMDA receptor overactivation, with the potential to address seizures as well as cognitive and behavioral manifestations of GRIN-NDD.
- The trial builds on strong Phase 1b/2a data showing substantial seizure reduction and clinical improvement, using a disease-specific endpoint developed with caregiver input.
GRIN Therapeutics has dosed the first patient in its global phase 3 Beeline trial evaluating radiprodil, an investigational therapy for individuals with GRIN-related neurodevelopmental disorder (GRIN-NDD) caused by gain-of-function variants, according to a company announcement. The milestone marks the start of the first phase 3 program specifically designed to test a targeted treatment intended to address the underlying biology of GRIN-NDD rather than individual symptoms alone, the company stated in a press release.1
GRIN-NDD is a rare and complex neurodevelopmental condition driven by pathogenic variants in genes encoding subunits of the N-methyl-D-aspartate (NMDA) receptor, stated GRIN. Gain-of-function variants lead to receptor overactivation, contributing to seizures, developmental delay, behavioral challenges, and cognitive impairment. Radiprodil is designed as a selective negative allosteric modulator of the NMDA receptor GluN2B subunit, with the goal of directly counteracting this overactivation and potentially modifying the course of disease.
“This study reflects a truly collaborative effort between investigators, patient communities, and industry partners,” said Kristen Park, MD, pediatric epileptologist in the Division of Neurology at Children’s Hospital Colorado and principal investigator for the Beeline trial at that site. Park noted that GRIN-NDD currently has limited treatment options and emphasized that the trial will evaluate whether radiprodil can address not only seizures but also cognitive and behavioral manifestations of the disorder.1
Trial design and endpoints
The Beeline trial (NCT07224581) is a global phase 3 study designed to evaluate the efficacy and safety of radiprodil in patients aged 1 month to 18 years with confirmed gain-of-function GRIN variants.1,2
In addition to traditional clinical outcome measures and assessments of seizure reduction, the study incorporates a disease-specific endpoint: the GRIN-specific Clinical Global Impression (GRIN-CGI) scale. This tool was developed in collaboration with caregivers to better capture clinically meaningful change across the broad spectrum of GRIN-NDD manifestations.1
According to GRIN Therapeutics, the inclusion of both disease-specific and conventional endpoints reflects the heterogeneity of GRIN-NDD and the need to evaluate outcomes beyond seizure frequency alone. The trial is being conducted across multiple regions globally, with collaboration from Angelini Pharma outside North America to support potential future access for patients in Europe and other regions if the therapy is approved.
Radiprodil’s mechanism of action differentiates it from non-targeted anticonvulsant therapies commonly used in this population. By selectively modulating the GluN2B subunit of the NMDA receptor, radiprodil is intended to directly address the dysregulated receptor signaling that underlies GRIN-NDD, rather than providing symptomatic control alone. The company has stated that this approach offers the potential to impact multiple disease manifestations arising from receptor overactivation.
"This study reflects a truly collaborative effort between investigators, patient communities, and industry partners," said Kristen Park, MD, pediatric epileptologist in the Division of Neurology at Children's Hospital Colorado and Principal Investigator for the Phase 3 Beeline trial at the Children's Hospital Colorado trial site, in a statement.
"GRIN-NDD is one of the most complex neurodevelopmental disorders with limited treatment options today. The Beeline trial gives us the opportunity to further evaluate whether radiprodil can address not only seizures but also the cognitive and behavioral aspects of the disease and provide the kind of treatment option that patients and families have been hoping for,” added Park.
Phase 1 & 2 data for radiprodil
The phase 3 Beeline trial builds on results from the phase 1b/2a open-label Honeycomb study. In that earlier trial, patients with countable motor seizures who received radiprodil experienced a median reduction of 86% in seizure frequency compared with baseline. During the study, 71% of patients achieved more than a 50% reduction in countable motor seizures, and six of seven patients were seizure-free on at least 80% of days during the eight-week maintenance period.
Beyond seizure outcomes, clinicians and caregivers generally assessed patients as improved over the course of the Honeycomb study, as measured by Clinician and Caregiver Global Impressions of Change and the Aberrant Behavior Checklist–Community. The most common adverse events observed were associated with infections or the underlying disease, and serious adverse events were similarly attributed to these factors and assessed as unrelated to radiprodil.
Radiprodil has received multiple regulatory designations, including Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease designations from the FDA, as well as Priority Medicines designation from the European Medicines Agency and a positive opinion for orphan designation from the EMA’s Committee for Medicinal Products for Human Use. The Beeline trial represents the most advanced evaluation of radiprodil to date in GRIN-NDD and will play a central role in determining whether targeted modulation of NMDA receptor activity can translate into meaningful clinical benefit for this rare patient population.
"With the first patient dosed, the Beeline trial marks a pivotal moment for GRIN Therapeutics and the community. For the first time, through the Phase 3 Beeline trial, patients have the opportunity to receive a drug that specifically targets the abnormal receptor leading to their condition – a drug that aims to address the underlying biology of GRIN-NDD, potentially modifying the course of disease," said Michael Panzara, MD, MPH, chief medical officer, GRIN Therapeutics.
References:
- GRIN Therapeutics announces first patient dosed in global phase 3 Beeline trial of investigational radiprodil for GRIN-related neurodevelopmental disorder. GRIN Therapeutics. Published January 9, 2026. Accessed January 9, 2026. https://www.prnewswire.com/news-releases/grin-therapeutics-announces-first-patient-dosed-in-global-phase-3-beeline-trial-of-investigational-radiprodil-for-grin-related-neurodevelopmental-disorder-302656999.html
- Beeline: A phase 3 study in GRIN-related neurodevelopmental disorder. Clinicaltrials.gov. Updated November 4, 2025. Accessed January 9, 2026. https://clinicaltrials.gov/study/NCT07224581
