Pharmacokinetics, Safety/tolerability, and Effect on Seizure Frequency and Behavior of Individually Titrated Radiprodil Doses in Children with Grin-related Disorder: Top Line Multicenter Study Data
Abstract number :
1.502
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1462
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Author: Pierandrea Muglia, MD – GRIN Therapeutics, A Neurvati Neurosciences Company
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
Stephen Traynelis, PhD – Emory University School of Medicine
Bruce Leuchter, MD – GRIN Therapeutics, A Neurvati Neurosciences Company
Presenting Author: Michael Panzara, MD, MPH – GRIN Therapeutics, A Neurvati Neurosciences Company
Rationale: Radiprodil is an oral, negative allosteric modulator of NMDARs with high GluN2B binding affinity being studied as a potential treatment for children with GRIN-related neurodevelopmental disorder. This severe disorder with high unmet need is characterized by epilepsy, developmental delay, and behavioral problems and caused by pathogenic variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D. We present top line analyses from an ongoing study of individually titrated radiprodil doses in children with GRIN-related neurodevelopmental disorder.
Methods: In this phase 1b, open-label, multicenter, standard-of-care, add-on study (EudraCT: 2022-000317-14), Patients (pts) ≥6 mo to ≤12 y of age with gain of function (GOF) GRIN1, GRIN2A, GRIN2B, or GRIN2D variants were eligible. Two cohorts are included: pts with drug-resistant seizures with or without behavioral symptoms and pts with behavioral symptoms (CGI-S ≥4) but without a countable number of seizures to qualify for the seizure cohort. Part A includes a ≤5-wk screening period, a 4-wk observation period, an individualized dose-escalation period, and an 8-wk maintenance period. Eligible seizure cohort pts must have ≥1 countable motor seizure (generalized or focal) per week and ≥4 during the observation period. Radiprodil 0.05 mg/kg BID was incrementally increased to an optimal dose and exposure level using a dedicated, physiologically based pharmacokinetic model based on individually measured drug exposure, safety/tolerability, and initial efficacy. Part B assessed long-term safety. Primary endpoints are safety/tolerability; efficacy endpoints include change from baseline in seizure frequency and non-seizure behavioral outcomes.
Results: Fifteen pts aged 2–12 y are enrolled (seizure cohort, n=8; behavioral cohort, n=7). Baseline demographic and disease characteristics were generally balanced and representative of the target population. GRIN1, GRIN2A, and GRIN2B GOF variants were evenly represented. Patients had high baseline seizure activity despite treatment with multiple anti-seizure medications. Radiprodil was generally well tolerated. Most common adverse events (AEs) involved infection or underlying disease symptoms. Three serious AEs of infections unrelated to radiprodil were reported. A median reduction from baseline of nearly 86% in countable motor seizures was observed during the 8-week maintenance period after radiprodil treatment; 71% of pts had ≥50% reductions. Both clinicians and caregivers described clinical improvement in most patients over the course of the study regardless of the occurrence of motor seizures.
Conclusions: Radiprodil appears to be well-tolerated to date with potential signs of meaningful clinical effects in this severe disorder with high unmet need. These results support advancing radiprodil to the next development phase as a potential selective treatment for GRIN-related neurodevelopmental disorder.
Funding: GRIN Therapeutics, Inc., a Neurvati Neurosciences Company
Anti-seizure Medications