Beeline: A Phase 3 Study in GRIN-related Neurodevelopmental Disorder

A Multinational, Multicenter Study With an Open-Label Phase 1b and a Randomized, Double-Blind, Placebo-Controlled Phase 3 Followed by an Open-Label Extension to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Radiprodil in Participants With GRIN-Related Neurodevelopmental Disorder

The Phase 3 portion of Study RAD-GRIN-101 is a multinational, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy and safety of radiprodil in participants with GRIN-related neurodevelopmental disorder (GRIN-NDD) with a gain-of-function (GoF) genetic variant.

This study will enroll two cohorts: one cohort of participants with a minimal number of countable motor seizures (with or without behavioral symptoms) (Phase 3 Cohort 1: Qualifying Seizures Cohort); and a second cohort with disease symptoms but no seizures or fewer seizures than required for the Qualifying Seizures Cohort (Phase 3 Cohort 2: Without Qualifying Seizures Auxiliary Cohort).

Participants in each cohort will be randomized 1:1 to receive active drug (radiprodil) or matching placebo (Part A). Following completion of Part A, all eligible participants (including those previously on placebo) may continue into the open-label extension period (Part B) to receive radiprodil.

The placebo-controlled portion is expected to be approximately 16 weeks for participants in Phase 3 Cohort 1 and 28 weeks for participants in Phase 3 Cohort 2.

The study will evaluate the effect of radiprodil on seizures and non-seizure symptoms and assess safety.

Participants are assigned in a 1:1 ratio to receive either radiprodil or placebo during Part A with the opportunity to receive radiprodil in the Open-Label Extension, Part B. The dosing regimen includes a fixed titration schedule over 4 weeks.

This study is divided into the following parts:

Part A: Randomized, double-blind, placebo-controlled

• Screening/Observation Period: To assess eligibility
• Titration Period (approximately 4 weeks): Titration of radiprodil or placebo to target dose
• Maintenance Period (Part A): Target dose of radiprodil or placebo maintained for 12 weeks (Phase 3 Cohort 1) or 24 weeks (Phase 3 Cohort 2)
• Tapering and Follow-up Period: Gradual decrease and Follow-up Period for participants not entering Part B

Part B: Open-label safety follow-up period

• Open-Label Treatment Period: Participants will continue to receive radiprodil until such time as either the participant withdraws/is withdrawn from the study, sponsor terminates the study, or market access is available
• Tapering and Follow-up Period: Gradual decrease and follow-up observation period for participants upon leaving the study

Inclusion Criteria:

Part A, Participant:

• Diagnosed with GRIN-NDD with GRIN1, GRIN2A, GRIN2B, or GRIN2D gene variants known to result in GoF of the NMDA receptor
• Phase 3 Cohort 1 (Qualifying Seizures Cohort) ONLY: Experiencing at least 1 CMS per week and ≥4 CMS (generalized or focal) during screening
• With history of inadequate response to at least 2 standard antiseizure medications (ASMs)
• Phase 3 Cohort 2 (Without Qualifying Seizures Auxiliary Cohort) ONLY: With significant neurodevelopmental symptoms and a GRIN-CGI-S score ≥4
• On a stable dose of standard ASMs for at least 4 weeks prior to screening and should remain on stable doses throughout study participation
• On stable nonpharmacological treatments such as ketogenic diet and should remain stable throughout study participation

Part B:

- Participant has completed Part A and is eligible to continue study participation according to the judgement of the investigator and sponsor.

Exclusion Criteria:

PART A, Participant:

• Has clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN-NDD) that would preclude or jeopardize participant's safe participation or study drug administration or the conduct of the study according to the judgement of the investigator or sponsor.
• Is receiving >4 standard ASMs at screening
• Has a body weight of less than 5 kg at screening

Part B:

- Participant has clinically relevant medical, neurologic, or psychiatric condition and/or behavioral disorder (including those related to GRIN-NDD) that would preclude or jeopardize participant's safe participation of study drug administration or the conduct of the study according to the judgement of the investigator or sponsor.