radiprodil (RGH-896) / AbbVie, GRIN Therap - LARVOL DELTA

Development of Novel Clinical Global Impression Scales Specific to the Common Signs and Symptoms of GRIN-Related Neurodevelopment Disorder (AES 2025) - "The development and validation of GRIN-CGI-S and GRIN-CGI-C scales will facilitate assessment of the efficacy of radiprodil across GRIN-NDD symptom domains identified by caregivers as being important to treat."

Clinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • Psychiatry • GRIN2A • GRIN2B • GRIN2D

Study to Evaluate the Pharmacokinetics and Safety Effects Following Coadministration of Carbamazepine or Itraconazole With Radiprodil in Healthy Adults (clinicaltrials.gov) - P1 | N=30 | Terminated | Sponsor: GRIN Therapeutics, Inc. | Recruiting ➔ Terminated; Study was terminated due to the lack of operational capabilities of the sites to segregate participants as needed.

Trial termination • CNS Disorders

Phase 1, Open-label, Drug-drug Interaction Study to Assess Effect Between Radiprodil and the Co-administered Drugs. (clinicaltrials.gov) - P1 | N=18 | Completed | Sponsor: GRIN Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • CNS Disorders

Beeline: A Phase 3 Study in GRIN-related Neurodevelopmental Disorder (clinicaltrials.gov) - P3 | N=100 | Recruiting | Sponsor: GRIN Therapeutics, Inc.

New P3 trial • CNS Disorders • Developmental Disorders • Psychiatry

New advances in small molecule drugs targeting NMDA receptors. (PubMed, Acta Pharmacol Sin) - "Among various therapeutic indications, depression has emerged as an especially active area of investigation, with mechanistically diverse compounds ranging from broad-spectrum channel blockers (ketamine, dextromethorphan, esmethadone) to glycine site modulators (rapastinel, 4-chlorokynurenine, D-cycloserine) and allosteric modulators (apimostinel, zelquistinel), progressing through clinical pipelines. Beyond depression, NMDA receptor-targeted drug discovery is also advancing in other challenging CNS disorders, including neurodegenerative diseases (salzanemdor, NYX-458), pain (NYX-2925), epilepsy (radiprodil), and stroke (nelonemdaz, NP10679). Collectively, these developments reflect the maturation of NMDA receptor pharmacology and reaffirm the broad therapeutic potential of NMDA receptor modulation, while highlighting promising directions for future drug discovery."

Journal • Review • Cardiovascular • CNS Disorders • Depression • Epilepsy • Mental Retardation • Pain • Psychiatry

Inhibition of GluN2B-containing N-methyl-d-aspartate receptors by radiprodil. (PubMed, Brain) - "In addition, radiprodil delays the onset of seizures (458 ± 90 sec vs 207 ± 23 sec of vehicle group) in response to the in vivo administration of the chemoconvulsant pentylenetetrazole. These data support the potential utility of GluN2B-selective antagonists like radiprodil for clinical treatments of neurological conditions, where clinical etiologies may involve increased current mediated by GluN2B-containing NMDA receptors."

Journal • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Mental Retardation • Movement Disorders • Psychiatry • GRIN2A • GRIN2B

Phase 1, Open-label, Drug-drug Interaction Study to Assess Effect Between Radiprodil and the Co-administered Drugs. (clinicaltrials.gov) - P1 | N=18 | Active, not recruiting | Sponsor: GRIN Therapeutics, Inc. | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders

Study to Evaluate the Pharmacokinetics and Safety Effects Following Coadministration of Carbamazepine or Itraconazole With Radiprodil in Healthy Adults (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: GRIN Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders

Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies. (PubMed, Pediatr Neurol) - "Targeted approaches for channelopathies include antisense oligonucleotides and gene therapies, such as zorevunersen and ETX101 for SCN1A-related Dravet syndrome, alongside novel small molecules for other ion channel disorders. Advances in targeting neurotransmitter receptor dysfunctions, including γ-aminobutyric acid and glutamate receptor variants, highlight the use of modulators such as gaboxadol, radiprodil, and l-serine, alongside emerging gene therapies...Future directions focus on addressing the challenges in developing and implementing gene-based therapies, integrating systems biology, leveraging artificial intelligence for data analysis, and fostering collaboration among stakeholders. The rapidly advancing field of precision therapeutics for DEEs holds promise to improve outcomes through tailored, equitable, and patient-centered care."

Journal • Review • CNS Disorders • Developmental Disorders • Epilepsy • Gene Therapies • Metabolic Disorders • Movement Disorders • XBP1

Phase 1, Open-label, Drug-drug Interaction Study to Assess Effect Between Radiprodil and the Co-administered Drugs. (clinicaltrials.gov) - P1 | N=18 | Not yet recruiting | Sponsor: GRIN Therapeutics, Inc.

New P1 trial • CNS Disorders

Study to Evaluate the Pharmacokinetics and Safety Effects Following Coadministration of Carbamazepine or Itraconazole With Radiprodil in Healthy Adults (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: GRIN Therapeutics, Inc.

New P1 trial • CNS Disorders

An Open-label, 2 Part, Study to Assess the Pharmacokinetics of a Spray Dried Dispersion Formulation of Radiprodil Under Fasted and Fed Conditions in Healthy Adult Subjects: Part A (ANZCTR) - P1 | N=18 | Completed | Sponsor: GRIN Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion

An Open-label, 2 Part, Study to Assess the Pharmacokinetics of a Spray Dried Dispersion Formulation of Radiprodil Under Fasted and Fed Conditions in Healthy Adult Subjects: Part B (ANZCTR) - P1 | N=18 | Completed | Sponsor: GRIN Therapeutics, Inc. | Recruiting ➔ Completed

Trial completion

GRIN Therapeutics Receives Priority Medicines (PRIME) Designation from EMA for Radiprodil in the Treatment of GRIN-Related Neurodevelopmental Disorder (PRNewswire) - "GRIN Therapeutics...today announced that the European Medicines Agency (EMA) has granted Priority Medicine (PRIME) designation to radiprodil, the company's investigational, potent negative allosteric modulator selectively targeting the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), for the treatment of GRIN-related neurodevelopmental disorder (NDD). This decision follows the recent announcements that radiprodil was awarded Breakthrough Therapy designation for the treatment of seizures associated with GRIN-related NDD with gain-of-function (GoF) mutations and Orphan Drug designation for the treatment of GRIN-related NDD by the U.S. Food and Drug Administration (FDA) in February and March 2025, respectively."

PRIME • CNS Disorders

GRIN Therapeutics Receives FDA Orphan Drug Designation for Radiprodil for the Treatment of GRIN-Related Neurodevelopmental Disorder (PRNewswire) - "GRIN Therapeutics, Inc...today announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug designation for its investigational drug, radiprodil, for the treatment of GRIN-related neurodevelopmental disorder (NDD)....The company is on track to initiate a pivotal Phase 3 trial for radiprodil in mid-2025 for the treatment of GRIN-related NDD with GoF mutations..."

New P3 trial • Orphan drug • Developmental Disorders

GRIN Therapeutics Receives FDA Breakthrough Therapy Designation for Radiprodil (PRNewswire) - "GRIN Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to radiprodil, the company's investigational, potent negative allosteric modulator selectively targeting the N-methyl-D-aspartate receptor subtype 2B (NR2B or GluN2B), for the treatment of seizures associated with GRIN-related neurodevelopmental disorder with gain-of-function (GoF) mutations...Breakthrough Therapy designation of radiprodil was supported by positive data from the Phase 1b Honeycomb study in pediatric patients with confirmed GoF mutations across GRIN genotypes...The company remains on track to initiate a Phase 3 pivotal trial for radiprodil in GRIN-related neurodevelopmental disorder in mid-2025."

Breakthrough therapy • New P3 trial • CNS Disorders

An Open-label, 2 Part, Study to Assess the Pharmacokinetics of a Spray Dried Dispersion Formulation of Radiprodil Under Fasted and Fed Conditions in Healthy Adult Subjects: Part B (ANZCTR) - P1 | N=18 | Not yet recruiting | Sponsor: GRIN Therapeutics, Inc.

New P1 trial

A Mouse Model Harboring Seizure-associated Gain-of-function grin2bvariant: From Functional Evaluation to Rescue Pharmacology (AES 2024) - "These data indicate that the heterozygous S810R mice mimic patient's phenotype, show an altered synaptic connectivity and activity, and a significant reduction in seizure threshold. Radiprodil can significantly reduce the enhanced current amplitude of evoked EPSCs in S810R mice and may delay the latency of GTCS induced by PTZ."

Preclinical • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Mood Disorders • Psychiatry • GRIN2B

Pharmacokinetics, Safety/Tolerability, and Effect on Seizure Frequency and Behavior of Individually Titrated Radiprodil Doses in Children With GRIN-Related Disorder: Preliminary Multicenter Study Data (AES 2024) - P1 | "Radiprodil has the potential to be a selective treatment for GRIN-related disorder and appears to be well tolerated to date. Recruitment efforts support the feasibility of enrolling a large enough cohort to allow for effectively evaluating the safety/tolerability of radiprodil across GRIN variants."

Clinical • PK/PD data • CNS Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Psychiatry • GRIN2A • GRIN2B • GRIN2D

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 (AES 2024) - P1 | "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."

Clinical • PK/PD data • CNS Disorders • Developmental Disorders • Epilepsy • Infectious Disease • Psychiatry • GRIN2A • GRIN2B • GRIN2D

An Open-label, 2 Part, Study to Assess the Pharmacokinetics of a Spray Dried Dispersion Formulation of Radiprodil Under Fasted and Fed Conditions in Healthy Adult Subjects: Part A (ANZCTR) - P1 | N=18 | Not yet recruiting | Sponsor: GRIN Therapeutics, Inc.

New P1 trial

Honeycomb: Evaluation of Radiprodil in Children with GRIN-related Disorder (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: GRIN Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Epilepsy

A Phase 1 Study to Evaluate the Effect of Multiple Doses of Rabeprazole on the Pharmacokinetics of a Single Dose of Radiprodil in Healthy Adult Participants (ANZCTR) - P1 | N=18 | Completed | Sponsor: GRIN Therapeutics, Inc. | Not yet recruiting ➔ Completed | Initiation date: Aug 2024

Trial completion • Trial initiation date

Honeycomb: Evaluation of Radiprodil in Children with GRIN-related Disorder (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: GRIN Therapeutics, Inc. | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2025 ➔ Nov 2026

Trial completion date • Trial primary completion date • CNS Disorders • Epilepsy

Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development. (PubMed, Epilepsia) - "These investigational treatments include azetukalner (XEN1101), a potent, KV7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Nav1.1 protein expression and improve..."

Journal • Metastases • CNS Disorders • Depression • Epilepsy • Major Depressive Disorder • Mood Disorders • Psychiatry • NAV1