Clinician Information

Targeting NMDA Dysregulation to Treat Challenging Neurodegenerative Disorders

Extensive research has confirmed the role of the N-methyl-D-aspartate (NMDA) receptor in the regulation of physiological functions including synaptic plasticity, long-term potentiation, learning, and memory. In the brain and nervous system, the activity of the NMDA receptor is tightly regulated, and excessive activation is associated with the clinical manifestations in several neurodevelopmental syndromes.

Building on our deep understanding of NMDA biology and the ability to modulate the activity of the NMDA receptor subunit NR2B, GRIN Therapeutics is advancing a targeted approach to the potential treatment of GRIN-related disorders and other pediatric neurodegenerative disorders.

Precision modulation of the NMDA receptor presents an opportunity for development of targeted therapeutics with potential utility in the treatment of neurodevelopmental disorders including GRIN-related disorders, tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). Radiprodil is an investigational oral, selective, negative allosteric modulator of the NR2B subunit of the NMDA receptor.

Radiprodil for the Treatment for GRIN-related Disorders

In in vitro assay studies, radiprodil has been shown to attenuate the measured overactivity of NMDA receptors containing NR2B subunits coded by GRIN2B with gain-of-function (GoF) mutations. In studies in both acute and sub-chronic animal models, radiprodil has shown anticonvulsant effects including age-dependent anticonvulsant activity with the strongest protective effects in rat pups whose brain developmental status corresponds with that of human infants (Auvin et al., 2020). In addition, there is initial preliminary evidence in patients with GRIN1 and GRIN2D related disorders caused by in vitro established GoF mutations that broad spectrum NMDA antagonists can reduce seizure burden (Li et al., 2016; Xu et al., 2021).

Progress in Pipeline Development


About the Honeycomb Study

GRIN Therapeutics is conducting the Honeycomb Study, a Phase 1b open-label clinical trial to evaluate the safety, tolerability and pharmacokinetics of radiprodil as an add-on therapy to standard of care and its impact on symptoms including seizures, behavioral changes, sleep disruption and changes in motor function in children with GRIN-related disorders caused by GoF variants. This trial will include up to 24 participants between the ages of six months and 12 years who have been confirmed to have GoF variants causing GRIN-related disorders, including variants on the GRIN1, GRIN2A, GRIN2B, and GRIN2D genes. Upon completion of the treatment, participants may have the option to participate in a long-term extension study.

For additional information about the Honeycomb Study, visit or

Radiprodil Phase 1B Currently Enrolling in Europe


  • Evaluate safety and tolerability of radiprodil
  • Identify the optimal close range for future studies
  • Determine pharmacokinetics (pk) and plasma exposure of radiprodil

Key Secondary

  • Measure the impact of radiprodil on:
    • Seizure burden
    • EEG
    • Behavioral symptoms
    • Sleep
    • Motor function
    • Caregiver burden
    • Global impression of effect

Key Inclusion /
Exclusion Criteria

  • Confirmed gain-of-function (GoF) variant
  • Age between 6 months and 12 years of age
  • For seizure cohort:
    • At least 1 observable seizure per week
    • Seizures did not improve after two mediations
  • For behavioral cohort:
    • Significant behavioral symptoms

Radiprodil Phase 1B – ongoing trial

Targeting Other Neurodevelopmental Disorders

Based on its observed mechanism of action, radiprodil could also have potential utility in the treatment of other neurodevelopmental disorders associated with abnormal expression of NMDA receptors, including TSC and FCD.

Potential radiprodil market opportunity

With the ability to target the NR2B-subunit of the NMDA receptor, radiprodil has the potential to target the pathogenesis of malformation of cortical development (MCD)-associated epilepsies including TSC and FCD. It has been shown to have anticonvulsant activity in a range of epilepsy and seizures models and in models characterized by enhanced NMDA signaling. Möddel et al showed increased NR2B expression in dysplastic cortex resected from drug resistant epilepsy patients correlated with the presence of prolonged ictal-like epileptiform activity in vitro (Möddel et al., 2005). The differential expression of NR2B-containing heteromeric NMDA receptors, the role of the NR2B-NMDA receptor in the generation of epileptiform activity in TSC and FCD, the positive effects of NR2B-modulation ex-vivo, and in vivo and in vitro data showing antiepileptic effects of radiprodil all indicate that it has the potential to control seizures in these patient populations.

Tuberous sclerosis complex

  • Characterized by increased expression of NR2B in tubers vs. normal cortex
  • Risk of epilepsy, autism and intellectual disability
  • Poor outcomes from surgical or pharmacological treatment; only ~1/3 of patients achieve seizure control with pharmacological treatment alone

Focal cortical dysplasia

  • Group of developmental disorders arising from malformations of cortical development
  • Increased NR2B expression in dysplastic cortex
  • Epilepsy often treatment-resistant with only 1 in 5 patients achieving seizure control
Astroscape - box logo - PNG

About the Astroscape Study

GRIN Therapeutics is advancing the Astroscape study, an open-label proof of concept basket study to assess the safety and tolerability of radiprodil at multiple dose levels in the treatment of FCD Type II and TSC.

Astroscape: Proof of concept basket study in FSD/TSC