Commentary

Article

Radiprodil in TSC and FCD: Targeting Seizures through NMDA Modulation

Author(s):

Bruce Leuchter, MD, president and chief executive officer at Neurvati Neurosciences, provided clinical insight on the newly initiated Astroscape trial of radiprodil for the treatment of tuberous sclerosis complex and focal cortical dysplasia type II.

Bruce Leuchter, MD, president and chief exeucitve officer at Neurvati Neurosciences and GRIN Therapeutics

Bruce Leuchter, MD

Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) are challenging neurodevelopmental disorders that often require a multifaceted approach to management, primarily focused on seizure control, behavioral support, and quality of life improvement. For both conditions, antiseizure medications are the primary treatment to control seizures; however, many patients do not achieve full seizure control with medication alone, especially those with drug-resistant epilepsy.

Last month, GRIN Therapeutics announced the initiation of a new study, dubbed Astroscape, that assesses the efficacy and safety of the company’s investigational agent radiprodil in patients with TSC and FCD type II. Radiprodil, a selective and potent negative allosteric modulator of the N-methylD-asparate (NMDA) receptor subtype 2B, has shown an antiseizure effect in a number of in vitro and in vivo preclinical seizure and epilepsy models and specifically in models characterized by an enhanced GluN2B-NMDA transmission. Additionally, the therapy demonstrated significant impacts on seizure frequency in a previous phase 1 study (NCT05818943) of patients with GRIN-related neurodevelopmental disorder.

To understand more about the ins and outs of Astroscape, as well as the reasoning behind exploring radiprodil in TSC and FCD, NeurologyLive® reached out to Bruce Leuchter, MD, president and chief exeucitve officer at Neurvati Neurosciences and GRIN Therapeutics. Leuchter spoke on the unique mechanism of action behind radiprodil and its potential impact on these conditions. In addition, he gave an overview of the main objectives and goals of the study, including exploring the drug’s effects on behavioral, sleep, and quality-of-life outcomes. Furthermore, Leuchter touched on the heterogeneity of TSC and FCD, and how the study emphasizes tailored inclusion criteria and detailed patient assessments to provide meaningful insights.

NeurologyLive: Discuss the mechanism of action behind radiprodil and why we believe it can be successful in treating TSC and FCD type II?

Bruce Leuchter, MD: In some cases, neurodevelopmental disorders are caused when a receptor in the brain critical for normal function, called the NMDA receptor, becomes dysfunctional. In the brain, NMDA receptors help regulate different physiological functions, including learning and memory. When these receptors are dysfunctional, neurodevelopmental syndromes can emerge with symptoms that include seizures, intellectual disabilities, and neurobehavioral symptoms. The ability to precisely control the activity of NMDA receptors could play a role in the treatment of a range of neurodevelopmental disorders.

Radiprodil is an oral selective and potent negative allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B or GluN2B), meaning that it binds to a portion of the receptor and reduces its activation. Both tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II are associated with lesions that overexpress GluN2B, which justifies our development of radiprodil as a potential therapeutic in these conditions.

Provide more specifics on the open-label trial; how is it ran? Some of the ins and outs of what types of patients are included, goals, etc.

The open-label Astroscape study will evaluate different doses of radiprodil in children and adolescents between the ages of six months and 18 years with TSC or FCD type II who experience seizures which at least two anti-seizure medications have failed to control. Target enrollment will include approximately 20 participants with TSC and 10 participants with FCD type II. The study will evaluate safety and tolerability of radiprodil as well as pharmacokinetic measures and the effect of radiprodil on the frequency and severity of epileptic seizures. We are also assessing non-seizure outcomes including symptoms related to behavior, sleep and quality of life as secondary endpoints in the study. Upon completion of treatment, participants may have the option to enroll in a long-term extension study.

Are there any specific challenges or things to be cognizant of when running a trial in these disease states?

As in many neurodevelopmental conditions and rare diseases, TSC and FCD type II are heterogeneous conditions where symptoms and progression can vary widely. As a result, they require careful planning in clinical trial inclusion and exclusion criteria that can reflect the patient experience while also ensuring a consistent group for analysis. Our team will take into account each participant’s specific symptoms and severity levels to ensure that the results are meaningful to these patient communities.

In addition, What are some of the greatest unmet needs for patients with TSC and FCD type II? Both from a pharmacological and nonpharmacological standpoint.

Patients with TSC and FCD type II are in urgent need of treatment options – there are currently no approved disease modifying therapies available for those with FCD type II and no targeted therapies for patients with TSC.

TSC is a multi-system genetic disorder caused by a mutation in the TSC1 or TSC2 genes that causes non-cancerous tumors to form in many different organs including the brain, eyes, heart, kidneys, skin and lungs. The disease impacts the central nervous system and can cause cognitive impairment, developmental delays, seizures, behavioral problems and autism spectrum disorder. TSC is the leading genetic cause of epilepsy and autism. While some patients are treated with antiseizure drugs, only about one third become seizure free and many require surgery in an attempt to control seizure activity.

FCD type II is a rare disorder characterized by malformations of cortical development caused by abnormal brain formation in utero. Genetic factors may play a role in causing the condition in some cases. The abnormal morphology and function of brain cells disrupts normal cell layers resulting in a high risk of seizures and disruption of brain function. While antiseizure medications represent the standard of care to try to control seizures in people living with FCD type II, many individuals experience drug-resistant seizures and only about one in five achieve sufficient seizure control with these medications alone. Similar to TSC, many patients are treated with surgery to achieve seizure control.

What does the timeline of the study look like? Any interim analyses planned?

We look forward to working with families impacted by these disorders and our investigators to advance this promising development program as rapidly as possible. Currently, our estimated primary completion date is July 2025 and estimated study completion date is July 2026 with no interim analyses planned.

REFERENCES
1. GRIN Therapeutics Announces Initiation of Astroscape Clinical Trial of Radiprodil for Treatment of Tuberous Sclerosis Complex and Focal Cortical Dysplasia Type II. News release. October 8, 2024. Accessed November 1, 2024. https://www.prnewswire.com/news-releases/grin-therapeutics-announces-initiation-of-astroscape-clinical-trial-of-radiprodil-for-treatment-of-tuberous-sclerosis-complex-and-focal-cortical-dysplasia-type-ii-302269822.html
Related Videos
Alireza Atri, MD, PhD
Lars Lannfelt, MD, PhD
 Brent Forester, MD, MSc
Todd Feaster, PsyD
Michael Woodward, MD, FRACP; Anthony Caggiano, MD, PhD
Howard Fillit, MD
Margherita Carboni, PhD
R. Nolan Townsend; Sandi See Tai, MD; Kim G. Johnson, MD
Ralph Kern, MD, MHSc
© 2024 MJH Life Sciences

All rights reserved.