GRIN Therapeutics – Advancing a targeted approach to the treatment of GRIN disorders and other causes of pediatric epilepsy

Advancing a targeted approach to the treatment of GRIN-related disorders and other types of pediatric epilepsy

Neurodevelopmental disorders represent significant areas of unmet need in healthcare. People affected by these disorders, predominantly children and young adults, can face a range of severe and devastating symptoms. In many cases, there are only limited or no treatments available. GRIN Therapeutics is dedicated to the research and development of precision therapeutics for pediatric neurodevelopmental disorders with the goal of bringing hope to patients and caregivers.

GRIN Therapeutics is advancing promising research and development to assess the safety and efficacy of the investigational therapy radiprodil for the treatment of serious neurodevelopmental disorders including GRIN-related disorders, tuberous sclerosis complex (TSC), and focal cortical dysplasia (FCD).

In many cases, pediatric neurodevelopmental disorders are rare diseases that are not widely known or understood. In our effort to potentially bring new options to people living with pediatric neurodevelopmental disorders, GRIN Therapeutics is privileged to work with many of the global leaders in research, patient care, and advocacy to help build broader awareness of the impact of these disorders among patients, caregivers and communities.

The Role of N-methyl-D-aspartate (NMDA) Receptors in Neurodevelopmental Disorders

Neurodevelopmental disorders involve a malfunction of the brain and nervous system. They are generally associated with devastating symptoms that can include seizures and epilepsy, delayed development, difficulties with language and speech, impaired motor skills and behavioral problems, among other symptoms. In many cases, a diagnosis is not confirmed until symptoms become obvious or severe. Treatments, when available, typically involve a combination of physical and behavioral therapies, drugs, and home/school-based support.

In some cases, neurodevelopmental disorders are associated with a dysfunctional receptor known as NMDA. 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, an investigational oral selective modulator of the NR2B sub-unit of the NMDA receptor, is currently being developed by GRIN Therapeutics for the potential treatment of GRIN-related disorders as well as TSC and FCD.

About GRIN-related Disorders

GRIN-related disorders were first classified in 2010 and are a family of rare, genetically defined pediatric neurodevelopmental disorders caused by mutations in a group of genes known as “GRIN” genes that includes GRIN1, GRIN2A, GRIN2B, and GRIN2D. While symptoms of GRIN-related disorders can present as early as infancy, a diagnosis is often not confirmed until age two or later when a child fails to reach developmental milestones. A diagnosis can be established through genetic testing. Most people living with GRIN-related disorders develop disabilities that require continuous supervision. Currently, there are no FDA approved therapies for GRIN-related disorders.

There are several known classes of GRIN-related disorders, including:

GRIN1-related Disorders

Individuals affected by GRIN1-related disorders experience mild-to-severe developmental delays and intellectual disabilities. Other common manifestations include epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavioral problems.

GRIN2A-related Disorders

Individuals affected by GRIN2A-related disorders may experience developmental delays or intellectual disabilities. Many also develop speech disorders, epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavioral problems.

GRIN2B-related Disorders

Individuals affected by GRIN2B-related disorders experience developmental delays and intellectual disabilities. Other common manifestations include epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavioral problems.

GRIN2D-related Disorders

Individuals affected by GRIN2D-related disorders experience moderate-to-severe developmental delays and intellectual disabilities. Other common manifestations include epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavioral problems.

Additional information about GRIN-related disorders is available from international organizations including:

GRIN2B Foundation

CureGRIN

GRIN Europe

Living with GRIN-related Disorders

The Mighty - Seeking Refuge During a War While Raising a Child with GRIN2B Disorder

Patient Worthy- Rare Community Profiles: The Importance of Community While Raising a Child with GRIN2B Disorder

GRIN Therapeutics is advancing the development of radiprodil, an investigational drug that has been shown in preclinical studies to target a receptor on the NMDA subunit called “NR2B.” Research has shown that abnormal activity of the NMDA receptor leads to the clinical manifestations of GRIN-related disorders and other neurological conditions including tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II.

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 gain-of-function (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, and who meet other eligibility criteria. 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 thehoneycombstudy.com or clinicaltrials.gov.

Targeting Additional Disorders Associated with Abnormal Expression of NR2B

Based on its mechanism of action as observed in preclinical studies, radiprodil could play a role in the treatment of disorders associated with abnormal expression of NR2B including TSC and FCD. GRIN Therapeutics is conducting a study to assess the safety and potential benefits of radiprodil in individuals with TSC and FCD type II. Details may be found at clinicaltrials.gov.

About 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. Tumors impacting the central nervous system can cause cognitive impairment, developmental delays, seizures, behavioral problems and autism spectrum disorder. TSC patients can experience a range of symptoms and they often vary in level of severity from person to person. An estimated one million people worldwide are living with TSC, with approximately 50,000 in the United States.

TSC is the leading genetic cause of epilepsy and autism. While some patients are treated with antiseizure drugs, only about one-third of treated patients become seizure-free[1]. Currently, there are no approved therapies that address the root cause of TSC.

[1] Salussolia CL et al. Annu Rev Genomics Hum Genet 2019;20:217-40.

More information about TSC is available from international organizations including:

TSC Alliance

TSC

About FCD Type II

FCD type II is a rare neurodevelopmental disorder caused by abnormal brain formation in utero. Genetic factors may play a role in causing the condition in some cases. The abnormal formation of brain cells and cell layers results in a high risk of seizures and disruption of brain function.Many individuals with the disorder are diagnosed in early childhood after symptoms present. The condition is often detected by magnetic resonance imaging (MRI).

Antiseizure medications can sometimes be used to control seizures in people living with FCD type II. However, many individuals experience drug-resistant seizures, and only about 1 in 5 achieve sufficient seizure control with medication alone.

Additional information about FCD type II is available from organizations including:

Epilepsy Foundation

About the Astroscape Study

GRIN Therapeutics is planning to launch the Astroscape study, an open-label proof of concept study to assess the safety and tolerability of different doses of radiprodil in people living with TSC or FCD Type II. The study will evaluate the effect of radiprodil on the frequency and severity of epileptic seizures and on other symptoms related to behavior, motor skills, sleep and quality of life. Approximately 30 patients will be treated with radiprodil. Participants may have the option to participate in a long-term extension phase of the study.

For additional information about the Astroscape Study, visit astroscapestudy.com or clinicaltrials.gov.

Our Commitment to Patients
and Families

At GRIN Therapeutics, we are privileged to work closely with leaders from different advocacy and treatment communities to continually ensure that our efforts reflect the unique needs of the individuals and families we serve.

To contact GRIN Therapeutics patient advocacy, click here.

Our Team

The GRIN Therapeutics team includes recognized leaders in neurodevelopmental and central nervous system disorders, clinical research and drug development, and patient advocacy who are dedicated to making a positive difference for patients and families.

Bruce Leuchter, M.D.

President, CEO, Board Member

Michael A. Panzara, M.D., MPH

Chief Medical Officer

Elliott Ruiz

Senior Vice President, Finance

Megan Weaver, M.D.

Senior Vice President, Clinical Development Operations

Hillary Savoie, PhD

Director, Community Engagement & Communications

Russell Chin, M.D.

Medical Director

Jennifer Pinheiro

Senior Director, Development Operations and Outsourcing

Kenneth Hess

Director, Business Development

Vijay Rai

Associate Director of Clinical Operations

Ashley Horn

Executive Assistant

Melissa Maitea

Executive Assistant, Office of the CEO and Executive Operations

Jemima Monchery

Clinical Trial Manager

Benjamin Millen

Analyst, Finance and Business Development

Board of Directors

Deborah Dunsire

Chairwoman, Board Member

Pierre Jacquet

Board Member

Kiran Reddy