Neurelis Files IND for Potentially First Therapy to Treat Cerebral Cavernous Malformations


In preclinical animal models, NRL-1049 showed an ability to decrease ROCK-2 activation, a pathway that is hyperactivated in patients with cerebral cavernous malformations.

Adrian L. Rabinowicz, MD, senior vice president, Clinical Development and Medical Affairs, Neurelis

Adrian L. Rabinowicz, MD

According to a recent announcement, Neurelis successfully filed an investigational new drug application (IND) for its rho kinase (ROCK) inhibitor NRL-1049 as a potential treatment for individuals with cerebral cavernous malformations (CCM). The company plans to initiate a study in early 2023 to assess the agent.1

CCM, a disease characterized by abnormally enlarged capillary cavities, most commonly found in the cerebral cortex, brainstem, and spinal cord, currently has no FDA-approved therapeutics to treat the condition. Patients with the condition have typically turned to antiepileptic drugs and surgical interventions to remove lesions; although, most cavernous malformations have been conservatively managed by observing for changes in appearance, recent hemorrhages, or other clinical symptoms.

"This is a significant milestone for Neurelis and represents an opportunity to further explore the clinical utility of NRL-1049 for the treatment of cerebral cavernous malformations," Adrian L. Rabinowicz, MD, senior vice president, Clinical Development and Medical Affairs, Neurelis, said in a statement.1 "Following favorable preclinical study results, we are excited to advance our mission to introduce new treatment options for patients with critical unmet medical needs."

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In July 2021, Neurelis acquired the rights of a portfolio of novel ROCK-2 inhibitors that target CCMs, including NRL-1049. In preclinical models, the agent’s ability to decrease ROCK-2 activation led to protection of the brain, possibly through maintaining the integrity of the blood-brain barrier. Presented at the Neuroscience 2022 Conference, held November 12 to 16 in San Diego, California, results showed lower rates of brain edema associated with brain protection. Additionally, a lower seizure rate in cold injury animals and decreased intracerebral hemorrhage in the model of stroke were also observed.

Familial CCMs, which arise from autosomal dominant mutations in the CCM1, CCM2, and/or CCM3 genes, account for at least 20% of all cases. Despite this, previous research has identified that mutations in these genes cause hyperactivation of the ROCK signaling pathway in brain vascular endothelial cells, which then leads to the loss of endothelial integrity, subsequently causing capillary malformation and eventually, the potential for lesions. In the general population, the prevalence of CCMs accounts between 0.2% to 0.5%; however, this condition accounts for a larger proportion (8% to 15%) of all brain and spinal vascular malformations.

"We are excited that the preclinical studies have shown that NRL-1049 is safe and efficacious in animal models,” Enrique Carrazana, MD, chief medical officer, Neurelis, said in a statement.1 "Based on the significance of these data, Neurelis is developing further studies in humans to assess the safety of NRL-1049 in the treatment of chronic and acute conditions that affect the functioning of the blood-brain barrier. If successfully developed and approved, NRL-1049 has the potential to provide relief to people suffering from CCMs."

1. Neurelis announces filing of its investigational new drug application for NRL-1049, a rho kinase (ROCK) inhibitor with potential to treat cerebral cavernous malformations. News release. Neurelis. January 9, 2023. Accessed January 11, 2023.
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