Gene Therapy CAP-002 Gains FDA Orphan Drug Designation for STXBP1 Developmental and Epileptic Encephalopathy

Peter Anastasiou

According to an announcement, the FDA recently granted orphan drug designation to Capsida’s CAP-002, an investigational gene therapy, as a potential treatment for patients with developmental and epileptic encephalopathy caused by syntaxin-binding protein 1 (STXBP1) mutations. The agent is currently in investigational drug application (IND)-enabling studies, with an IND expected to be filed in the first half of 2025.¹

Genetic epilepsy caused by mutations in the STXBP1 gene is a developmental epileptic encephalopathy estimated to affect 1 in every 30,000 children globally. This type of epilepsy, which is characterized by early-onset developmental delay, intellectual disability or cognitive dysfunction, and a wide range of seizure types, has no approved treatments.² CAP-002, an intravenously administered gene therapy, is designed to stably supplement STXBP1 protein throughout the brain after a single infusion, aiming to correct the underlying disease pathology and improve quality of life.

"FDA's granting Orphan Drug Designation signals the significant potential that CAP-002 demonstrates based upon our preclinical data,” Peter Anastasiou, chief executive officer at Capsida, said in a statement.¹ "There are no disease-modifying therapies available for STXBP1 developmental and epileptic encephalopathy and CAP-002 could be the first, bringing hope for patients and families affected by this devastating disorder."

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The STXBP1 protein, found in every brain neuron, is crucial for normal neurotransmission. Preclinical studies have shown that gene supplementation has the potential to treat and even fully correct this disorder. These studies indicated that rescuing neurological symptoms depends on delivering STXBP1 to neurons throughout the brain at levels beyond those achievable by standard serotypes like AAV9. Capsida conducted these studies using a proprietary mouse model in collaboration with Mingshan Xue, PhD, of Baylor College of Medicine and Texas Children's Hospital.

To date, STXBP1 encephalopathy with epilepsy has been typically treated through antiseizure medications (ASM) such as phenobarbital, valproic acid, and vigabatrin. About 20% of individuals with the disease require more than 1 ASM and approximately 25% are refractory to ASM therapy. Treatment per orthopedics, physical medicine and rehabilitation, physical therapy, and occupational therapy to help avoid contractures and falls, with positioning and mobility devices as needed.

"Receiving Orphan Drug Designation moves us one step closer to our goal of transforming the lives of people living with STXBP1 developmental and epileptic encephalopathy," Swati Tole, MD, chief medical officer at Capsida, said in a statement.¹ "We are committed to advancing CAP-002, with our IND filing in the first half of 2025, and bringing novel gene therapies to people with high unmet medical needs."

Capsida has a number of investigational gene-based treatment strategies in development, including CAP-003, an IV-delivered agent for patients with Parkinson disease associated with GBA mutations (PD-GBA). In a non-human primate (NHP) study, recently presented results showed a brainwide RNA expression with CAP-003 that was more than 200-fold greater than IV administered AAV9 along with substantial increases in GCase protein and enzyme activity compared with untreated animals.

Presented at the Society for Neuroscience annual meeting, held October 5-9, in Chicago, Illinois, CAP-003 at a dose of 5.5E13 vg/kg produced a 488% increase in GCase brain protein level, which were 8-24-times higher than ICM AAV9, which was reported in a previously conducted NHP study. CAP-003 at doses of 2.2E13 vg/kg also resulted in a 335% increase in GCase protein. In the analysis, the average GCase activity in the brain of treated NHPs showed significant positive correlation with GCase protein levels in the cerebrospinal fluid (CSF) and trend of positive correlation with GCase activity in the CSF. In comparison with untreated animal models, NHPs on CAP-003 at doses of 5.5E13 vg/kg demonstrated a 1068% increase in GCase protein in CSF, with a 103% increase in CGase activity in CSF.^3,4

REFERENCES
1. FDA Grants Orphan Drug Designation to Capsida Biotherapeutics for Potential Treatment of STXBP1 Developmental and Epileptic Encephalopathy. News release. Capsida Biotherapeutics. October 30, 2024. Accessed November 11, 2024. https://www.prnewswire.com/news-releases/fda-grants-orphan-drug-designation-to-capsida-biotherapeutics-for-potential-treatment-of-stxbp1-developmental-and-epileptic-encephalopathy-302290436.html
2. Mercimek-Andrews S. STXBP1 encephalopathy with epilepsy. National Library of Medicine. Updated September 28, 2023. Accessed November 11, 2024. https://www.ncbi.nlm.nih.gov/books/NBK396561/
3. New Data Demonstrate Substantial Therapeutic Potential of Capsida's IV Gene Therapy for Parkinson's Disease Associated with GBA Mutations. News release. Capsida. October 7, 2024. Accessed October 25, 2024. https://www.prnewswire.com/news-releases/new-data-demonstrate-substantial-therapeutic-potential-of-capsidas-iv-gene-therapy-for-parkinsons-disease-associated-with-gba-mutations-302267777.html
4. Unlocking the Potential of Gene Therapy for All. Capsida. October 2024. Accessed November 11, 2024. https://capsida.com/wp-content/uploads/Capsida-Non-Confidential-Corporate-Deck-10042024.pdf