Capsida Biotherapeutics' CAP-002, a novel, first-in-class intravenously administered gene therapy, has received Orphan Drug Designation (ODD) from the FDA for the treatment of developmental and epileptic encephalopathy (DEE) due to syntaxin-binding protein 1 (STXBP1) mutations. This designation highlights the potential of CAP-002 to address a critical unmet need in patients with STXBP1-related DEE, a condition characterized by treatment-resistant seizures, severe developmental delay, and other neurological abnormalities. The company plans to advance the therapy to clinical trials in early 2025.
Addressing STXBP1 Mutations in DEE
Mutations in the STXBP1 gene, which encodes a protein crucial for neurotransmission in all brain neurons, are a primary cause of DEE. These mutations lead to a range of severe symptoms, including intellectual disability, motor abnormalities, and an increased risk of sudden unexpected death in epilepsy. Currently, there are no approved disease-modifying therapies available for STXBP1-related DEE, underscoring the urgent need for innovative treatments.
CAP-002: A Novel Gene Therapy Approach
CAP-002 is designed to deliver a functional copy of the STXBP1 gene to neurons throughout the brain. The therapy utilizes engineered capsids to achieve widespread neuronal expression while minimizing off-target effects, particularly in the liver. Preclinical studies have demonstrated that CAP-002 can effectively cross the blood-brain barrier (BBB) and achieve therapeutically relevant levels of STXBP1 protein expression in neurons.
Preclinical Evidence of Efficacy
Data presented at the American Society of Gene & Cell Therapy (ASGCT) 2024 Annual Meeting showcased the potential of CAP-002. In mouse models, the therapy demonstrated the ability to correct neurological phenotypes associated with STXBP1 mutations. Studies in non-human primates (NHPs) revealed that a single intravenous infusion of CAP-002 resulted in brain-wide STXBP1 gene expression, transducing up to 70% of neurons at therapeutically relevant doses. These levels of gene expression raised neuronal STXBP1 protein to levels comparable to those that reversed disease phenotype in a mouse model. Furthermore, CAP-002 exhibited a favorable safety profile in NHPs, with no significant clinical pathology, histopathology, or immunogenicity findings.
Capsida's Perspective
"Receiving [an] ODD moves us 1 step closer to our goal of transforming the lives of people living with STXBP1 developmental and epileptic encephalopathy," said Swati Tole, MD, chief medical officer at Capsida Biotherapeutics. Susan Catalano, PhD, chief scientific officer, added, "These data demonstrate that our STXBP1 program effectively crosses the blood-brain barrier in NHPs following IV delivery and achieves breakthrough levels of widespread brain transduction and STXBP1 protein expression needed to achieve disease-modifying impact as demonstrated in the mouse model data... We look forward to advancing our STXBP1 program into clinical development in the first half of 2025."
Peter Anastasiou, CEO of Capsida Biotherapeutics, emphasized the significance of the ODD, stating, "FDA's granting [an] ODD signals the significant potential that CAP-002 demonstrates based upon our preclinical data... 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."
