CAP-003 Demonstrates Disease-Modifying Properties in Preclinical Study of GBA-Related Parkinson Disease

A late-breaking poster presented at the Society for Neuroscience annual meeting, held October 5-9, in Chicago, Illinois, highlighted the therapeutic potential of CAP-003 (Capsida), an intravenously (IV) delivered gene therapy in development for Parkinson disease associated with GBA mutations (PD-GBA). Using non-human primates (NHP), 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.

"Capsida's wholly owned novel gene therapy offers the potential to normalize GCase activity in patients with a single IV infusion safely, enabling the potential for long-term disease modification and substantial slowing of disease progression," Peter Anastasiou, chief executive officer at Capsida, said in statement.¹ "These data give us confidence that we are on track to enter the clinic with CAP-003 in the first half of 2025."

CAP-003 is a gene therapy designed to supplement the GCase enzyme, which is affected by GBA mutations. The goal of the agent is to restore normal enzyme activity and slow the progression of the disease. In NHPs, results showed that all CAP-003 doses exceeded 30% efficacy threshold for normalizing GCase activity in patients. GCase activity, including in substantial nigra, was 2-8-fold higher than the threshold needed to overcome the expected deficit in patients.

At doses of 5.5E13 vg/kg, CAP-003 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. Furthermore, glucosylsphingosine (GluSph) showed decreased levels in the terminal plasma of CAP-003 treated NHPs, providing evidence of lysosomal activity and target engagement. In the preclinical studies, CAP-003 at doses of 2.2E13 vg/kg and 5.5E13 vg/kg resulted in decreased changes of 59% and 79% in GluSph, respectively.

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. Overall, these data raise confidence in the use of CSG GCase biomarkers in the clinic.

READ MORE: The Potential of Device-Assisted Therapies in PD: Insights From the Phase 1/2 DIVE-I Trial

Compared with historical IV-delivered AAV9 (4-week in-life, non-GBA cargo), NHPs on CAP-003 demonstrated significantly reduced DNA and RNA biodistribution to the liver and DRGs. Specifically, investigators observed a 19-fold lower liver biodistribution, and a 17-fold lower expression in DRGs with CAP-003. Notably, this did not result in any adverse histopathology.

Approximately 5-15% of patients with PD have mutations in the GBA gene, making it numerically the most important genetic risk factor for PD. Clinically, GBA-PD is identical to sporadic PD, aside from the earlier age at onset, more frequent cognitive impairment, and more rapid progression. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism.

In recent years, there has been greater industry interest in identifying effective treatments for GBA-PD, with several agents currently in low-level clinical trials right now. In August 2023, BIAL R&D announced the first patients dosed in their phase 2 trial, ACTIVATE (NCT05819359), to investigate BIA 28-6156, an allosteric activator of GCase, as a treatment for patients with GBA-PD. The multicenter, randomized, double-blind, placebo-controlled study will assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of 2 fixed dose levels of BIA 28-6156 (10 mg and 60 mg/day).³

More recently, at the 2024 International Congress of Parkinson’s Disease and Movement Disorders, data from a phase 1 first-in-human trial demonstrated the early efficacy and safety of GT-02287 in healthy volunteers. GT-02287, an orally-bioavailable, brain-penetrant molecule, is also in development for patients with PD with or without a GBA1 mutation. All told, the therapy was safe and generally well tolerated at single (2.4, 4.8, 7.7, 10.0, and 15.0 mg/kg) and multiple (4.8, 7.7, 10.0, and 13.5 mg/kg) doses, with nausea and headache as the most common AEs.⁴

REFERENCES
1. 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
2. Unlocking the Potential of Gene Therapy for All. Capsida. October 2024. Accessed October 25, 2024. https://capsida.com/wp-content/uploads/Capsida-Non-Confidential-Corporate-Deck-10042024.pdf
3. BIAL R&D Announces First Patient Dosed in its Phase 2 Clinical Trial of BIA 28-6156 to Treat Parkinson's Disease Patients With a Pathogenic Variant in the Glucocerebrosidase (GBA1) Gene. News Release. Bial. Published May 25, 2023. Accessed October 25, 2024. https://prnmedia.prnewswire.com/news-releases/bial-rd-announces-first-patient-dosed-in-its-phase-2-clinical-trial-of-bia-28-6156-to-treat-parkinsons-disease-patients-with-a-pathogenic-variant-in-the-glucocerebrosidase-gba1-gene-301833969.html
4. Gain Therapeutics Announces Positive Topline Results from the Phase 1 Clinical Trial of GT-02287, a Novel GCase-Targeting Small Molecule Therapy for Parkinson’s Disease. News release. Gain Therapeutics. August 29, 2024. Accessed October 25, 2024. https://finance.yahoo.com/news/gain-therapeutics-announces-positive-topline-113000099.html