Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102, an intravenous AAV9-based gene therapy for Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA) (4898)

Objective: To develop a gene therapy treatment for Mucopolysaccharidosis IIIA (MPS-IIIA) based on intravenous administration of ABO-102. Background: MPS-IIIA is a lysosomal storage disorder manifesting early in childhood with severe neurodegeneration. Design/Methods: Transpher A is Phase 1/2 clinical trial assessing the safety and efficacy of a single intravenous administration of ABO-102, a self-complementary AAV9-based vector expressing the human SGSH gene for the treatment of MPS IIIA. Primary endpoints are safety and neurocognitive development and secondary endpoints include among others evaluation of biomarkers and liver volume. Results: Fourteen patients have been enrolled across three dose cohorts (Cohort 1, 5x1012 vg/kg, n=3; Cohort 2, 1x1013 vg/kg, n=3; Cohort 3, 3x1013 vg/kg, n=8). Cohorts 1 and 2 have completed 24 months follow-up, and Cohort 3 patients were followed for a median of 19.6 months (range 11.3–26.5 months). Intravenous administration of ABO-102 was well tolerated, with no serious drug-related adverse events. ABO-102 treatment was associated with rapid, dose-dependent reduction in CSF heparan sulfate (HS), sustained for the duration of the observation period in all patients. CSF HS levels have reached the lower level of quantitation of the assay by Day 180 post-dosing in Cohort 3 patients. A rapid (day 30 post-treatment) and sustained reduction in liver volume was also measured post ABO-102 treatment and was approximately normal size for height and weight in several patients. Neurocognitive function measured by the Mullen scale (primary endpoint) tracked along the normal range in patients treated with the highest dose at younger age (≤30 months), with a follow up of 12–18 months. Several other patients showed signs of cognitive stabilization. Conclusions: OVerall, intravenous administration of ABO-102 in children with MPS-IIIA showed a favorable long-term safety tolerability profile and led to durable and dose-dependent improvement in biomarkers, with clinical neurological benefit in the youngest patients treated before neurodegeneration was advanced. Disclosure: Dr. Flanigan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with 4D Molecular Therapeutics, Audentes, and Dynacure. Dr. Flanigan has received research support from Abeona, PTC Therapeutics, Sarepta Therapeutics, and Audentes Therapeutics. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis. Dr. Smith has received research support from Abeona Therapeutics. Dr. Couce has received research support from Abeona Therapeutics. Dr. Truxal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abeona Therapeutics. Dr. Truxal has received research support from Abeona Therapeutics. Dr. McBride has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Homology Medicine. Dr. McBride has received research support from Abeona Therapeutics, Biomarin, and Shire. Dr. Simmons has nothing to disclose. Dr. de Castro has received research support from Abeona Therapeutics. Dr. Cope has nothing to disclose. Dr. Oreiro has nothing to disclose. Dr. Jaensch has nothing to disclose. Dr. Fuller has received research support from Abeona Therapeutics. Dr. Ruiz has nothing to disclose.