The AAV-based gene therapy was well-tolerated and showed enough promising effect to warrant further investigation, researchers reported.
Investigative first-in-human, adeno-associated viral (AAV)-based gene therapy ABO-101 has been associated with generally good tolerance and a clear biochemical response in children with mucopolysachharidosis IIIB (MPS-IIB).
In new late-breaking phase 1/2 study data presented at WORLDSymposium 2021 Virtual meeting this week, an international team of investigators reported outcomes from a dozen patients with the neurodegenerative lysosomal disorder showing benefit from the gene therapy including normalized enzyme activity in plasma up to 6 months and improved central nervous system (CNS) biomarkers.
The Transpher B research team, led by Dr. Maria J. de Castro, of the Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain, believe the findings warrant longer assessment to observe continued benefit with ABO-101 for the infant and young pediatric population.
MPS-IIB is a lysosomal storage condition driven by N-Acetyl-Alpha-Glucosaminidase (NAGLU) gene defect that results in accumulated glycosaminoglycan (GAG) heparan sulfate (HS). Mean patient age at manifestation is 12-24 months, and is generally associated with CNS symptoms such as slowed then regressed development, impulsivity, hyperactivity, disturbed sleep, seizures, and progression to dementia.
ABO-101 is a single-stranded AAV9 vector which carries the NAGLU gene under the CMV promoter’s control. Previously, intravenous (IV) administration of the investigative gene therapy showed broad CNS and peripheral distribution in a mouse model of MPS-IIB—including long-term NAGLU expression, improved neurologic symptoms, and survival.
In the Transpher B study, 19 patients were screened and 12 have since been enrolled in 3 cohorts, including 2 pairs of siblings. At the time of data presentation, investigators shared outcomes for 2 patients in cohort 1, 5 patients in cohort 2, and 4 patients in cohort 3.
Investigators provided a single IV administration of the gene therapy over 15-45 minutes, followed by a two-day hospital stay. Patients were given steroids (1 mg/kg prednisone or prednisolone) for the first 3 months, including tapering.
Patient outcomes for improved MPS-IIB was compared to natural history studies. The trial was run for 24 months, followed by a long-term follow-up of up to 3 years. Mean follow-up as of January 2021 was 31 months in cohort 1, 17 months in cohort 2, and 7 months in cohort 3.
IV administration of ABO-101 was well-tolerated, with no patients reporting infusion-related adverse events and 1 serious treatment-related adverse event (prolonged hospitalization to monitor vomiting and fever post-treatment).
ABO-101 normalized patient plasma enzyme activity by day 7, remaining at normal limits for up to 3 months in cohort 1, and 6 months in cohort 2 and 3. It also induced rapid CFS HS reduction in as early as 30 days, with sustained benefit up to 24 months in the only patient to reach that timepoint in cohort 1.
De Castro and colleagues additionally observed rapidly decreased systemic biomarkers, including HS in plasma and urine, sustained in patients from cohorts 2 and 3.
The limited follow-up duration precluded appropriate assessment of CNS-related outcomes in patients. That said, the improvements in patients with MPS-IIB were dose-dependent and sustained, and highlighted the potential efficacy of the gene therapy in the rare condition.
“In summary, intravenous administration of ABO-101 in children with MPS-IIIB was well tolerated and showed a clear biochemical response, including normalization of enzyme activity in plasma up to 6 months, improvements in CNS and systemic biomarkers, and reductions in liver volume,” investigators concluded. “Longer follow-up is required to evaluate neurodevelopmental changes.”