Gene Therapy Stabilizes Disease Progression in GM1 Gangliosidosis


Positive results from a phase 1/2 study of AXO-AAV-GM1 were presented at WORLDSymposium.

New data on AXO-AAV-GM1 (AAV9-GLB1) shows that the gene therapy is associated with increased serum β-gal enzyme activity, decreased GM1 ganglioside levels, and stable disease progression in children with GM1 gangliosidosis.

Data from the phase 1/2 study (NCT03952637) assessing the gene therapy, developed by Axovant Sciences, were presented by Cynthia Tifft, MD, PhD, director, pediatric undiagnosed diseases program, and head, glycosphingolipid disorders unit, National Institutes of Health National Human Genome Research Institute, at the 18th Annual WORLDSymposium, February 7-11, 2022 in San Diego, CA.

“The deficit of beta galactosidase enzyme caused by biallelic mutations in GLB1 produces toxic accumulation of GM1 ganglioside, particularly in the CNS, where its rate of synthesis is the highest and the result is progressive cerebral atrophy, neuro degeneration, and in infantile disease the presence of a cherry red macula. But GM1 is a multi-system disease and includes progressive cardiomyopathy, the skeletal changes of dysostosis multiplex, and hepatosplenomegaly, particularly in the most severely affected patients,” Tifft said during her presentation.

The trial has so far enrolled 10 participants in 3 cohorts. Two cohorts are assessing low-dose AXO-AAV-GM1 (1.5x1013 vg/kg) in participants with type 2 GM1 gangliosidosis (late-infantile onset, n = 4; juvenile-onset, n =1) and participants with type 1 GM1 gangliosidosis (early-infantile onset, n = 2). A third cohort is assessing high-dose AXO-AAV-GM1 (4.5x1013 vg/kg) in 3 participants with juvenile-onset, type 2 GM1 gangliosidosis. The cohorts have had follow-up lengths of 17 to 24 months, 0.2 to 1 month, and 3 to 11 months, respectively.

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The gene therapy was generally well-tolerated, with 3 serious adverse events (AEs) that were not related to treatment. Treatment-related AEs included aspartate transaminase elevations in 6 low-dose participants and 1 high-dose participant; these did not have associated sequelae and did not require clinical intervention. No gamma-glutamyl transferase or bilirubin elevations were reported. Other common treatment-related AEs included iron deficiency anemia, elevated fibrin D dimer, elevated ferritin, and vomiting.

In terms of efficacy, serum β-gal activity remained above baseline levels in 2 of 5 type 2 low-dose participants at 12 months and increased to normal levels in all high-dose participants at 6 months. Cerebrospinal fluid GM1 ganglioside levels remained below baseline levels in all type 2 low-dose participants and decreased to normal levels in all high-dose participants at the same time points. Data is not yet available for the type 1 cohort and all cohorts continue to enroll participants.

All participants exhibited rapid, 2- to 4-fold decreases of urinary oligosaccharides. Volumetric MRI data revealed maintenance of brain volume and ventricular volume in 4 of 5 type 2 low-dose participants at 12 months and there was no clinical evidence of disease progression in these participants at 12 months as well as high-dose participants at 6 months. Disease progression was assessed via Vineland-3, Clinical Global Impression, Upright/Floor Mobility Scores and Speech/Swallow Severity Scores.

“Summarizing the preliminary results of this ongoing trial, we conclude that AXO-AAV-GM1 was generally well tolerated, with no drug-related serious AEs. Biomarker results today demonstrate a dose-related increase in betagalactosidase enzyme in serum and a dose-related decrease in GM1 ganglioside in CSF and a consistent decline in oligosaccharide excretion,” Tifft said.

Tifft C, D’Souza P, Johnston JM, et al. Phase 1/2 trial of AXO-AAV-GM1 (AAV9-GLB1) gene therapy for infantile- and juvenile-onset GM1 gangliosidosis. Presented at: 18th Annual WORLDSymposium. February 7-11, 2022; San Diego, CA.
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