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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

AXO-AAV-GM2 Gene Therapy for Infantile- and Juvenile-onset GM2 Gangliosidosis: Preliminary Results from an Ongoing Phase 1/2 Trial

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts II
Location: Ballroom C
Start Time: 5/18/2022 9:00
End Time: 5/18/2022 9:15

Introduction: GM2 gangliosidosis, known as Tay-Sachs (TSD) and Sandhoff (SD) disease, are rare, recessive lysosomal storage disorders caused by mutations in HEXA and HEXB genes, respectively, encoding β-hexosaminidase A (HexA) enzyme. HexA enzyme deficiency causes build-up of GM2 ganglioside, leading to diffuse neurodegeneration, progressive symptoms, and early death. No disease-modifying treatments currently exist. Methods: This is an ongoing, open-label, dose-ranging, Phase 1/2 trial (NCT04669535) of AXO-AAV-GM2 gene therapy for treatment of GM2 gangliosidosis. AXO-AAV-GM2 uses AAVrh8 vectors encoding the HEXA and HEXB genes. The study includes subjects with infantile-onset (6-20 months old) and juvenile-onset (2-12 years old) GM2 gangliosidosis, enrolled in 4 cohorts: Cohort 1 (1.42x1014 vg), Cohort 2 (1.95x1014 vg), Cohort 3 (2.18x1014 vg), and Cohort 4 (3.56x1014 vg). With each dose level, increasing volumes of vector are infused bilaterally into the thalamus, and by intracisternal magna (ICM)/intrathecal (IT) administration into the CSF. Infusion volumes range from 180-1,250 mcl/thalamus + 4.0-8.4 mL ICM/IT in Cohorts 1 and 4, respectively. CT and MRI are used to confirm bithalamic catheter placement and absence of acute surgery-related thalamic injury. Subjects receive immunosuppression with rituximab, sirolimus, and corticosteroids for up to 6 months. The primary endpoint is safety/tolerability; secondary endpoints include neurodevelopmental and motor function assessments, disease severity, MRI, and biomarkers. Results: As of March 2022, 5 subjects have been dosed: Cohort 1 (n=1 infantile-onset SD, followed 13 months); Cohort 2 (n=2 juvenile-onset TSD, n=1 infantile-onset TSD, followed 3-9 months); and Cohort 3 (n=1 juvenile-onset SD, with no follow-up data to-date). In the infantile subjects, pre-treatment brain MRIs revealed extensive signal abnormalities in white matter, thalami, caudate and putamen. In the juvenile subjects, baseline brain MRIs ranged from normal to extensive parenchymal volume loss and thalamic atrophy. The surgical procedure was generally well-tolerated, with MRI evidence of accurate targeting and resolution of focal hyperintensities at sites of thalamic injection. Most adverse events (AEs) have been mild or moderate. No AEs led to interruption or discontinuation of the AXO-AAV-GM2 procedure or study withdrawal. As of November 2021, 5 serious adverse events (SAEs) were reported in a single subject who had extensive parenchymal volume loss and disease progression at baseline and succumbed to C. diff infection 6 months after dosing. The investigators and independent data safety monitoring board (DSMB) determined 1 SAE of 'neurologic decompensation' to be ‘Possibly Related’ to AXO-AAV-GM2 and underlying disease, and the fatal SAE of ‘C. diff infection’ as ‘Unrelated’ to AXO-AAV-GM2. Another subject had AEs of AST and ALT elevations that did not require intervention or have associated clinical sequelae. Following review, the DSMB recommended continued enrollment, and FDA agreed with enhanced subject monitoring. Conclusion: This is the first report of the Phase 1/2 trial for AXO-AAV-GM2 gene therapy for GM2 gangliosidosis using an innovative combined bithalamic, ICM and IT delivery method. The procedure was well-tolerated, with MRI evidence of accurate bithalamic targeting in all 5 subjects dosed to-date. The death of the subject with the most advanced disease points to a critical window for intervention, during which disease stabilization may be possible.

Florian Eichler1, Terence Flotte2, Haley Andonian1, Oguz Cataltepe2, Rebecca Artinian2, Albert Misko1, Benjamin Thorp3, John Jameson3, Michael Sheehan3, Toby Vaughn3, Donna Valencia3, Erika De Boever3

1Massachusetts General Hospital, Center for Rare Neurologic Diseases, Boston, MA,2University of Massachusetts Chan Medical School, Worcester, MA,3Sio Gene Therapies, Inc, New York, NY
  F. Eichler: 1; Commercial Interest i.e. Company X; bluebird bio. 1; For what role? i.e. Speaker; Consultant, Investigator. 2; Commercial Interest i.e. Company X; SwanBio Therapeutics. 2; For what role? i.e. Speaker; Founder, Consultant. 3; Commercial Interest i.e. Company X; Poxel. 3; For what role? i.e. Speaker; Consultant. 4; Commercial Interest i.e. Company X; Minoryx Therapeutics. 4; For what role? i.e. Speaker; Consultant. 5; Commercial Interest i.e. Company X; Aspa. 5; For what role? i.e. Speaker; Investigator.

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