A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease

NCT04669535 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: AXO-GM2-001
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

Brief Summary

The AXO-GM2-001 study is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of a bilateral thalamic and intracisternal/intrathecal infusion of AXO-AAV-GM2 in pediatric participants with GM2 Gangliosidosis (also known as Tay-Sachs or Sandhoff Diseases), a set of rare and fatal pediatric neurodegenerative genetic disorders caused by defects in the HEXA (leading to Tay-Sachs disease) or HEXB (leading to Sandhoff disease) genes that encode the two subunits of the β-hexosaminidase A (HexA) enzyme. AXO-AAV-GM2 is an investigational gene therapy that aims to restore HexA function by introducing a functional copy of the HEXA and HEXB genes via co-administration of two vectors utilizing the neurotropic adeno-associated virus recombinant human 8 serotype (AAVrh.8) capsid carrying the human HEXA or HEXB cDNA. The trial is expected to enroll pediatric participants with Tay-Sachs or Sandhoff Diseases, where infantile-onset participants will range from 6 months to 20 months old, and juvenile-onset participants will range from 2 years to 12 years old.

Conditions

Tay-Sachs Disease; Sandhoff Disease

Keywords

GM2 Gangliosidosis; Hexosaminidase A Deficiency; HexA Deficiency; TSD; SD; Lysosomal Storage Disorders; Tay-Sachs Disease; Sandhoff Disease

Outcome Measures

Primary Outcomes (1)

• Incidence, Severity, Seriousness and Relatedness to Treatment of Treatment Emergent Adverse Events

  The measure of total numbers of total treatment emergent adverse events (TEAEs), serious adverse events (SAEs) after treatment with the vector whether related or unrelated to treatment as well as the number of adverse events (AEs) related to AXO-AAV-GM2 vector and neurosurgical procedures.

  At least through 24 weeks post-treatment (infantile-onset participants) to 48 weeks post-treatment (juvenile-onset participants). All AEs are reported through the transition of the study to long-term follow-up.

Secondary Outcomes (4)

• Number of Participants With Clinically Significant Abnormal Vital Signs Per Investigator Assessment

  24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

• Number of Participants With Clinically Significant Abnormal Physical Exam Per Investigator Assessment

  24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

• Number of Participants With Clinically Significant Abnormal Clinical Safety Laboratory Tests on Blood/Urine/CSF

  24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

• Serum Cellular and Antibody Immune Response to Vector Capsid/Transgene

  24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)

Study Arms (1)

AXO-AAV-GM2

EXPERIMENTAL

AXO-AAV-GM2 infusion

Biological: AXO-AAV-GM2 Starting Dose; Biological: AXO-AAV-GM2 Low Dose; Biological: AXO-AAV-GM2 Middle Dose; Biological: AXO-AAV-GM2 High Dose

Interventions

AXO-AAV-GM2 Starting Dose BIOLOGICAL

1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

Also known as: AAVrh8-HEXA and AAVrh8-HEXB

AXO-AAV-GM2

AXO-AAV-GM2 Low Dose BIOLOGICAL

1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

Also known as: AAVrh8-HEXA and AAVrh8-HEXB

AXO-AAV-GM2

AXO-AAV-GM2 Middle Dose BIOLOGICAL

1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

Also known as: AAVrh8-HEXA and AAVrh8-HEXB

AXO-AAV-GM2

AXO-AAV-GM2 High Dose BIOLOGICAL

1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).

Also known as: AAVrh8-HEXA and AAVrh8-HEXB

AXO-AAV-GM2

Eligibility Criteria

• Age: 6 Months - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female participants with genetically diagnosed TSD or SD mutations of either HEXA gene or HEXB gene
• a. Stage 1 juvenile-onset participants must be ≥ 2 years old and ≤ 12 years old at time of gene transfer i. Diagnosis consistent with juvenile-onset TSD or SD b. Stage 1 infantile-onset participants must be between 6-20 months of age at the time of gene transfer i. Diagnosis consistent with infantile-onset TSD or SD
• Juvenile onset participants must demonstrate a minimum of 2 of the following age-appropriate clinical features/abilities, confirmed by the site examiner at the time of screening and reaffirmed prior to the initiation of immunosuppression:
• A Gross Motor Function Classification-MLD (GMFC-MLD) score of 0, 1 or 2. The minimum gross motor function (GMFC-MLD level 2) is the 'ability to walk with support and walking without support is not possible (fewer than 5 steps)'. (Participants aged 2-12 years) Note: Any form of support is permitted; however, the participant must initiate each step and complete it for a total of 5 steps.
• Fine Motor Function
• For Participants aged 4-12 years: A Manual Ability Classification System (MACS) score of I, II, III, or IV. The minimum level of manual ability (level IV) corresponds to 'Handles a limited selection of easily managed objects in adapted situations'.
• For participants aged 2-4 years: attainment of fine motor function/coordination abilities and milestones with normal or a reduced quality of performance. That is, the ability to coordinate fingers and both hands to play, such as swinging a bat or opening a container (pathways.org) OR the ability to use fingertips to pick up small objects, i.e., the child uses pad of his/her thumb and any fingertip to grasp a pellet or small object as described in BSID III Fine Motor Sub-test Item #26. .
• Speech:
• For participants aged 4-12 years, a speech disturbance score of 0, 1, 2 or 3 on the speech disturbance subset of the Scale for Assessment and Rating of Ataxia (SARA). The minimum speech requirement is a speech disturbance in which most words can be understood, with occasional words difficult to understand secondary to dysarthria.
• Participants aged 2-4 years who have attained the communication milestone of ability to consistently use 2-3 word phrases may be assessed in line with this criterion using the speech disturbance subset of the SARA.
• For participants aged 2-4 years who have not yet attained the above communication milestone, the minimum requirement is the ability to imitate at least one word, even if the imitation consists of vowels only (BSID III, expressive communication subtest, item #16)
• Infantile onset participants must demonstrate current\* or historical† ability to sit without support for at least 5 seconds
• \* As assessed in item 22 of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale or documented medical records
• † Documented within available medical records
• In addition, infantile onset participants must demonstrate a minimum of 3 of the following developmental skills confirmed by the site examiner at the time of screening and reaffirmed prior to the initiation of immunosuppression:

You may not qualify if:

• Presence of G269S or W474C mutation in HEXA
• Evidence of lower respiratory tract aspiration not easily manageable with thickening of feedings or substitution of a modified bottle nipple, as judged on a multi-texture contrast swallow.
• History of multiple aspiration pneumonias occurring in the past twelve months.
• Respiratory support in the form of ventilation (invasive or non-invasive).
• History of drug-resistant seizures or status epilepticus
• History and/or findings of spinal cord disease that would preclude the lumbar puncture and ICM/IT infusion procedures including:
• Infectious process involving the spinal canal which may cause adhesions or septations in the spinal and/or subarachnoid space
• Previous spinal surgeries
• History of trauma, bleeding in the spinal canal
• Vascular or cystic lesions, or any other mass lesion
• Congenital deformities and malformations involving the spinal canal
• Posterior fossa findings (low lying cerebellar tonsils, crowded foramen magnum, small or absent cisterna manga)
• The participant's parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol-defined schedule of assessments
• Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
• Immunizations of any kind in the month prior to screening

Sponsors & Collaborators

• Terence Flotte: lead
• University of Massachusetts, Worcester: collaborator
• Massachusetts General Hospital: collaborator

Study Sites (2)

Massachusetts General Hospital, Center for Rare Neurological Diseases

Boston, Massachusetts, 02114, United States

Location

University of Massachusetts Medical Health Center

Worcester, Massachusetts, 01655, United States

Location

Related Publications (2)

• Eichler F, Cataltepe OI, Daci R, Puri AS, Taghian T, Jiang X, Shazeeb MS, Kuhn A, Hader A, Celik H, Vardar Z, Lewis CJ, Artinian R, Nagy A, Vachha B, Thompson R, Gallagher T, Bateman S, Parzych J, Spanakis SG, Vaughn TA, Pier K, De Boever E, Abbott MA, D Ambrosio E, Kokoski D, Blackwood M, Drummond E, Ratai EM, Townsend EL, McLaughlin H, Tifft CJ, Keeler AM, Sena-Esteves M, Gray-Edwards HL, Flotte TR. Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial. Nat Med. 2025 Sep;31(9):2927-2935. doi: 10.1038/s41591-025-03822-4. Epub 2025 Aug 15.

  PMID: 40817303 DERIVED

• De BP, Rosenberg JB, Selvan N, Wilson I, Yusufzai N, Greco A, Kaminsky SM, Heier LA, Ricart Arbona RJ, Miranda IC, Monette S, Nair A, Khanna R, Crystal RG, Sondhi D. Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease. Hum Gene Ther. 2023 Sep;34(17-18):905-916. doi: 10.1089/hum.2023.067.

  PMID: 37624739 DERIVED

MeSH Terms

Conditions

Tay-Sachs Disease; Sandhoff Disease; Gangliosidoses, GM2; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

Gangliosidoses; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

While encouraging, the results of this study also demonstrate important limitations of this therapeutic approach. First, the infusion of 1.25 ml of vector material into the parenchyma of the thalamus likely is at or near the maximum feasible dose. With less than complete clinical efficacy and limited ability to increase the dose further, the clinical utility of this approach is far from optimal.

Results Point of Contact

• Title: Dr. Terence Flotte
• Organization: UMass Chan Medical School

terry.flotte@umassmed.edu

508-856-8992

Study Officials

• Terence Flotte, MD

  University of Massachusetts Medical Health Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dean

Study Record Dates

• First Submitted: November 23, 2020
• First Posted: December 17, 2020
• Study Start: January 15, 2021
• Primary Completion: May 23, 2024
• Study Completion: December 16, 2024
• Last Updated: September 2, 2025
• Results First Posted: May 22, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)