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

• ClinicalTrials.gov Identifier: NCT04669535
• Recruitment Status: Not yet recruiting
• First Posted: December 17, 2020
• Last Update Posted: December 17, 2020
• Sponsor: Sio Gene Therapies
• Collaborators: University of Massachusetts, Worcester; Massachusetts General Hospital
• Information provided by (Responsible Party): Sio Gene Therapies

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Tay-Sachs Disease; Sandhoff Disease	Biological: AXO-AAV-GM2 Starting Dose; Biological: AXO-AAV-GM2 Low Dose; Biological: AXO-AAV-GM2 Middle Dose; Biological: AXO-AAV-GM2 High Dose	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two-Stage, Dose-Escalation and Safety & Efficacy Study of Bilateral Intraparenchymal Thalamic and Intracisternal/Intrathecal Administration of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease
• Estimated Study Start Date: December 2020
• Estimated Primary Completion Date: November 2024
• Estimated Study Completion Date: June 2028

Arms and Interventions

Arm

Intervention/treatment

Experimental: AXO-AAV-GM2; AXO-AAV-GM2 infusion

Biological: AXO-AAV-GM2 Starting Dose; 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).; Other Name: AAVrh8-HEXA and AAVrh8-HEXB; Biological: AXO-AAV-GM2 Low Dose; 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).; Other Name: AAVrh8-HEXA and AAVrh8-HEXB; Biological: AXO-AAV-GM2 Middle Dose; 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).; Other Name: AAVrh8-HEXA and AAVrh8-HEXB; Biological: AXO-AAV-GM2 High Dose; 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).; Other Name: AAVrh8-HEXA and AAVrh8-HEXB

Outcome Measures

Primary Outcome Measures :

1. Incidence, severity, seriousness and relatedness to treatment of treatment emergent adverse events [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]

Secondary Outcome Measures :

1. Number of participants with abnormal vital signs [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
2. Number of participants with abnormal physical exam per investigator assessment [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
3. Number of participants with abnormal clinical safety laboratory tests on blood/urine/CSF [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
4. Electroencephalograms alpha, beta, delta, and theta wave frequencies (Hz) [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
5. Serum cellular and antibody immune response to vector capsid/transgene [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 12 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female subjects born between 37 - 42 weeks gestation with genetically diagnosed TSD or SD mutations of either HEXA gene or HEXB gene

   a. Juvenile-onset subjects must be ≥ 2 years old and ≤ 12 years old at time of gene transfer

   i. Diagnosis consistent with juvenile-onset TSD or SD

   b. Infantile-onset subjects must be between 6-20 months of age at the time of gene transfer

   i. Diagnosis consistent with infantile-onset TSD or SD

   ii. Current or historical ability to sit without support for at least 5 seconds

2. Surgical readiness for gene transfer by the routes of administration confirmed by the study neurosurgeon, based on examination and magnetic resonance imaging (MRI) findings
3. Subjects receiving off-label Zavesca® (miglustat) and/or Tanganil® (acetyl-leucine) must be willing to discontinue these therapies 30 days prior to the start of screening
4. Ability to reliably travel to the study sites for study visits according to the Schedule of Assessments
5. Subjects must have a swallowing evaluation test performed (within 6 months) prior to administration of gene replacement therapy

Exclusion Criteria:

1. Presence of G269S or W574C mutation
2. History of drug-resistant seizures or status epilepticus
3. History and/or findings of spinal cord disease that would preclude the lumbar puncture and ICM/IT infusion procedures
4. The subject'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
5. Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
6. Immunizations of any kind in the month prior to screening
7. Cardiomyopathy or other cardiac disease based on echocardiogram and/or electrocardiogram, (ECG) that in the opinion of the Investigator would deem the subject unsafe to undergo surgical gene transfer
8. Indwelling ferromagnetic devices that would preclude MRI//MRS/DTI imaging
9. Ongoing medical condition that is deemed by the Investigator to interfere with the conduct or assessments of the study
10. Current clinically significant infections including any requiring systemic treatment including but not limited to human immunodeficiency virus (HIV), Hepatitis A, B, or C
11. History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI
12. Clinically significant laboratory abnormalities in liver functional tests, hematology, and blood chemistry parameters
13. Subjects for whom any of the proposed study procedures or medications would be contraindicated
14. Failure to thrive, defined as falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
15. Subject is not suitable for participation in the study in the opinion of the Principal Investigator

Contacts and Locations

Contacts

Contact: Clinical Trials; 646-887-2651; patients@siogtx.com

Locations

United States, Massachusetts

Massachusetts General Hospital, Center for Rare Neurological Diseases

Boston, Massachusetts, United States, 02114

Contact: Florian Eichler, MD 617-724-6510 feichler@partners.org

Contact: Haley Andonian 617-724-1379 handonian@partners.org

University of Massachusetts Medical Health Center

Worcester, Massachusetts, United States, 01655

Contact: Terence Flotte, MD 508-856-2107 Terry.flotte@umassmed.edu

Contact: Karen Longtine, RN 508-856-6970 Karen.Longtine@umassmed.edu

Sponsors and Collaborators

Sio Gene Therapies

University of Massachusetts, Worcester

Massachusetts General Hospital

Investigators

• Study Director: Erika De Boever, DDS, PhD; Sio Gene Therapies

More Information

• Responsible Party: Sio Gene Therapies
• ClinicalTrials.gov Identifier: NCT04669535
• Other Study ID Numbers: AXO-GM2-001
• First Posted: December 17, 2020
• Last Update Posted: December 17, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sio Gene Therapies:

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

Additional relevant MeSH terms:

Tay-Sachs Disease; Sandhoff Disease; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders; Gangliosidoses, GM2; Gangliosidoses; Sphingolipidoses; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors