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

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

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.

Inclusion Criteria:

1. 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

2. 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:

   1. 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.

   2. 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. .

   3. 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)

3. 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:

   1. Head control - While supine, with head in midline turns head symmetrically (score of 3 on GMFM item 1)
   2. Uses hands to support self while sitting
   3. Reach for an object that is held out for them above their chest while supine
   4. Transfer of object from hand to hand while supine
   5. Eye tracking while supine
   6. Looks at an object of interest for at least 3 continuous seconds

4. Surgical readiness for gene transfer by the routes of administration confirmed by the study neurosurgeon*, based on examination and MRI findings

   The following findings will disallow the performance of the BiTh procedure thereby excluding the participant from participation:

   • Any scalp and skull related lesion (e.g., vascular, infectious) over the surgical entry area
   • Any intracranial lesion (e.g., vascular, cystic, other mass lesions), significant immaturity or deformity of the brain anatomy that would make the intended surgical trajectory high risk

   The following findings will disallow the performance of the ICM/IT procedure thereby excluding the participant from participation:

   • Any skin related lesion (e.g., vascular, infectious) over the lumbar puncture site
   • Any intraspinal or intracranial lesion in posterior fossa (e.g., vascular, cystic, other mass lesions) or significantly deformed, distorted brain, spinal and cisternal anatomy that make the intended intrathecal trajectory high risk or not feasible * Participants otherwise eligible for study participation but deemed not currently fit for neurosurgery may be re-screened at the discretion of the investigator

5. Participants 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

6. Ability to reliably travel to the study sites for study visits according to the Schedule of Assessments

Exclusion Criteria:

1. Presence of G269S or W474C mutation in HEXA

2. 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.

3. History of multiple aspiration pneumonias occurring in the past twelve months.

4. Respiratory support in the form of ventilation (invasive or non-invasive).

5. History of drug-resistant seizures or status epilepticus

6. 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)

7. 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

8. Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered

9. Immunizations of any kind in the month prior to screening

10. Cardiomyopathy or other cardiac disease based on echocardiogram and/or electrocardiogram, (ECG) that in the opinion of the Investigator would deem the participant unsafe to undergo surgical gene transfer

11. Indwelling ferromagnetic devices that would preclude MRI//MRS/DTI imaging

12. Ongoing medical condition that is deemed by the Investigator to interfere with the conduct or assessments of the study

13. Current clinically significant infections including any requiring systemic treatment including but not limited to human immunodeficiency virus (HIV), Hepatitis A, B, or C

14. 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

15. Clinically significant laboratory abnormalities:

    Based on age-specific reference range and determined by the investigator:

    • Total WBC count
    • Hemoglobin
    • Creatinine
    • Pancreatic enzymes

    Based on the following thresholds:

    • Platelet count (< 150,000/μL)
    • Prothrombin (PT), partial thromboplastin time (PTT) >2X normal
    • Liver transaminases (Hy's Law: > 3x elevations above the ULN of ALT or AST and serum total bilirubin > 2xULN)

16. Participants for whom any of the proposed study procedures or medications (i.e., sirolimus, trimethoprim/sulfamethoxazole) would be contraindicated

17. Failure to thrive, defined as falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline

18. Participant is not suitable for participation in the study in the opinion of the Principal Investigator