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

• Register: ClinicalTrials.gov
• Last refreshed on: 27 January 2025
• Main ID: NCT04669535
• Date of registration: 23/11/2020
• Prospective Registration: Yes
• Primary sponsor: Terence Flotte
• Public title: A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease
• Scientific 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
• Date of first enrolment: January 15, 2021
• Target sample size: 9
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/ct2/show/NCT04669535
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Terence Flotte, MD
• Affiliation: University of Massachusetts Medical Health Center

Key inclusion & exclusion criteria

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



Age minimum: 6 Months
Age maximum: 12 Years
Gender: All

Health Condition(s) or Problem(s) studied

Tay-Sachs Disease

Sandhoff Disease

Intervention(s)

Biological: AXO-AAV-GM2 Starting Dose

Biological: AXO-AAV-GM2 Middle Dose

Biological: AXO-AAV-GM2 High Dose

Biological: AXO-AAV-GM2 Low Dose

Primary Outcome(s)

Incidence, severity, seriousness and relatedness to treatment of treatment emergent adverse events [Time Frame: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)]

Secondary Outcome(s)

Number of participants with clinically significant abnormal physical exam per investigator assessment [Time Frame: 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 [Time Frame: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)]

Number of participants with clinically significant abnormal vital signs per investigator assessment [Time Frame: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)]

Serum cellular and antibody immune response to vector capsid/transgene [Time Frame: 24 weeks (infantile-onset participants) to 48 weeks (juvenile-onset participants)]

Secondary ID(s)

AXO-GM2-001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

University of Massachusetts, Worcester

Massachusetts General Hospital