LYS-GM101 gene therapy trial in patients with GM1 gangliosidosis

• Register: EUCTR
• Last refreshed on: 10 January 2022
• Main ID: EUCTR2019-004949-32-FR
• Date of registration: 09/03/2020
• Prospective Registration: Yes
• Primary sponsor: Lysogene
• Public title: LYS-GM101 gene therapy trial in patients with GM1 gangliosidosis
• Scientific title: An open-label adaptive-design study of intracisternal administration of adeno-associated viral vector serotype rh.10 carrying the human ß-galactosidase cDNA for the treatment of GM1 gangliosidosis
• Target sample size: 18
• Recruitment status: NA
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-004949-32
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: Adaptive design If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, United Kingdom, United States

Contacts

• Name: Sophie Olivier
• Affiliation: Lysogene SA

• Name: Sophie Olivier
• Affiliation: Lysogene SA

Key inclusion & exclusion criteria

Inclusion criteria:
Stage 1: Safety phase
1. Confirmed GM1 gangliosidosis diagnosis based on genotyping confirming the ß-gal gene mutations and/or deficiency of ß-gal enzymatic activity
2. Study population:
a. Children with early infantile GM1 gangliosidosis less than 12 months of age at screening and with swallowing ability (presence of feeding tube is permitted)
b. Children with late infantile GM1 gangliosidosis less than 3 years of age at screening and with ability to sit with hand support or props)
3. Signed written informed consent before any study related procedure is performed
4. Patient medical status sufficiently stable and ability of parents/legal guardian, in the opinion of the Investigator, to adhere to the study visit schedule and other protocol requirements.

Stage 2: Confirmatory phase
Following DSMB review of 3-month safety from patients enrolled during the safety phase, enrollment in Stage 2 will be initiated. After the interim analysis on 6-month data of patients enrolled in the safety cohort, the final eligibility criteria for patients with early and late infantile GM1 gangliosidosis will be confirmed or may be revised based on the results of the interim analysis.
Are the trial subjects under 18? yes
Number of subjects for this age range: 18
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Uncontrolled seizure disorder. Patients who are stable on anticonvulsive medications may be included
2. More than 40% brain atrophy as measured by total brain volume on MRI
3. Current participation in a clinical trial of another investigational medicinal product
4. Past participation in gene therapy trials
5. History of hematopoietic stem cell transplantation
6. Any condition that would contraindicate treatment with immunosuppressants
7. Presence of concomitant medical condition or anatomical abnormality precluding lumbar puncture or intracisternal injection
8. Presence of any permanent item (e.g., metal braces) precluding undergoing MRI
9. History of non-GM1 gangliosidosis medical condition that would confound scientific rigor or interpretation of results
10. Rare and unrelated serious comorbidities, e.g. Down syndrome, intraventricular hemorrhage in the new-born period, extreme low birth weight (<1500 grams), or known bleeding disorders
11. Any vaccination 1 month prior to immunosuppressant treatment
12. Serology consistent with HIV exposure or consistent with active hepatitis B or C infection
13. Grade 2 or higher lab abnormalities for LFT, bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT, and a PTT, according to CTCAE latest version (v5.0, dated 27 Nov 2017).


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

GM1 gangliosidosis
MedDRA version: 20.0 Level: SOC Classification code 10010331 Term: Congenital, familial and genetic disorders System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: LYS-GM101
Product Code: LYS-GM101
Pharmaceutical Form: Suspension for injection
INN or Proposed INN: adeno-associated virus (AAV) serotype rh.10 expressing human betagalactosidase (AAVrh.10-CAG-ßgal)
Current Sponsor code: LYS-GM101
Other descriptive name: Adeno-associated virus serotype rh.10 expressing beta-galactosidase
Concentration unit: vector genomes (vg)/mL
Concentration type: equal
Concentration number: 1.8E+13-

Primary Outcome(s)

Main Objective: Stage 1 (safety phase): The primary objective is to assess the safety/tolerability of intracisternal administration of LYS-GM101 in early and late infantile GM1 gangliosidosis patients.
Stage 2 (confirmatory phase): The primary objective is to demonstrate efficacy of intracisternal administration of LYS-GM101 in early and late infantile GM1 gangliosidosis patients.

Secondary Objective: Stage 1:
- To collect preliminary efficacy data in infantile GM1 gangliosidosis.
- To rank the primary and secondary efficacy endpoints and confirm timepoints of primary interest for Stage 2, based on natural history data and preliminary efficacy and/or biomarker data collected in infantile GM1 gangliosidosis patients during Stage 1
Stage 2: To assess the safety and tolerability of LYS-GM101 in infantile GM1 gangliosidosis patients

Primary end point(s): - In stage 1, the primary endpoint is safety/tolerability of LYS-GM101 drug product.
- In stage 2, the primary endpoint is efficacy. Safety and preliminary efficacy data of patients included in stage 1 will condition enrollment in stage 2.

Timepoint(s) of evaluation of this end point: Stage 1 (safety cohort): 4 first patients will receive a single dose of product. Enrollment in the stage 2 (confirmatory cohort) will start after review of the 3 month safety data of the first cohort by the DSMB.
Three-month post administration of the 4 patients of the safety cohort, data will be reviewed by the DSMB. In the absence of unexpected safety signal, all additional patients enrolled in the study will receive the same dose in the confirmatory phase.
Based on the rapidity of decline described in natural history data, it is anticipated that timepoints of primary interest will be at one and two years for early infantile and late infantile, respectively.

Secondary Outcome(s)

Secondary end point(s): The primary and secondary efficacy endpoints for early and late infantile
GM1 gangliosidosis patients will be confirmed when the first 4 patients have reached 6-month follow-up (interim analysis). They will be selected among the efficacy variables collected during the dose escalation phase based on the interim analysis at 6 months and supported by the natural
history studies and registry data. It is expected that selected endpoints for the confirmatory phase will differ based on GM1 gangliosidosis clinical type.
In Stage 1, efficacy data will be analyzed as secondary endpoints. The data collected during and analyzed after Stage 1, as well as natural history data, will allow for ranking of the Stage 2 endpoints and time points. The selection of the primary endpoint for each subtype of GM1 gangliosidosis patients, the definition of all secondary endpoints and timepoints will be confirmed in a protocol amendment that will be submitted to regulatory and ethical authorities before implementation.

Timepoint(s) of evaluation of this end point: Considering the different patterns of progression between the early infantile and late infantile forms, different primary endpoints and timepoints for each group of patients are likely to be selected for Stage 2.

Secondary ID(s)

19440

NCT04273269

P1-GM-101

Source(s) of Monetary Support

Lysogene SA