A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late-onset GM2

• Register: EUCTR
• Last refreshed on: 17 February 2025
• Main ID: EUCTR2019-002375-34-AT
• Date of registration: 06/12/2019
• Prospective Registration: Yes
• Primary sponsor: Genzyme Corporation
• Public title: A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late-onset GM2
• Scientific title: A multicenter, multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability of venglustat in late-onset GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) together with a separate basket for juvenile/adolescent late-onset GM2 gangliosidosis and ultra-rare diseases within the same and similar glucosylceramide-based sphingolipid pathway - AMETHIST
• Date of first enrolment: 27/04/2021
• Target sample size: 104
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-002375-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: For secondary population: open-label treatment with venglustat only If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Austria, Brazil, Czech Republic, Czechia, France, Germany, Italy, Japan, Portugal, Russian Federation, Spain, Turkey, United Kingdom, United States

Contacts

• Affiliation: Sanofi-Aventis Deutschland GmbH

• Affiliation: Sanofi-Aventis Deutschland GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
- Primary population and adult secondary population: age = 18 years
- Juvenile/adolescent secondary population: 2 = age < 18 years with weight = 10 kg
- Participants with a diagnosis of late onset GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) caused by genetic ß-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes (primary population only); a secondary population will enroll patients with diagnosis of juvenile/adolescent GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile adult galactosialidosis
- For primary population, the participant has the ability to perform the 9-HPT at the screening visit in < = 240 seconds for the 2 consecutive trials of the dominant hand and the 2 consecutive trials of the nondominant Hand.
- Participants with a history of seizures well controlled by medication other than strong or moderate inducer or inhibitor of CYP3A4
- Participant is cooperative, able to ingest oral medication, willing to travel to a study site (if applicable), and able to comply with all aspects of the study, including all assessments, according to the Investigator's judgement
- Signed written informed assent/consent
- Contraception for sexually active male participants or female patient; not pregnant or breastfeeding; no sperm donating for male participant
Are the trial subjects under 18? yes
Number of subjects for this age range: 10
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 76
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by ß-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes and/or is without clinical features
- For primary population and participants with juvenile/adolescent late
onset GM2 gangliosidosis and GM1 gangliosidosis, the participant cannot understand and perform all age-appropriate study assessments with the exception of 25FWT and PROs.
- Relevant medical disorders that would compromise his/her safety
- Documented diagnosis of hepatitis B, C, human immunodeficiency virus 1 or 2
- World Health Organization (WHO) grade > 2 cortical cataract or a grade > 2 posterior subcapsular cataract; patients with nuclear cataracts will be accepted
- Participant who requires invasive ventilatory support
- Current treatment by anticoagulants, cataractogenic medications or any medications that may worsen the vision of patient with cataract
- Previous treatment with substrate reduction therapy (SRT) within 3 months prior to study enrollment, strong or moderate inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives prior to enrollment. This also includes the consumption of grapefruit, grapefruit juice or grapefruit products within 72hrs prior to starting investigational medicinal product (IMP) administration.
- Current participation in another study
- Use of investigational medicinal product (IMP) within 3 months or 5 half-lives prior to enrollment, whichever is longer, before study
enrollment (for N-acetyl-leucine, within 5 half-lives before study
enrollment).
- Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin > 2 x the upper limite of normal (ULN) at the time of screening unless the participant has the diagnosis of Gilbert syndrome and maintains a level of bilirubin < 5 mg/dl and direct bilirubin < 20% (1 mg/dl) of total bilirubin level
- Renal insufficiency is defined by estimated glomerular filtration rate
(eGFR) < 30 mL/min/1.73m2 at the screening visit


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

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Tay-Sachs disease Sandhoff disease
MedDRA version: 23.0 Level: LLT Classification code 10043147 Term: Tay-Sachs disease System Organ Class: 100000004850
MedDRA version: 23.0 Level: LLT Classification code 10081314 Term: Sandhoff disease System Organ Class: 100000004850

Intervention(s)

Product Name: Venglustat
Product Code: GZ402671
Pharmaceutical Form: Tablet
INN or Proposed INN: Venglustat
CAS Number: 1401090-53-6
Current Sponsor code: GZ402671
Other descriptive name: Genz-682452-AU
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Venglustat
Product Code: GZ402671
Pharmaceutical Form: Tablet
INN or Proposed INN: Venglustat
CAS Number: 1401090-53-6
Current Sponsor code: GZ402671
Other descriptive name: Genz-682452-AU
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 6-

Product Name: Venglustat
Product Code: GZ402671
Pharmaceutical Form: Tablet
INN or Proposed INN: Venglustat
CAS Number: 1401090-53-6
Current Sponsor code: GZ402671
Other descriptive name: Genz-682452-AU
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 4-

Primary Outcome(s)

Primary end point(s): 1 - Change in cerebrospinal fluid (CSF) GM2 biomarker ; Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population
2 - Change in the 9-hole pegboard test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population
3 - Assessment of pharmacodynamic (PD) response in plasma and CSF:
- GL-1, GM1 biomarkers ; Concentration of GL-1 biomarker with pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
- GL-1, GM2 biomarkers ; Concentration of GL-1 with GM2 for GM2 gangliosidosis in secondary population
- GL-1, GM2, GM3 biomarkers ; Concentration of GL-1 with GM2, GM3 for sialidosis in secondary population
- GL-1, GM1, GM3 biomarkers ; Concentration of GL-1 with GM1, GM3 for galactosialidosis in secondary population
- GL-1 biomarker ; Concentration of GL-1 for saposin C deficiency in secondary population

Secondary Objective: Primary population (adult participants with late-onset GM2 gangliosidosis):
- To assess the effect of venglustat on selected performance test and scale over a 104-week period
- To determine the safety and tolerability of venglustat when administered orally once daily over a 104-week period
- To assess the pharmacokinetics (PK) of venglustat in plasma and cerebrospinal fluid (CSF)

Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosidosis):
- To assess the effect of venglustat on selected performance tests and scale over a 104-week period
- To determine the safety and tolerability of venglustat when administered once daily over a 104-week period
- To assess the PK of venglustat in plasma and CSF

Main Objective: - Primary population: To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period

- Secondary population: To assess PD response (plasma and CSF GL-1 biomarker and disease specific biomarkers) of venglustat when administered once daily over a 104-week period

Timepoint(s) of evaluation of this end point: 1, 2, 3 : From baseline to Week 104

Secondary Outcome(s)

Secondary end point(s): 1 - Safety/tolerability: Adverse events ; Number of patients with adverse events
2 - Assessment of pharmacokinetic (PK) parameters in plasma: Cmax ; Maximum venglustat concentration (Cmax)
Assessment of PK parameters in plasma: tmax ; Time to maximum venglustat concentration (tmax)
Assessment of PK parameters in plasma: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
3 - Assessment of PK parameters in CSF: Cmax ; Maximum venglustat concentration (Cmax)
Assessment of PK parameters in CSF: tmax ; Time to maximum venglustat concentration (tmax)
Assessment of PK parameters in CSF: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
4 - Change in 25-foot walk test (FWT) ; Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
5 - Change in Friedreich's Ataxia Rating Scale (FARS) ; Change in FARS score from baseline to Week 104
6 - Change in 9-hole peg test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population

Timepoint(s) of evaluation of this end point: 1, 2, 3, 4, 5, 6 : From baseline to Week 104

Secondary ID(s)

EFC15299

2019-002375-34-DE

Source(s) of Monetary Support

Genzyme Corporation

Ethics review

Status: Approved
Approval date: 27/04/2021
Contact: