Tay-Sachs Disease, Sandhoff Disease
Conditions
Interventions
Drug: venglustat GZ402671
- Pharmaceutical form: tablet
- Route of administration: oral
Drug: placebo
- Pharmaceutical form: tablet
- Route of administration: oral
Sponsors
Obara Kentaro
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Primary population and adult secondary population: age >= 18 years - Juvenile/adolescent secondary population: 2 >= age = 10 kg - Participants with a diagnosis of late onset GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) caused by genetic beta-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
Exclusion criteria
Exclusion criteria: - Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by beta-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 25-foot walk test (25FWT) and patient-reported outcome (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, 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/1.73m^2 at the screening visit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Change in cerebrospinal fluid (CSF) GM2 biomarker [ Time Frame: From baseline to Week 104 ], Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population 2. Change in the 9-hole pegboard test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population 3. Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population 4. Assessment of PD response in plasma: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population 5. Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population 6. Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population 7. Assessment of PD response in plasma: GL-1 biomarker [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 for saposin C deficiency in secondary population 8. Assessment of PD response in CSF: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population 9. Assessment of PD response in CSF: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population 10. Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population 11. Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Con | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ], Number of patients with adverse events 2. Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline up to Week 12 ], Maximum venglustat concentration (Cmax) 3. Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline up to Week 12 ], Time to maximum venglustat concentration (tmax) 4. Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline up to Week 12 ], Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h) 5. Assessment of PK parameters in plasma: plasma concentrations [ Time Frame: From baseline up to Week 104 ], Plasma venglustat concentration 6. Assessment of PK parameters : CSF venglustat concentration [ Time Frame: Week 104 ], CSF venglustat concentration 7. Change in 25-foot walk test (FWT) [ Time Frame: From baseline to Week 104 ], Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline) 8. Absolute change in CSF GM2 biomarker [Time Frame: From baseline to Week 104] 9. Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS) [ Time Frame: From baseline to Week 104 ], Change in the neurological examination of the FARS score from baseline to Week 104 10. Change in 9-hole peg test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population 11. Acceptability assessment Venglustat tablets acceptability will be assessed through the route of venglustat administration collected in the eCRF and study intervention compliance [Time Frame: From baseline to Week 104] | — |
Countries
Argentina, Brazil, Czechia, France, Germany, Italy, Japan, Portugal, Russian Federation, Spain, Turkey, United Kingdom, United States
Contacts
Public ContactUnit Clinical
Sanofi K.K.
Outcome results
None listed