A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2

Study Overview
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Brief Summary
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Primary Objectives: Primary population (adult participants with late-onset GM2 gangliosidosis): To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosialidosis): 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 Secondary Objectives: Primary population: To assess the PD of daily oral dosing of venglustat and 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: 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 To assess the acceptability and palatability of the venglustat tablet

Detailed Description
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The total duration is up to approximately 223 weeks, including a 60-day screening period, a 104-week primary analysis treatment period, a 104-week open-label extension treatment period and a 6-week post-treatment safety observation period.

Official Title
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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

Conditions
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Tay-Sachs Disease, Sandhoff Disease

Intervention / Treatment
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* Drug: venglustat GZ402671
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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 β-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: Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by β-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, 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 The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GZ402671<br>Primary population: participant will receive venglustat dose once daily during the primary analysis period (104 weeks) and the open-label extension period (104 weeks). Secondary population: participant will receive venglustat at various doses once daily during the primary analysis period open-label (104 weeks) and the open-label extension period (104 weeks). | Drug: venglustat GZ402671<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Placebo Comparator: Placebo<br>Primary population: participants will receive placebo once daily during the primary analysis period (104 weeks) and will receive venglustat dose once daily during the open-label extension period (104 weeks). | Drug: placebo<br>* Pharmaceutical form: tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebrospinal fluid (CSF) GM2 biomarker | Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population | From baseline to Week 104 | 
| 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 | From baseline to Week 104 | 
| Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers | Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in plasma: GL-1, GM2 biomarkers | Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers | Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers | Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in plasma: GL-1 biomarker | Concentration of GL-1 for saposin C deficiency in secondary population | From baseline to Week 104 | 
| Assessment of PD response in CSF: GL-1, GM1 biomarkers | Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in CSF: GL-1, GM2 biomarkers | Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers | Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers | Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population | From baseline to Week 104 | 
| Assessment of PD response in CSF: GL-1 biomarker | Concentration of GL-1 for saposin C deficiency in secondary population | From baseline to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/tolerability: Adverse events | Number of patients with adverse events | From baseline to Week 104 | 
| Assessment of pharmacokinetic (PK) parameters in plasma: Cmax | Maximum venglustat concentration (Cmax) | From baseline up to Week 12 | 
| Assessment of PK parameters in plasma: tmax | Time to maximum venglustat concentration (tmax) | From baseline up to Week 12 | 
| 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) | From baseline up to Week 12 | 
| Assessment of PK parameters in plasma: plasma concentrations | Plasma venglustat concentration | From baseline up to Week 104 | 
| Assessment of PK parameters: CSF venglustat concentration | CSF venglustat concentration | Week 104 | 
| Change in 25-foot walk test (FWT) | Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline) | From baseline to Week 104 | 
| Absolute change in CSF GM2 biomarker |  | From baseline to Week 104 | 
| Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS) | Change in the neurological examination of the FARS score from baseline to Week 104 | From baseline to Week 104 | 
| Change in 9-hole peg test (9-HPT) | Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population | From baseline to Week 104 | 
| Acceptability assessment | Venglustat tablets acceptability will be assessed through the route of venglustat administration collected in the eCRF and study intervention compliance | From baseline to Week 104 |