a multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late-onset gm2

Conditions: Tay-Sachs Disease; Sandhoff Disease

Summary: 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

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.

Eligibility 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 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.