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

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

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

Study Overview

• Status: Terminated
• Conditions: Tay-Sachs Disease; Sandhoff Disease
• Intervention / Treatment: Drug: venglustat GZ402671; Drug: placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Córdoba, Argentina, X5004FHP
    • Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001
  • Buenos Aires
    • Pilar, Buenos Aires, Argentina, B1629ODT
      • Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002
• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035 003
      • Hospital de Clinicas de Porto Alegre _investigational site number 0760001
• Czechia
  • Prague, Czechia, 12808
    • Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001
• France
  • Paris, France, 75013
    • APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001
• Germany
  • Giessen, Germany, 35390
    • Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001
• Italy
  • Milan, Italy, 20133
    • Investigational Site Number : 3800001
• Japan
  • Akita
    • Akita, Akita, Japan, 010-1495
      • Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001
  • Miyagi
    • Sendai, Miyagi, Japan, 983-8512
      • Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002
• Portugal
  • Lisbon, Portugal, 1649-035
    • Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002
• Russia
  • Moscow, Russia, 125367
    • Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001
• Spain
  • Barcelona [Barcelona]
    • L'Hospitalet de Llobregat, Barcelona [Barcelona], Spain, 08907
      • Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004
  • Catalunya [Cataluña]
    • Esplugues de Llobregat, Catalunya [Cataluña], Spain, 08950
      • Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001
  • Galicia [Galicia]
    • Santiago de Compostela, Galicia [Galicia], Spain, 15706
      • Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06500
    • Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001
• United Kingdom
  • Manchester, United Kingdom, M13 9wl
    • Investigational Site Number : 8260003
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 OQQ
      • Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Genetics - Investigational site number 8400006
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002
  • New York
    • New York, New York, United States, 10016
      • NYU Langone - 550 First Avenue-Investigational site number 8400001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GZ402671; 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; Pharmaceutical form: tablet Route of administration: oral
Placebo Comparator: Placebo; 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; Pharmaceutical form: tablet Route of administration: oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104	Lumbar puncture was performed for obtaining CSF samples at specified timepoints to assess the presence of GM2 biomarker in PP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: PP: Annualized Rate of Change From Baseline in the 9-HPT to Week 104	9-HPT is a test of upper extremity (arm and hand) function.Participant is seated at table with small, shallow container holding pegs and block containing 9 empty holes.On start command when stopwatch is started,participant picks up 9 pegs one at a time as quickly as possible, puts them in 9 holes and once they are in holes, removes them again as quickly as possible one at a time,replacing them into shallow container. Both dominant and non-dominant hands are tested twice (2 consecutive trials of dominant hand followed immediately by 2 consecutive trials of non-dominant hand).Total time (ranging up to 300 seconds):averaged, converted to reciprocals which were averaged and back-transformed to obtain global 9-HPT.Higher value on 9-HPT is indicative of higher disability.Mean annualized rate of change in 9-HPT was obtained from exponential transformation of mean slope of log-transformed 9-HPT.Baseline: last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF Biomarkers (Glucosylceramide [GL-1] and GM2) to Week 104 in Juvenile/Adolescent Late-onset GM2 Gangliosidosis Participants	Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM2 biomarkers in juvenile/adolescent late-onset GM2 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 and GM1 Biomarkers to Week 104 in GM1 Gangliosidosis Participants	Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM1 biomarkers in GM1 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM2 and Monosialodihexosylganglioside (GM3) Biomarkers to Week 104 in Sialidosis Type 1 Participant	Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM2 and GM3 biomarkers in sialidosis type 1 participant of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on sialidosis type 1 participant from secondary PD population (all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD).	Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM1 and GM3 Biomarkers to Week 104 in Juvenile/Adult Galactosialidosis Participants	Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM1 and GM3 biomarkers in juvenile/adult galactosialidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on juvenile/adult galactosialidosis participant from secondary PD population which included all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD.	Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 Biomarker to Week 104 in Saposin C Deficiency Participants	Plasma and CSF samples were planned to be collected at specified timepoints to assess the presence of GL-1 biomarkers in saposin C deficiency participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) to Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104	Lumbar puncture was performed for obtaining CSF samples at specified timepoints to assess the presence of GM2 biomarker in PP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104	The 25FWT is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible for 2 trials (can use assistive devices). The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The amount of time (in seconds) to walk 25 feet is recorded (ranging up to 180 seconds). The 25FWT score is defined as the average of 2 trials. A higher value on the 25FWT is indicative of higher disability. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.	Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104	The FARS-neuro includes 23 items and is composed of 4 sections that assesses different neurological faculties: bulbar activity (4 items), upper limb coordination (5 items assessed right and left side), lower limb coordination (2 items assessed right and left side), peripheral nervous system (5 items assessed right and left side) and upright stability (7 items). Total score is calculated as the sum of scores on items of this section and ranges from 0 to 117; mean is presented. Higher value indicates higher disability. Baseline=last available value before or equal to first dose of study drug date in PAP. PP: primary efficacy population: all randomized participants with diagnosis of late-onset GM2 gangliosidosis aged >=18 years. SP: secondary efficacy population: all enrolled participants with diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1, or juvenile/adult galactosialidosis.	Baseline (Day 1) and Week 104
PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)	An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAE were AEs that developed, worsened or became serious during the TE period.	From first dose of study drug (Day 1) up to end of PAP, 104 weeks
PAP: PP: Plasma Venglustat Concentration	Plasma samples were collected at specified timepoints to obtain venglustat concentrations for PP in PAP.	Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Plasma Venglustat Concentration	Plasma samples were collected at specified timepoints to obtain venglustat concentration for SP in PAP. Data is presented by dose level for all diseases combined for SP in PAP.	Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: CSF Venglustat Concentration	CSF samples were collected via lumbar puncture at Week 104 to obtain venglustat concentrations for PP and SP in PAP. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.	Week 104
PAP: PP and SP: Maximum Plasma Concentration Observed (Cmax) of Venglustat	Plasma samples were collected at specified timepoints to obtain Cmax of venglustat. The mean of Cmax, irrespective of the timepoint where the patient-individual Cmax value was observed is presented as opposed to endpoint 13 wherein mean of plasma venglustat concentration at each specified timepoint is presented. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.	Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Time to Reach Maximum Plasma Concentration (Tmax) of Venglustat	Plasma samples were collected at specified timepoints to obtain tmax of venglustat. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.	Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Area Under the Plasma Concentration Versus Time Curve Calculated Over a Predefined Time Period 0 to 24 Hours (AUC0-24) of Venglustat	Plasma samples were collected at specified timepoints to obtain AUC0-24 of venglustat. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.	Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Percent Change From Baseline in the 9-HPT to Week 104	9-HPT is a test of upper extremity (arm and hand) function.Participant is seated at table with small, shallow container holding pegs & block containing 9 empty holes.On start command (stopwatch started),participant picks up 9 pegs one at a time as quickly as possible, puts them in 9 holes & once they are in holes, removes them again as quickly as possible one at a time,replacing them into shallow container,2 consecutive trials of dominant hand followed immediately by 2 consecutive trials of non-dominant hand.Total time (ranging up to 300 seconds):averaged, converted to reciprocals which were averaged and back-transformed to obtain global 9-HPT.Higher value indicates higher disability.Baseline: last available value before or equal to first dose of study drug date in PAP.Secondary efficacy population:all enrolled participants with diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis,GM1 gangliosidosis,saposin C deficiency,sialidosis type 1 or juvenile/adult galactosialidosis.	Baseline (Day 1) and Week 104
PAP: SP: Number of Participants With >=80% Compliance as Per Method of Intake	For the secondary pediatric population, the acceptability and palatability of venglustat tablets was assessed through the route of venglustat administration collected in the electronic case report form and study drug compliance throughout PAP. The assessment was based on tablet always swallowed as whole or chewed and swallowed at least once. Number of participants with >=80% compliance for each is presented here.	Baseline (Day 1) to Week 104

Collaborators and Investigators

• Sponsor: Genzyme, a Sanofi Company
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

General Publications

• Nicoli ER, Annunziata I, d'Azzo A, Platt FM, Tifft CJ, Stepien KM. GM1 Gangliosidosis-A Mini-Review. Front Genet. 2021 Sep 3;12:734878. doi: 10.3389/fgene.2021.734878. eCollection 2021.

Helpful Links

• EFC15299 Plain Language Results Summary

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Actual): December 26, 2024
• Study Completion (Actual): December 26, 2024

Study Registration Dates

• First Submitted: January 6, 2020
• First Submitted That Met QC Criteria: January 6, 2020
• First Posted (Actual): January 9, 2020

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 9, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Gangliosidoses, GM2; Gangliosidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Tay-Sachs Disease; Sandhoff Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Venglustat
• Other Study ID Numbers: EFC15299 (Other Identifier: Sanofi Identifier); 2019-002375-34 (EudraCT Number); U1111-1197-7905 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No