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

NCT04221451 | Terminated Phase 3 Results DMC FDA Drug

• 3 other identifiers: EFC15299U1111-1197-79052019-002375-34
• Study Type: interventional
• Target: 75
• Locations: 13 countries
• Sites: 23

Brief 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

Conditions

Tay-Sachs Disease; Sandhoff Disease

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (12)

• PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104

  Baseline (Day 1) and Week 104

• PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104

  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

  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)

  From first dose of study drug (Day 1) up to end of PAP, 104 weeks

• PAP: PP: Plasma Venglustat Concentration

  Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12

Study Arms (2)

GZ402671

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

venglustat GZ402671 DRUG

Pharmaceutical form: tablet Route of administration: oral

GZ402671

placebo DRUG

Pharmaceutical form: tablet Route of administration: oral

Placebo

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (23)

Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004

Los Angeles, California, 90095, United States

Location

Emory Genetics - Investigational site number 8400006

Atlanta, Georgia, 30322, United States

Location

NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005

Bethesda, Maryland, 20892, United States

Location

Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002

Boston, Massachusetts, 02114, United States

Location

NYU Langone - 550 First Avenue-Investigational site number 8400001

New York, New York, 10016, United States

Location

Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002

Pilar, Buenos Aires, B1629ODT, Argentina

Location

Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001

Córdoba, X5004FHP, Argentina

Location

Hospital de Clinicas de Porto Alegre _investigational site number 0760001

Porto Alegre, Rio Grande do Sul, 90035 003, Brazil

Location

Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001

Prague, 12808, Czechia

Location

APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001

Paris, 75013, France

Location

Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001

Giessen, 35390, Germany

Location

Investigational Site Number : 3800001

Milan, 20133, Italy

Location

Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001

Akita, Akita, 010-1495, Japan

Location

Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002

Sendai, Miyagi, 983-8512, Japan

Location

Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002

Lisbon, 1649-035, Portugal

Location

Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001

Moscow, 125367, Russia

Location

Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004

L'Hospitalet de Llobregat, Barcelona [Barcelona], 08907, Spain

Location

Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001

Esplugues de Llobregat, Catalunya [Cataluña], 08950, Spain

Location

Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002

Santiago de Compostela, Galicia [Galicia], 15706, Spain

Location

Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001

Ankara, 06500, Turkey (Türkiye)

Location

Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001

Cambridge, Cambridgeshire, CB2 OQQ, United Kingdom

Location

Investigational Site Number : 8260003

Manchester, M13 9WL, United Kingdom

Location

Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002

Salford, M6 8HD, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34539759 DERIVED

Related Links

• EFC15299 Plain Language Results Summary

MeSH Terms

Conditions

Tay-Sachs Disease; Sandhoff Disease

Condition Hierarchy (Ancestors)

Gangliosidoses, GM2; Gangliosidoses; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

The study was early terminated based on the absence of positive trends on clinical endpoints; there were no safety concerns. For sialidosis type 1 and juvenile/adult galactosialidosis, due to the rarity of the disease and the specificity of the endpoint, reporting individual-level data would risk compromising participant privacy and confidentiality.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2020
• First Posted: January 9, 2020
• Study Start: June 29, 2020
• Primary Completion: December 26, 2024
• Study Completion: December 26, 2024
• Last Updated: January 28, 2026
• Results First Posted: January 28, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

DE (1); GB (3); JP (2); TU (1); IT (1); CZ (1); US (5); BR (1); PT (1); RU (1); FR (1); ES (3); AR (2)