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: Active, not recruiting
• 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
  • Praha 2, 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
  • Milano, Italy, 20133
    • Investigational Site Number : 3800001
• Japan
  • Akita
    • Akita-shi, Akita, Japan, 010-1495
      • Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001
  • Miyagi
    • Sendai-shi, Miyagi, Japan, 983-8512
      • Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002
• Portugal
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002
• Russian Federation
  • Moscow, Russian Federation, 125367
    • Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001
• Spain
  • Barcelona [Barcelona]
    • 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
  • Ankara, Turkey, 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: 7 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

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
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
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
Absolute change in CSF GM2 biomarker		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

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.

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Actual): January 18, 2024
• Study Completion (Estimated): February 25, 2026

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 (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gangliosidoses, GM2; Gangliosidoses; Tay-Sachs Disease; Sandhoff Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Venglustat
• Other Study ID Numbers: EFC15299; 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