NCT04221451: AMETHIST

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

Terminated Phase 3 Results posted Last updated 28 January 2026

What this trial tests

Phase 3 trial testing venglustat GZ402671 in Tay-Sachs Disease in 75 participants. Terminated before completion.

Timeline

29 June 2020

Primary endpoint
26 December 2024

26 December 2024

Quick facts

Lead sponsor	Genzyme, a Sanofi Company
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	75
Start date	29 June 2020
Primary completion	26 December 2024
Estimated completion	26 December 2024
Sites	23 locations across France, Italy, Japan, Russia, United Kingdom, Germany, Argentina, Portugal

Drugs / interventions tested

• venglustat GZ402671 — full drug profile →
• placebo

Conditions studied

• Tay-Sachs Disease — all drugs for Tay-Sachs Disease →
• Sandhoff Disease — all drugs for Sandhoff Disease →

Sponsor

Genzyme, a Sanofi Company — full company profile →

Who can join

2 and older, any sex, with Tay-Sachs Disease or Sandhoff Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104 Primary · Baseline (Day 1) and 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.

Group	Value	95% CI
PAP: PP: Placebo	-11.33	± 4.23
PAP: PP: Venglustat	-47.57	± 3.04

PAP: PP: Annualized Rate of Change From Baseline in the 9-HPT to Week 104 Primary · Baseline (Day 1) and 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

Group	Value	95% CI
PAP: PP: Placebo	0.95	± 1.92
PAP: PP: Venglustat	2.49	± 1.35

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 Primary · Baseline (Day 1) and Week 104

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.

GL-1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	-82.35	± 9.94

GL-1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	-79.28	± 2.56

GM2: CSF

Group	Value	95% CI
PAP: SP: Venglustat	-43.41	± 23.14

GM2: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	-55.91	± 11.76

PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 and GM1 Biomarkers to Week 104 in GM1 Gangliosidosis Participants Primary · Baseline (Day 1) and Week 104

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.

GL-1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	17.42	± 188.41

GL-1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	-80.42	± 8.17

GM1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	-32.35	± 17.46

GM1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	-52.32	± 16.76

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 Primary · Baseline (Day 1) and Week 104

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).

GL-1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GL-1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM2: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM2: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM3: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM3: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM1 and GM3 Biomarkers to Week 104 in Juvenile/Adult Galactosialidosis Participants Primary · Baseline (Day 1) and Week 104

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.

GL-1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GL-1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM1: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM1: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM3: CSF

Group	Value	95% CI
PAP: SP: Venglustat	NA

GM3: Plasma

Group	Value	95% CI
PAP: SP: Venglustat	NA

PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104 Secondary · Baseline (Day 1) and 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.

Group	Value	95% CI
PAP: PP: Placebo	-17.64	± 2.36
PAP: PP: Venglustat	-32.83	± 1.70

PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104 Secondary · Baseline (Day 1) and 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 indicati

PP

Group	Value	95% CI
PAP: PP: Placebo	1.4	± 4.2
PAP: PP: Venglustat	8.9	± 31.0

SP: juvenile/adolescent late-onset GM2 gangliodosis

Group	Value	95% CI
PAP: SP: Venglustat	29.6	± 66.5

SP: GM1 gangliosidosis

Group	Value	95% CI
PAP: SP: Venglustat	0.4	± 0.8

PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104 Secondary · Baseline (Day 1) and 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 dat

PP

Group	Value	95% CI
PAP: PP: Placebo	0.4	± 6.0
PAP: PP: Venglustat	-1.0	± 8.5

SP: juvenile/adolescent late-onset GM2 gangliodosis

Group	Value	95% CI
PAP: SP: Venglustat	2.8	± 10.6

SP: GM1 gangliosidosis

Group	Value	95% CI
PAP: SP: Venglustat	-2.5	± 17.0

SP: sialidosis type 1

Group	Value	95% CI
PAP: SP: Venglustat	NA

PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Secondary · From first dose of study drug (Day 1) up to end of PAP, 104 weeks

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.

TEAEs

Group	Value	95% CI
PAP: PP: Placebo	19
PAP: PP: Venglustat	40
PAP: SP: Venglustat	14

TESAEs

Group	Value	95% CI
PAP: PP: Placebo	4
PAP: PP: Venglustat	8
PAP: SP: Venglustat	6

PAP: PP: Plasma Venglustat Concentration Secondary · Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12

Plasma samples were collected at specified timepoints to obtain venglustat concentrations for PP in PAP.

0 hour

Group	Value	95% CI
PAP: PP: Venglustat	112	± 43.7

0.5 hours

Group	Value	95% CI
PAP: PP: Venglustat	125	± 54.1

3 hours

Group	Value	95% CI
PAP: PP: Venglustat	188	± 60.8

8 hours

Group	Value	95% CI
PAP: PP: Venglustat	149	± 47.3

12 hours

Group	Value	95% CI
PAP: PP: Venglustat	132	± 44.5

24 hours

Group	Value	95% CI
PAP: PP: Venglustat	105	± 38.5

PAP: SP: Plasma Venglustat Concentration Secondary · Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12

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.

4 mg: 0 hour

Group	Value	95% CI
PAP: SP: Venglustat	56.4

4 mg: 3 hours

Group	Value	95% CI
PAP: SP: Venglustat	144

4 mg: 8 hours

Group	Value	95% CI
PAP: SP: Venglustat	101

4 mg: 12 hours

Group	Value	95% CI
PAP: SP: Venglustat	92.3

4 mg: 24 hours

Group	Value	95% CI
PAP: SP: Venglustat	58.1

6 mg: 0 hour

Group	Value	95% CI
PAP: SP: Venglustat	61.5	± 34.1

6 mg: 0.5 hours

Group	Value	95% CI
PAP: SP: Venglustat	85.9	± 56.8

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events:From first dose of study drug (Day 1) up to 104 weeks (PAP) and from 104 weeks up to 6 weeks post last drug in OLE, maximum duration 200 weeks due to study termination. Deaths were collected from first dose of study drug (Day 1) up to end of follow-up, maximum 200 weeks due to study termination.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

PAP: PP: Placebo

Serious: 4/19 (21%)

Deaths: 0/19

PAP: PP: Venglustat

Serious: 8/40 (20%)

Deaths: 0/40

PAP: SP: Venglustat

Serious: 6/16 (38%)

Deaths: 1/16

OLE: PP: Delayed Venglustat

Serious: 4/16 (25%)

Deaths: 1/16

OLE: PP: Early Venglustat

Serious: 2/34 (6%)

Deaths: 0/34

OLE: SP: Venglustat

Serious: 2/14 (14%)

Deaths: 0/14

Serious adverse events (29 terms)

Reaction	System	PAP: PP: Placebo	PAP: PP: Venglustat	PAP: SP: Venglustat	OLE: PP: Delayed Venglustat	OLE: PP: Early Venglustat	OLE: SP: Venglustat
Urinary Tract Infection	Infections and infestations	—	—	—	—	—	—
Tibia Fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Burn Infection	Infections and infestations	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—
Cystitis	Infections and infestations	—	—	—	—	—	—
Infected Bite	Infections and infestations	—	—	—	—	—	—
Respiratory Tract Infection Viral	Infections and infestations	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—	—	—	—	—
Hypophagia	Metabolism and nutrition disorders	—	—	—	—	—	—
Acute Psychosis	Psychiatric disorders	—	—	—	—	—	—
Completed Suicide	Psychiatric disorders	—	—	—	—	—	—
Mania	Psychiatric disorders	—	—	—	—	—	—
Persecutory Delusion	Psychiatric disorders	—	—	—	—	—	—
Suicidal Ideation	Psychiatric disorders	—	—	—	—	—	—
Dyskinesia	Nervous system disorders	—	—	—	—	—	—
Respiratory Failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—
Faecaloma	Gastrointestinal disorders	—	—	—	—	—	—
Oesophageal Achalasia	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Cholelithiasis	Hepatobiliary disorders	—	—	—	—	—	—
Hepatic Mass	Hepatobiliary disorders	—	—	—	—	—	—
Intervertebral Disc Protrusion	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Urinary Retention	Renal and urinary disorders	—	—	—	—	—	—

Other adverse events (163 terms — click to expand)

Reaction	System	PAP: PP: Placebo	PAP: PP: Venglustat	PAP: SP: Venglustat	OLE: PP: Delayed Venglustat	OLE: PP: Early Venglustat	OLE: SP: Venglustat
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—
Covid-19	Infections and infestations	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Urinary Tract Infection	Infections and infestations	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Pain In Extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Respiratory Tract Infection	Infections and infestations	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Accidental Overdose	Injury, poisoning and procedural complications	—	—	—	—	—	—
Ligament Sprain	Injury, poisoning and procedural complications	—	—	—	—	—	—
Post Lumbar Puncture Syndrome	Injury, poisoning and procedural complications	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Vitamin D Deficiency	Metabolism and nutrition disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Paraesthesia	Nervous system disorders	—	—	—	—	—	—
Vertigo	Ear and labyrinth disorders	—	—	—	—	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Muscular Weakness	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Weight Decreased	Investigations	—	—	—	—	—	—
Conjunctivitis	Infections and infestations	—	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—	—
Irritability	Psychiatric disorders	—	—	—	—	—	—
Balance Disorder	Nervous system disorders	—	—	—	—	—	—
Disturbance In Attention	Nervous system disorders	—	—	—	—	—	—
Speech Disorder	Nervous system disorders	—	—	—	—	—	—
Tremor	Nervous system disorders	—	—	—	—	—	—
Cataract Cortical	Eye disorders	—	—	—	—	—	—
Cataract Nuclear	Eye disorders	—	—	—	—	—	—

Most-reported serious reactions: Urinary Tract Infection, Tibia Fracture, Burn Infection, Cellulitis, Cystitis, Infected Bite, Respiratory Tract Infection Viral, Sepsis.

Data from ClinicalTrials.gov NCT04221451 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies.
   Leal AF, Benincore-Flórez E, Solano-Galarza D, Garzón Jaramillo RG, et al · · 2020 · cited 90× · PMID 32867370 · DOI 10.3390/ijms21176213
2. GM1 Gangliosidosis-A Mini-Review.
   Nicoli ER, Annunziata I, d'Azzo A, Platt FM, et al · · 2021 · cited 69× · PMID 34539759 · DOI 10.3389/fgene.2021.734878
3. Diagnosing neuronopathic Gaucher disease: New considerations and challenges in assigning Gaucher phenotypes.
   Daykin EC, Ryan E, Sidransky E. · · 2021 · cited 51× · PMID 33483255 · DOI 10.1016/j.ymgme.2021.01.002
4. Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial.
   Peterschmitt MJ, Saiki H, Hatano T, Gasser T, et al · · 2022 · cited 48× · PMID 34897099 · DOI 10.3233/jpd-212714
5. The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment.
   Toro C, Zainab M, Tifft CJ. · · 2021 · cited 46× · PMID 34450229 · DOI 10.1016/j.neulet.2021.136195
6. Therapeutic Approaches in Lysosomal Storage Diseases.
   Fernández-Pereira C, San Millán-Tejado B, Gallardo-Gómez M, Pérez-Márquez T, et al · · 2021 · cited 43× · PMID 34944420 · DOI 10.3390/biom11121775
7. Targeting shared molecular etiologies to accelerate drug development for rare diseases.
   Zanello G, Garrido-Estepa M, Crespo A, O'Connor D, et al · · 2023 · cited 25× · PMID 37366158 · DOI 10.15252/emmm.202217159
8. Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model.
   Viel C, Clarke J, Kayatekin C, Richards AM, et al · · 2021 · cited 23× · PMID 34686711 · DOI 10.1038/s41598-021-00404-5