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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

A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late onset GM2 (AMETHIST)

75

Primary Population: The mean age of participants in the study was 37.8 (range 21, 72) years old in the placebo arm and 37.0 (range 18, 70) years old in the venglustat arm. A total of 9 (47.4%) participants were male in the placebo arm and 21 (52.5%) were male in the venglustat arm. The ratio of male to female participants in the primary population overall was approximately 1.03. A total of 17 (89.5%) participants were White, none were Asian, and 2 (10.5%) had not reported race in the placebo arm; 35 (87.5%) participants were White, 3 (7.5%) Asian, and 2 (5.0%) had not reported race in the venglustat arm. The following indications are categorized by the number of participants who had each diagnosis: - Tay-Sachs disease: 44 (74.6%) - Sandhoff disease: 15 (25.4%) Between arms, the disease states were distributed evenly. Secondary Population: Of the 16 participants in the secondary population, 13 were pediatric and 3 were adults. Ages of the pediatric participants spanned from 2 to 17 years old. The mean age of participants in the secondary population was 12.4 (range 2, 31) years old. A total of 5 (31.3%) participants were male. The ratio of male to female participants was approximately 0.46. The following indications were categorized by diagnosis: - Juvenile/adolescent GM2 gangliosidosis - GM1 gangliosidosis - Sialidosis type 1 - Juvenile galactosialidosis

Primary population: - Randomized and exposed: 59 (Placebo: 19, Venglustat: 40) - Completed the primary analysis treatment period: 51 (Placebo: 17, Venglustat: 34) - Did not complete the primary analysis treatment period: 8 (Placebo: 2, Venglustat: 6) - Completed the primary analysis period (PAP): 52 (Placebo: 17, Venglustat: 35) - Did not complete the PAP: 7 (Placebo: 2, Venglustat: 5) Secondary population (Venglustat): - Enrolled: 16 - Completed the primary analysis treatment period: 14 - Did not complete the primary analysis treatment period: 2 - Completed the PAP: 14 - Did not complete the PAP: 2

Primary Analysis Period (PAP): Primary Population: Overall, 19 (100%) participants in the placebo arm and 40 participants (100%) in the venglustat arm experienced at least 1 treatment-emergent adverse event (TEAE). The most frequently reported preferred terms (PTs) (>15% of participants) in the placebo arm were fall (10 participants [52.6%]), contusion (4 participants [21.1%]), headache (4 participants [21.1%]), COVID-19 (3 participants [15.8%]), nausea (3 participants [15.8%]), constipation (3 participants [15.8%]), arthralgia (3 participants [15.8%]), back pain (3 participants [15.8%]), fatigue (3 participants [15.8%]), pyrexia (3 participants [15.8%]), and weight decreased (3 participants [15.8%]). The most frequently reported PTs (>15% of participants) in the venglustat arm were fall (22 participants [55.0%]), COVID-19 (13 participants [32.5%]), headache (10 participants [25.0%]), contusion (9 participants [22.5%]), cough (8 participants [20.0%]), urinary tract infection (7 participants [17.5%]), nausea (7 participants [17.5%]), and arthralgia (7 participants [17.5%]). No fatal TEAEs were reported in the primary population during the PAP. Treatment-emergent serious adverse events (SAEs) occurred in a similar percentage of participants in the venglustat and placebo arms (8 [20.0%] participants and 4 [21.1%] participants, respectively). The most frequently reported events (PTs) in the venglustat arm were urinary tract infection reported in 2 (5.0%) participants and PT tibia fracture reported in 2 (5.0%) participants. Secondary Population: Fourteen (87.5%) participants in the secondary population experienced at least one TEAE. The PTs reported in most participants (>15%) in the secondary population group were COVID-19 (7 participants [43.8%]), nasopharyngitis (5 participants [31.3%]), headache (4 participants [25.0%]), and vomiting (3 [18.8%]). A total of 6 (37.5%) participants experienced treatment-emergent SAEs. One SAE of respiratory failure had a fatal outcome. Open-label extension period: Overall, 35 (70%) participants in the primary population and 10 participants (71.4%) in the secondary population experienced at least one TEAE. The most frequently occurring events (PTs) in the primary population were fall reported in 6 (12.0%) participants, headache reported in 5 (10.0%) participants, COVID-19 reported in 4 (8.0%) participants, nasopharyngitis reported in 3 (6.0%) participants, pneumonia reported in 3 (6.0%) participants, urinary tract infection reported in 3 (6.0%) participants, nausea reported in 3 (6.0%) participants, constipation reported in 3 (6.0%) participants, and arthralgia reported in 3 (6.0%) participants. The most frequently occurring event (PT) in the secondary population was urinary tract infection reported in 2 (14.3%) participants. One fatal TEAE was reported in the primary population. No death was reported in the secondary population. Treatment-emergent SAEs occurred in 6 (12.0%) participants from the primary population and 2 (14.3%) participants in the secondary population.

Primary efficacy endpoints (Primary Population): Percent change of cerebrospinal fluid (CSF) GM2 biomarker: The percent change (standard error [SE]) in the CSF GM2 biomarker decreased from baseline to Week 104 by 11.33% (4.23) in the placebo arm and 47.57% (3.04) in the venglustat arm. The estimated difference between arms of 36.24% (SE: 5.20; 90% confidence interval [CI]: [-44.80 to -27.68]; p<0.0001) is statistically significant. Annualized rate of change in 9-HPT: The annualized rate of change in 9-HPT was 0.95% per year (SE: 1.92; 90% CI: -2.16 to 4.15) and 2.49% per year (SE: 1.35; 90% CI: 0.28 to 4.74) in the placebo arm and venglustat arm, respectively. The difference between the two arms, 1.54 (SE: 2.35; 90% CI: [-2.33 to 5.39]; p=0.7435), is not statistically significant. Efficacy in Secondary Population: Primary efficacy endpoints (Secondary Population): Plasma and CSF GL-1 biomarker and a pathway specific biomarker: Plasma GL-1 samples were available for 14 of 16 participants both at baseline and Week 104. The median (min, max) decreased by 4.47 micro g/mL (-5.7, -2.5), or 80.99% (-88.4, -69.4), from baseline to Week 104. CSF samples were obtained from 12 of 16 participants. At Week 104, median (min, max) GL-1 levels in CSF decreased by 6.16 micro g/mL (-20.1, 14.9), or 84.27% (-91.3, 299.6), from baseline. Data for the participants with sialidosis type 1 and the participants with galactosialidosis is not being presented due to the possibility of participant identification. Juvenile/Adolescent GM2 gangliosidosis: The median (min, max) GL-1 in both the plasma and CSF in participants with juvenile/adolescent GM2 gangliosidosis (n=7) decreased from baseline to Week 104 by 4.37 micro g/mL (-5.7, -2.5), or 80.89% (-82.0, -75.8), and 6.88 micro g/mL (-10.5, -3.5), or 87.31% (-91.3, -62.4), respectively. Median (min, max) GM2 levels in both the plasma and CSF also decreased by Week 104 by 400.00 ng/mL (-744.0, -193.0), or 56.42% (-75.9, -36.9), and 92.80 ng/mL (-262.0, 1.3), or 51.38% (-61.9, 4.0), respectively. GM1 gangliosidosis: Median (min, max) GL-1 in plasma decreased from baseline to Week 104 by 4.32 micro g/mL (-5.6, -2.6), or 82.87% (-88.4, -69.4), in participants with GM1 gangliosidosis (n=6), and 2.53 micro g/mL (-8.5, 14.9), or 70.23% (-89.5, 299.6), in CSF. Median (min, max) GM1 decreased from baseline to Week 104 in both plasma and CSF by 98.05 ng/mL (-257.2, -30.4), or 52.95% (-78.2, -26.9), and 16.75 ng/mL (-32.4, -8.3), or 29.08% (-56.0, -15.3), respectively. Secondary efficacy endpoint(s) (Secondary Population): Annualized rate of change in 9-HPT: Juvenile/adolescent GM2 gangliosidosis: The median (min, max) of percent change in the 9-HPT from baseline to Week 104 was -10 (-20, 35). GM1 gangliosidosis: The median (min, max) of percent change in the 9-HPT from baseline to Week 104 was -3.1 (-14, 78). Change in 25 FWT: Juvenile/adolescent GM2 gangliosidosis: Over the 104-week PAP, the median (min, max) of percent change from baseline in the 25 FWT was 5.0 (-11, 471). GM1 gangliosidosis: Over the 104-week PAP, the median (min, max) percent change was 8.0 (-12, 16). Change in neurological examination of the FARS over time: Juvenile/adolescent GM2 gangliosidosis: The median (min, max) change from baseline to Week 104 was -3.2 (-5, 18) for 6 out of 7 participants in this group. GM1gangliosidosis: The median (min, max) change from baseline to Week 104 was -1.5 (-32, 16). This analysis included 6 out of 7 participants in the group.

A total of 59 participants in the primary population were randomized and treated (40 in the venglustat and 19 in the placebo), and 16 in the secondary population were treated. This study did not meet the clinical primary and secondary endpoints in participants in the primary population and was therefore terminated. An overall stability was noted for the clinical endpoints for the secondary population. The safety profile of venglustat remains consistent with previously reported results of venglustat.

Oct. 15, 2025

https://authors.elsevier.com/sd/article/S1098-3600(25)00262-X

No

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

https://jrct.mhlw.go.jp/latest-detail/jRCT2021200023

Obara Kentaro

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp@sanofi.com

Clinical Study Unit

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp@sanofi.com

Complete

Oct. 08, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- 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 beta-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

- Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by beta-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 25-foot walk test (25FWT) and patient-reported outcome (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/1.73m^2 at the screening visit

Both

Tay-Sachs Disease, Sandhoff Disease

Drug: venglustat GZ402671
- Pharmaceutical form: tablet
- Route of administration: oral
Drug: placebo
- Pharmaceutical form: tablet
- Route of administration: oral

1. Change in cerebrospinal fluid (CSF) GM2 biomarker [ Time Frame: From baseline to Week 104 ], Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population
2. Change in the 9-hole pegboard test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population
3. Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
4. Assessment of PD response in plasma: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population
5. Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population
6. Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population
7. Assessment of PD response in plasma: GL-1 biomarker [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 for saposin C deficiency in secondary population
8. Assessment of PD response in CSF: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
9. Assessment of PD response in CSF: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population
10. Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population
11. Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population
12. Assessment of PD response in CSF: GL-1 biomarker [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 for saposin C deficiency in secondary population

1. Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ], Number of patients with adverse events
2. Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline up to Week 12 ], Maximum venglustat concentration (Cmax)
3. Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline up to Week 12 ], Time to maximum venglustat concentration (tmax)
4. Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline up to Week 12 ], Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
5. Assessment of PK parameters in plasma: plasma concentrations [ Time Frame: From baseline up to Week 104 ], Plasma venglustat concentration
6. Assessment of PK parameters : CSF venglustat concentration [ Time Frame: Week 104 ], CSF venglustat concentration
7. Change in 25-foot walk test (FWT) [ Time Frame: From baseline to Week 104 ], Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
8. Absolute change in CSF GM2 biomarker [Time Frame: From baseline to Week 104]
9. Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS) [ Time Frame: From baseline to Week 104 ], Change in the neurological examination of the FARS score from baseline to Week 104
10. Change in 9-hole peg test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population
11. Acceptability assessment Venglustat tablets acceptability will be assessed through the route of venglustat administration collected in the eCRF and study intervention compliance [Time Frame: From baseline to Week 104]

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Jan. 21, 2020

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