18-month double-blind, randomized, placebo-controlled, multicenter, Phase 3 study to evaluate the safety and efficacy of oral nizubaglustat (AZ-3102) in late-infantile and juvenile forms of Niemann-Pick type C disease and in late-infantile and juvenile-onset forms of GM1 gangliosidosis or GM2 gangliosidosis

Niemann-Pick type C disease and GM1/GM2 gangliosidoses

Change from Baseline to Week 72 in cale for Assessment and Rating of Ataxia (SARA) score, using both total SARA and functional SARA.

1. Change from Baseline to Weeks 24, 48, and 72 in: • SARAGAIT/POSTURE • SARASPEECH • SARAKINETICS • Vineland Adaptative Behavior Scale (VABS) comprehensive interview form • Penetration-Aspiration Scale (PAS), 2. Change from Baseline to Weeks 24, 48, and 72 in: • 9-Hole Peg Test (9-HPT-D): change in the number of pegs per second placed in 50-seconds using the dominant hand • Goal attainment scale (GAS) • Clinical global impression of change (CGI-C) • Participant/caregiver global impression of change (PGI-C) • Seizure frequency and duration, as per the seizure diary, Cont.Translation- Portuguese and French, 3. Time-to-event comparison between nizubaglustat and placebo over the study duration for pre-defined detrimental events of: • An increase in total SARA score of ≥2 points and/or an increase in functional SARA of ≥1.5 points • A decrease in PAS of ≥1 point • Participants leaving the study due to participant/caregiver perception of disease progression/lack of efficacy., 4. For subprotocol AZA-001-301-NPC only, change from Baseline in NPC Clinical Severity Scale (NPC-CSS) score, 5. The concentrations of nizubaglustat and its metabolites in plasma. The main PK parameters assessed will be: •Maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) • Plasma trough concentration (Ctrough) at Week 4 • Area under the plasma concentration-time curve from the time of dosing (zero) to 24 hours post-dose (AUC0-24) at Baseline • Accumulation ratio for Cmax., 6. Change from Baseline to Weeks 4, 24, 48 and 72 in the plasma GlcCer C16:0; C18:0 concentration., 7. Change from Baseline to Weeks 24 and 48 comparing nizubaglustat and placebo in terms of: •Total and functional SARA score, 8. Change from Baseline to Weeks 24, 48 and 72 comparing nizubaglustat and placebo in terms of: •Total time to perform the timed 'up and go' (TUG) test in ambulant participants •Oropharyngeal swallow response (OSR) •Robbins scale, 9. Change from Baseline to Weeks 24, 48 and 72 comparing nizubaglustat and placebo in terms of: •The Leeds Sleep Evaluation Questionnaire (LSEQ) •EQ-5D-5L score for participants aged ≥15 years or EQ 5D-Y score for participants aged <15 years •Burden Scale for the Caregiver (BSFC) short version, 10. The concentrations of nizubaglustat and its metabolites in cerebrospinal fluid (CSF). The main PK parameters assessed will be: •CSF Cmax and Tmax •CSF Ctrough at Week 72 •AUC0-24 at Baseline •Accumulation ratio for Cmax, 11. Change from Baseline to Week 72 in GlcCer C16:0; C18:0 concentration in CSF., 12. Change from Baseline to Weeks 4, 24, 48 and 72 in the plasma concentrations of: • Glial fibrillary acidic protein (GFAP) • Neurofilament light chain (NfL), 13. For subprotocol AZA-001-301-NPC only: • N-palmitoyl-O-phosphocholinesterase (PPCS) • Cholestane-3β-5α-6β-triol (C-triol) • 24(S)-hydroxycholesterol., 14. For subprotocol AZA-001-301-GMx only: • Participants with GM1 gangliosidosis - monosialoganglioside GM1 and lyso-monosialoganglioside GM1 • Participants with GM2 gangliosidosis - monosialoganglioside GM2 and lyso-monosialoganglioside GM2., 15. Incidence and severity of treatment-emergent adverse events (TEAEs). Change in vital sign parameters, electrocardiogram (ECG) parameters, and laboratory safety parameters from Baseline to each study visit. Incidence of treatment-emergent abnormal laboratory values and ECG abnormalities.

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