The RAINBOW study: a phase 2 trial evaluating the 3-month pharmacokinetic and pharmacodynamic data and 18-month clinical and safety outcomes of nizubaglustat in GM2 gangliosidoses or Niemann–Pick type C disease

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INTRODUCTION: GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. METHODS: In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. RESULTS: Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. CONCLUSIONS: Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.

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