AZP2006 in Progressive Supranuclear Palsy: Outcomes from a Phase 2a Multicenter, Randomized Trial, and Open-Label Extension on Safety, Biomarkers, and Disease Progression.

OBJECTIVES The aim was to evaluate the safety, tolerability, pharmacokinetics, and potential clinical efficacy of AZP2006, an oral pleiotropic drug modulating progranulin levels, in patients with progressive supranuclear palsy (PSP), a rare tauopathy. METHODS A randomized, double-blind, placebo-controlled, parallel-group trial was conducted at three sites in France. Eligible participants (age 40-80 years, diagnosed with probable or possible PSP) were randomized to receive AZP2006 (60 mg once per day [QD] or 80/50 mg QD [80 mg for 10 days followed by 50 mg]) or placebo for 12 weeks. Assessments included safety, pharmacokinetics (plasma and whole blood), pharmacodynamics (cerebrospinal fluid and plasma biomarkers), and exploratory clinical efficacy (PSP rating scale, clinical global impression, and activities of daily living). Approximately 2 years post-trial, an open-label extension (OLE) enrolled 15 patients who received active treatment (AZP2006) for 6 months. RESULTS Forty-one patients were screened, 36 randomized, and 34 completed the study. AZP2006 demonstrated acceptable tolerability and safety with no treatment-related serious adverse events. Pharmacokinetic analysis confirmed rapid absorption, a long half-life (60 mg: 764.3 hours; 80/50 mg: 684.7 hours), and steady-state by day 45 (60 mg) and day 28 (80/50 mg). Biomarker analyses indicated blood-brain barrier crossing, target engagement, and stabilized progranulin levels. Trends in efficacy favored slower disease progression in AZP2006 groups. The OLE demonstrated a slowed progression of the disease and revealed no notable safety concerns. CONCLUSIONS AZP2006 was well-tolerated and demonstrated favorable trends in biomarker and clinical outcomes. These preliminary signals support further investigation to determine whether a meaningful clinical benefit can be achieved in PSP with AZP2006. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.