AZP2006, a New Promising Treatment for Progressive Supranuclear Palsy patients. Phase 2a Study Assessing Tolerability, Safety and Pharmacokinetics. Effect on Biomarkers and Clinical Readouts

Background Progressive Supranuclear Palsy (PSP) is a rare progressive, fatal neurodegenerative 4‐repeat tauopathy. AZP2006 (INN: Ezeprogind) is a first‐in‐class disease‐modifying oral small molecule acting via its strong binding to the complex Progranulin (PGRN) / Prosaposin (PSAP), able to increase the circulating contents of PGRN (plasma and brain) in non‐clinical models. Preclinically, AZP2006 promotes neuron survival, synaptic function, decreases Tau hyperphosphorylation and reduces neuroinflammation (in vitro and in vivo models of Alzheimer’s disease, PSP and Parkinson’s disease). In healthy volunteers Phase 1 studies, AZP2006 was well tolerated with a good safety profile. Method AZP2006 safety, tolerability and pharmacokinetic profiles in plasma, whole blood, and CSF were investigated in a randomized, double‐blind, placebo‐controlled, parallel group study comparing 2 doses of AZP2006 (60 mg once daily during the 12‐week treatment period and 80 mg once daily for 10 days followed by 50 mg once daily) with placebo in 36 men and women aged ≥40 years and ≤80 years diagnosed with probable or possible PSP. Patients were observed for an additional 12‐week follow‐up period (NCT04008355). In secondary objectives, CSF biomarkers including PGRN for the target engagement and markers of neurodegeneration (NfL, phospho‐tau T181) as well as markers of neuroinflammation (sTREM2, interleukins, etc.) were quantified. In addition, exploratory efficacy objectives evaluating clinical endpoints (PSP‐RS total, PSP Gait, PSP Ocular, CGI‐ds, Schwab and England ADL) were investigated. Result AZP2006 was safe and well tolerated; no related SAEs were reported. PK profile confirmed the long AZP2006 half‐life (as predicted in a prior popPK model). High brain penetrance was observed and AZP2006 CSF expected levels were achieved. In addition, the target engagement was confirmed by significant increase (vs baseline) of PGRN plasma levels. A PD‐PK analysis is planned. Conclusion AZP2006 treatment showed promising effects after a 3‐month‐treatment. Considering these promising results, an open‐labelled extension (OLE) was started (60 mg daily) in France. In addition, a larger Phase 2b/3 study in PSP patients testing AZP2006 efficacy over 12‐month‐treatment is under preparation.