Abstract
BACKGROUND: Inhibition of Nod-like receptor protein 3 (NLRP3) inflammasome within the central nervous system (CNS) is a promising therapeutic target for the treatment of Parkinson's disease (PD). OBJECTIVES: This phase 1b open-label study was conducted in elderly healthy volunteers (HV) and PD patients. The study was designed to assess safety and tolerability and to evaluate the central and systemic pharmacokinetic profile and anti-inflammatory effects of a total daily dose of 300 mg NT-0796 (oral 150 mg suspension capsule formulation every 12 h). METHODS: Four elderly HV and 10 subjects with PD received 150 mg open-label NT-0796 every 12 h for either 7 or 28 days, respectively. Blood and cerebrospinal fluid (CSF) were collected via serial sampling or lumbar punctures for pharmacokinetic and biomarker analyses. Standard safety parameters were monitored throughout. RESULTS: NT-0796 was safe and well tolerated with minimal adverse events. A reduced peak-to-trough ratio along with moderately higher exposure than the solution formulation (used in the first-in-human study) was observed, along with significant CSF exposure in elderly HV and subjects with PD. NT-0796 drove reductions in systemic inflammatory markers including high-sensitivity C-reactive protein, fibrinogen, interleukin (IL)-6, and IL-18. Furthermore, reductions in neuroinflammation, including IL-1β, were indicative of NT-0796's target engagement within the central nervous system (CNS) of subjects with PD. CONCLUSIONS: CNS inhibition of NLRP3 with NT-0796 reduced neuroinflammation over a sustained 28-day dosing period and demonstrates the potential for long-term dosing of NT-0796 in future studies of patients with neurodegeneration. © 2025 NodThera Limited. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.