An Open‐Label Phase 1b Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ANX005 in Patients with Huntington's Disease
An Open‐Label Phase 1b Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ANX005 in Patients with Huntington's Disease
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Original abstract
Abstract Background The classical complement pathway is implicated in the progression of neurodegenerative disease through its ability to drive aberrant removal of synapses, neuroinflammation, and neuronal damage. ANX005 is a humanized monoclonal antibody targeting C1q that blocks classical complement pathway activation. Objective The aim was to assess the safety, pharmacokinetics (PK), pharmacodynamics, and clinical activity of ANX005 in patients with Huntington's disease (HD). Methods ANX005‐HD‐01 (NCT04514367) was a multicenter, open‐label, phase 1b study in patients with early‐manifest HD. Primary endpoints included safety, tolerability, PK, and complement C1q and C4a/C4 levels in the serum and cerebrospinal fluid (CSF). Exploratory clinical activity endpoints included changes from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) and component scores. Results All patients who received study drug (n = 28) experienced ≥1 treatment‐emergent adverse event, mostly transient infusion‐related reactions on the first dose. Three patients with elevated baseline antinuclear antibodies withdrew from the study due to treatment‐related AEs (pneumonitis) or serious AEs (systemic lupus erythematous, hemolysis). Twenty‐three patients (82.1%) received all planned ANX005 infusions. Steady‐state PK was achieved by week 6, with full saturation of ANX005 observed in serum and the CSF. Stabilization or possible improvement in cUHDRS and total functional capacity through 36 weeks was observed in a patient subgroup with higher baseline complement activity, based on baseline C4a/C4 ratio in CSF. Conclusion Overall, AEs with ANX005 administration were manageable, and most patients received all planned doses. Evidence of clinical improvement with ANX005 was observed in patients with higher baseline complement activity, supporting future study in patients with HD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.