A Phase 2 Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous ANX005 in Patients with, or at Risk of, Manifest Huntington’s Disease (HD)
Rajeev Kumar1, Daniel Claassen2, Ann Mongan3, Benjamin Hoehn3, Ping Lin3, Ellen Cahir-Mcfarland3, Chenying Guo3, Vladislav Volman3, Lori Taylor3, Priya Chandra3, Ted Yednock3, Henk-Andre Kroon3
1Rocky Mountain Movement Disorders Center, 2Vanderbilt University Medical Center, 3Annexon Biosciences
Objective:
Report final results of ANX005-HD-01, a phase 2 study of patients with or at risk of manifest HD.
Background:
ANX005 is a humanized monoclonal antibody designed to inhibit C1q.
Design/Methods:
Eligible patients (CAP>400) received intravenous ANX005 every 2 weeks through week 22 (NCT04514367). Endpoints were assessed on-treatment through week 24, with off-treatment follow-up through week 36. Primary objectives included safety/tolerability, pharmacokinetics (PK), and C1q, C4a, and NfL levels (CSF and plasma). Exploratory objectives of clinical efficacy included cUHDRS and total functional capacity (TFC).
Results:
All safety population (n=28) patients experienced transient infusion-related reactions during the first dose, mainly transient maculopapular rash. Two serious adverse events occurred, lupus-like presentation and idiopathic pneumonitis, which reversed or improved upon treatment discontinuation. Steady-state PK were achieved by week 6 in the blood and CSF. ANX005 demonstrated complete and durable C1q inhibition in CSF and serum, consistent with drug levels. Mean plasma and CSF NfL levels for 24-week completers (n=23) tracked with NfL natural history. Clinical disease progression was stable in the overall patient population throughout the entire 9-month study as measured by mean change in cUHDRS and TFC relative to baseline. Subgroup analysis indicated that patients with high baseline C4a/C4 (n=12) exhibited clinical improvement in cUHDRS at all timepoints, with a significant difference from patients with low baseline C4a/C4 (n=11) at week 24 (p=0.037). Consistent separation in TFC between the two subgroups was observed throughout the study. Rapid and sustained reduction in downstream complement activation and neuroinflammation, as measured by CSF C3a and C3 levels, respectively, was also observed through the 9-month study. A trend of decreased CSF YKL40 suggested a positive impact of ANX005 on microglial activity in patients exhibiting improved clinical response.
Conclusions:
ANX005 was generally well-tolerated, maintained full target engagement, and showed clinical improvement in a subgroup of HD patients.