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Abstract
Background ANX005 is a humanized monoclonal antibody designed to inhibit C1q.
Aims Report final results of ANX005-HD-01: a Phase 2 study of patients with or at risk of manifest HD.
Methods/Techniques Eligible patients (CAP>400) received intravenous ANX005 every 2 weeks (wk) through wk22 (NCT04514367). Endpoints were assessed on-treatment through wk24, with off-treatment follow-up through wk36 (n=23). Primary objectives included safety/tolerability, pharmacokinetics (PK), and C1q, C4a, and NfL levels (CSF and plasma). Exploratory objectives of clinical efficacy included cUHDRS and TFC.
Results/Outcome 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 wk6 in the blood and CSF. Complete elimination of C1q activity was observed in CSF and serum, consistent with drug levels, and persisted into the off-treatment period. Mean plasma and CSF NfL for 24-wk completers tracked with NfL natural history (Table 1). No significant decline in mean cUHDRS or TFC was observed for patients at wk24 or wk36 relative to baseline (Figure 1A-B). Subgroup analysis indicated that patients with high baseline C4a/C4 (n=12) exhibited clinical improvement (higher cUHDRS) over baseline at all timepoints, with a significant difference from patients with low baseline C4a/C4 at wk24 (Figure 1C; p=0.037). Consistent separation in TFC between two subgroups was observed throughout study (Figure 1D).
Conclusions ANX005 was generally well-tolerated, maintained full target engagement, and showed clinical improvement in a subgroup of HD patients.
Mean Percentage Change (± 95% Confidence Intervals) from Baseline in NfL
Mean Change From Baseline in cUHDRS in All Patients (A), in TFC in All Patients (B), in cUHDRS in Subgroups of Patients With High vs Low Baseline Complement Activation (C), and in TFC in Subgroups of Patients With High vs Low Baseline Complement Activation (D)