Category: Huntington's Disease
Objective: To assess the safety, PK/PD, exploratory biomarkers, and efficacy of ANX005 in patients with, or at risk for, manifest HD.
Background: Increased complement activation has been implicated in synapse elimination, neuroinflammation, and neurodegeneration in disorders such as HD. ANX005, a humanized monoclonal antibody targeting C1q, was designed to inhibit the classical complement pathway, potentially preserving synapses to improve neuronal function and prevent subsequent neurodegeneration.
Method: Eligible patients (CAP score >400) enrolled in this multicenter, open-label, phase 2 study (NCT04514367) received intravenous dosing of ANX005 every 2 weeks through week 22. Patients who received ≥1 dose were included in the safety analysis (n=28). Primary objectives included safety, tolerability, and drug, C1q, and neurofilament light chain (NfL) levels in blood and cerebrospinal fluid (CSF). Exploratory objectives included complement activity and change in composite Unified Huntington’s Disease Rating Scale (cUHDRS) as a measure of clinical efficacy.
Results: Interim results from this ongoing phase 2 trial show that ANX005 was generally well tolerated, with full target engagement of C1q in serum and CSF. All patients experienced an infusion-related reaction: 93% occurred on day 1, and 96% were primarily rashes (27/28). There were 2 serious AEs (systemic lupus erythematosus and idiopathic pneumonitis), which resolved or stabilized upon drug discontinuation. In total, 56% (13/23) of patients who completed 24 weeks of treatment demonstrated improved clinical function as measured by change in cUHDRS from baseline. 75% of patients (9/12) exhibiting high baseline complement activity (C4a/C4) improved in cUHDRS, compared with 36% of patients (4/11) with low baseline complement activity. Changes in mean plasma and CSF NfL levels appeared consistent with disease natural history.
Conclusion: These results support a novel role for complement activation in HD and indicate the potential for disease modification with continued development of ANX005. Off-drug observation from week 24 to 36 is ongoing.
To cite this abstract in AMA style:R. Kumar, D. Claassen, A. Mongan, A. Grover, B. Hoehn, P. Lin, R. Arnold, E. Cahir-Mcfarland, T. Yednock, S. Keswani. Phase 2 study evaluating safety, PK/PD, biomarkers, and efficacy of ANX005 in patients with Huntington’s disease (HD) [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/phase-2-study-evaluating-safety-pk-pd-biomarkers-and-efficacy-of-anx005-in-patients-with-huntingtons-disease-hd/. Accessed September 25, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/phase-2-study-evaluating-safety-pk-pd-biomarkers-and-efficacy-of-anx005-in-patients-with-huntingtons-disease-hd/