Dysregulated deposition of C1q on synapses is thought to play a role in various neurodegenerative diseases, including Huntington’s disease (HD). This activates complement, causes migration of immune cells into the cells, and activates microglia, leading to the engulfment of synapses and eventual neuronal cell death. To knock down C1q (at the top of the cascade) with a monoclonal antibody would potentially prevent neuroinflammation and synapse and cell loss downstream. Rajeev Kumar, MD, Rocky Mountain Movement Disorders Center, Englewood, CO, explains the recent trial investigating ANX005 (NCT04514367) over 24 weeks in 28 patients with manifest or late pre-manifest HD and CAP scores around 400. Initially, the participants had induction dosing over a 24-hour prolonged perfusion before being given a dose a day for five to six weeks, then one every two weeks until the end of the period. The study lasted 36 weeks. The results found the unified HD rating scale (UHRDS), functional capacity score, and neurofilament light (Nfl) to remain stable. The groups were divided into those with a high level of complement activity in the brain (ratio of active component (C4a) to inactive component (C4)) and those with lower levels. The high ratio groups showed quick improvement in composite UHDRS and in subcomponents of the UHDRS, such as the total motor score (significantly improved by the end of the dosing period). They also found a reduction in biomarkers of neuroinflammation (such as YKL40) in those with a high baseline level of complement activation C4a/C4 ratio compared to those with a low ratio. In terms of adverse effects, the three discontinued patients had various autoimmune reactions that resolved within several weeks or a couple of months. ANX005 is a unique therapy that has a different mode of action in HD and has the possibility of being combined with knockdown therapies. The lack of an increase in Nfl levels is a good result as previous HD knockdown studies have had this effect. In the future, they are looking to do a Phase II/III double-blind, multi-center, placebo-controlled study. This interview took place at the AAN Annual Meeting 2023 in Boston, MA.
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