ANX005 Demonstrates Safety in Huntington Disease, With Improvements Found in Subgroups of Patients

Rajeev Kumar, MD

Final results from a phase 2 study (NCT04514367) assessing Annexon Biosciences’ investigational agent ANX005 showed that the therapy was generally well tolerated, maintained full target engagement, and showed clinical improvement in a subgroup of patients with Huntington disease (HD) with high baseline C4a/C4 levels.

These data were presented by Rajeev Kumar, MD, medical director, Rocky Mountain Movement Disorder Center, at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts. In the open-label trial, 28 individuals with HD received ANX005 intravenously (IV) on days 1 and 5 or 6, followed by maintenance dosing every 2 weeks through week 22, with follow-up visits on weeks 24, 268, and 36.

In terms of safety, the primary objective of the trial, investigators observed transient infusion-related reactions, mainly transient maculopapular rash, in all patients during the first dose. Lupus-like presentation and idiopathic pneumonitis, the only 2 recorded serious adverse events (AEs), were reversed or improved upon treatment discontinuation. ANX005, a humanized monoclonal antibody designed to inhibit C1q, showed complete and durable inhibition of this complement component in cerebrospinal fluid (CSF) and serum that was consistent with drug levels.

"Animal models with transgenic Huntington mouse models have shown improvements in neural pathology with treatments that target neuroinflammation. As well, knockup models of Alzheimer disease have shown that reduction in C1q improves the pathology of those mice,” Kumar told NeurologyLive®. "In this case, we’ve opted to target the very initiation of the complement targeting C1q, and as a result, we can not only prevent the development of the membrane attack complex and cell death, but we can hopefully, by acting upstream, reduce the development of chemoattractant molecules. As a result, we hope to reduce the migration of neuroinflammatory migrating lymphocytes as well as activation of microglia."

For those who completed 24 weeks of treatment, mean plasma and CSF neurofilament light levels tracked with NfL natural history. Using composite Unified Huntington’s Disease Rating Scale (cUHDRS) and total functional capacity (TFC), 2 commonly used measures in HD research, investigators observed clinical disease progression that was stable in the overall patient population. Additionally, a trend of decreased CSF YKL40 suggested a positive impact of ANX005 on microglial activity in patients who exhibited improved clinical response.

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In a subgroup analysis, patients with high baseline C4a/C4 (n = 12) demonstrated clinical improvement in cUHDRS at all time points, with a significant difference observed between those with low baseline C4a/C4 (n = 11) at week 24 (P = .037). Notably, these 2 groups were consistently separated on analyses of TFC throughout the study. Throughout the 9-month study, patients demonstrated rapid and sustained reductions in downstream complement activation and neuroinflammation, as measured by CSF C3a and C3 levels.

"There seemed to be a symptomatic effect. That symptomatic effect may be because we’re rescuing dysfunctional synapses, which have a high level of complement deposition. We may be improving function," Kumar said.

He added, "We’re hopeful that this therapy will not just be a symptomatic therapy, but instead a disease-modifying therapy. We may see an improvement because of this rescue [inhibition], but if we can knockdown neuroinflammation­–which contributes to cell death­–we can hopefully slow disease progression. This therapy is obviously different than gene targeting therapies, but there’s no reason why this couldn’t be combined with gene targeting therapy. For example, huntingtin-lowering therapies, antisense oligonucleotide therapies, sRNA therapies, or RNA transcription modulation therapies. We’re hoping that eventually, we have a cocktail to administer to our patients to slow disease progression in HD."

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REFERENCES
1. Kumar R, Claassen D, Mongan A, et al. A phase 2 open-label study to assess the safety, tolerability, pharmacokinectis, and pharmacodynamics of intravenous ANX005 in patients with, or at risk of, manifest huntington disease (HD). Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. 003366