Investigational Agent ANX005 Shows Safety and Pharmacodynamic Activity in Early Huntington Disease Trial

Early-phase data from a multicenter, open-label, phase 1b trial (NCT04514367) suggested that targeted inhibition of the classical complement pathway with ANX005 (Annexon Biosciences) is generally tolerable and engages its intended target in patients with early-manifest Huntington disease (HD). Findings from this study, dubbed ANX005-HD-01, provide initial clinical evidence supporting further exploration of complement blockade as a potential disease-modifying strategy.¹

Study Design and Population

Led by Rajeev Kumar, MD, co-founder and CEO of Stealth Biotech in ANX005-HD-01 evaluated intravenous ANX005, a humanized monoclonal antibody targeting C1q, the initiating protein of the classical complement cascade, in adults with early-manifest or premanifest HD. Participants (n = 28) were at least 18 years of age with CAG-age production greater then 400 and sufficient functional independence (Unified Huntington’s Disease Rating Scale [UHDRS] independence score greater then 80%). Patients received 75 mg/kg on days 1 and 5/6, followed by biweekly 100 mg/kg maintenance doses through week 22, with follow-up through week 36.

Primary endpoints included safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of complement engagement (C1q, C4a/C4 levels) in serum and cerebrospinal fluid (CSF). Exploratory efficacy measures assessed change from baseline in the composite UHDRS and its components, including total functional capacity (TFC), total motor score (TMS), cognitive testing, and Symbol Digit Modalities Test (SDMT).¹

Safety and Tolerability

All patients experienced at least 1 treatment-emergent adverse event (TEAE), most of which were mild to moderate and infusion-related (rash, pruritus, flushing, tachycardia). Three patients (10.7%) with mildly elevated baseline antinuclear antibodies (ANA) withdrew due to serious AEs, including systemic lupus erythematosus–like syndrome, pneumonitis, and hemolytic anemia. Notably, no deaths or grade 4 events were reported. Prophylactic corticosteroids, antihistamines, and acetaminophen were administered prior to the first infusion, and infusion interruptions were temporary and resolved without discontinuation in most cases.¹

Pharmacokinetics, Pharmacodynamics and Clinical Activity

Steady-state serum and CSF concentrations of ANX005 were achieved by week 6, with full C1q target engagement maintained through the 24-week dosing period. Free ANX005 was largely undetectable by weeks 28–36, reflecting clearance after treatment cessation. C4a/C4 ratios in CSF were used as a marker of complement activity, with subgroup analyses suggesting that patients with higher baseline complement activity may exhibit stabilization or modest improvements in cUHDRS and TFC.¹

In the per-protocol population (n = 23), mean cUHDRS scores and component measures remained generally stable over 36 weeks. Subgroup analyses based on baseline complement activity indicated potential clinical benefit in patients with elevated complement activation, although the study was not powered to evaluate efficacy definitively.¹

Clinical Context and Next Steps

Complement activation contributes to synaptic loss and neuroinflammation in HD, and preclinical data suggest that C1q inhibition can prevent corticostriatal synapse loss and cognitive decline in HD models.² ANX005 represents a first-in-class approach targeting this pathway. While standard HD management remains symptomatic,7 therapies modulating neuroinflammatory mechanisms are of growing interest given the absence of disease-modifying options. Prior immunomodulatory agents, including laquinimod, minocycline, pepinemab, and cannabinoid combinations, have not met primary efficacy endpoints in HD.³

ANX005-HD-01 was designed for safety and PK/PD assessment rather than powered efficacy evaluation. The exploratory clinical findings are hypothesis-generating, and safety signals warrant careful monitoring, particularly in patients with elevated baseline autoantibody titers. Ongoing studies are needed to confirm the potential disease-modifying effects of C1q inhibition and to better define patient subgroups most likely to benefit.

Previous Trials Evaluating ANX005

ANX005 has been evaluated in previous trials for different disease states. Data from a phase 3, double-blind, placebo-controlled study (NCT04701164) revealed that a single dose of investigational ANX005 at 30 mg/kg doses led to significant and sustained improvement in patient health for those with Guillain-Barré syndrome (GBS) over a 6-month period. A biologics license application submission was expected to come in the first half of 2025, with ANX005 poised to potentially become the first approved therapy for GBS.^4,5

Presented at 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9 in San Diego, California, the study featured 242 patients with GBS, at least 16 years of age, who were randomly assigned 1:1:1 to a single intravenous (IV) infusion of ANX005 at doses of either 30 or 75 mg, or placebo, for an 8-week treatment period. Results showed that both doses inhibited complement; however, only the 30 mg/kg dose group achieved the primary outcome of change in GBS Disability score (GBS-DS) trichotomy.

Led by Quazi Deen Mohammad, MD, MBBS, FCPS, a neurologist in Dhaka, Bangladesh, the trial featured only patients who were not receiving either intravenous immunoglobulin (IVIg) or plasma exchange. All told, those assigned to the ANX005 30 mg/kg group had 2.4-times greater odds of improved health at week 8 relative to placebo (OR, 2.4; 95% CI, 1.29-4.50; P = .0058), all while maintaining a safe profile. Notably, patients started to see improvements in function as early as week 1 of treatment (OR, 7.2; 95% CI, 3.07-16.96; P <.001).

REFERENCES
1. Movement Disorders Society. ANX005-HD-01 Phase 1b study of ANX005 in Huntington disease. Wiley Online Library. 2026. https://doi.org/10.1002/mds.
2. Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Huntington disease. Science. 2016;352(6293): 712-716. https://doi.org/10.1126/science.aad8371
3. Huntington Study Group. Laquinimod in Huntington disease: a phase II study. Neurology. 2015;84: 771-778. https://doi.org/10.1212/WNL.0000000000001284
4. Kroon HA, Islam Z, Collins P, et al. Efficacy and Safety of Targeted Immunotherapy with ANX005 in Treating Guillain-Barré Syndrome: A Phase 3 Multicenter Study. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA. ABSTRACT 004954
5. Annexon Provides 2025 Outlook with Strong Momentum Accelerating into Breakthrough Year. News release. Annexon. January 13, 2025. Accessed April 4, 2025. https://ir.annexonbio.com/news-releases/news-release-details/annexon-provides-2025-outlook-strong-momentum-accelerating