Inhibition of C1q, Initiator of the Classical Complement Cascade, by ANX005 for the Treatment of Guillain-Barré Syndrome: Results from a Phase 1b Study (763)

Objective: To assess anti-C1q antibody ANX005 in patients with Guillain-Barré Syndrome (GBS).

Background: GBS is a serious, life-threatening autoimmune disorder causing acute neuronal injury and progressive paralysis, sometimes leading to permanent disability or death. Symptoms peak within 4 weeks and recovery ranges from months to years. Although not FDA-approved, IVIg and plasma exchange are the standard of care in the US. Onset is associated with autoantibody-induced activation of the classical complement cascade. Inhibition of C1q, the initiating molecule of the cascade, early in the course of GBS may minimize disease severity and accelerate recovery.

Design/Methods: A phase 1b double-blind, placebo-controlled, single ascending dose study assessed safety, pharmacokinetics, and pharmacodynamics of ANX005 (n=23) vs placebo (n=8) in patients with GBS in Bangladesh. Neurofilament light chain (NfL), a nerve damage biomarker, and functional efficacy measures were assessed.

Results: In 23 patients aged 18–58 years, ANX005 infusions up to 75 mg/kg were well tolerated with no drug-related serious adverse events (AEs) or discontinuations. The most common AE was infusion-related reactions, manifesting as transient low-grade rashes. Doses ≥18 mg/kg fully inhibited C1q in serum and CSF; inhibition was sustained for up to 3 weeks with 75 mg/kg (n=6). ANX005 resulted in early decline in serum NfL vs placebo from week 2 to 4 post-dose (P=.012) and a dose-dependent improvement in Medical Research Council sum score at week 1. Early improvement correlated with GBS-Disability Score reduction (r²=0.48; P<.0001). At week 8, 28% of patients treated with ANX005 18–75 mg/kg improved by ≥3 points on GBS-Disability Score vs 0% with placebo. Trends for improvement were observed in length of ICU stay and duration of mechanical ventilation.

Conclusions: The classical complement inhibitor ANX005 was well tolerated and demonstrated robust target engagement, impact on biomarkers of neuronal damage, and preliminary evidence of efficacy. A phase 2 trial is planned.

Disclosure: Dr. Islam has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Fogarty International Center, Department of Health and Human Services, National Institutes of Health, and Annexon Biosciences USA. Dr. Papri has nothing to disclose. Dr. Jahan has nothing to disclose. Dr. Azad has nothing to disclose. Dr. Kroon has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences. Dr. Humphriss has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences. Dr. Sankaranarayanan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences. Dr. Yednock has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences. Dr. Keswani has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences. Dr. Keswani has received compensation for serving on the Board of Directors of Proneurotech. Dr. Deen Mohammad has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon Biosciences.