Guillain-Barré syndrome (GBS) is an acute, often rapidly progressive immune-mediated neuropathy. For roughly four decades its treatment has rested on two pillars — intravenous immunoglobulin (IVIg) and plasma exchange (PE) — with no targeted alternative. That is finally beginning to change, and the most important recent development is the first positive placebo-controlled pivotal trial in GBS in a generation.
ANX005 (C1q inhibitor): the first positive pivotal trial in decades
ANX005 is a recombinant antibody against complement protein C1q, blocking the classical complement pathway at an upstream point — the aim being to halt complement-mediated nerve damage before it happens. In a pivotal Phase 3 trial conducted in Bangladesh and the Philippines (regions with high GBS incidence and limited IVIg access), a single 30 mg/kg infusion met its primary endpoint, producing a highly significant 2.4-fold improvement on the GBS disability scale at week 8. Benefits appeared as early as week 1, were sustained through six months, and were accompanied by earlier gains in muscle strength and less time on mechanical ventilation.
Notably, the higher 75 mg/kg dose — which suppressed complement for two to three weeks rather than one — did not meet the primary endpoint. This fits the emerging understanding that classical complement drives tissue damage early but aids nerve repair after acute injury, so a shorter, well-timed window of inhibition may be optimal. ANX005 was generally well tolerated, the most common adverse event being a mild, transient infusion-related rash. A regulatory submission has been anticipated, which could make ANX005 the first GBS-specific approved therapy.
Eculizumab (C5 inhibitor): Phase 3 did not meet its endpoint
Eculizumab is a humanized monoclonal antibody targeting terminal complement protein C5. After an encouraging Phase 2 signal, its Phase 3 trial (a Japanese study of eculizumab added to IVIg) did not show a statistically significant benefit over IVIg alone on the primary endpoint — time to regain independent walking. Common adverse events were headache and upper respiratory infection; meningococcal vaccination is mandatory. So while complement remains a rational target in GBS, terminal C5 blockade added to IVIg has not demonstrated clear benefit — in contrast to the upstream C1q approach.
Current standard: IVIg and plasma exchange
IVIg and PE remain first-line and are of broadly equivalent efficacy. PE works by removing circulating pathogenic antibodies and immune complexes; IVIg is thought to modulate immune function and is more convenient and widely available. PE carries risks tied to vascular access (catheter infection, thrombosis) and hemodynamic shifts; IVIg can rarely cause thromboembolism, renal dysfunction, aseptic meningitis, or transfusion-related acute lung injury. Combination regimens (IVIg plus eculizumab, immunoadsorption then IVIg, or PE then IVIg) have not outperformed monotherapy in network meta-analyses.
Comparative overview
| Therapy | Mechanism | Key finding | Notable risks |
|---|---|---|---|
| ANX005 | C1q inhibition (upstream) | Positive Phase 3: 2.4-fold GBS-DS improvement at wk 8 (30 mg/kg) | Mild infusion rash |
| Eculizumab | C5 inhibition (terminal) | Phase 3 missed primary endpoint (add-on to IVIg) | Meningococcal infection; vaccination required |
| IVIg | Immune modulation | Proven, first-line | Thromboembolism, renal, aseptic meningitis, TRALI |
| Plasma exchange | Antibody removal | Proven, first-line | Access-related infection/thrombosis, hypotension |
The direction of travel is clear: upstream complement inhibition has produced the field's first positive pivotal result, and GBS may soon have its first targeted, disease-specific therapy.
Further reading: ANX005 Phase 3 (Annexon; reported at the 2024 Peripheral Nerve Society meeting and 2025 AAN); eculizumab Phase 2 (Misawa et al., Lancet Neurology 2018) and Phase 3 (Kuwabara et al., Journal of the Peripheral Nervous System 2024); ANX005 Phase 1 (Mohammad et al., 2025).