Early Targeted C1q Inhibition With Tanruprubart Improves Functional Recovery in Guillain-Barré Syndrome: Results From a Phase Three Study
Henk-André Kroon1, Zhahirul Islam2, Jose Navarro3, Khan Abul Kalam Azad4, Glenn Morrison1, Erik Pulkstenis1, Quazi Deen Mohammad5
1Annexon Biosciences, 2Laboratory of Gut-Brain Axis, 3José R. Reyes Memorial Medical Center, 4Dhaka Medical College and Hospital, 5National Institute of Neuroscience (NINS)
Objective:
Determine whether C1q inhibition with tanruprubart improves functional recovery in Guillain-Barré syndrome (GBS), and whether effects are amplified with earlier treatment or in patients with limited axonal damage (consistent with motor forms of GBS).
Background:
Early diagnosis and treatment are critical in GBS, as complement-mediated nerve inflammation and injury progress rapidly during the acute phase. C1q activation initiates this cascade. The extent of neuroinflammation and nerve damage at treatment initiation determines the speed and range of functional recovery. Tanruprubart, a monoclonal antibody that selectively and rapidly inhibits C1q, has demonstrated early improvement in muscle strength and disability in patients with GBS.
Design/Methods:
This phase 3, double-blind, placebo-controlled study (NCT04701164) evaluated 242 patients with GBS, aged ≥16 years with GBS disability score (GBS-DS) 3–5, randomized to a single IV infusion of tanruprubart (30 or 75 mg/kg) or placebo (not receiving IVIg or plasma exchange). Patients were treated within 10 days of weakness onset. Treatment effects on GBS-DS at Week 8 were evaluated by time from onset of weakness to dosing and baseline neurofilament light (NfL), a biomarker of axonal damage.
Results:
Overall, tanruprubart 30 mg/kg treatment showed an adjusted common odds ratio (aOR) for GBS-DS improvement at Week 8 of 2.4 compared to placebo (95% CI: 1.29–4.50; p=0.0058). Benefit was greater with treatment started ≤5 days from onset of weakness vs >5 days (aOR 3.4, 95% CI: 1.17–10.46, p=0.031) or when baseline serum NfL was <115 pg/mL vs ≥115 pg/mL (≤40% percentile; aOR 3.9, 95% CI: 1.55–10.14, p=0.005).
Conclusions:
Patients diagnosed and treated early in the disease course (≤5 days from onset), or with limited axonal damage (low baseline NfL), achieved greater functional improvement (GBS-DS). These results support the pivotal role of classical complement activation in GBS, highlight the need for rapid diagnosis, and the benefit of early targeted C1q inhibition.
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