Astrocytic and Axonal Injury Biomarkers in AQP4 Antibody–Positive NMOSD

BACKGROUND AND OBJECTIVES: Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of astrocytic and axonal injury, respectively, in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-Ab+ NMOSD). We evaluated serum GFAP and NfL levels during treatment with complement component 5 inhibitors eculizumab or ravulizumab and examined associations between pretreatment biomarker levels, clinical characteristics, and on-trial relapse risk using samples from the PREVENT (eculizumab) and CHAMPION-NMOSD (ravulizumab) phase 3 trials. METHODS: Serum GFAP and NfL levels were analyzed retrospectively in PREVENT and prospectively in CHAMPION-NMOSD and compared with levels in demographically matched external healthy donors. Associations between baseline clinical characteristics and high biomarker levels (≥2 SDs above the healthy donor mean) were evaluated using logistic regression with a test-and-validate strategy. Changes throughout treatment were assessed relative to pretreatment baseline. Biomarker changes associated with adjudicated on-trial relapses were examined. Associations between baseline biomarker levels and time to first adjudicated on-trial relapse were assessed using Kaplan-Meier analyses. RESULTS: Samples were available from 41 PREVENT and 55 CHAMPION-NMOSD patients. Pretreatment baseline GFAP and NfL levels were elevated in patients compared with healthy donors. High baseline GFAP levels were associated with older age at initial presentation, less time since last relapse, and higher baseline Hauser Ambulation Index (HAI) score. High baseline NfL levels were associated with older age and higher baseline HAI score. High baseline GFAP and NfL levels using age-adjusted Z-scores were evaluated and would not have materially changed the conclusions. The median GFAP levels declined rapidly (within 4-6 weeks) and were sustained with both eculizumab and ravulizumab. The median NfL levels declined significantly with ravulizumab but not eculizumab. In PREVENT, adjudicated on-trial relapses were associated with increased GFAP levels in placebo-treated patients, while GFAP increases were attenuated in eculizumab-treated patients. DISCUSSION: Serum GFAP and NfL levels are elevated in patients with NMOSD and are associated with clinical features of disability. Complement component 5 blockade biologically suppresses astrocytic injury in NMOSD, validating GFAP as a pharmacodynamic biomarker and mechanistic readout of target engagement in randomized phase 3 trials. This aligns with earlier findings across different compounds in separate phase 3 trials.