Complement Inhibitors Ravulizumab and Eculizumab Impact Measures of Neuroaxonal Damage

Dean Wingerchuk, MD

In an analysis of the phase 3 PREVENT (NCT01892345) and CHAMPION-NMOSD trials (NCT04201262), findings showed that both ravulizumab (Ultomiris; Alexion) and eculizumab (Soliris; Alexion), 2 FDA-approved therapies for neuromyelitis optica spectrum disorder (NMOSD), decreased glial fibrillary acidic protein (GFAP) levels over time. Ravulizumab, a more recently approved agent, also appeared to significantly reduce neurofilament light (NfL), another biomarker of neuroaxonal damage.¹

The placebo-controlled PREVENT study and externally controlled CHAMPION-NMOSD trial evaluated the efficacy and safety of eculizumab and ravulizumab, respectively, leading to their approvals in 2019 and 2024. At baseline, median serum GFAP levels were significantly elevated in patients with aquaporin-4-antibody-positive NMOSD vs external healthy donor (HD) samples (PREVENT: 123.0 [n = 41] vs 89.2 [n = 45]; P = .0007; CHAMPION-NMOSD: 129.0 [n = 55] vs 89.2; P <.0001). Additionally, serum NfL levels were elevated as well (PREVENT: 10.8 [n = 41] vs 8.5 [n = 47]; P = .0238; CHAMPION-NMOSD: 9.8 [n = 55] vs 8.5; P = .0162).

Presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, GFAP and NfL levels were assessed using Quanterix’s single-plex Simoa platform at baseline, select study visits, and relapse visits. During adjundicated on-trial relapses in PREVENT, eculizumab reduced mean fold change (FC) GFAP from baseline (FC: 2.7; n = 3) vs placebo (FC: 8.7; n = 7). In PREVENT, median GFAP levels remained elevated with placebo (n = 15) but were significantly diminished from baseline at week 4 with eculizumab (P = .0068). Overall, median values continued to be low at week 24.

The analysis, led by Dean Wingerchuk, MD, a neurologist and clinical epidemiologist at Mayo Clinic, demonstrated significantly reduced NfL and GFAP levels with ravulizumab at week 6 of CHAMPION-NMOSD (P = .0325 and P = .0441; n = 55), respectively, and levels appeared to decrease through week 130. Notably, ravulizumab reduced NfL levels in cerebrospinal fluid and serum whereas eculizumab showed no change in NfL when compared with placebo. Additionally, median GFAP levels declined faster with ravulizumab than median NfL levels.

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Previous research has shown that astrocyte injury results in the release of astrocyte contents in the cerebrospinal fluid and serum, including GFAP, an intermediate filament protein predominantly expressed by astrocytes that forms that astrocyte cytoskeleton. Therefore, serum GFAP has been proposed as a biomarker of disease activity in NMOSD. Several studies to date have examined the relationship between GFAP concentration and disease activity, with promising insights published thus far.

A 2021 analysis of the pivotal phase 3 N-MOmentum study (NCT022000770), the trial that led to inebilizumab’s (Uplizna; Horizon) approval, showed that GFAP may assist in predicting NMSOD activity, attack risk, and treatment effects. At baseline, 62 participants (29%) from the trial exhibited high serum GFAP concentrations and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (HR, 3.09; 95% CI, 1.6-6.1; P = .001). Of note, the attack related increase in serum GFAP occurred primarily in placebo-treated participants (FC: 20.2; IQR, 4.4-98.3; P = .001) and was not observed in inebilizumab-treated participants (FC: 1.1; IQR, 0.8-24.6; P >.05).²

A previously published study in 2021 further established serum GFAP and NfL as disease severity and prognostic biomarkers in patients with AQP4+ NMOSD. In patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was found to be non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = − 1.28, p = 0.01).³

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REFERENCES
1. Wingerchuk D, Bennett J, Berthele A, et al. Evaluation of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels during eculizumab and ravulizumab treatments in aquaporin-4-positive (AQP4+) neuromyelitis optica spectrum disorder. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. ABSTRACT 002303
2. Atkas O, Smith MA, Rees WA, et al. Serum glial fibrillary acidic protein: a neuromyelitis optica spectrum disorder biomarker. Annals of Neurol. 2021;89(5):895-910. doi:10.1002/ana.26067
3. Schindler P, Grittner U, Oechtering J, et al. Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. Journal of Neuroinflamm. 2021;18:105. doi:10.1186/s12974-021-02138-7