Researchers analyzed levels of sGFAP in participants from the N-MOmentum study that assessed inebilizumab (Uplizna; Viela Bio) in relapsing-remitting MS.
Data from N-MOmentum, a prospective, multicenter, double-blind, placebo-controlled, randomized, phase 2/3 clinical trial (NCT02200770), suggest that serum glial fibrillary acidic protein (sGFAP) is an accurate biomarker of neuromyelitis optica spectrum disorder (NMOSD) activity, attack risk, and treatment effects.
Researchers found that participants with sGFAP concentrations of at least 170 pg/mL (≥2 standard deviations above healthy donor mean concentration) had a 3-fold greater chance of adjudicated attack than participants with participants with lower baseline concentrations (hazard ratio [HR], 3.09 [95% CI, 1.57-6.10]; P = .001).
“Astrocyte injury results in the release of astrocyte contents in cerebrospinal fluid (CSF) and serum, including GFAP, an intermediate filament protein predominantly expressed by astrocytes that forms the astrocyte cytoskeleton. Therefore, sGFAP could be a biomarker of disease activity in NMOSD,” wrote first author Orhan Aktas, MD, group leader, Molecular Neurology Research, and professor, Department of Neurology, Heinrich-Heine-University, and colleagues.
N-MOmentum compared inebilizumab-treated and placebo-treated participants with relapsing-remitting multiple sclerosis (RRMS). Aktas and colleagues measured sGFAP levels in these participants by single molecule arrays (SIMOA) in 215 participants (98 [92%] were aquaporin 4-immunoglobulin G [AQP4-IgG]-seropositive) for a total of 1260 serial and attack-related samples and compared these to control samples from healthy donors and patients with RRMS. Most participants were women (n = 194; 90%).
They found that median concentrations of sGFAP increased within 1 week of an attack, from median baseline levels of 168.4 pg/mL (interquartile range [IQR], 128.9-449.7) to median levels of 2160.1 pg/mL (IQR, 302.7-9455.0; P = .0015).
sGFAP was also found to correlate with attack severity, with minor attacks correlating with a median 1.06-fold change (FC; IQR, 0.9-7.4)) from baseline and major attacks correlating with a median 34.32-FC (IQR, 8.7-107.5; P = .023). Attack-related increases in sGFAP mainly occurred in placebo-treated participants (20.2-FC [IQR, 4.4-98.3]; P = .001) and not inebilizumab-treated participants (1.1-FC [IQR, 0.8-24.6]; P >.05).
Aktas and colleagues observed that 19 (31%) of 62 patients with elevated sGFAP at baseline experienced an adjudicated NMOSD attack during the 28-week randomized controlled period (RCP) as compared to 19 (12%) of 153 patients without elevated sGFAP, equating to a 3-fold higher risk (HR, 3.09 [95% CI, 1.57-6.10]; P = .001). This trend held true in both placebo- (HR, 2.35 [95% CI, 0.94-5.87]; P = .06) and inebilizumab-treated patients (HR, 4.15 [95% CI, 1.67-10.32]; P = .002).
“In clinical practice, the current goal of disease-modifying therapy is to induce a state of clinical remission. Our data suggest that normalizing sGFAP levels might also guide treatment, in the context of clinical parameters,” Aktas and colleagues wrote.
Inebilizumab was found to reduce the risk of an adjudicated attack by 61% compared with placebo in participants with elevated baseline sGFAP levels (HR, 0.39 [95% CI, 0.15-0.96]; P = .041) and by 79% in participants without elevated baseline sGFAP levels (HR, 0.21 [95% CI, 0.08-0.51]; P <.001).
sGFAP concentrations decreased with inebilizumab treatment after week 4 in participants who did not experience an adjudicated NMOSD attack during the RCP. A statistically significant 12.9% reduction from baseline was seen at week 16 (IQR, –25.6 to –1.6) and continued to be significant up to the end of the RCP (P <.05). There were no significant changes seen in sGFAP levels in placebo-treated participants without attacks, and by the end of the RCP, 9 of 26 participants (35%) in the placebo group had elevated sGFAP concentrations compared to 19 of 117 (16%) in the inebilizumab group.
“sGFAP may be a clinically informative biomarker for both attack risk and severity. sGFAP elevation in some participants without clinical attacks but with new MRI lesions reveals that subclinical disease activity and/or blood–brain barrier breakdown may be present in NMOSD. These results underscore the potential of soluble CNS-derived biomarkers like GFAP for the assessment of ongoing neural injury and thus, the identification of NMOSD patients at risk for relapse,” Aktas and colleagues concluded.