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 (NMOSD)
Dean Wingerchuk1, Jeffrey Bennett2, Achim Berthele3, Stacey Clardy4, Ho Jin Kim5, Jin Nakahara6, Jerome De Seze7, Makoto Kinoshita8, Ruba Deeb Bou-Chahine9, Yasmin Mashhoon9, Becky Parks9, Kerstin Allen9, Ketan Thakar9, Dan Carlin9, Jeannette Stankowski9, Sean Pittock10
1Mayo Clinic, Phoenix, 2University of Colorado School of Medicine, 3School of Medicine, Technical University Munich, 4University of Utah, 5National Cancer Center, 6Keio University School of Medicine, 7CHU de Strasbourg, 8Osaka General Medical Center, 9Alexion, AstraZeneca Rare Disease, 10Mayo Clinic, Rochester
Objective:
Evaluate serum GFAP and NfL levels during treatment with complement component 5‒inhibitor therapies (C5ITs) eculizumab and ravulizumab in AQP4+ NMOSD.
Background:
GFAP and NfL are biomarkers of astrocyte and neuronal injury, respectively. The placebo-controlled PREVENT (NCT01892345) and externally controlled CHAMPION-NMOSD (NCT04201262) trials evaluated the efficacy and safety of eculizumab and ravulizumab, respectively, in adults with AQP4+ NMOSD.
Design/Methods:
In PREVENT and CHAMPION-NMOSD, GFAP and NfL levels (pg/mL) were assessed using Quanterix's single-plex Simoa platforms at baseline, select study visits, and relapse visits. All relapses were independently adjudicated. External healthy donor (HD) samples were demographically matched for both trials.
Results:
Median baseline serum GFAP levels were significantly elevated in AQP4+ NMOSD patients in each trial vs HDs (PREVENT: 123.0 [n=41] vs 89.2 [n=45], P=0.0007; CHAMPION-NMOSD: 129.0 [n=55] vs 89.2, P<0.0001), as were serum NfL levels (10.8 [n=41] vs 8.5 [n=47], P=0.0238; 9.8 [n=55] vs 8.5, P=0.0162). During adjudicated on-trial relapses in PREVENT, eculizumab reduced mean fold change (FC) GFAP from baseline (2.7-FC [n=3]) vs placebo (8.7-FC [n=7]). In PREVENT, median GFAP levels remained elevated with placebo (n=15) but were significantly diminished from baseline at week (W) 4 (P=0.0068) with eculizumab (n=26), and median values continued to appear low at W24; NfL levels appeared unchanged (placebo and eculizumab). In CHAMPION-NMOSD, GFAP and NfL median levels were significantly reduced from baseline with ravulizumab at W6 (P=0.0325 and P=0.0441; n=55), respectively, and levels appeared to decrease through W130. Median GFAP levels declined faster with ravulizumab than median NfL levels. Ravulizumab reduced NfL levels similarly in cerebrospinal fluid and serum.
Conclusions:
Decreasing serum GFAP and NfL levels over time suggest sustained reduction in damage to astrocytes and neurons in AQP4+ NMOSD, respectively, strengthening their suitability as potential biomarkers of therapeutic efficacy in AQP4+ NMOSD. Analyses of potential associations to patients’ clinical profiles are warranted.