Serum Ravulizumab Concentrations Maintained Above Therapeutic Threshold in AQP4+ NMOSD

In a pharmacokinetics (PK) and pharmacodynamics (PD) analysis of the CHAMPION-NMOSD open-label, phase 3 study (NCT04201262), results showed that serum ravulizumab (Ultomiris; Alexion) concentrations were maintained above the therapeutics threshold in patients with antiaquaporin (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) through 50 weeks of treatment.¹ These findings suggest that an 8-week dosing interval of ravulizumab may potentially be a new therapy option for relapse prevention in adults with the rare autoimmune disease.

In 60 minutes after dose administration in all patients, serum ravulizumab concentrations achieved the therapeutic threshold (175 μg/mL) or above it and were maintained from the first dose to week 50. Following week 50 with a maintenance ravulizumab dose, the mean (SD) C_max and C_trough were 1877.6 (413.61) and 754.1 (220.71) μg/mL, respectively (n = 52).

These findings were presented as an abstract presentation at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by lead author Stephan Ortiz, PhD, RPh, executive director, non-clinical, clinical and quantitative pharmacology at Alexion, AstraZeneca Rare Disease. In the analysis, PK and PD were used to describe the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with AQP4+ NMOSD from CHAMPION-NMOSD.

In the trial, researchers evaluated ravulizumab on efficacy and safety in 58 adult patients with anti-AQP4 NMOSD who experienced at least 1 attack or relapse in the 12 months prior to the screening visit. The participants also had Expanded Disability Status Scale scores of 7 or less, had a body weight of at least 40 kg at trial entry, and were allowed to stay on stable supportive immunosuppressive therapy for the duration of the study. The patients received a weight-based intravenous loading dose of ravulizumab (2400–3000 mg), then a maintenance dose on day 15 (3000–3600 mg) and every 8 weeks following.

In the PK, investigators analyzed the maximum observed concentration, C_max assessed at the end of infusion, and concentration at the end of the dosage interval, C_trough assessed at predose, for ravulizumab. As for the PD assessments, time-matched observed serum free C5 concentration up to 50 weeks was assessed. By the end of the first ravulizumab infusion, immediate and complete inhibition of serum free C5 (terminal complement) was observed (free C5 serum concentrations <0.5 μg/mL) and sustained throughout the treatment period in patients with NMOSD.

In another recent analysis of the trial, ravulizumab demonstrated superiority in preventing on-trial relapse in monotherapy (HR, 0.021; 95% CI, 0–0.176; relapse risk reduction [RRR], 97.9%; P <.0001) and immunosuppressive therapy (IST) groups (HR, 0.031; 95% CI, 0–0.234; RRR, 96.9%; P <.0001) compared with placebo based on time to first adjudicated on-trial relapse. Notably compared with placebo, significant differences were observed in patients who had previously received rituximab (n = 20; RRR, 93.7%; P = .0078) or not (n = 38; RRR, 98.1%; P <.0001).²

In terms of treatment-emergent adverse events (AEs), 93.1% of patients on ravulizumab reported them and serious AEs were observed in 13.8% of patients. Two vaccinated patients had a meningococcal infection (2.4 out of 100 patient-years). Those affected patients recovered with no sequelae and 1 continued with the trial, no deaths were reported. The efficacy and safety data continued consistently with the primary treatment period despite the longer follow-up (median treatment duration, 90.9 weeks).

In 2018, ravulizumab was approved by FDA to treat adults with paroxysmal nocturnal hemoglobinuria. Following that in 2021, that indication was expanded to include children and adolescents. For more context, the regimen has a long elimination half life which allows maintenance dosing for every 8 weeks. The serum half life and duration of action with ravulizumab is prolonged compared with eculizumab (Soliris; Alexion) as a result of 4 amino acid substitutions into the frame of eculizumab that augments endosomal pH-dependent C5 binding and enhances recycling. In June 2019, the FDA approved eculizumab for the treatment of AQP4-IgG-positive NMOSD.

REFERENCES
1. Ortiz S, Pittock S, Berthele A, et al. Pharmacokinetics and Pharmacodynamics of Ravulizumab in Adults with Anti-Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder During the Phase 3 CHAMPION-NMOSD trial. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 004.
2. Levy M, Pittock S, Michael Barnett et al. Efficacy subgroup analyses from the phase 3 CHAMPION-NMOSD trial in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 003.