To describe the pharmacokinetics (PK) and pharmacodynamics (PD) of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the CHAMPION-NMOSD trial (NCT04201262).

Ravulizumab has a long elimination half-life allowing maintenance dosing every 8 weeks. As a result of 4 amino acid substitutions into the eculizumab frame that augment endosomal pH-dependent C5 binding and enhance recycling, the serum half-life and duration of action of ravulizumab is prolonged compared with eculizumab.

Patients aged ≥18 years received a weight-based intravenous loading dose of ravulizumab (2400–3000 mg) on day 1, then weight-based maintenance doses (3000–3600 mg) on day 15 and once every 8 weeks thereafter. PK assessments included maximum observed concentration (C_max, assessed at the end of infusion) and concentration at the end of the dosage interval (C_trough, assessed predose) for ravulizumab. PD assessments included time-matched observed serum free C5 concentration up to 50 weeks.

The PK/PD analysis included 58 ravulizumab-treated patients. Serum ravulizumab concentrations at or above the therapeutic threshold (175 μg/mL) were achieved within 60 minutes after dose administration and maintained from first dose to week 50 in all patients. Following a maintenance ravulizumab dose at week 50, the mean (standard deviation) C_max and C_trough were 1877.6 (413.61) and 754.1 (220.71) μg/mL, respectively (n=52). Immediate and complete inhibition of serum free C5 (terminal complement) was observed (free C5 serum concentrations <0.5 μg/mL) by the end of the first ravulizumab infusion and sustained throughout the treatment period in patients with NMOSD.

Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Inhibition of serum free C5 was complete and sustained throughout the treatment period. The 8-week dosing interval of ravulizumab represents a potential new therapy option for relapse prevention in adults with AQP4+ NMOSD.