Ravulizumab pharmacokinetics and pharmacodynamics in patients with generalized myasthenia gravis
Tuan Vu, Stephan Ortiz, Masahisa Katsuno, Djillali Annane, Renato Mantegazza, Kathleen N. Beasley, Rasha Aguzzi, James F. Howard
Abstract
Abstract Introduction The terminal complement C5 inhibitor ravulizumab has a long elimination half-life, allowing maintenance dosing every 8 weeks. In the 26-week, double-blind, randomized, placebo-controlled period (RCP) of the CHAMPION MG study, ravulizumab provided rapid and sustained efficacy and was well tolerated in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). This analysis evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and potential immunogenicity of ravulizumab in adults with AChR Ab+ gMG. Methods Data were analyzed from 86 patients who received ravulizumab in the CHAMPION MG RCP. Ravulizumab dosing was weight-based: initial loading dose of 2400/2700/3000 mg on Day 1 and maintenance doses of 3000/3300/3600 mg on Day 15 and then every 8 weeks. PK parameters were estimated from serum ravulizumab concentrations determined pre- and post-dose; PD effects of ravulizumab on serum free C5 concentrations were measured; and immunogenicity was assessed using anti-drug antibody and neutralizing-antibody assays. Results Target serum ravulizumab concentrations (> 175 µg/mL) were achieved immediately after the first ravulizumab dose (within 30 min of infusion completion) and maintained throughout the 26-week treatment period irrespective of patient body weight. Following the final maintenance dose, mean C max was 1548 µg/mL and C trough 587 µg/mL; no meaningful differences were noted among body-weight categories. Inhibition of serum free C5 was immediate, complete (< 0.5 μg/mL), and sustained throughout treatment in all patients. No treatment-emergent anti-drug antibodies were observed. Conclusions PK/PD evidence supports the use of ravulizumab every 8 weeks for immediate, complete, and sustained inhibition of terminal complement C5 in adults with AChR Ab+ gMG. Trial registration ClinicalTrials.gov ID: NCT03920293 (April 18, 2019).