Ravulizumab pharmacokinetics and pharmacodynamics in patients with generalized myasthenia gravis

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 Cmax was 1548 µg/mL and Ctrough 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).

Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

“…Pharmacokinetic and pharmacodynamic profiles similar to those reported here were observed in studies in patients with atypical hemolytic uremic syndrome, generalized myasthenia gravis, and paroxysmal nocturnal hemoglobinuria ( 13 , 20 , 21 ). The immediate, complete, and sustained suppression of C5 after ravulizumab administration may account for the adjudicated on-trial relapse risk reduction as observed in the CHAMPION-NMOSD trial ( 14 ).…”

Mapping current trends and hotspots in myasthenia gravis from 2003 to 2022: a bibliometric analysis

“…Ravulizumab is a monoclonal antibody complement inhibitor approved by the Food and Drug Administration (FDA) in April 2022 for AChR-Ab-generalized MG. A phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with AChR-Ab-generalized MG indicated improved clinical outcomes for patients treated with ravulizumab, and the drug was well tolerated ( 41 ). The latest pharmacokinetics and pharmacodynamics research based on the data from this phase 3 study supports dosing every 8 weeks for immediate, complete, and sustained inhibition of terminal complement C5, and it could reduce the burden on patients ( 42 ).…”

Association Between Myasthenia Gravis–Activities of Daily Living (MG-ADL) and EQ-5D-5L Utility Values: The Additional Effect of Efgartigimod on Utilities

“…In the EU and UK, several health authorities will soon assess new treatments for gMG (including efgartigimod and ravulizumab) in terms of their value for money, with MG-ADL as the primary clinical trial endpoint [21,27]. Analyses including the one presented in the current study are needed to capture the clinical and economic facets of treatment comprehensively and accurately for two major reasons.…”