No evidence for hypogammaglobulinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with ravulizumab.

Introduction: Ravulizumab (ALXN1210) is a long-lasting recycling IgG monoclonal antibody with an increased affinity for the neonatal Fc receptor (FcRn). The FcRn is essential for regulating IgG homeostasis. Saturation of the FcRn pathway is seen under high IgG doses as they compete with endogenous IgG to bind the FcRn by their Fc regions, resulting in enhanced IgG clearance.

Patients/methods: Between Jan 2016 and Jun 2019 (median observation time 21.6 months (6-37.7 months)) serum IgG concentrations and IgG1-4 subclasses were evaluated over a longitudinal course (post-hoc analysis) in 12 ravulizumab-treated adult patients with paroxysmal nocturnal hemoglobinuria (PNH) (58% (7/12) males, median age 50 years (yrs) (18-70 yrs)). All patients were enrolled in one of the three ravulizumab-PNH-related trials (201-, 301-, or 302-study) at the University Hospital Essen.

Results: Baseline IgG concentrations were documented in 11 out of the 12 patients prior to ravulizumab treatment (median IgG 9.9 g/L (5-13.5 g/L)). In two female patients a clinically not relevant hypogammaglobulinemia with an associated IgG1 or a combined IgG1/IgG2 deficiency prior to treatment was documented. The data were further stratified with regard to various treatment intervals as multiple analyses were obtained. Throughout observation time IgG concentrations remained within physiologic ranges with no evidence of a treatment-related IgG depletion (median IgG at study endpoint 10.1 g/L (6-13.4 g/L)).

Conclusion: In ravulizumab-treated PNH patients, IgG and IgG subclass levels which are regulated by the FcRn remained unaffected. Therefore, no treatment associated hypogammaglobulinemia is to be feared under chronic ravulizumab therapy.