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. 2020 Mar 27;15(3):e0230869.
doi: 10.1371/journal.pone.0230869. eCollection 2020.

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

Ferras Alashkar  1 , Scott Rottinghaus  2 , Colin Vance  3 , Dörte Herich-Terhürne  1 , Ulrich Dührsen  1 , Roland Assert  4 , Alexander Röth  1
Affiliations

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

Ferras Alashkar et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

A.R. and U.D. receive honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc. S.R. is an employee and stockholder of Alexion Pharmaceuticals, Inc. The commercial affiliation of A.R., U.D., and S.R. does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. IgG concentrations at baseline in adult PNH patients prior to enrollment in the ALXN1210 studies (n = 11).
Fig 2
Fig 2. Longitudinal course of IgG concentrations under treatment with ravulizumab (n = 12).
Fig 3
Fig 3. Longitudinal course of IgG subclass (IgG1, IgG2, IgG3, and IgG4) concentrations under treatment with ravulizumab (n = 12).
See this image and copyright information in PMC

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References

    1. Risitano A. M. and Rotoli B., “Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents.,” Biologics, vol. 2, no. 2, pp. 205–22, June 2008. 10.2147/btt.s1420 - DOI - PMC - PubMed
    1. Hill A., DeZern A. E., Kinoshita T., and Brodsky R. A., “Paroxysmal nocturnal haemoglobinuria.,” Nat. Rev. Dis. Prim., vol. 3, no. 1, p. 17028, December 2017. - PMC - PubMed
    1. Brodsky R. A., Ginsburg D., Smith B. R., Nathan D. G., Orkin S. H., and Rappeport J. M., “Paroxysmal nocturnal hemoglobinuria.,” Blood, vol. 124, no. 18, pp. 2804–11, October 2014. 10.1182/blood-2014-02-522128 - DOI - PMC - PubMed
    1. Lee S. C.-W. and Abdel-Wahab O., “The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance.,” J. Clin. Invest., vol. 124, no. 10, pp. 4227–30, 2014. 10.1172/JCI77984 - DOI - PMC - PubMed
    1. Hillmen P. et al., “Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria,” Blood, vol. 110, no. 12, pp. 4123–4128, December 2007. 10.1182/blood-2007-06-095646 - DOI - PubMed

Publication types

Grants and funding

A.R. and U.D. received honoraria, consulting fees, and research support from Alexion Pharmaceuticals, Inc. S.R. is an employee and stockholder of Alexion Pharmaceuticals, Inc. F.A. was supported as a Clinician Scientist within the University Medicine Essen Academy (UMEA) program, funded by the German Research Foundation (DFG; grant FU356/12-1) and the Faculty of Medicine, University of Duisburg-Essen. The 3 clinical studies (ALXN1210-PNH-201, ALXN1210-PNH-301, and ALXN1210-PNH-302) were sponsored by Alexion Pharmaceuticals, Inc., Boston, MA, USA. Alexion Pharmaceuticals, Inc., the marketing-authorization holder of ravulizumab, was offered an opportunity to provide a scientific accuracy review. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit. Alexion Pharmaceuticals, Inc. did not play any role in the study design, data collection, or decision to publish the manuscript.