Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults

Thomas Barbour; Marie Scully; Gema Ariceta; Spero Cataland; Katherine Garlo; Nils Heyne; Yosu Luque; Jan Menne; Yoshitaka Miyakawa; Sung-Soo Yoon; David Kavanagh; 311 Study Group Members

doi:10.1016/j.ekir.2021.03.884

Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults

Kidney Int Rep. 2021 Mar 24;6(6):1603-1613. doi: 10.1016/j.ekir.2021.03.884. eCollection 2021 Jun.

Authors

Thomas Barbour¹, Marie Scully², Gema Ariceta³, Spero Cataland⁴, Katherine Garlo⁵, Nils Heyne⁶, Yosu Luque⁷, Jan Menne⁸, Yoshitaka Miyakawa⁹, Sung-Soo Yoon¹⁰, David Kavanagh^{11

12}; 311 Study Group Members

Collaborators

311 Study Group Members:
Sunil Babu, Nilufer Broeders, Nicole Lietar, Fiona Brown, Philip Campbell, Josep M Campistol, Paramit Chowdhury, Theo Kasimatis, Lino Cirami, Leonardo Caroti, Guilia Antognoli, Yahsou Delmas, Vladimir Dobronravov, Anja Gaeckler, Cyril Garrouste, Gregory Greenwood, Siân Griffin, Chiu-Ching Huang, I-Ru Chen, Susan Huang, Jin Seok Kim, Gaetano La Manna, Moglie Le Quintrec, Guillaume Jeantet, Iino Fumie, Eric Rondeau, Hermann Haller, Johan Morelle, Eric Goffin, Anja Muhlfeld, Shashi Nagaraj, Gowthami Arepally, Doyeun Oh, Masayoshi Okumi, Manuel Praga Terente, Francois Provot, Ulf Schönermarck, Michael Fischereder, Natalia Ramos Terrada, Barbara Seitz-Polski, Guillaume Favre, Sonia Boyer-Suavet, Maria Vinogradova, Tatiana Kirsanova, Edwin Ks Wong

Affiliations

¹ Kidney Care, The Royal Melbourne Hospital, Melbourne, Australia.
² Department of Haematology, University College London Hospitals, London, UK.
³ Paediatric Nephrology Department, University Hospital Vall d'Hebron, Barcelona, Spain.
⁴ Division of Hematology, The Ohio State University Medical Center, Columbus, Ohio, USA.
⁵ Clinical Development, Alexion Pharmaceuticals, Inc., Boston, Massachusetts, USA.
⁶ Section of Nephrology and Hypertension, Tübingen University Hospital, Tübingen, Germany.
⁷ Intensive Care Nephrology and Transplantation Department, APHP, Sorbonne Université, Paris, France.
⁸ KRH Klinikum Mitte-Location Siloah, Hannover, Germany.
⁹ Department of General Internal Medicine, Saitama Medical University, Saitama, Japan.
¹⁰ Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
¹¹ Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
¹² National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

Abstract

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare, complex, multisystem disease of dysregulated complement activity, characterized by progressive thrombotic microangiopathy (TMA), acute kidney injury, and multiorgan dysfunction, which often progresses to chronic kidney disease. Results from the prospective clinical trial of ravulizumab (NCT02949128) reveal rapid resolution of TMA in patients with aHUS, with sustained efficacy and safety in a 26-week initial evaluation period.

Methods: The aim of this analysis was to characterize the long-term efficacy and the safety profile of ravulizumab in adults with aHUS who had completed the initial evaluation period of the trial. Complete TMA response, hematologic and kidney functions, and safety were evaluated for all patients available for follow-up in the extension period (median follow-up: 76.7 weeks; range: 0.6-118.3). This trial included a total of 58 patients, 49 of whom entered the extension period.

Results: A total of 4 additional patients achieved complete TMA response during the follow-up period. Normalization of platelet count, serum lactate dehydrogenase (LDH), and hemoglobin observed in the 26-week initial evaluation period was sustained until the last available follow-up, as were the improvements in the estimated glomerular filtration rate (eGFR) and patient quality of life. All efficacy endpoints were correlated with the sustained inhibition of complement C5. Most adverse events (AEs) occurred early during the initial evaluation period and decreased substantially during the extension period. No patient developed a meningococcal infection or died during the extension period.

Conclusion: This analysis reveals that ravulizumab administered every 8 weeks is efficacious with an acceptable safety profile for the long-term treatment of adults with aHUS and provides additional clinical benefit beyond 6 months of treatment.

Keywords: atypical hemolytic uremic syndrome; complement; hemolytic uremic syndrome; kidney failure; ravulizumab; thrombotic microangiopathy.