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, 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, 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, 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

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.

© 2021 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.

Figures

Figure 1
Figure 1
Patient disposition. Of the 8 patients who discontinued the study, 1 discontinued owing to protocol violation (the patient received frozen plasma, a prohibited procedure), 5 because of their own (patient) decision, and 2 because of the physician’s decision. An additional 3 patients discontinued the study drug during the extension period but remained enrolled in the study. Of these 3 patients, 2 discontinued the drug owing to physician’s decision and 1 because of their own (patient) decision. aHUS, atypical hemolytic uremic syndrome; STEC, Shiga toxin-producing Escherichia coli; TMA, thrombotic microangiopathy.
Figure 2
Figure 2
Kaplan–Meier graph depicting the time to complete TMA response. Patients who did not have a response were censored on the day of the last study visit or at study discontinuation. ∗Patient achieved initial complete TMA response measurement at day 169; however confirmatory measurement was not achieved until the extension period (day 239). BL, baseline; TMA, thrombotic microangiopathy.
Figure 3
Figure 3
Observed laboratory values over time. (a) platelet count; (b) lactate dehydrogenase; (c) hemoglobin. Data are shown as mean (error bars, 95% confidence interval).
Figure 4
Figure 4
Observed eGFR values over time. eGFR, estimated glomerular filtration rate. Data are shown as mean (SD; error bars, 95% confidence interval).
Figure 5
Figure 5
FACIT-Fatigue score over time. Data are shown as mean (error bars, 95% confidence interval). FACIT, Functional Assessment of Chronic Illness Therapy.

References

    1. Brodsky R.A. Complement in hemolytic anemia. Blood. 2015;126:2459–2465.
    1. Fakhouri F., Zuber J., Frémeaux-Bacchi V., Loirat C. Haemolytic uraemic syndrome. Lancet. 2017;390:681–696.
    1. Campistol J.M., Arias M., Ariceta G. An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document. Nefrologia. 2015;35:421–447.
    1. Fakhouri F., Hourmant M., Campistol J.M. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis. 2016;68:84–93.
    1. Greenbaum L.A., Fila M., Ardissino G. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016;89:701–711.
    1. Legendre C.M., Licht C., Muus P. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–2181.
    1. Licht C., Greenbaum L.A., Muus P. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015;87:1061–1073.
    1. Vilalta R., Al-Akash S., Davin J. Eculizumab therapy for pediatric patients with atypical hemolytic uremic syndrome: efficacy and safety outcomes of a retrospective study. Haematologica. 2012;97:479.
    1. Menne J., Delmas Y., Fakhouri F. Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study. BMC Nephrol. 2019;20:125.
    1. European Medicines Agency EU/3/09/653. Available at: Accessed December 23, 2020.
    1. U.S. Food and Drug Administration Eculizumab (Soliris) Available at: Accessed December 23, 2020.
    1. Fremeaux-Bacchi V., Fakhouri F., Garnier A. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clin J Am Soc Nephrol. 2013;8:554–562.
    1. Noris M., Caprioli J., Bresin E. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844–1859.
    1. Schaefer F., Ardissino G., Ariceta G. Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome. Kidney Int. 2018;94:408–418.
    1. Sheridan D., Yu Z.X., Zhang Y. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS One. 2018;13
    1. Rondeau E., Scully M., Ariceta G. The long-acting C5 inhibitor, ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Kidney Int. 2020;97:1287–1296.
    1. Tanaka K., Adams B., Aris A.M. The long-acting C5 inhibitor, ravulizumab, is efficacious and safe in pediatric patients with atypical hemolytic uremic syndrome previously treated with eculizumab. Pediatr Nephrol. 2021;36:889–898.
    1. European Medicines Agency Summary of Product Characteristics – Ultomiris (ravulizumab) Available at:
    1. U.S. Food and Drug Administration Highlights of prescribing information – ravulizumab. Available at:
    1. Alexion Pharmaceuticals ULTOMIRIS® (ravulizumab) receives approval in Japan for atypical hemolytic uremic syndrome (aHUS) in adults and children. Available at: Accessed December 23, 2020.
    1. Levey A.S., Bosch J.P., Lewis J.B. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–470.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150.
    1. Menne J. Is ravulizumab the new treatment of choice for atypical hemolytic uremic syndrome (aHUS)? Kidney Int. 2020;97:1106–1108.
    1. Wong E.K., Kavanagh D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Transl Res. 2015;165:306–320.
    1. Noris M., Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–1687.
    1. Levy A., Chen P.G.F., Tomazos I. PRO5 comparing productivity losses from treating atypical hemolytic uremic syndrome patients in the united states with eculizumab or ravulizumab in an infusion clinic or at home. Value Health. 2019;22:S841.

Source: PubMed

3
Suscribir