Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study

• Type of Material: Article
• Authors: Jan Menne, Klinik für Nieren- und Hochdruckerkrankungen; Yahsou Delmas, CHU de Bordeaux; Fadi Fakhouri, CHU de Nantes; Christoph Licht, Hospital for Sick Children; Asa Lommele, Alexion Pharma GmbH; Enrico E. Minetti, Niguarda Hospital; Francois Provot, CHU de Lille; Eric Rondeau, Hopital Tenon; Neil S. Sheerin, University of Newcastle upon Tyne; Jimmy Wang, Alexion Pharmaceuticals, Inc.; Laurent E. Weekers, CHU de Liege; Larry Greenbaum, Emory University
• Language: English
• Date: 2019-04-10
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12882-019-1314-1
• Title of Journal or Parent Work: BMC Nephrology
• ISSN: 1471-2369
• Volume: 20
• Issue: 1
• Start Page: 125
• End Page: 125
• Grant/Funding Information: Alexion Pharmaceuticals, Inc., was responsible for the collection, management, and analysis of information contained in the C11–003 Long-term Follow-up study.; lexion Pharmaceuticals, Inc., contributed to data interpretation, preparation, review, and approval of the manuscript for submission.; Medical writing and editorial support were provided by Peloton Advantage, LLC, an OPEN Health company (Parsippany, NJ), and funded by Alexion Pharmaceuticals, Inc.
• Keywords: COMPLEMENT INHIBITOR ECULIZUMAB; Alternate complement pathway; Urology & Nephrology; Science & Technology; Atypical hemolytic uremic syndrome; DISEASE; DISCONTINUATION; RENAL-TRANSPLANT RECIPIENTS; Thrombotic microangiopathy; Life Sciences & Biomedicine; Eculizumab
• Research Categories: Health Sciences, Medicine and Surgery; Biology, General

Abstract

Background: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. Methods: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. Results: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. Conclusions: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. Trial registration: ClinicalTrials.gov NCT01522170, January 31, 2012.