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

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.

Ravulizumab for the Treatment of aHUS in Adults: Improving Quality of Life

“…In the present issue ( Figure 1 ), Barbour et al. 5 reported on long-term efficacy of the long-acting C5 inhibitor, ravulizumab, for the treatment of aHUS in adults, extending the previous 26-week follow-up study. The patients were followed for a median of 76.7 weeks.…”

Atypical hemolytic uremic syndrome after myomectomy: A case report

“…Plasma exchange was effective for the acute management of this patient; however, the underlying cause of complement dysfunction still needed to be addressed to prevent ongoing renal damage. Eculizumab is a monoclonal, humanized anti-C5 antibody that prevents cleavage of C5 into C5a and C5b, which prevents activation of the alternate complement pathway and formation of C5b-9, the membrane attack complex (MAC) [ 8 ]. Since its approval for treatment of aHUS in 2011, eculizumab has been demonstrated to be an organ-sparing, life-saving treatment, and early intervention is associated with better outcomes [ 8 , 18 ].…”

“…Eculizumab is a monoclonal, humanized anti-C5 antibody that prevents cleavage of C5 into C5a and C5b, which prevents activation of the alternate complement pathway and formation of C5b-9, the membrane attack complex (MAC) [ 8 ]. Since its approval for treatment of aHUS in 2011, eculizumab has been demonstrated to be an organ-sparing, life-saving treatment, and early intervention is associated with better outcomes [ 8 , 18 ]. The patient was planned to have at least six months of therapy, based upon her clinical response and absence of recognized complement mutations [ 19 ].…”

“…Eculizumab and its long-acting counterpart, ravulizumab, are humanized monoclonal IgG antibodies that bind to complement protein C5, and are the only FDA-approved treatments for aHUS [ 8 , 9 ]. Prompt diagnosis and treatment are key to reducing the high degree of morbidity and mortality associated with aHUS.…”

Expanding Horizons in Complement Analysis and Quality Control

“…For these disorders, the functional testing is utilized primarily to determine if the level of inhibition is appropriate to block complement function sufficiently ( 66 ). It is important when utilizing complement testing in this way to not only keep in mind how the drug will affect common complement tests [reviewed in ( 67 – 69 )] but also how the specific type of complement test may affect the result received ( 67 , 70 ).…”