Abstract
BackgroundEculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).MethodsIn five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated.ResultsOf 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment.ConclusionsAs expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.
Highlights
Atypical haemolytic uraemic syndrome is a rare, genetic, potentially life-threatening disease predominantly caused by uncontrolled activation of the alternative complement pathway [1,2,3]
Identification of complement abnormalities occurred during the parent studies and included analysis of complement factor I (CFI), complement factor B (CFB), complement factor H (CFH), membrane cofactor protein (MCP) and C3 mutations, complement factor H-related proteins 1-3 (CFHR1-3) deletions/polymorphisms and CFH autoantibodies [7, 9,10,11]
thrombotic microangiopathy (TMA) manifestation rates were lowest during labelled dosing regimens (74% lower than off treatment), higher during non-labelled regimens (39% lower than off treatment) and highest off treatment
Summary
Atypical haemolytic uraemic syndrome (aHUS) is a rare, genetic, potentially life-threatening disease predominantly caused by uncontrolled activation of the alternative complement pathway [1,2,3]. Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P 1⁄4 0.0082). Patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Results show that maintaining eculizumab treatment minimizes risk of TMA, in patients with identified complement abnormalities.
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