Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

“…This finding might be a reason of the LDH normalization in less than 60% patients in this study especially under the diverse patient characteristics mentioned above, which could lead to the reduced achievement of complete TMA response. Prior studies suggest that eculizumab is well tolerated [10,11]. In this study, each of the ARs was reported in very few patients, although some reactions were classified as serious.…”

Atypical hemolytic uremic syndrome

“…Of note, these data come from the historical studies treated with plasma therapy [14,23,24]. Recent advances of therapy including early initiation of plasma therapy or eculizumab administration significantly improved the mortality and prognosis of aHUS [62,68]. In the near future, the data showing prognosis of aHUS patients depending on the genetic background treated with eculizumab will be clarified.…”

Clinical guides for atypical hemolytic uremic syndrome in Japan

“…Decreased platelet counts observed in patients with aHUS usually resolve after 1 to 2 weeks of eculizumab therapy [41][42][43].…”