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 m(2) 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.

Figure 1

Patient disposition in trial 1 and trial 2. ^aAdditional inclusion and exclusion criteria were reported previously. ^bMeasured by low platelet count (<150 × 10⁹/l) and a decrease of at least 25% lower than the average of three measures before the most recent TMA complication. ^cBoth patients who withdrew during the extension study had a history of kidney transplant, poor renal function, and CKD at the start of eculizumab treatment. These patients discontinued from the study after 67 and 82 weeks of treatment because of worsening of severe CKD due to aHUS before eculizumab initiation. ^dThe patient was hospitalized for pyrexia; while hospitalized, the patient experienced intestinal hemorrhage (distal ileum), which was considered a severe adverse event unrelated to eculizumab. The exact cause of the intestinal hemorrhage remains unknown. The patient died 37 days after admission. ^ePatients may have had greater than 104 weeks of data at the time of the cutoff. AE, adverse event; aHUS, atypical hemolytic uremic syndrome; CKD, chronic kidney disease; PE/PI, plasma exchange/plasma infusion; TMA, thrombotic microangiopathy.

Figure 2

Effect of eculizumab on serum complement inhibition over 2 years of treatment in trial 1 and trial 2. Results from a pharmacodynamic assay that quantified serum complement activity by measuring the degree of hemolysis, as determined by means of a spectrophotometer. Inhibition of complement activity is indicated by 20% or lower hemolysis. Bars represent s.e.

Figure 3

Mean change from baseline in platelet counts over 2 years of eculizumab treatment in trial 1 (P=0.001 at the 2-year cutoff). Bars represent s.e.

Figure 4

Mean change from baseline in hemoglobin concentration over 2 years of eculizumab treatment in trial 1 and trial 2 (P=0.0075 and P=0.0044, respectively, at the 2-year cutoff). Bars represent s.e.

Figure 5

Mean change from baseline in eGFR over 2 years of eculizumab treatment in trial 1 (P=0.0062) and trial 2 (P=0.0959 at the 2-year cutoff). Bars represent s.e. eGFR, estimated glomerular filtration rate.

Figure 6

Least-squares mean change from baseline on patient HRQoL through 2 years of eculizumab treatment in trial 1 and trial 2 (P<0.0001 in both trials at the 2-year cutoff). Bars represent s.e. A change from baseline of 0.06 in EQ-5D score is considered clinically meaningful. EQ-5D, EuroQol 5-Dimension Questionnaire; HRQoL, health-related quality of life.