Eculizumab (ECU) Significantly Improves Health-Related Quality of Life (HRQoL) in Patients with Atypical Hemolytic Uremic Syndrome (aHUS)

Abstract

Abstract 4772 BackgroundaHUS is a rare, genetic, life-threatening, disease caused by chronic uncontrolled complement activation, which leads to systemic thrombotic microangiopathy (TMA). Despite plasma exchange/infusion (PE/PI), >50% of patients (pts) will either die, require kidney dialysis or have permanent renal damage within the first year of diagnosis. In addition to causing progressive organ damage, the uncontrolled complement activation and subsequent TMA might be expected to impact HRQoL. In 2 prospective, controlled, single-arm phase II trials of aHUS pts receiving ECU, a terminal complement inhibitor, TMA was stopped, there was no longer a need for PE/PI or new dialysis. In one of the trials (C08-002), dramatically, 4/5 pts on dialysis permanently discontinued dialysis as of most recent follow-up. The current analysis evaluates the impact of ECU on HRQoL in aHUS pts. MethodsIn trial C08-002, 17 pts with aHUS resistant to PE/PI (persistent TMA despite ≥4 PE/PI sessions 1 wk before screening) received ECU. In trial C08-003, 20 pts previously received chronic PE/PI (≥1 every 2 wks and <3 per wk for ≥8 wks prior to ECU). Clinical data, including pt-reported outcomes, were collected at baseline and through the 26-wk treatment and ongoing extension studies up to data cut-off (mean [SD] duration of ECU treatment: C08-002=58 [29] wks and C08-003=60 [12] wks). HRQoL was measured with the EQ-5D self-reporting questionnaire and a 20-cm visual analogue scale (VAS) validated for a number of disease populations. EQ-5D has 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and 3 levels (no problem, some problems and extreme problems). Change in HRQoL was calculated using the US time trade-off (TTO) index and VAS valuation techniques, and ANOVA analysis. A change of >0.06 is considered a clinically meaningful change ResultsC08-002: 15/17 pts received ECU until Wk 26 (2 discontinued at Wks 1 and 6; protocol violation and an adverse event unrelated to ECU, respectively) and 13 continued into the extension study. Median age=28 yrs and 29% were on dialysis immediately prior to ECU. Median time from diagnosis to screening =10 mo. All patients had eGFR ≤60 mL/min/1.73m2.C08-003: 20 pts received ECU for 26 wks and 19 continued into the extension study. Median age=28 yrs. Median time from diagnosis to screening=48 mo. Median duration of eGFR ≤60 mL/min/1.73m2=180 days at baseline.HRQoL: In both cohorts of distinct trial pts, ECU substantially improved HRQoL through Wk 26, and sustained this thereafter during long-term ECU therapy (table). In trial C08-002, improvements were seen as early as Day 7 (0.12, p=0.0346). Point estimate improvement (95%CI) in HRQoL from baseline to1 yr was 0.32 (0.27-0.36) for C08-002 and 0.09 (0.05-0.14) for C08-003. On an individual pt basis, 87% and 73% of C08-002 and C08-003 pts, respectively, achieved a clinically meaningful change that represented a clinically important large or moderate improvement in HRQoL measures, respectively. ConclusionsaHUS pts have an impaired HRQoL both from a direct impact of aHUS morbidity and management requirements (such as PE/PI), but also from the systemic nature of the disease. In patients with aHUS, significant improvements in HRQoL were achieved rapidly with ECU (as early as Day 7). Sustained long-term treatment with ECU maintained the improvements in HRQoL.C08-002 trialC08-003 trialECU Treatment (BL Through 1 yr)ECU Treatment (BL Through Wk 26)ECU Treatment (BL Through 1 yr)ECU Treatment (BL Through Wk 26)Point estimate change (95% CI) in EQ-5D from BL (using US TTO index scores)0.33 (0.28–0.37) (n=12) (p>0.0001)0.32 (0.27–0.36) (n=10) (p>0.0001)0.12 (0.07–0.17) (n=17) (p>0.0001)0.09 (0.05–0.14) (n=15) (p=0.0001)Mean (SD) change in VAS from BL31.9 (23) (n=12) (p=0.0010)35.5 (17) (n=10) (p=0.002)10.2 (17) (n=17) (p=0.02)9.1 (15) (n=15) (p=0.03)Percentage of pts with a clinically meaningful benefit in the US TTO value80%*87%*73%*73%*Effect Sizes† for EQ-5D (response is change in the index using the US TTO value)1.11.00.60.4BL=baseline; TTO=time trade off*15 pts were evaluable for C08-002 and 11 for C08-003†Effect sizes were considered large for C08-002 and medium for C08-003 Disclosures:Muus:Alexion: Honoraria, Research Funding. Off Label Use: The research described is a clinical trial of eculizumab in patients with aHUS, an indication in which its use is not approved. Licht:Alexion: Honoraria, Research Funding. Goodship:Alexion: Honoraria, Research Funding. Greenbaum:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding. Legendre:Alexion: Honoraria, Research Funding.