Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Previously Receiving Chronic Plasma Exchange/Infusion (PE/PI): Extension Study Results,

Chronic uncontrolled complement activation drives systemic thrombotic microangiopathy (TMA) and life-threatening complications in aHUS. In the initial 26-wk, phase II trial of eculizumab, (ECU) a terminal complement inhibitor, in pts with aHUS requiring chronic PE/PI for an extended period of time, a statistically significant and sustained suppression of TMA was observed. In addition, no pt required PE/PI, no new dialysis was required and all pts either maintained/improved renal function in the absence of PE/PI (Licht ASN 2011). We report longer follow-up data from this trial.

Pts ≥12 yrs with aHUS, receiving chronic PE/PI on an unchanged regimen were enrolled in a controlled, open-label, single-arm, phase II trial. After an 8-week observation period, pts discontinued PE/PI and started ECU (900mg/week for 4 wks, 1200mg at wk 5, then 1200mg q2 wks). Pts received a meningococcal vaccine. Primary endpoint: TMA event-free status defined as ≥12 consecutive wks of stable platelet count, no PE/PI and no new dialysis. Secondary endpoints included TMA intervention rate (no. of PE/PI and new dialysis events/pt/day), renal function, and safety. Pts continued into an extension trial.

Of 20 pts (median age=28 yrs) who received ECU through Wk 26 of the initial trial, 19 pts continued ECU treatment into the extension trial. Mean (SD) duration of ECU treatment was 60 (12) wks at data cut-off. Median time from diagnosis to screening=48 mo (0.66–286). Median time from overt clinical symptoms of aHUS to screening=8.6 mo (1.2–45). Median no. of PE/PI sessions per pt during current clinical presentation=62 (20–230). Median duration of eGFR ≤60 mL/min/1.73m²=180 days (23–485). Six pts had no complement regulatory factor mutation (CRFM) identified. Ongoing treatment with long-term ECU was associated with continued improvements in TMA intervention rate and TMA event-free status and further improvement in renal function (Table). Long-term ECU treatment showed a highly significant time-dependent improvement in eGFR (p<0.0001) with a significant improvement from baseline of 8 mL/min/1.73m² at 1 yr (p<0.0001). PE/PI or new dialysis was not required with chronic ECU treatment in any pt through Wk 26 or during ongoing long-term ECU therapy (through data cut-off). ECU was similarly effective in pts with/without identified CRFMs. ECU was well tolerated; only 7 pts had adverse events deemed possibly or probably related to drug (mild to moderate in severity). The extension trial continues.

Despite PE/PI, >50% of pts with aHUS are expected to die, require dialysis or have permanent renal damage within the first year of diagnosis. In this trial, all pts treated with ECU for a mean duration of >1 year are still alive and none progressed to ESRD or required new dialysis with sustained ECU treatment. Importantly, compared with historical outcomes with chronic PE/PI, initiation of sustained, long-term ECU therapy, without PE/PI, was associated with a highly significant time-dependent improvement in eGFR. Switching to chronic ECU therapy significantly changed the course of the disease in severe and prolonged renal insufficiency pts, resulting in sustained suppression of TMA. These data further demonstrate ECU to be the new standard of care for aHUS.

Licht:Alexion: Honoraria, Research Funding. Off Label Use: Eculizumab but as part of clinical controlled trials. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Legendre:Alexion: Research Funding. Douglas:Alexion: Genzyme, but not relevant to current submission, Research Funding. Hourmant:Alexion: Research Funding. Delmas:Alexion: Research Funding. Herthelius:Alexion: Research Funding. Trivelli:Alexion: Research Funding. Goodship:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding.