Interim Analysis of Safety Outcomes during Treatment with Eculizumab: Results from the International Paroxysmal Nocturnal Hemoglobinuria Registry

Background/Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, life-threatening disorder characterized by complement-mediated intravascular hemolysis and a prothrombotic state. Eculizumab, a terminal complement inhibitor inhibits intravascular hemolysis and thrombosis, and decreases mortality risk in patients with PNH. More information is needed regarding outcomes associated with long-term treatment. The International PNH Registry (NCT01374360) is an ongoing prospective, multinational, observational study established to record the natural history of patients with PNH and collect data on long-term efficacy and safety of eculizumab treatment. The objective of this analysis was to assess safety outcomes in patients in the PNH Registry by treatment status with eculizumab.

Methods: Patients enrolled in the Registry as of July 5, 2016, were eligible for the current analyses. Patient-time was classified as ever-treated with eculizumab or untreated with eculizumab. The patient-time in the eculizumab-treated group was assessed starting at initiation of eculizumab and followed through last Registry follow-up. The untreated-with-eculizumab group included those who never received eculizumab treatment prior to enrollment in the Registry; these patients contributed untreated patient-time starting at enrollment and followed through last untreated follow-up (initiation of eculizumab or last Registry follow-up). For the eculizumab-treated group, baseline was defined as the date of eculizumab initiation; for the untreated-with-eculizumab group, baseline was defined as the date of Registry enrollment. Patients who were enrolled while untreated and later initiated treatment with eculizumab contributed patient-time to both groups. Incidence rates were calculated for outcomes of interest reported on case report forms, except for subtypes of infections and malignancies where write-in text describing the infection or malignancy was coded by the authors to be one of the subtypes of interest.

Results: Of the 4448 patients enrolled in the Registry, 4013 had non-missing data on demographics, enrollment date, and eculizumab status and were included in the current analyses (eculizumab-treated, n=1587; untreated-with-eculizumab at enrollment, n=3058); 632 patients contributed patient-time to both groups. The mean (standard deviation) follow-up time for the eculizumab-treated and untreated-with-eculizumab groups was 50.0 (30.9) and 32.1 (25.0) months, respectively. Mean age at baseline was similar in the eculizumab-treated and untreated-with-eculizumab groups (43.4 vs 44.8 years, respectively). At baseline, 91% in the eculizumab-treated group had LDH ≥1.5x upper limit of normal prior to treatment, compared with 50% of untreated-with-eculizumab patients. More patients in the eculizumab-treated group had a history of thrombotic events (TE; 23% vs 9%) or other major adverse vascular events (MAVE; 12% vs 9%) compared with untreated-with-eculizumab patients. Rates of TE, other MAVE, solid tumors, impaired renal function (IRF), impaired hepatic function (IHF), pulmonary hypertension, and mortality were substantially lower in the eculizumab-treated group during follow-up compared with the untreated-with-eculizumab group, while estimated rates of overall infections and hematologic malignancies were similar in the 2 treatment groups (Table). In the subset of 632 patients enrolled while untreated with eculizumab but later started eculizumab after enrollment, rates of TE, other MAVE, solid tumors, IRF, IHF, and pulmonary hypertension were lower following initiation of eculizumab. Of the 18 cases of Neisseria infection in 16 patients in the eculizumab-treated group (Table), 13 were confirmed meningococcal infections (12 resolved, 1 ongoing at time of data cut-off). One patient in the untreated-with-eculizumab group had a Neisseria infection. No fatal outcomes due to meningococcal infection or other encapsulated organisms were reported in any group in this analysis.

Conclusions: With 6399 patient-years of eculizumab exposure in the largest global Registry of patients with PNH, eculizumab appears to be safe with no new safety findings identified. Rates of complications of PNH are lower in patients treated with eculizumab compared with those who are untreated. The benefit-risk ratio for patients treated with eculizumab remains favorable.

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