Summary
Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based ...on long‐term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient‐years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy‐six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit‐risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.
Background: Pregnancy outcomes in patients with atypical hemolytic uremic syndrome (aHUS) are not well-documented. Here, we present characteristics of and outcomes for patients with aHUS who became ...pregnant while enrolled in the Global aHUS Registry. Methods: The observational Global aHUS Registry (NCT01522183), initiated in April 2012, collects demographics, disease history, treatment, and outcomes data for patients with aHUS, regardless of treatment approach. This descriptive analysis includes patients from the Registry with evaluable pregnancy data supplemented with pharmacovigilance information; the number of pregnancies, outcomes, and exposure to eculizumab were evaluated. Results: As of April 1, 2019, 44 pregnancies were recorded in 41 patients, with 24 pregnancies exposed to eculizumab. Pathogenic variants were identified in 48.8% of patients. Three patients were on dialysis and 6 patients had a kidney graft at the time of pregnancy. Excluding elective terminations, 85.3% of pregnancies resulted in live births. Elective terminations were recorded in 22.7% of pregnancies, miscarriages occurred in 9.1% of pregnancies, and late fetal death in 2.3% of pregnancies. No malformations or anomalies were reported. Conclusions: Our results show that in women with aHUS, even on dialysis or with a kidney graft, pregnancy is possible with careful monitoring for aHUS flares and prematurity. Prophylactic or therapeutic eculizumab offers disease control with low-risk of fetal abnormalities.
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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Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Roeth:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Socié:Alexion Pharmaceuticals, Inc.: Consultancy. Caby-Tosi:Alexion Europe SAS: Employment, Equity Ownership. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Bedrosian:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Brodsky:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding.
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