Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.

Assessment of human antihuman antibodies to eculizumab after long‐term treatment in patients with paroxysmal nocturnal hemoglobinuria

“…Our study was not designed to assess non-study procedure-related AEs. However, investigators related three mild AEs (fatigue, arthralgia, and headache) in one patient as probably related to eculizumab; these AEs were not unexpected since they have been reported in previous clinical studies [4][5][6][7]. In summary, this analysis demonstrates that long-term treatment with commercial eculizumab in patients with PNH is associated with minimal risk for the development of HAHAs.…”

“…This current laboratory study, M07-003 (registered at http://www.clinical trials.-gov as NCT01412047), addresses a postapproval commitment to the FDA and the European Medicines Agency (EMA) to examine immunogenicity of eculizumab after longterm treatment. The development of neutralizing and non-neutralizing HAHAs associated with eculizumab use was assessed in patients with PNH who participated in the open-label, long-term study E05-001 [7]. Briefly, the study included 195 patients with PNH who participated in three prospective trials: a phase two pilot study [5]; and two phase three studies [4,6].…”

“…Briefly, the study included 195 patients with PNH who participated in three prospective trials: a phase two pilot study [5]; and two phase three studies [4,6]. The E05-001 study comprised a 104-week treatment period and a 16-week post-treatment follow-up period for patients who terminated treatment early [7].…”

“…No sequelae, including rebound hemolysis, were linked to the detection of ADAs in these studies or HAHAs in the present study. Additionally, in the extension study, E05-001, 5 of 161 patients (3.1%) experienced transient positive results on HAHA assays after a follow-up of >66 months, without a discernible impact on clinical response or pharmacodynamic effects of eculizumab, which continued to block complement activity [7,9]. Of these five patients, three have participated in the present HAHA study; testing for antibody formation was negative at the time of enrollment.…”

Paroxysmal Nocturnal Hemoglobinuria: From Bench to Bed

“…Researchers concluded that long-term treatment with eculizumab resulted in sustained improvement in patient's outcome by rapidly reducing hemolysis and significantly reducing the frequency of severe and life-threatening morbidities, improving patient's survival [25], which is corresponding to the study done by Kelly et al [19].…”