The results from this study demonstrate the long-term safety and efficacy of chronic eculizumab treatment in a large cohort of patients with PNH (n
= 195). The median eculizumab treatment duration was 30·3 months, with a maximum duration of 66 months. Inhibition of terminal complement activity with eculizumab has previously been reported to rapidly and significantly reduce chronic haemolysis, leading to reductions in transfusion requirements (Hillmen et al
) and TEs (Hillmen et al
), as well as improvements in renal function (Hillmen et al
). The current study shows that these results are sustained with long-term treatment.
Thrombotic events are a severe and life-threatening complication of PNH and are reportedly the most frequent cause of death in patients with PNH (Hillmen et al
). TE has been shown to be a significant risk factor for early mortality (relative risk: 15·4; 95% CI, 9·3–25·4; P
< 0·001) in untreated patients (de Latour et al
). Furthermore, following the occurrence of a first TE, there is a greater risk of subsequent TEs, which places patients with a history of TE at a heightened risk of premature mortality (Nishimura et al
; de Latour et al
). Given that TE in PNH patients appears to be related to severe and ongoing uncontrolled terminal complement activation, management of TE is difficult in PNH patients, as many continue to report TE despite prophylactic use of anticoagulation therapies (Moyo et al
; de Latour et al
; Kelly et al
). We observed an 81·8% reduction in the incidence of TEs with long-term eculizumab treatment. Eighty-four patients in this study received concomitant anticoagulant therapy, which was discontinued in 11 patients. Despite six of these 11 patients having a history of TE, none of them experienced a TE following withdrawal of anticoagulation therapy while receiving eculizumab alone. This experience is consistent with other reports (Emadi & Brodsky, 2009
; Kelly et al
Thrombotic events were observed in 16% (3 of 19) of patients who discontinued treatment with eculizumab, all within 8 weeks of taking their last dose. This finding highlights the importance of adherence to eculizumab treatment at the recommended dose and schedule over the long term, as continuous therapy is paramount in maintaining sustained inhibition of the underlying uncontrolled terminal complement activation. If discontinuation of eculizumab therapy becomes necessary, the potential risk of thrombosis as well as possible preventive measures should be considered.
Chronic kidney disease in PNH patients is caused by several factors, including chronic exposure to free haemoglobin, which increases renal accumulation of haemosiderin, tubulointerstitial inflammation and kidney damage (Nath et al
). Renal impairment is known to progress over time (Hillmen et al
) and is associated with an increase in mortality (Kim et al
). Continued improvement in CKD was observed with sustained eculizumab treatment, with 44·8% of patients showing improvement after 36 months of treatment, compared with 24·4% showing improvement in CKD after only 6 months of treatment. The improvement in renal function in all nine patients with early-stage CKD (stage 1–2) over 36 months suggests that patients treated with eculizumab at earlier stages of kidney damage have a greater likelihood of improvement in renal function, and there is evidence that sustained long-term therapy with eculizumab can reverse early stage renal damage sustained prior to treatment initiation. These are unique findings in a patient population known to be at risk for progressive decline in renal function (Hillmen et al
), and they suggest that eculizumab may have a protective role that can lead to improvement in, or less progression of, renal disease.
Reduction in the incidence of TE and CKD, the two major causes of death in PNH, by administration of eculizumab would be expected to lead to improved patient survival. In the current prospective, multinational study in a large cohort of 195 patients, we demonstrated a patient survival of 97·6% (95% CI, 93·7%–99·1%) at 3 years, which was maintained over 66 months of eculizumab treatment. This result is similar to the 5-year survival rate of 95·5% observed in a single-centre, retrospective analysis of 79 patients (Kelly et al
). These survival rates seen with eculizumab therapy are a substantial improvement over historical 5-year survival rates of approximately 65% in PNH patients with evidence of haemolysis (Hillmen et al
; Kelly et al
) and are similar to survival rates of age- and sex-matched healthy subjects (Kelly et al
). These results further emphasize the role of uncontrolled complement activation in the pathophysiology of PNH-related mortality.
Long-term treatment with eculizumab also resulted in sustained haematological improvement in patients. Transfusion independence was achieved by 52% (102 of 195) of patients within the first 6 months of treatment, which increased to 82% by the last 6 months of treatment. The number of units of PRBCs transfused was reduced by 55% over the 36-month period. In addition, there was a continuous improvement in haemoglobin levels, which was achieved despite the reduction in transfusions.
The standard eculizumab maintenance dose of 900 mg every 14 ± 2 d was sufficient to maintain inhibition of haemolysis in 89% of patients. In the 21 patients who did report breakthrough haemolysis, shortening the dosing interval to <14 d was sufficient to maintain inhibition of haemolysis, and none of these patients discontinued treatment because of a lack of therapeutic effect. It is important that patients be monitored for any signs or symptoms of breakthrough haemolysis so that the dosing can be adjusted accordingly or, in cases of persistent breakthroughs, to ensure the patient has not developed human anti-human antibodies (HAHA) or neutralizing antibodies to eculizumab. Subsequent to the end of the study, a more sensitive analysis became available for the identification of HAHA in patients receiving eculizumab. With this new analysis, two of the patients in the long-term extension study were found to have low positive values for neutralizing antibodies, which exceeded the prespecified threshold for the in vitro assay (data not shown). This finding had no impact on the clinical response to eculizumab therapy or on the pharmacokinetic and pharmacodynamic effects of eculizumab, which continued to block complement activity.
Eculizumab was well tolerated over the long term and demonstrated a positive safety profile. Although nearly all patients reported at least one AE, this is to be expected considering the duration of the study; importantly, discontinuation from treatment due to a nonfatal AE was seen in only five patients (2·6%) over the entire period of study. With no comparator group in this open-label extension, we compared the AE rate of the early treatment group with that of the later treatment group to understand the risk of long-term eculizumab treatment. The probability of a patient experiencing one or more AEs was significantly lower in the last 6 months of the eculizumab treatment period than in the first 6 months of therapy. This suggests that there is no cumulative toxicity with long-term administration of eculizumab and that the risk–benefit profile of eculizumab improves with extended use. Serious infection-related AEs were observed throughout the study, although there was no evidence that their occurrence was related to time on eculizumab treatment.
There is an increased incidence of infections with N. meningitidis
in individuals with genetic deficiencies of C5–C9 (Figueroa & Densen, 1991
). Thus, blocking terminal complement activity with eculizumab increases a patient's susceptibility to meningococcal infections. Two cases of meningococcal sepsis were reported during the approximately 467 patient-years of exposure to eculizumab. Both patients were successfully treated without sequelae. Patient education on the signs and symptoms of potential meningococcal infections remains important to ensure that any infections are identified as quickly as possible. This is particularly crucial outside of a closely monitored clinical study, where continuous vigilance and proactive antibiotic treatment are essential to avoid a potentially fatal infection (http://soliris.net/sites/default/files/assets/soliris_pi.pdf
In conclusion, long-term treatment with eculizumab resulted in sustained improvement in patient outcomes by rapidly reducing haemolysis and significantly reducing the frequency of severe and life-threatening morbidities, such as TEs and CKD, and thus, improving patient survival. There was evidence that eculizumab improved kidney function over time and also provided sustained protection against further renal damage, particularly when administered early and prior to advanced renal impairment. Eculizumab therapy was well tolerated with a favourable safety profile; very few patients discontinued treatment during long-term therapy. Over the course of this study, survival rates were high and consistent with the improvements observed in another overlapping cohort of patients in whom survival was seen to be similar to age- and sex-matched normal control subjects (Kelly et al
). The International PNH Registry (www.pnhregistry.com
) is providing further opportunities to continue studying and understanding the long-term benefits of eculizumab in patients with PNH outside the clinical trial setting.