Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome

Abstract

Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

Orphan drug policies and use in pediatric nephrology

“…Patients may develop end-stage renal failure either during the first episode or after several recurrences and the disease may recur after renal transplantation. Patients were previously exclusively treated with plasma exchange or infusions but the prognosis regarding renal function and mortality was poor until the introduction of eculizumab, which was shown to be highly effective in both adults and children with aHUS [24,25]. Current international consensus (2015) recommends the start of eculizumab treatment upon diagnosis of aHUS, although treatment can be discontinued in a small subset of patients, particularly those with autoantibodies [23].…”

HUS and atypical HUS

“…As expected, complement inhibition is effective in patients who have a mutation in complement molecules or autoantibodies against factor H. The efficacy of therapeutic complement inhibition in patients with secondary HUS has not been systematically assessed, but it has been shown to be beneficial in a number of patients who do not have a mutation in any of the studied complement proteins. 117 These include patients with autoimmunity (eg, scleroderma), 118 systemic lupus erythematosus, 119,120 or catastrophic antiphospholipid syndrome 121,122 and secondary HUS associated with postpartum period, 123 HIV infection, 124 use of cytotoxic drugs, 35 and either bone marrow or solid organ transplantation. 27,28 On the basis of these multiple single cases, it seems that complement is involved in at least some patients with secondary HUS.…”

All Things Complement

“…In phase 2 clinical trials, treatment with eculizumab led to a rapid increase in the platelet count and steady improvement in renal function (77,78), and it has been approved for treatment of aHUS. These studies have demonstrated the safety and efficacy of C inhibition in patients with glomerular disease, and that inhibition can be maintained chronically.…”

“…Data suggest that eculizumab is superior to plasma exchange/infusion for the treatment of aHUS, although it is not effective in all patients (77,78). The response to treatment does not seem to depend upon identification of a genetic defect in a C-related gene (77,78), although a small subset of patients are resistant to the drug due to a genetic variant in the C5 gene (79).…”

“…The response to treatment does not seem to depend upon identification of a genetic defect in a C-related gene (77,78), although a small subset of patients are resistant to the drug due to a genetic variant in the C5 gene (79). Earlier treatment with eculizumab is associated with better renal outcomes (80), and patients with worse renal function at presentation are less likely to achieve complete remission of thrombotic microangiopathy-related symptoms (77).…”