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FDA approves eculizumab for atypical hemolytic uremic syndrome
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The monoclonal antibody eculizumab has received accelerated approval from the FDA for the treatment of pediatric and adult atypical hemolytic uremic syndrome.
Eculizumab (Soliris, Alexion Pharmaceuticals) inhibits the production of the terminal complement components C5a and the membrane attack complex C5b-9 by binding to complement protein C5. Prevention of the formation of C5a and the terminal complement complex inhibits complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremic syndrome (aHUS), according to an FDA press release.
In March 2007, eculizumab received approval for the treatment of patients with paroxysmal nocturnal hemoglobinuria.
Accelerated approval is based on data from two prospective, single-arm trials enrolling 37 adults and adolescents with aHUS, and one retrospective trial of 19 pediatric and 11 adult patients with aHUS.
In a prospective trial of adult and adolescent patients (n=17) with plasma therapy-resistant aHUS, treatment with eculizumab eliminated the need for dialysis, sustained improvement in the estimated glomerular filtration rate and sustained improvement in hematologic parameters that correlate with aHUS disease activity. Five patients required dialysis at entry; four discontinued dialysis for the duration of treatment with eculizumab. Fifty-three percent of patients enrolled for a median duration of 251 days experienced a median improvement in eGFR of at least 15 mL/min/1.73 m2.
Hematologic normalization was defined as achievement or maintenance of normal platelet counts and LDH levels for at least 4 weeks. This was achieved in 76% patients for a median of 37 weeks (range, 25 to 62 weeks or more). The need for plasma therapy was eliminated in most patients, and improvement in other laboratory markers of hemolysis and evidence for suppression of terminal complement activity were observed.
In the second prospective trial of adult and adolescent patients who required chronic plasma therapy (n=20), eculizumab treatment resulted in plasma therapy cessation and maintained renal function, as indicated by stable dialysis requirements and eGFR parameters. Ninety percent of patients maintained hematologic normalization (median duration of 38 weeks) after discontinuing chronic plasma therapy.
The outcomes from a retrospective trial of 19 pediatric patients (median age: 6 years; range: 2 months to 17 years; n=20) were consistent with the outcomes observed in the prospective studies. Fifty percent of pediatric patients who previously required dialysis were able to discontinue dialysis after eculizumab therapy, according to the press release. Additionally, seven of 19 (37%) patients exhibited an improvement in eGFR of at least 15 mg/min/1.73 m2, and eight of 19 (42%) pediatric patients achieved or maintained normal hematologic parameters for at least 4 weeks. The requirement for plasma therapy was eliminated in most patients.
The most frequently reported adverse events in aHUS single-arm prospective trials (>15% combined per patient incidence) were hypertension, upper respiratory tract infection, diarrhea, headache, anemia, vomiting, nausea, urinary tract infection and leukopenia.
Eculizumab is associated with life-threatening and fatal meningococcal infections. The FDA has developed a Risk Evaluation and Mitigation Strategy (REMS) to alleviate this risk. Health care providers are required to enroll in a registration program, certify that they will counsel and provide educational materials to patients about the risks of eculizumab, and agree to promptly report cases of meningococcal infection, according to the press release. A boxed warning is included in the product labeling to inform health care providers and patients of the serious risk for meningococcal infection; it also recommends immunization with a polyvalent meningococcal vaccine.
Children treated with eculizumab may also be at increased risk for serious infections due to Streptococcus pneumoniae and Haemophilus influenza type b (Hib). Pediatric patients should also receive vaccinations for the prevention of these infections, according to Advisory Committee on Immunizations Practices guidelines.
The safety and efficacy of eculizumab has not been established for the treatment of typical HUS, which is usually associated with an infection caused by bacteria producing Shiga-toxin.
Eculizumab is administered as an IV infusion. The recommended dosing for adult patients with aHUS is 900 mg weekly for the first 4 weeks, followed by 1,200 mg weekly 1 week later, and 1,200 mg every 2 weeks thereafter. The dosage regimen for pediatric patients is based upon body weight, according to the FDA.