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Hereditary angioedema (HAE) causes episodic swelling of the skin and mucosae, which can be fatal if it occludes the airway. This autosomal dominant disease is identified by findings of low serum complement 4 (C4) levels and absolute or functional deficiencies of complement 1 (C1) esterase inhibitor. The C1 inhibitor inactivates complement proteases C1r and C1s, coagulation protease factors XI and XII, and the vasoactive protease kallikrein-1. For decades, acute HAE attacks have been treated in Europe with C1-inhibitor replacement. Concerns about possible viral contamination held up FDA approval of the plasma-derived inhibitor in the U.S.; a pasteurized product was not approved until 2009, leaving American patients without effective treatment. Preventive therapies have been aimed at stimulating inhibitor synthesis or reducing inhibitor consumption, but neither strategy works reliably or is without unwanted side effects.
Suddenly, researchers report three new agents for treating and preventing HAE attacks. Zuraw and colleagues studied a nanofiltered C1-esterase inhibitor concentrate that has undergone an additional filtration step to remove viruses that might escape measures such as pasteurization. In a comparison of the nanofiltered concentrate with placebo in 68 patients, median times to unequivocal relief of attacks were 2 hours and >4 hours, respectively (P=0.02). Given prophylactically in 22 patients, the same drug reduced the attack rate as well as the severity and duration of attacks.
Kinins mediate HAE swelling, and kallikrein activates it. Ecallantide is recombinant plasma kallikrein inhibitor. In a double-blind, placebo-controlled study, Cicardi and colleagues randomized 71 patients with acute attacks to ecallantide or placebo. At 4 hours, patient-reported treatment outcome scores and mean symptom complex severity scores were significantly better with ecallantide than with placebo. Cicardi and another group of investigators also evaluated icatibant, an even more specific inhibitor of kinins that binds to the bradykinin B2 receptor. In two double-blind randomized trials in 56 and 74 patients with cutaneous or abdominal attacks, icatibant provided symptom relief significantly sooner than placebo.
Zuraw BL et al. Nanofiltered C1-inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010 Aug 5; 363:513.
Cicardi M et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010 Aug 5; 363:523.
Cicardi M et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010 Aug 5; 363:532.
Morgan BP. Hereditary angioedema — Therapies old and new. N Engl J Med 2010 Aug 5; 363:581.
Comment
These drugs are needed and appear to work. The nanofiltered concentrate both prevented and treated attacks, but it is a plasma product and therefore still requires stringent oversight.