Kallikrein inhibitor · angioedema
Ecallantide is a 60-amino-acid recombinant protein, made in yeast, that blocks plasma kallikrein. It was engineered from a Kunitz domain of a human protein and found through phage display screening. It treats sudden attacks of hereditary angioedema, a genetic condition causing episodes of severe swelling, and is injected under the skin by a healthcare professional.
Hereditary angioedema stems from too little working C1-inhibitor, the body's main brake on plasma kallikrein. Without that brake, kallikrein cuts high-molecular-weight kininogen into bradykinin, a peptide that widens blood vessels and is thought to cause the swelling, inflammation and pain of an attack in the skin, gut or airway6. Ecallantide binds plasma kallikrein tightly, selectively and reversibly and blocks its binding site, so less bradykinin is made during an attack6. It treats attacks as they happen; it does not correct the underlying C1-inhibitor deficiency.
Ecallantide was studied in people during acute attacks. In a double-blind trial of 72 patients, patient-reported treatment outcome scores four hours after dosing were better with ecallantide than placebo (median 50 vs 0), symptom severity scores also favored it, and there were no treatment-related serious adverse events1.
A second phase 3 trial, EDEMA4, enrolled 96 patients and again found greater symptom improvement at four hours, apparent within two hours and maintained through 24 hours2. A review of the trial database found that 8 of 230 patients (3.5%) given it under the skin had reactions meeting anaphylaxis criteria, none on first exposure, all within an hour, and all resolving with standard treatment3. It was also studied to reduce blood loss in heart surgery, but a 2008 review reported that trial was being ended4, and a trial in ACE-inhibitor-induced angioedema was stopped when an interim analysis found a much higher placebo response than expected, despite a trend favoring the drug5.
The FDA approved ecallantide as Kalbitor in 2009 to treat acute attacks of hereditary angioedema, and the label now covers patients 12 years and older6. It must be given by a healthcare professional with appropriate support to manage anaphylaxis and hereditary angioedema6.
The label carries a boxed warning for anaphylaxis, seen in about 4% of treated patients in trials and occurring within the first hour; allergic symptoms can resemble an attack, so patients are monitored closely6. The most common reactions were headache, nausea, fatigue, diarrhea, upper respiratory infection, injection-site reactions, nasopharyngitis, vomiting, itching, upper abdominal pain and fever. About 20% of patients developed antibodies to the drug, and those who do may face higher hypersensitivity risk6.
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