Food allergy, anaphylaxis, dermatology, and drug allergy
Critical role of kallikrein in hereditary angioedema pathogenesis: A clinical trial of ecallantide, a novel kallikrein inhibitor

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Background

Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene mutation. Patients with HAE experience intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein activation generates bradykinin, the likely mediator of the swelling and pain characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits kallikrein. This is the first placebo-controlled assessment in human beings of a therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that the contact cascade is the putative pathway responsible for HAE pathology.

Objective

To determine the safety and efficacy of ecallantide in patients with HAE.

Methods

This double-blind, placebo-controlled, ascending-dose study assessed efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m2 intravenously) in individuals experiencing acute HAE attacks (N = 49). Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort.

Results

Ecallantide treatment ameliorated the symptoms of HAE attacks: 72.5% (29/40) of patients treated with ecallantide versus 25.0% (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (P = .0169). Ecallantide was well tolerated at all doses.

Conclusion

Ecallantide, a potent, specific inhibitor of plasma kallikrein, significantly improved HAE symptoms over placebo. The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE. Further clinical trials are underway.

Clinical implications

Ecallantide is a promising new therapy for HAE attacks.

Section snippets

Study design

The EDEMA1 study was a multicenter, randomized, placebo-controlled, double-blind, ascending-dose trial evaluating 4 doses of ecallantide in patients experiencing acute attacks of HAE. Patients were randomized to treatment with a single dose of ecallantide (5, 10, 20, or 40 mg/m2 intravenously) or placebo (PBS) by intravenous infusion. Twelve patients were assigned to each dose cohort, with 10 patients randomized to receive ecallantide and 2 to placebo. On the basis of the patient's calculated

Treatment assignments, patient demographics, and baseline characteristics

Forty-eight patients were randomized to intravenous treatment with ecallantide (n = 40, 83.3%) or to receive placebo (n = 8, 16.7%). Ten patients each were randomized to be treated with a dose of 5, 10, 20, or 40 mg/m2 ecallantide. As a result of the simultaneous HAE attacks of 2 patients at different study sites, an additional patient (40 mg/m2 ecallantide cohort) was enrolled beyond the protocol-designated population of 48 patients. Only 1 of these patients was randomized to treatment. The

Discussion

In this first placebo-controlled clinical trial of a kallikrein inhibitor to treat HAE, ecallantide was a safe and effective treatment. The primary efficacy endpoint of the study was achieved, with 72.5% of patients treated with ecallantide reporting significant improvement in symptoms within 4 hours compared with 25.0% of placebo patients (P = .0169). During the study, 5 patients treated with ecallantide and 3 patients who received placebo received additional medication for HAE symptoms on the

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    Supported by Dyax-Genzyme LLC.

    Disclosure of potential conflict of interest: L. Schneider has consulting arrangements with and has received grant support from Dyax-Genzyme LLC. A. H. Williams used to be employed by Dyax Corp. W. Lumry has consulting arrangements with Abbott Laboratories, Alcon Laboratories, AstraZeneca, Boehringer Ingelheim, Dyax, Genentech, GlaxoSmithKline, Jerini, MedPointe, Merck, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and Verus Pharmaceuticals; has received grant support from Abbott Laboratories, ICON Laboratories, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Dyaz, Dynavax, Genentech, GlaxoSmithKline, Immunex, IVAX, Jerini, Johnson & Johnson/Janssen, Lev Pharmaceuticals, MedPointe, Merck, Novartis, Pharmacia-Upjohn, Pfizer, Sanofi-Aventis, Schering-Plough, and Sepracor Pharmaceuticals; and is on the speakers' bureau for Abbott Laboratories, Alcon Laboratories, AstraZeneca, Boehringer Ingelheim, Dey Laboratories, Genentech, GlaxoSmithKline, KOS Pharmaceuticals, MedPointe, Merck, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and Verus Pharmaceuticals. A. Vegh has received grant support from Dyax and is on the speakers' bureau for Schering-Plough, Merck, and IVAX. T. Schmalbach is employed by Dyax.

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