General Information

Kalbitor (ecallantide) is a human plasma kallikrein inhibitor.

Kalbitor is specifically indicated for the treatment of acute attacks of hereditary angioedema in patients 16 years of age and older.

Kalbitor is supplied as a solution for subcutaneous administration. The recommended initial dose is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.

Clinical Results

FDA Approval
The FDA approval of Kalbitor was based on the results of two placebo-controlled phase 3 clinical studies, known as EDEMA3 and EDEMA4. In both trials, the effects of Kalbitor were evaluated using the Mean Symptom Complex Severity (MSCS) score and the Treatment Outcome Score (TOS).

EDEMA3
This randomized, double-blind, placebo-controlled trial enrolled 72 subjects who were randomized to receive Kalbitor or placebo for acute attacks of HAE. The primary endpoint was the TOS at 4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS at 4 hours. Kalbitor demonstrated a greater decrease from baseline in the MSCS (p=0.041) than placebo and a greater TOS (p=0.045) than patients treated with placebo; these results were statistically significant. In addition, more patients in the placebo group (36%) required medical intervention to treat unresolved symptoms within 24 hours compared to the Kalbitor-treated group (14%).

EDEMA4
This randomized, double-blind, placebo-controlled trial enrolled 96 patients who were randomized to receive Kalbitor 30 mg subcutaneous or placebo for acute attacks of HAE. The primary endpoint was the change from baseline in MSCS score at 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with Kalbitor demonstrated a greater decrease from baseline in the MSCS (p=0.010) than placebo and a greater TOS (p=0.003) than patients with placebo; these results were statistically significant. At 24 hours, patients treated with Kalbitor also demonstrated a greater decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater TOS (89 vs. 55, p = 0.03). More patients in the placebo group (50%) required medical intervention to treat unresolved symptoms within 24 hours compared to the Kalbitor-treated group (33%).

Mechanism of Action

Kalbitor (ecallantide) is a human plasma kallikrein inhibitor. Hereditary angioedema is a genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH). It is characterized by low levels of C 1 - INH activity and low levels of C4. C 1 - INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain