Pharmacology Update

Ecallantide Injection (Kalbitor®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A kallikrein inhibitor has been approved by the FDA for the treatment of acute attacks of hereditary angioedema (HAE). Ecallantide is a recombinant protein, produced in yeast cells, that provides symptomatic improvement by inhibiting the formation of bradykinin. It is marketed by Dyax Corp, as Kalbitorâ.

Indications

Ecallantide is indicated for the treatment of acute attacks of hereditary angioedema in patients 16 years of age and older.1

Dosage

The recommended dose is three 10 mg doses (30 mg) administered subcutaneously. The dose may be repeated within a 24-hour period if the attack persists.

Ecallantide is supplied as a 10 mg/mL single-use vial.

Potential Advantages

Ecallantide improves the symptoms of HAE attacks and reduces the need for medical intervention compared to placebo.1,2

Potential Disadvantages

Serious hypersensitivity reactions have been reported including anaphylaxis reaction that occurs in about 4% of patients. Ecallantide must be administered by a health care professional with appropriate medical support to manage anaphylaxis and angioedema.1 Common adverse events include headache (16.1%), nausea (12.9%), diarrhea (10.6%), fatigue (11.8%), upper respiratory infection (8.2%), and injection site reactions (redness, swelling, itching, bruising; 7.4%).1 Antibodies to ecallantide have been reported in about 5% of patients and the incidence of seroconversion appears to increase with increasing exposure.2 Patients who seroconvert may be at greater risk of a hypersensitivity reaction.1

Comments

Hereditary angioedema is a rare, autosomal-dominant disorder caused by a genetic mutation of the complement-1 esterase inhibitor (C1-INH) gene.3,4 It is characterized by intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tracts, and limbs that can be severely debilitating and even life-threatening. C1-INH is the endogenous inhibitor of the kallikrein-kinin cascade and the mutation in C1-INH gene allows this system to become unregulated, leading to excess bradykinin production and attacks of angioedema. Ecallantide is a selective, reversible inhibitor of kallikrein. Its efficacy was evaluated in two randomized, double-blind placebo-controlled trials in 168 study participants with hereditary angioedema.1,2 Participants with at least one moderate or severe symptom were randomized to 30 mg ecallantide subcutaneously or placebo. Primary endpoints were assessed (at 4 hours) with two scoring systems, the Means Symptom Complex Severity (MSCS) score and Treatment Outcome Score (TOS). These scoring systems measure severity of attack symptoms and symptom response to therapy, respectively, at 4 hours. Changes in MSCS and TOS at 4 hours were statistically better with ecallantide than placebo. A higher percentage of participants (68.6%) achieved onset of sustained improvement in overall response by 4 hours compared to placebo (41.1%).2 In addition, in both studies, fewer participants treated with ecallantide required medical intervention (14% and 33%) compared to placebo (36% and 50%) within 24 hours. Ecallantide is generally well tolerated. However, anaphylaxis occurs in about 4% of patients.

Clinical Implications

HAE can be severely debilitating and life-threatening. The prevalence ranges from 1 in 10,000 to 1 in 50,000. There are currently no other FDA-approved drugs for the treatment of acute attacks. Current treatments, which include fresh-frozen plasma, hydration, and narcotics, have met with only limited success. In 2008, a human C1 inhibitor was approved for prophylaxis against HAE attacks. Ecallantide is the first safe and efficacious agent approved for treatment of acute attacks of this serious but rare condition. Ecallantide is also being evaluated for the reduction of peri-operative blood loss during cardiopulmonary bypass surgery.

References

1. Kalbitor Prescribing Information. Cambridge, MA: Dyax Corp.; November 2009.

2. Pulmonary-Allergy Drugs Advisory Committee. Advisory Committee Briefing Document: Kalbitorâ (ecallantide) for Acute Attacks of Hereditary Angioedema (BLA 125277). Available at: www.fda.gov/ohrms/dockets/AC/ 09/briefing/2009-4413b1-03-Dyax.pdf. Accessed Jan. 14, 2010.

3. Epstein TG, Bernstein JA. Current and emerging management options for hereditary angioedema in the US. Drugs 2008;68:2561-2573.

4. Schneider L, et al. Critical role of kallikrein in hereditary angioedema pathogenesis. J Allergy Clin Immunol 2007;120:416-422.