Clinical Pearls & Morning Reports
Published February 22, 2017
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Hereditary angioedema with C1 inhibitor deficiency is a rare genetic disease that is characterized by recurrent swelling episodes, typically affecting the subcutaneous or submucosal tissues of the hands and feet, abdomen, face, larynx, or genitourinary tract. Swelling of the larynx can be life-threatening because of the risk of asphyxiation. Banerji et al. conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial that evaluated lanadelumab, a monoclonal antibody inhibitor of kallikrein, in patients at least 18 years of age with a documented diagnosis of hereditary angioedema with C1 inhibitor deficiency (type I or II). An Original Article explains.
Q: What is the link between the generation of plasma kallikrein and the symptoms of hereditary angioedema?
A: Hereditary angioedema is caused by a deficiency or dysfunction of C1 inhibitor, a key regulator of the complement, coagulation, and kallikrein–kinin cascades. In hereditary angioedema with C1 inhibitor deficiency, activation of the kallikrein–kinin cascade leads to uncontrolled generation of plasma kallikrein and consequent proteolysis of high-molecular-weight kininogen. This results in excessive bradykinin production, which causes vasodilation, vascular leakage, and subsequent angioedema and pain.
Q: What are some of the shortcomings of currently approved prophylactic therapies for hereditary angioedema?
A: All patients with hereditary angioedema with C1 inhibitor deficiency must have ready access to an on-demand medication for treatment of acute attacks. In addition, some patients benefit from prophylactic treatment, on the basis of a variety of criteria, including the frequency and severity of attacks, a history of airway swelling, and patient preference. Currently approved prophylactic therapies include attenuated androgens (e.g., danazol) and a plasma-derived C1 inhibitor. Although both treatments significantly reduce the frequency and severity of attacks, they have potential shortcomings. Androgens are daily medications and may have side effects; studies indicate that approximately 25% of patients with hereditary angioedema with C1 inhibitor deficiency who receive androgens discontinue them owing to unacceptable side effects. The C1 inhibitor is administered intravenously every 3 to 4 days, which is a difficult schedule for some patients, and carries a theoretical risk of infection and loss of venous access owing to repetitive administration. Neither attenuated androgens nor the C1 inhibitor prevents all attacks of angioedema.
A: In the study by Banerji et al., in the primary efficacy and modified intention-to-treat analyses, two administrations of lanadelumab at a total dose of 300 mg or 400 mg appeared to be effective in preventing attacks of angioedema, resulting in 100% and 88% fewer attacks, respectively, than the number of attacks with placebo.
A: The most common treatment-related adverse events were injection-site pain (occurring in 25% of the patients who received lanadelumab and in 23% of those who received placebo) and headache (occurring in 8% of the patients who received lanadelumab and in 15% of those who received placebo). There were no deaths or discontinuations due to an adverse event that emerged during treatment and no important safety signals in patients who received lanadelumab or placebo. There were no serious adverse events in patients who received lanadelumab. Although the efficacy results of this trial are encouraging, the duration of the trial was relatively short. A phase 3 trial evaluating the safety and efficacy of 6 months of lanadelumab treatment is under way.