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Plasma kallikrein blocking antibody
Prophylaxis against attacks of hereditary angioedema†,$
Lanadelumab is a recombinant, fully human, monoclonal plasma kallikrein-blocking antibody (IgG1/κ-light chain). It was approved as a breakthrough preventive against attacks of hereditary angioedema (HAE) in patients ≥12 years of age. Lanadelumab is produced in Chinese hamster ovary cells.8 It is formulated as a subcutaneous injection for self-administration every 2 or 4 weeks. The most common adverse reactions are injection site reactions, upper respiratory infections, headache, rash, myalgia, dizziness, and diarrhea.8,97 Transaminase elevations have occurred and the drug may interfere with the assessment of clinical measurement of coagulation tests. The half-life of lanadelumab is ~2 weeks.98
Hereditary angioedema (HAE) is a rare genetic disorder, associated with the deficiency or dysfunction of protein C1-esterase inhibitor.98 C1-esterase inhibitor is responsible for controlling the enzyme cascade that results in the production of the pro-inflammatory peptide, bradykinin from plasma kallikrein. Bradykinin is a potent vasodilator, and under stress conditions, patients with HAE have insufficient C1-esterase inhibitor activity to prevent accumulation of the edema and swelling associated with excess bradykinin.97-99 Swelling in the mouth, gut, and airway are painful and potentially life-threatening. On average, untreated individuals have an attack every 1–2 weeks and attacks generally last 2–5 days.100 Angioedema attacks are most often associated with trauma, medical procedures, emotional stress, menstruation, oral contraceptive use, infections, or the use of medications.97-99 Attacks are unpredictable, so the severity and frequency of previous attacks is not predictive of future attacks.98 HAE is classified as type I, characterized by low levels of a normal C1-esterase inhibitor in the plasma; type II, characterized by a normal level of a dysfunctional C1-esterase inhibitor in the plasma; or type III, estrogen-dependent HAE.98,99 Mutations in the SERPING1 gene cause types I and II, and mutations in the F12 gene are associated with some cases of type III HAE.100 The F12 gene codes for proinflammatory coagulation Factor XII, which plays a role in the production of bradykinin.100 Certain mutations in the F12 gene result in excessive Factor XII activity and overproduction of bradykinin.100
Lanadelumab acts to occlude the proteolytic active site on plasma kallikrein, thereby blocking its proteolytic activity. Lanadelumab was studied in adult and adolescent patients with type I or II HAE (NCT02586805).97-99 At a dose of 300 mg every 2 weeks, lanadelumab was associated with a ≥50% reduction in the HAE attack rate in all 27 subjects studied, a ≥70% reduction in 24/27 subjects, and a ≥90% reduction 18/27 subjects. Twelve subjects were attack-free for the entire 26-week treatment period. The average wholesale price for a single 300-mg dose of lanadelumab is $13,242.101 Dosing every 2 weeks yields an annual drug cost of approximately $371,000.
Chapter 39. Histamine, Bradykinin, and Their Antagonists > The Endogenous Kallikrein-Kininogen-Kinin System
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals