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N Engl J Med. 2017 Feb 23;376(8):717-728. doi: 10.1056/NEJMoa1605767.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

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From the Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.B.), Dyax, Burlington (C. Soo, R.I., D.J.S., C.T., J.A.K., R.F., H.K., R.M., C. Stevens, J.C.B., Y.C., B.A.), and ICON Clinical Research, Marlborough (J.G.S.) - all in Massachusetts; the Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York (P.B.), and Winthrop University Hospital, Mineola (M.D.-L.) - both in New York; Triumpharma, Amman, Jordan (M.S., A.A.-G.); Asthma and Allergy Research Associates, Dallas (W.L.); the Division of Allergy and Immunology, Washington University School of Medicine, St. Louis (H.J.W.); Allergy and Asthma Medical Group, Walnut Creek (J.J.), and the Department of Rheumatology, Allergy, and Immunology, University of California, San Diego, San Diego (M.R.) - both in California; Baker Allergy, Asthma, and Dermatology, Lake Oswego, OR (J.B.); the Department of Internal Medicine-Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati (J.A.B.); the Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa (R.L.); the Institute for Asthma and Allergy, Chevy Chase, MD (H.H.L.); the Department of Medicine and Pediatrics, Penn State Hershey Allergy, Asthma, and Immunology, Hershey, PA (T.C.); and the Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, and Luigi Sacco Hospital Milan, Milan (M.C.).



Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.


We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.


No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.


In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; number, NCT02093923 .).

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