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Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

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  • 1From 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.).

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Summary

Lanadelumab effectively reduced hereditary angioedema attacks by inhibiting plasma kallikrein. This investigational therapy shows promise for preventing swelling episodes in patients with C1 inhibitor deficiency.

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Area of Science:

  • Immunology
  • Pharmacology
  • Genetics

Background:

  • Hereditary angioedema (HAE) with C1 inhibitor deficiency involves recurrent swelling due to uncontrolled plasma kallikrein and bradykinin.
  • High-molecular-weight kininogen cleavage is a key pathway in HAE pathogenesis.

Purpose of the Study:

  • To evaluate the safety and efficacy of lanadelumab, a novel kallikrein inhibitor, for HAE prophylaxis.
  • To assess the pharmacodynamic effects of lanadelumab on HAE biomarkers.

Main Methods:

  • Phase 1b, multicenter, double-blind, placebo-controlled trial.
  • Randomized assignment of 37 patients with HAE to lanadelumab or placebo.
  • Multiple ascending doses of lanadelumab (30-400 mg) administered twice, 14 days apart.

Main Results:

  • Lanadelumab demonstrated dose-proportional pharmacokinetics with a half-life of approximately 2 weeks.
  • Significant reduction in cleaved high-molecular-weight kininogen levels observed with 300 mg and 400 mg lanadelumab doses.
  • 100% and 88% reduction in angioedema attacks in the 300 mg and 400 mg groups, respectively, compared to placebo.

Conclusions:

  • Lanadelumab effectively reduced HAE attacks and biomarker cleavage in a phase 1b trial.
  • The drug was well-tolerated, with angioedema attacks and injection site pain as most common adverse events.
  • Lanadelumab shows potential as a prophylactic treatment for HAE with C1 inhibitor deficiency.