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Original Investigation
November 27, 2018

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema AttacksA Randomized Clinical Trial

Author Affiliations
  • 1Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Division of Rheumatology, Allergy & Immunology, University of California, San Diego
  • 3Department of Internal Medicine/Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 4Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, ASST Fatebenefratelli Sacco, Milan, Italy
  • 5Barts Health NHS Trust, London, United Kingdom
  • 6Icahn School of Medicine at Mount Sinai, New York, New York
  • 7Clinical Research Center of Alabama, Birmingham
  • 8Department of Dermatology and Allergy, Dermatological Allergology, Charité—Universitätsmedizin Berlin, Berlin, Germany
  • 9Haemophilia Centre Rhine Main, Mörfelden-Walldorf, Germany
  • 10Rheumatology Allergy and Immunology, NYU Winthrop Hospital, Mineola, New York
  • 11Institute for Asthma and Allergy, Chevy Chase, Maryland
  • 12Department of Medicine and Pediatrics, Pennsylvania State University, Allergy, Asthma, and Immunology, Hershey
  • 13Allergy and Asthma Clinical Research, Walnut Creek, California
  • 14Clinical Research of Charlotte, Charlotte, North Carolina
  • 15Immunology Department, Midwest Immunology Clinic, Plymouth, Minnesota
  • 16Ottawa Allergy Research Corporation and University of Ottawa Medical School, Ottawa, Ontario, Canada
  • 17Allergy Asthma Research Associates Research Center, Dallas, Texas
  • 18Medical Research of Arizona, Scottsdale
  • 19Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Virginia Commonwealth University, Richmond
  • 20Triumpharma, Amman, Jordan
  • 21Asthma and Allergy Associates PC, Colorado Springs, Colorado
  • 22University of Puerto Rico School of Medicine, San Juan
  • 23Division of Allergy, Clinical Immunology & Rheumatology, University of Kansas Medical Center, Kansas City
  • 24Allergy Associates of Utah, Murray
  • 25AIRE Medical of Los Angeles, University of California, Los Angeles
  • 26Division of Allergy and Immunology, Washington University, St Louis, Missouri
  • 27Centre de Recherche Appliqué en Allergie de Québec, Quebec, Canada
  • 28Toledo Institute of Clinical Research, Toledo, Ohio
  • 29Department of Dermatology, University Medicine Mainz, Mainz, Germany
  • 30Shire, Lexington, Massachusetts
JAMA. 2018;320(20):2108-2121. doi:10.1001/jama.2018.16773
Key Points

Question  Is lanadelumab, a monoclonal antibody that inhibits plasma kallikrein, effective in preventing hereditary angioedema attacks?

Findings  In this randomized clinical trial involving 125 patients with hereditary angioedema type I or II, treatment with lanadelumab for 26 weeks significantly reduced the mean attack rate (0.26-0.53 attacks/month) compared with placebo (1.97 attacks/month).

Meaning  These findings support the use of lanadelumab for the prevention of hereditary angioedema attacks.

Abstract

Importance  Current treatments for long-term prophylaxis in hereditary angioedema have limitations.

Objective  To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.

Design, Setting, and Participants  Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.

Interventions  Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.

Main Outcome and Measures  Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.

Results  Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were −1.49 (95% CI, −1.90 to −1.08; P < .001); −1.44 (95% CI, −1.84 to −1.04; P < .001); and −1.71 (95% CI, −2.09 to −1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).

Conclusions and Relevance  Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.

Trial Registration  EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805

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