Effect of Lanadelumab Compared with Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial

Aleena Banerji, Marc A. Riedl, Jonathan A. Bernstein, Marco Cicardi, Hilary J. Longhurst, Bruce L. Zuraw, Paula J. Busse, John Anderson, Markus Magerl, Inmaculada Martinez-Saguer, Mark Davis-Lorton, Andrea Zanichelli, H. Henry Li, Timothy Craig, Joshua Jacobs, Douglas T. Johnston, Ralph Shapiro, William H. Yang, William R. Lumry, Michael E. ManningLawrence B. Schwartz, Mustafa Shennak, Daniel Soteres, Rafael H. Zaragoza-Urdaz, Selina Gierer, Andrew M. Smith, Raffi Tachdjian, H. James Wedner, Jacques Hebert, Syed M. Rehman, Petra Staubach, Jennifer Schranz, Jovanna Baptista, Wolfram Nothaft, Marcus Maurer

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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.

Original languageEnglish (US)
Pages (from-to)2108-2121
Number of pages14
JournalJAMA - Journal of the American Medical Association
Volume320
Issue number20
DOIs
StatePublished - Nov 27 2018

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All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Banerji, A., Riedl, M. A., Bernstein, J. A., Cicardi, M., Longhurst, H. J., Zuraw, B. L., Busse, P. J., Anderson, J., Magerl, M., Martinez-Saguer, I., Davis-Lorton, M., Zanichelli, A., Li, H. H., Craig, T., Jacobs, J., Johnston, D. T., Shapiro, R., Yang, W. H., Lumry, W. R., ... Maurer, M. (2018). Effect of Lanadelumab Compared with Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. JAMA - Journal of the American Medical Association, 320(20), 2108-2121. https://doi.org/10.1001/jama.2018.16773