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

Educational Objective
To learn about medications for the prevention of hereditary angioedema attacks.
1 Credit CME
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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Article Information

Corresponding Author: Aleena Banerji, MD, Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Cox 201, Boston, MA 02114 (abanerji@mgh.harvard.edu).

Correction: This article was corrected on April 23, 2019, to increase the upper range of treatment emergent antibodies to 1280 in the Antidrug Antibodies subsection.

Accepted for Publication: October 3, 2018.

Author Contributions: Dr Banerji had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Banerji, Riedl, Bernstein, Cicardi, Longhurst, Zuraw, Zanichelli, Li, Craig, Jacobs, Yang, Manning, Shennak, Soteres, Rehman, Baptista, Nothaft, Maurer.

Acquisition, analysis, or interpretation of data: Banerji, Riedl, Bernstein, Cicardi, Longhurst, Zuraw, Busse, Anderson, Magerl, Martinez Saguer, Davis-Lorton, Zanichelli, Li, Craig, Jacobs, Johnston, Shapiro, Yang, Lumry, Manning, Schwartz, Shennak, Soteres, Zaragoza-Urdaz, Gierer, Smith, Tachdjian, Wedner, Hebert, Staubach, Schranz, Baptista, Nothaft.

Drafting of the manuscript: Banerji, Zuraw, Busse, Magerl, Zanichelli, Li, Craig, Jacobs, Johnston, Yang, Shennak, Soteres, Tachdjian, Schranz, Baptista, Nothaft, Maurer.

Critical revision of the manuscript for important intellectual content: Banerji, Riedl, Bernstein, Cicardi, Longhurst, Zuraw, Anderson, Magerl, Martinez Saguer, Davis-Lorton, Zanichelli, Li, Craig, Jacobs, Johnston, Shapiro, Yang, Lumry, Manning, Schwartz, Shennak, Soteres, Zaragoza-Urdaz, Gierer, Smith, Tachdjian, Wedner, Hebert, Rehman, Staubach, Baptista, Nothaft, Maurer.

Statistical analysis: Banerji, Zanichelli, Manning, Hebert, Baptista, Maurer.

Administrative, technical, or material support: Banerji, Craig, Shennak, Gierer, Tachdjian, Wedner.

Supervision: Banerji, Riedl, Cicardi, Zuraw, Busse, Zanichelli, Johnston, Manning, Shennak, Soteres, Zaragoza-Urdaz, Tachdjian, Staubach, Schranz, Nothaft, Maurer.

Conflict of Interest Disclosures: Dr Banerji reports grants from Shire, and being on advisory boards for Alnylam, BioCryst, CSL Behring, Pharming, and Shire. Dr Riedl reports grants, scientific consulting fees, and speaking fees to his institution from BioCryst, CSL Behring, Pharming, and Shire; and scientific consulting fees to his institution from Adverum, Alnylam, Ionis, and Kalvista. Dr Bernstein reports grants and personal fees from CSL Behring, Pharming, and Shire; and personal fees from BioCryst. Dr Cicardi reports grants, membership on advisory boards, and speaker fees from Pharming and Shire; and advisory boards and speaker fees from Adverum, BioCryst, and CSL Behring. Dr Longhurst reports personal fees for consulting and travel support for scientific meetings from Shire; personal fees and nonfinancial and other support from BioCryst and CSL Behring; other support from Pharming; and personal fees from Kalvista. Dr Zuraw reports personal fees for consultations from Adverum, BioCryst, CSL Behring, and Shire; chair, advisory board membership, and grants from the US Hereditary Angioedema Association; and adjudication board membership with Genentech, Novartis, and Sanofi. Dr Busse reports consulting and research fees from Pharming, and Shire; consulting fees from CSL Behring, Global Life Sciences, Pearl Therapeutics, and Teva; and medico-legal fees support from the Law Offices of Victoria Broussard. Dr Anderson reports personal fees and other support for clinical research and consultation from CSL Behring and Shire; personal fees and other support for consultation from Pharming; and clinical research fees from BioCryst. Dr Magerl reports clinical research fees, personal fees, and nonfinancial support for consultations from Shire; and personal fees and nonfinancial support for consultations from BioCryst, CSL Behring, and Pharming. Dr Martinez-Saguer reports honoraria, research funding, travel grants from, serving as a consultant for, and being on the advisory boards of BioCryst, CSL Behring, Pharming, and Shire. Dr Davis-Lorton reports being a principal investigator for Novartis and Shire; advisory boards for CSL Behring, Pharming, and Shire; and speaker bureaus for CSL Behring, Pharming, and Shire. Dr Li reports grants, personal fees, and nonfinancial support from CSL Behring, Pharming, and Shire. Dr Craig reports grants and personal fees for consultations, research, and speaking from CSL Behring and Shire; grants and personal fees for speaking from Grifols; grants and personal fees for research and consultations from BioCryst; and advisory medical board membership for the US Hereditary Angioedema Association. Dr Jacobs reports grants and personal fees from CSL Behring and Shire; and personal fees from Pharming. Dr Johnston reports personal fees for consultations and speaking from CSL Behring and Shire; and consulting fees from BioCryst and Pharming. Dr Shapiro reports personal fees for clinical research and speaking from Shire and research support from Dyax and BioCryst. Dr Yang reports being a consultant and a member of the advisory board for CSL Behring and Shire; an unrestrictive educational grants from CSL Behring, Novartis, and Shire; and research grants from Aimmune, AstraZeneca, BioCryst, CSL Behring, DBV Technologies, Dyax/Shire, Galderma, Genentech/Roche, GlaxoSmithKline, Merck, Pfizer, Pharming, Sanofi-Genzyme, and Shire; and membership on the Canadian Hereditary Networks Guideline Publication Committee, and medical advisor to Hereditary Angioedema Canada. Dr Lumry reports grants from BioCryst, CSL Behring, Pharming, and Shire; consulting fees to his institution from Adverum, BioCryst, CSL Behring, Pharming, and Shire; travel support from CSL Behring and Shire; fees to his institution for being on the advisory board for BioCryst, speakers bureau fees to his institution from Alk, Genentech, and Stallergenes/Geer; manuscript preparation fees to his institution from Pharmacy Times; development of educational presentations to his institution from Medscape/WebMD; and medical advisory board payment to his institution from the US Hereditary Angioedema Association. Dr Manning reports grants and personal fees from CSL Behring and Shire; advisory board member for Shire; grants from Dyax; speaker bureau fees from Pharming; and personal fees and advisory board member for Salix. Dr Schwartz reports consulting fees from Dyax, Helix, Sanofi-Aventis, and ViroPharma; research support from CSL Behring, Dyax, and Merck; royalties from Virginia Commonwealth University Innovation Gateway; and payment to participate in the “Atopic Dermatitis in America” study from the Asthma and Allergy Foundation of America. Dr Soteres reports other income from Shire; being an investigator in the conduct of the study; and personal fees for consulting, advisory boards, and speaking from Shire. Dr Zaragoza-Urdaz reports consulting fees from BioCryst, Shire, and ViroPharma; and lecture fees from Baxter, Dyax, Pharming, Shire, Teva, and ViroPharma. Dr Gierer reports research grants from Dyax, Genentech/Novartis, and Shire. Dr Smith reports investigator fees from Shire. Dr Tachdjian reports advisory board and speaking honoraria from Shire, CSL Behring, and Pharming; and research grants from Shire and CSL Behring. Dr Wedner reports grants from Shire. Dr Hebert reports investigator fees from and being on an advisory board of Shire and consultant fees from GlaxoSmithKline, Merck, Novartis, Teva, Shire, CSL Behring, and Sanofi. Dr Staubach reports fees for advisory board membership from AbbVie, Beiersdorf, Celgene, CSL Behring, Genentech, Janssen, Leti, MSD, Novartis, Octapharma, Sanofi, Shire, Sobi, and UCB; consulting fees from CSL Behring; grants from Novartis and Shire; speaker fees from AbbVie, Astellas, CSL Behring, Janssen, Leo, Leti, Lilly, MSD, Pfleger, Novartis, and Shire; and travel support from CSL Behring, Janssen, MSD, Novartis, and Pfizer. Dr Schranz reports being a full-time employee of and owning stock/options in Shire. Ms Baptista reports being a full-time employee of and owning stock and options in Shire. Dr Nothaft reports being a full-time employee of and owning stock and options in Shire. Dr Maurer reports grants and personal fees for consultations and speaking from Shire; and grants and personal fees from BioCryst, Pharming, and Shire. No other disclosures were reported.

The HELP Investigators: Clinical sites for this study are listed in order by country and site location. PI indicates Principal Investigator, I indicates Investigator, C indicates Coordinator, and N indicates Nurse. Canada: Edmonton: Bruce Ritchie (PI);Ottawa: William H. Yang (PI); Denise Acker (C); Jenna Falbo (C); Stephanie Santucci (C). Quebec City: Jacques Hébert (PI); Toronto: Gordon Sussman (PI); Kachelle Mortimer (C). Germany: Berlin: Markus Magerl (PI); Marcus Maurer (I). Mainz: Petra Staubach (PI); Sebastian Zimmer (I). Möerfelden-Walldorf: Inmaculada Martinez-Saguer (PI); Carmen Escuriola Ettingshausen (I); Zeynep Gutowski (C). Italy: Marco Cicardi (PI); Francesca Perego (I); Maddalena A. Wu (I); Andrea Zanichelli (I). Jordan: Mustafa Shennak (PI); Ahmad Al-Ghazawi (I). Puerto Rico: Rafael H. Zaragoza-Urdaz (PI); Edith M. Hernandez (C). United Kingdom: Hilary J. Longhurst (PI); Geetha Boyapati (N); Rohit Ghurye (I); Emily Zinser (I). United States: Ann Arbor, Michigan: Alan P. Baptist (PI); Laurie Carpenter (C); Esther Teich (C). Austin, Texas: William R. Otto (PI). Belleville, New Jersey: Mark E. Weinstein (PI); Deborah A. Scalcione (C); Jacqueline M. Weinstein (C). Birmingham, Alabama: John Anderson (PI); Diane Paige (C). Boston, Massachusetts: Aleena Banerji (PI); Gita Bhattacharya (C); Boston, Massachusetts: David I. Hong (PI). Centennial, Colorado: Isaac Melamed (PI). Charlotte, North Carolina: Douglas T. Johnston (PI); Rebecca Schreiner (C). Chevy Chase, Maryland: H. Henry Li (PI); Athena Economides (I); Mark D. Scarupa (I); Amir Shahlae (I); Carla Ward (I); Martha White (I). Cincinnati, Ohio: Jonathan A. Bernstein (PI); Cheryl K. Bernstein (C). Colorado Springs, Colorado: Daniel Soteres (PI); Jaime Altman (C). Dallas, Texas: William R. Lumry (PI); Dalea A. Aguilar (C); Kimberly Poarch (I). Draper, Utah: Duane Harris (PI). Durham, North Carolina: Patricia Lugar (PI); Katherine E. Prince (C). Hershey, Pennsylvania: Timothy Craig (PI); Cathy Mende (C); Theresa Smith (C). Independence, Ohio: Cristine Radojicic (PI). Kansas City, Kansas: Selina Gierer (PI); Leslie Glasco (C); Theresa Howard (C); Caitlin McMillian (C). Milwaukee, Wisconsin: Heidi Zafra (PI). Mineola, New York: Mark Davis-Lorton (PI); Kimberly Byrnes (C). Murray, Utah: Andrew M. Smith (PI); Stephanie Carmona (C); Cheryl J. Rogers (C); Melissa Thornburgh (C). New York, New York: Paula J. Busse (PI); Olia Ali (C); Shanika Gregory (C); Tukisa D. Smith (I). Ocean, New Jersey: Ellen Sher (PI). Pittsburgh, Pennsylvania: Andrej A. Petrov (PI). Plymouth, Minnesota: Ralph Shapiro (PI). Richmond, Virginia: Lawrence B. Schwartz (PI). San Diego, California: Marc A. Riedl (PI); Jennifer C. Blair (C); Sandra Christiansen (I); Bruce L. Zuraw (I). Santa Monica, California: Raffi Tachdjian (PI); Scott Ewy (C); Jason Lui (C); Araik Sinanyan (C). Scottsdale, Arizona: Michael E. Manning (PI); Thomas Tyma (C). Shreveport, Louisiana: Peter B. Boggs (PI). Spokane, Washington: Richard G. Gower (PI); E. Suzanne Levitch (I); Mary Wilber (C); Christi Witte (C). St Louis, Missouri: H. James Wedner (PI); Tarisa Mantia (C). Tampa, Florida: Richard F. Lockey (PI); Amber N. Pepper; Catherine R. Smith (C); P. Michelle Twitmyer (C). Toledo, Ohio: Syed M. Rehman (PI); Kehkashan Q. Arshad (C). Walnut Creek, California: Joshua Jacobs (PI); Tara Mostofi (I); Jennifer Murphy (C); Dipti Patel (C).

Funding/Support: This study was funded by Dyax Corp (now Shire Human Genetic Therapies).

Role of the Funder/Sponsor: Dyax Corp (now Shire Human Genetic Therapies) was involved in the design and conduct of the study; and the collection, management, analysis, and interpretation of the data; and in the review of the manuscript for medical accuracy. The decision to submit the manuscript to JAMA was made by the authors independently.

Meeting Presentations: Results from this study were presented at the American College of Allergy, Asthma and Immunology Annual Scientific Meeting, October 29, 2017, Boston, Massachusetts; the Western Society of Allergy, Asthma & Immunology Annual Scientific Session, January 21-25, 2018, Kapalua, Hawaii; the American Academy of Allergy, Asthma & Immunology/World Allergy Organization Joint Congress, March 2-5, 2018, Orlando, Florida; the European Academy of Allergy and Clinical Immunology Congress, May 26-30, 2018, Munich, Germany; the Eastern Allergy Conference, May 31-June 3, 2018, Palm Beach, Florida; and the Aspen Allergy Conference, July 22-26, 2018, Aspen, Colorado.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients and their families who participated in this study. We also thank the research assistants and clinical nurse researchers for their assistance. Ayman Ibrahim, MD (former Shire employee), provided clinical development support. Gagan Jain, PhD (current Shire employee), provided support for the health-related quality of life analysis. Peng Lu, MD, PhD (current Shire employee), provided clinical development support and support with the steady-state analysis. Shirley Teng, PhD, CMPP, of Excel Medical Affairs, provided writing assistance. Funding for writing was provided by Shire Human Genetic Therapies.

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