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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flowchart of Study Enrollment in a Trial of Lanadelumab for Hereditary Angioedema

All patients received injections every 2 weeks, with those in the every-4-week groups receiving placebo in between active treatments. aOne patient was determined to be a screen failure after randomization to the group that received 150 mg of lanadelumab every 4 weeks. This patient was not treated and was withdrawn from the study. This patient was counted in the randomized population but was excluded from both the intent-to-treat and safety populations.

Figure 2.. Primary and Secondary Efficacy End Points and Maximum Severity of Investigator-Confirmed Hereditary Angioedema Attacks From Days 0-182

All patients received injections every 2 weeks, with those in the every-4-week groups receiving placebo in between active treatments. A, Attack rates are model-based mean attacks per month, with a month defined as 4 weeks. The mean attack rate for each group is presented with error bars representing 95% CI. B, Maximum hereditary angioedema attack severity is the most severe attack reported by the patient. For patients who did not complete the study, all available data were used for classification.

Figure 3.. Overview of Investigator-Confirmed Hereditary Angioedema Attacks and Use of On-Demand Medication

Each horizontal line represents data for an individual patient. Profiles are presented in order by the attack rate during the run-in period. The width of the blue boxes indicates the duration of the attack and the height indicates the severity of the attack. Orange circles indicate the use of on-demand medication. The dotted line at day 70 represents the start of steady state (days 70-182). The solid line represents end of the run-in period. All patients received injections every 2 weeks, with those in the every-4-week groups receiving placebo in between active treatments. aDiscontinued the study and did not complete the treatment period. bDiscontinued the study but completed the treatment period. See eTable 2 in Supplement 2 for a summary of treatment duration for patients who did not complete the study and reasons for discontinuation.