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

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 150mg every 4 weeks (n = 28), 300mg every 4 weeks (n = 29), 300mg 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 pointwas 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 AmongpatientswithhereditaryangioedematypeIor II, treatment with subcutaneous lanadelumab for26weeks significantly reduced the attack ratecomparedwith 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.