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 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.

Effectiveness and safety of lanadelumab in ethnic and racial minority subgroups of patients with hereditary angioedema: results from phase 3 studies.

BACKGROUND: The COVID-19 pandemic has highlighted disparities in healthcare, particularly in the United States, even though disparities have existed since the organization of the modern healthcare system. Recruitment of patients from racial and ethnic minority groups is often minimal in phase 3 clinical trials, and is further exacerbated in the case of trials for rare diseases such as hereditary angioedema (HAE). This can lead to a gap in the understanding of minority patients' experiences with these diseases and their response to potential treatment options. METHODS: We reviewed data from phase 3 double-blind (HELP) and open-label extension (HELP OLE) trials of lanadelumab, a monoclonal antibody developed for long-term prophylaxis against attacks of HAE. Efficacy (attack rate reduction) and safety (adverse events) results from White patients were compared descriptively to those from Hispanic/Latino patients, Black/African Americans, and other minority Americans. RESULTS: Not surprisingly, few minorities were recruited across both studies: 9.5% Black, 2.4% Asian, and 7.1% Hispanic/Latino versus 88.1% White and 91.7% non-Hispanic/non-Latino received lanadelumab in HELP, and 4.7% Black, 0.9% Asian, 0.9% other, and 6.1% Hispanic/Latino versus 93.4% White and 93.4% non-Hispanic/non-Latino were enrolled in HELP OLE. Although these studies were conducted in the United States, Canada, Europe, and Jordan, all minorities were from the United States. Despite the number of minority patients being far less than expected for the population, there was no evidence that either efficacy or adverse event profiles differed between ethnic or racial groups. CONCLUSIONS: The HELP and HELP OLE studies described herein recruited far fewer minorities than would be ideal to represent these populations. However, evidence suggests that the effectiveness and tolerance of lanadelumab are similar between the groups. Nonetheless, the disparity in recruitment into research for minorities has significant room for improvement. Trial registration NCT02586805, registered 26 October 2015, https://clinicaltrials.gov/ct2/show/record/NCT02586805 . NCT02741596, registered 18 April 2016, https://clinicaltrials.gov/ct2/show/NCT02741596 .