Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. DermNet Editor in Chief: Adjunct A/Prof Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. March 2019.
In August 2018, the US FDA (Food and Drug Administration) approved lanadelumab (trade name Takhzyro™) for the prevention of hereditary angioedema attacks in patients aged ≥ 12 years. This drug was evaluated by the FDA under Priority Review, which is reserved for medicines that represent significant improvements in safety or efficacy in treating serious conditions.
The HELP study was a multicentre, randomised, double-blind, placebo-controlled parallel-group study in 125 individuals (115 adults and ten adolescents), 12 years of age or older, with symptomatic type I or II hereditary angioedema.
Patients were randomised to receive lanadelumab in the following doses:
Before randomisation, patients ≥ 18 years of age were required to complete a 2-week long-term prophylaxis washout period. All patients then entered a 4-week run-in period to determine the baseline angioedema attack rate. Patients with ≥1 investigator-confirmed angioedema attack during the 4-week run-in period were eligible for study enrolment and randomisation. The primary efficacy endpoint was the rate of investigator-confirmed attacks during the treatment period (from Day 0 to Day 182).
The mean monthly attack rate at baseline during the run-in period was:
Results showed that subcutaneous injections every two or four weeks reduced the mean monthly number of attacks across all three lanadelumab treatment arms significantly compared with placebo (P < 0.001). At 300 mg every two weeks, lanadelumab reduced the number of mean monthly angioedema attacks by 87% compared to placebo (adjusted P < 0.001).
During the treatment period, the mean numbers of attacks per month were:
Compared with placebo, the mean differences in the attack rate per month were:
The mean reduction in hereditary angioedema attack rate was consistently higher across the lanadelumab treatment arms compared to placebo, regardless of the baseline history of prior long-term prophylaxis, laryngeal attacks, or attack rate during the run-in period.
Additional pre-defined exploratory endpoints included the percentage of patients who were attack free for the entire 26-week treatment period and the percentage of patients achieving threshold reductions in angioedema attack rates (≥ 50%, ≥ 70%, ≥ 90%) compared to baseline.
A ≥ 50% reduction in angioedema attack rate was observed in 100% of patients on lanadelumab 300 mg every 2 or 4 weeks and in 89% on lanadelumab 150 mg every four weeks compared to 32% in patients on placebo.
A ≥ 70% reduction in angioedema attack rates was observed in 89%, 76%, and 79% of patients on lanadelumab 300 mg every two weeks, 300 mg every four weeks, and 150 mg every four weeks, respectively, compared to 10% of placebo patients.
A ≥ 90% reduction in attack rates was observed in 67%, 55%, and 64% of patients on lanadelumab 300 mg every two weeks, 300 mg every four weeks, and 150 mg every four weeks, respectively, compared to 5% of placebo patients.
Compared with 2% of patients in the placebo group, the percentage of patients who were attack-free for the entire 26-week treatment period was:
There were relatively few patients in each treatment group. The study was limited to 26 weeks, and conclusions on long-term safety and efficacy cannot be made.
The Angioedema Quality of Life Questionnaire (AE-QoL) measures the patient-reported impact of angioedema over a 4-week recall period across four domains: fear/shame, functioning, fatigue/mood, and nutrition.
All treatment groups in the HELP study showed an improvement in the AE-Qol total score compared to placebo.
The percentage of patients who achieved a clinically meaningful improvement in AE-QoL total score, compared to 37% of patients in the placebo group, was:
At week 26, patients reported clinically meaningful improvement (a reduction of 6 points) across all domains in the AE-Qol total score.
The least squares mean change from baseline [SD] across all lanadelumab treatment arms vs placebo were:
The most commonly observed adverse reaction associated with lanadelumab in the HELP study was injection site reactions occurring in more than 1 in 10 patients, including injection site pain, injection site erythema, and injection site bruising.
Adverse reactions observed at a lower frequency (≥ 1/100 to < 1/10) and classified as common included:
The safety of lanadelumab was evaluated in a subgroup of 23 patients aged 12 to 17 years. Results of the subgroup analysis were consistent with the overall study results for all patients.
Treatment with lanadelumab has been associated with the development of treatment-emergent anti-drug antibodies in 11.9% of patients (10/84). All antibody titres were low and did not change the pharmacokinetic and pharmacodynamic characteristics of lanadelumab or the clinical response.
The long-term safety and efficacy of lanadelumab for prophylaxis to prevent hereditary angioedema attacks was evaluated in an open-label HELP study extension.
This study enrolled patients who completed the double-blind HELP study (‘rollover patients’; n = 109) and those who did not participate in the double-blind study (‘non-rollover patients’; n = 103), which included patients who may or may not be currently using another prophylactic therapy and who had an historical baseline attack rate of more than 1 attack every 12 weeks.
Rollover patients received a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. After that, lanadelumab was administered every two weeks.
Non-rollover patients received 300 mg lanadelumab every two weeks regardless of the first attack. All patients received their last dose on Day 350 (maximum of 26 doses), followed by a 4-week follow-up.
Interim results from the HELP Study open-label extension found treatment with lanadelumab was generally well-tolerated and consistent with the previously observed safety profile. At the time of the interim analysis, patients had been exposed to lanadelumab for a mean (SD) of 8.21 (2.17) months and continued to experience a reduction in hereditary angioedema attacks.
Hereditary angioedema is a lifelong disease that is potentially life-threatening and results in a substantial decrease in quality of life.
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