Introduction The HELP study HELP study extension Future potential
In August 2018, the US Food and Drug Administration (FDA) approved lanadelumab (brand name Takhzyro™) for the prevention of hereditary angioedema attacks in patients aged ≥ 12 years. This drug was evaluated by the FDA under its 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 10 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 and older were required to complete a 2-week long-term prophylaxis washout period (discontinuing any medicines used to prevent angioedema). All patients then entered a 4-week run-in period prior to enrolment in the study to determine the baseline angioedema attack rate. Patients with one or more 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 rates for the different treatment arms at baseline during the run-in period were:
Results showed that subcutaneous injections every 2 or 4 weeks reduced the mean monthly number of attacks across all three lanadelumab treatment arms significantly compared with placebo (p < 0.001). At 300 mg q2w, lanadelumab reduced the mean number of angioedema attacks per month by 87% compared with 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 with 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 in the HELP study included the percentage of patients who were attack-free for the entire 26-week treatment period and the percentage of patients who achieved threshold reductions in angioedema attack rates (≥ 50%, ≥ 70%, ≥ 90%) compared to baseline.
A 50% or greater reduction in angioedema attack rate was observed in 100% of patients on lanadelumab 300 mg q2w or q4w and in 89% of patients on lanadelumab 150 mg q4w compared with 32% in patients on placebo.
A 70% or greater reduction in angioedema attack rate was observed in 89%, 76%, and 79% of patients on lanadelumab 300 mg q2w, 300 mg q4w, and 150 mg q4w, respectively, compared with 10% of patients on placebo.
A 90% or greater reduction in angioedema attack rate was observed in 67%, 55%, and 64% of patients on lanadelumab 300 mg q2w, 300 mg q4w, and 150 mg q4w, respectively, compared with 5% of patients on placebo.
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 HELP 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 with placebo.
The percentage of patients who achieved clinically meaningful improvement in AE-QoL total score compared with 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. Across all lanadelumab treatment arms versus placebo at 26 weeks, patients reported:
The most commonly observed adverse reaction associated with lanadelumab in the HELP study was injection site reactions, including injection site pain, injection site erythema, and injection site bruising. These injection site reactions occurred in more than one in 10 patients.
Other adverse reactions observed at a lower frequency (≥ 1/100 to < 1/10) with lanadelumab and classified as common included:
The safety of lanadelumab was evaluated in a subgroup of 23 patients aged 12–17 years. The results of this subgroup analysis were consistent with the overall study results for all patients.
Treatment with lanadelumab was associated with the development of treatment-emergent anti-drug antibodies in 10 out of 84 patients (11.9%). 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 both patients who completed the double-blind HELP study (‘rollover patients’; n = 109) and patients who did not participate in the double-blind study, which included patients who may or may not have been currently using another prophylactic therapy and who had an historical baseline attack rate of more than one attack every 12 weeks ('non-rollover patients'; n = 103).
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 2 weeks.
Non-rollover patients received lanadelumab 300 mg q2w 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 its previously observed safety profile. At the time of the interim analysis, patients had been exposed to lanadelumab for a mean of 8.21 (SD, 2.17) months and continued to experience a reduction in hereditary angioedema attacks.
Hereditary angioedema is a potential life-threatening lifelong disease that results in a substantial decrease in quality of life.
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We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).
