Key clinical-trial evidence for lanadelumab

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.


Introduction

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.

HELP Study

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.

Study design

Patients were randomised to receive lanadelumab in the following doses:

  • Lanadelumab 150 mg every 4 weeks (n=28)
  • Lanadelumab 300 mg every 4 weeks (n=29)
  • Lanadelumab 300 mg every 2 weeks (n=27)
  • Placebo (n=41) for 26 weeks.

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:

  • 3.2 (lanadelumab 150 mg every four weeks)
  • 3.7 (lanadelumab 300 mg every four weeks)
  • 3.5 (lanadelumab 300 mg every two weeks).
  • 4 (placebo).

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:

  • 0.48 (lanadelumab 150 mg every four weeks)
  • 0.53 (lanadelumab 300 mg every four weeks)
  • 0.26 (lanadelumab 300 mg every two weeks)
  • 1.97 (placebo group).

Compared with placebo, the mean differences in the attack rate per month were:

  • -1.49 (95% CI, -1.90 to -1.08; P < 0.001)
  • -1.44 (95% CI, -1.84 to -1.04; P <0 .001)
  • -1.71 (95% CI, -2.09 to -1.33; P <0 .001).

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:

  • 44% in the lanadelumab 300 mg (q2wks) group
  • 31% in the 300 mg (q4wks) group
  • 39% in the 150 mg (q4wks) group.

Study limitations

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.

Health-related Quality of Life (HELP Study)

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:

  • 65% (odds ratio vs placebo = 3.2 [95% CI 1.1, 9.2]) in the lanadelumab 150 mg (q4wks) group
  • 63% (2.9 [1.1, 8.1]) in the lanadelumab 300 mg (q4wks) group
  • 81% (7.2 [2.2, 23.4]) in the lanadelumab 300 mg (q2wks) group.

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:

  • Less fear and shame about unpredictable attacks (-18.8 [23.7] with lanadelumab vs -9 [24.0] with placebo)
  • Less impairment in their ability to work, socialise and perform other physical activities (-29.3 [22.9] vs -5.4 [22.7] )
  • Reduced fatigue during the day and better sleep at night (-13 [23.1] vs -1.8 [23.3])
  • Fewer restrictions in food and drink (-17 [22.3] vs -0.5 [22.5]).

Adverse events (HELP Study)

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:

Children

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.

Immunogenicity

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.

HELP study extension

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.

What is the future potential for lanadelumab?

Hereditary angioedema is a lifelong disease that is potentially life-threatening and results in a substantial decrease in quality of life.

  • Lanadelumab has a novel mechanism of action and may be of benefit to patients whose angioedema is not optimally controlled by other medicines.
  • The decrease in attack rate — and, in some cases, the virtual elimination of acute attacks — is likely to decrease anxiety and stress about future attacks, and allow for increased freedom for patients participating in sports or social activities, and increased productivity at work.
  • Subcutaneous treatment for prophylaxis may decrease the burden and complexity of administration compared to intravenous administration.
  • Patients report that the ability to self-administer therapy may lead to increased feelings of control over the disease, a greater ability to lead a normal life, and a decreased burden on caregivers.
  • In areas where access to healthcare or access to on-demand therapy is limited, long-term prophylactic therapy could potentially be life-saving.
  • Note that new biological therapies are frequently found to have safety concerns long after they have been introduced into the market that were not detected in pre-approval trials.
  • Further trials are needed to confirm the long term efficacy and safety of lanadelumab.
New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

 

Related information

 

References

  • Maurer M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the management of hereditary angioedema — the 2017 revision and update. Allergy 2018; 73: 1575–96. PubMed
  • Banerji A, Busse P, Shennak M, et al. Inhibiting plasma kallikrein for hereditary angioedema prophylaxis. N Engl J Med 2017; 376: 717–28. PubMed
  • Riedl MA, Tachdjian R, Schranz J, et al. Consistent lanadelumab treatment effect in patients with hereditary angioedema (HAE) regardless of baseline attack frequency in the phase 3 HELP study. J Allergy Clin Immunol 2018; 141 (Suppl 2): AB47. Journal
  • Riedl MA, Bernstein JA, Craig T, et al. An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy 2017; 7: 36. https://doi.org/10.1186/s13601-017-0172-9. PubMed
  • Banerji A, Riedl MA, Bernstein JA, Cicardi M, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA 2018; 320: 2108–2121. PubMed
  • Lumry WR, Weller K, Magerl M, et al. Lanadelumab markedly improves health-related quality of life in hereditary angioedema patients in the HELP study [abstract no. 152]. J Allergy Clin Immunol 2018; 141(2 Suppl): AB47. Journal

On DermNet NZ

Other websites

  • Lanadelumab — US FDA prescribing information PDF [accessed January 2019]
  • Lanadelumab — Medscape data sheet
  • Lanadelumab — Product monograph Canada PDF {accessed February 2019]
  • The international WAO/EAACI guideline for the management of hereditary angioedema — 2017 revision and update. Allergy 2018; 73: 1575–96. PubMed
  • Zuraw BL, Banerji A, Bernstein JA, et al. US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract 2013; 1: 458–67. PubMed

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