Lanadelumab (Takhzyro™): HELP Study Analysis for HAE
In August 2018, the U.S. Food and Drug Administration (FDA) granted approval to lanadelumab (trade name Takhzyro™) for the prevention of attacks of hereditary angioedema in patients aged 12 years and older. This approval was notable, as the FDA evaluated the drug under its priority review process, reserved for therapies that demonstrate significant improvements in safety or efficacy in the treatment of serious conditions.
HELP Study Details on Lanadelumab
The key study that supported this approval was the HELP trial. This was a multicenter, randomized, double-blind and placebo-controlled placebo, designed with parallel groups. It involved 125 participants (115 adults and 10 adolescents) aged 12 years or older suffering from symptomatic hereditary angioedema (HAE) type I or II.
Clinical Trial Design and Assignment
Patients were randomly assigned to receive one of the following doses of lanadelumab or placebo:
- Lanadelumab 150 mg every 4 weeks (q4w) (n = 28)
- Lanadelumab 300 mg every 4 weeks (q4w) (n = 29)
- Lanadelumab 300 mg every 2 weeks (q2w) (n = 27)
- Placebo for 26 weeks (n = 41).
Prior to randomization, participants over 18 years of age had to complete a prophylaxis washout period prophylaxis of two weeks, which involved suspending any prior prophylactic medication for HAE. Subsequently, all subjects went through a 4-week pre-enrollment period to establish their baseline angioedema attack rate baseline. Only patients who experienced one or more investigator-confirmed angioedema attacks during these 4 weeks were eligible for final enrollment.
The primary efficacy endpoint efficacy primary of the study was the rate of investigator-confirmed attacks during the total treatment period (Day 0 to Day 182).
To contextualize the treatment response, the mean monthly attack rates at study baseline, during the pre-enrollment period, were distributed among the groups as follows:
- Lanadelumab 150 mg every 4 weeks: 3.2 attacks
- Lanadelumab 300 mg every 4 weeks: 3.7 attacks
- Lanadelumab 300 mg every 2 weeks: 3.5 attacks
- Placebo: 4.0 attacks
The findings demonstrated that subcutaneous injections indurations every two or four weeks significantly reduced the monthly attack frequency for all three lanadelumab arms compared to placebo (p < 0.001). Specifically, the 300 mg every two weeks dose achieved an 87% mean reduction in monthly attacks compared to placebo (adjusted p < 0,001).
Key Efficacy Results
During the 26-week treatment period, the mean monthly attack rates recorded were:
- Lanadelumab 150 mg every 4 weeks: 0.48 attacks
- Lanadelumab 300 mg every 4 weeks: 0.53 attacks
- Landelumab 300 mg every 2 weeks: 0.26 attacks
- Placebo: 1.97 attacks.
When comparing the mean attack rates per month with the control group, the observed differences were:
- Lanadelumab 150 mg every 4 weeks: -1.49 (95% Confidence Interval [CI]: -1.90, -1.08; p < 0,001)
- Lanadelumab 300 mg every 4 weeks: -1.44 (95% CI: -1.84, -1.04; p < 0,001)
- Lanadelumab 300 mg every 2 weeks: -1.71 (95% CI: -2.09, -1.33; p < 0,001).
Efficacy proved consistent across the lanadelumab treatment groups, showing a greater reduction in the rate of hereditary angioedema attacks compared to placebo, regardless of whether the patient had previously received any long-term prophylactic therapy or presented with a history of laryngeal attacks or a specific rate during the initial evaluation period.
The HELP study also evaluated pre-defined exploratory endpoints. These included the percentage of patients who remained completely attack-free throughout the 26-week treatment period and the percentage who achieved specific attack rate reduction thresholds (≥ 50%, ≥ 70%, ≥ 90%) compared to their baseline.
A 50% or greater reduction in HAE attack rate was observed in 100% of patients treated with 300 mg lanadelumab (either every two or four weeks) and in 89% of patients treated with 150 mg every four weeks. This contrasts sharply with only 32% of patients who received placebo.
Furthermore, a 70% or greater reduction in angioedema attack rate was achieved in 89%, 76%, and 79% of patients who received…
Efficacy Results: Attack Reduction Rates and Symptom-Free Periods
Patients treated with lanadelumab showed significant reductions in the rate of angioedema attacks. Specifically, reduction rates of 90% or more in attack frequency were observed in the following groups:
- 67% of patients who received lanadelumab 300 mg every two weeks (q2w).
- 55% of patients who received lanadelumab 300 mg every four weeks (q4w).
- 64% of patients who received lanadelumab 150 mg every four weeks (q4w).
This contrasts markedly with only 5% of patients in the placebo group who achieved a similar 90% or greater reduction in angioedema attack rate. Additionally, the proportion of patients completely attack-free during the entire 26-week treatment period was notably higher with lanadelumab compared to placebo (only 2%):
- 44% in the lanadelumab 300 mg every 2 weeks group.
- 31% in the lanadelumab 300 mg every 4 weeks group.
- 39% in the lanadelumab 150 mg every 4 weeks group.
Key Study Limitations
It is crucial to consider certain restrictions in the findings of the HELP study. One limiting factor was the relatively small number of patients included in each treatment arm. Additionally, since the study was limited to a 26-week duration, it is not possible to draw definitive conclusions regarding the long-term safety and efficacy of lanadelumab.
Impact on Health-Related Quality of Life
Health-Related Quality of Life (HRQoL) was assessed using the Angioedema Quality of Life questionnaire (AE-QoL). This instrument measures the self-perception of the impact of angioedema over a 4-week period, evaluating four key domains: fear/embarrassment, functioning, fatigue/mood, and nutrition.
All lanadelumab treatment regimens in the HELP study demonstrated an overall improvement in the total AE-QoL score compared to placebo. The percentage of patients achieving a clinically meaningful improvement in total AE-QoL score consistently exceeded the 37% observed in the placebo group:
- 81% in the lanadelumab 300 mg q2w group (odds ratio vs. placebo = 7.2 [95% CI: 2.2–23.4]).
- 65% in the lanadelumab 150 mg every 4 weeks group (odds ratio vs. placebo = 3.2 [95% CI: 1.1–9.2]).
- 63% in the lanadelumab 300 mg every 4 weeks group (2.9 [95% CI: 1.1–8.1]).
At the end of week 26, patients on lanadelumab treatment reported clinically significant improvements (a reduction of 6 points or more) in all AE-QoL domains compared to baseline. Overall, and comparing to placebo at 26 weeks, lanadelumab-treated patients reported:
- Less fear and embarrassment associated with unexpected attacks (mean square change from baseline of -18.8 [SD 23.7] with lanadelumab vs. -9 [SD, 24.0] with placebo).
- Less impairment in the ability to work, socialize, and perform other physical activities (-29.3 [22.9] vs. -5.4 [22.7]).
- Less daytime fatigue and better quality of nighttime sleep (-13 [23.1] vs. -1.8 [23.3]).
- Fewer dietary restrictions (-17 [22.3] vs. -0.5 [22.5]).
Adverse Events Reported with Lanadelumab
The most frequent adverse event associated with the use of lanadelumab during the HELP study was injection site reactions. These included injection site pain, erythema (redness), and bruising in the puncture area. Such local reactions occurred in more than one in ten treated patients.
Other adverse events classified as common, observed with a lower frequency (between ≥ 1/100 and <<1>
- Hypersensitivity.
- Dizziness.
- Maculopapular (morbilliform) rash.
- Myalgia (muscle pain).
- Increased levels of alanine transaminase and aspartate transaminase.
Safety in the Pediatric Population
The safety of the drug was examined in a specific subgroup of 23 adolescent patients, aged between 12 and 17 years. The findings obtained in this group were consistent with the overall results observed across the entire study population.
Immunogenicity Assessment
Treatment with lanadelumab was associated with the development of emergent anti-drug antibodies in 10 of the 84 patients evaluated (11.9%). It is important to note that all detected antibody titers were low, and they were not observed to affect the pharmacokinetic or pharmacodynamic characteristics of lanadelumab, nor did they negatively impact the clinical response achieved.
Continuation of the HELP Study for Lanadelumab
The long-term safety and efficacy of lanadelumab, administered as continuous prophylaxis to prevent hereditary angioedema (HAE) attacks, were examined in the open-label extension of the HELP study.
This follow-up study included two patient groups: those who had completed the double-blind phase of the HELP study ("renewed patients"; n = 109) and those who had not previously participated in the double-blind study ("unrenewed patients"; n = 103). Unrenewed patients may have previously been using another prophylactic treatment and were required to have a historical rate of at least one attack every 12 weeks.
The dosing regimen varied: renewed patients received a single initial dose of 300 mg of lanadelumab on Day 0. Their second dose was administered after the first confirmed angioedema attack. Subsequently, they received lanadelumab every two weeks. On the other hand, unrenewed patients began receiving 300 mg of lanadelumab every two weeks immediately, regardless of the occurrence of an initial attack.
All participants completed treatment with their last scheduled dose on Day 350 (a maximum of 26 administrations), followed by a four-week post-therapy follow-up period.
Interim analyses of this extension confirmed that treatment with lanadelumab was generally well tolerated, maintaining a safety profile consistent with prior data. At the time of the interim analysis, patients had been exposed to lanadelumab for an average of 8.2 months (SD, 2.17), and they continued to show significant reductions in the frequency of hereditary angioedema attacks.
Future Potential of Lanadelumab in HAE Treatment
Hereditary angioedema represents a chronic and potentially serious condition that substantially impacts patients' quality of life.
- Lanadelumab presents an innovative mechanism of action that could offer significant benefits to those patients whose angioedema is not adequately controlled with existing therapies.
- The resulting decrease in attack rate, and even the potential elimination of acute episodes, translates into a reduction in anxiety and stress associated with anticipating future events. This encourages greater participation in sports, social activities, and better work productivity.
- Subcutaneous administration for prophylaxis reduces the logistical burden and complexity compared to intravenous administration regimens.
- Patient reports indicate that the ability to self-administer prophylactic therapy promotes a greater sense of control over their disease, facilitating the achievement of a more normal life and reducing the burden on caregivers.
- In regions with limited access to specialized care or "on-demand" administered therapies, a long-term prophylactic treatment like lanadelumab has the potential to be life-saving.
- It is prudent to remember that new biologic therapies often reveal long-term safety issues that were not detected during pre-approval clinical trials.
- Additional and prolonged studies are required to fully corroborate the long-term efficacy and safety profile of lanadelumab.
If you are not based in New Zealand, we suggest consulting with the national drug approval agency for more information about medicines (for example, the Australian Therapeutic Goods Administration and the US Food and Drug Administration) or a national or state-approved formulary (for example, the New Zealand Formulary and New Zealand Formulary for Children and the British National Formulary and British National Formulary for Children). Australian Therapeutic Goods Administration and and the U.S. Food and Drug Administration.) or a national or state-approved formulary (e.g., the New Zealand Formulary y , New Zealand Formulary for Children and , British National Formulary y , and British National Formulary for Children).).
