Lanadelumab (1) – Takhzyro®

• Clinical trials
  • The randomised, double-blind, placebo-controlled Phase III HELP trial is used for the benefit assessment.

Patients aged 12 years and over with recurrent attacks of hereditary angioedema (HAE)

• mortality
  • No deaths occurred in the HELP trial.
• Morbidity – HAE attacks
  • The figure shows the total number of confirmed HAE attacks during the treatment phase (day 0 to day 182) as the attack rate per month; in addition, the number of confirmed moderate to severe HAE attacks, the number of confirmed laryngeal attacks and the number of confirmed HAE attacks leading to a visit to A&E or hospital admission were also recorded.
  • The monthly attack rate in the two lanadelumab arms (300 mg every 2 weeks and every 4 weeks, respectively) was 0.3 and 0.6 on average; in the placebo arm, the average monthly rate was 2.5.
  • With regard to moderate to severe HAE attacks, the mean monthly attack rate in the two lanadelumab arms (300 mg every 2 weeks and every 4 weeks, respectively) 0.2 and 0.4 respectively; in the placebo arm, the mean rate per month was 1.4.
  • Statistically significant differences in favour of treatment with lanadelumab were observed in both dosage arms (300 mg every 2 weeks and every 4 weeks, respectively) compared with placebo treatment in terms of the number of HAE attacks (rate ratio [95% CI]: 0.1 [0.1 to 0.2]; p < 0.001 and 0.3 [0.2 to 0.4]; p < 0.001) and the number of moderate to severe HAE attacks (rate ratio [95% CI]: 0.2 [0.1 to 0.3]; p < 0.001 and 0.3 [0.2 to 0.5]; p < 0.001, respectively).
  • Serious HAE attacks, defined as laryngeal attacks or HAE attacks leading to a visit to A&E or hospital admission, occurred rarely or not at all during the study. No statistically significant difference between lanadelumab and placebo was demonstrated for either endpoint.
  • The median time to the first attack was 59 days and 28 days, respectively, in the lanadelumab arms (300 mg every 2 weeks and every 4 weeks, respectively) and 8 days in the control arm.
  • Statistically significant differences in favour of treatment with lanadelumab were observed in both dosage arms (300 mg every 2 weeks and every 4 weeks, respectively) compared with placebo treatment (HR [95% CI]: 0.3 [0.1 to 0.5]; p < 0.001 and 0.4 [0.2 to 0.7]; p < 0.001, respectively).
  • In the lanadelumab arms (300 mg every 2 weeks and every 4 weeks, respectively), 12 (44.4 per cent) and 9 (31 per cent) patients, respectively, achieved freedom from attacks; in the control arm, this figure was 1 patient.
  • Statistically significant differences were observed in favour of treatment with lanadelumab in both dosage arms (300 mg every 2 weeks and every 4 weeks, respectively) compared with placebo treatment (RR [95% CI]: 18.2 [2.5 to 132.2]; p < 0.001 and 12.7 [1.7 to 95.0]; p = 0.001, respectively).
• Quality of life – AE-QoL
  • In the two lanadelumab arms (300 mg every 2 weeks and every 4 weeks, respectively), the AE-QoL score decreased by an average of 20.9 and 18 points, respectively, from Day 0 to Day 182; whilst in the placebo arm the mean reduction was 3.8 points.
  • The differences are statistically significant in favour of treatment with lanadelumab in both dosage arms (300 mg every 2 weeks and every 4 weeks, respectively) compared with placebo treatment (mean difference [95% CI]: –16.6 [–28.5 to –4.6]; p = 0.0025 and –12.7 [–24.5 to –0.8]; p = 0.0315, respectively).
  • Hedges’ g in the lanadelumab treatment arm at a dose of 300 mg every 2 weeks exceeds the irrelevance threshold of 0.2, meaning that the effect reaches a clinically relevant extent. In the 300 mg every 4 weeks treatment arm, however, the lower limit of the confidence interval for Hedges’ g does not lie outside the irrelevance threshold.
  • Based on the responder analyses with an MCID of 6 points in the total score, the proportion of patients showing a response in the lanadelumab treatment arms was 80.8% and 63% respectively, and thus statistically significantly higher than the 36.8% in the placebo arm (RR [95% CI]: 2.2 [1.4 to 3.5]; p = 0.0008 and 1.7 [1.0 to 2.8]; p = 0.0383, respectively).
  • A statistically significant and, according to Hedges’ g, clinically relevant advantage over placebo was also observed for lanadelumab in the ‘Function’ domain for both treatment arms; with the reduction in score from Day 0 to Day 182 averaging 35.4 and 24.3 points respectively, compared with 4.7 points in the placebo arm (mean difference [95% CI]: –30.6 [–45.1 to 16.0]; p < 0.0001 and –18.9 [–33.2 to –4.5]; p = 0.0046).
  • The results in the nutrition domain – a reduction of 15.9 points on average from Day 0 to Day 182, compared with a reduction of 2 points – are also statistically significant for the lanadelumab 300 mg every 2 weeks treatment arm (mean difference [95% CI]: –18.5 [–33.0 to –4.1]; p = 0.0059). According to Hedges’ g, a clinically relevant difference is observed for the lanadelumab 300 mg every 2 weeks treatment arm in the nutrition domain.
  • No statistically significant difference was observed between the treatment groups in the AE-QoL domains of fatigue/mood and anxiety/shame.
• Side effects
  • Overall, the incidence of adverse events (AEs) was similar across all treatment arms.
  • Severe AEs occurred in 8 out of 56 patients (14.3 per cent) in the two lanadelumab arms during the treatment phase; in the placebo arm, 4 out of 41 patients (9.8 per cent) experienced severe AEs.
  • Serious AEs, however, occurred in 4 out of 56 patients treated with lanadelumab (4.8 per cent) and in no patients in the placebo arm.
  • No significant differences were observed between the treatment groups with regard to side effects.
• Overall assessment / Conclusion
  • To assess the extent of the additional benefit of lanadelumab for patients aged 12 years and over with recurrent attacks of hereditary angioedema (HAE), the overall results from the randomised, double-blind, placebo-controlled Phase III HELP trial are available regarding mortality, morbidity, quality of life and side effects from the randomised, double-blind, placebo-controlled Phase III HELP trial.
  • Within the HELP trial, the use of long-term prophylaxis (with C1 inhibitors) was not permitted; the use of C1 inhibitors was only permitted as acute treatment for HAE attacks. Patients in the control arm of the trial who were receiving long-term prophylaxis prior to the start of the trial (approximately half of the patients) had to discontinue this treatment before enrolment. It can be assumed that these patients did not receive prophylaxis for their HAE that met the current standard of care during the HELP study.
  • No deaths occurred in the HELP study.

Courtesy translation only, please refer to the German original.