onship between TAKHZYRO and cHMWK is described by an indirect exposure-response pharmacological model. The cHMWK formation rate was maximally reduced by 53.7% with an IC50 of 5705 ng/ml.
Clinical efficacy and safety
HELP study
The HELP study was a multicenter, randomised, double-blind, placebo-controlled parallel-group study in 125 (115 adults and 10 adolescents) subjects with symptomatic type I or II HAE. Subjects were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab 150 mg every 4 weeks [q4wks], lanadelumab 300 mg every 4 weeks [q4wks], or lanadelumab 300 mg every 2 weeks [q2wks] by SC injection) for the 26-week treatment period.
The median (range) age of the study population was 42 (12 to 73) years with 88 female subjects (70%). A history of laryngeal angioedema attacks was reported in 65% (81/125) of subjects and 56% (70/125) were on prior long term prophylaxis (LTP). During the study run-in period, the mean attack rate was 3.7 attacks/month with 52% (65/125) of subjects experiencing ≥3 attacks/month.
All TAKHZYRO treatment arms produced statistically significant reductions in the mean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population (ITT) (Table 2).
Table 2. Results of primary and secondary efficacy measures-ITT population
Endpoint statisticsa
Placebo
(N=41)
Lanadelumab
150mg q4wks
(N=28)
300 mg q4wks
(N=29)
300 mg q2wks
(N=27)
Primary endpoint - Number of HAE attacks from Day 0 to 182
LS Mean (95% CI) monthly attack rateb
1.97 (1.64, 2.36)
0.48 (0.31, 0.73)
0.53 (0.36, 0.77)
0.26 (0.14, 0.46)
% Reduction relative to placebo (95% CI)c
76 (61, 85)
73 (59, 82)
87 (76, 93)
Adjusted p-valuesd
<0.001
<0.001
<0.001
Secondary endpoint - Number of HAE attacks requiring acute treatment from Day 0 to 182
LS Mean (95% CI) monthly attack rateb
1.64 (1.34, 2.00)
0.31 (0.18, 0.53)
0.42 (0.28, 0.65)
0.21 (0.11, 0.40)
% Reduction relative to placebo (95% CI)c
81 (66, 89)
74 (59, 84)
87 (75, 93)
Adjusted p-valuesd
<0.001
<0.001
<0.001
Secondary endpoint - Number of moderate or severe HAE attacks from Day 0 to 182
LS Mean (95% CI) monthly attack rateb
1.22 (0.97, 1.52)
0.36 (0.22, 0.58)
0.32 (0.20, 0.53)
0.20 (0.11, 0.39)
% Reduction relative to placebo (95% CI)c
70 (50, 83)
73 (54, 84)
83 (67, 92)
Adjusted p-valuesd
<0.001
<0.001
<0.001
Note: CI=confidence interval; LS=least squares.
a Results are from a Poisson regression model accounting for over dispersion with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and the logarithm of time in days each subject was observed during the treatment period as an offset variable in the model.
b Model-based treatment period HAE attack rate (attacks/4 weeks).
c % reduction relative to placebo corresponds to 100% * (1-rate ratio). The rate ratio is ratio of the model-based treatment period HAE attack rates.
d Adjusted p-values for multiple testing.
The mean reduction in HAE attack rate was consistently higher across the TAKHZYRO treatment arms compared to placebo regardless of the baseline history of LTP, laryngeal attacks, or attack rate during the run-in period. The percentage of subjects who were attack free is provided in Table 3.
Table 3. Percentage of subjects who were attack free through treatment
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