TAKHZYRO (Page 4 of 8)

14 CLINICAL STUDIES

Trial 1 (NCT02586805)

The efficacy of TAKHZYRO for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlled parallel-group study (Trial 1).

The study included 125 adult and pediatric patients (12 years of age and older) with Type I or II HAE who experienced at least one investigator-confirmed attack per 4 weeks during the run-in period. Patients were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mg q4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the 26-week treatment period. Patients ≥18 years of age were required to discontinue other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks.

Overall, 90% of patients had Type I HAE. A history of laryngeal angioedema attacks was reported in 65% of patients and 56% were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52% of patients overall.

All TAKHZYRO treatment arms produced clinically meaningful and 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) as shown in Table 3.

Table 3 Results of Primary and Secondary Efficacy Measures-ITT Population

Endpoint Statistics	Placebo(N=41)	TAKHZYRO
		150 mg q4wks(N=28)	300 mg q4wks(N=29)	300 mg q2wks(N=27)
CI=confidence interval; LS=least squares.Note: 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 patient was observed during the treatment period as an offset variable in the model.
* Primary efficacy endpoint. † Model-based treatment period HAE attack rate (attacks/4 weeks). ‡ Calculated as the ratio of the model-based treatment period HAE attack rates (lanadelumab/placebo) minus 1 multiplied by 100. § Adjusted p-values for multiple testing.
Number of HAE Attacks from Day 0 to 182*
LS Mean (95% CI) monthly attack rate †	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)‡		76(61, 85)	73(59, 82)	87(76, 93)
Adjusted p-values §		<0.001	<0.001	<0.001
Number of HAE Attacks Requiring Acute Treatment from Day 0 to 182
LS Mean (95% CI) monthly attack rate †	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)‡		81(66, 89)	74(59, 84)	87(75, 93)
Adjusted p-values §		<0.001	<0.001	<0.001
Number of Moderate or Severe HAE Attacks from Day 0 to 182
LS Mean (95% CI) monthly attack rate †	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)‡		70(50, 83)	73(54, 84)	83(67, 92)
Adjusted p-values §		<0.001	<0.001	<0.001

The mean reduction in HAE attack rate was consistently higher across the TAKHZYRO 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 (≥50%, ≥70%, ≥90%) reductions in HAE attack rates compared to run-in during the 26-week treatment period. A ≥50% reduction in HAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wks compared to 32% of placebo patients. A ≥70% reduction in HAE attack rates was observed in 89%, 76%, and 79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% of placebo patients. A ≥90% reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 5% of placebo patients.

The percentage of attack-free patients for the entire 26-week treatment period was 44%, 31%, and 39% in the TAKHZYRO 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% of placebo patients.

Trial 2 (NCT02741596)

Patients who completed Trial 1 were eligible to rollover into an open-label extension study. Rollover patients, regardless of randomization group in Trial 1, received a single dose of TAKHZYRO 300 mg at study entry and were followed until the first HAE attack occurred. All efficacy endpoints were exploratory in this uncontrolled, unblinded study. At week 4 post-dose, approximately 80% of patients who had been in the 300 mg q2wks treatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received open-label treatment with TAKHZYRO 300 mg q2wks.