Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATC code: B06AC05.

Mechanism of action

Lanadelumab is a fully human, monoclonal antibody (IgG1/ κ-light chain). Lanadelumab inhibits active plasma kallikrein proteolytic activity. Increased plasma kallikrein activity leads to angioedema attacks in patients with HAE through the proteolysis of high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin. Lanadelumab provides sustained control of plasma kallikrein activity and thereby limits bradykinin generation in patients with HAE.

Pharmacodynamic effects

In adult and adolescent (12 to less than 18 years of age) patients, concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of TAKHZYRO 150 mg every 4 weeks, 300 mg every 4 weeks or 300 mg every 2 weeks in subjects with HAE.

The PK-PD relationship 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.
For children aged 2 to less than 6 years (150 mg every 4 weeks) and 6 to less than 12 years (150 mg every 2 weeks), the observed mean percent change from baseline in cHMWK levels was similar to that observed in adult and adolescent (12 to less than 18 years of age) patients.

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 randomised 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, lanadelumab 300 mg every 4 weeks or lanadelumab 300 mg every 2 weeks by subcutaneous 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 Lanadelumab
Placebo        150mg          300 mg         300 mg
Endpoint statisticsa                              every          every          every (N=41)
4 weeks        4 weeks        2 weeks
(N=28)         (N=29)         (N=27)
Primary endpoint - Number of HAE attacks from Day 0 to 182
LS Mean (95% CI) monthly attack         1.97 (1.64,     0.48 (0.31,    0.53 (0.36,    0.26 (0.14, rateb                                      2.36)           0.73)          0.77)          0.46) % Reduction relative to placebo                         76 (61, 85)   73 (59, 82)     87 (76, 93) (95% CI)c
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         1.64 (1.34,     0.31 (0.18,    0.42 (0.28,    0.21 (0.11, rateb                                      2.00)           0.53)          0.65)          0.40) % Reduction relative to placebo                         81 (66, 89)   74 (59, 84)     87 (75, 93) (95% CI)c
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         1.22 (0.97,     0.36 (0.22,    0.32 (0.20,    0.20 (0.11, rateb                                      1.52)           0.58)          0.53)          0.39) % Reduction relative to placebo                         70 (50, 83)   73 (54, 84)     83 (67, 92) (95% CI)c
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 
Lanadelumab

Criteria                  Placebo         150 mg           300 mg         300 mg every            every          every
4 weeks          4 weeks        2 weeks
Treatment period (Day 0 to Day 182, 26 weeks)
N                         41              28                29            27 Attack free                      2%             39%              31%            44% 
The percentage of patients who were attack free for the last 16-weeks (Day 70 to Day 182) of the study was 77% in the 300 mg every 2 weeks group, compared to 3% of patients in the placebo group.

100% of the subjects on 300 mg every 2 weeks or every 4 weeks and 89% on 150 mg every 4 weeks achieved at least a 50% reduction in HAE attack rate compared to the run-in period.

Health related quality of life

All TAKHZYRO treatment groups observed an improvement in Angioedema Quality of Life Questionnaire (AE-QoL) total and domain (functioning, fatigue/mood, fear/shame, and nutrition) scores compared to the placebo group; the largest improvement was observed in the functioning score as shown in Table 4. A reduction of 6 points is considered a clinically meaningful improvement. The percentage of patients who achieved a clinically meaningful improvement in AE-QoL total score was 65% (Odds ratio vs placebo, [95% CI]= 3.2 [1.1, 9.2]), 63% (2.9 [1.1, 8.1]), and 81% (7.2 [2.2, 23.4]), in TAKHZYRO 150 mg every 4 weeks, 300 mg every 4 weeks, and 300 mg every 2 weeks groups, respectively, compared to 37% of patients in the placebo group.

Table 4. Change in AE-QoL scorea - placebo vs TAKHZYRO at week 26 in HELP study 
TAKHZYRO
LS mean change (SD) from baseline at week 26                           Placebo total

AE-QoL Total score                                                    -4.7 (18.8)       -19.5 (18.6) 
Functioning score                                                     -5.4 (22.7)       -29.3 (22.9) 
Fatigue/Mood score                                                    -1.8 (23.3)       -13.0 (23.1) 
Fear/Shame score                                                      -9.0 (24.0)       -18.8 (23.7) 
Nutrition score                                                       0.5 (22.5)        -17.0 (22.3) 
Note: AE-QoL= Angioedema Quality of Life; LS=least squares; SD=standard deviation.
a
Lower scores indicate lower impairment (or better health-related quality of life).



HELP study extension
Long-term safety and efficacy, pharmacokinetics (PK), and impact on health-related quality of life (HRQoL) of TAKHZYRO for prophylaxis to prevent HAE attacks were evaluated in an open-label uncontrolled HELP study extension.

A total of 212 adult and adolescent (≥ 12 years) subjects with symptomatic type I or II HAE received at least one dose of lanadelumab 300 mg every 2 weeks in this study, including 109 subjects who entered as rollover subjects from the HELP study. Rollover subjects, regardless of randomisation group in the HELP Study, received a single dose of lanadelumab 300 mg at study entry and did not receive additional treatment until the occurrence of an HAE attack. After the first HAE attack, all subjects received open-label treatment with lanadelumab 300 mg every 2 weeks. The study also included 103 new or non-rollover subjects (including 19 subjects from Phase1b study) who had an historical baseline attack rate of ≥1 attack per 12 weeks. The non-rollover subjects received lanadelumab 300 mg every 2 weeks at study entry. Subjects were allowed to initiate self-administration after receiving the first 2 doses from a health care professional in clinic and completing appropriate training.

The majority of subjects (173/212; 81.6%) who were treated in this study completed at least 30 months of treatment (either as a rollover or non-rollover subjects). The mean (SD) time in the HELP study extension was 29.6 (8.20) months. The majority of subjects self-administered lanadelumab (60.6% of 8,018 injections).

There was a sustained reduction in attack rates compared to baseline during the HELP study extension, with a similar response to TAKHZYRO observed in both rollover (92.4%) and non-rollover groups (82.0%) and an overall reduction rate of 87.4%. Though the magnitude of the attack rate reduction in the HELP study limited the potential for further reductions in the HELP extension study, mean attack rates for the rollover subjects decreased further at the time of the final analysis and ranged from 0.08 to 0.26 attacks per month. In addition, the mean (SD) percentage of attack-free days was 97.7 (6.0)% and the mean (SD) duration of the attack-free period was 415.0 (346.1) days. The proportion of patients with a maximum attack-free period of 6 months or more or 12 months or more was 81.8% and 68.9%, respectively.

Paediatric population

SPRING study
The safety and efficacy of TAKHZYRO for prophylaxis to prevent HAE attacks in children were evaluated in an open-label, multicenter, Phase 3 SPRING study. Dosing regimens were based on the following pre-defined age groups: children from 2 to less than 6 years of age were to receive lanadelumab 150 mg every 4 weeks and children from 6 to less than 12 years of age were to receive lanadelumab 150 mg every 2 weeks. The overall treatment period was 52 weeks, equally divided into Treatment Period A and B. The study enrolled 21 paediatric subjects who had a baseline attack rate of ≥ 1 attack per 3 months (12 weeks) and a confirmed diagnosis of type I or II HAE.

In Treatment Period A, subjects aged 2 to < 6 years (n=4) and 6 to < 12 years (n=17) received lanadelumab 150 mg every 4 weeks and 150 mg every 2 weeks, respectively. The youngest patient included in the study was 3.5 years old.

In Treatment Period B, subjects receiving lanadelumab 150 mg every 2 weeks (i.e., subjects 6 to less than 12 years of age) could reduce dosing to 150 mg every 4 weeks if they were well-controlled (e.g., attack free) for 26 weeks with lanadelumab treatment. Seven subjects in the 6 to less than 12 years age group switched to 150 mg every 4 weeks during Treatment Period B, and one subject (enrolled in the 2 to less than 6 years age group) turned 6 years of age during Treatment Period A and switched to
150 mg every 2 weeks during Treatment Period B after experiencing recurrent attacks.



The total exposure was 5.5 patient-years in the “every 4 weeks”- dosing regimen group (age range 3.5- 10.4 years) and 14.47 patient-years in the “every 2 weeks”-dosing regimen group (age range 6- 10.9 years).

The TAKHZYRO dose regimen in both age groups produced reduction in mean HAE attack rate compared to baseline and an increased percentage of attack-free subjects in Treatment Period A (Table 5). Similar results were observed for the overall, 52-week treatment period.

Table 5. Results of efficacy measures
TAKHZYRO
Criteria                                     150 mg                 150 mg Total every 4 weeksa         every 2 weeksa

Treatment Period A (26 weeks)

N                                                 4                     17           21 Baseline attack rate, mean (SD)               1.9 (1.0)             1.8 (1.6)     1.8 (1.5) b
Attack rate (attacks/month ),
0.2 (0.3)             0.1 (0.2)     0.1 (0.2) mean (SD)
Attack-free subjects N (%)                    3 (75.0)              14 (82.4)     17 (81.0) a
The actual treatment received during the given study period.
b
Month is defined as 28 days. Calculated over the 26-week treatment period.

Immunogenicity

Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.

Pharmacokinetic Properties

5.2        Pharmacokinetic properties
The single and multiple dose pharmacokinetics of lanadelumab have been studied in patients with HAE. Pharmacokinetics of lanadelumab showed linear dose-exposure response with doses up to 400 mg and reproducible exposure following subcutaneous administration up to 12 months. The absolute bioavailability of lanadelumab after subcutaneous administration has not been determined. In the HELP study, patients treated with 300 mg every2 weeks presented mean (SD) area under the curve over the dosing interval at steady-state (AUCtau,ss), maximum concentration at steady-state (Cmax,ss) and minimum concentration at steady-state (Cmin,ss) of 408 µg*day/ml (138), 34.4 µg/ml (11.2), and 25.4 µg/ml (9.18), respectively. The anticipated time to reach steady state concentration was approximately 70 days.

Absorption

Following subcutaneous administration, the time to maximum concentration is approximately 5 days.
The site of subcutaneous injection (thigh, arm, or abdomen) and self-administration did not affect the absorption of lanadelumab.

Distribution

The mean (SD) volume of distribution of lanadelumab in patients with HAE is 14.5 litres (4.53).
Lanadelumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.
Elimination

Lanadelumab has a mean (SD) total body clearance of 0.0297 L/h (0.0124) and a terminal elimination half-life of approximately 14 days.

Special populations

No dedicated studies have been conducted to evaluate the pharmacokinetics of lanadelumab in special patient populations including gender, or pregnant women.

Population pharmacokinetic analyses, showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution of lanadelumab.


Paediatric population
Following subcutaneous administration of 150 mg every 4 weeks (2 to less than 6 years of age) and 150 mg every 2 weeks (6 to less than 12 years of age), the overall exposure (i.e., Cavg,ss) to lanadelumab was similar compared with adult and adolescent (12 to less than 18 years of age) patients who received TAKHZYRO 300 mg every 2 weeks (ratio to adults ranged from 0.8 to 1.11).

Renal and hepatic impairment

As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of lanadelumab.

Accordingly, in a population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 ml/min/1.73 m2 [mild, N=98] and 30 to 59 ml/min/1.73m2 [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab.