Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Shire Pharmaceuticals Ireland Limited, Blocks 2 & 3 Miesian Plaza, 50-58 Baggot Street Lower, Dublin 2, Ireland, Tel: +44(0)1256 894 959, E-mail: medinfoEMEA@shire.com
Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema
ATC code: B06AC05
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.
Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after SC 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.
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.
Table 2. Results of primary and secondary efficacy measures-ITT population:
| Endpoint statisticsa | Placebo (N=41) | Lanadelumab | ||
|---|---|---|---|---|
| 150 mg 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.
Table 3. Percentage of subjects who were attack free through treatment:
| Criteria | Placebo | Lanadelumab | ||
|---|---|---|---|---|
| 150 mg q4wks | 300 mg q4wks | 300 mg q2wks | ||
| 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 q2wks group, compared to 3% of patients in the placebo group.
100% of the subjects on 300 mg q2wks or q4wks and 89% on 150 mg q4wks achieved at least a 50% reduction in HAE attack rate compared to the run-in period.
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 q4 wks, 300 mg q4 wks, and 300 mg q2 wks 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:
| LS mean change (SD) from baseline at week 26 | Placebo | TAKHZYRO total |
|---|---|---|
| AE-QoL Total score | -4.7 (18.8) | -19.5 (18.6) |
| AE-QoL Total 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).
Long-term safety and efficacy of TAKHZYRO for prophylaxis to prevent HAE attacks was evaluated in an open-label HELP study extension.
A total of 212 adult and adolescent subjects with symptomatic type I or II HAE received at least one dose of lanadelumab in this study, including 109 subjects who entered as rollover subjects from the HELP study and 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 Subjects were allowed to initiate self-administration after receiving the first 2 doses from a health care professional in clinic and completing appropriate training. Interim analysis indicates that the effect was sustained up to one year of treatment.
The European Medicines Agency has deferred the obligation to submit the results of studies with TAKHZYRO in one or more subsets of the paediatric population in the prevention of hereditary angioedema attacks.
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 q2 wks 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.
Following SC administration, the time to maximum concentration is approximately 5 days. The site of SC injection (thigh, arm, or abdomen) and self-administration did not affect the absorption of lanadelumab.
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.
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.
No dedicated studies have been conducted to evaluate the pharmacokinetics of lanadelumab in special patient populations including gender, age, pregnant women or the presence of renal or hepatic impairment.
In a population pharmacokinetic analysis, after correcting for body weight, no influence of gender or age (12 to 75 years) was apparent on the clearance or volume of distribution of lanadelumab.
Although body weight was identified as an important covariate describing the variability of clearance, a 300 mg q2wks dose regimen provided sufficient exposure for the indication (see section 5.1).
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.
In repeat-dose studies evaluating once weekly SC injection in both rats (up to 28 days) and cynomolgus monkeys (up to 6 months) lanadelumab was well-tolerated at doses of up to and including 50 mg/kg (highest dose tested) with no organs of toxicity identified. Exposures in cynomolgus monkeys following 6 months of administration were approximately 23-fold greater than that noted at 300 mg q2 wks based on AUC.
Lanadelumab is not expected to interact directly with DNA or other chromosomal material, as it is made up entirely of naturally occurring amino acids and contains no inorganic or synthetic linkers or other nonprotein portions; therefore no genotoxicity evaluation has been conducted. Carcinogenicity has not been evaluated in animals as based on the weight of evidence approach, lanadelumab is considered to have a low risk for carcinogenicity.
The effects of lanadelumab on fertility were evaluated in sexually mature cynomolgus monkeys. In a 13-week study, once weekly SC administration of lanadelumab had no effects on male or female fertility at doses of 10 or 50 mg/kg (highest dose tested). Exposures in sexually mature cynomolgus monkeys in the fertility study were approximately 20-and 22-fold greater than that noted at 300 mg q2 wks based on C max and AUC, respectively.
In the ePPND study in pregnant c ynomolgus monkeys administered once weekly doses of 10 or 50 mg/kg (highest dose tested), there were no lanadelumab-related effects on pregnancy and parturition, embryo-foetal development, survival, grow th, and/or postnatal development of offspring. Exposures in the ePPND study were approximately 32-fold greater than that noted at 300 mg q2 wks based on AUC.
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