Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: CSL Behring GmbH, Emil-von-Behring-Strasse 76, D-35041 Marburg, Germany
Pharmacotherapeutic group: Drugs used in hereditary angioedema
ATC code: B06AC07
Garadacimab is a fully human IgG4/lambda recombinant monoclonal antibody which binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. The inhibition of FXIIa, the first factor activated in the contact system, prevents HAE attacks by blocking the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks.
Concentration-dependent inhibition of FXIIa-mediated kallikrein activity was demonstrated after subcutaneous administration of ANDEMBRY once monthly in patients with HAE.
The efficacy of ANDEMBRY for the routine prevention of recurrent attacks of hereditary angioedema in adult and adolescent patients 12 years of age and older with Type I or II HAE was studied in a phase 3, multicenter, randomised, double-blind, placebo-controlled parallel group study.
The study contained 64 patients aged 12 years and older including 58 adult and 6 pediatric patients who experienced at least 2 attacks during the up to 2-month run-in period. Patients were randomised into 2 parallel treatment arms in a 3:2 ratio (garadacimab 200 mg monthly after an initial 400 mg loading dose or volume-match placebo) for a 6-month treatment period. Patients were required to discontinue other prophylactic HAE treatment prior to entering the study. All patients were allowed to use on-demand medications for treatment of HAE attacks during the study.
Overall, 87.5% of patients had Type I HAE. A family history of HAE was reported for 89.1%, a history of laryngeal edema attacks for 59.4% of patients and 32.8% were on prior prophylactic HAE treatments. During the study run-in period, attack rates of ≥3 attacks/month were observed in 59.4% of patients overall. Mean baseline number of attacks per month was 3.07 in the ANDEMBRY group compared to 2.52 in the placebo group.
The primary efficacy endpoint was the time-normalised number of HAE attacks from day 1 through the end of the 6-month treatment period. The key secondary endpoints were: the percent reduction in the mean time-normalised number of HAE attacks, the number of subjects who were attack free from day 1 through the end of the first 3-months the percent of subjects with good or excellent responses to the SGART from day 1 through the end of the 6-month treatment period.
Table 2. Results of key primary and secondary efficacy measures (ITT analysis set):
| ANDEMBRY 200 mg (N=39) | Placebo (N=25) | |
|---|---|---|
| Number of evaluable patients, n | 39 | 24a |
| Primary endpoint | ||
| Total number of HAE attacks from Day 1 to 182 | 63 | 264 |
| Time-normalised number of HAE attacks from Day 1 to 182 | ||
| Mean (95% CI) | 0.27 (0.05, 0.49) | 2.01 (1.44, 2.57) |
| P-value* | <0.001 | |
| Adjusted LS meanb (95% CI) | 0.22 (0.11, 0.47) | 2.07 (1.49, 2.87) |
| Secondary endpoints | ||
| Percent reduction in time-normalised number of HAE attacks relative to placeboc | ||
| Mean (95% CI) | 86.51 (57.84, 95.68) | |
| P-value* | <0.001 | |
| Percent (number) of subjects who were attack free from day 1 through the end of month 3 | 71.79 (28) | 8.33 (2) |
| P-value* | <0.001 | |
| Percent (number) of subjects with good or excellent response to SGART at day 182 | 82 (31) | 33 (8) |
| P-value* | <0.001 | |
HAE – hereditary angioedema; ITT – intent to treat; N – number of patients in the ITT analysis set; LS – least squares; CI – confidence interval; SGART – Subjects Global Assessment of Response to Therapy
a One patient had a treatment period of less than 30 Days and was therefore not included in the analysis
b After adjusting for baseline attack rate
c Median percent reduction for this endpoint was 100
* A hierarchical testing procedure controls for the overall alpha level of 5% (2-sided)
Additional non-hierarchically tested secondary endpoints from day 1 to 182 were the mean (median) time-normalised number of HAE attacks requiring on-demand treatment, 0.23 (0.0) in subjects treated with ANDEMBRY compared to 1.86 (1.35) in the placebo group, and the mean (median) time-normalised number of moderate to severe HAE attacks, 0.13 (0.0) in subjects treated with ANDEMBRY compared to 1.35 (0.83) in the placebo group.
The exploratory endpoint of Angioedema Quality of Life Questionnaire (AE-QoL) total and domain (functioning, fatigue/mood, fear/shame, and nutrition) scores, compared to the placebo at day 182 (Table 3) showed improvement in the ANDEMBRY treated patients. A reduction of six points in the AE-QoL has been defined as the minimal clinically important difference (MCID). Changes from baseline greater than the MCID were observed in 88% of patients treated with ANDEMBRY.
Table 3. AE-QoL total score and domains change from baseline to day 182 (ITT analysis set)a:
| AE-QoL total score and domains change from baseline to day 182b, mean (SD) | ANDEMBRY 200 mg (N=39) | Placebo (N=25) |
|---|---|---|
| Patients Included in the Analysis, n | 33 | 20 |
| Total Score | -26.5 (17.9) | -2.2 (19.1) |
| Functioning | -35.8 (23.2) | 1.9 (29.6) |
| Fatigue/Mood | -21.1 (22.9) | -5.8 (27.1) |
| Fears/Shame | -28.0 (24.1) | -2.5 (18.6) |
| Nutrition: | -16.7 (23.3) | -0.6 (16.5) |
ITT = intention-to-treat; N = number of patients in the ITT Analysis Set; SD = standard deviation.
a Angioedema Quality of Life is only answered by patients of age ≥18 years.
b A lower AE-QoL score represents greater improvement
The efficacy profile in pediatric patients 12 years of age and older (n=6) was consistent with that of the overall population.
Patients who completed VANGUARD (n=57) in addition to patients from a phase 2 study (n=35) rolled over into the VANGUARD open-label extension study which also enrolled 69 new patients. From the start of treatment through 16.7 months (median duration of exposure 9.49 months) 96/161 (59.6%) patients remained attack-free. The safety and efficacy profile in adolescent patients ages 12 years and older (n=10) was consistent with that of the overall population.
Normal C1-INH HAE includes patients with known or unknown mutations. The safety and efficacy of garadacimab was evaluated in 6 patients with known mutations: HAE-FXII (n=3) or HAE-PLG (plasminogen) (n=3) in the phase 2 study 2001.
Among the three genetically confirmed HAE-FXII patients enrolled, one withdrew during the second month of the treatment period due to lack of efficacy after showing a reduction in overall attack rate from 4.35 to 3.51 attacks per month and a reduction in severe attacks from 1.09 to 0.58 attacks per month. The remaining two patients completed the initial 12-week treatment period, with one demonstrating a reduction in attack rate from 3.24 to 0.36 attacks per month and the other becoming attack-free from an initial attack rate of 3.20 attacks per month. Both patients continued garadacimab for the duration of the second treatment period of 20 and 17 months, after which both patients rolled over into the phase 3 extension study and received garadacimab for an additional 18 months and remained attack free.
Additionally, the 3 patients with HAE-PLG completed the initial 12-week treatment period and did not continue into the treatment extension period. One patient reported a decrease in their monthly overall attack rate to 1.75 and a severe attack rate to 0.35 during the treatment period, compared to 3.20 and 1.60, respectively, during the run-in period. The remaining two patients reported an increase in their monthly attack rates to 6.8 and 3.17 during the treatment period compared to 2.28 and 1.45 during the run-in period respectively. None of the reported attacks was classified as severe attack.
Overall, the safety profile of garadacimab in patients with nC1-INH was similar to that observed in patients with HAE-C1-INH.
Treatment with ANDEMBRY has been associated with development of low-titer treatment emergent anti-drug antibodies (ADA) in 2.9% (5/172) of treated subjects. Due to the low titer of ADA registered in these subjects, neutralizing antibodies could not be detected. However, although the clinical relevance of ADA could not be fully established, available data indicate that there was no apparent impact of the presence of ADA on safety or efficacy.
The European Medicines Agency has deferred the obligation to submit the results of studies with ANDEMBRY in one or more subsets of the paediatric population in the prevention of hereditary angioedema attacks (see section 4.2 for information on paediatric use).
In the VANGUARD pivotal trial, patients treated with 200 mg garadacimab subcutaneous once monthly 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 10300 (3380) mcg∙h/mL, 21.2 (6.58) mcg/mL, and 9.30 (3.73) mcg/mL, respectively. Steady-state exposure of garadacimab was achieved after the initial subcutaneous administration of loading dose of 400 mg (2 doses of 200 mg).
Following subcutaneous administration, the time to maximum concentration is approximately 6 days. The site of subcutaneous injection (thigh, arm, or abdomen) did not affect the absorption of garadacimab. The absorption rate of garadacimab was 0.00824/h. The mean absolute bioavailability of garadacimab in HAE patients was 39.5% on the basis of the population pharmacokinetic analysis.
The mean (SD) apparent volume of distribution of garadacimab in patients with HAE was 7.42 litres (4.20). Garadacimab is a monoclonal antibody and is not expected to bind to plasma proteins.
Similar to other monoclonal antibodies, garadacimab is expected to be degraded by enzymatic proteolysis into small peptides and amino acids. Therefore, specific metabolism studies were not conducted with garadacimab.
Garadacimab had a mean (SD) apparent clearance of 0.0217 L/h (0.00793) and a terminal elimination half-life of approximately 19 days.
No dedicated studies have been conducted to evaluate the pharmacokinetics of garadacimab in special patient populations including gender, age, pregnant women.
In a population pharmacokinetic analysis, after correcting for body weight (43.3 to 153 kg), no influence of gender, age (12 to 73 years), race, or ethnicity was apparent on clearance or volume of distribution of garadacimab.
Although body weight was identified as an important covariate describing the variability of clearance and volume of distribution, the difference was not clinically relevant and no dose adjustments are recommended.
Dedicated studies on subjects with renal or hepatic impairment were not conducted.
As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of garadacimab.
Based on population pharmacokinetic analysis, hepatic impairment had no effect on the pharmacokinetics of garadacimab.
In a population pharmacokinetic analysis, renal impairment (estimated glomerular filtration rate: ≥90 mL/min [normal, N=149], 60 to <90 mL/min [mild, N=22], and 30 to <60 mL/min [moderate, N=1]) had no effect on the pharmacokinetics of garadacimab.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.
Male and female fertility were unaffected based upon no observed adverse findings on mating, fecundity, fertility indices, on maternal reproductive parameters, embryo survival or sperm assessment in sexually mature rabbits that received garadacimab intravenously once every three days resulting in approximately 83- and 103-fold the exposure (based on AUC) in females and males, respectively, at the recommended human dose of 200 mg subcutaneously once monthly.
In a pre- and post-natal development study, pregnant rabbits were administered garadacimab subcutaneously once every five days from implantation through weaning. There was no maternal and off-spring, through six months of age, garadacimab-related toxicity in rabbits receiving subcutaneous garadacimab resulting in approximately 53-fold the clinical exposure (based on AUC) at the recommended human dose of 200 mg subcutaneously once monthly.
Garadacimab crossed the placenta in rabbits. With subcutaneous administration of garadacimab corresponding to approximately 53-fold the clinical exposure (based on AUC) at the recommended human dose of 200 mg subcutaneously once monthly, at gestation day 29, fetal plasma concentrations were 40.8% of maternal concentrations.
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