Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Takeda Manufacturing Austria AG, Industriestrasse 67, 1221 Vienna, Austria, medinfoEMEA@takeda.com
Pharmacotherapeutic group: Antithrombotic agents, enzymes
ATC code: B01AD13
rADAMTS13 is a recombinant form of the endogenous ADAMTS13. ADAMTS13 is a plasma zinc metalloprotease that regulates the activity of von Willebrand factor (VWF) by cleaving large and ultra-large VWF multimers to smaller units and thereby reducing the platelet binding properties of VWF and its propensity to form microthrombi. rADAMTS13 is expected to reduce or eliminate the spontaneous formation of VWF-platelet microthrombi that leads to platelet consumption and thrombocytopenia in patients with cTTP.
Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited (see section 4.4).
The clinical efficacy and safety were assessed in two ongoing studies (Study 281102 and Study 3002).
ADZYNMA was studied in a global phase 3, prospective, randomized, controlled, open-label, multicentre, two-period crossover study followed by a single arm continuation period (Study 281102) evaluating the efficacy and safety of the prophylactic and on-demand ERT with ADZYNMA compared to plasma-based therapies in patients with severe cTTP (ADAMTS13 activity <10%).
The efficacy of ADZYNMA in the prophylactic treatment of patients with cTTP was evaluated in 46 patients in the prophylaxis cohort who were randomized to receive 6 months of prophylactic treatment with either 40 IU/kg (± 4 IU/kg) of ADZYNMA or plasma-based therapies (period 1) once weekly (for patients who were previously treated with plasma-based therapies once weekly prior to joining the study) or every other week then crossed over to the other treatment for 6 months (period 2). After periods 1 and 2, all patients entered a 6 month single arm treatment period with ADZYNMA (period 3). The initial ADZYNMA prophylactic treatment frequency was every other week for 35 (76.1%) patients and once weekly for 9 (19.6%) patients.
The mean (SD) age was 30.5 (16.0) years (range: 3 to 58 years). Of the 46 patients, 4 (8.7%) were <6 years of age, 4 (8.7%) were ≥6 to <12 years of age, 4 (8.7%) were ≥12 to <18 years of age, and 34 (73.9%) were ≥18 years of age. The mean (SD) weight was 65.9 kg (21.8) (range: 18.5 to 102.4 kg), and the majority of patients were white (65.2%), and were female (58.7%) of whom 74.1% were of child-bearing potential.
Prior to joining the study, the majority (69.6%) of patients received FFP treatment, 21.7% received solvent/detergent (S/D) plasma and 6.5% received FVIII-VWF concentrate.
The efficacy of prophylactic treatment with ADZYNMA in patients with cTTP was evaluated based on the incidence of acute TTP events (as defined by a drop in platelet count [≥50% of baseline or a platelet count <100 x 109/L] and an elevation of lactate dehydrogenase [LDH] [>2 × baseline or >2 × upper limit normal (ULN)]), subacute TTP events (as defined by a thrombocytopenia event or a microangiopathic haemolytic anaemia event; and organ specific signs and symptoms including but not limited to renal dysfunction events, neurological symptoms events, fever, fatigue/lethargy, and/or abdominal pain), and TTP manifestations (such as thrombocytopenia, microangiopathic haemolytic anaemia, neurological symptoms, renal dysfunction, and abdominal pain); as well as the incidence of supplemental doses prompted by subacute TTP events (see Table 2).
Table 2. Prophylactic cohort efficacy results in cTTP patients (periods 1 and 2):
| ADZYNMA N=45 | Plasma-Based Therapies N=46 | |
| Acute TTP events | ||
| Number of subjects with event (number of events) | 0 (0) | 1 (1) |
| Subacute TTP events | ||
| Number of subjects with event (number of events) | 1 (1) | 6 (7) |
| Number of subjects receiving a supplemental dose prompted by a subacute event | 0 | 4 |
| Number of supplemental doses prompted by a subacute event | 0 | 9 |
| TTP manifestations | ||
| Thrombocytopenia eventsa | ||
| Number of subjects with event (number of events) | 13 (49) | 23 (91) |
| Model based annualized event rate,b LSM (SE) | 0.92 (0.262) | 1.72 (0.457) |
| Microangiopathic haemolytic anaemia eventsc | ||
| Number of subjects with event (number of events) | 8 (23) | 12 (32) |
| Model based annualized event rate,b LSM (SE) | 0.37 (0.136) | 0.59 (0.194) |
| Neurological symptoms eventsd | ||
| Number of subjects with event (number of events) | 4 (18) | 7 (29) |
| Model based annualized event rate,b LSM (SE) | 0.13 (0.068) | 0.23 (0.109) |
| Renal dysfunction eventse | ||
| Number of subjects with event (number of events) | 5 (11) | 2 (5) |
| Model based annualized event rate,b LSM (SE) | 0.17 (0.090) | 0.08 (0.052) |
| Abdominal pain events | ||
| Number of subjects with event (number of events) | 2 (4) | 6 (8) |
| Model based annualized event rate,b LSM (SE) | 0.09 (0.055) | 0.17 (0.086) |
LSM = least squares mean; SE = standard error; TTP = thrombotic thrombocytopenic purpura.
a Drop in platelet count ≥25% of baseline or a platelet count <150 x 109/L.
b From a negative binominal mixed-effects model.
c Elevation of LDH >1.5 × baseline or >1.5 x ULN.
d Nervous system disorders (e.g., headache, confusion, memory issues, irritability, paraesthesia, dysarthria, dysphonia, visual disturbances, focal or general motor symptoms including seizures).
e An increase in serum creatinine >1.5 × baseline.
Overall ADZYNMA efficacy results were consistent throughout the study, including period 3, and across age groups.
The efficacy of the on-demand enzyme replacement therapy for acute TTP episodes was evaluated based on the proportion of acute TTP events responding to ADZYNMA in both the prophylactic and the on-demand cohorts throughout the duration of the study.
An acute TTP event responding to ADZYNMA was defined as a resolved TTP event when platelet count was ≥150 x 109/L or platelet count was within 25% of baseline, whichever occurs first, and LDH ≤1.5 x baseline or ≤1.5 x ULN, without requiring the use of another ADAMTS13-containing agent.
The on-demand cohort included 5 adult patients (≥18 years of age) and 1 paediatric patient (<6 years of age). Patients enrolled in this cohort had a total of 7 acute TTP events. Of these 6 patients, 2 patients were randomized to receive on-demand treatment with ADZYNMA and 4 patients were randomized to receive plasma-based therapies. All 7 acute TTP events resolved after treatment with either ADZYNMA or plasma-based therapies within 5 days.
Most patients (66.7%) were male, white (50%) with a median (min, max) age of 20 (5, 36) years, a mean (SD) weight of 56.4 (18.6) kg and a median (min, max) weight of 64.3 (23.0, 74.0) kg.
Patients who completed the phase 3 study (Study 281102) were eligible to enrol in a long-term continuation study (Study 3002). The prophylaxis cohort included 65 patients among which 40 rolled over from Study 281102 and 25 were naïve patients. Of the 40 roll-over patients, 7 (17.5%) were ≥12 to <18 years of age, and 33 (82.5%) were ≥18 years of age. Of the 25 naïve patients, 3 (12%) were <6 years of age, 3 (12%) were ≥6 to <12 years of age, 3 (12%) were ≥12 to <18 years of age, and 16 (64%) were ≥18 years of age. The on-demand cohort included 1 patient aged ≥6 to <12 years. All patients were treated with ADZYNMA. The mean and maximum prophylactic treatment durations were 0.98 years and 2.17 years, respectively. Incidence rates of acute and subacute TPP events and TPP manifestations were consistent with the results from Study 281102.
Overall, the efficacy in paediatric patients was similar to that observed in the adult population.
This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.
The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The pharmacokinetic (PK) profile of ADZYNMA was determined based on clinical study ADAMTS13 activity data analyses.
Following single-dose intravenous administration of ADZYNMA at 5 IU/kg, 20 IU/kg, and 40 IU/kg to adults and adolescents, dose-related increases in individual ADAMTS13 activity were observed and reached a maximum at approximately 1 hour post-administration or earlier. At clinical dose of 40 IU/kg the mean (SD) half-life and mean residence time (MRT) in adults and adolescents were 47.8 (13.7) hours and 63.8 (16.0) hours, respectively.
The population PK parameters of ADAMTS13 activity following intravenous administration of ADZYNMA at 40 IU/kg in adults, adolescents, and younger children are described in Table 3.
Table 3. Pharmacokinetic parameters of ADAMTS13 activity following intravenous administration of ADZYNMA in cTTP patients:
| Parameter (unit) | Mean (SD) Min; Max (N=83) |
| Cmax (IU/mL) | 1.13 (0.29) 0.72; 2.29 |
| AUC (IU*h/mL) | 72.8 (37.4) 38.7; 274 |
| Duration ADAMTS13 activity above 10% (days) | 8.85 (2.45) 4.51; 14.0 |
AUC = area under ADAMTS13 activity-time curve; Cmax = maximum ADAMTS13 activity.
Note: 1 IU/mL ADAMTS13 activity corresponds to 100% average normal activity.
ADZYNMA intravenous administration at 40 IU/kg resulted in approximately greater than 5-fold higher ADAMTS13 activity exposures (Cmax, AUC, and duration above 10% ADAMTS13 activity) and lower variability when compared to plasma-based therapies.
Besides body-weight dosing regimen, no intrinsic factors such as age, gender, race, baseline estimated glomerular filtration rate (eGFR), and baseline bilirubin were identified as covariates impacting ADAMTS13 PK.
ADAMTS13 activity PK characteristics (MRT, steady-state volume of distribution [Vss], and clearance [CL]) were similar across age groups in patients with cTTP. Body weight-based ADZYNMA dosing provides similar ADAMTS13 activity PK parameters (Cmax and average ADAMTS13 activity [Cave]) across the different age groups including paediatric patients <12 years of age.
In infants <10 kg body weight, median duration above 10% ADAMTS13 activity was estimated to be shorter (approximately 5-6 days) compared to adults (approximately 10 days).
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity, toxicity to reproduction and development, local tolerance and immunogenicity. Studies to evaluate the mutagenic and carcinogenic potential of rADAMTS13 have not been performed.
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