Adzynma
(Apadamtase Alfa)Adzynma Prescribing Information
ADZYNMA (ADAMTS13, recombinant-krhn) is a human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) indicated for prophylactic or on demand enzyme replacement therapy (ERT) in adult and pediatric patients with congenital thrombotic thrombocytopenic purpura (cTTP)
The safety and effectiveness of ADZYNMA has been established in pediatric patients. Clinical trials included patients aged 2 years and older. Based on data from population pharmacokinetic (PK) analysis, no additional dose adjustments beyond body weight are required for this age group. The recommended body-weight based dosing regimen in pediatric patients is the same as that in adults.
ADZYNMA was studied in a global, prospective, randomized, active-controlled, open-label, multicenter, two-period crossover study followed by a single arm continuation period (Study 1) evaluating the efficacy and safety of the prophylactic and on demand ERT with ADZYNMA compared to plasma-based therapies in patients with cTTP.
The efficacy of ADZYNMA in the prophylactic treatment of patients with cTTP was evaluated in Study 1, in 46 patients who were randomized to receive 6 months of treatment with either 40 IU/kg of ADZYNMA or plasma-based therapies (Period 1), then crossed over to the other treatment for 6 months (Period 2). Thirty-five patients have entered the 6-month single arm period with ADZYNMA (Period 3).
The median (min-max) age of patients was 32.5 years (range 3-58 years), with a mean weight of 67.6 kg. Most patients were white (65.2%), not Hispanic or Latino (80.4%) and were female (58.7%). Twenty of the 27 female patients (74.1%) were of child-bearing potential. Baseline characteristics are listed in
| Characteristic | Prophylactic CohortThe prophylactic cohort includes the patients who were originally enrolled in the prophylaxis cohort and the patients who moved to the prophylaxis cohort from the on demand cohort. (N=46) |
|---|---|
| cTTP Pre-Study Treatment | 45 (97.8) |
| Fresh Frozen Plasma (FFP) [n (%)] | 32 (69.6) |
| Solvent/Detergent Treated Plasma [n (%)] | 10 (21.7) |
| FVIII-VWF Concentrations [n (%)] | 3 (6.5) |
| Acute TTP Events (in the 12 Months prior to screening) [n (%)]Acute TTP events were defined in protocol by a drop in platelet count (≥50% of baseline or a platelet count <100,000/μL) and an elevation of lactate dehydrogenase (LDH) (>2 ×baseline or >2 ×upper limit normal (ULN)). | |
| Yes | 8 (17.4) |
| No | 38 (82.6) |
The efficacy of prophylactic treatment with ADZYNMA in patients with cTTP was demonstrated based on the incidence of protocol defined acute and subacute TTP events and TTP manifestations (see
No patients receiving ADZYNMA had an acute TTP event throughout the study, including Period 3 (with a median duration of exposure to ADZYNMA of 14 months for patients 12 to <18 years of age and patients ≥18 years of age; and 4 and 1 months in patients 6 to <12 and <6 years of age, respectively). One acute TTP event occurred in a patient receiving plasma-based therapies (FFP) prophylactically during Period 1 (see
No subacute TTP events were reported in patients receiving ADZYNMA during Periods 1 and 2. In Period 3, two patients receiving ADZYNMA prophylaxis had two subacute events of which one was treated with four supplemental doses, 2 of FFP and 2 of ADZYNMA. Four patients receiving plasma-based therapies had five subacute TTP events in Periods 1 and 2. A total of seven supplemental doses, 2 of FVIII-VWF concentrate, 1 of FFP and 4 of ADZYNMA were given to three of these patients (see
| ADZYNMA N=37 | Plasma-Based Therapies N=38 | |
|---|---|---|
| SD = standard deviation; TTP = thrombotic thrombocytopenic purpura. | ||
Acute TTP events Acute TTP events were defined by a drop in platelet count (≥50% of baseline or a platelet count <100,000/μL) and an elevation of lactate dehydrogenase (LDH) (>2× baseline or >2×upper limit normal (ULN)). | ||
| Number of subjects with event (number of events) | 0 (0) | 1 (1) |
| Mean annualized event rate (SD)Annualized event rate for a subject = number of events/duration of the observation period (years). Data shown are non-model based. | 0 (0.000) | 0.05 (0.304) |
Subacute TTP events Subacute events were defined by a thrombocytopenia event or a microangiopathic hemolytic anemia 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. | ||
| Number of subjects with event (number of events) | 0 (0) | 4 (5) |
| Mean annualized event rate (SD) | 0 (0.000) | 0.27 (0.836) |
TTP manifestations TTP manifestations not shown also included renal dysfunction, neurological symptoms and abdominal pain. The clinical significance of the observed difference for the presented manifestations is unknown. | ||
| Thrombocytopenia eventsThrombocytopenia events were defined as a drop in platelet count ≥25% of baseline or a platelet count <150,000/μL. | ||
| Number of subjects with event (number of events) | 9 (30) | 19 (75) |
| Mean annualized event rate (SD) | 2.0 (4.706) | 4.44 (6.312) |
| Microangiopathic hemolytic anemia eventsMicroangiopathic hemolytic anemia events were defined as an elevation of LDH >1.5 ×baseline or >1.5 xULN. | ||
| Number of subjects event (number of events) | 5 (7) | 11 (20) |
| Mean annualized event rate (SD) | 0.38 (1.028) | 1.47 (3.274) |
Overall, the efficacy results for ADZYNMA were consistent throughout the study, including Period 3 and across age groups. For outcome of ADZYNMA use in pregnancy
The efficacy of the on-demand (OD) enzyme replacement therapy was evaluated based on the proportion of acute TTP events responding to ADZYNMA in both the Prophylactic and the OD 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 ≥150,000/μL 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.
Five adult patients (≥18 years of age) enrolled in the OD cohort and had a total of six acute TTP events. Of these five patients, two patients were randomized to receive on-demand treatment with ADZYNMA and three patients were randomized to receive plasma-based therapies. All 6 acute TTP events resolved after treatment with either ADZYNMA or plasma-based therapies.
ADZYNMA is a lyophilized powder in single-dose vials containing nominally 500 or 1500 International Units (IU) per vial and comes with 5 mL of Sterile Water for Injection. Each carton and vial label for ADZYNMA states the actual potency of ADAMTS13 in IU.
The safety of ADZYNMA for use during pregnancy has not been established in controlled clinical trials. Limited data with ADZYNMA use during pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes.1 In determining whether ADZYNMA should be used in pregnancy, healthcare providers should balance the potential benefits with the potential risks.
The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
There have been four cTTP patients exposed to ADZYNMA during pregnancy.
Two patients in a long-term extension study were found to be pregnant early in the first trimester while receiving prophylaxis with ADZYNMA. Both patients were discontinued from the study to comply with the protocol requirements. The first patient had no further exposure to ADZYNMA and had a first trimester miscarriage approximately two months after study discontinuation. The investigator assessed the event was unrelated to ADZYNMA. The second patient resumed treatment with ADZYNMA under a compassionate use program and delivered a healthy full-term baby with no safety concerns reported by the investigator.
Two additional cTTP patients were treated with ADZYNMA in a compassionate use program during pregnancy. The first patient, in the third trimester of her second pregnancy, experienced a stroke and thrombocytopenia that was refractory to daily plasmapheresis. At 33 weeks of gestation, ADZYNMA treatment was started once weekly. ADAMTS13 activity levels normalized, thrombocytopenia resolved, and a healthy baby was delivered at 37 weeks with no safety concerns reported by the treating physician due to ADZYNMA.1 The second patient had an exacerbation of her cTTP during her second trimester of pregnancy despite prior daily plasma exchange. Her pregnancy was considered to be at risk, with inadequate response to plasma-based therapies. ADZYNMA was started once weekly and induced clinical remission. The baby was delivered by a cesarean section at week 29 and the treating physician reported no adverse events due to ADZYNMA.
Whether ADZYNMA should be used in pregnancy is solely up to the medical judgment of the healthcare provider.
In an embryo-fetal development study in rats, ADZYNMA was administered in female rats at 80, 200, or 400 IU/kg [up to 10x human equivalent dose (HED)] every third day from 2 weeks before mating through Day 16 of gestation and was not associated with any adverse maternal findings or treatment-related effects on embryo-fetal development. In a pre- and post-natal development study in rats, ADZYNMA was administered at 80, 200, or 400 IU/kg [up to 10x HED] by intravenous (IV) bolus injection every three days from Day 6 of gestation to weaning at approximately Day 21 of lactation. There were no adverse maternal effects or findings in F1 or F2 offspring.
ADZYNMA is contraindicated in patients who have manifested life threatening hypersensitivity reactions to ADZYNMA or its components
ADZYNMA is a purified bivariant human recombinant “A disintegrin and metalloproteinase with thrombospondin motifs 13” (rADAMTS13) expressed in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology (a mixture of Native rADAMTS13 Q23 and Variant rADAMTS13 R23 with a controlled range of the two variants ratio). ADZYNMA is produced and formulated without the addition of any exogenous raw materials of human or animal origin in the cell culture, purification, or formulation of the final product. The purification process for rADAMTS13 does not include use of a monoclonal antibody reagent. To enhance viral safety, the production process also incorporates two dedicated viral clearance steps – a solvent/detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses. Recombinant ADAMTS13 has a molecular weight of approximately 172 kDa. Proteins that may be present in the final product, other than rADAMTS13, are trace quantities of host cell (CHO) proteins.
ADZYNMA (rADAMTS13) is a sterile, nonpyrogenic, preservative free, white powder supplied in single-dose vials for IV use after reconstitution. Each single-dose vial contains nominally 500 IU or 1500 IU of rADAMTS13, sodium chloride (9.4 mg), calcium chloride dihydrate (1.6 mg), L-histidine (16.7 mg), mannitol (161.4 mg), sucrose (53.8 mg), and polysorbate 80 (2.7 mg). Each vial of ADZYNMA is labeled with the specific number of units of ADAMTS13 potency expressed in IU as measured with a fluorescence resonance energy transfer (FRET) assay using a synthetic 73-amino-acid peptide (FRETS-VWF73). The potency assignment employs an ADAMTS13 concentrate standard that is referenced to a WHO (World Health Organization) international standard for ADAMTS13 concentrates and is evaluated by appropriate methodology to ensure accuracy of the results.
After reconstitution with 5 mL of Sterile Water for Injection, USP, the 500 IU and the 1500 IU vials result in a nominal potency of 100 IU/mL and 300 IU/mL, respectively. All dosage strengths yield a clear, colorless solution, free from particles with a pH of approximately 7.0.
Hypersensitivity reactions may occur. Discontinue ADZYNMA if hypersensitivity symptoms occur and administer appropriate emergency treatment. (
Allergic-type hypersensitivity including anaphylactic reactions may occur with ADZYNMA. Patients should be informed of the early signs of hypersensitivity including but not limited to tachycardia, tightness of the chest, wheezing and/or acute respiratory distress, hypotension, generalized urticaria, pruritus, rhinoconjunctivitis, angioedema, lethargy, nausea, vomiting, paresthesia, and restlessness. If signs and symptoms of severe allergic reactions occur, immediately discontinue administration of ADZYNMA and provide appropriate supportive care.
Immunogenicity: Patients may develop antibodies to rADAMTS13 which could potentially result in a decreased or lack of response to rADAMTS13. Patients may develop antibodies to host cell proteins which could potentially result in adverse reactions. There are no data on risk in previously untreated patients (subjects naïve to plasma-based products). (
There is a potential for immunogenicity with ADZYNMA. Patients may develop neutralizing antibodies to ADAMTS13, which could potentially result in a decreased or lack of response to ADAMTS13. Neutralizing antibodies were not reported in the cTTP clinical trials. All subjects had been previously exposed to ADAMTS13 through plasma-based products. There are no data on immunogenicity with ADZYNMA in previously untreated patients (subjects naïve to plasma-based products)
Patients may develop antibodies to host cell proteins which could potentially result in adverse reactions. There are no data on immunogenicity to host cell proteins in previously untreated patients (subjects naïve to plasma-based products).