Adzynma Drug Information

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. Prophylactic Enzyme Replacement Therapy 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 Table 4. Table 4: Baseline Characteristics of the Prophylactic Cohort Characteristic Prophylactic Cohort The 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 Fresh Frozen Plasma (FFP) 32 Solvent/Detergent Treated Plasma 10 FVIII-VWF Concentrations 3 Acute TTP Events (in the 12 Months prior to screening) 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 No 38 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 Table 5 ), as well as the incidence of supplemental doses prompted by subacute TTP events over a 6-month time period.

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 Table 5 ). 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 Table 5 ). Table 5: Prophylactic Cohort Efficacy Results in cTTP Patients ≥12 Years of Age (Periods 1 and 2) 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 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 0.05 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 4 Mean annualized event rate (SD) 0 0.27 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 events Thrombocytopenia 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 19 Mean annualized event rate (SD) 2.0 4.44 Microangiopathic hemolytic anemia events Microangiopathic 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 11 Mean annualized event rate (SD) 0.38 1.47 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.

On-Demand Enzyme Replacement Therapy 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.