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The clinical efficacy and safety were assessed in two ongoing studies. ^{1 1. Patel M, et al. Blood. 2023;142(Suppl 1):1260. 2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}  

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 ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.} evaluating the efficacy and safety of the prophylactic and on-demand enzyme replacement therapy (ERT) with ADZYNMA compared to plasma-based therapies in patients with severe cTTP (ADAMTS13 activity < 10%). 

Prophylactic ERT in patients with cTTP ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}

• The efficacy of ADZYNMA 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 (period 3). The initial treatment frequency was every other week for 35 (76.1%) patients and once weekly for 9 (19.6%) patients. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
• 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
• 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
• 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 below). ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}

Prophylactic cohort efficacy results in cTTP patients (periods 1 and 2) ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
 

Bild

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.

On-demand ERT for acute TTP episodes ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}

The efficacy of the on-demand ERT 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}

• 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
• 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}
• 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. ^{2 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.}

Continuation study ^{1 1. Patel M, et al. Blood. 2023;142(Suppl 1):1260.}

Patients who completed the phase 3 study ² 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596.  were eligible to enrol in a long-term continuation study  ¹ 1. Patel M, et al. Blood. 2023;142(Suppl 1):1260. . The prophylaxis cohort included 65 patients among which 40 rolled over from the phase 3 study  ² 2. Scully M, et al. N Engl J Med. 2024;390(17):1584-1596. 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.

Acronyms

ADAMTS13, A disintegrin and metalloproteinase with a thrombospondin motifs 13

ERT, Enzyme replacement therapy

FFP, Fresh frozen plasma

FVIII, Factor VIII

LDH, Lactate dehydrogenase
rADAMTS13, Recombinant ADAMTS13

S/D, Solvent detergent 

SD, Standard deviation
cTTP, Congenital thrombotic thrombocytopenic purpura
TTP, Thrombotic thrombocytopenic purpura

ULN, Upper limit of normal