Enrylaze

Pharmacotherapeutic group: Other antineoplastic agents ATC code: L01XX02. Mechanism of action Asparaginase is an enzyme that catalyses the conversion of the amino acid L‑asparagine into L‑aspartic acid and ammonia.‍‍‍‍‍‍​​​‍​​​​​​ The pharmacological effect of Enrylaze is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore is dependent on an exogenous source of asparagine for survival. Clinical efficacy and safety The efficacy and safety of Enrylaze was determined in the clinical trials, an open-label, two-part, multi-cohort, multi-centre, multi-agent chemotherapeutic trial that treated 228 adult and paediatric patients with ALL or LBL who developed hypersensitivity to a long-acting E. coli -derived asparaginases. The median age of patients was 10 years (range, 1 to 25 years). Prior long-acting E. coli -derived asparaginase treatments included pegaspargase for all patients apart from one who received other type of E. coli -derived asparaginase. In Study JZP458‑201, 190 (83%) patients experienced a hypersensitivity (Grade ≥ 3) to a long-acting E. coli -derived asparaginases, 15 (7%) patients experienced silent inactivation, and 23 (10%) patients experienced an allergic reaction with inactivation. The number of courses of Enrylaze received ranged from 1 to 15. Patients received 6 doses of Enrylaze, either intramuscularly at 25 mg/m 2 or 37.5 mg/m 2 three times a week (Monday/Wednesday/Friday), or 25 mg/m 2 on Monday and Wednesday then 50 mg/m 2 on Friday by intravenous infusion or an intramuscular injection as a replacement for each dose of E. coli derived asparaginase remaining on a patient's treatment plan. The determination of efficacy was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) levels ≥ 0.1 U/mL. Serum trough asparaginase activity ≥ 0.1 U/mL has been demonstrated to correlate with asparagine depletion that predicts clinical efficacy (see section 5.2). Observed NSAA levels during the clinical trials for indicated dosing schedules are presented in Table 2. Table 2: Observed NSAA levels ≥ 0.1 U/mL during the clinical trials Time Point Intramuscularly 25 (MW)/ 50 (F) mg/m 2 Intravenously 25 (MW)/ 50 (F) mg/m 2 Last 48‑hour 95.9% [90.4%, 100.0%] 89.8% [82.1%, 97.5%] Last 72‑hour 89.8% [81.3%, 98.3%] 40.0% [26.4%, 53.6%] MW=Monday, Wednesday MWF=Monday, Wednesday, Friday The other recommended dosing schedules are based on interpolation from pharmacokinetic (PK) and response rates observed with the very similar investigated regimens. Paediatric population No clinically significant difference is expected in probability of achieving a therapeutic NSAA ≥ 0.1 U/mL based on age (1 month to 39 years) following the proposed Body surface area (BSA)‑based dosing regimens.