Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Jazz Pharmaceuticals Ireland Ltd, 5th Floor, Waterloo Exchange, Waterloo Road, Dublin 4, D04 E5W7, Ireland
Pharmacotherapeutic group: Other antineoplastic agents
ATC code: L01XX02
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.
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/m² or 37.5 mg/m² three times a week (Monday/Wednesday/Friday), or 25 mg/m² on Monday and Wednesday then 50 mg/m² 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/m² | Intravenously 25 (MW)/ 50 (F) mg/m² |
|---|---|---|
| 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.
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.
The PK of Enrylaze was determined based on SAA. Patients received 6 doses of Enrylaze at various doses intramuscularly on Monday, Wednesday and Friday or 25 mg/m² administered intramuscularly or intravenously on Monday and Wednesday and 50 mg/m² on Friday as a replacement for each dose of a long-acting E. coli-derived asparaginase remaining on their original treatment plan. Recombinant crisantaspase maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase approximately proportionally over a dose range from 12.5 to 50 mg/m². The trough SAA at 48-hour (Ctrough,48) or 72-hour (Ctrough,72) post the last dose for recombinant crisantaspase are summarised in Table 3.
Table 3. Enrylaze pharmacokinetic parameters based on SAA:
| PK Parametera | Mean (95% CI) after last dose | |||
|---|---|---|---|---|
| 25/25/50 mg/m² Monday, Wednesday, Friday | 25/25/50 mg/m² Monday, Wednesday, Friday | |||
| Intramuscularly | Intravenously | |||
| Ctrough,48 (U/mL) | N=49 | 0.66 (0.54-0.77) | N=59 | 0.25 (0.20-0.29) |
| Ctrough,72 (U/mL) | N=49 | 0.47 (0.35-0.59) | N=50 | 0.10 (0.07-0.13) |
a Ctrough,48: Trough SAA at 48 hour post the last 25 mg/m² dose in cycle 1; Ctrough,72: Trough SAA at 72 hour post the last 50 mg/m² dose in cycle 1.
The median Tmax of recombinant crisantaspase is 16 hours following intramuscular administration. The mean absolute bioavailability for intramuscular administration is 38%.
Following intravenous administration, the geometric mean (CV) volume of distribution of recombinant crisantaspase is 1.75 L/m² (14).
Recombinant crisantaspase is expected to be metabolized into small peptides by catabolic pathways.
Following intravenous administration, the geometric mean (CV) clearance of recombinant crisantaspase is 0.14 L/hour/m² (20).
The geometric mean (CV) half-life is 8.6 hours (13) following intravenous administration and 18.8 hours (11%) following intramuscular administration.
There was no dedicated study on renal or hepatic impairment with Enrylaze. During treatment dose adjustment is not required for patients with total bilirubin ≤3 times the Upper Limit of Normal; there is limited data with Enrylaze in patients with total bilirubin >3 times to ≤10 times the ULN.
Dose adjustment is not required for patients with pre-existing mild or moderate hepatic impairment (total bilirubin >1 to 3 times the ULN or AST > than the ULN). There are insufficient data in patients with pre-existing severe hepatic impairment to support a dose recommendation.There are insufficient data in patients with mild, moderate or severe renal impairment to support a dose recommendation.
There were no clinically significant differences in the pharmacokinetics of Enrylaze based on weight (9 to 131 kg) or sex (n=138 male; n=88 female) after the dose was adjusted by body surface area (BSA).
The volume of distribution and clearance of recombinant crisantaspase increase with increasing BSA (0.44 to 2.53 m²).
Age impacts absorption rate constant whereas younger subjects have higher absorption rate constant value, leading to earlier Tmax.
Black or African American patients (n=24) had 25% lower clearance which may increase SAA exposure compared to population average (n=226). No dose adjustment is needed in African American population. There were no clinically significant differences in clearance between Hispanic (n=73) and Non-Hispanic (n=139) patients.
As with other asparaginase preparations, development of specific neutralising antibodies were identified with repeated dosing.
In a study, recombinant crisantaspase was administered intravenously to groups of rats for up to 14 consecutive days. Adverse effects in naïve animals, which were typical for asparaginases, were noted at exposures greater than 3.6 times the maximum human exposure.
Carcinogenicity, mutagenicity, and reproductive toxicity studies have not been conducted with Enrylaze.
In embryofoetal development studies in rats and rabbits, Erwinia chrysanthemi L-asparaginase produced maternal toxicity, increased resorptions, post implantation loss, embryofoetal toxicity, and/or gross abnormalities at exposures lower than those observed clinically (margins of exposure <1).
In rat fertility and pre- and post-natal development studies with Erwinia chrysanthemi L-asparaginase, there were no adverse effects on fertility or development, but the exposures were lower than those observed clinically (margins of exposure <1).
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