158: Model-Informed Development of Recombinant Erwinia Asparaginase (JZP458) in Patients With Acute Lymphoblastic Leukemia

Statement of Purpose, Innovation or Hypothesis: L‐asparaginase is a cornerstone of multi‐agent chemotherapeutic regimens for acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL/LBL). Erwinia-derived asparaginase addresses a critical need for patients who cannot complete E. coli-derived asparaginase therapy due to hypersensitivity reactions (HSRs) and silent inactivation. Switching to an Erwinia asparaginase has been challenging due to Erwinaze^® manufacturing issues. Recombinant Erwinia asparaginase JZP458 (Rylaze^®) was developed in collaboration with the Children’s Oncology Group (COG) to provide a high-quality drug with reliable supply. Population pharmacokinetic (PPK) modeling and simulations were essential in JZP458 clinical development and regulatory approval. Here, we report PPK model development and simulations for JZP458.

Description of Methods & Materials: AALL1931 (NCT04145531) is a pivotal phase 2/3 trial of JZP458 (in collaboration with COG) in patients with ALL/LBL who developed HSRs/silent inactivation to an E. coli-derived asparaginase. Efficacy endpoints were the proportions of patients achieving nadir serum asparaginase activity (NSAA) levels (≥0.1 IU/mL) at 72 and 48 hours post-dose in Course 1. A PPK model was developed from SAA data from AALL1931 and a phase 1 study using nonlinear mixed-effects modeling (NONMEM); effects of covariates were assessed and quantified. Model-based simulations of SAA-time profiles using the NHANES database were performed to evaluate various dosing regimens, including regimens not tested in AALL1931. The current PPK model was built from final data from AALL1931 with an updated model structure to best describe the pharmacokinetics of JZP458. Exposure-safety analyses were conducted for 5 asparaginase-related adverse events.

Data & Results: In total, 4269 SAA data points from 250 participants (phase 1, n=24; AALL1931, n=226) were analyzed. A one-compartment model with 2 first-order absorption rate constants (KA1, KA2) was the best fit, with a flexible change point absorption function for intramuscular (IM) and zero-order input for intravenous (IV). The model included the effects of disease (healthy vs ALL/LBL), body surface area (BSA), and race (ie, Black/African American) on clearance; disease and BSA on volume of distribution; and age on KA1. Simulation results were consistent with trial data and predict therapeutic NSAA levels are achieved in the vast majority of patients with IM JZP458 at 25 mg/m² every 48 hours or 25/25/50 mg/m² Monday/Wednesday/Friday (MWF) or IV JZP458 at 25 mg/m² every 48 hours, or a mixed regimen of 25/25/50 mg/m² IV/IV/IM MWF Table 1. No clinically significant difference is expected in the probability of achieving therapeutic NSAA based on race, age, or BSA following proposed BSA-based dosing regimens. There were no apparent exposure-safety trends for hepatotoxicity, pancreatitis, hypertriglyceridemia, or thrombosis, although the small number of thrombosis precluded any conclusion regarding this adverse event. Hypersensitivity appeared to be associated with exposure, but the effect is confounded by route of administration. The risk of hypersensitivity seems to be higher with IV as compared to IM, consistent with the class of asparaginases.

Interpretation, Conclusion or Significance: Observed data and PPK model-based simulations demonstrate that JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules, including dosing regimens not directly tested in trials. The accelerated development and approval of JZP458 showcase an innovative use of a model-based approach to address critical medical needs.

Disclosures: YL, SG, CC, SA, and HZ are employees of and own shares/options in Jazz Pharma. DM consulted for Jazz.

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Additional Information/Authors: This study was supported by Jazz Pharmaceuticals. Medical writing support, under the direction of the authors, was provided by Natasha Tracey, PhD, and Mai Moawed, B. Pharm of CMC Affinity, a division of IPG Health Medical Communications, with funding from Jazz Pharmaceuticals, in accordance with Good Publication Practice (GPP 2022) guidelines.