Efficacy, Safety, and Population Pharmacokinetic Modeling of Intravenous Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma: Results from Study AALL1931

Introduction: L-asparaginase is an important component of multi-agent chemotherapy regimens for pediatric and adult patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). JZP458, a recombinant Erwiniachrysanthemi asparaginase with an identical amino acid sequence to the native compound, is derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of a highly purified enzyme with minimal cross-reactivity to E. coli-derived asparaginases. JZP458 was developed to address historical global shortages of native asparaginase Erwinia chrysanthemi (Erwinaze®/Erwinase®). AALL1931 is a 2-part, open-label, phase 2/3 trial conducted in collaboration with the Children's Oncology Group investigating efficacy, safety, and pharmacokinetics (PK) of JZP458 in patients with ALL/LBL (ClinicalTrials.gov Identifier: NCT04145531). Based on interim results from Part A of AALL1931, intramuscular (IM) JZP458 (Rylaze®) was approved in June of 2021 by the US Food and Drug Administration for the treatment of ALL/LBL. Here, we report the efficacy and safety of intravenous (IV) JZP458 from Part B of AALL1931. Part B was exploratory in nature and aims to determine an IV JZP458 dosing regimen that provides adequate serum asparaginase activity (SAA) with an acceptable safety profile in patients with ALL/LBL following hypersensitivity to E. coli-derived asparaginases.

Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli-derived asparaginase (PEG). Each remaining dose of PEG was substituted with 6 doses of IV JZP458 over 2 weeks (1 course) at 25/25/50 mg/m² on Monday/Wednesday/Friday (MWF). Efficacy was assessed by the proportions of patients achieving the last 72- and 48-hour nadir SAA (NSAA) levels ≥0.1 IU/mL during Course 1. A population PK (PopPK) model was also developed for JZP458 based on SAA data.

Results: 61 patients received ≥1 dose of IV JZP458 and were included in this analysis (data cutoff: July 19, 2021). The median (range) age was 10 (1, 24) years. The mean (95% CI) SAA levels (IU/mL) were 0.10 (0.07, 0.13) at 72 hours and 0.25 (0.20, 0.29) at 48 hours. The proportions (95% CI) of patients achieving NSAA levels ≥0.1 IU/mL at 72 and 48 hours in Course 1 were 40% (26%, 54%) and 90% (82%, 98%), respectively. PopPK modeling and simulation suggested that 51% (49%, 54%) and 91% (90%, 92%) of patients would achieve NSAA levels ≥0.1 IU/mL at 72 and 48 hours in Course 1, respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29 (48%) patients. Incidences of any grade TRAEs of interest were: allergic reactions (23%), hepatotoxicity (11%), pancreatitis (0%), and thrombosis (0%). TRAEs leading to discontinuation occurred in 15 (25%) patients and included hypersensitivity reactions (15%), vomiting (3%), infusion-related reaction (3%), nausea (2%), and hyperammonemic encephalopathy (2%). No TRAEs led to death. The geometric mean half-life for JZP458 was estimated at 19.1 hours and 8.3 hours for IM and IV administration, respectively. PopPK model-based simulation predicted that NSAA levels ≥0.1 IU/mL are best maintained when IV JZP458 is administered at 25 mg/m² every 48 hours (90% of patients [95% CI: 89%, 92%] at the last 48-hours) or when JZP458 is administered IV at 25 mg/m² Monday/Wednesday and IM at 50 mg/m² on Friday due to the longer half-life for IM (92% of patients [95% CI: 91%, 93%] at the last 72-hours; 93% of patients [95% CI: 92%, 94%] at the last 48-hours).

Conclusions: Results from the AALL1931 study demonstrate that IV administration of JZP458 at 25 mg/m² every 48 hours is feasible and efficacious with a safety profile consistent with other asparaginases. PopPK modeling supports that JZP458 dosing at 25 mg/m² IV every 48 hours or 25/25/50 mg/m² IV/IV/IM MWF would achieve sustained asparaginase activity (NSAA levels ≥0.1 IU/mL in ≥90% of patients) thereby providing dosing flexibility to patients and physicians.

Maese:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Choi:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lin:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki:Etsuko Aoki: Current Employment, Current equity holder in publicly-traded company. Agarwal:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wu:Jazz Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Iannone:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman:Jazz Pharmaceuticals: Other: Was an employee of Jazz Pharmaceuticals at the time of the study and holds stock ownership and/or stock options in Jazz Pharmaceuticals. Silverman:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Raetz:Pfizer: Research Funding; BMS: Other: Data and Safety Monitoring Board. Rau:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.