A Randomized Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Recombinant Erwinia Asparaginase (JZP-458) in Healthy Adult Volunteers

Abstract

L-asparaginase has been an important component of acute lymphoblastic leukemia (ALL) therapy for over 40 years, and is standard therapy during ALL induction and consolidation treatment. L-asparaginases are immunogenic and can induce hypersensitivity reactions; inability to receive asparaginase has been associated with poor patient outcomes. There are L-asparaginases of varied bacterial origins, with the most commonly used being Escherichia coli (E. coli); therefore, to ensure that patients who develop hypersensitivity to E. coli-derived asparaginases receive an adequate therapeutic course, alternative preparations are warranted. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli-derived asparaginases. To evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP-458, a randomized, single-center, open-label, phase I study was conducted with JZP-458 given via i.m. injection or i.v. infusion to healthy adult volunteers. At the highest doses tested for each route of administration (i.e., 25 mg/m² i.m. and 37.5 mg/m² i.v.), JZP-458 achieved serum asparaginase activity (SAA) levels ≥ 0.1 IU/mL at 72 hours postdose for 100% of volunteers. Bioavailability for i.m. JZP-458 was estimated at 36.8% based on SAA data. All dose levels were well-tolerated, with no unanticipated adverse events (AEs), no serious AEs, and no grade 3 or higher AEs. Based on PK and safety data, the recommended JZP-458 starting dose for the pivotal phase II/III study in adult and pediatric patients is 25 mg/m² i.m. and 37.5 mg/m² i.v. on a Monday/Wednesday/Friday dosing schedule.

Figure 1

Individual SAA‐time profiles. ERW, asparaginase Erwinia chrysanthemi; SAA, serum asparaginase activity. Note: Different colored lines represent individual healthy volunteers (N = 6 for each dosing cohort). Numbers in purple boxes represent SAA ranges at 72 hours postdose.

Figure 2

Mean (95% CI) SAA‐time profiles. CI, confidence interval; SAA, serum asparaginase activity. Note: Gray lines represent 95% CIs (N = 6 for each dosing cohort).

Figure 3

Mean SAC‐time profiles and the correlation between SAC and SAA for JZP‐458. (a) Mean SAC‐time profiles for JZP‐458 i.m. Note: LLOQ = 1.00 ng/mL. Values below the LLOQ were set to zero. (b) Mean SAC‐time profiles for JZP‐458 i.v. Note: LLOQ = 1.00 ng/mL. Values below the LLOQ were set to zero. (c) Correlation between SAC and SAA for JZP‐458 i.m. and i.v. administration. Note: Regression line equation: SAC = 1407.9 × SAA; Pearson correlation coefficient = 0.9779. ERW, asparaginase Erwinia chrysanthemi; LLOQ, lower limit of quantitation; SAA, serum asparaginase activity; SAC, serum asparaginase concentration.

Figure 4

Mean SAA‐time profiles and corresponding mean plasma L‐asparagine levels. Note: LLOQ: asparaginase activity = 0.0250 IU/mL; L‐asparagine = 0.0250 µg/mL. Values below the LLOQ were set to zero. ERW, asparaginase Erwinia chrysanthemi; LLOQ, lower limit of quantitation; SAA, serum asparaginase activity.