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

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.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Inability to receive asparaginase secondary to hypersensitivity has been associated with poor patient outcomes, thus alternative asparaginase preparations are needed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This study evaluated safety, tolerability, and pharmacokinetics of a single dose of i.m. or i.v. JZP‐458, a recombinant Erwinia asparaginase with no immunologic cross‐reactivity to Escherichia coli (E. coli)‐derived asparaginases in healthy adult volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ At the highest doses tested (i.e., 25 mg/m² for i.m. and 37.5 mg/m² for i.v.), JZP‐458 achieved serum asparaginase activity levels ≥ 0.1 IU/mL at 72 hours postdose in each route for 100% of the healthy volunteers with complete asparagine depletion and no unanticipated adverse events (AEs), serious AEs, or grade ≥ 3 AEs. The recommended pivotal phase II/III JZP‐458 starting dose for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who develop hypersensitivity to E. coli‐derived asparaginases is 25 mg/m² i.m. and 37.5 mg/m² i.v. on a Monday/Wednesday/Friday dosing schedule.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ JZP‐458 may become a treatment alternative for patients with ALL/LBL who develop hypersensitivity to E. coli‐derived asparaginases.

Acute lymphoblastic leukemia (ALL) is the most common cancer among children and the most frequent cause of death from cancer before 20 years of age. In the past several decades, a substantial improvement in the survival of patients with ALL was achieved as a result of multi‐agent chemotherapeutic regimens. ¹ L‐asparaginase has been an important component of ALL therapy for over 40 years, and is standard therapy during ALL induction and consolidation in all pediatric regimens and most adult protocols. ² , ³ L‐asparaginase hydrolyzes the amino acid asparagine to aspartic acid and ammonia. Leukemic blast cells express only limited amounts of asparagine synthetase and are dependent on the availability of extracellular asparagine for growth. These cells may be selectively killed when L‐asparaginase depletes the circulating endogenous asparagine pool. ² , ³ The dependence of leukemic cells on exogenous asparagine supplies the rationale for asparaginase treatment.The pharmacodynamic (PD) goal of asparaginase therapy is asparagine depletion. Asparagine levels are difficult to measure accurately when asparaginase is present in blood because the enzyme can continue to break down asparagine ex vivo if the sample is not immediately processed and stored on ice. Therefore, monitoring of serum asparaginase levels is more reliable than measurement of asparagine itself. In clinical practice, serum asparaginase activity (SAA) levels serve as a surrogate marker for asparagine depletion. Although the level of asparaginase activity required for complete asparagine depletion still remains under debate, nadir SAA levels ≥ 0.1 IU/mL have been used in various studies and treatment protocols and are the accepted threshold for demonstrating adequate asparagine depletion. ⁴ , ⁵ Due to the short half‐life, the administration schedule of some L‐asparaginases is an important variable requiring dosing every 48–72 hours, a schedule that in clinical practice translates to a dosing schedule of Monday/Wednesday/Friday for 2 weeks, for a total of 6 doses. Clinical practice guidelines also recommend checking SAA levels after dosing to make any necessary adjustments to maintain nadir SAA levels ≥ 0.1 IU/mL. If the 48‐ or 72‐hour postdose level is below the lower limit of quantification (LLOQ), this may indicate a need for higher or more frequent dosing. The route of administration of L‐asparaginases is also an important component; in clinical practice, both the i.m. and i.v. routes are used routinely, depending on the treating oncologist’s preference and/or institutional guidelines. ⁴ L‐asparaginases are immunogenic and can induce hypersensitivity reactions with high titers of neutralizing antibodies that may limit their therapeutic effect. ³ , ⁶ Previous studies reported hypersensitivity reactions in up to 30% of patients treated with asparaginases, leading to early discontinuation of asparaginase treatment in some of those patients. ⁷ , ⁸ , ⁹ Unfortunately, the inability to receive asparaginase due to hypersensitivity reactions is associated with poor patient outcomes. ¹⁰ , ¹¹ High‐risk and slow early responding standard‐risk patients with ALL who do not complete their prescribed asparaginase course have a significantly inferior event‐free survival (EFS) compared with patients who complete their prescribed course. ¹⁰ , ¹¹ Additionally, some patients may develop antibodies to asparaginases that neutralize the asparaginase without leading to clinical hypersensitivity; this is known as silent inactivation. ³ Alternative asparaginase preparations are needed to ensure that patients who develop hypersensitivity to Escherichia coli (E. coli)‐derived asparaginases are able to complete their full treatment course. Asparaginase Erwinia chrysanthemi (ERW; crisantaspase) is an effective treatment option for patients with ALL who have developed hypersensitivity to E. coli‐derived asparaginase. ³ , ¹² However, since 2016, there has been a worldwide shortage of ERW due to ongoing manufacturing issues, which have resulted in disruptions in the ability to make the product available on a consistent basis. ¹³ Both JZP‐458 and ERW are forms of Erwinia asparaginase or crisantaspase. JZP‐458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform. The primary amino acid sequence of JZP‐458 is the same as Erwinia asparaginase, and the activity is comparable based on a broad range of in vitro measurements (Jazz Pharmaceuticals data on file). Therefore, similar to Erwinia asparaginase, JZP‐458 is also expected to have no immunologic cross‐reactivity to E. coli‐derived asparaginases. ¹⁴ JZP‐458 is being developed as a component of a multi‐agent chemotherapeutic regimen to treat patients with ALL or lymphoblastic lymphoma (LBL) who develop hypersensitivity to E. coli‐derived asparaginases.JZP‐458 was evaluated in a randomized, single‐center, open‐label phase I study. The study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single dose of JZP‐458 in healthy adult volunteers following either an i.m. injection or a 2‐hour i.v. infusion. Data from this study will facilitate the selection of an appropriate starting dose and dosing regimen of JZP‐458 for use in a pivotal phase II/III study in adult and pediatric patients with ALL or LBL who develop hypersensitivity to E. coli‐derived asparaginases.