FDA Biologics License Application for JZP-458 Initiated for 2 Leukemia Indications

The submission of a Biologics License Application (BLA) has been initiated seeking approval of JZP-458 as a part of a multi-agent chemotherapy regimen as treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who developed hypersensitivity or silent inactivation to E. coli-derived asparaginases, announced Jazz Pharmaceuticals in a press release.¹

The BLA will be reviewed under the Real-Time Oncology Review (RTOR) pilot program, which was designed by the FDA’s Oncology Center of Excellence to expedite the delivery of safe and effective therapies to patients with cancer.

"Given the urgent need for a reliable and high-quality recombinant asparaginase option for patients with hypersensitivity to E. coli-derived asparaginase, we are committed to bringing JZP-458 to market as quickly as possible and pleased to be initiating our BLA submission," said Robert Iannone, MD, MSCE, executive vice president, Research and Development of Jazz Pharmaceuticals, in a statement. "Receiving a Fast Track designation for JZP-458 from the FDA in October 2019 and being able to submit the BLA under the RTOR program is significant, potentially allowing us to more quickly address patient needs with a new asparaginase option."

Plans are in the works to launch JZP-458 in mid-2021 following the completion of the BLA submission, the FDA review, and the potential approval.

A pivotal phase 2/3 clinical trial (NCT04145531) is currently underway, evaluating the therapy as treatment of patients with ALL or LBL who are hypersensitive to E. coli-derived asparaginases. . This study was announced during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.²

The open-label, multicenter dose-confirmation pharmacokinetic study includes 2 co-primary end points, response rate during the first course of therapy and occurrence of treatment-emergent adverse events. Secondary end points include proportions of patients with the last 48-hour nadir serum asparaginase activity (NSAA) level ≥ 0.1 IU/mL and ≥ 0.4 IU/mL during the first course of therapy and with the last 72-hour NSAA level ≥ 0.4 IU/mL during the first course. Pharmacokinetics of JZP-458 and the incidence of anti-drug antibody formation against the drug serve as 2 other secondary end points.

The study includes 2 sequential parts, in which part A determines the dose of intramuscular JZP-458 and confirms the efficacy and safety while part B explores the appropriate dose and schedule of intravenous JZP-458. Blood samples are also collected to determine SAA levels. Patients will also be evaluated for adverse events, and the immunogenicity of the therapy will be explored.

A phase 1 study of healthy adult patients, JZP-458 appeared to maintain adequate of ≥0.1 IU/mL SAA, which is a surrogate marker for asparagine depletion, for up to 72 hours. The therapy demonstrated an adequate safety profile, as well.

To be included in the study, patients must have an ALL or LBL diagnosis, have had an allergic reaction to long-acting E. coli-derived asparaginase OR have silent inactivation, 1 or more course of E. coli-derived asparaginase remaining in their treatment plan, and have fully recovered from their prior allergic reaction in the opinion of the investigator. Patients are ineligible to enroll if they have previously received asparaginase Erwinia chrysanthemi or JZP-458, relapsed disease, are concurrently receiving another investigational agent, have a history of grade ≥ 3 pancreatitis, or prior history of asparaginase-associated grade ≥ 3 hemorrhagic event or asparaginase-associated thrombus requiring anticoagulation therapy.

_Reference

_{1. Jazz Pharmaceuticals Announces Initiation of Biologics License Application Submission for JZP-458 for the Treatment of Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma. News Release. December 21, 2020. Accessed December 21, 2020. https://prn.to/37DkpVN}

_{2. Maese L, Rau RE, Raetz EA, et al. A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases. Presented at: 2020 ASCO Virtual Scientific Meeting. Virtual. Abstract TPS7568.}