JZP458 receives CHMP recommendation for approval in ALL, lymphoblastic lymphoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of JZP458, a recombinant erwinia asparaginase or chrysantaspase, for use in combination with multiagent chemotherapy for the treatment of adult and pediatric patients 1 month of age and older with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who have developed hypersensitivity or silent inactivation to Escherichia coli (E. coli) asparaginase derivative.¹

The European Commission will review the CHMP recommendation and is expected to take a final decision on approval soon.

“Today’s CHMP positive opinion is good news for those in the ALL and LBL community who cannot be treated with E. coli-derived asparaginase due to hypersensitivity reactions,” said Robert Iannone, MD, MSCE, executive vice president, global head of research and development, Jazz Pharmaceuticals, in a news release.

Asparaginase is central to multiagent chemotherapy regimens in ALL. However, up to 30% of patients will develop hypersensitivity to E. coli-derived asparaginase, requiring patients to stop treatment or switch to a non-E. coli-derived asparaginase preparation. Patients who are unable to receive asparaginase due to hypersensitivity, including those unable to compete on all prescribed doses, have been shown to have poor outcomes.

JZP458 is a recombinant Erwinia asparaginase or chrysantaspase that uses a Pseudomonas fluorescens expression platform. It was developed for use in conjunction with multi-agent chemotherapy regimens in the treatment of adult and pediatric ALL and LBL patients who have developed hypersensitivity to E. coli-derived asparaginase products.

In June 2021, the FDA approved JZP458 for the treatment of this patient population, which became commercially available in July 2021 in the United States at the recommended dose of 25 mg/m2 administered intramuscularly every 48 hours.²

JZP458 was evaluated in the Phase 2/3 study JZP458-201 (NCT04145531),^2.3 an open-label, multicohort, multicenter study of 102 ALL or LBL patients with hypersensitivity to E. coli-derived asparaginase as part of a multi-agent chemotherapy regimen.

The median patient age was 10 years (range, 1-24). Patients received 6 doses of JZP458 intramuscularly on Monday, Wednesday and Friday at 25 mg/m² (cohort 1a), 37.5 mg/m2² (cohort 1b) and 25/25/50 mg/m2² (group 1c).

The primary endpoint was the proportion of patients able to maintain nadir serum asparaginase activity (NSAA) above 0.1 U/mL at 72 hours and at 48 hours during the first treatment cycle. The results showed that the percentage of patients maintaining NSAA 0.1 U/mL at 48 hours after a 25 mg/m dose² Rylaze dose was 93.6% (95% CI, 92.6%-94.6%).

Regarding safety, the most common adverse effects occurring in more than 20% of patients were abnormal liver tests, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia

References

1. Jazz Pharmaceuticals Receives Positive CHMP Opinion for JZP458 (a recombinant erwinia asparaginase or chrysantaspase) for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Press release. Jazz Pharmacy. July 21, 2023. Accessed July 21, 2023. https://investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-receives-chmp-positive-opinion-jzp458
2. FDA approves asparaginase erwinia chrysanthemi (recombinant) for leukemia and lymphoma. Press release. FDA. June 30, 2021. Accessed July 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-asparaginase-erwinia-chrysanthemi-recombinant-leukemia-and-lymphoma
3. Maese L, Loh ML, Choi MR, et al. Recombinant erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the AALL1931 phase 2/3 study. Blood. 2023;141(7):704-712 . doi:10.1182/blood.2022016923