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 the approval of JZP458, a recombinant Erwinia asparaginase or crisantaspase, for use in combination with multi-agent chemotherapy for the treatment of adult and pediatric patients 1 month and older with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who developed hypersensitivity or silent inactivation to Escherichia coli (E. coli)–derived asparaginase.¹

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

“Today’s positive CHMP opinion is welcome news for those in the ALL and LBL community who are unable to be treated with E. coli-derived asparaginase due to hypersensitivity reactions," Robert Iannone, MD, MSCE, executive vice president, global head of research and development of Jazz Pharmaceuticals, stated in a news release. “We look forward to receiving the final decision that will help bring us one step closer to delivering a reliable supply of recombinant Erwinia asparaginase to patients in the European Union.”

Asparaginase is fundamental to multi-agent chemotherapy regimens in ALL. However, as many as 30% of patients will develop hypersensitivity to E. coli-derived asparaginase, requiring patients to discontinue treatment or switch to a non–E. coli-derived asparaginase preparation. Patients who are not able to receive asparaginase because of hypersensitivities, including those not able to compete all prescribed doses, have been shown to have poor outcomes.

JZP458 is a recombinant Erwinia asparaginase or crisantaspase that uses a Pseudomonas fluorescens expression platform. It is being developed for use alongside multi-agent chemotherapy regimens in the treatment of pediatric and adult patients with ALL and LBL who 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 a 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, multi-cohort, multicenter trial in 102 patients with ALL or LBL with hypersensitivity to E. coli-derived asparaginase as part of a multi-agent chemotherapeutic 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/m² (cohort 1b), and 25/25/50 mg/m² (cohort 1c).

The primary end point was the proportion of patients who were 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 proportion of patients maintaining NSAA ≥ 0.1 U/mL at 48 hours after a 25 mg/m² dose of Rylaze 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 test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia

References

1. Jazz Pharmaceuticals receives CHMP positive opinion for JZP458 (a recombinant Erwinia asparaginase or crisantaspase) for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. News release. Jazz Pharmaceuticals. 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. News 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 phase 2/3 AALL1931 study. Blood. 2023;141(7):704-712. doi:10.1182/blood.2022016923