Jazz Pharmaceuticals recently announced positive results from a phase II/III trial, developed and conducted in close collaboration with the Children's Oncology Group, evaluating the IM administration of Rylaze (asparaginase erwinia chrysanthemi [recombinant]-rywn) in adult and pediatric patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who have developed hypersensitivity to an E coli–derived asparaginase. These results were presented as an oral presentation at the recent American Society of Clinical Oncology (ASCO) 2022 Annual Meeting.

The results from the trial confirm the interim trial analysis presented in December 2021 at the 63rd American Society of Hematology Annual Meeting and demonstrated that >90% of patients in Cohort 1c receiving the IM dosing regimen of 25/25/50 mg/m2 administered Monday/Wednesday/Friday (MWF) achieved nadir serum asparaginase activity (NSAA) levels >0.1 IU/mL at 48 and 72 hours, with a safety profile consistent with what has been described for other asparaginases.

Data presented at ASCO included efficacy and safety results from the phase II/III open-label, multicenter, pharmacokinetic (PK) trial of Rylaze (also known as JZP458) in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E coli–derived asparaginase. These results are from Part A of the trial, which investigated three cohorts via IM administration:

• Cohort 1a (n = 33): studied a dose of 25 mg/m2 MWF
• Cohort 1b (n = 83): studied a dose of 37.5 mg/m2 MWF
• Cohort 1c (n = 51): studied a dose of 25 mg/m2 on Monday and Wednesday, and 50 mg/m2 on Friday.

The primary efficacy endpoint of the trial was the percentage of patients with NSAA levels >0.1 IU/mL at the last 72 hours during the first treatment course. The key secondary endpoint was the percentage of patients with NSAA levels >0.1 IU/mL at the last 48 hours during the first treatment course.

A population PK (PPK) model was developed based on serum asparaginase activity data from the clinical trial to characterize the PK of JZP458 when given IM and to inform dosing decisions. Simulated data from the PPK model matched the observed data well.

Based on a PPK modeling and simulation analysis, the percentage of patients predicted to achieve NSAA levels >0.1 IU/mL with a 95% CI in Cohort 1c at the last 72 and 48 hours in Course 1 were 92% (91%, 93%) and 94% (93%, 95%), respectively, based on modeled data.

In Cohort 1c in this trial, the following treatment-related adverse events (TRAEs) leading to termination of therapy were noted:

Patients, n (%)/Cohort 1c: 25/25/50 mg/m2 MWF (n = 51):

• Any TRAE leading to study drug discontinuation/5 (10)
• Pancreatitis/4 (8)
• Drug hypersensitivity/Any TRAE leading to study drug discontinuation/1 (2)
• Anaphylactic reaction/0
• Increased alanine aminotransferase/0
• Hyperammonemia/0.

There were no reports of TRAEs resulting in death, and the safety profile was consistent with the published literature on asparaginase administered as a component of a multiagent chemotherapeutic regimen.

Rob Iannone, MD, MSCE, executive vice president, global head of research and development of Jazz Pharmaceuticals, stated, "We are excited to share these results from the Phase 2/3 trial of Rylaze highlighting the clinically meaningful nadir serum asparaginase activity from the Monday/Wednesday/Friday dosing regimen, which supports a new dosing schedule that aligns with current clinical practice, Rylaze is an example of how Jazz and the Children's Oncology Group have advanced a critically needed treatment from development through FDA approval, and then continue to explore additional dosing and administration options to address the needs of patients."

The primary investigator, Luke Maese, associate professor of pediatric hematology-oncology at the University of Utah, Primary Children's Hospital and Huntsman Cancer Institute, stated, "Asparaginase-based therapies remain a cornerstone in ALL and LBL treatment, and Rylaze has been an important option for patients who develop a hypersensitivity to an E. coli-derived asparaginase since its approval last year. It's encouraging to see these data further support an IM Monday/Wednesday/Friday dosing schedule for Rylaze, which is more in line with clinical practice in the U.S., in addition to the currently approved schedule of every 48 hours."

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