Benzinga | Dec 12, 2021 09:40AM EST

Jazz Pharmaceuticals Presented Interim Phase 2/3 Results of Rylaze in Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma at ASH 2021; Said Rylaze Maintains Clinically Meaningful Level of Asparaginase Activity Throughout the Entire Duration of Treatment

Jazz Pharmaceuticals plc (NASDAQ:JAZZ) today announced initial positive results from a Phase 2/3 trial of intramuscular (IM) administration of Rylaze(tm) (asparaginase erwinia chrysanthemi (recombinant)-rywn) in adult and pediatric patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) who have developed hypersensitivity or silent inactivation to an E. coli-derived asparaginase. The study was developed and conducted in close collaboration with the Children's Oncology Group (COG). These initial results will be presented for the first time today at the 63rd American Society of Hematology (ASH) Annual Meeting.

Three cohorts with unique, IM administration dosing schedules were evaluated in the trial, demonstrating a safety profile consistent with other asparaginases. In Cohort 1c, a dosing regimen of Rylaze administered 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on Friday demonstrated a positive benefit-to-risk profile, showing that Rylaze maintains a clinically meaningful level of nadir serum asparaginase activity (NSAA) 0.1 IU/mL at both 48 and 72 hours. Rylaze was approved by the U.S. Food and Drug Administration (FDA) on June 30, 2021 under the Real-Time Oncology Review (RTOR) program for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in adult and pediatric patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze was approved at the dosing schedule of 25 mg/m2 every 48 hours based on data from Cohort 1a, in conjunction with data produced by a preliminary population pharmacokinetic (PPK) model.

These data will support additional regulatory filings for Rylaze, including a supplemental Biologics Licensing Application (sBLA) in early 2022 for a Monday/Wednesday/Friday (M/W/F) IM dosing schedule that will be reviewed under the FDA RTOR program. These data will also support regulatory submissions in Europe in mid-2022, with potential for approval in 2023.

"Asparaginase is an integral part of ALL therapy that is associated with improvement in survival rates. Following FDA approval earlier this year, Rylaze is already providing patients who have developed hypersensitivity to E. coli-derived asparaginase with a much-needed, effective therapeutic option with reliable supply and consistently high quality," said Rob Iannone, M.D., M.S.C.E., executive vice president, research and development and chief medical officer of Jazz Pharmaceuticals. "Rylaze is proof of Jazz's ability to take medicines from concept through development, approval and launch, and we look forward to working with the FDA through the sBLA submission with these additional data in early 2022 in support of a label expansion for M/W/F dosing."

"The results from the Phase 2/3 study for Rylaze help to expand our knowledge of its dosing and safety profile, and support Monday/Wednesday/Friday dosing, which is more in line with clinical practice," said primary study investigator Dr. Luke Maese, associate professor at the University of Utah, Primary Children's Hospital and Huntsman Cancer Institute. "The accelerated development and approval of Rylaze ensured that many patients with LBL and ALL most of whom are children who cannot tolerate E. coli-derived asparaginases have a new treatment option that maintains therapeutic levels of asparaginase activity throughout duration of treatment."

Interim Trial Results

Data presented at ASH 2021 include initial analyses from an ongoing Phase 2/3 open-label, multicenter, dose confirmation and pharmacokinetic (PK) study 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. Preliminary data are from Part A of the study, which investigated three Cohorts via IM administration:

Cohort 1a (n=33): studied a dose of 25 mg/m2 Monday/Wednesday/FridayCohort 1b (n=53): studied a dose of 37.5 mg/m2 Monday/Wednesday/FridayCohort 1c (n=52): studied a dose of 25 mg/m2 on Monday and Wednesday and 50 mg/m2 on FridayPart B of the Phase 2/3 study remains active to further confirm the dose and schedule of the intravenous (IV) route of administration for Rylaze.

Efficacy Findings

The primary efficacy endpoints of the trial were the proportion of patients with a last 72-hour (from Friday to Monday) NSAA levels of 0.1 IU/mL during the first treatment course, in addition to safety and tolerability of Rylaze in patients with ALL/LBL.

The key secondary endpoint included the proportion of patients achieving the last 48-hour NSAA 0.1 IU/mL during the first treatment course.

The proportion of patients with observed NSAA levels 0.1 IU/mL with a 95% CI during Course 1 from these initial results is as follows (primary and key secondary endpoints):

Cohort 1a

Cohort 1b

Cohort 1c

At 48 hours

97% (CI: 91%, 100%)

98% (CI: 95%, 100%)

96% (CI: 90%, 100%)

At 72 hours

66% (CI: 48%, 83%)

80% (CI: 70%, 91%)

90% (CI:81%, 98%)

Based on a PPK modeling and simulation analysis versus observed data for Cohort 1c, the proportion of patients predicted to achieve NSAA levels 0.1 IU/mL with a 95% CI from these initial results is as follows:

Observed

Model Prediction

At 48 hours

96% (CI: 90%, 100%)

93% (CI: 92%, 94%)

At 72 hours

90% (CI:81%, 98%)

91% (CI: 90%, 92%)

The mean serum asparaginase activity (SAA) levels were also determined: mean SAA levels (95% CIs) from the initial data in Cohorts 1a, 1b and 1c at 48 hrs were 0.45 IU/mL (0.37, 0.53), 0.84 IU/mL (0.68, 0.99), and 0.66 IU/mL (0.54, 0.77); and at 72 hrs were 0.15 IU/mL (0.12, 0.19), 0.30IU/mL (0.23, 0.37), and 0.46 IU/mL (0.34, 0.58), respectively. These results reflect the higher dose on Friday from Cohort 1c.

Safety Findings

Grade 3/4 treatment-emergent adverse events (TEAEs), regardless of causality, occurred in 78/137 (57%) patients. There were no treatment-related TEAEs leading to death. The most commonly reported non-hematologic TEAEs (in 20% in any cohort) regardless of causality included: vomiting, nausea, fatigue, decreased appetite, pyrexia, abdominal pain, alanine aminotransferase (ALT) increased, febrile neutropenia, back pain, headache, sinus tachycardia, stomatitits, pain in extremity, aspartate aminotransferase (AST) increased and hyperglycemia. Treatment-related TEAEs leading to study drug discontinuation occurred in 6/137 (4%) of patients.

Overall, the safety profile of Rylaze was consistent with the reported safety information for patients with ALL/LBL receiving asparaginase with combination chemotherapy.

Further study analyses (including PK and safety analyses) are ongoing, and full study results will be reported at a later date.