Regulatory Decision Summary for Asparlas

The purpose of this submission is to seek market authorization for Asparlas as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most commonly diagnosed cancer in children. Asparaginase is a critical component of multi-agent chemotherapeutic regimens for pediatric ALL. Oncaspar (Pegaspargase) is the only asparaginase product used for newly diagnosed ALL in Canada. There is a need for novel asparaginase products to provide treatment options and ensure a stable supply of asparaginase products to Canadian patients.

Asparlas (calaspargase pegol), a new pegylated E coli-derived L-asparaginase, was compared with Oncaspar as a component of a multi-agent chemotherapeutic regimen in two multicentre, randomized, controlled clinical studies DFCI 11-001 and AALL07P4 in pediatric (≥ 1 year of age) and young adult patients with newly diagnosed ALL. In Study DFCI 11-001, patients (n = 230) were randomized to receive Asparlas 2,500 international units (IU)/m² every three weeks (n = 114) or Oncaspar 2,500 IU/m² every two weeks (n = 116) as a component of the Dana Farber Cancer Institute ALL consortium regimen. In Study AALL07P4, patients (n = 97) were randomized to receive Asparlas 2,500 IU/m² (n = 42) or pegaspargase 2,500 IU/m² (n = 55) as a component of the augmented Berlin-Frankfurt-Münster (BFM) ALL regimen. The dosing frequency was the same for Asparlas and Oncaspar. The intervals between the two doses ranged from 2 to 5.5 weeks.

The efficacy of Asparlas was determined based on the achievement and maintenance of nadir asparaginase activity ≥ 0.1 IU/mL in patients treated with Asparlas. Following a single dose administration of 2,500 IU/m² in Study AALL07P4, the majority of patients achieved asparaginase activity ≥ 0.1 IU/mL on Day 18 and Day 25. The nadir serum asparaginase activity (NSAA) level ≥ 0.1 IU/mL is expected to be maintained in 99% of the patients receiving Asparlas 2,500 IU/m² Q3W based on modelling and simulation results.

In Study DFCI 11-001, the most common adverse reactions reported in ≥ 20% of patients treated with Asparlas were hypoalbuminemia, alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, hypertriglyceridemia, hyperglycemia, and blood fibrinogen decreased. The safety findings between the Asparlas and Oncaspar groups were generally similar and no new asparaginase-related adverse reactions were observed. In Study AALL07P4, adverse events associated with asparaginase were generally increased in the Asparlas group compared to the pegaspargase group. The small sample size and higher representation of older patients in the study limit the interpretation of these findings. However, the role of a higher exposure to asparaginase activity in the Asparlas group cannot be ruled out, as the same numbers of doses were administered for Asparlas and pegaspargase in Study AALL07P4. This uncertainty is adequately managed via labelling (i.e., risks are described in the Product Monograph) and enhanced post-market surveillance for Asparlas.

Overall, based on the evidence reviewed, the anticipated benefit of Asparlas outweighs the potential risks and remaining uncertainties as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL in pediatric and young adult patients age 1 to 21 years. A Notice of Compliance is recommended.

The recommended dose of Asparlas is 2,500 IU/m2 administered as intravenous infusion no more frequently than every 21 days.

An updated Risk Management Plan (RMP) for Asparlas was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Asparlas has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

A Notice of Compliance was recommended.

For further details about Asparlas, please refer to the Product Monograph, approved by Health Canada and available through the .Drug Product Database