Pharmacokinetics and Pharmacodynamics of Novel Long-Acting Pegylated Recombinant Asparaginase Comparing with Pegaspargase: A Dose-Escalation, Phase Ia Trial in Chinese Healthy Subjects
Authors: Fan Kai , Chen Qing , He Yunfeng , Tang Guanghui , Xu Liexing , Sun Jing 
Published: December 2024

Asparaginase is a critical agent in the treatment of Acute Lymphoblastic Leukemia (ALL) and lymphoblastic lymphoma (LL). The addition of asparaginase to multi-drug chemotherapy significantly improved the rates of complete remission and progression free survival of patients. PD5K3, a new generation of long-acting asparaginase, is obtained by site-directed mutagenesis of asparaginase sequence derived from Escherichia coli and subsequent saturation modification with polyethylene glycol (5K-SPA-PEG) to achieve a longer half-life and lower immunogenicity.

Preclinical studies have shown that the enzyme activity of PD5K3 is comparable to that of pegaspargase and Asparlas. PD5K3 significantly inhibits the proliferation of various human leukemia or lymphoma cells lines in vitro, such as HL-60, Jurkat, L1210 and Raji cells, with IC50 ranged from 0.262 to 2.250 IU/ml, and the inhibitory effect is comparable to pegaspargase. PD5K3 can significantly inhibit the growth of Nalm-6-Luc human B-lymphoblastic leukemia in NCG mice in a dose-dependent manner, and the anti-tumor effect is comparable to pegaspargases and Asparlas. After intravenous administration to rats and dogs, the half-life of plasma asparaginse activity of PD5K3 is comparable to that of Asparlas, but significantly longer than pegaspargases. After administration to dogs, plasma asparagine concentrations decreased and were not detectable (&lt; 0.1 μg/mL) for all treatment groups at the 5 minutes postdose time point and remained undetectable for 35 days for both PD5K3 and Asparlas groups, and 18 days for pegaspargases group.

A phase Ia clinical trial (NCT06527781) to evaluate the safety and tolerability of PD5K3 in healthy adult Chinese subjects has been completed. Several dose levels were planned to be evaluate in this trial, with 14 subjects in each group. Eight subjects in each dose level will be randomized to receive PD5K3 and 2 subjects receive placebo in double-blind mode, and 4 subjects receive open-labelled pegaspargase. The enrollment of first 2 dose levels (250 and 500 U/m^2) has been completed and the results of 500 U/m^2 meet the termination criteria. The results showed that compared with pegaspargase, PD5K3 exhibited better tolerance and lower immunogenicity. The major adverse events were pharmacologically related toxicities, including decreased antithrombin III activity (grade 1), neutrophil count (grade 3), and white blood cell count (grade 2). PD5K3 maintained plasma asparaginase activity for a longer period compared with pegaspargase. PD5K3 and pegaspargase showed comparable asparaginase activity in plasma from 4 days postdose to 14 days. The enzyme activity in the pegaspargase groups decreased relatively quickly within 14 to 28 days after administration, while that in PD5K3 group remained high. According to preliminary dose extrapolation predictions based on quantitative pharmacology, PD5K3 is expected to maintain plasma asparaginase activity level ≥ 0.1 IU/ml for 21 days after administration at the dose of 1500 U/m^2. Previously published reports have concluded that ≥ 0.1 IU/ml is an appropriate target level of asparaginase activity associated with complete asparagine depletion, and considered to be effective in the treatment of ALL/LL.

Based on the results of phase Ia, a multicenter, dose-escalation and dose-expansion Phase Ib clinical trial is now planned to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PD5K3 in combined chemotherapy regimen in patients. Eligible patients (aged 12 to 40 years) had newly diagnosed ALL/LL or relapsed/refractory ALL/LL which could be still benefit from the VDCP regimen as assessed by the investigators.