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Abstract Background The POWER study (NCT03782376) evaluated efficacy and safety of a single ustekinumab intravenous (IV) reinduction dose versus placebo under continued ustekinumab subcutaneous (SC) treatment in adult patients with moderately to severely active Crohn’s disease who demonstrated a secondary loss of response to ustekinumab every 8 weeks (q8w) maintenance therapy. Methods Patients were randomly assigned 1:1 at Week 0 to ustekinumab IV reinduction (ustekinumab ∼6 mg/kg and SC placebo) or continuous maintenance (IV placebo and SC ustekinumab 90 mg q8w). Clinical and biomarker assessments occurred at Weeks 0, 8, 16, and 24 with optional ileocolonoscopy at Weeks 0 and16. The primary endpoint was clinical response (≥100-point decrease from baseline Crohn’s Disease Activity Index [CDAI] score or CDAI <150) at Week 16. Safety events were analyzed through Week 36 and serum samples were collected for pharmacokinetic analyses and anti-ustekinumab antibody detection. Results Overall, 215 patients were randomized: 108 to the IV reinduction group and 107 to the SC group. In the IV reinduction group, 49.1% achieved clinical response at Week 16 versus 37.4% in the SC group (adjusted treatment difference 11.5% [95% CI: −1.5%, 24.5%; P = .089]). Proportions of patients with endoscopic remission and improvement, normalization of inflammatory biomarkers, and improvement in IBDQ score were greater in the IV reinduction group vs the SC group. No new safety signals were identified. Conclusions Although the primary endpoint of clinical response was not met at Week 16, ustekinumab IV reinduction showed numerical improvements in objective endpoints including inflammatory biomarkers and endoscopic outcomes compared with SC maintenance therapy. Safety and immunogenicity results were consistent with the established profile of ustekinumab. Lay Summary Some patients with Crohn’s disease who respond to biologic treatment may lose response over time. The POWER study evaluated the efficacy and safety of receiving an additional intravenous dose of ustekinumab in patients who initially lost response to ustekinumab. Graphical abstract Graphical Abstract

A new pegylated recombinant L-asparaginase (MC0609) was designed to improve pharmacokinetic characteristics and to further reduce immunogenicity in comparison with the currently marketed pegylated Escherichia coli L-asparaginase (pegaspargase, Oncaspar(®)). Comparative pharmacokinetics (PK), bioavailability, pharmacodynamics and immunogenicity studies were performed in CD(®) rats and Beagle dogs after intravenous (i.v.) and intramuscular (i.m.) single-dose administration of MC0609 or Oncaspar(®). Bioanalytical data on enzymatic activity in serum of animals were used to develop a population pharmacokinetic (PopPK) model to simulate different dosages of MC0609 comparable to the activity time profile of Oncaspar(®). In contrast to Oncaspar(®), which showed an accelerated elimination over time, a constant serum elimination of enzymatic activity over time was seen for MC0609. Linear PK of MC0609 resulted in a prolonged and dose-dependent duration of enzymatic activity and longer depletion of L-asparagine in peripheral blood. The different PK characteristics of MC0609 and Oncaspar(®) were confirmed by PopPK analysis and model development. The PK parameters of Oncaspar(®) in dog scaled to body surface area were in the same range than the parameters determined in paediatric acute lymphoblastic leukaemia patients. Therefore, the dog is considered a clinically relevant model for PK evaluation of Oncaspar(®). Distinct differences in immunogenic potential of both preparations were detected after single-dose administration of a therapeutic dose to dogs. An absolute bioavailability of 66 % was calculated for the intramuscular administration of MC0609. The new pegylated recombinant L-asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar(®) in rat and dog.

Purpose A new pegylated recombinant l -asparaginase (MC0609) was designed to improve pharmacokinetic characteristics and to further reduce immunogenicity in comparison with the currently marketed pegylated Escherichia coli l -asparaginase (pegaspargase, Oncaspar ® ). Methods Comparative pharmacokinetics (PK), bioavailability, pharmacodynamics and immunogenicity studies were performed in CD ® rats and Beagle dogs after intravenous (i.v.) and intramuscular (i.m.) single-dose administration of MC0609 or Oncaspar ® . Bioanalytical data on enzymatic activity in serum of animals were used to develop a population pharmacokinetic (PopPK) model to simulate different dosages of MC0609 comparable to the activity time profile of Oncaspar ® . Results In contrast to Oncaspar ® , which showed an accelerated elimination over time, a constant serum elimination of enzymatic activity over time was seen for MC0609. Linear PK of MC0609 resulted in a prolonged and dose-dependent duration of enzymatic activity and longer depletion of l -asparagine in peripheral blood. The different PK characteristics of MC0609 and Oncaspar ® were confirmed by PopPK analysis and model development. The PK parameters of Oncaspar ® in dog scaled to body surface area were in the same range than the parameters determined in paediatric acute lymphoblastic leukaemia patients. Therefore, the dog is considered a clinically relevant model for PK evaluation of Oncaspar ® . Distinct differences in immunogenic potential of both preparations were detected after single-dose administration of a therapeutic dose to dogs. An absolute bioavailability of 66 % was calculated for the intramuscular administration of MC0609. Conclusions The new pegylated recombinant l -asparaginase preparation MC0609 revealed striking differences in PK/PD properties compared with Oncaspar ® in rat and dog.