Comparability of biosimilar romiplostim with originator: Protein characterization, animal pharmacodynamics and pharmacokinetics.

The results of preclinical studies of romiplostim analogue GP40141 are presented. The effect of a cell proliferation, phosphorylation of the TPO receptor and JAK2 phosphorylation were studied in the presence of romiplostim and in the presence of GP40141 in a cell line of mice (Mus musculus) lymphoblasts with stable expression of human TPO receptor 32D-hTPOR clone 63. Binding to the TPO receptor and to the neonatal Fc receptor (FcRn) was examined for both romiplostim and the developed analogue. In Sprague-Dawley rats, the dynamics of platelet count after the administration of romiplostim or GP40141 were determined. The pharmacokinetics of romiplostim and GP40141, as well as the dynamics of platelet count, were studied in cynomolgus monkeys. The serum concentrations of romiplostim were determined using a modified colorimetric enzyme-linked immunosorbent assay (ELISA). The data obtained allow us to assert the similarity of the biological action of Nplate® and GP40141.

The efficacy and safety of GP40081 (insulin aspart biphasic 30) compared with NovoMix® 30 in Type 2 diabetes patients.

Aim: To evaluate the safety and efficacy of insulin Aspart-Mix biosimilar candidate GP40081 (GP-Asp30) compared with NovoMix® 30 (NN-Asp30). Materials & methods: In a randomized open-label, active-controlled, 26-week non-inferiority clinical trial 264 patients with Type 2 diabetes mellitus were randomized 1:1 to receive once-daily GP-Asp30 or NN-Asp30. The primary safety end point was the immune response rate. Efficacy outcomes were a mean change in HbA1c (primary), frequency of achieving a glycemic g fasting plasma glucose levels, 7-point glucose profiles, and insulin doses. Results: The immune response developed in 10/126 (8%) participants in the GP-Asp30 group and in 10/125 (8%) participants in the NN-Asp30 group (p = 1.000). The mean difference in HbA1c change between groups was 0.12 (95%CI [-0.14, 0.38]). Other secondary efficacy and safety outcomes weren't statistically different between the two groups. Conclusion: GP-Asp30 demonstrated similar safety and efficacy compared with NN-Asp30 and may be considered a biosimilar insulin.

PKPD Modeling and Simulations to Support Biosimilar Development of Biphasic Insulin Aspart 30.

This paper presents an analysis of data from a comparative study of biosimilarity in terms of pharmacokinetics and pharmacodynamics in healthy volunteers using a hyperinsulinemic euglycemic clamp for reference and test biphasic insulin aspart 30 (BIAsp 30). As a result of the study, one of the secondary pharmacodynamic (PD) endpoints did not satisfy the classical criterion of 80%-125% (the lower limit for PD parameter area under the glucose infusion rate-time curve [ AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ ] turned out to be 79.5%). The main hypothesis explaining this result is that the sample size is insufficient to conduct a PD test with 90% statistical power, since the sample size has been calculated based on the coefficient of variation (CV) of pharmacokinetic (PK) parameters. To test this hypothesis, population PKPD (popPKPD) modeling and subsequent simulations of the required number of PD profiles were used. Two popPKPD models were constructed (a one-compartment double simultaneous absorption model for PK and an effect compartment Emax model for PD) to describe the PKPD data of reference and test insulins. As a result, using real data along with model-based simulation data, a biosimilarity test for PD was performed, and the lower limit for AUC GIR 0 - t ${\rm{AUC}}_{{\rm{GIR}}_{0 - {\rm{t}}}}$ became 82.6%, while the CV decreased from 31.7% to 24.1%. Thus, popPKPD modeling and simulations have been shown to be effective in interpreting and supporting the results of clinical biosimilarity trials.

Clinical Pharmacology of Insulin Aspart Biosimilar GP40071: Pharmacokinetic/Pharmacodynamic Comparability in Hyperinsulinemic Euglycemic Clamp Procedure.

Insulin aspart is a short-acting insulin analogue that is used to control postprandial glycemia levels in diabetic patients. The aim of this clinical trial was to compare the pharmacokinetics and pharmacodynamics of GP40071 (GP-Asp) and NovoRapid Penfill (Novo-Asp) in a hyperinsulinemic euglycemic clamp (HEC). This trial was conducted as a part of a GP40071 biosimilar clinical development program. This was a phase I randomized, double-blind, two-period crossover study. Twenty-six healthy male volunteers aged 18 to 45 years who met the inclusion criteria underwent the procedure of an HEC following a single subcutaneous injection of 0.3 IU/kg of either GP-Asp or Novo-Asp into the abdomen. After doses, plasma glucose levels were monitored every 5 minutes for 8 hours. The adjustment of the glucose infusion rate (GIR) was based on the blood glucose measurements. The GIR values were used to evaluate the PD profiles of the studied drugs. Regular blood sampling was performed during the study to obtain sufficient pharmacokinetic data. The 90% confidence intervals for the geometric mean ratios of the pharmacokinetic (AUCins.0-t , Cins.max ) and pharmacodynamic (GIRmax , AUCGIR0-t ) parameters of GP-Asp were within the 80%-125% comparability limits. The safety profiles of the drugs were also comparable. Bioequivalence, similar PD, and safety of GP-Asp and Novo-Asp were demonstrated.

Modeling of Pharmacokinetic Profiles of Insulin Aspart and Biphasic Insulin Aspart 30/70.

This study includes modeling and simulation of insulin aspart pharmacokinetics (PK). The authors used PK data of biosimilar insulins-insulin aspart and biphasic insulin aspart 30/70-to develop a predictive population PK model for the insulins. The model was built via Monolix software, taking into account the weight-based dosing and the dose and body-weight effects on the parameters. The model-based simulations were performed using the R package mlxR for various administered doses and various ratios of insulin aspart forms for a better understanding of the insulin behavior. The optimal model was a 1-compartment model with a combination of zero- and first-order absorptions, with absorption lag for the soluble form of insulin aspart and first-order absorption for the insulin aspart protamine suspension. The assumption of identical behavior of 2 insulins at the distribution and elimination phases was made. The developed PK model was fitted successfully to the experimental data, and all fitted parameters displayed a moderate coefficient of variation. The PK model allows us to predict PK profiles for various doses and formulations of insulin aspart and can be used to improve the accuracy, safety, and ethics of novel clinical trials of insulin.

Neuroprotective action of Cortexin, Cerebrolysin and Actovegin in acute or chronic brain ischemia in rats.

This study was the first to compare the neuroprotective activity of Cerebrolysin®, Actovegin® and Cortexin® in rodent models of acute and chronic brain ischemia. The neuroprotective action was evaluated in animals with acute (middle cerebral artery occlusion) or chronic (common carotid artery stenosis) brain ischemia models in male rats. Cortexin® (1 or 3 mg/kg/day), Cerebrolysin® (538 or 1614 mg/kg/day) and Actovegin® (200 mg/kg/day) were administered for 10 days. To assess the neurological and motor impairments, open field test, adhesive removal test, rotarod performance test and Morris water maze test were performed. Brain damage was assessed macro- and microscopically, and antioxidant system activity was measured in brain homogenates. In separate experiments in vitro binding of Cortexin® to a wide panel of receptors was assessed, and blood-brain barrier permeability of Cortexin® was assessed in mice in vivo. Cortexin® or Cerebrolysin® and, to a lesser extent, Actovegin® improved the recovery of neurological functions, reduced the severity of sensorimotor and cognitive impairments in rats. Cortexin® reduced the size of necrosis of brain tissue in acute ischemia, improved functioning of the antioxidant system and prevented the development of severe neurodegenerative changes in chronic ischemia model. Radioactively labeled Cortexin® crossed the blood-brain barrier in mice in vivo with concentrations equal to 6-8% of concentrations found in whole blood. During in vitro binding assay Cortexin® (10 µg/ml) demonstrated high or moderate binding to AMPA-receptors (80.1%), kainate receptors (73.5%), mGluR1 (49.0%), GABAA1 (44.0%) and mGluR5 (39.7%), which means that effects observed in vivo could be related on the glutamatergic and GABAergic actions of Cortexin®. Thus, Cortexin, 1 or 3 mg/kg, or Cerebrolysin®, 538 or 1614 mg/kg, were effective in models acute and chronic brain ischemia in rats. Cortexin® contains compounds acting on AMPA, kainate, mGluR1, GABAA1 and mGluR5 receptors in vitro, and readily crosses the blood-brain barrier in mice.

Efficacy and safety of GP40021 insulin lispro biphasic compared with Humalog Mix 25 in Type 2 diabetes mellitus patients.

Aim: To compare safety (immunogenicity) and efficacy of a biosimilar insulin GP-Lis25 and a reference insulin Ly-Lis25 (Humalog Mix 25) in Type 2 diabetes mellitus (T2D) patients. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 210 T2D patients, randomized 1:1 to twice-daily GP-Lis25 or Ly-Lis25. The primary end point was immune response at 26th week. Noninferiority margin for HbA1c was 0.4%. Results: Immune response frequency was similar in GP-Lis25 and Ly-Lis25 groups both at week 12 (p = 0.651) and 26 (p = 0.164). The difference of HbA1c change at week 26 was (95% CI) 0.01 (-0.27-0.28)%. Fasting plasma glucose, seven-point glucose profile and insulin dose were similar between groups. Safety did not differ between groups. Conclusion: GP-Lis25 and Ly-Lis25 demonstrated similar safety and efficacy. ClincalTrials.gov identifier: NCT04023344.

Safety and efficacy of GP40061 compared with originator insulin glargine (Lantus®): a randomized open-label clinical trial.

Aim: To compare safety (immunogenicity) and efficacy of GP40061 insulin glargine (GP-Gla) and Lantus® (Sanofi glargine, Sa-Gla) in people with diabetes mellitus. Materials & methods: This randomized open-label, 26-week clinical trial enrolled 180 Type 1 diabetes mellitus patients (HbA1c 6.5-12.0%), randomized 1:1 to once daily GP-Gla (n = 90) or Sa-Gla (n = 90). The primary end point was immune response at 26th week. Results: The frequency of immune response was similar in GP-Gla and Sa-Gla (p = 1.000). Groups were similar in terms of other safety end points. Mean HbA1c change from baseline was -0.66% for GP-Gla and -0.77% for Sa-Gla, and did not differ between groups (p = 0.326). Insulin doses, fasting plasma glucose and seven-point glucose profiles were similar between groups. Conclusion: GP-Gla and Sa-Gla demonstrated similar safety and efficacy. ClinicalTrials.gov Identifier: NCT04022993.