Pharmacokinetic and pharmacodynamic bioequivalence of biosimilar MYL‐1601D with US and European insulin aspart in healthy volunteers: A randomized, double‐blind, crossover, euglycaemic glucose clamp study

Abstract

Aim: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL-1601D biosimilar with originator, NovoLog (Ref-InsAsp-US), and NovoRapid (Ref-InsAsp-EU).Materials and Methods: This was a double-blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration-time curve from 0 to 12 hours (AUC 0-12h ) and maximum plasma insulin aspart concentration (C max ). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUC GIR0-12h ) and maximum GIR (GIR max ). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS-mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL-1601D vs. Ref-InsAsp-US) and 95% CIs (MYL-1601D vs. Ref-InsAsp-EU) of primary PD variables, were to be within 80% to 125% to show BE.Results: MYL-1601D showed PK BE to both Ref-InsAsp-US (AUC 0-12h geometric LS-mean ratio 102.17, 90% CI [100.26; 104.11]; C max 106.13 [100.71; 111.85]) and Ref-InsAsp-EU

Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Aspart (MYL-1601D) Compared with Originator Insulin Aspart (Novolog®) in Patients with Type 1 Diabetes After 24 Weeks: A Randomized Open-Label Study

“…The analytical comparison showed that MYL-1601D and reference product are highly similar molecules with respect to physicochemical and functional properties [ 9 ]. The current study was designed to address the residual uncertainty and to detect differences between the treatments groups with immunogenicity parameters [ 27 ] as the primary endpoint following demonstration of PK-PD similarity in a euglycemic clamp study, which was more sensitive to detect any difference between the biosimilar and reference product compared with HbA1C in the diabetes patients [ 10 ]. Further, the study design, including primary and secondary endpoints, population selection, treatment duration, proposed margins, and statistical assumptions, was in accordance with the US-FDA scientific advice to ensure robust patient exposure to detect differences in immunogenicity, efficacy, and safety parameters.…”

“…The qualitative and quantitative composition of MYL-1601D has been identical to that of Ref-InsAsp-US and Ref-InsAsp-EU in physicochemical analyses and nonclinical studies with no clinically meaningful differences observed [ 9 ]. A euglycemic clamp study demonstrated pharmacokinetic (PK) and pharmacodynamic (PD) similarity of MYL-1601D versus both Ref-InsAsp-US and Ref-InsAsp-EU in healthy volunteers [ 10 ].…”