Physicochemical and functional characterization of MYL-1501D, a proposed biosimilar to insulin glargine

Abstract

Insulin glargine is a long-acting analogue of human insulin that has been used to manage hyperglycemia in patients with diabetes mellitus (DM) for nearly 20 years. Insulin glargine has a relatively constant concentration-time profile that mimics basal levels of insulin and allows for once-daily administration. MYL-1501D is a biosimilar insulin glargine designed to offer greater access of insulin glargine to patients, with comparable efficacy and safety to the marketed reference product. We conducted a comprehensive panel of studies based on a formal analysis of critical quality attributes to characterize the structural and functional properties of MYL-1501D and reference insulin glargine products available in the United States and European Union. MYL-1501D was comprehensively shown to have high similarity to the reference products in terms of protein structure, metabolic activity (both in vitro cell-based assays and in vivo rabbit bioassays), and in vitro cell-based assays for mitogenic activity. The structural analyses demonstrated that the primary protein sequence was identical, and secondary and tertiary structures are similar between the proposed biosimilar and the reference products. Insulin receptor binding affinity and phosphorylation studies also established analytical similarity. MYL-1501D demonstrated high similarity in different metabolic assays of glucose uptake, adipogenesis activity, and inhibition of stimulated lipolysis. Rabbit bioassay studies showed MYL-1501D and EU-approved insulin glargine are highly similar to US-licensed insulin glargine. These product quality studies show high similarity between MYL-1501D and licensed or approved insulin glargine products and suggest the potential of MYL-1501D as an alternative cost-effective treatment option for patients and clinicians.

Assessing the Structural and Functional Similarity of Insulin Glargine Biosimilars

“…The maximum mass deviation of biosimilars from Lantus ® across batches was observed to be 0.025 Da and 0.01 Da, for A chain and B chain, respectively (Table S2 in ESM 2). The reported molecular masses of intact protein 4,9 and of A chain and B chain were well aligned with their respective theoretical masses for insulin glargine as reported in the literature. 9…”

“…The results obtained were comparable with the theoretical values reported in a similar study involving characterization of MYL-1501 (a proposed insulin glargine biosimilar). 9 The peak pattern resulted in comparable chromatograms with slight difference in peptide masses and retention times (RT) (Figure 2b). Cys-linked peptides at positions A6-A11, A7-B7, and A20-B19 were confirmed for all DPs (Table S4 in ESM 2).…”

“…Environment of chromatophores (intrinsic) in insulin glargine formulation was found in agreement with the theoretical values as well as a recent report on characterization of proposed biosimilar of insulin glargine. 9 Therefore, all insulin glargine biosimilars were found to compare well with Lantus ® (Table S5 in ESM 2).…”

“…5 However, only a few reports exist in public domain on thorough evaluation of the quality of biosimilars of insulin and its analogues. 6 -9…”

“…5 However, only a few reports exist in public domain on thorough evaluation of the quality of biosimilars of insulin and its analogues. [6][7][8][9] Insulin glargine is the first basal long-acting insulin analogue produced in Escherichia coli by recombinant DNA technology. Its onset of action starts within 90 minutes, and it remains active for 24 hours long in diabetes mellitus patients.…”