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.
Highlights
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 [1, 2]
Peptide mapping and MS/MS analysis confirmed that the primary amino acid sequence of MYL-1501D was identical to the sequences of US- and EU-licensed insulin glargine
The panel of structural and functional studies conducted to evaluate the comparability of MYL-1501D to US- and EU-licensed preparations of insulin glargine demonstrated high similarity among the follow-on biologic and reference products
Summary
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 [1, 2]. The delayed absorption and slower release of insulin glargine is due to its low aqueous solubility at neutral pH [3, 6]. Asparagine at position 21 of the human insulin A-chain is replaced with glycine, and the carboxyl terminus of the insulin B-chain is elongated with the addition of 2 positively charged arginine molecules [3, 7]. The more positively charged amino acid sequence of insulin glargine causes a shift in the isoelectric point toward a neutral pH that, upon subcutaneous injection, creates a depot and a slower rate of absorption [7, 8]
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