Insulin glargine biosimilars

Recombinant human insulin analogue in which asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B chain. The reference product is produced in Escherichia coli; several biosimilars use Pichia pastoris.

The added arginines shift the isoelectric point to about 6.7, so the product is soluble in the acidic injection solution but precipitates at the neutral pH of subcutaneous tissue. The microprecipitate dissolves slowly, giving a flat, prolonged absorption profile without the peak of intermediate insulins.

After subcutaneous injection, onset within one to two hours, no pronounced peak, and a duration of about 24 hours, permitting once-daily dosing. The 300 U/mL formulation (Toujeo) has a flatter and longer profile than the 100 U/mL because of its smaller depot surface area, and the two are not interchangeable unit for unit.

Once daily at the same time each day, titrated to fasting glucose. Supplied at 100 U/mL in 10 mL vials, 3 mL cartridges and 3 mL pre-filled pens; the reference product also at 300 U/mL. Pen device design and dose accuracy are assessed as part of every biosimilar application.

• Type 1 diabetes mellitus in adults, adolescents and children
• Type 2 diabetes mellitus requiring basal insulin

Anti-insulin antibodies are common with all insulins and cross-react between glargine and human insulin; they rarely affect glycaemic control. Comparative programmes rest on analytical similarity, pharmacokinetic and pharmacodynamic equivalence in euglycaemic clamp studies, and a comparative safety and immunogenicity study in type 1 diabetes, usually 26 to 52 weeks, with HbA1c as the efficacy measure.

Lantus was approved by FDA on 20 April 2000 (NDA 021081) and authorised in the EU on 9 June 2000 (EMEA/H/C/000284). In the United States insulins were regulated as drugs until 23 March 2020, when approved insulin NDAs were deemed biologics licences, opening the 351(k) biosimilar pathway. Lilly's Basaglar (2015) reached the US market through the earlier 505(b)(2) route and is not a biosimilar in the register. Semglee became the first interchangeable biosimilar of any kind in the United States on 28 July 2021.

Sources: Purple Book (S016), EMA medicines data (S017); the March 2020 transition from the FDA transition provisions of the BPCIA.

Insulin glargine is where the regulatory map differs most across markets. In the EU the first biosimilar insulin, Abasaglar, was authorised in 2014; in the US the pathway only opened in 2020; in India, Wockhardt's Glaritus was permitted in 2007 and a dozen manufacturers and importers have followed. Device, sterility and manufacturing scale matter as much as the clinical package, and the 100 U/mL to 300 U/mL distinction has to be handled carefully in labelling and substitution.