Insulin glargine

Accession Number DB00047 (BTD00045, BIOD00045, DB01308) Groups Approved Biologic Classification Protein Based Therapies Hormones / Insulins Description

Insulin glargine is produced by recombinant DNA technology using a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. It is an analogue of human insulin made by replacing the asparagine residue at position A21 of the A-chain with glycine and adding two arginines to the C-terminus (positions B31 and 32) of the B-chain. The resulting protein is soluble at pH 4 and forms microprecipitates at physiological pH 7.4. Small amounts of insulin glargine are slowly released from microprecipitates giving the drug a long duration of action (up to 24 hours) and no pronounced peak concentration.

Protein structure

Protein chemical formula

C267H404N72O78S6 Protein average weight 6063.0 Da Sequences >A chain GIVEQCCTSICSLYQLENYCG >B chain FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR

Insulin glargine is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours. Insulin glargine is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged two years and above.

The originator product, Sanofi’s Lantus (insulin glargine), was approved by the US Food and Drug Administration (FDA) in April 2000 and by the European Medicines Agency (EMA) in June 2000 [1]. Lantus generated an estimated US$6.4 billion in net sales income globally for Sanofi in 2015.

The patents on Lantus expired in 2014 in both Europe and the US [1]. Some of the insulin glargine biosimilars and non-originator biologicals approved or in development are presented in Table 1.

Table 1: Biosimilars and non-originator biologicals of insulin glargine approved or in development

Company name, Product name Stage of development Country Biocon/Mylan, Basalog/MYL-1501D Similar biologic’ launched in India in 2009 India/USA [1]. Received Japanese approval in March 2016 [2] and launched in July 2016. Submitted to EMA for approval in November 2016 [3] Eli Lilly/Boehringer Abasaglar/ Basaglar/ Approved by EMA in September 2014 [4], by FDA in Ingelheim, US/Germany LY2963016 August 2014 [5], by Japan in January 2015 [6] and by Australia in May 2015 [7] Kalbe Pharma, Indonesia - Launched in Indonesia March 2017 [8] Samsung Bioepis/Merck SB9/MK-1293 Submitted to FDA for approval in August 2016 and to (MSD), South Korea/USA [9] EMA in December 2015 [9]. Approved by EMA in November 2016 [10] Wockhardt, India Glaritus ‘Similar biologic’ launched in India in March 2009 [1] EMA: European Medicines Agency; FDA: US Food and Drug Administration. .

Eli Lilly/Boehringer Ingelheim’s application for approval of its insulin glargine product in the US, called Basaglar, was submitted to FDA using a new drug application and not via the abbreviated biosimilars pathway [4]. Similarly, Samsung Bioepis/Merck’s application for approval of its insulin glargine product (SB9/MK-1293) in the US was also submitted to the FDA using a new drug application and not via the abbreviated biosimilars pathway [10].

References 1. GaBI Online - Generics and Biosimilars Initiative. Biologicals patent expiries [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from: www.gabionline.net/Biosimilars/General/Biologicals-patent-expiries 2. GaBI Online - Generics and Biosimilars Initiative. Biocon receives Japanese approval for insulin glargine biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8] Available from: www.gabionline.net/Biosimilars/News/Biocon-receives- Japanese-approval-for-insulin-glargine-biosimilar 3. GaBI Online - Generics and Biosimilars Initiative. Mylan and Biocon submit insulin glargine biosimilar to EMA [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 15]. Available from: www.gabionline.net/Biosimilars/News/Mylan-and- Biocon-submit-insulin-glargine-biosimilar-to-EMA 4. GaBI Online - Generics and Biosimilars Initiative. European approval for biosimilar insulin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from: www.gabionline.net/Biosimilars/News/European-approval-for-biosimilar- insulin 5. GaBI Online - Generics and Biosimilars Initiative. FDA grants tentative approval for insulin treatment [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from: www.gabionline.net/Biosimilars/News/FDA-grants-tentative- approval-for-insulin-treatment 6. GaBI Online - Generics and Biosimilars Initiative. Japanese approval for insulin glargine biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from: www.gabionline.net/Biosimilars/News/Japanese-approval-for-insulin- glargine-biosimilar 7. GaBI Online - Generics and Biosimilars Initiative. Australian approval for biosimilar insulin [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Apr 8]. Available from: www.gabionline.net/Biosimilars/News/Australian-approval-for-biosimilar- insulin 8. GaBI Online - Generics and Biosimilars Initiative. Merck outlines biosimilars programme [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2014 Nov 15]. Available from: www.gabionline.net/Biosimilars/News/Merck-outlines-biosimilars- programme 9. GaBI Online - Generics and Biosimilars Initiative. FDA accepts application for Merck’s insulin glargine biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Sep 2]. Available from: www.gabionline.net/Biosimilars/News/FDA-accepts- application-for-Merck-s-follow-on-insulin-glargine 10. GaBI Online - Generics and Biosimilars Initiative. EMA approves biosimilars of insulin glargine and teriparatide [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 15]. Available from: www.gabionline.net/Biosimilars/News/EMA-approves- biosimilars-of-insulin-glargine-and-teriparatide