Abasaglar® (insulin glargine): research revealed Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315 000. Prescribing information is available at the end of this presentation. August 2015 - UK/GLA/00102

Introduction to biosimilars and Abasaglar® PK/PD data Part 1: Biosimilars Introduction to biosimilars and Abasaglar® PK/PD data

1922 1923 1963 Insulin molecule isolated1 Lilly: first commercially available insulin for human use1 Synthetic insulin produced2 Rosenfeld L. Clin Chem 2002; 48(12): 2270–2288. Lasker S et al. J Diabet 2010; 1: 1-8.

1979 1982 1996 Genentech: first commercial production of recombinant human insulin2,3 Lilly: first recombinant human insulin (Humulin) approved for use4,5 Lilly: first human insulin analogue, Insulin lispro (Humalog)6 Lasker S et al. J Diabet 2010; 1: 1-8. Greene J et al. N Engl J Med 2015; 372(12): 1171–1175 DeVries J et al. Diabetes, Obesity and Metabolism 2015; 17: 445–451. Humulin Prescribing Information. February 2015.. Humalog Prescribing Information. March 2015.

1922 2000 1923 2004 1963 Insulin molecule isolated Sanofi-Aventis: insulin glargine (Lantus®) analogue7 Lilly: first insulin for human use Synthetic insulin produced Novo Nordisk: insulin detemir (Levemir®) analogue8 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000309/WC500186925.pdf Hilgenfeld R et al. Drugs 2014; 74(8): 911–927. EMA Assessment Report: Levemir (insulin detemir). 2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000528/WC500120034.pdf Accessed: April 2015.

Novo Nordisk: insulin degludec 2013 2014 2015 Novo Nordisk: insulin degludec (Tresiba®)9 Insulin degludec for diabetes mellitus. Drug Ther Bull 2013; 51(7):78–81.

2013 2014 2015 Lilly: first approved biosimilar Insulin (Abasaglar®)10 and first rapid acting insulin (Humalog) 200 units/ml 6,11 6. Humalog Prescribing Information. March 2015. Abasaglar Prescribing Information. May 2015. EMA Humalog 200 authorisation 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation /human/000088/WC500050334.pdf. Accessed April 2015.

insulin glargine U-300 (Toujeo®)12 2013 2014 2015 Sanofi: insulin glargine U-300 (Toujeo®)12 EMA assessment report: Toujeo (insulin glargine) 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000309/WC500186925.pdf Accessed: June 2015.

Biosimilar medicines versus traditional medicines • Large molecules derived from microorganisms, human or animal cells • Made up of proteins, sugars and nucleic acids • Biosimilars are similar copies of a reference biologic Traditional medicines • Simpler, smaller structures • Chemically synthesised • Copies are called generics European Commission Information Document. Accessible from http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf Last accessed February 2015.

A biosimilar medicine must demonstrate1 Biosimilars Biosimilar medicines A biosimilar medicine must demonstrate1 Biosimilars • Similar active ingredient2 • Similar in vitro and in vivo non-clinical characteristics2 • Similar PK and PD1 • Similar efficacy2 • Similar safety2 • Not generics3 • Potential for cost saving4 • Around since 2006; 19 now approved5 • Set to change the EU diabetes marketplace6 EMEA Guideline 2006. Accessible from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf. Last accessed April 2015. EMEA Guideline 2014 CHMP/437/04. Accessible from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf Declerck P GaBI J 2012; 1: 13–6. EuropaBio Guide to Biological Medicines, Focus on Biosimilar Medicines 2011. Accessible from: http://www.europabio.org/guide-biological-medicines-focus-biosimilar-medicines. Last accessed April 2015. GaBi 2015. Accessible from http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Last accessed April 2015. DeVries J et al. Diab Obes Metab 2015; 17: 445 – 451.

Abasaglar® development programme “The totality of evidence” Phase 3 studies1-3 • Identical amino acid sequence to Lantus® insulin glargine • Highly similar to Lantus® based on principles of biosimilarity including bioequivalence criteria • Comprehensive development program to demonstrate similarity at high standards Element 1 T1DM Element 2 T2DM Phase 1 studies4-6 PK / PD of Abasaglar® versus Lantus® Preclinical studies Biochemical and physicochemical characterisation Blevins TC, Dahl D, Rosenstock J et al. 2015 Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom. 12482 [Epub ahead of print]. Deeg Met al. ADA 2014: 70-OR. Linnebjerg Het al. ADA 2014: 889-P. Zhang et al. X ADA 2014: 890-P. Heise T et al. ADA 2014: 891-P. PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus Data from BI & Lilly alliance

Abasaglar®: phase 1 data Pharmacokinetics Pharmacodynamics Duration of action Dosing Abasaglar®: phase 1 data

PK: serum insulin concentration profiles similar for Abasaglar® and Lantus®*1 Data from Linnebjerg H et al. ADA 2014: 889-P. *Healthy subjects Linnebjerg H et al. ADA 2014: 889-P.

PK: serum insulin concentration profiles similar for Abasaglar® and Lantus® at two dose levels1 Data from Zhang X et al. ADA 2014: 890-P. Zhang X et al. ADA 2014: 890-P.

PD: mean glucose infusion rates similar between Abasaglar® and Lantus® Data from Linnebjerg H et al. ADA 2014: 889-P. *Healthy subjects Linnebjerg H et al. ADA 2014: 889-P.

Duration of action: survival curves for Abasaglar® and Lantus® were similar1 (log rank test of equality, p=0.859) Data from Heise T et al. ADA 2014: 891-P. • Cox proportional hazard estimate (Abasaglar®/Lantus®) duration of action was 1.063; p=0.87771 • Results demonstrate similar duration of action Abasaglar®/Lantus®1 Heise T et al. ADA 2014: 891-P.

Phase 1: conclusions Abasaglar® insulin glargine demonstrates highly similar pharmacokinetic and pharmacodynamic properties to Lantus® insulin glargine Linnebjerg H et al. American Diabetes Association 74th Scientific Sessions, San Francisco, CA, June 13-17, 2014: 889-P. Heise T et al. American Diabetes Association 74th Scientific Session, San Francisco, CA, June 13-17, 2014: 891-P. Zhang X et al. American Diabetes Association 74th Scientific Sessions, San Francisco, CA, June 13-17, 2014: 890-P.

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Part 2: ELEMENT 2 study Phase 3 clinical study comparing efficacy and safety of Abasaglar® insulin glargine to Lantus® insulin glargine in type 2 diabetes

ELEMENT 21: EFFICACY AND SAFETY WITH ABASAGLAR® INSULIN GLARGINE COMPARED WITH LANTUS® INSULIN GLARGINE IN PATIENTS WITH T2DM HbA1c Immunogenicity Hypoglycaemia Primary endpoint To demonstrate the non-inferiority of Abasaglar® insulin glargine to Lantus® insulin glargine as measured by change in HbA1c from baseline to 24 weeks, when used in combination with OADs Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom. 12482 [Epub ahead of print].

ELEMENT 2: Study design Data from Rosenstock J et al. 2015. a3 patients (Abasaglar®) discontinued before receiving study drug. IGlar=insulin glargine; BMI=body mass index; FBG=fasting blood glucose; HbA1c=glycosylated hemoglobin; OAD=oral antidiabetic drug; QD=once daily;  SC=subcutaneous; T2DM; type 2 diabetes mellitus.

ELEMENT 2: baseline demographics and patient characteristics Data from Rosenstock J et al. 2015 and Supplement to: Rosenstock J et al. 2015. Data are mean ± standard deviation unless otherwise indicated. aFull analysis set, n numbers reflect maximum sample size for all demographics / characteristics with the exception of FBG. bBy SMBG. *p=<0.05. P>0.05 for all treatment comparisons except where indicated. BMI=body mass index; FBG=fasting blood glucose; HbA1c=glycosylated hemoglobin; SMBG= self-monitored blood glucose.

ELEMENT 2: similar changes in HbA1c and similar % of patients reaching target HbA1c1 Data from Rosenstock J et al. 2015. HbA1c=glycosylated hemoglobin; NS=not significant. Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12482. [Epub ahead of print].

ELEMENT 2: similar total, nocturnal and severe hypoglycaemia1 Data from Rosenstock J et al. 2015. Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12482. [Epub ahead of print].

ELEMENT 2: similar incidence of Treatment-Emergent Antibody Response (TEAR)1 Data from Rosenstock J et al. ADA 2014: 64-OR. TEAR criteria • If antibody was not detected at baseline • If antibody was detected at baseline % antibody binding ≥1.26% absolute increase in % antibody binding of 1% and 30% relative increase from baseline LOCF=last observation carried forward. Rosenstock J et al. ADA 2014: 64-OR.

ELEMENT 2: negligible effect of overall TEAR status on change in clinical outcomes1 Data from Deeg M et al. ADA 2014: 70-OR. Data are least squares mean (standard error) change from baseline to LOCF endpoint. p >0.05 for all treatment-by-TEAR interactions. HbA1c=glycosylated hemoglobin; LOCF=last observation carried forward; TEAR=treatment-emergent antibody response. Deeg M et al. ADA 2014: 70-OR.

ELEMENT 2 summary1,2 Abasaglar® insulin glargine compared with Lantus® insulin glargine demonstrated similar: Adverse-event profile Incidence of treatment-emergent antibody response Glucose-lowering effect (FBG, SMBG, HbA1c) Changes in body weight Hypoglycaemia incidence and rates Allergic and injection site reactions Insulin doses Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12482. [Epub ahead of print]. Deeg M et al. ADA 2014: 70-OR.

ELEMENT 2 summary1,2 In patients with T2DM, Abasaglar® insulin glargine compared with Lantus® insulin glargine, in combination with oral antidiabetic drugs, provided equivalent efficacy and similar safety profiles, with no clinically meaningful differences. Rosenstock J et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12482. [Epub ahead of print]. Deeg M et al. ADA 2014: 70-OR.

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Part 3: ELEMENT 1 study Phase 3 clinical study comparing efficacy and safety of Abasaglar® insulin glargine to Lantus® insulin glargine in type 1 diabetes

ELEMENT 1: EFFICACY AND SAFETY WITH ABASAGLAR® INSULIN GLARGINE COMPARED WITH LANTUS® INSULIN GLARGINE IN PATIENTS WITH T1DM HbA1c Immunogenicity Hypoglycaemia Primary endpoint To demonstrate non-inferiority of Abasaglar® insulin glargine to Lantus® insulin glargine as measured by change in HbA1c from baseline to 24 weeks in T1DM

ELEMENT 1: Study design Data from Blevins T et al. ADA 2014: 69-OR. a1 patient (Abasaglar®) discontinued before receiving study drug. IGlar=insulin glargine; BMI=body mass index; HbA1c=glycosylated hemoglobin; NPH=Neutral Protamine Hagedorn; QD=once daily; SC=subcutaneous; T1DM; type 1 diabetes mellitus; TID=thrice daily.

ELEMENT 1: Baseline patient characteristics Data from Blevins T et al. ADA 2014: 69-OR. Data are mean ± standard deviation unless otherwise indicated. aFull analysis set, n numbers reflect maximum sample size. BMI=body mass index; FBG=fasting blood glucose; HbA1c=glycosylated hemoglobin; SMBG=self-monitored blood glucose.

ELEMENT 1: similar HbA1c changes from baseline and over time1 Data from Blevins T et al. ADA 2014: 69-OR. *p=0.03; no significant differences between treatments at any other time point. Blevins T et al. ADA 2014: 69-OR.

ELEMENT 1: similar total, nocturnal and severe hypoglycaemia1 Data from Blevins T et al. ADA 2014: 69-OR. All p-values >0.05. Blevins T et al. ADA 2014: 69-OR.

ELEMENT 1: similar Treatment-Emergent Antibody Response (TEAR)1 Data from Deeg M et al. ADA 2014: 70-OR. TEAR criteria • If antibody was not detected at baseline • If antibody was detected at baseline % antibody binding ≥1.26% absolute increase in % antibody binding of 1% and 30% relative increase from baseline Deeg M et al. ADA 2014: 70-OR.

ELEMENT 1: negligible effect of overall TEAR status on change in clinical outcomes1 Data from Deeg M et al. ADA 2014: 70-OR. Data are least squares mean (standard error) change from baseline to LOCF endpoint. p >0.05 for all treatment-by-TEAR interactions. HbA1c=glycosylated hemoglobin; LOCF=last observation carried forward; TEAR=Treatment-Emergent Antibody Response. . Deeg M et al. ADA 2014: 70-OR.

ELEMENT 1 summary1,2 At 24 and 52 weeks, in patients with T1DM, Abasaglar® insulin glargine compared to Lantus® insulin glargine demonstrated similar: Insulin doses (basal, prandial, total) Incidence of treatment-emergent antibody response Glucose-lowering effect (HbA1c, FBG, mean BG) Changes in body weight Hypoglycaemia incidence and rates Allergic and injection site reactions Adverse-event profile Blevins T et al. ADA 2014: 69-OR. Deeg M et al. ADA 2014: 70-OR.

ELEMENT 1 summary1,2 Abasaglar® insulin glargine provided an equivalent efficacy and a similar safety profile compared to Lantus® insulin glargine, with no clinically meaningful differences Blevins T et al. ADA 2014: 69-OR. Deeg M et al. ADA 2014: 70-OR.

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Where does Abasaglar® fit in the 2015 insulin landscape? Consider the basal insulin landscape for type 1 and 2 diabetes: Ultimately, the right insulin regimen for patients with diabetes is the one tailored to their needs.1 Insulin analogues can bring flexibility and convenience to diabetes management.1 • NPH • Concentrated insulin • Insulin glargines, insulin degludec, etc. Barnett A et al. Int J Clin Pract 2008; 62(11): 1647‒1653.

Abasaglar® Abbreviated prescribing information

Humulin® and Humalog® Abbreviated prescribing information

Humulin® and Humalog® Abbreviated prescribing information