ADA 2014 Data Disclosures on LY Insulin Glargine (LY IGlar)

ADA 2014 Data Disclosures on LY2963016 Insulin Glargine (LY IGlar)
This presentation includes reference to Boehringer Ingelheim and Lilly Diabetes Alliance products Adverse events should be reported. Reporting forms and further information can be found at: Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on BIV Prescribing information for Abasaglar®▼ (insulin glargine injection [rDNA origin] 100 units/mL) can be found at the end of this presentation

Contents LY IGlar background Phase 1 PK and PD studies
Comparative PK and PD of LY Insulin Glargine and EU- and US-approved Versions of Lantus® Insulin Glargine in Healthy Subjects (889-P) Duration of Action of 2 Insulin Glargine Products, LY and Lantus®, in Subjects with Type 1 Diabetes Mellitus (891-P) Comparative PK and PD of 2 Insulin Glargine Products, LY and Lantus®, in Healthy Subjects at 2 Dose Levels (890-P) Phase 3 efficacy and safety studies Similar Efficacy and Safety with LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1DM: The ELEMENT 1 Study (69-OR) Similar Efficacy and Safety with LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T2DM: The ELEMENT 2 Study (64-OR) Evaluation of Immunogenicity of LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1DM or T2DM (70-OR) BIV PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus Lantus is a registered trademark of Sanofi-Aventis

LY IGlar Development Programme
“The Totality of Evidence” Identical amino acid sequence to Lantus® insulin glargine (IGlar) Highly similar to IGlar based on principles of biosimilarity including bioequivalence1,2 Comprehensive development programme to demonstrate similarity Phase 3 studies3–5 ELEMENT 1 T1DM ELEMENT 2 T2DM Phase 1 studies6–8 PK / PD of LY IGlar versus IGlar Preclinical studies BIV Key information Biologicals that are authorised based on similarity to an already marketed protein product are sometimes referred to as biosimilars; in the US, “biosimilar” is a regulatory designation given to biological treatments that are authorised through a biosimilar pathway (e.g. Biologic License Application) LY IGlar may be designated as a biosimilar in some geographic regions (e.g. the EU) and not in others (e.g. the US) However, in the US, IGlar was licensed as a “drug” (through the New Drug Application [NDA] pathway) so a similar version is also required to go through an NDA pathway Nonetheless, the scientific principles in demonstrating the similarity of LY IGlar to IGlar are consistent with those of demonstrating biosimilarity: e.g. the FDA intends to use a “risk-based totality of the evidence” approach for biosimilar application reviews and recommends that the sponsor use a stepwise approach to support a demonstration of biosimilarity (which includes preclinical studies on pharmacology, chemical and biophysical attributes, in addition to Phase 1 and 3 clinical studies on efficacy and safety) The chemical and biological (in vitro characteristics/receptor binding affinity) analytical characterisation demonstrated that LY IGlar is highly similar to IGlar; preclinical studies (on metabolic responses) confirmed similarity of LY IGlar and IGlar Phase 1 studies confirmed similarity of PK and PD between LY IGlar and IGlar The safety and efficacy of LY IGlar have been investigated in a comprehensive Phase 3 clinical trial programme in patients with T1DM and T2DM that was designed to meet FDA and EMA regulatory requirements Biochemical and physicochemical characterisation 1. FDA DRAFT Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product; 2. EMEA, Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues, 2015; 3. Blevins et al. ADA 2014: 69-OR; 4. Rosenstock et al. ADA 2014: 64-OR; 5. Deeg et al. ADA 2014: 70-OR; 6. Linnebjerg et al. ADA 2014: 889-P; 7. Zhang et al. ADA 2014: 890-P; 8. Heise et al. ADA 2014: 891-P. PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus Lantus is a registered trademark of Sanofi-Aventis

The LY IGlar Phase 1 Programme
BIV

Core Comparative PK / PD Studies for the Support of the Phase 3 Programme
Core trials fulfill the regulatory need to demonstrate similarity between LY IGlar and the IGlar products in different regions (US and EU) LY IGlar vs. EU-approved IGlar (Study ABEA1) LY IGlar vs. US-approved IGlar (Study ABEO1) US-approved IGlar vs. EU-approved IGlar (Study ABEN1) BIV Studies ABEA, ABEN, and ABEO are randomized, double-blind, 2-treatment, single-dose (0.5 U/kg), crossover, replicate euglycemic clamp studies in healthy subjects Objectives of the 3 trials were to assess the similarity of insulin exposure (PK) and insulin action (PD) between treatments* The core comparative PK/PD studies support the Phase 3 programme ABEO will allow for PK/PD bridging of LY IGlar to US-approved IGlar. ABEA will allow for PK/PD bridging of LY IGlar to EU-approved IGlar Study ABEN established a scientific bridge that justified presenting the analyses of clinical efficacy and safety with a comparator group comprising EU- and US-approved IGlar in the multinational Phase 3 clinical studies (ABEB and ABEC) Tests of similarity between LY IGlar and IGlar used standard bioequivalence criteria Similarity was defined as the 90% CI of the ratio of the geometric means of key PK and PD parameters between LY IGlar and IGlar being completely contained within the interval 0.80–1.25 The same analysis of PD parameters was required for EU submission using 95% CIs *Industry-standard bioequivalence limits (0.8–1.25 of 90% CI). Same analysis of PD using 95% CIs in the EU All randomized, double-blind, 2-treatment, single-dose (0.5 U/kg), 4-period, crossover, replicate euglycemic clamp studies in healthy subjects1 Objectives were to assess the similarity of insulin exposure (PK) and insulin action (PD) between treatments*1 *Industry-standard bioequivalence limits (0.8–1.25 of 90% CI). Same analysis of PD using 95% CIs in the EU CI=confidence interval; PD=pharmacodynamic; PK=pharmacokinetic 1. Linnebjerg et al. ADA 2014: 889-P

Additional PK / PD Studies
Additional data regarding duration of action and bioavailability across different doses LY IGlar vs. IGlar (Study ABEE1) T1DM patients Duration of action Randomized Double-blind Single-dose (0.3 U/kg) Crossover Euglycemic clamp LY IGlar vs. IGlar (Study ABEM2) Healthy subjects 2 different doses: 0.3 and 0.6 U/kg Randomized Double-blind Crossover Euglycemic clamp BIV Studies ABEE and ABEM provide additional data regarding duration of action and bioavailability across different doses The primary objective of ABEE was to assess the duration of action of LY IGlar with respect to that of IGlar in subjects with T1DM and to assess duration of action without confounding endogenous insulin secretion, as occurs in healthy subjects ABEE was the only study that did not have serum insulin concentration C-peptide corrected In ABEM, 2 doses of LY IGlar were evaluated to increase the sensitivity and to help judge magnitude of any observed differences. A similar dose-response with each dose would add strength to the evidence of biosimilarity PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus 1. Heise et al. ADA 2014: 891-P; 2. Zhang et al. ADA 2014: 890-P

Criteria for Determining Similarity between LY IGlar and IGlar
The Phase 1 studies ABEA, ABEO, and ABEN were designed to test LY IGlar and IGlar against predefined acceptance limits that are standard in bioequivalence studies as defined by regulatory bodies1–3 The 90% CI of the ratio of the geometric means of key PK and PD parameters between LY IGlar and IGlar being completely contained within the interval 0.8–1.25*1–3 BIV Phase 1 studies were designed to test LY IGlar and IGlar against predefined acceptance limits that are standard in bioequivalence studies as defined by regulatory bodies It is not possible to describe IGlar and LY IGlar as “bioequivalent” since this term is not applicable to formulations containing complex therapeutic proteins that are manufactured by different companies Tests of similarity, however, were performed using standard bioequivalence criteria as specified by the FDA, which involves the calculation of a 90% CI for the ratio of the averages (population geometric means) The same analysis of PD was required for EU submission using 95% CIs 1. Linnebjerg et al. ADA 2014: 889-P 2. FDA DRAFT Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, Section I, Lines 3. EMEA, Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues, 2015 *US submission CI=confidence interval; PD=pharmacodynamic; PK=pharmacokinetic

Comparative Pharmacokinetics and Pharmacodynamics of LY Insulin Glargine and EU- and US-approved Versions of Lantus® Insulin Glargine in Healthy Subjects Helle Linnebjerg1, Eric Chen Quin Lam2, Mary E. Seger1*, David Coutant1, Laiyi Chua2, Chew Lan Chong2, Maria M. Ferreira3, Danny Soon2, Xin Zhang1 1Eli Lilly and Company, Indianapolis, Indiana, USA; 2Lilly-NUS Centre for Clinical Pharmacology, Singapore; 3PAREXEL International Bloemfontein Early Phase Unit, Bloemfontein, South Africa *Author has since retired from institution listed BIV Lantus is a registered trademark of Sanofi-Aventis Linnebjerg et al. ADA 2014: 889-P

Study Rationale, Aim, and Design
Even with identical amino acid sequences, protein-based therapeutics manufactured by distinct processes must be shown to be similar1,2 These studies3 aimed to demonstrate similarity in the pharmacokinetics and pharmacodynamics between LY insulin glargine (LY IGlar) and EU- and US‑approved versions of Lantus® insulin glargine (EU IGlar and US IGlar) These were 3 Phase 1, single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence, with a ≥7-day washout between doses During each period, a manual 24-hour euglycemic clamp procedure was performed Glucose was infused intravenously at a variable rate to maintain a target blood glucose level of 5 mg/dL (0.3 mmol/L) below each subject’s mean pre-dose fasting blood glucose BIV IGlar used in Phase 3 trials of LY IGlar is sourced from both the US and the EU (i.e. EU-approved or US-approved) These studies aimed to demonstrate similarity in the pharmacokinetics (PK) and pharmacodynamics (PD) between LY IGlar and EU- and US‑approved versions of IGlar (EU IGlar and US IGlar) In addition, these studies provide support for a scientific bridge that formed the basis for presenting LY IGlar analyses of clinical efficacy and safety with a single comparator group comprising EU IGlar and US IGlar for each multinational Phase 3 study Background The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies 1. EMA CHMP. Guideline On Similar Biological Medicinal Products 2014; 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 2012; 3. Linnebjerg et al. ADA 2014: 889-P Lantus is a registered trademark of Sanofi-Aventis

Study Design BIV These were 3 Phase 1, single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence, with a ≥7-day washout between doses During each period, a manual 24-hour euglycemic clamp procedure was performed Background The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies PD=pharmacodynamic; PK=pharmacokinetic; T=test treatment; R=reference treatment Linnebjerg et al. ADA 2014: 889-P

Study Assessments Serial blood samples were taken up to 24 hours post-dose to determine concentrations of LY IGlar and/or IGlar, and C-peptide, in serum PK parameter estimates for LY IGlar and/or IGlar were calculated by standard non-compartmental methods. The PD parameters were derived from the euglycemic clamp procedure, where the glucose infusion rate over time was used as a measure of insulin effect Log-transformed PK and PD parameter estimates were analyzed using a linear mixed effects model with period, sequence, and treatment as fixed effects and subject as a random effect. A non-parametric approach was used to evaluate time of maximum observed drug concentration Sample sizes were planned to provide at least 90% power to demonstrate that the 90% confidence interval of the ratios of key PK or PD parameters between treatments would be contained within 0.8–1.25 BIV Blood samples were collected pre-dose and up to 24 hours post-dose to assess PK PD was assessed by a euglycemic clamp lasting up to 24 hours Sample sizes were planned to provide at least 90% power to demonstrate that the 90% confidence interval of the ratios of key PK or PD parameters between treatments would be contained within 0.8–1.25 Background The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses PD=pharmacodynamic; PK=pharmacokinetic Linnebjerg et al. ADA 2014: 889-P

Correction for Endogenous Insulin
For the primary analysis, serum concentrations of LY IGlar and IGlar were corrected for endogenous insulin using C-peptide data1 Correction was warranted because: the studies were conducted in healthy subjects the assay used to detect serum LY IGlar and IGlar demonstrates cross-reactivity with endogenous insulin BIV For the primary analysis, serum concentrations of LY IGlar and IGlar were corrected for endogenous insulin using C-peptide data1 because the studies were conducted in healthy subjects, and the assay used to detect serum LY IGlar and IGlar demonstrates cross-reactivity with endogenous insulin Background The pharmacokinetics and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses 1. Owens DR. Human insulin: clinical pharmacological studies in normal man. New York: Springer Publishing; 1986

Results BIV

Summary of Studies BIV-00061153
The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 separate studies Background The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses aMean ± standard deviation BMI=body mass index; N=number of subjects; PD=pharmacodynamics; PK=pharmacokinetics Linnebjerg et al. ADA 2014: 889-P

PK Profiles of LY IGlar vs. EU IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration BIV PK profiles were similar between LY IGlar and EU IGlar Background The PK and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses *Healthy subjects PK=pharmacokinetic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

PK Profiles of LY IGlar vs. US IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration BIV PK profiles were similar between LY IGlar and US IGlar Background The PK and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses *Healthy subjects PK=pharmacokinetic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

PK Profiles of EU IGlar vs. US IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration BIV PK profiles were similar between EU IGlar and US IGlar C-peptide-corrected serum insulin concentration profiles were similar for all glargine products Background The PK and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses C-peptide-corrected serum insulin concentration profiles were similar for all glargine products *Healthy subjects PK=pharmacokinetic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

Comparison of PK Parameters of LY IGlar and IGlar
BIV As the 90% CI for the ratios of geometric LS means for the PK parameters (AUC(0–24) and Cmax) were completely contained in the prespecified bioequivalence limit of 0.80–1.25, similarity in the PK properties of LY IGlar, EU IGlar, and US IGlar was demonstrated Background The PK and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses 90% CIs for the ratios of LS geometric means for AUC(0–24) and Cmax were completely contained within the prespecified bioequivalence limits (0.8–1.25) aModel: log (parameter)=period+sequence+treatment+error, subject (random), period sequence treatment (categorical) AUC(0–24)=area under the concentration-time curve from time 0 to 24 hours; CI=confidence interval; Cmax=maximum observed drug concentration; CV%=coefficient of variation; LS=least squares; n=number of observations; N=number of subjects; PK=pharmacokinetic Linnebjerg et al. ADA 2014: 889-P

Comparison of tmax of LY IGlar and IGlara
No statistically significant difference in tmax between treatments (95% CIs for median differences contain 0; p >0.05) BIV Pharmacokinetic (PK) profiles were similar between LY IGlar, EU IGlar, and US IGlar, and there was no statistically significant difference in tmax between the 3 treatments (95% CIs for median differences contain 0; p >0.05) Background The PK and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses atmax analyzed using a Wilcoxon signed-rank test and median differences using Hodges-Lehmann method CI=confidence interval; N=number of subjects; tmax=time of maximum observed drug concentration Linnebjerg et al. ADA 2014: 889-P

PD Profiles of LY IGlar vs. EU IGlar*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom) BIV Mean glucose infusion rate profiles were similar between LY IGlar and EU IGlar The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles Background The pharmacokinetics and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses Mean glucose infusion rate profiles were similar between LY IGlar and EU IGlar *Healthy subjects PD=pharmacodynamic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

PD Profiles of LY IGlar vs. US IGlar*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom) BIV Mean glucose infusion rate profiles were similar between LY IGlar and US IGlar The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles Background The pharmacokinetics and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses Mean glucose infusion rate profiles were similar between LY IGlar and US IGlar *Healthy subjects PD=pharmacodynamic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

PD Profiles of EU IGlar vs. US IGlar*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom) BIV Mean glucose infusion rate profiles were similar between US IGlar and EU IGlar The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles Background The pharmacokinetics and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses Mean glucose infusion rate profiles were similar between EU IGlar and US IGlar *Healthy subjects PD=pharmacodynamic; SD=standard deviation Linnebjerg et al. ADA 2014: 889-P

Comparison of PD Parameters of LY IGlar and IGlar
BIV As the 90% CIs for the ratios of LS geometric means for Gtot and Rmax were completely contained within the prespecified bioequivalence limits (0.8–1.25), similarity in the PD properties of LY IGlar, EU IGlar, and US IGlar was demonstrated Background The pharmacokinetics and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses 90% CIs for the ratios of LS geometric means for Gtot and Rmax were completely contained within the prespecified bioequivalence limits (0.8–1.25) aModel: log (parameter)=period+sequence+treatment+error, subject (random), period sequence treatment (categorical) CI=confidence interval; CV%=coefficient of variation; Gtot=total glucose infusion over the clamp duration; LS=least squares; n=number of observations; N=number of subjects; PD=pharmacodynamic; Rmax=maximum glucose infusion rate Linnebjerg et al. ADA 2014: 889-P

Safety Results The most common treatment-emergent AEs reported across all studies were procedural complications and headache No differences in the types or incidence of drug-related AEs were noted between treatments No safety concerns were noted in the clinical laboratory, vital sign, or ECG data BIV AEs were similar for LY IGlar, EU IGlar, and US IGlar There were no safety concerns noted in clinical laboratory, vital sign, or ECG data Background The pharmacokinetics and pharmacodynamics of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses AE=adverse event; ECG=electrocardiogram Linnebjerg et al. ADA 2014: 889-P

Conclusions The studies demonstrated that the PK (AUC[0–24] and Cmax) and PD (Rmax and Gtot) properties of LY IGlar, EU IGlar, and US IGlar were similar following subcutaneous dosing The 90% confidence intervals for the ratios of least squares geometric means were completely contained within the prespecified bioequivalence limits (0.8–1.25) No safety concerns were noted in the adverse-event, clinical laboratory, vital sign, or electrocardiogram data BIV Across the studies, similarity in the PK and PD properties of LY IGlar, EU IGlar, and US IGlar was observed Background The PK and PD of LY IGlar, EU IGlar, and US IGlar were compared in 3 single-site, randomized, double-blind, 2-treatment, 4-period, crossover, replicate euglycemic clamp studies Fasted, normal-weight, healthy subjects received subcutaneous 0.5 U/kg doses of 2 different insulin glargine products on 2 occasions each, following a randomized sequence A minimum 7-day washout separated doses AUC(0–24)=area under the concentration-time curve from time 0 to 24 hours; Cmax=maximum observed drug concentration; Gtot=total glucose infusion over the clamp duration; PD=pharmacodynamic; PK=pharmacokinetic; Rmax=maximum glucose infusion rate Linnebjerg et al. ADA 2014: 889-P

Duration of Action of 2 Insulin Glargine Products, LY and Lantus®, in Subjects with Type 1 Diabetes Mellitus Tim Heise1, Xin Zhang2, Eric Chen Quin Lam3, Mary E. Seger2*, David Coutant2, Laiyi Chua3, Helle Linnebjerg2 1Profil, Neuss, Germany; 2Eli Lilly and Company, Indianapolis, Indiana, USA; 3Lilly-NUS Centre for Clinical Pharmacology, Singapore *Author has since retired from institution listed BIV [INSERT DATAVISION DOC #] Lantus is a registered trademark of Sanofi-Aventis Heise et al. ADA 2014: 891-P

Study Design This was a Phase 1, single-site, randomized, double-blind, single-dose, 2-period, 2-sequence, crossover euglycemic clamp study Fasted male subjects with T1DM received single subcutaneous doses of 0.3 U/kg LY insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), with a ≥7-day washout between doses This study compared the duration of action (time post-dosing at which a subject’s blood glucose was >150 mg/dL [8.3 mmol/L] without any glucose infusion) of 0.3 U/kg LY IGlar and IGlar in subjects with T1DM during a euglycemic clamp procedure During each period, a euglycemic clamp procedure, lasting up to 42 hours post-dose, was performed. Blood samples were taken to determine: duration of action and pharmacodynamic parameters for LY IGlar and IGlar serum concentrations of LY IGlar, IGlar, and insulin lispro for pharmacokinetic evaluation; analyzed using a validated radioimmunoassay method BIV This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of a single dose (0.3 U/kg) of 2 insulin glargines – LY IGlar and IGlar Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar There was a minimum 7-day washout between separated doses The duration of action was assessed with a euglycemic clamp technique lasting up to 42 hours post-dose, and was defined as the time period between administration of the dose and the end of action; end of action was defined as the time when a subject’s blood glucose was consistently >150 mg/dL (8.3 mmol/L), without any glucose The study was conducted in patients with T1DM to ensure the absence of endogenous insulin, which could confound the results Background The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM T1DM=type 1 diabetes mellitus Lantus is a registered trademark of Sanofi-Aventis Heise et al. ADA 2014: 891-P

Euglycemic Clamp Procedure
Washout pre-study insulin Run-in period Euglycemic clamp Resume pre-study insulin Euglycemic Clamp Procedure LY IGlar / IGlar SC (0.3 U/kg) (0 hours) −48 hours: start switching subjects on insulin detemir or IGlar to NPH insulin (tailored washout regimen) By −22 hours: last dose of intermediate-acting insulin administered −12 to −9 hours: total dose of short- or rapid-acting insulin to be <8 units By −9 hours: last dose of short- or rapid-acting insulin −4 hours: stop basal rate of any continuous SC insulin infusion; washout complete for all subjects Begin variable IV infusion of insulin lispro or glucose at −1 to −6 hours (automated clamp using a Biostator) Target blood glucose level: 100 mg/dL (5.6 mmol/L); maintained for ≥1 hours before dosing From −1 hour, insulin lispro infusion rate (if any) minimized while ensuring no glucose infused Variable IV glucose infusion to maintain target glucose level for ≤42 hours Insulin lispro infusion terminated when LY IGlar / IGlar effect is seen (defined as a drop in blood glucose of approximately 5 mg/dL [0.3 mmol/L]) Clamp ended at 42 hours post-dose, unless blood glucose reaches 250 mg/dL (13.8 mmol/L) before this time End of action = time post-dosing at which a subject’s blood glucose level is >150 mg/dL [8.3 mmol/L] without any glucose infusion2 BIV A washout of pre-study insulin was conducted followed by a run-in period prior to initiation of the euglycemic clamp procedure Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of a single dose (0.3 U/kg) of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in type 1 diabetes mellitus (T1DM) Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar There was a minimum 7-day washout between separated doses IV=intravenous; NPH=Neutral Protamine Hagedorn; SC=subcutaneous 1. Heise et al. ADA 2014: 891-P; 2. Lepore M et al. Diabetes 2000;49:2142–2148

Estimating Duration of Action
Estimates of duration of action were compared for LY IGlar and IGlar using a linear mixed effects model with treatment, period, and sequence as fixed effects and subject as a random effect1 As 14 / 40 clamps were terminated at 42 hours, before end of action (EoA) was reached, a time-to-event (survival) analysis that allows for censored observations was applied Each EoA observation was considered an “event”, and “survival” was defined as EoA not yet being reached Duration of action was “censored” (i.e. not recorded) when a subject did not reach EoA before clamp termination Estimated time-to-event (survival) curves for LY IGlar and IGlar were plotted and compared using the log-rank test of equality Cox proportional hazard model2 was used to estimate the hazard ratio BIV Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Estimates of duration of action were compared for LY IGlar and IGlar using a linear mixed effects model with treatment, period, and sequence as fixed effects and subject as a random effect Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of a single dose (0.3 U/kg) of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in type 1 diabetes mellitus (T1DM) Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar There was a minimum 7-day washout between separated doses 1. Heise et al. ADA 2014: 891-P; 2. Cox DR. J R Stat Soc Series B 1972;20:187–220

Subject Demographics BIV-00061153
A total of 20 male subjects with type 1 diabetes mellitus (T1DM), aged 23–54 years, entered and completed the study Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar *All of the 20 subjects who entered the study completed the study as planned BMI=body mass index; HbA1c=glycosylated haemoglobin; N=number of subjects; SD=standard deviation Heise et al. ADA 2014: 891-P

Results BIV

Mean (± SD) Glucose Infusion Rate and Corresponding Blood Glucose Levels
BIV The mean glucose infusion rates were similar for LY IGlar and IGlar Blood glucose levels were similar for LY IGlar and IGlar Blood glucose profiles and smoothed (locally weighted scatterplot smoothing function) glucose infusion rate profiles were similar for LY IGlar and IGlar Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in type 1 diabetes mellitus (T1DM) Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and Iglar SD=standard deviation Heise et al. ADA 2014: 891-P

Time-to-event (Survival) Plot of Duration of Action for LY IGlar and IGlar
BIV The survival curves for LY IGlar and IGlar appear to be similar over the 42-hour clamp interval (log-rank test of equality with p value = 0.859), where “survival” means a subject’s blood glucose did not rise to 150 mg/dL (8.3 mmol/L) The Cox proportional hazard estimate (LY IGlar/IGlar) for duration of action was 1.063; p = , demonstrating that duration of action is similar for the 2 treatments Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in type 1 diabetes mellitus (T1DM) Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and Iglar Survival curves for LY IGlar and IGlar were similar (log-rank test of equality, p = 0.859) Cox proportional hazard estimate (LY IGlar / IGlar) for duration of action was 1.063; p = Results demonstrate similar duration of action for LY IGlar and IGlar Test of equality of survival curves (based on log-rank test): Chi-square statistic = 0.031, p = 0.859 Heise et al. ADA 2014: 891-P

Comparison of Duration of Action of LY IGlar and IGlar Based on Survival Analysis (All Subjects)
BIV The duration of action for LY IGlar and IGlar were similar over 42 hours in patients with type 1 diabetes mellitus (T1DM) As 35% of clamps were terminated at 42 hours (before end of action was reached), a linear mixed effects model and time-to-event survival analysis that allows for censored observations was applied to compare the duration of action The results for mean duration of action are based only on subjects who reached end of action before 42 hours (i.e. not censored); therefore, the results are underestimates of the actual duration of action for each of the treatments Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and Iglar aDuration of action was “censored” (i.e. not recorded) when a subject did not reach EoA before clamp termination; bMaximum and mean are based on subjects who reached EoA before 42 hours (i.e. not censored); cThe Xth percentile of the survival time (duration of action) is the time beyond which (100−X)% of the subjects are expected to “survive” (i.e. EoA has not been reached); dDue to censoring CI=confidence interval; EoA=end of action; NA=not applicable; SE=standard error Heise et al. ADA 2014: 891-P

Comparison of Gtot and Rmax of LY IGlar and IGlar
No statistically significant difference in Gtot and Rmax between LY IGlar and IGlar, with the 90% CIs for the ratios of LS geometric means containing 1 BIV Pharmacodynamic profiles for LY IGlar and IGlar were similar over 42 hours following a single dose of 0.3 U/kg in type 1 diabetes mellitus (T1DM) patients No statistically significant difference in Gtot and Rmax between LY IGlar and IGlar, with the 90% CIs for the ratios of LS geometric means containing 1 Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar Statistical model: log (parameter)=period+sequence+treatment+error, subject (random), period sequence treatment (categorical) CI=confidence interval; CV%=coefficient of variation; Gtot=total glucose infusion over the clamp duration; LS=least squares; N=number of subjects; Rmax=maximum glucose infusion rate Heise et al. ADA 2014: 891-P

Mean (± SD) Serum Insulin Concentration with LY IGlar and IGlar
BIV Pharmacokinetic (PK) profiles appeared to be comparable between LY IGlar and IGlar, based on visual comparison of the available PK data at a single dose of 0.3 U/kg in subjects with type 1 diabetes mellitus (T1DM) Data available from 17 subjects were used to generate the mean profile. Points were plotted if there were 3 or more quantifiable observations per scheduled time point Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY and Iglar Serum insulin concentration profiles were similar for LY IGlar and IGlar 11 subjects did not have analyzable insulin concentration data for both study periods, mostly due to concentrations being below the lower limit of quantification. Data available from 17 subjects were used to generate the mean profile. The pharmacokinetic assay detects endogenous insulin as well as IGlar / LY IGlar; however, due to the limited quantifiable concentrations available, the concentrations were not corrected for endogenous insulin SD=standard deviation Heise et al. ADA 2014: 891-P

Adverse Events and Tolerability with LY IGlar and IGlar
Frequency of Treatment-emergent Adverse Events (All Causalities) BIV Single subcutaneous doses of LY IGlar and IGlar were well tolerated in subjects with type 1 diabetes mellitus (T1DM) Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which 1 subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar aMedDRA version 14.1; bAEs with a change in severity are counted only once AE=adverse event; ECG=electrocardiogram; MedDRA=Medical Dictionary for Regulatory Activities; N=number of subjects Heise et al. ADA 2014: 891-P

Safety Results LY IGlar (0.3 U/kg) was well tolerated, with a similar AE profile observed to that following IGlar dosing (0.3 U/kg) No safety concerns noted in the AE, clinical laboratory, vital sign, or ECG data No drug-related AEs reported BIV Single subcutaneous doses of LY IGlar and IGlar were well tolerated in subjects with type 1 diabetes mellitus (T1DM), with no safety concerns noted in the AE, clinical laboratory, vital sign, or ECG data, and no drug-related AEs reported Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar AE=adverse event; ECG=electrocardiogram Heise et al. ADA 2014: 891-P

Conclusions In subjects with T1DM, following a single 0.3 U/kg dose of LY IGlar and IGlar: Duration of action was similar for both treatments No statistically significant difference in Rmax and Gtot was observed between LY IGlar and IGlar during a 42-hour glucose clamp Pharmacokinetic profiles appeared to be similar between LY IGlar and IGlar Single subcutaneous doses of 0.3 U/kg LY IGlar and IGlar were well tolerated in subjects with T1DM BIV The duration of action and pharmacodynamic effects of a single 0.3 U/kg dose of LY IGlar and IGlar, in subjects with T1DM, were demonstrated to be similar Background This was a randomized, double-blind, 2-period, crossover euglycemic clamp study that compared the duration of action of 2 insulin glargines – LY IGlar and IGlar The primary objective of the study was to assess the duration of action of LY IGlar compared with IGlar in T1DM Duration of action was defined as the time after dosing at which a subject’s blood glucose level was >150 mg/dL (8.3 mmol/L) without any glucose infusion Fasted male subjects with T1DM (N = 20; aged 23–54 years) received single subcutaneous doses of 0.3 U/kg LY IGlar and Iglar Gtot=total glucose infusion over the clamp duration; Rmax=maximum glucose infusion rate; T1DM=type 1 diabetes mellitus Heise et al. ADA 2014: 891-P

Comparative Pharmacokinetics and Pharmacodynamics of 2 Insulin Glargine Products, LY and Lantus®, in Healthy Subjects at 2 Dose Levels Xin Zhang1, Eric Chen Quin Lam2, Mary E. Seger1*, David Coutant1, Laiyi Chua2, Lai Hock Tan2, Danny Soon2, Helle Linnebjerg1 1Eli Lilly and Company, Indianapolis, Indiana, USA; 2Lilly-NUS Centre for Clinical Pharmacology, Singapore *Author has since retired from institution listed BIV Lantus is a registered trademark of Sanofi-Aventis Zhang et al. ADA 2014: 890-P

Study Design and Rationale
This was a Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study to evaluate the pharmacokinetics and pharmacodynamics of LY insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar) at 2 dose levels (0.3 and 0.6 U/kg)1 The study was carried out to supplement the results of a larger, core study at the 0.5 U/kg dose level2 Fasted healthy subjects were randomly assigned to a dosing sequence, with ≥6-day washout between doses1 During each period, a manual 24-hour euglycemic clamp procedure was performed Glucose was infused intravenously at a variable rate to maintain a target blood glucose level of 5 mg/dL (0.3 mmol/L) below the mean pre-dose fasting blood glucose for each subject BIV Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses Lantus is a registered trademark of Sanofi-Aventis 1. Zhang et al. ADA 2014: 890-P; 2. Linnebjerg et al. ADA 2014: 889-P

Statistical Analyses PK parameter estimates for LY IGlar and IGlar were calculated by standard non-compartmental methods. The PD parameters were derived from the euglycemic clamp procedure, where the glucose infusion rate over time was used as a measure of insulin effect Log-transformed PK and PD parameter estimates were analyzed using a linear mixed effects model with period, sequence, and treatment as fixed effects and subject as a random effect. A non- parametric approach was used to evaluate time of maximum observed drug concentration BIV Serum LY IGlar, IGlar, and C-peptide concentrations were determined from serial blood samples up to 24 hours post-dose Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses PD=pharmacodynamic; PK=pharmacokinetic Zhang et al. ADA 2014: 890-P

Correction for Endogenous Insulin
For the primary analysis, serum concentrations of LY IGlar and IGlar were corrected for endogenous insulin using C-peptide data using the following equation1: [LY IGlar or IGlar] = [immunoreactive LY IGlar or IGlar] – F*[C-peptide] where F is the average of the ratios of immunoreactive LY IGlar or IGlar to C-peptide at baseline (−30 and 0 minutes) Correction was warranted because: the study was conducted in healthy subjects the assay used to detect serum LY IGlar and IGlar demonstrates cross-reactivity with endogenous insulin BIV Serum concentrations of LY IGlar and IGlar were corrected for the presence of endogenous insulin using C-peptide data because the study involved healthy subjects, and the assay used to detect serum LY IGlar and IGlar demonstrates cross-reactivity with endogenous insulin Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses 1. Owens DR. Human insulin: clinical pharmacological studies in normal man. New York: Springer Publishing; 1986

Dosing and Assessments
Dosing Schedule (U/kg) Serial blood samples were taken pre-dose and up to 24 hours post-dose to determine serum LY IGlar, IGlar, and C-peptide concentrations BIV Healthy subjects received LY IGlar or IGlar at 2 different dose levels depending on their study treatment sequence indicated in the dosing schedule above Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses Zhang et al. ADA 2014: 890-P

Results BIV

Subject Demographics BIV-00061153
Of a total of 24 healthy subjects (20 males and 4 females) aged 23–52 years who entered the study, 23 subjects received all 4 doses of study drug (LY IGlar and IGlar) and completed the study as planned Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses a1 subject was withdrawn after dosing in Period 2 (subject decision); 23 subjects completed the study BMI=body mass index; N=number of subjects studied; SD=standard deviation Zhang et al. ADA 2014: 890-P

PK of LY IGlar and IGlar with different doses*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration BIV There was no statistically significant difference in PK between LY IGlar and IGlar for both doses (all the corresponding 90% confidence intervals of the ratios of geometric least squares means for the primary PK parameters of area under the concentration-time curve from time 0 to 24 hours and maximum observed drug concentration spanned 1) Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses C-peptide-corrected serum insulin concentration profiles were similar for LY IGlar and IGlar at each dose level *Healthy subjects PK=pharmacokinetics; SD=standard deviation Zhang et al. ADA 2014: 890-P

Mean C-peptide Concentration with Different Doses of LY IGlar and IGlar*
Mean (± SD) C-peptide Concentration BIV Profiles of mean C-peptide concentration, an indicator of endogenous insulin production, are similar at each dose between LY IGlar and IGlar, suggesting a similar degree of suppression of endogenous insulin with LY IGlar and IGlar Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses C-peptide concentration profiles are similar at each dose between LY IGlar and IGlar, suggesting a similar degree of suppression of endogenous insulin *Healthy subjects SD=standard deviation Zhang et al. ADA 2014: 890-P

Comparison of PK Parameters with Different Doses of LY IGlar and IGlar*
BIV No statistically significant difference in PK between LY IGlar and IGlar for both doses (90% CIs for the ratios of LS geometric means contained 1) and consistent AUCs and Cmax across dose levels demonstrated that the PK of LY IGlar and IGlar are similar Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses No statistically significant differences in AUCs and Cmax between LY IGlar and IGlar, with the 90% CIs for the ratios of LS geometric means containing 1 AUCs and Cmax were also consistent across dose levels *Healthy subjects AUC(0–24)=area under the concentration-time curve from time 0 to 24 hours; AUC(0–∞)=AUC from 0 to infinity; CI=confidence interval; Cmax=maximum observed drug concentration; CV%=coefficient of variation; LS=least squares; N=number of subjects; PK=pharmacokinetic Zhang et al. ADA 2014: 890-P

Comparison of tmax with Different Doses of LY IGlar and IGlar*
BIV No statistically significant difference in tmax between LY IGlar and IGlar (90% CIs for the median differences contained 0) demonstrated that the pharmacokinetics (PK) of LY IGlar and IGlar are similar Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses No statistically significant difference in tmax between LY IGlar and IGlar, with the 90% CIs for the median differences containing 0 *Healthy subjects CI=confidence interval; N=number of subjects; tmax=time of maximum observed drug concentration Zhang et al. ADA 2014: 890-P

PD of LY IGlar and IGlar with 0.3 U/kg dosing*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Glucose Levels (Bottom) BIV There was no statistically significant difference in PD between LY IGlar and IGlar for the 0.3 U/kg dose (1.0 contained within 90% confidence interval), demonstrating that the PD of LY IGlar and IGlar are similar Mean blood glucose levels were similar for LY IGlar and IGlar The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles at each dose level Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses *Healthy subjects PD=pharmacodynamics; SD=standard deviation Zhang et al. ADA 2014: 890-P

PD of LY IGlar and IGlar with 0.6 U/kg dosing*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Glucose Levels (Bottom) BIV There was no statistically significant difference in PD between LY IGlar and IGlar for the 0.6 U/kg dose (1.0 contained within 90% confidence interval), demonstrating that the PD of LY IGlar and IGlar are similar Mean blood glucose levels were similar for LY IGlar and IGlar Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses Mean glucose infusion rate profiles were similar between treatments at each dose level. The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles at each dose level *Healthy subjects PD=pharmacodynamics; SD=standard deviation Zhang et al. ADA 2014: 890-P

Comparison of PD Parameters with Different Doses of LY IGlar and IGlar*
BIV The PD of LY IGlar and IGlar are similar and consistent across dose levels Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses The PD properties (Gtot and Rmax) were not statistically significantly different between LY IGlar and IGlar, with the 90% CIs for the ratios of geometric means containing 1, and were consistent across dose levels *Healthy subjects CI=confidence interval; CV%=coefficient of variation; Gtot=total glucose infusion over the clamp duration; LS=least squares; N=number of subjects; PD=pharmacodynamic; Rmax=maximum glucose infusion rate Zhang et al. ADA 2014: 890-P

Drug-related, Treatment-emergent Adverse Events with Different Doses of LY IGlar and IGlar*
Frequency of Drug-related, Treatment-emergent Adverse Events BIV LY IGlar was well tolerated, with no safety concerns noted in AEs The total number of drug-related AEs reported across all dose levels was similar between LY IGlar and IGlar The types of drug-related AEs reported were similar between treatments Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses *Healthy subjects aMedDRA version 15.0; bAEs with a change in severity are counted only once AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; N=number of subjects Zhang et al. ADA 2014: 890-P

Safety Summary with Different Doses of LY IGlar and IGlar*
No safety concerns were noted in the AE, clinical laboratory, vital sign, or ECG data No episodes of hypoglycaemia were recorded The types of drug-related AEs reported were similar between treatments BIV LY IGlar was well tolerated, with no safety concerns noted in the clinical laboratory, vital sign, or ECG data No episodes of hypoglycaemia were recorded Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses *Healthy subjects AE=adverse event; ECG=electrocardiogram Zhang et al. ADA 2014: 890-P

Conclusions There were no statistically significant differences in PK (AUCs and Cmax) or PD (Rmax and Gtot) properties of LY IGlar and IGlar in healthy subjects following single subcutaneous doses of 0.3 and 0.6 U/kg Single subcutaneous doses of 0.3 and 0.6 U/kg LY IGlar and IGlar were well tolerated in healthy subjects BIV There were no statistically significant differences in PK and PD parameters observed at 2 different doses of LY IGlar and IGlar Background This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg) The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each A minimum 6-day washout separated doses AUC=area under the curve; Cmax=maximum observed drug concentration; Gtot=total glucose infusion over the clamp duration; PD=pharmacodynamic; PK=pharmacokinetic; Rmax=maximum glucose infusion rate Zhang et al. ADA 2014: 890-P

The LY IGlar Phase 3 Programme
BIV

Similar Efficacy and Safety with LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1DM: The ELEMENT 1 Study Thomas Blevins1, Dominik Dahl2, Julio Rosenstock3, Liza L. Ilag4, William J. Huster4, Robyn K. Pollom4, Melvin J. Prince4 for the ELEMENT 1 Study Group 1Texas Diabetes & Endocrinology, Texas, USA; 2Gemeinschaftspraxis für Innere Medizin und Diabetologie, Hamburg, Germany; 3Dallas Diabetes and Endocrine Center at Medical City, Texas, USA; 4Eli Lilly and Company, Indiana, USA BIV Lantus is a registered trademark of Sanofi-Aventis Blevins et al. ADA 2014: 69-OR

Phase 3 Open-label Study in T1DM (ELEMENT 1): Design
≥18 years T1DM ≥1 years HbA1c ≤11% BMI ≤35 kg/m2 Basal-bolus with QD NPH, IGlar or detemir Study Criteria BIV ELEMENT 1 is a prospective, Phase 3, open-label, parallel trial in patients with T1DM that compared the efficacy and safety of LY IGlar versus IGlar, taken once daily in combination with insulin lispro before meals 3 times a day Insulin dose adjustments were conducted to help patients achieve glycaemic targets (HbA1c <7%, fasting blood‑equivalent glucose ≤108 mg/dL [6.0 mmol/L], and other pre-prandial capillary blood glucoses 70–130 mg/dL [3.9–7.2 mmol/L]) while minimizing the risk of hypoglycaemia The treatment period was composed of a titration period and a maintenance period It was expected that most of the basal and bolus insulin dose adjustments should occur during the initial titration period (Weeks 0–6). However, titration could extend up to Week 12 for patients who needed more intensification to achieve glycaemic targets. It was then expected that insulin dose adjustments during the maintenance period would be for safety such as hypoglycaemia or unacceptable hyperglycaemia Background 24-week treatment (pre-filled pen injector) with 28-week extension (active control continued to complete 52 weeks on study insulins) and a 4-week post-treatment follow-up 1:1 randomization scheme, stratified by country, HbA1c, and time of basal insulin injection Countries: Belgium, Germany, Greece, Hungary, Japan, Mexico, Poland, Romania, United States a1 patient (LY IGlar) discontinued before receiving study drug BMI=body mass index; HbA1c=glycosylated haemoglobin; IGlar=Lantus® insulin glargine; LY IGlar=LY insulin glargine; NPH=Neutral Protamine Hagedorn; QD=once daily; SC=subcutaneous; T1DM; type 1 diabetes mellitus; TID=thrice daily Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Objectives Primary Key secondary
To demonstrate non-inferiority of LY IGlar to IGlar on change in HbA1c from baseline to 24 weeks in T1DM (the non-inferiority margin was 0.4% and, if met, the upper limit of the 95% CI was compared with the 0.3% non-inferiority margin) Key secondary Non-inferiority of IGlar to LY IGlar Change in HbA1c at 6, 12, 36, and 52 weeks 7-point SMBG profiles Proportion of patients with HbA1c <7% or ≤6.5% Change in body weight Insulin dose Hypoglycaemia Adverse events Incidence of anti-insulin antibodies BIV The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM If the upper limit of the 95% CI on the change in HbA1c from baseline to the 24-week endpoint for LY IGlar versus IGlar was less than +0.4%, then LY IGlar was declared non-inferior to IGlar If the 0.4% non-inferiority margin was met, then the upper limit of the 95% CI was compared with the 0.3% non-inferiority margin to control for the family-wise type 1 error rate at a 1-sided level Secondary objectives of ELEMENT 1 included the non-inferiority of IGlar to LY IGlar at the non-inferiority margin of –0.4%, safety, and additional measures of glycaemic control If LY IGlar was declared non-inferior to IGlar in the primary treatment comparison, and IGlar was declared non-inferior to LY IGlar in the secondary treatment comparison, then LY IGlar was considered to have equivalent efficacy to IGlar Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up CI=confidence interval; HbA1c=glycosylated haemoglobin; SMBG=self-monitored blood glucose; T1DM; type 1 diabetes mellitus Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Baseline Patient Characteristics
Demographics IGlar N = 267a LY IGlar N = 268a p value Age (years) 41 ± 13 41 ± 14 0.72 Sex, male (%) 58 >0.99 Race, Caucasian / Asian / other (%) 75 / 19 / 6 74 / 18 / 8 0.29 Weight (kg) 75 ± 15 76 ± 17 0.46 BMI (kg/m2) 25 ± 4 26 ± 4 0.50 HbA1c (%) 7.8 ± 1.0 7.8 ± 1.1 FBG by SMBG (mmol/L) 8.2 ± 3.0 8.4 ± 3.0 0.49 Basal insulin, IGlar / other (%) 88 / 12 81 / 19 0.06 Diabetes duration (years) 17 ± 11 16 ± 11 0.73 BIV Patient characteristics were generally similar between treatment groups A total of 535 patients who were randomized and received at least 1 dose of study drug were included in the full analysis set analyses 253 patients (94.4%) in the LY IGlar group and 256 patients (95.9%) in the IGlar group completed the 24-week treatment period 245 patients (91.4%) and 245 patients (91.8%) in the LY IGlar and IGlar groups, respectively, completed the 52‑week study Age of patients was similar across groups, with an overall mean age of years The majority of patients were white (74.5%); race “other” consisted of American Indian or Alaska Native, Black or African American, or multiple All patients entered the study on 1 of the basal insulins allowed (Neutral Protamine Hagedorn [NPH] insulin, IGlar, or insulin detemir) Basal insulin Prior to randomization, more than 80% of patients in both treatment groups were using IGlar (LY IGlar: 81.3%; IGlar: 87.6%; p = 0.056) Basal insulin other: LY IGlar (detemir n = 24, 9%; NPH n = 26, 9.7%); IGlar (detemir n = 20, 7.5%; NPH n = 13, 4.9%) Prandial insulin Prior to randomization, most patients in both treatment groups were using either lispro (LY IGlar: 46.3%; IGlar: 45.3%) or aspart (LY IGlar: 38.8%; IGlar: 39.3%) There were few patients on pre-study regular insulin (LY IGlar: 7.1%; IGlar: 7.9%) or glulisine (LY IGlar: 7.5%; IGlar: 7.5%) Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up 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 haemoglobin; SMBG=self-monitored blood glucose Blevins et al. ADA 2014: 69-OR

ELEMENT 1: HbA1c Change from Baseline and over Time with LY IGlar and IGlar
24 Weeks LOCF ∆ = 0.108 95% CI (-0.002, 0.219) p=0.055 ∆ = 0.020 95% CI (-0.099, 0.140) p=0.737 52 Weeks LOCF Change in HbA1c (%) IGlar (N=268) LY IGlar (N=267) * BIV Both treatment groups had within-group, statistically significant (p <0.001) decreases in least squares mean HbA1c values from baseline, which began at Visit 4 (Week 6) and continued through to the 52‑week endpoint (LOCF) While there was some separation that was statistically significant at 12 weeks (towards end of titration phase) and still slightly present at Week 24, it was no longer statistically significant then or later at 36 and 52 weeks. Furthermore, the difference was small (Δ = 0.108) and not statistically significant, AND most importantly the 95% CI is within the prespecified margins to demonstrate equivalence in clinical efficacy (see next bullet points) The criterion for primary efficacy outcome (change in HbA1c at 24 weeks) was met (i.e. non-inferiority of LY IGlar to IGlar was demonstrated at the 0.4% and 0.3% non-inferiority margins); the least squares mean difference between treatment (LY IGlar – IGlar) in change from baseline to the 24-week endpoint (LOCF) was 0.108% (95% CI −0.002, 0.219). IGlar was also non-inferior to LY IGlar in the secondary treatment comparison at the −0.4% non-inferiority margin; thus, LY IGlar and IGlar were considered to have equivalent efficacy; similar results were seen at 52 weeks Full analysis set: based on the intent-to-treat principle, all patients who were randomized and who have taken at least 1 dose of study medication. Patients were assigned to the treatment arm to which they were randomized Most importantly, non-inferiority of LY IGlar to IGlar was demonstrated at both 0.4% and 0.3% non-inferiority margins. IGlar was also non-inferior to LY IGlar in the secondary treatment comparison at the −0.4% non-inferiority margin; thus, LY IGlar and IGlar were considered to have equivalent efficacy based on the full analysis set population Actual HbA1c values, least squares mean (standard error) Baseline: LY IGlar = 7.76 (0.07), IGlar = 7.79 (0.07) 24 weeks LOCF: LY IGlar = 7.42 (0.05), IGlar = 7.31 (0.05) 52 weeks LOCF: LY IGlar = 7.52 (0.06), IGlar = 7.50 (0.06) Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Data are least squares mean ± standard error *p = 0.03; no significant differences between treatment at any other time point CI=confidence interval; HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Other Glucose Measures
BIV No statistically significant treatment differences were observed for self-monitored blood glucose (SMBG) FBG and mean BG at any visit or the 24- and 52-week endpoints (LOCF) At the 24- and 52-week endpoints (LOCF), the proportion of patients achieving target HbA1c values was similar between treatment groups SMBG The FBG and daily mean BG values are from 7-point SMBG profiles Patients should have performed 3 × 7-point SMBG profiles during the 2-week period prior to these visits. The 7 points were before the morning, mid-day, and evening meals; 2 hours after the morning and mid-day meals, bedtime; and at 3 AM Summary of SMBG data (data not shown at ADA): There were no statistically significant differences between treatment groups for daily mean BG values, the morning pre-meal BG values, the daily pre-meal mean BG values, or the bedtime to 3 AM excursion. While the LY IGlar group had statistically significantly lower mean BG values compared with the IGlar group at bedtime (24- and 52-week endpoints) and 3 AM (24-week endpoint), and for the daily 2-hour post-prandial mean BG value (52-week endpoint), none indicated a consistent or clinically significant trend Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up BG values are least squares mean ± standard error aNumbers reflect maximal sample size; bFrom 7-point self-monitored blood glucose BG=blood glucose; FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Daily Insulin Dose and Body Weight
BIV There were no statistically significant differences between treatment groups at baseline or endpoints (LOCF) for daily prandial and basal insulin dose, and at baseline or change from baseline at endpoints (LOCF) for total daily insulin dose Similarly, there were no statistically significant differences between treatment groups at baseline or change from baseline at endpoints (LOCF) for mean body weight All 24-week and 52-week time points are LOCF Titration Insulin dose adjustments were done in both treatment groups to help patients achieve glycaemic targets (glycosylated haemoglobin [HbA1c] <7%, fasting blood-equivalent glucose ≤108 mg/dL [6.0 mmol/L], and other pre-prandial capillary blood glucoses 70–130 mg/dL [3.9–7.2 mmol/L], while minimizing/avoiding hypoglycaemia) Dosage adjustments were to be completed by Week 12, with any further adjustments made after Week 12 only for safety concerns such as hypoglycaemia or unacceptable hyperglycaemia Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Data are least squares mean ± standard error. LOCF=last observation carried forward Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Total, Nocturnal, and Severe hypoglycaemia
BIV There were no statistically significant treatment differences for the overall incidence or overall rate of hypoglycaemia (total, nocturnal, and severe) Severe hypoglycaemia rate (events/patients/1 year, mean [standard deviation]) LY IGlar = 0.07 (0.46), IGlar = 0.08 (0.46) Severe hypoglycaemia events between bedtime and waking (nocturnal) LY IGlar, N = 5; IGlar, N = 7 Severe hypoglycaemia events between waking and bedtime (daytime) LY IGlar, N = 8; IGlar, N = 10 hypoglycaemia definitions hypoglycaemia: any time a patient felt that he/she was experiencing a sign or symptom that was associated with hypoglycaemia OR had a blood glucose (BG) level ≤70 mg/dL (≤3.9 mmol/L), even if it was not associated with signs, symptoms, or treatment consistent with current guidelines Total hypoglycaemia: included any event that met the criteria for documented symptomatic hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), asymptomatic hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), unspecified hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), probable symptomatic hypoglycaemia, or severe hypoglycaemia Nocturnal hypoglycaemia: hypoglycaemic events that occurred between bedtime and waking were analyzed by the BG ≤70 mg/dL (≤3.9 mmol/L) threshold Severe hypoglycaemia: defined as a hypoglycaemic event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These events may have been associated with sufficient neuroglycopenia to induce seizure or coma. BG measurements may not have been available during such an event, but neurological recovery attributable to the restoration of BG to normal was considered sufficient evidence that the event was induced by low plasma glucose Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up All p values >0.05 Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Summary of Adverse Events
BIV The overall incidence and type of AEs reported for LY IGlar were comparable with those of IGlar1 There was 1 death (IGlar) during the 52-week study. The event was not considered by the investigator to be related to study drug or study procedures A total of 44 patients (8.2%) experienced at least 1 serious AE during the 52-week study, with a similar incidence in both treatment groups (LY IGlar: 20 patients [7.5%]; IGlar: 24 patients [9.0%]; p = 0.534). hypoglycaemia was the most frequently reported serious AE (LY IGlar: 13 patients [4.9%]; IGlar: 12 patients [4.5%]) Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Data are n (%) All p values >0.05 aPatients may be counted in >1 category AE=adverse event; TEAE=treatment-emergent adverse event Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Summary of Allergic Events and Injection Site Reactions
BIV The overall incidence of treatment-emergent allergic events reported for LY IGlar was comparable with that of IGlar Most events were mild in severity, and none was reported as serious or led to discontinuation Special Topic Assessment of Allergic Events (Summary and Analysis of Incidence by System Organ Class [SOC] and Preferred Term [PT]) SOC=Skin and Subcutaneous Tissue Disorders included: PT=pruritus, rash, dermatitis allergic, photosensitivity reaction, urticaria SOC=Musculoskeletal Disorders: PT=arthralgia, arthritis SOC=General Disorders and Injection Site Reactions: PT=injection site reaction, injection site induration, injection site nodule, local swelling SOC=Immune System Disorders: PT=drug hypersensitivity, hypersensitivity SOC=Respiratory, Thoracic, and Mediastinal Disorders included: PT=allergic respiratory symptom, asthma Refer to back-up slides for a breakdown of data by SOC and PT Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Data are n (%) for patients with ≥1 treatment-emergent AE All p values >0.05 aPatients may be counted in >1 category; bPhotosensitivity reaction, urticaria AE=adverse event Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Incidence of Treatment-emergent Antibody Response (TEAR)
BIV The incidence of TEAR was not statistically significantly different between treatment groups at any visit, 52-week endpoint (LOCF), or overall (where overall refers to throughout the treatment period) TEAR is defined as patients who were antibody-negative at baseline and developed antibody binding values ≥1.26% post-baseline, or patients with detectable antibody levels at baseline with at least a 1% increase in antibody binding value and which is 30% greater than baseline (1.26% = 1% + the assay cut-off of 0.26%) Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up LOCF=last observation carried forward Blevins et al. ADA 2014: 69-OR

Summary of Results from ELEMENT 1
LY IGlar compared with IGlar at 24 weeks and 52 weeks demonstrated similar: glucose-lowering effect (HbA1c, FBG, mean BG) insulin doses (basal, prandial, total) changes in body weight hypoglycaemia incidence and rate adverse-event profile allergic and injection site reactions incidence of treatment-emergent antibody response BIV LY IGlar and IGlar can be considered to have equivalent efficacy based on the non-inferiority of LY IGlar to IGlar (primary treatment comparison; both 0.4% and 0.3% non-inferiority margins) and of IGlar to LY IGlar (secondary treatment comparison; −0.4% non-inferiority margin) for change in HbA1c from baseline to the 24-week endpoint (last observation carried forward [LOCF]) There were no statistically significant differences between treatment groups in the proportion of patients who achieved HbA1c target values of <7.0% and ≤6.5% at the 24‑ and 52-week endpoints (LOCF), supporting the primary endpoint analyses There were no statistically significant differences between treatment groups for daily mean BG values and FBG values There were no statistically significant differences between treatment groups for the change from baseline to 24- and 52-week endpoints (LOCF) for daily basal, prandial, or total insulin dose or in body weight Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up BG=blood glucose; FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin Blevins et al. ADA 2014: 69-OR

ELEMENT 1: Conclusions LY IGlar compared with IGlar, used in combination with insulin lispro, provided equivalent efficacy and a similar safety profile, with no clinically meaningful differences in patients with type 1 diabetes mellitus BIV Both LY IGlar and IGlar, when used in combination with insulin lispro in patients with type 1 diabetes mellitus (T1DM), provided effective (and similar) glucose control with similar safety profiles LY IGlar provides a well-tolerated and effective once-daily basal insulin option for treatment of patients with T1DM in combination with insulin lispro, with an efficacy and safety profile similar to that of IGlar Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with T1DM The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Blevins et al. ADA 2014: 69-OR

Similar Efficacy and Safety with LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T2DM: The ELEMENT 2 Study Julio Rosenstock1, Priscilla Hollander2, Anuj Bhargava3, Liza Ilag4, Robyn K. Pollom4, William J. Huster4, Melvin Prince4 for the ELEMENT 2 Study Group 1Dallas Diabetes and Endocrine Center at Medical City, Texas, USA; 2Baylor Endocrine Center, Texas, USA; 3Iowa Diabetes and Endocrinology Research Center, Iowa, USA; 4Eli Lilly and Company, Indiana, USA BIV Lantus is a registered trademark of Sanofi-Aventis Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Study Design Study Criteria ≥18 years T2DM ≥2 OADs ± IGlar
HbA1c ≥7% and ≤11% if insulin-naïve HbA1c ≤11% if previously on IGlar BMI ≤45 kg/m2 Study Criteria BIV ELEMENT 2 was a global, double-blind, Phase 3 trial evaluating LY IGlar and IGlar in patients with T2DM The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 OADs and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs Patients who were randomized to treatment (LY IGlar or IGlar) were provided with insulin vials and syringes. The insulin vials were enclosed in a cover, for blinding purposes Background Patients were stratified by country, HbA1c value (<8.5%, ≥8.5%), use of sulfonylurea (yes or no), and time of basal insulin injection (daytime, evening/bedtime) Countries: Czech Republic, France, Germany, Greece, Hungary, Italy, Republic of Korea, Mexico, Poland, Puerto Rico, Spain, Taiwan, United States a3 patients (LY IGlar) discontinued before receiving study drug BMI=body mass index; FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; IGlar=Lantus® insulin glargine; LY IGlar=LY insulin glargine; OAD=oral antidiabetic drug; QD=once daily; SC=subcutaneous; T2DM; type 2 diabetes mellitus Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Objectives Primary Key secondary
To demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks, when used in combination with OADs (the non-inferiority margin was 0.4% and, if met, the upper limit of the 95% confidence interval was compared with the 0.3% non-inferiority margin) Key secondary Non-inferiority of IGlar to LY IGlar Change in HbA1c over time 7-point SMBG Fasting blood glucose changes over time (by SMBG) Proportion of patients with HbA1c <7% or ≤6.5% Change in body weight Insulin dose Hypoglycaemia Adverse events Incidence of anti-insulin antibodies BIV The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks, at the non-inferiority margin of +0.4% If the 0.4% non-inferiority margin was met, then the upper limit of the 95% confidence interval was compared with the 0.3% non-inferiority margin to control for the family-wise type 1 error rate at a 1-sided level Secondary objectives of ELEMENT 2 included the non-inferiority of IGlar to LY IGlar at the non-inferiority margin of −0.4%, safety, and additional measures of glycaemic control If LY IGlar was declared non-inferior to IGlar in the primary treatment comparison, and IGlar was declared non-inferior to LY IGlar in the secondary treatment comparison, then LY IGlar was considered to have equivalent efficacy to IGlar Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 OADs and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs HbA1c=glycosylated haemoglobin; OAD=oral antidiabetic drug; SMBG=self-monitored blood glucose Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Patient Disposition
BIV A total of 759 patients were randomized; 3 patients (LY IGlar) discontinued before receiving study drug Therefore, a total of 756 patients were randomized and received at least 1 dose of study drug, and were thus included in the full analysis set analysis; 376 patients in the LY IGlar treatment group and 380 patients in the IGlar treatment group Of the patients included in the full analysis set population, 334 patients (88.8%) in the LY IGlar group and 328 (86.3%) in the IGlar group completed the 24-week treatment period Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Baseline Demographics and Patient Characteristics
BIV In the total population, patient characteristics were generally similar between treatment groups The age of patients was similar across treatment groups, with an overall mean age of years The majority of patients were white (78.4%) and 50.0% of the patients were male The characteristics in the insulin-naïve and prior IGlar populations were generally consistent with the total population Nearly 60% of patients were insulin-naïve1; more than 80% of patients were using 2 oral antidiabetic drugs (OADs) Full analysis set: based on the intent-to-treat principle, all patients who were randomized and who have taken at least 1 dose of study medication Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 OADs and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs 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; bTotal (IGlar, N = 359; LY IGlar, N = 353): insulin-naïve (IGlar, N = 224; LY IGlar, N = 209): prior IGlar (IGlar, N = 135; LY IGlar, N = 144); *p = 0.04 BMI=body mass index; FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: FBG Changes over Time
BIV No statistically significant treatment differences were observed at any visit or endpoint (LOCF) for FBG Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs FBG=fasting blood glucose; LOCF=last observation carried forward; LSM=least squares mean; SE=standard error Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: 7-point SMBG BIV-00061153
SMBG was collected at 7 time points (pre-meal for each meal, 2 hours after morning and midday meals, bedtime, and 3 AM) In type 2 diabetes mellitus (T2DM) patients, the 24-hour glucose profiles were similar at most time points over 24 hours for LY IGlar and IGlar No significant differences between treatment groups were observed for daily mean blood glucose measurement (derived from SMBG profiles) at endpoint At endpoint, mean (least squares) blood glucose values were significantly lower in the LY IGlar group at midday pre-meal time point compared with IGlar. No statistically significant treatment differences were observed for any other time point Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with T2DM The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs *p = 0.04 LOCF=last observation carried forward; PPG=post-prandial glucose; SMBG=self-monitored blood glucose Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: HbA1c Changes over Time
BIV Both treatment groups had within-group, statistically significant (p <0.001) decreases in least squares mean HbA1c values from baseline, which began at Visit 4 (Week 6) and continued through to the 24‑week endpoint (LOCF) Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward; LSM=least squares mean; SE=standard error Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Change at Study End in HbA1c and % of Patients Reaching Target HbA1c
BIV In the total population, the primary efficacy outcome was met, demonstrating non-inferiority of LY IGlar to IGlar for change in HbA1c at 24 weeks at 0.4% and 0.3% non-inferiority margins Similar results were seen in the patient subpopulations who were either insulin-naïve or were on IGlar at study entry In the total population, there were no statistically significant differences between treatment groups in the proportion of patients who achieved HbA1c target values of <7.0% and ≤6.5% at endpoint, supporting the primary endpoint analyses; similar results were seen in the patient subpopulations who were either insulin-naïve or were on IGlar at study entry Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks1 The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs HbA1c=glycosylated haemoglobin; NS=not significant Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Insulin Dose and Body Weight Changes at Study End
BIV The increases in mean daily basal insulin dose from baseline to endpoint (LOCF) were similar in both treatment groups; there were no statistically significant differences between treatment groups for the change in daily basal insulin dose from baseline at any visit or at endpoint (LOCF) There was no statistically significant difference between treatment groups in body weight at baseline, endpoint, or change from baseline to endpoint (LOCF) Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs Data are least squares mean ± standard error aN = 374 for body weight LOCF=last observation carried forward Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Insulin Dose Subgroup Analysis
BIV There was no significant differential treatment effect on the change in basal insulin dose from baseline to endpoint (LOCF) for insulin-naïve patients compared with patients entering the study with prior IGlar treatment Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs Data are least squares mean ± standard error *p = LOCF=last observation carried forward Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Total, Nocturnal, and Severe hypoglycaemia
BIV There were no statistically significant treatment differences for the overall incidence or overall rate of total and nocturnal hypoglycaemia Overall, 4 patients (2 patients in each treatment group) reported severe hypoglycaemia hypoglycaemia definitions: hypoglycaemia: any time a patient felt that he/she was experiencing a sign or symptom that was associated with hypoglycaemia OR had a blood glucose (BG) level ≤70 mg/dL (≤3.9 mmol/L), even if it was not associated with signs, symptoms, or treatment consistent with current guidelines Total hypoglycaemia: included any event that met the criteria for documented symptomatic hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), asymptomatic hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), unspecified hypoglycaemia with BG ≤70 mg/dL (≤3.9 mmol/L), probable symptomatic hypoglycaemia, or severe hypoglycaemia Nocturnal hypoglycaemia: hypoglycaemic events that occurred between bedtime and waking were analyzed by the BG ≤70 mg/dL (≤3.9 mmol/L) threshold Severe hypoglycaemia: defined as a hypoglycaemic event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These events may have been associated with sufficient neuroglycopenia to induce seizure or coma. BG measurements may not have been available during such an event, but neurological recovery attributable to the restoration of BG to normal was considered sufficient evidence that the event was induced by low plasma glucose Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs All p values >0.05 SD=standard deviation Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Summary of Adverse Events
BIV 1 patient (0.3%) in the LY IGlar group and 1 patient (0.3%) in the IGlar group died during the study; the deaths were not considered by the investigator to be related to study drug or study procedures There were no significant differences between LY IGlar and IGlar in the rate of serious, study drug-related, or treatment-emergent AEs Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs aPatients may be counted in >1 category AE=adverse event; TEAE=treatment-emergent adverse event Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Summary of Allergic Events and Injection Site Reactions
BIV The overall incidence of treatment-emergent allergic events reported for LY IGlar was comparable with that of IGlar Most events were mild or moderate in severity, and none led to discontinuation; 1 event of severe asthma (LY IGlar) was reported as serious Special Topic Assessment of Allergic Events (Summary and Analysis of Incidence by System Organ Class [SOC] and Preferred Term [PT]) SOC=Skin and Subcutaneous Tissue Disorders included: PT=pruritus, rash, dermatitis, angiooedema, rash macular, rash papular, rash pruritic, rash vesicular SOC=Musculoskeletal Disorders: PT=arthralgia, peri-arthritis SOC=General Disorders and Injection Site Reactions: PT=injection site reaction, injection site pruritus, injection site induration SOC=Respiratory, Thoracic, and Mediastinal Disorders included: PT=asthma, nasal oedema Refer to ADA back-up slides for a breakdown of data by SOC and PT Injection site reaction The summary and analysis of the incidence of injection site AEs for patients who completed the Skin Evaluation Questionnaire and Insulin Questionnaire-Injection Sites by treatment group for the full analysis set population Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs aPatients may be counted in >1 category; bMacular rash, papular rash, pruritic rash, vesicular rash AE=adverse event Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Incidence of Treatment-emergent Antibody Response (TEAR)
BIV In patients with type 2 diabetes mellitus (T2DM), the incidence of TEAR was not statistically significantly different between treatment groups at any visit or overall TEAR is defined as patients who were antibody-negative at baseline and developed antibody binding values ≥1.26% post-baseline, or patients with detectable antibody levels at baseline with at least a 1% increase in antibody binding value and which is 30% greater than baseline (1.26% = 1% + the assay cut-off of 0.26%) Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with T2DM The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs LOCF=last observation carried forward Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Summary LY IGlar compared with IGlar demonstrated similar:
glucose-lowering effect (FBG, SMBG, HbA1c) insulin doses changes in body weight hypoglycaemia incidence and rates adverse-event profile allergic and injection site reactions incidence of treatment-emergent antibody response BIV LY IGlar was well tolerated, with similar safety profiles for LY IGlar and IGlar (hypoglycaemia, adverse-event profile, antibody responses) There were no new safety findings in either treatment group Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; SMBG=self-monitored blood glucose Rosenstock et al. ADA 2014: 64-OR

ELEMENT 2: Conclusion LY IGlar compared with IGlar, in combination with oral antidiabetic drugs, provided equivalent efficacy and similar safety profiles, with no clinically meaningful differences in patients with type 2 diabetes mellitus BIV Both LY IGlar and IGlar, when used in combination with oral antidiabetic drugs, provided effective (and similar) glucose control, with similar safety profiles In type 2 diabetes mellitus (T2DM) patients, the similarity between treatments is observed irrespective of whether patients are insulin-naïve or previously treated with IGlar Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with T2DM The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks The study included a 24-week treatment period and a 4-week post-treatment follow-up The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs Rosenstock et al. ADA 2014: 64-OR

Evaluation of Immunogenicity of LY Insulin Glargine Compared with Lantus® Insulin Glargine in Patients with T1DM or T2DM Mark A. Deeg, Liza L. Ilag, William J. Huster, Robyn K. Pollom, Jason S. Zielonka, Melvin J. Prince, Robert J. Konrad Eli Lilly and Company, Indiana, USA BIV Lantus is a registered trademark of Sanofi-Aventis Deeg et al. ADA 2014: 70-OR

Objective To compare the immunogenicity profile of LY insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar) in patients with T1DM (ELEMENT 1) and T2DM (ELEMENT 2) using the following measurements: Proportion of patients with detectable antibodies Treatment-emergent antibody response (TEAR) Treatment-emergent allergic events Relationships between clinical outcomes (HbA1c, basal insulin dose, and total hypoglycaemia) and TEAR status BIV Anti-insulin glargine antibodies were measured in 52- and 24-week studies of LY IGlar versus IGlar in patients with T1DM (open-label) (ELEMENT 1) and T2DM (double-blind) (ELEMENT 2), respectively Background The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies HbA1c=glycosylated haemoglobin; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus Lantus is a registered trademark of Sanofi-Aventis Deeg et al. ADA 2014: 70-OR

Proportion of Patients with Detectable Antibodies: ELEMENT 1
BIV There were no statistically significant differences between LY IGlar and IGlar in the proportion of patients with detectable antibodies to insulin at any visit, endpoint (LOCF), or overall (i.e. throughout the treatment period) for type 1 diabetes mellitus (T1DM) patients Background Anti-insulin glargine antibodies were measured in a 52-week study of LY IGlar versus IGlar in patients with T1DM (open-label) (ELEMENT 1) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies LOCF=last observation carried forward Deeg et al. ADA 2014: 70-OR

Treatment-emergent Antibody Response (TEAR): ELEMENT 1
BIV With TEAR defined as per criteria described below, the incidence of TEAR was not significantly different between LY IGlar and IGlar at 52-week endpoint (last observation carried forward), overall at 24 weeks, or overall at 52 weeks Visually, there are numerical differences observed but these are small and not clinically significant, especially considering that all patients were previously on insulin (with >250 patients in each treatment group), with the majority (~85%) of them on pre-study IGlar The definition of TEAR for patients who were negative for insulin antibodies at baseline was such that these patients had to have insulin antibody binding values of ≥1.26% to be considered to have a TEAR The definition of TEAR for patients negative at baseline was designed to take account of variability near the cut-off point of the assay (detectable antibody if ≥0.26%) Background Anti-insulin glargine antibodies were measured in a 52-week study of LY IGlar versus IGlar in patients with type 1 diabetes mellitus (open-label) (ELEMENT 1) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Deeg et al. ADA 2014: 70-OR

Relationship between HbA1c and Insulin Antibody Level at Endpoint: ELEMENT 1
BIV There were no statistically significant treatment-by-endpoint insulin antibody level interactions with endpoint HbA1c in type 1 diabetes mellitus (T1DM) patients In this scatterplot of detectable insulin antibodies at endpoint (last observation carried forward) versus HbA1c at endpoint for ELEMENT 1, the value for the insulin antibody level at endpoint was transformed using the Ln to improve model fit. The level of detectability for the assay was 0.26% Background Anti-insulin glargine antibodies were measured in a 52-week study of LY IGlar versus IGlar in patients with T1DM (open-label) (ELEMENT 1) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies HbA1c=glycosylated haemoglobin Deeg et al. ADA 2014: 70-OR

Effect of Overall TEAR Status on Change in Clinical Outcomes: ELEMENT 1
BIV There were no significant treatment-by-TEAR interactions for HbA1c, basal insulin dose, and total hypoglycaemia rate, indicating no statistically significant differential treatment effect on these clinical outcomes based on TEAR status during the 52-week study P values for treatment-by-TEAR interaction HbA1c: p = 0.376 Insulin dose: p = 0.975 hypoglycaemia rate: p = 0.434 Background Anti-insulin glargine antibodies were measured in a 52-week study of LY IGlar versus IGlar in patients with type 1 diabetes mellitus (open-label) (ELEMENT 1) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Data are least squares mean (standard error) change from baseline to LOCF endpoint p >0.05 for all treatment-by-TEAR interactions HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward; TEAR=treatment-emergent antibody response Deeg et al. ADA 2014: 70-OR

Proportion of Patients with Detectable Antibodies: ELEMENT 2
BIV In type 2 diabetes mellitus (T2DM) patients, there were no statistically significant treatment differences in the proportion of patients with detectable insulin antibodies after Visit 4, at endpoint (LOCF), or overall (i.e. throughout the treatment period) A statistically significant difference between treatment groups in the proportion of patients with detectable insulin antibodies was observed at Week 4 (LY IGlar: 26 patients [7.2%]; IGlar: 13 patients [3.6%]; p = 0.047) Numerically, more patients with LY IGlar had detectable antibodies overall (24 weeks) but these were not statistically significant and include patients with low % binding levels, even if observed at a single visit or returned to being non-detectable by the end of the study and the antibody levels observed were low (LY IGlar: 2.40%; IGlar: 1.12 %; p=0.184; least squares mean treatment difference (95% confidence interval) of 1.28% (−0.73%, 3.30%) Background Anti-insulin glargine antibodies were measured in a 24-week study of LY IGlar versus IGlar in patients with T2DM (ELEMENT 2) (double-blind) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies LOCF=last observation carried forward Deeg et al. ADA 2014: 70-OR

Treatment-emergent Antibody Response (TEAR): ELEMENT 2
BIV There were no statistically significant differences between LY IGlar and IGlar in the number of patients with a TEAR at 24-week endpoint (last observation carried forward) or overall (i.e. throughout the treatment period) at 24 weeks in type 2 diabetes mellitus (T2DM) patients The definition of TEAR for patients who were negative for insulin antibodies at baseline was such that these patients had to have insulin antibody binding values of ≥1.26% to be considered to have a TEAR The definition of TEAR for patients negative at baseline was designed to take account of variability near the cut-off point of the assay (detectable antibody if ≥0.26%) Background Anti-insulin glargine antibodies were measured in a 24-week study of LY IGlar versus IGlar in patients with T2DM (ELEMENT 2) (double-blind) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Deeg et al. ADA 2014: 70-OR

Relationship between HbA1c and Insulin Antibody Level at Endpoint: ELEMENT 2
BIV There were no statistically significant treatment-by-endpoint insulin antibody level interactions with endpoint HbA1c in type 2 diabetes mellitus (T2DM) patients In this scatterplot of detectable insulin antibodies at endpoint (last observation carried forward) versus HbA1c at endpoint for ELEMENT 2, the value for the insulin antibody level at endpoint was transformed using the Ln to improve model fit.2 The level of detectability for the assay was 0.26% Background Anti-insulin glargine antibodies were measured in a 24-week study of LY IGlar versus IGlar in patients with T2DM (ELEMENT 2) (double-blind) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies HbA1c=glycosylated haemoglobin Deeg et al. ADA 2014: 70-OR

Effect of Overall TEAR Status on Change in Clinical Outcomes: ELEMENT 2
BIV There were no significant treatment-by-TEAR interactions for these clinical outcomes (HbA1c, basal insulin dose, and total hypoglycaemia rate), indicating no statistically significant differential treatment effect on these clinical outcomes for patients who did or did not develop TEAR during the 24-week study P values for treatment-by-TEAR interaction HbA1c: p = 0.185 Insulin dose: p = 0.457 hypoglycaemia rate: p = 0.676 Background Anti-insulin glargine antibodies were measured in a 24-week study of LY IGlar versus IGlar in patients with type 2 diabetes mellitus (ELEMENT 2) (double-blind) The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Data are least squares mean (standard error) change from baseline to LOCF endpoint p >0.05 for all treatment-by-TEAR interactions HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward; TEAR=treatment-emergent antibody response Deeg et al. ADA 2014: 70-OR

Summary of Allergic Events and Injection Site Reactions
BIV The assessment of allergic events was performed by an initial blinded review of preferred terms by system organ class in order to identify all possible cases Allergic events Most events were mild or moderate in severity, and none led to discontinuation Within each study, no statistically significant treatment differences in the incidence of these events were observed Injection site reactions Most patients reporting injection site adverse events reported having mild or moderate pain associated with the injection Background Anti-insulin glargine antibodies were measured in 52- and 24-week studies of LY IGlar versus IGlar in patients with type 1 diabetes mellitus (open-label) (ELEMENT 1) and type 2 diabetes mellitus (ELEMENT 2) (double-blind), respectively The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Supplementary information Summary and analysis of the incidence of allergic events and the summary and analysis of the incidence of injection site reactions were evaluated for patients who completed the Skin Evaluation Questionnaire (SKE) and Insulin Questionnaire-Injection Sites (IQIS) by treatment group for the ELEMENT 1 and ELEMENT 2 studies Special Topic Assessment of Allergic Events (Summary and Analysis of Incidence by System Organ Class [SOC] and Preferred Term [PT]) SOC=Skin and Subcutaneous Tissue Disorders included: PT=pruritus, rash, dermatitis, other SOC=Musculoskeletal Disorders: PT=arthralgia, arthritis, peri-arthritis SOC=General Disorders and Injection Site Reactions: PT=injection site reaction, injection site induration, injection site nodule, local swelling SOC=Immune System Disorders: PT=drug hypersensitivity, hypersensitivity SOC=Respiratory, Thoracic, and Mediastinal Disorders included: PT=allergic respiratory symptom, asthma, nasal oedema Injection site reaction The summary and analysis of the incidence of injection site adverse events for patients who completed the SKE and IQIS by treatment group for the full analysis set population Medical Dictionary for Regulatory Activities (MedDRA): electronic dictionary of medical terminology MedDRA terminology applies to all phases of drug development Terminology is structured so that selection of a data entry term leads to automatic assignment of grouping terms higher in the hierarchy Each lowest level term is linked to only 1 preferred term (PT) PTs should be unambiguous, specific, and self-descriptive Each PT has a primary system organ class (SOC) An SOC is the highest level of the hierarchy that provides the broadest concept for data retrieval and may have a number of PTs associated with it Data are n (%) for patients with ≥1 treatment-emergent adverse event All p values >0.05 aPatients may be counted in >1 category; bMacular rash, papular rash, pruritic rash, vesicular rash, photosensitivity reaction, urticaria; cInduration, nodule, swelling Deeg et al. ADA 2014: 70-OR

Immunogenicity Summary
In patients with T1DM or T2DM treated with LY IGlar or IGlar, there were no treatment differences in: proportion of patients with detectable antibodies at baseline and throughout the treatment period the incidence of TEAR relationships between clinical outcomes (HbA1c, basal insulin dose, and total hypoglycaemia) and TEAR status the incidence of treatment-emergent allergic events BIV These clinical safety data demonstrate a similar immunogenicity profile of LY IGlar and IGlar in patients with T1DM or T2DM. There were no treatment differences in: the proportion of patients with detectable antibodies at baseline and throughout the treatment period the incidence of TEAR relationships between clinical outcomes (HbA1c, basal insulin dose, and total hypoglycaemia) and TEAR status the incidence of treatment-emergent allergic events Background Anti-insulin glargine antibodies were measured in 52- and 24-week studies of LY IGlar versus IGlar in patients with T1DM (open-label) (ELEMENT 1) and T2DM (ELEMENT 2) (double-blind), respectively The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies HbA1c=glycosylated haemoglobin; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus; TEAR=treatment-emergent antibody response Deeg et al. ADA 2014: 70-OR

Immunogenicity Conclusions
LY IGlar and IGlar have a similar immunogenicity profile, with no effects of anti-insulin glargine antibodies on efficacy and safety outcomes in patients with type 1 diabetes mellitus or type 2 diabetes mellitus BIV These clinical safety data demonstrate a similar immunogenicity profile of LY IGlar and IGlar, with no effects of anti-insulin glargine antibodies on efficacy and safety outcomes in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) Background Anti-insulin glargine antibodies were measured in 52- and 24-week studies of LY IGlar versus IGlar in patients with T1DM (open-label) (ELEMENT 1) and T2DM (ELEMENT 2) (double-blind), respectively The amino acid sequences of LY IGlar and IGlar are identical Subtle differences in protein products manufactured using living cells may affect the immune response and clinical outcomes, including anti-insulin glargine antibodies Insulin antibodies were quantified as percent binding using a classical radioimmunoassay format. After adding a radiolabeled tracer (LY ) to a serum sample, percent binding represents the percent of the total amount of tracer that co‑precipitates with the antibodies Deeg et al. ADA 2014: 70-OR

BACK-UP SLIDES BIV

ELEMENT 1: Summary of Allergic Events By System Organ Class and Preferred Term
BIV The overall incidence of treatment-emergent allergic events reported for LY IGlar was comparable with that of IGlar Most events were mild in severity, and none was reported as serious or led to discontinuation Medical Dictionary for Regulatory Activities (MedDRA): electronic dictionary of medical terminology MedDRA terminology applies to all phases of drug development Terminology is structured so that selection of a data entry term leads to automatic assignment of grouping terms higher in the hierarchy Each lowest level term is linked to only 1 preferred term (PT) PTs should be unambiguous, specific, and self-descriptive Each PT has a primary system organ class (SOC) An SOC is the highest level of the hierarchy that provides the broadest concept for data retrieval and may have a number of PTs associated with it Background ELEMENT 1 was a global Phase 3 trial that evaluated LY IGlar and IGlar in patients with type 1 diabetes mellitus (T1DM) The primary objective of ELEMENT 1 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline to 24 weeks in patients with T1DM The study included a 24-week treatment period, a 28-week extension period, and a 4-week post-treatment follow-up Data are n (%) for patients with ≥1 treatment-emergent allergic event All p values >0.05 Blevins et al. ADA 2014: 69-OR

ELEMENT 2: Summary of Allergic Events By System Organ Class and Preferred Term
BIV The overall incidence of treatment-emergent allergic events reported for LY IGlar was comparable with that of IGlar1 Most events were mild or moderate in severity, and none led to discontinuation; 1 event of severe asthma (LY IGlar) was reported as serious1 Medical Dictionary for Regulatory Activities (MedDRA): electronic dictionary of medical terminology MedDRA terminology applies to all phases of drug development Terminology is structured so that selection of a data entry term leads to automatic assignment of grouping terms higher in the hierarchy Each lowest level term is linked to only 1 preferred term (PT) PTs should be unambiguous, specific, and self-descriptive Each PT has a primary system organ class (SOC) An SOC is the highest level of the hierarchy that provides the broadest concept for data retrieval and may have a number of PTs associated with it Background ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus1 The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in glycosylated haemoglobin from baseline at 24 weeks1 The study included a 24-week treatment period and a 4-week post-treatment follow-up1 The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs1 Reference Rosenstock J, Hollander P, Bhargava A, et al. Similar efficacy and safety with LY insulin glargine compared with Lantus® insulin glargine in patients with T2DM: the ELEMENT 2 study. Oral presentation at the 74th Scientific Sessions of the American Diabetes Association, June 13–17, 2014, San Francisco; Abs. 64-OR Rosenstock et al. ADA 2014: 64-OR

Date of preparation: May 2015 | UK/GLA/00036

ADA 2014 Data Disclosures on LY Insulin Glargine (LY IGlar)

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ADA 2014 Data Disclosures on LY Insulin Glargine (LY IGlar)

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