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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:
www.mhra.gov.uk/yellowcard. Adverse events and product complaints should also be
reported to Lilly: please call Lilly UK on 01256 315 000.
Prescribing information for Abasaglar®▼ (insulin glargine injection [rDNA origin] 100 units/mL)
can be found at the end of this presentation
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Contents
•
•
LY IGlar background
Phase 1 PK and PD studies
– Comparative PK and PD of LY2963016 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, LY2963016 and Lantus®,
in Subjects with Type 1 Diabetes Mellitus (891-P)
– Comparative PK and PD of 2 Insulin Glargine Products, LY2963016 and Lantus®,
in Healthy Subjects at 2 Dose Levels (890-P)
•
Phase 3 efficacy and safety studies
– Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with
Lantus® Insulin Glargine in Patients with T1DM: The ELEMENT 1 Study (69-OR)
– Similar Efficacy and Safety with LY2963016 Insulin Glargine Compared with
Lantus® Insulin Glargine in Patients with T2DM: The ELEMENT 2 Study (64-OR)
– Evaluation of Immunogenicity of LY2963016 Insulin Glargine Compared with
Lantus® Insulin Glargine in Patients with T1DM or T2DM (70-OR)
PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
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 FDA DRAFT Guidance for Industry: Clinical Pharmacology Data to Support a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
PD=pharmacodynamic; PK=pharmacokinetic;
containing recombinant human insulin and insulin analogues, 2015;
T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus
3. Blevins et al. ADA 2014: 69-OR; 4. Rosenstock et al. ADA 2014: 64-OR;
Lantus is a registered trademark of Sanofi-Aventis
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.
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
The LY IGlar Phase 1 Programme
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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)
US-approved IGlar
vs.
EU-approved IGlar
LY IGlar
vs.
US-approved IGlar
(Study ABEO1)
(Study ABEN1)
• 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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
LY IGlar
vs.
IGlar
(Study ABEE1)
(Study ABEM2)
T1DM patients
Duration of action
Healthy subjects
2 different doses:
0.3 and 0.6 U/kg
Randomized
Double-blind
Single-dose (0.3 U/kg)
Crossover
Euglycemic clamp
PD=pharmacodynamic; PK=pharmacokinetic; T1DM=type 1 diabetes mellitus
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Randomized
Double-blind
Crossover
Euglycemic clamp
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
1. Linnebjerg et al. ADA 2014: 889-P
2. FDA DRAFT Guidance for Industry: Clinical Pharmacology Data to Support a
*US submission
Demonstration of Biosimilarity to a Reference Product, Section I, Lines 539-542
CI=confidence interval;
3. EMEA, Guideline on non-clinical and clinical development of
PD=pharmacodynamic; PK=pharmacokinetic
similar biological medicinal products containing recombinant
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
human insulin and insulin analogues, 2015
Comparative Pharmacokinetics and
Pharmacodynamics of LY2963016 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;
Centre for Clinical Pharmacology, Singapore;
3PAREXEL International Bloemfontein Early Phase Unit, Bloemfontein, South Africa
*Author has since retired from institution listed
2Lilly-NUS
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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 LY2963016 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
1. EMA CHMP. Guideline On Similar Biological Medicinal Products 2014;
2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating
Lantus is a registered trademark of Sanofi-Aventis
Biosimilarity to a Reference Product 2012;
3. Linnebjerg et al. ADA 2014: 889-P
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Study Design
Screening
Follow-up
Up to 6 weeks
before Period 1
dosing
5–14 days after
Period 4 / early
termination
Period: 1
2
3
4
Treatment sequence 1:
T
R
T
R
Treatment sequence 2:
R
T
R
T
Clamp*
= dosing and
24-hour clamp
*Including collection
of serial blood
samples for PK and
PD assessments
Day: −1
Admission
1
Dose
2
Discharge
Washout ≥7 days
PD=pharmacodynamic; PK=pharmacokinetic; T=test treatment; R=reference treatment
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
PD=pharmacodynamic; PK=pharmacokinetic
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
1. Owens DR. Human insulin: clinical pharmacological studies
in normal man. New York: Springer Publishing; 1986
Results
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Summary of Studies
LY IGlar
= comparison
The PK and PD were compared
among the 3 insulin glargine products
in 3 separate studies
EU
IGlar
US
IGlar
LY IGlar vs.
EU IGlar
(N = 80)
LY IGlar vs.
US IGlar
(N = 91)
EU IGlar vs.
US IGlar
(N = 40)
Sex, male / female (%)
70.0 / 30.0
93.4 / 6.6
82.5 / 17.5
Age (years)a
32.0
10.9
32.7
9.0
31.9
9.9
Weight (kg)a
74.8
12.5
70.2
10.3
67.8
9.4
BMI (kg/m2)a
24.9
3.2
24.1
2.8
23.8
2.4
Demographics
aMean
standard deviation
BMI=body mass index; N=number of subjects;
PD=pharmacodynamics; PK=pharmacokinetics
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
PK Profiles of LY IGlar vs. EU IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration
*Healthy subjects
PK=pharmacokinetic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
PK Profiles of LY IGlar vs. US IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration
*Healthy subjects
PK=pharmacokinetic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
PK Profiles of EU IGlar vs. US IGlar*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration
• C-peptide-corrected serum insulin concentration profiles were
similar for all glargine products
*Healthy subjects
PK=pharmacokinetic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
Comparison of PK Parameters of LY IGlar and IGlar
Parameter
(units)
AUC(0–24)
(pmol∙hr/L)
Cmax (pmol/L)
•
Treatment
N (n)
Geometric
Mean (CV%)
LY IGlar
79 (156)
1810 (40)
EU IGlar
80 (157)
1980 (36)
LY IGlar
87 (165)
1720 (42)
US IGlar
89 (167)
1900 (35)
EU IGlar
40 (75)
2000 (35)
US IGlar
40 (76)
2060 (39)
LY IGlar
80 (158)
112 (39)
EU IGlar
80 (158)
119 (34)
LY IGlar
88 (167)
103 (41)
US IGlar
89 (169)
111 (34)
EU IGlar
40 (76)
120 (33)
US IGlar
40 (77)
122 (37)
Ratio of LS Geometric
Means (90% CI)a
0.91 (0.87, 0.96)
0.90 (0.86, 0.94)
0.98 (0.91, 1.05)
0.95 (0.90, 1.00)
0.92 (0.87, 0.96)
0.99 (0.92, 1.06)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
Comparison of tmax of LY IGlar and IGlara
Treatment
Median tmax
N
LY IGlar
12.00
80
EU IGlar
13.50
80
LY IGlar
12.00
88
US IGlar
12.00
89
EU IGlar
12.00
40
US IGlar
12.00
40
Median Difference (95% CI) [p
value]
0.00 (−0.75, 0.75)
[0.82]
0.50 (−0.76, 1.25)
[0.48]
−0.75 (−1.50, 0.50)
[0.28]
• No statistically significant difference in tmax between treatments (95%
CIs for median differences contain 0; p >0.05)
at
max
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
PD Profiles of LY IGlar vs. EU IGlar*
Mean Blood
Mean Glucose Infusion
Glucose (mmol/L)
Rate (mg/kg/min)
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom)
6
5
4
3
2
1
0
LY IGlar
EU IGlar
0
4
8
12
16
20
24
0
4
8
12
16
Time (hour)
20
24
6
5
4
3
2
•
Mean glucose infusion rate profiles were similar between LY IGlar and EU IGlar
*Healthy subjects
PD=pharmacodynamic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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)
•
Mean glucose infusion rate profiles were similar between LY IGlar and US IGlar
*Healthy subjects
PD=pharmacodynamic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
PD Profiles of EU IGlar vs. US IGlar*
Mean Glucose Infusion
Mean Blood
Rate (mg/kg/min)
Glucose (mmol/L)
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Blood Glucose Levels (Bottom)
•
EU IGlar
US IGlar
6
5
4
3
2
1
0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
6
5
4
3
2
Time (hour)
Mean glucose infusion rate profiles were similar between EU IGlar and US IGlar
*Healthy subjects
PD=pharmacodynamic; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
Comparison of PD Parameters of LY IGlar and IGlar
Parameter
(units)
Gtot (mg/kg)
Rmax
(mg/kg/min)
•
Treatment
N (n)
Geometric
Mean (CV%)
LY IGlar
80 (158)
2580 (45)
EU IGlar
80 (158)
2710 (40)
LY IGlar
88 (171)
1670 (60)
US IGlar
88 (170)
1820 (74)
EU IGlar
40 (76)
1870 (84)
US IGlar
40 (77)
1880 (77)
LY IGlar
80 (158)
2.85 (46)
EU IGlar
80 (158)
2.88 (41)
LY IGlar
88 (171)
2.12 (54)
US IGlar
88 (170)
2.27 (58)
EU IGlar
40 (76)
2.35 (67)
US IGlar
40 (77)
2.44 (63)
Ratio of LS
Geometric Means
(90% CI)a
0.95 (0.91, 1.00)
0.91 (0.85, 0.98)
1.00 (0.89, 1.13)
0.99 (0.94, 1.04)
0.93 (0.88, 0.98)
0.97 (0.88, 1.07)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
AE=adverse event; ECG=electrocardiogram
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Linnebjerg et al. ADA 2014: 889-P
Duration of Action of 2 Insulin Glargine
Products, LY2963016 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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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 LY2963016 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
T1DM=type 1 diabetes mellitus
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Euglycemic Clamp Procedure
LY IGlar / IGlar SC (0.3 U/kg) (0 hours)
Washout
pre-study
insulin
−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
Run-in period
• 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
Euglycemic clamp
Resume
pre-study
insulin
• 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
IV=intravenous; NPH=Neutral Protamine Hagedorn; SC=subcutaneous
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
1. Heise et al. ADA 2014: 891-P;
2. Cox DR. J R Stat Soc Series B 1972;20:187–220
Subject Demographics
Parameter
Age (years)
Mean ± SD
(N = 20)*
41.5
9.1
Sex, male (%)
100
Race, white (%)
100
Weight (kg)
84.1
9.8
BMI (kg/m2)
25.6
2.4
HbA1c (%)
7.99
0.62
Duration of diabetes (years)
18.9
9.8
*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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Results
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Mean Glucose Infusion
Rate (mg/kg/min)
Mean ( SD) Glucose Infusion Rate and
Corresponding Blood Glucose Levels
LY IGlar (0.3 U/kg)
IGlar (0.3 U/kg)
2.0
1.5
1.0
0.5
0.0
0
8
16
24
32
40
48
Blood Glucose
(mmol/L)
Time (hour)
15
12
9
6
3
0
Smoothing factor ranged
from 0.075 to 0.2
0
8
16
24
32
40
48
Time (hour)
SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Time-to-event (Survival) Plot of Duration of Action
for 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 = 0.8777
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Comparison of Duration of Action of LY IGlar and
IGlar Based on Survival Analysis (All Subjects)
Summary Statistics
IGlar (0.3 U/kg)
LY IGlar (0.3 U/kg)
Number (%) of events
13 (65.0)
13 (65.0)
Number (%) censoreda
7 (35.0)
7 (35.0)
2.0–41.5b
2.8–40.5b
19.50 (12.23, 39.50)
19.75 (7.00, 37.00)
40.00 (20.00, NAd)
37.13 (20.00, NAd)
25.54 (3.91)
23.78 (3.75)
Duration of action (hour)
Range
25th percentilec (95% CI)
Median (95% CI)
Meanb (SE)
of action was “censored” (i.e. not recorded) when a subject did not reach EoA before clamp termination;
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
aDuration
bMaximum
Heise et al. ADA 2014: 891-P
Comparison of Gtot and Rmax of LY IGlar and IGlar
Parameter
(units)
Treatment
(0.3 U/kg)
N
Geometric
Mean (CV%)
Gtot
(mg/kg)
LY IGlar
20
4.60 (1090)
IGlar
19
6.52 (1160)
Rmax
(mg/kg/min)
LY IGlar
20
0.530 (254)
IGlar
19
0.611 (310)
Ratio of LS
Geometric Means
(90% CI)
0.77 (0.46, 1.30)
0.91 (0.52, 1.61)
• 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
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Mean ( SD) Serum Insulin Concentration
with LY IGlar and IGlar
Serum Insulin (pmol/L)
120
LY IGlar (0.3 U/kg)
IGlar (0.3 U/kg)
100
80
60
40
20
0
6
12
18
24
30
36
42
Time (hour)
•
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Adverse Events and Tolerability with
LY IGlar and IGlar
Frequency of Treatment-emergent Adverse Events (All Causalities)
MedDRA Preferred
Terma
Headache
Back pain
Abdominal pain upper
Arthralgia
Dizziness
Nausea
Total
Number of AEsb
(Number of Subjects with AEs)
0.3 U/kg IGlar
0.3 U/kg LY IGlar
(N = 20)
(N = 20)
2 (2)
1 (1)
1 (1)
1 (1)
1 (1)
1 (1)
1 (1)
1 (1)
3 (3)
6 (4)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
AE=adverse event; ECG=electrocardiogram
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Gtot=total glucose infusion over the clamp duration;
Rmax=maximum glucose infusion rate; T1DM=type 1 diabetes mellitus
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Heise et al. ADA 2014: 891-P
Comparative Pharmacokinetics and
Pharmacodynamics of 2 Insulin Glargine
Products, LY2963016 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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
LY2963016 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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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 nonparametric approach was used to evaluate time of maximum
observed drug concentration
PD=pharmacodynamic; PK=pharmacokinetic
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
1. Owens DR. Human insulin: clinical pharmacological
studies in normal man. New York: Springer
Publishing; 1986
Dosing and Assessments
Dosing Schedule (U/kg)
Sequence Period 1
Period 2
Period 3
Period 4
1
LY IGlar 0.3 LY IGlar 0.6 IGlar 0.3
IGlar 0.6
2
LY IGlar 0.6 IGlar 0.6
3
IGlar 0.3
LY IGlar 0.3 IGlar 0.6
4
IGlar 0.6
IGlar 0.3
LY IGlar 0.3 IGlar 0.3
LY IGlar 0.6
LY IGlar 0.6 LY IGlar 0.3
• Serial blood samples were taken pre-dose and up to 24 hours
post-dose to determine serum LY IGlar, IGlar, and C-peptide
concentrations
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
Results
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Subject Demographics
Parameter
Mean ± SD
(N = 24a)
Age (years)
32.1
Sex, male / female (%)
83.3 / 16.7
Race, Asian (%)
7.7
100
Weight (kg)
66.4
9.2
BMI (kg/m2)
22.7
2.8
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
PK of LY IGlar and IGlar with different doses*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration
Mean C-peptide-corrected
Insulin Concentration (pmol/L)
400
LY IGlar 0.3 U/kg
LY IGlar 0.6 U/kg
IGlar 0.3 U/kg
IGlar 0.6 U/kg
300
200
100
0
0
•
6
12
Time (hour)
18
24
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
Mean C-peptide Concentration with Different
Doses of LY IGlar and IGlar*
Mean C-peptide
Concentration (pmol/L)
Mean (± SD) C-peptide Concentration
LY IGlar 0.3 U/kg
LY IGlar 0.6 U/kg
IGlar 0.3 U/kg
IGlar 0.6 U/kg
600
400
200
0
0
6
12
18
24
Time (hour)
•
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
Comparison of PK Parameters with Different
Doses of LY IGlar and IGlar*
Parameter
(units)
AUC(0–24)
(pmol∙hr/L)
AUC(0–∞)
(pmol∙hr/L)
Cmax
(pmol/L)
•
•
Dose
(U/kg)
0.3
0.6
0.3
0.6
0.3
0.6
Treatment
N
Geometric
Mean (CV%)
LY IGlar
IGlar
LY IGlar
IGlar
LY IGlar
IGlar
LY IGlar
IGlar
LY IGlar
IGlar
LY IGlar
IGlar
23
23
24
24
23
22
24
24
23
23
24
24
1730 (20)
1690 (30)
3160 (27)
2940 (45)
2330 (39)
2390 (33)
4470 (15)
4310 (51)
108 (20)
105 (33)
180 (28)
174 (38)
Ratio of LS
Geometric Means
(90% CI)
1.03 (0.91, 1.16)
1.07 (0.95, 1.21)
0.97 (0.83, 1.12)
1.04 (0.90, 1.20)
1.03 (0.92, 1.15)
1.03 (0.92, 1.16)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
Comparison of tmax with Different Doses of
LY IGlar and IGlar*
•
Dose
(U/kg)
IGlar (N)
LY IGlar (N)
Median Difference
(Approximate 90% CI)
LY IGlar – IGlar
0.3
9.00 (23)
9.00 (23)
0.00 (−3.00, 3.00)
0.6
10.50 (24)
12.00 (24)
2.00 (0.00, 3.00)
Median tmax
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
PD of LY IGlar and IGlar with 0.3 U/kg dosing*
Mean Glucose Infusion
Rate (mg/kg/min)
Mean (± SD) Glucose Infusion Rate (Top) and
Corresponding Glucose Levels (Bottom)
6
LY IGlar 0.3 U/kg
IGlar 0.3 U/kg
4
2
0
0
4
12
16
20
24
20
24
Time (hour)
6
Mean Blood
Glucose (mmol/L)
8
5
4
3
2
0
4
8
12
16
*Healthy subjects
Time (hour)
PD=pharmacodynamics; SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
PD of LY IGlar and IGlar with 0.6 U/kg dosing*
Mean Blood
Mean Glucose Infusion
Glucose (mmol/L)
Rate (mg/kg/min)
Mean (± SD) Glucose Infusion Rate (Top) and
Corresponding Glucose Levels (Bottom)
•
6
LY IGlar 0.6 U/kg
IGlar 0.6 U/kg
4
2
0
0
4
8
12 16
Time (hour)
20
24
0
4
8
20
24
6
5
4
3
2
12 16
Time (hour)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
Comparison of PD Parameters with Different
Doses of LY IGlar and IGlar*
Parameter
(units)
Dose
(U/kg)
0.3
Gtot
(mg/kg)
0.6
0.3
Rmax
(mg/kg/min)
0.6
•
Treatment
N
Geometric
Mean (CV%)
LY IGlar
23
1060 (178)
IGlar
23
1050 (130)
LY IGlar
24
2260 (80)
IGlar
24
2590 (62)
LY IGlar
23
1.81 (100)
IGlar
23
1.70 (92)
LY IGlar
24
3.05 (59)
IGlar
24
3.25 (54)
Ratio of LS
Geometric Means
(90% CI)
0.98 (0.78, 1.24)
0.87 (0.70, 1.09)
1.04 (0.87, 1.25)
0.94 (0.79, 1.12)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Number of AEsb (Number of Subjects with AEs)
MedDRA Preferred
Terma
0.3 U/kg
IGlar
(N = 23)
0.3 U/kg LY
IGlar
(N = 23)
Vomiting
0.6 U/kg
IGlar
(N = 24)
0.6 U/kg
LY IGlar
(N = 24)
2 (1)
3 (2)
Dizziness
1 (1)
1 (1)
Headache
1 (1)
1 (1)
Hyperhidrosis
1 (1)
1 (1)
Abdominal discomfort
1 (1)
Head discomfort
1 (1)
Injection site erythema
1 (1)
Injection site pruritus
1 (1)
Nausea
1 (1)
Total
4 (1)
0
*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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
4 (3)
8 (4)
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
*Healthy subjects
AE=adverse event; ECG=electrocardiogram
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Zhang et al. ADA 2014: 890-P
The LY IGlar Phase 3 Programme
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Similar Efficacy and Safety with LY2963016
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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
Phase 3 Open-label Study in T1DM
(ELEMENT 1): Design
Treatment Period
Primary
Randomization N = 536 a
Endpoint
N = 267 (IGlar)
at 24 weeks
N = 268 (LY IGlar)
Screening
Titration Period
Study Criteria
•
•
•
•
•
Extension Period
Follow-up
LY IGlar QD SC + TID Insulin Lispro
≥18 years
T1DM ≥1 years
HbA1c ≤11%
BMI ≤35 kg/m2
Basal-bolus with
QD NPH, IGlar
or detemir
IGlar QD SC + TID Insulin Lispro
−2 (±1)
0
6
12
24
52
56
Week
a1
patient (LY IGlar) discontinued before receiving study drug
BMI=body mass index; HbA1c=glycosylated haemoglobin; IGlar=Lantus® insulin glargine; LY IGlar=LY2963016 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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
ELEMENT 1: Objectives
• Primary
– 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
CI=confidence interval; HbA1c=glycosylated haemoglobin;
SMBG=self-monitored blood glucose; T1DM; type 1 diabetes mellitus
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Baseline Patient Characteristics
IGlar
N = 267a
LY IGlar
N = 268a
p
value
41 ± 13
41 ± 14
0.72
58
58
>0.99
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
0.72
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
Demographics
Age (years)
Sex, male (%)
Race, Caucasian / Asian / other (%)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: HbA1c Change from Baseline and
over Time with LY IGlar and IGlar
24 Weeks LOCF
52 Weeks LOCF
Change in HbA1c (%)
IGlar (N=268)
LY IGlar (N=267)
∆ = 0.108
95% CI (-0.002, 0.219)
p=0.055
∆ = 0.020
95% CI (-0.099, 0.140)
p=0.737
*
0
6
12
24
36
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
52
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Other Glucose Measures
FBG
(mmol/L)b
Daily mean BG
(mmol/L)b
Patients with HbA1c
<7% (%)
IGlar
N = 267a
LY IGlar
N = 268a
p
value
Baseline
8.2 ± 0.2
8.4 ± 0.2
0.49
24 weeks LOCF
7.8 ± 0.2
8.0 ± 0.2
0.40
52 weeks LOCF
8.3 ± 0.2
8.0 ± 0.2
0.23
Baseline
8.7 ± 0.1
8.7 ± 0.1
0.76
24 weeks LOCF
8.3 ± 0.1
8.3 ± 0.1
0.95
52 weeks LOCF
8.5 ± 0.1
8.3 ± 0.1
0.13
Baseline
20
29
0.02
24 weeks LOCF
32
35
0.65
52 weeks LOCF
25
30
0.21
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Daily Insulin Dose and Body Weight
LY IGlar prandial
LY IGlar basal
IGlar (N = 267)
LY IGlar (N = 268)
90
0.6
Body Weight (kg)
Daily Insulin Dose (U/kg)
0.8
IGlar prandial
IGlar basal
0.4
0.2
0
Baseline
24 Weeks
Total daily insulin dose (U/kg)
Body weight (kg)
52 Weeks
80
70
60
Baseline
24 Weeks
52 Weeks
IGlar
N = 267a
LY IGlar
N = 268a
p value
Baseline
0.71 ± 0.02
0.72 ± 0.02
0.63
∆ at 24 weeks LOCF
0.00 ± 0.02
0.01 ± 0.02
0.70
∆ at 52 weeks LOCF
0.03 ± 0.02
0.03 ± 0.02
0.79
Baseline
74.8 ± 1.0
75.8 ± 1.0
0.46
∆ at 24 weeks LOCF
0.1 ± 0.2
0.4 ± 0.2
0.32
∆ at 52 weeks LOCF
0.4 ± 0.3
0.7 ± 0.3
0.25
Data are least squares mean standard error. LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Total, Nocturnal, and Severe
hypoglycaemia
IGlar (N = 268)
LY IGlar (N = 267)
Rate
Incidence
160
97
96
88
80
Patients (%)
Events/Patients/Year, Mean (SD)
100
86
60
40
20
4
140
120
100
80
80
77
60
40
20
4
17
0
0
Total
Nocturnal
Severe
All p values >0.05
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Total
16
Nocturnal
<1 <1
Severe
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Summary of Adverse Events
IGlar
(N = 267)
LY IGlar
(N = 268)
Deaths
1 (0.4)
0
Serious AEs
24 (9)
20 (8)
Discontinuations due to an AE
6 (2)
2 (0.7)
Injection site AEs
3 (1)
7 (3)
166 (62)
167 (62)
Possibly related to study drug
14 (5)
17 (6)
Possibly related to study procedure
2 (0.7)
2 (0.7)
Possibly related to study disease state (diabetes)
16 (6)
21 (8)
Special topic assessment of AEs (allergic)
11 (4)
20 (8)
AEsa
TEAEs
Data are n (%)
All p values >0.05
aPatients may be counted in >1 category
AE=adverse event; TEAE=treatment-emergent adverse event
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Summary of Allergic Events and
Injection Site Reactions
AEsa
Special topic assessment of allergic events
Pruritus, rash, dermatitis, other b
Arthralgia, arthritis
Injection site (reaction, induration, nodule, swelling)
Hypersensitivity
Allergic respiratory symptom, asthma
Injection site reaction (patient questionnaires)
Pain
Pruritus
Rash
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
IGlar
(N = 267)
LY IGlar
(N = 268)
11 (4.1)
4 (1.5)
5 (1.9)
2 (0.7)
1 (0.4)
0
3 (1.1)
2 (0.7)
1 (0.4)
1 (0.4)
20 (7.5)
7 (2.6)
4 (1.5)
6(2.2)
1 (0.4)
2 (0.7)
7 (2.6)
6 (2.2)
2 (0.7)
2 (0.7)
Blevins et al. ADA 2014: 69-OR
ELEMENT 1: Incidence of Treatment-emergent
Antibody Response (TEAR)
TEAR criteria
% antibody binding ≥1.26%
If antibody was not detected at baseline
Absolute increase in % antibody binding of 1%
AND 30% relative increase from baseline
Patients with TEAR (%)
If antibody was detected at baseline
Patients with
TEAR, n (%)
IGlar (N = 267)
LY IGlar (N = 268)
40
TEAR by week
30
20
10
0
0
6
12
24
Week
52
IGlar
LY IGlar
p value
Week 52 (LOCF)
12 (5)
18 (7)
0.27
Overall 24 weeks
17 (6)
25 (9)
0.20
Overall 52 weeks
25 (9)
29 (11)
0.57
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
BG=blood glucose; FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
Similar Efficacy and Safety with LY2963016 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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Study Design
Treatment Period
Phase 3
double-blind
N = 380 (IGlar)
N = 376 (LY IGlar)
Screening
Titration Period
Maintenance Period Follow-up
Patient-driven titration
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
(1U/d until FBG ≤5.6 mmol/L)
LY IGlar QD SC + OADs
IGlar QD SC + OADs
−2
a3
Primary
endpoint
at 24 weeks
Randomization (Total N = 759 a)
0
12
Week
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=LY2963016 insulin glargine;
OAD=oral antidiabetic drug; QD=once daily; SC=subcutaneous; T2DM; type 2 diabetes mellitus
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
24
28
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Objectives
• Primary
– 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
HbA1c=glycosylated haemoglobin; OAD=oral antidiabetic drug;
SMBG=self-monitored blood glucose
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Patient Disposition
Patients screened
N = 1026
Screen failures
N = 267
Patients randomized
N = 759
Patients discontinued before
receiving study drug
N = 3 (LY IGlar)
LY IGlar
N = 376
IGlar
N = 380
Discontinued
Adverse event = 10 (2.6%)
Death = 1 (0.3%)
Lack of efficacy = 2 (0.5%)
Lost to follow-up = 9 (2.4%)
Physician decision = 9 (2.4%)
Protocol violation = 5 (1.3%)
Patient decision = 16 (4.2%)
Discontinued
Adverse event = 5 (1.3%)
Death = 1 (0.3%)
Lack of efficacy = 1 (0.3%)
Lost to follow-up = 7 (1.9%)
Physician decision = 9 (2.4%)
Protocol violation = 8 (2.1%)
Patient decision = 11 (2.9%)
Completed 24-week
treatment period
N = 334 (88.8%)
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Completed 24-week
treatment period
N = 328 (86.3%)
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Baseline Demographics and
Patient Characteristics
Total
Insulin-naïve
Prior IGlar
IGlar
N = 380a
LY IGlar
N = 376a
IGlar
N = 236a
LY IGlar
N = 221a
IGlar
N = 144a
LY IGlar
N = 155a
59 ± 10
59 ± 10
58 ± 10
58 ± 11
60 ± 10
60 ± 9
278 (73)
264 (70)
182 (77)
158 (72)
96 (67)
106 (68)
199 (52)
179 (48)
131 (56)
106 (48)
68 (47)
73 (47)
Race, Caucasian / Asian /
black / other (%)
77 / 9 /
8/ 6
80 / 8 /
7/ 5
79 / 7 /
9/ 4
77 / 9 /
9/ 6
72 / 13 /
7/ 8
85 / 7 /
4 / 5*
Weight (kg)
90 ± 19
90 ± 20
91 ± 19
89 ± 20
88 ± 20
92 ± 20
BMI (kg/m2)
32 ± 5
32 ± 6
32 ± 5
32 ± 5
32 ± 6
32 ± 6
HbA1c (%)
8.3 ± 1.1
8.3 ± 1.1
8.4 ± 1.0
8.5 ± 1.0
8.1 ± 1.1
8.1 ± 1.2
FBG (mmol/L)b
8.9 ± 2.4
8.8 ± 2.5
9.5 ± 2.3
9.6 ± 2.4
7.8 ± 2.3
7.7 ± 2.2
38 / 62
41 / 59
0 / 100
0 / 100
100 / 0
100 / 0
Demographics
Age (years)
<65 years, n (%)
Sex, male, n (%)
Basal insulin, IGlar / none (%)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Fasting Glucose (mmol/L)
ELEMENT 2: FBG Changes over Time
10
IGlar (N = 359)
LY IGlar (N = 353)
9
8
7
6
5
0
FBG (mmol/L)
LSM ± SE
2
12
Week
24
IGlar
LY IGlar
p value
Baseline
8.9 ± 0.1
8.8 ± 0.1
0.84
Week 24 LOCF
6.1 ± 0.1
5.9 ± 0.1
0.27
Change at Week 24 LOCF
−2.6 ± 0.2
−2.7 ± 0.2
0.69
FBG=fasting blood glucose; LOCF=last observation carried forward;
LSM=least squares mean; SE=standard error
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: 7-point SMBG
IGlar (N = 375)
LY IGlar (N = 369)
Glucose (mmol/L)
13
12
11
10
9
Baseline
8
7
6
24 Weeks LOCF
*
5
*p = 0.04
LOCF=last observation carried forward; PPG=post-prandial glucose;
SMBG=self-monitored blood glucose
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: HbA1c Changes over Time
9.0
IGlar (N = 375)
LY IGlar (N = 369)
HbA1c (%)
8.5
8.0
7.5
7.0
6.5
0
4
8
16
12
Week
IGlar
HbA1c, %
LSM SE
24
20
LY IGlar
p value
Baseline
8.31
0.06
8.35
0.06
0.61
Endpoint LOCF
6.99
0.06
7.04
0.06
0.40
HbA1c=glycosylated haemoglobin; LOCF=last observation carried forward;
LSM=least squares mean; SE=standard error
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Change at Study End in HbA1c
and % of Patients Reaching Target HbA1c
Total
Change in HbA1c (%)
0.0
−1.34
−1.29
Insulin-naïve
−1.54
−1.48
IGlar
LY IGlar
Prior IGlar
−1.01
−1.02
-0.5
-1.0
∆ = −0.004
95% CI (−0.19, 0.19)
p = NS
-1.5
∆ = 0.052
-2.0
95% CI (−0.07, 0.18)
p = NS
Total
HbA1c <7%
∆ = 0.061
95% CI (−0.09, 0.21)
p = NS
Insulin-naïve
Prior IGlar
IGlar
(N = 375)
LY IGlar
(N = 369)
IGlar
(N = 232)
LY IGlar
(N = 217)
IGlar
(N = 143)
LY IGlar
(N = 152)
53%
49%
60%
54%
41%
41%
HbA1c=glycosylated haemoglobin; NS=not significant
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Insulin Dose and Body Weight
Changes at Study End
IGlar (N = 372a)
0.8
Daily Basal Insulin Dose
Body Weight
120
100
0.6
80
kg
U/kg
LY IGlar (N = 370)
0.4
60
40
0.2
20
0
Baseline
24 Weeks ∆ at 24 Weeks
(LOCF)
(LOCF)
0
Data are least squares mean standard error
aN = 374 for body weight
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Baseline
24 Weeks ∆ at 24 Weeks
(LOCF)
(LOCF)
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Insulin Dose Subgroup Analysis
Total
IGlar
(N = 372)
Daily Baseline
basal
insulin
dose Week 24
(U/kg) (LOCF)
Insulin-naïve
LY IGlar
(N = 370)
IGlar
(N = 229)
Prior IGlar
LY IGlar
(N = 218)
IGlar
(N = 143)
LY IGlar
(N = 152)
0.14
0.01
0.16
0.01
0.00
0.00
0.00
0.00
0.35
0.01
0.39
0.01*
0.48
0.03
0.50
0.03
0.44
0.03
0.42
0.03
0.53
0.03
0.60
0.03
Change at
Week 24
0.37
(LOCF)
0.02
0.36
0.02
0.46
0.03
0.45
0.03
0.19
0.03
0.22
0.03
Data are least squares mean standard error
*p = 0.038
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Total, Nocturnal, and Severe
hypoglycaemia
IGlar (N = 376)
LY IGlar (N = 373)
Incidence
Patients (%)
78 79
50
54
57
25
<1
0
Total
<1
Events/Patients/1 Year, Mean (SD)
100
75
Event Rates
80
Nocturnal Severe
All p values >0.05
SD=standard deviation
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
60
40
20
22
21
8
0
Total
7
Nocturnal
<1 <1
Severe
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Summary of Adverse Events
IGlar
(N = 380)
n (%)
LY IGlar
(N = 376)
n (%)
Deaths
1 (0.3)
1 (0.3)
Serious AEs
18 (5)
15 (4)
Discontinuations due to an AE
11 (3)
6 (2)
Injection site AEs
11 (3)
13 (4)
184 (48)
196 (52)
Possibly related to study drug
23 (6)
26 (7)
Possibly related to study procedure
8 (2)
6 (2)
Possibly related to study disease state (diabetes)
18 (5)
19 (5)
Special topic assessment of AEs (allergic)
27 (7)
21 (6)
AEsa
TEAEs
aPatients
may be counted in >1 category
AE=adverse event; TEAE=treatment-emergent adverse event
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Summary of Allergic Events and
Injection Site Reactions
IGlar
(N = 380)
n (%)
27 (7)
LY IGlar
(N = 376)
n (%)
21 (6)
Pruritus, rash, dermatitis, otherb
12 (3)
8 (2)
Arthralgia, peri-arthritis
9 (2)
7 (2)
Injection site (reaction, pruritis, induration)
4 (1)
5 (1)
Asthma, nasal edema
5 (1)
3 (1)
11 (3)
13 (4)
Pain
5 (1)
10 (3)
Pruritus
4 (1)
4 (1)
Rash
3 (1)
3 (1)
AEsa
Special topic assessment of allergic events
Injection site reaction (patient questionnaires)
aPatients
may be counted in >1 category;
rash, papular rash, pruritic rash, vesicular rash
AE=adverse event
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
bMacular
Rosenstock et al. ADA 2014: 64-OR
ELEMENT 2: Incidence of Treatment-emergent
Antibody Response (TEAR)
TEAR criteria
% antibody binding ≥1.26%
If antibody was not detected at baseline
Patients with TEAR (%)
If antibody was detected at baseline
Absolute increase in % antibody binding of 1%
AND 30% relative increase from baseline
40
TEAR by week
IGlar (N = 365)
30
LY IGlar (N = 365)
20
10
0
0
4
12
24
Week
Patients with
TEAR, n (%)
IGlar
LY IGlar
p value
Week 24 (LOCF)
7 (2)
12 (3)
0.35
Overall
14 (4)
14 (4)
>0.99
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; SMBG=self-monitored blood glucose
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Rosenstock et al. ADA 2014: 64-OR
Evaluation of Immunogenicity of LY2963016
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
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Objective
• To compare the immunogenicity profile of LY2963016
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
HbA1c=glycosylated haemoglobin; T1DM=type 1 diabetes mellitus; T2DM=type 2 diabetes mellitus
Lantus is a registered trademark of Sanofi-Aventis
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Proportion of Patients with Detectable Antibodies:
ELEMENT 1
By week
100
Patients (%)
IGlar (N = 267)
LY IGlar (N = 265)
75
50
25
0
0
6
12
24
52
Week
Patients with detectable
antibodies, n (%)
52
(LOCF)
IGlar
LY IGlar
p value
Overall 24 weeks
90 (34)
80 (30)
0.40
Overall 52 weeks
105 (39)
107 (40)
0.86
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Treatment-emergent Antibody Response (TEAR):
ELEMENT 1
TEAR criteria
% antibody binding ≥1.26%
If antibody was not detected at baseline
If antibody was detected at baseline
Absolute increase in % antibody binding of 1%
AND 30% relative increase from baseline
Patients with TEAR (%)
20
IGlar (N = 267)
LY IGlar (N = 265)
15
p = 0.57
p = 0.20
10
n = 25
p = 0.27
n = 18
5
n = 29
n = 25
n = 17
n = 12
0
Endpoint
(52 Weeks)
Overall
(24 Weeks)
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Overall
(52 Weeks)
Deeg et al. ADA 2014: 70-OR
Relationship between HbA1c and Insulin Antibody
Level at Endpoint: ELEMENT 1
HbA1c=glycosylated haemoglobin
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Effect of Overall TEAR Status on Change in
Clinical Outcomes: ELEMENT 1
IGlar (N = 265)
LY IGlar (N = 267)
HbA1c
-0.2
-0.4
-0.6
n = 25 n = 29 n = 242 n = 236
TEAR
No TEAR
0.08
0.06
0.04
0.02
0.00
-0.02
n = 25 n = 29 n = 241 n = 236
TEAR
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
No TEAR
∆ Episodes/30 days
∆ U/kg/day
∆%
0.0
Total Hypoglycemia Rate
Basal Insulin Dose
2
0
-2
-4
-6
n = 25 n = 29 n = 242 n = 236
TEAR
No TEAR
Deeg et al. ADA 2014: 70-OR
Proportion of Patients with Detectable Antibodies:
ELEMENT 2
By week
100
Patients (%)
IGlar (N = 365)
LY IGlar (N = 365)
75
50
25
p = 0.047
0
0
4
12
24
Week
Patients with detectable
antibodies, n (%)
Overall 24 weeks
LOCF=last observation carried forward
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
24
(LOCF)
IGlar
LY IGlar
p value
40 (11)
56 (15)
0.10
Deeg et al. ADA 2014: 70-OR
Treatment-emergent Antibody Response (TEAR):
ELEMENT 2
IGlar (N = 365)
LY IGlar (N = 365)
Patients with TEAR (%)
20
15
10
5
p = 0.35
n = 12
0
p >0.99
n = 14
n = 14
n= 7
Endpoint
(24 Weeks)
Overall
(24 Weeks)
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Relationship between HbA1c and Insulin Antibody
Level at Endpoint: ELEMENT 2
HbA1c=glycosylated haemoglobin
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
Effect of Overall TEAR Status on Change in
Clinical Outcomes: ELEMENT 2
IGlar (N = 365)
LY IGlar (N = 365)
HbA1c
∆ U/kg/day
∆%
-1.0
-1.5
-2.0
n = 14 n = 14 n = 351 n = 351
TEAR
No TEAR
0.6
0.4
0.2
0.0
n = 14 n = 14 n = 346 n = 350
TEAR
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
No TEAR
∆ Episodes/30 days
0.8
0.0
-0.5
Total Hypoglycemia Rate
Basal Insulin Dose
3
2
1
0
n = 14 n = 14 n = 347 n = 350
TEAR
No TEAR
Deeg et al. ADA 2014: 70-OR
Summary of Allergic Events and Injection Site
Reactions
ELEMENT 1
ELEMENT 2
IGlar
(N = 267)
LY IGlar
(N = 268)
IGlar
(N = 380)
LY IGlar
(N = 376)
11 (4)
20 (8)
27 (7)
21 (6)
Pruritus, rash, dermatitis, otherb
4 (2)
7 (3)
12 (3)
8 (2)
Arthralgia, arthritis, peri-arthritis
5 (2)
4 (2)
9 (2)
7 (2)
Injection site (reaction, pruritus, otherc)
2 (1)
6 (2)
4 (1)
5 (1)
1 (0.4)
1 (0.4)
--
--
0
2 (0.7)
5 (1)
3 (1)
3 (1)
7 (3)
11 (3)
13 (4)
Pain
2 (0.7)
6 (2)
5 (1)
10 (3)
Pruritus
1 (0.4)
2 (0.7)
4 (1)
4 (1)
Rash
1 (0.4)
2 (0.7)
3 (1)
3 (1)
Adverse eventsa
Special topic assessment of allergic vents
Hypersensitivity
Allergic respiratory symptom, asthma, nasal
edema
Injection site reaction (patient questionnaires)
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
HbA1c=glycosylated haemoglobin; T1DM=type 1 diabetes mellitus;
T2DM=type 2 diabetes mellitus; TEAR=treatment-emergent antibody response
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
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
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Deeg et al. ADA 2014: 70-OR
BACK-UP SLIDES
Data from BI-Lilly Diabetes Alliance
Date of preparation: May 2015 | UK/GLA/00036
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
ELEMENT 1: Summary of Allergic Events
By System Organ Class and Preferred Term
System Organ Class
Preferred Term
Patients with ≥1 treatment-emergent allergic event
Skin and subcutaneous tissue disorders
IGlar
(N = 267)
11 (4.1)
4 (1.5)
LY IGlar
(N = 268)
20 (7.5)
7 (2.6)
1 (0.4)
2 (0.7)
3 (1.1)
2 (0.7)
0
0
1 (0.4)
1 (0.4)
1 (0.4)
5 (1.9)
0
4 (1.5)
5 (1.9)
0
3 (1.1)
1 (0.4)
2 (0.7)
2 (0.7)
6 (2.2)
3 (1.1)
0
0
1 (0.4)
1 (0.4)
Local swelling
Immune system disorders
0
1 (0.4)
1 (0.4)
1 (0.4)
Drug hypersensitivity
Hypersensitivity
0
1 (0.4)
1 (0.4)
0
0
0
0
2 (0.7)
1 (0.4)
1 (0.4)
Pruritus
Rash
Dermatitis allergic
Photosensitivity reaction
Urticaria
Musculoskeletal and connective tissue disorders
Arthralgia
Arthritis
General disorders and administration site conditions
Injection site reaction
Injection site induration
Injection site nodule
Respiratory, thoracic, and mediastinal disorders
Allergic respiratory symptom
Asthma
Data are n (%) for patients with ≥1 treatment-emergent allergic event
All p values >0.05
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
Blevins et al. ADA 2014: 69-OR
ELEMENT 2: Summary of Allergic Events
By System Organ Class and Preferred Term
System Organ Class
Preferred Term
Patients with ≥1 treatment-emergent allergic event
Skin and subcutaneous tissue disorders
Pruritus
Rash
Dermatitis
Angioedema
Rash macular
Rash papular
Rash pruritic
Rash vesicular
Musculoskeletal and connective tissue disorders
Arthralgia
Peri-arthritis
General disorders and administration site conditions
Injection site reaction
Injection site pruritis
Injection site induration
Respiratory, thoracic, and mediastinal disorders
Asthma
Nasal edema
Data from BI-Lilly Diabetes Alliance. Date of preparation: May 2015 | UK/GLA/00036
IGlar
(N = 380)
n (%)
LY IGlar
(N = 376)
n (%)
27 (7.1)
12 (3.2)
4 (1.1)
3 (0.8)
2 (0.5)
0
1 (0.3)
1 (0.3)
1 (0.3)
1 (0.3)
9 (2.4)
8 (2.1)
1 (0.3)
4 (1.1)
3 (0.8)
1 (0.3)
0
5 (1.3)
5 (1.3)
0
21 (5.6)
8 (2.1)
4 (1.1)
3 (0.8)
1 (0.3)
1 (0.3)
0
0
0
0
7 (1.9)
7 (1.9)
0
5 (1.3)
3 (0.8)
1 (0.3)
1 (0.3)
3 (0.8)
2 (0.5)
1 (0.3)
Rosenstock et al. ADA 2014: 64-OR
Date of preparation: May 2015 | UK/GLA/00036
Date of preparation: May 2015 | UK/GLA/00036