Key regulatory events and major drug-segments for type-2 diabetes management

1. 1. Key Regulatory and Commercial Event Timelines for Farxiga (USA + EU)

2. Farxiga (dapagliflozin) was developed by BMS in partnership with AstraZeneca: First-in-class, Once-daily SGLT2
inhibitor approved for T2DM & HF treatment in USA & EU, whereas listed for T1DM in EU only
Jan-2007
ASZ/BMS Diabetes Alliance
(to co-develop & commercialize
Saxagliptin & Dapagliflozin)2
Jan-2014
Farxiga Approved in USA
for T2DM4
Nov-2012
Forxiga Approved in EU for
Type-II Diabetes3
May-2020
FDA Approves Farxiga to
Treat Heart Failure9
Oct-2020
EU Approves Forxiga to
Treat Heart Failure10
FARXIGA
Dec-2003
IND Application
Filed by BMS
(for Dapagliflozin)1
Saxagliptin & Dapagliflozin)2
Note: In USA market, ASZ has also given distribution right to Cardinal Health (NDC 55154-6932) and A-S Medication Solutions (NDC 50090-3481) for Farxiga brand
Dec-2010
NDA Filed for Farxiga for
Treatment of T2DM
(NDA202293)1
Dec-2013
ASZ Acquired BMS Diabetes
Business5
Jul-2013
Resubmit Dapagliflozin NDA (with
Long-term Data)4
Mar-2019
EU Approves Forxiga for Type-I Diabetes as an
Adjunct to Insulin6
Jul-2019
EU Approves to add Heart Claim Data on Forxiga
label in T2D7
Oct-2019
FDA Approves Farxiga to Reduce HF
Hospitalization Risk in T2DM Patients8
Sources: 1. FDA-IND 2. BMS-Annual Report 3. EMA-Forxiga 4. Drugs@FDA 5. ASZ Media 6. Forxiga D-I 7. EU-Heart Label 8. FDA- CVS Label 9. FDA-HF 10. EU-HF
ASZ – AstraZeneca, BMS – Bristol-Myers Squibb, IND – Investigation New Drug, NDA – New Drug Approval, T1DM – Type I Diabetes, T2DM – Type II Diabetes, HF – Heart Failure

3. 2. Trulicity Received FDA Approval for Additional Doses for Treatment of T2DM

4. Eli Lilly gets expanded FDA approval for two additional doses of its T2DM drug Trulicity
[03-Sept-2020] Eli Lilly has received approval from the US FDA for two additional doses of its T2DM drug Trulicity
(dulaglutide)1,3
The approval expands the label of
Once-Weekly Trulicity to include
3.0 mg & 4.5 mg doses based on data from
AWARD-11
The phase-III trial showed the additional
doses led to further benefits in A1C and
Results from AWARD-11
Randomized, Double-blind, Parallel-arm study [N=1842]
Trulicity 4.5mg Trulicity 3mg Trulicity 1.5mg
Reported significant A1C & weight reduction after 36-weeks
TRULICITY
Note: The AWARD-11 trial is currently being reviewed by EMA, and Lilly expects a recommendation decision on expanded doses in the EU by the end of 2020
Sources: 1. Eli Lilly Press Release 2. Trulicity Label Info 3. Drugs@FDA-Trulicity Suppl-36 4. Trulicity Website
doses led to further benefits in A1C and
Bodyweight Reduction when compared to
Trulicity 1.5 mg in people with T2DM
Primary Endpoint: Reduction in A1C
Secondary Endpoint: Weight Loss
Provides Better Glycemic Control in Long-term Management of T2DM
Availability of higher doses of Trulicity (4.5 mg or 3mg) offers powerful A1C reduction and weight loss in those group of
T2D patients whose diabetic condition was not controlled with current treatment. And it also helps HCPs to adjust the
different doses of Trulicity based on progressive diabetic conditions of patients.
Trulicity 4.5mg
-01.9% A1C
-10.4% Pound
Weight
Trulicity 3mg
-01.7% A1C
-08.8% Pound
Weight
Trulicity 1.5mg
-01.5% A1C
-06.8% Pound
Weight

5. 3. T2DM Therapeutic Area Landscape: SGLT2 and GLP1 (USA Market)
Note: IDF Diabetes Atlas

6. SGLT2 Inhibitors have been shown to be effective at lowering HbA1c levels, improving weight loss and
lowering blood pressure: used as monotherapy or in combination with other hyperglycemic agents
SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITORS
SGLT2 Inhibitors are newest class of oral-hyperglycemic
agents that have been FDA-approved for use with diet &
exercise to lower blood sugar in T2DM patients1,2
MoA: Prevents from reabsorbing glucose in kidney
SGLT2 is a glucose transporter
found in kidney: reabsorbs
90% of glucose and returns it
to the blood
SGLT2 Inhibitors prevent the
reabsorption of glucose that
Brand
Name
Generic Owner Compound Doses (mg) /
Frequency
Approval
Date
Invokana Canagliflozin J&J Small molecule 100 - 300
Once daily
Mar-2013
Farxiga Dapagliflozin ASZ/BMS Small molecule 5-10
Once daily
Jan-2014
Jardiance Empagliflozin BI Small molecule 1-25
Once daily
Aug-2014
Invokamet Canagliflozin +
Metformin
J&J Small molecule 50-150/500-
1000; BID
Aug-2014
Xigduo Dapagliflozin + ASZ/BMS Small molecule 5-10/500-1000 Oct-2014
List of current SGLT2 inhibitors: Approved by US-FDA2,3
Sources: 1. Journal of Diabetes Nursing-2019 2. Curr Opin Endocrinol Diabetes Obes.2018 3. J Investig Med High Impact Case Rep. 2017 4. Steglatro Label-Drugs@FDA
reabsorption of glucose that
has been filtered from renal
tubules
Clinical Benefits of SGLT2 Inhibitors1,2
• Effective HbA1c reduction
• Weight loss
• Small reduction in blood pressure
• Low risk of hypoglycemia
• CVS protection, benefits in heart failure
• Renoprotection (in diabetic nephropathy)
• Flexibility to use with others antidiabetics
• Once daily, oral agent
Xigduo Dapagliflozin +
Metformin
ASZ/BMS Small molecule 5-10/500-1000
Once daily
Oct-2014
Glyxambi Empagliflozin
+ Linagliptin
BI Small molecule 10-25/5
Once daily
Jan-2015
Synjardy Empagliflozin
+ Metformin
BI Small molecule 5-25/500-1000
BID
Aug-2015
Invokamet
XR
Canagliflozin +
Metformin
J&J Small molecule 50-150/500-
1000; BID
Aug-2014
Steglatro4 Ertugliflozin Merck Small molecule 5-15
Once daily
Dec-2017
04 SGLT2 Inhibitors are currently approved by the FDA for T2DM treatment:
Canagliflozin, Dapagliflozin, Empagliflozin, and most recently – Ertugliflozin
These drugs are administered orally once daily and given with or without food

7. GLP-1 agonists are a class of antidiabetic agents that mimic the actions of the glucagon-like peptide
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS
GLP-1 receptor agonists, also known as incretin-mimetics,
are agonists of the GLP-1 receptor. It has multiple
physiological effects that make it a great therapy option to
help improve glycemic control in T2DM patients1,2
MoA: Enhances glucose-dependent insulin secretion by
the pancreatic beta-cell, suppresses inappropriately
elevated glucagon secretion, and slows gastric emptying
Brand
Name
Generic Owner Duration of
Acton
Frequency Approval
Date
Rybelsus Semaglutide Nova
Nordisk
Short-acting 1st Oral GLP-1
Once daily
Sept-2019
Adlyxin Lixisenatide Sanofi Short-acting Once daily Jul-2016
Victoza Liraglutide Nova
Nordisk
Short-acting Once daily Jan-2010
Byetta Exenatide ASZ Short-acting Twice daily Apr-2005
List of current GLP-1 Agonists: Approved by US-FDA4,5
Sources: 1. Diabetes Spectrum-2017 2. Medscape-2020 3. BMJ Journal-2019 4. Diabetes Spectrum-2017 5. Diabetes, Metabolic Syndrome and Obesity-2016
Clinical Benefits of GLP-1 Agonist1,2,3
• Improvement in HbA1c levels
• Lower risk of causing hypoglycemia
• Beneficial in losing weight when used in
combination with diet & exercise
• Reduces biomarkers of CVS risks such as
C-reactive protein
Ozempic Semaglutide Nova
Nordisk
Long-acting Once weekly Dec-2017
Tanzeumi Albiglutide GSK Long-acting Once weekly Apr-2014
Trulicity Dulaglutide Eli Lily Long-acting Once weekly Sept-2014
Bydureon Exenatide QW ASZ Long-acting Once weekly Mar-2014
GLP-1 agonists are generally reserved for those who require two or more
antidiabetic agents in order to reach and maintain the goal HbA1c
Offers potent reduction in blood sugar level: average drop in A1c is 0.5 to 1.5%

8. Novel dual mechanism agents (such as SGLT1-SGLT2 Inhibitor and GLP-1/Glucagon Dual Agonist) have
emerged in late-phase trails that would change the existing treatment regimen for T2DM
T2DM PIPELINE OVERVIEW (USA MARKET)
P-III
Zynquista (sotagliflozin): Dual SGLT1-SGLT2 Inhibitor I Once-Daily Orally
Lexicon/Sanofi* *[Jul-19] End collaboration after mixed results in CKD
P-III
Bexagliflozin : SGLT2 Inhibitor I Once-Daily Orally
Theracos Inc.
P-I
YG1699 : Dual SGLT1-SGLT2 Inhibitor
Youngene Therapeutics Inc.
SGLT2
Inhibitors
Note: Q4 2019, BI has announced to initiate Phase 2 development of the GLP-1/glucagon dual agonist BI 456906
Sources: 1. Zynquista-NCTs 2. Bexagliflozin-NCTs 3. YG1699-NCT 4. Hanmi-NCTs
GLP-1
Agonists
P-III
ITCA 650 (Intarcia): Exenatide Implant I Twice-Yearly NDA
P-II
P-I
Efinopegdutide (Hanmi): GLP-1/Glucagon Dual Agonist I SC – Once Weekly
Cotadutide (AstraZeneca) I Once-weekly
GLP-1/Glucagon Dual Agonist
OPK-88003 (Opko Health) I Once-Weekly
GLP-1/Glucagon Dual Agonist
BI456906 (BI*) I Once-weekly
GLP-1/Glucagon Dual Agonist
LY3305677 (Eli Lilly)
GLP-1/Glucagon Dual Agonist

9. Guideline recommendations based on CVS and renal benefits of SGLT2 inhibitors and GLP-1 agonists plays
a pivot role for high adoption of these novel therapies in most of T2DM patients
T2DM MARKET TRENDS: SGLT2 INHIBITORS + GLP-1 AGONITS
Current Dynamics Opportunity/ Strength
Generic therapies such as
Sulfonylurea and Thiazolidines are
used in early-treatment, both in
combination with Metformin and as
monotherapy
Branded oral therapies (DPP-4 &
CV & CKD benefits seen with SGLT2
inhibitors and GLP-1 agonists are likely
to drive the market in T2DM patients
with co-morbidities
High prevalence of obesity in T2DM
patients favour the use of SGLT2
Threat/ Weakness
More expensive than oral anti-
diabetes
SGLT2 inhibitors and GLP-1
agonists are generally not
recommended as 1st Line
treatment , and also have black-
Branded oral therapies (DPP-4 &
SGLT2 inhibitors) and injected
therapy (GLP-1 agonists) are typically
added on to generics after failure of
monotherapy
patients favour the use of SGLT2
inhibitors and GLP-1 agonists – shown
to induce significant weight loss
Oral Rybelsus is likely to expand usage
to earlier lines of therapy, taking high
share from other oral drugs
Longer-acting drugs such as ITCA-650
Exenatide implants (yearly or twice-a-
year) may shift the current treatment
paradigm
treatment , and also have black-
box warnings on label
Growth of biosimilar insulins
Tighter controls by
payers/regulatory bodies (such
as mandatory rebates or
discounts on drug prices)

10. 2.