This slide deck was developed for a lecture at a conference on Drug Discovery and Development organized by the prestigious NIPER, Hyderabad in Mar 2017

1. DEVELOPMENT OF DIABETES MEDICINES:
SWEET OR SOUR OUTCOMES
DR.AMMAR RAZA
SR. DIRECTOR & HEAD- MEDICAL AFFAIRS & PHARMACO VIGILANCE, DR. REDDY’S BIOLOGICS
Email:
ammar.diabetes@gmail.com
ammarrazas@drreddys.com
Conference on Drug Discovery and Development
Focus on Cancer & Diabetes
NIPER, Hyderabad (March 16-17,2017)

2. AGENDA
 What is Diabetes? Pathophysiology – the “Omnious Octet “
 Problem of Diabetes – Globally and Locally
 Drug Development Process – lengthy, costly and risky
 Drug Development in Diabetes – rising costs, increasing complexity
(CVOTs to be conducted), Sweet & sour outocmes
 Case studies
 Two successful new classes of drugs
 One drug that hasn’t made it yet
 Summary of challenges in development of drugs for Diabetes – Focus
on CVOTs
 Key summary & conclusions Image copyrighted; being used for educational purpose only

3. WHAT IS DIABETES?
Group of longstanding derangements characterized by hyperglycemia resulting from
defects in:
 Insulin secretion
 Insulin action
 Both
Chronic high blood sugar levels of diabetes are associated with long-term damage, dysfunction
and failure of various organs, especially:
 Eyes
 Kidneys
 Nerves
 Heart
 Blood vessels
American Diabetes Association [ADA] – 1997
D I A B E T E S

4. Diabetes…. Big, Bigger….
No. of people with
Diabetes
>415 million
No. of people with diabetes in every country
Undiagnosed diabetes
One in 2 adults with
diabetes
People with diabetes 90% live in low- & middle-income
countries
Greatest number of
people with diabetes
40 and 59 years of age
Projection 2040 642 million
In 2015: World wide (Diabetes Atlas 2015)
Diabetes Atlas 7th Edition http://www.diabetesatlas.org/ (last accessed 05 Mar 2017)
Wild S et al. 2004
171 mio in 2000 to 366 mio in 2030
*Wild S et al. Diabetes Care 2004
NowThen

5. DIABETES:A BIG GLOBAL PROBLEM
Bigger local problem
5
IDF Atlas 20152
415
million
642
million
2015 2040
Now
THEN
2000 2030
171
million
366
million
Wild S et al 20041
NOW
32
million
79
million
2000 2030
THEN
1. Wild S et al. Diabetes Care 2004; 2. Diabetes Atlas 7th Edition http://www.diabetesatlas.org/ (last accessed 05 Mar 2017)
No. of people with Diabetes
2015 2040
69.2
million
123.5
million
2015: 1 in 11 adults have diabetes
2040: 1 in 10 will have diabetes
Every 6 sec a person dies from diabetes (5.0 mio deaths)
The Indian Express-28-Feb-2017

6. DIABETES IS SINGLE ……
Simple……
 But Not
Image may be copyrighted; being used for educational purpose only

7. 7
MULTIPLE PATHOPHYSIOLOGICAL FAILURES CONTRIBUTE TO
HYPERGLYCAEMIA:THE ‘OMINOUS OCTET’
Adapted from: DeFronzo RA. Diabetes 2009;58:773–95. Wolters Kluwer Health.
Islet α-cell
Increased
lipolysis
Increased
glucose
reabsorption
Increased glucagon
secretion
Increased
hepatic glucose
production
Neurotransmitter dysfunction
Decreased
glucose uptake
Islet β-cell
Decreased incretin effect
Impaired insulin
secretion
Hyper-
glycaemia

8. UNMET NEEDS IN DIABETES
 Increasing global burden- more so local burden
 Complex pathophysiology – progressive disease; multiple defects; most drugs fail;
need to go beyond A1c control
 Poor control linked to complications (esp. microvascular)
 A given drug can become ineffective over time
Successful treatment of T2D therefore needs a constant supply of new drugs
Mittermayer F et al. Current Diabetes Reviews, 2015, 11, 17-31

9. Image copyrighted; being used for educational purpose only

10. DRUG DEVELOPMENT COSTS:‘INCEPTION TO INGESTION’
$2.6
billion
Total cost to develop and gain marketing approval for a NEW drug
10-12
years
New drug to get thru’ the Food and Drug Administration's (FDA) approval process
and hit the market—if it ever does
$312
million
Often post-approval research and tests to evaluate dosing strength and a host of
other factors
2013: TOTAL cost of a drug DEVELOPMENT is $2.87 billion
DiMasi JA et al. Journal of Health Economics 47 (2016) 20–33
Image copyrighted; being used for educational purpose only

11. DRUG DEVELOPMENT IS ‘RISKY’
‘Risk’ (possibility of loss or injury)
……………depends on which stakeholder you ask:
1. Risk to Patient (Focus of Regulators, IRBs, Investigators)
 Drug must provide a good chance of net benefit to patient (efficacy and safety)
2. Risk of Therapeutic Failure (Focus of Investigators, Investors)
 Drug must have promise in order to promote investigator interest and patient enrollment
3. Development Risk (Focus of Managers, Owners and Investors)
 Drug must have a reasonable chance for return on investment.
All three types of risk need to be considered when setting strategy for global drug
development

12. 2016: DRUG DEVELOPMENT COSTS
DiMasi JA et al. Journal of Health Economics 47 (2016) 20–33
Key Result 1:
• Overall probability of clinical success (i.e., the likelihood that a drug that
enters clinical testing will eventually be approved) estimated to be
11.83%
Methodology:
R& D costs of 106 randomly
selected new drugs were
obtained from a survey of 10
pharmaceutical firms
DiMasi JA et al.
Key Result 2:
Diabetes drugs: among the most costly (particularly for
phase III [92% higher than the overall average])

13. DIABETES DRUG DEVELOPMENT
MEDICINES IN DEVELOPMENT | 2016 REPORT
source: Tufts Center for the Study of Drug Development.
https://www.scientificamerican.com/article/cost-to-develop-new-pharmaceutical-drug-now-exceeds-2-5b/ (last accessed on 05 mar2017)
>170
1 in 13
44%
Medicines for Diabetes & Diabetes-Related Conditions in
Development
Investigational diabetes drugs receives U.S. marketing approval
New endocrine drugs approved in US in 1995-15 for diabetes &
related conditions
Large molecule drug approvals: 33% of diabetes & 20% of non-endocrine
Mean CD time for diabetes drugs increased NOTABLY: after declining from
1995-02 to 2002-08 (~ 7%)

14. Source: http://www.outsourcing-pharma.com/Clinical-Development/Diabetes-drugs-the-riskiest-to-develop-says-Tufts-report
Images may be copyrighted; being used for educational purpose only

15. DIABETES DRUG DEVELOPMENT IS RISKIER COMPAREDTO ALL
DRUG DEVELOPMENT *
INCREASED TIME & PATIENT NUMBERS1
2000–2008 2009–2014
4.7 years 6.7 years
Average U.S. clinical development time
No. of randomized patients & patient-years in NDAs
2005 - 2010
X 2.5 – 4.0
1. DiMasi JA et al. Journal of Health Economics 47 (2016) 20–33 *Tufts report: http://csdd.tufts.edu/files/uploads/SeptOctImpactRpt2016-summary.pdf

16. DevelopmentJourneyforaantidiabetic
Drug Development Funnel
http://www.fda.gov/downloads/AboutFDA/Transparency/Basics/UCM247465.pdfImage copyrighted; being used for educational purpose only

17. Diabetes Spectrum 2014 May; 27(2): 82-86. https://doi.org/10.2337/diaspect.27.2.82
History of Diabetes Medicines
Image copyrighted; being used for educational purpose only

18. What is Apple Known for?
Phlorizin
1st SGLT Inhibitor
Dapagliflozin
1st SGLT2 inhibitor
Isolated from apple tree bark (1835)
Apple Tree to first SGLT2 inhibitor
Isolated from apple tree bark (1835)
Glycosuric effect revealed (1865)
Renal effects identified in rat (1903) and man
(1933)
Antidiabetic effect discovered (1987)
Found to inhibit SGLT1
and SGLT2
Dr. Ammar Raza. From Apple bark to a Novel Diabetes Treatment, Pharma Bio World, Feb 2016, Pg 39-40
Case
study 1

19. DAPAGLIFLOZIN-INDUCED URINARY GLUCOSE EXCRETION IN
PATIENTS WITH T2DM
Komoroski B, Clin Pharmacol Ther. 2009;85:513–519.

20. OTHER METABOLIC EFFECTS OF DAPAGLIFLOZIN
Merovci A, J Clin Invest 2014; Euglycemic hyperinsulinemic clamp technique
18%
Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-
mediated tissue glucose disposal increased by ~ 18%

21. Pre-diabetes
Drug-naïve
Monotherapy OAD
Combination OAD
Insulin therapy
Monotherapy
Metformin add-on
SU add-on
SU comparator
TZD add-on
DPP4 Inhibitor add-on
Insulin
add-on
PHASE III CLINICALTRIALS ACROSS
THE TYPE 2 DIABETES MELLITUSTREATMENT SPECTRUM
OAD = oral antidiabetic drug; SU = sulphonylurea

22. EXTENSIVE CLINICAL DEVELOPMENT PROGRAM: 11,801 PATIENTS TREATED
22
Case
study 1

23. –39.2
–121.4
–297.5 –306.4
-350
-300
-250
-200
-150
-100
-50
0
Meanchangefrombaseline(cm3)
MRI SUBSTUDY: WHAT KIND OF FAT IS GONE?
MR, magnetic resonance; SAT, subcutaneous tissue; VAT, visceral adipose tissue.
Bolinder J, et al. J Clin Endocrinol Metab 2012;97:1020–31. adipose
Subcut aneous
fat volume (cm3)
Visceral fat
volume (cm3)
Dapagliflozin 10 mg
+ metformin
Placebo
+ metformin
Dapagliflozin 10 mg
+ metformin
Placebo
+ metformin
Subcutaneous
fat
Visceral fat

24. Int J Clin Pract 67(4):307-316, 2013
FDA requirements
for regulatory approval
WHY CV SAFETY FOR ANTIDIABETIC MEDICINES IS
NEEDED?
FDA Issues Safety Alert on
Rosiglitazone
21st May 2007
Sponsor should compare the incidence of important CV
events with the investigational agent to incidence with the
control group and calculate a 2-sided 95% confidence
interval (95% CI) for the estimated risk ratio.
Pre-marketing data showing:
- Upper bound of 95% CI between 1.3 and 1.8
would support approval; post-marketing trial
needed to show upper bound is <1.3
- Upper bound of 95% CI <1.3 would support
approval; post-marketing CV trial may not be
necessary
- Point estimate of 1.5 would not be reassuring,
even if upper bound of 95% CI is <1.8
FDA Criteria for Assessing CV Safety

25. META ANALYSIS FOR RISK OF CV EVENTS
• A meta-analysis of CV events among 21 Phase IIb/III trials, showed no increase in the primary CV composite endpoint of CV death, stroke, MI and
hospitalisation for unstable angina with dapagliflozin1,2
1. EMDAC background document. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/
endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. Last accessed September 2014; 2. Dapagliflozin. Summary of product characteristics, 2014.
Patients at risk
Dapagliflozin 5699 5497 4943 4680 3518 3415 2770 1830 1780 1701 1627 1572 1498 263 254 249 242 236 234 222 220 221 210 189 176 3
Control 3240 3097 2757 2611 1955 1869 1484 970 924 873 828 805 749 137 131 129 125 123 119 113 111 107 106 90 80 1
CV events were adjudicated by an independent committee.
CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; UA, unstable angina.

26. DAPAGLIFLOZIN:
CARDIOVASCULAR SAFETY1
A cardiovascular meta-analysis was conducted using pooled data from 21 phase 2b/3 studies
1. EMDAC Background document. Available at: http://www.fda.gov/downloads/advisorycommittees
/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdf , p103.
Source: CV events 30-MU Meta-Analysis Report
Data on Hospitalization for heart failure is from pooling of data for a meta-analysis. It is not derived from a dedicated heart failure study.
Dapagliflozin is not indicated for treatment of heart failure.
CI, confidence interval; CV, cardiovascular; Dapa, dapagliflozin, MI, myocardial infarction; Revasc, revascularisation
Event
Patients with Event
Favours
Dapa Control
Hazard Ratio
vs. Control
(95% CI)
Dapa
N=5936
Control
N=3403
CV Death 20 18 0.70 (0.36, 1.36)
MI 30 33 0.57 (0.34, 0.95)
Stroke 25 18 1.00 (0.54, 1.86)
Unstable Angina 26 20 0.87 (0.46, 1.59)
Unplanned Coronary
Revasc
58 55 0.73 (0.50, 1.07)
Hospitalisation
for Heart Failure
10 16 0.36 (0.16, 0.84)
HR (95% CI)
0.1 1 10

27. RESEARCH HYPOTHESIS
27
• Hypothesis-generating data
derived from a meta-analysis of
Ph2b & 3 adjudicated MACE -
possible favourable effect of
dapagliflozin on CV risk.
•DECLARE study aims to test the
hypothesis that treatment with
dapagliflozin reduces CV events in
high-risk CV patients with T2DM
compared to placebo
• To rule out an unacceptable
increase in CV risk with
dapagliflozin treatment.
Kaplan-Meier Estimate for Primary Endpoint (MACE+UA):All phase
2b and 3 Patients

28. DECLARE – DAPAGLIFLOZIN EFFECTS ON CARDIOVASCULAR EVENTS
Primary endpoint
• MACE: CV death, MI, ischemic stroke
Screening
Placebo
Dapagliflozin (10 mg/d)
~6 years April 2013–2019
Median follow-up ~4.5 yrs
Duration is event-driven: 1390 events
Powered for superiority
1:1
Double-blind
Inclusion criteria
•T2DM, ≥40 yrs
•Established CVD or multiple risk
factors
N ~17,150 All other DM agents per treating MD
CV, cardiovascular; DM, diabetes mellitus; MI, myocardial infarction; T2DM, type 2 diabetes mellitus
https://clinicaltrials.gov/ct2/show/NCT01730534
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM379659.pdf

29. SGLT2 Inhibitor Cardio-Vascular OutcomesTrials
a≥20 yrs in Japan and also ≤65 years in India
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CANA, canagliflozin; CKD, chronic kidney disease; DAPA, dapagliflozin; EMPA, empagliflozin; ERTU,
ertugliflozin; ESKD, end stage kidney disease; HbA1c, glycated hemoglobin; MI, myocardial infarction; PBO, placebo; TBD, to be determined
Inzucchi SE, et al. Diab Vasc Dis Res 2015;12:90–100
EMPA-REG
Outcome
CANVAS CANVAS-R CREDENCE DECLARE Ertugliflozin CVOT
n 7042 4330 5700 3700 17 150 3900
Interventions
(randomization)
EMPA/PBO (2:1) CANA/PBO (2:1) CANA/PBO (1:1) CANA/PBO (1:1) DAPA/PBO
(1:1)
ERTU/PBO (2:1)
Primary endpoint CV death, non-
fatal MI, non-fatal
stroke
CV death, non-fatal
MI, non-fatal stroke
Progression of
albuminuria
ESKD, serum
creatinine doubling,
renal/CV death
CV death,
non-fatal MI,
non-fatal
ischemic
stroke
CV death, non-fatal
MI, non-fatal stroke
Target no. events 691 ≥420 TBD TBD 1390 TBD
Estimated median
follow-up
~3 years 6–7 years 3 years ~4 years 4–5 years 5–7 years
Estimated reporting 2015 2017/2018 2017 2019 2019 2021
The first CVOT for an SGLT2 inhibitor (EMPA-REG) has demonstrated a CV benefit, which is consistent
with the effect that SGLT2 inhibitors have on CV risk factors (i.e. blood pressure, weight and body fat mass)
and their low risk of hypoglycemia

30. COMPLETED CV OUTCOME TRIALS
Indian J EndocrMetab_2017_21_1_4_196026_f1

31. All subjects
n=5346
Phase 2b 2
n=423 Study 008
Phase 3
n=4250
Patients with T2D
n=40
Study 002
Patients with hepatic
impairment
n=18
Study 020
Patients with renal
impairment
n=32
Study 019
Monotherapy
n=832
n=401
+ 66 OL
Study 011 3
n=365
Study 038
Add-on to MET 5
n=743
Study 014
Add-on to SU 6
n=768
Study 040
Add-on to TZD 7
n=565
Study 013
Initial comb.
with MET 4
n=1306
Study 039
Healthy subjects
n=583
21 Studies
Clinical pharmacology
n=673
Saxagliptin clinical development programme1
1. Onglyza, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at:
http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed: 7 May, 09. 2. Rosenstock J, et al. Diabetes Obes Metab. 2008;10:376-86. 3.
Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-22. 4. Jadzinsky M, et al. Diabetes Obes Metab. 2009;11:611-22. 5. Defronzo RA, et al. Diabetes Care.
2009;32:1649-55. 6. Chacra AR, et al. Int J Clin Pract. 2009 Sep;63(9):1395-406. 7. Hollander P, et al. J Clin Endocrinol Metab. 2009 Dec;94(12):4810-9.
Add-on
studies
n=2076
Triple on
Therapy TIMI STUDY GROUP / HADASSAH MEDICAL ORG
N=16500
Add on to
Insulin &
India RCT
Case
study 2
US FDA approval
in Jul 2009

32. LONG-TERM SAFETY OF SAXAGLIPTIN IN PATIENTS WITH
TYPE 2 DIABETES: 4 YEAR DATA
Rosenstock J, et al. Diabet Med. 2013;30(12):1472-6.
A longer time to
discontinuation or rescue for
inadequate glycemic control
was observed with saxagliptin
plus metformin vs. placebo plus
metformin.
Time to discontinuation or use of rescue
medication for inadequate glycemic control
Saxagliptin monotherapy
or add-on to metformin
was found to be well
tolerated, with no
increased risk of
hypoglycemia, for up to 4
years.
Discontinuedorrescued(%)

33. SAXAGLIPTIN
5 mg/d
PLACEBO
Follow upVisits
Q6 months
FinalVisit
DocumentedType 2 Diabetes
N = 16,492
Primary EP
CV Death, MI,
Ischemic Stroke
Duration
Event driven (n=1040)
Median duration 2.1y
LTFU 0.2%
W/C 2.4%
Established CV Disease or Multiple Risk Factors
Major Secondary EP: CV death, MI, ischemic stroke, or hosp. for
heart failure, unstable angina, or coronary revascularization
RANDOMIZED 1:1 DOUBLE BLIND
All other DM Rx per treating MD
SAXAGLIPTIN ASSESSMENT OFVASCULAR OUTCOMES RECORDED IN
PATIENTS WITH DM
2.5 mg/d if eGFR ≤ 50 ml/min
Scirica BM et al. NEJM 2013; 369: 1317 - 26

34. RATE OF RISK OF HOSPITALIZATION
FOR HF OVERTIME
Scirica BM, et al. American Heart Association Scientific Sessions. November 2013.
0%
2%
4%
6%
8%
0 180 360 540 720 900
HospitalizationforHF
Days
Saxagliptin Placebo
Overall HR 1.27
(1.07-1.51)
P=0.007
3.5%
2.8%
HR 1.80
(1.29-2.54)
P=0.001
1.1%
0.6%
HR 1.48
(1.14-1.87)
P=0.003
1.9%
1.3%
n = 16,492
HR is
coming
down with
TIME
• Low observed event rate during the course of the trial may lead to increased recruitment of high-risk patients
and these may adversely reflect on outcome of trials
John M et al. i n d i a n h e a r t j o u r n a l 6 8 ( 2 0 1 6 ) 5 6 4 – 5 7 1

35. DPP4I CARDIOVASCULAR OUTCOMETRIALS
Trial (year) Population
(randomized)
Treatment Follow-up Primary endpoint Main CV outcome(s)
EXAMINE
(NCT00968708; 2013)13
ACS 15–90 days before
randomization (n=5380)
Alogliptin vs PBO Median 1.5 years Composite CV death, MI,
stroke
 No increase in 1°
endpoint
(HR: 0.96, p<0.001 for
non-inferiority)
SAVOR-TIMI 53
(NCT01107886; 2013)14
History or risk of CV
events (n=16,492)
Saxagliptin vs PBO Median 2.1 years Composite CV death, MI,
stroke
 No increase in 1°
endpoint
(HR: 1, p=0.99 for
superiority)
TECOS (NCT00790205;
2015)15
CV disease (n=14,671) Sitagliptin vs PBO Median 3.0 years Composite CV death, MI,
stroke, hospitalization for
unstable angina
 No increase in 1°
endpoint
(HR: 0.98, p<0.001 for
non-inferiority)
CARMELINA
(NCT01897532)20
High CV risk (n=8300) Linagliptin vs PBO 4 years Composite CV death,
MI, stroke,
hospitalization for
unstable angina
 Results expected
January2018
CAROLINA
(NCT01243424)21
High CV risk (n=6000) Linagliptin vs
glimepiride
7.7 years Composite CV death,
MI, stroke,
hospitalization for
unstable angina
 Results expected
September 2018
** Results from Examine, Savor Timi & TECOS.
White WB, Cannon CP, Heller SR et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. New Engl J Med 2013; 369: 1327-35.
Scirica BM, Bhatt DL, Braunwald E et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med 2013; 369: 1317-26.
Green JB, Bethel MA, Armstrong PW et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. New Engl J Med 2015.
DPP4i CV OutcomeTrials have shown CV Neutrality for the class**

36. CARDIOVASCULAR OUTCOME TRIALS (CVOT): CHALLENGES
 High cost – hundreds of millions of dollars
 High patient numbers – recruitment distribution (e.g. 40%
from US); large no. of sites across countries and
investigators
 Challenges in lab shipments, IVRS based randomization,
different cost structures, temperature controlled transport
of drugs, customs, clearance across borders, translation
of documents and variable ethics committee practices
 Adhering to local regulatory practices and local practices
of ‘‘standard of care’’.
 Long follow up periods – getting complete patient data
(challenges in patient retention, changes in investigator
and staffing of trial sites and interpretation of missing
data)
John M et al. i n d i a n h e a r t j o u r n a l 6 8 ( 2 0 1 6 ) 5 6 4 – 5 7 1
 Need to work with both endocrine and cardiology sites
 Event number-driven duration
 Needs different skills and approach at all levels (sponsor staff,
site staff, investigators, EC etc.)
 Design trials to satisfy needs for different regulatory agencies
 When conducted in a community - would potentially limit the no.
of subjects who could enter other drug developmental
programs
• CV safety trials with insulin- challenges of increased risk of hypo, need to have treat-to-target models to ensure
glycemic equipoise and challenges of blinding when using 2 different types of insulin
• increased risk of CV events in subjects with severe hypo which should be factored into the trial analysis

37. CV OUTCOMETRIAL RESULTS: EXAMPLES OF BENEFIT
Empagliflozin
Similar results shown with LEADER trial with Liraglutide (GLP 1
agonist)

38. Source: https://www.forbes.com/sites/johnlamattina/2015/04/13/should-the-fda-require-cv-outcome-studies-for-diabetes-drugs-before-
approval/#4c9bdb311307
Source: ://www.medscape.com/viewarticle/850492

39. Alternative Approaches……
Discussions of alternative methodologies (see report published by Sager et al., 2015)

40. GLUCOKINASE ACTIVATORS: MIXED OUTCOMES
Phase1Phase2
More than 100 patents for glucokinase activators have been filed, but results to date have been disappointing 2
2. DeFronzo RA et al. Diabetes Spectrum 2014 May; 27(2): 100-112. https://doi.org/10.2337/diaspect.27.2.100; 3. Nakamura A et al. J Diabetes Invest Vol. 6 No. 2 March 2015
Case
study 3
Image may be copyrighted; being used for educational purpose only

41. GLUCOKINASE ACTIVATORS: MIXED OUTCOMES
• AZ, Roche, Merck,Amgen ….. efficacy waned over time, leading to discontinuation of the clinical development
programs
• Hepatic-specific activators: TTP 399 (Trans Tech Pharm), GKM-001 [AdvinusTherapeutics] and PF-04991532 [Pfizer]2
• Their use is associated with an increased incidence of hypoglycemia and dyslipidemia3
2. DeFronzo RA et al. Diabetes Spectrum 2014 May; 27(2): 100-112. https://doi.org/10.2337/diaspect.27.2.100; 3. Nakamura A et al. J Diabetes Invest Vol. 6 No. 2 March 2015

42. DIABETES DRUG DEVELOPMENT: SWEET OR SOUR OUTCOMES
SUMMARY & CONCLUSIONS
 Diabetes: A silent killer
 Increasing globally at alarming rate- increase more prominent in developing countries like India
 Not a simple disease – multifactorial pathophysiology “OMNIOUS OCTET”
 Clear unmet need to develop more medicines
 Drug development in general carries high risk & costs have increased significantly (over billion), long process
 probability of clinical success 11.8%
 Diabetes Drug Development:
 Long history – over half a dozen new classes of drugs for diabetes introduced in last two decades
 Three case studies – SGLT2 inhibitor (starting from apple bark), DPP4 inhibitor and GKA
 Requirement for CV outcome trials & challenges of conducting such LARGE trials
 Examples of CV outcome trials and their outcomes – sometimes sweet, sometimes sour; potential alternative
approaches, evolving thinking and science
>170
Drugs
1 in 13
Approved
CD time
Increased
~7%
No. of
patients
Increased
300
No. of
pharmas