1. Getting drugs
to reach the
market
becomes
harder and
harder...
Antidiabetic
drugs
Nicolas Bernard Pauline Flipo Mélanie Tilte Florent Zoonekynd

2. Diabetes worldwide
Raised fasting blood glucose, 2008
Fasting blood glucose ≥ 7,0 mmol/L or medication for raised blood glucose
Prevalence (%)
WHO
2

3. T2DM complications
Eye complications Skin complications Nephropathy
Glaucoma Bacterial & fungal
Cataracts infections Hypertension
Retinopathy Diabetic
dermopathy Hearing loss
Foot complications Gastroparesis
Cardiovascular
Neuropathy diseases Hyperosmolar
Calluses hyperglycemic
Foot ulcers Myocardial nonketotic
Poor circulation infarction syndrome
Amputation Stroke
Peripheral arterial
Neuropathy Ketoacidosis disease
American Diabetes Association
3

4. What was the situation in the
early 2000s ?
Avandia®: Rosiglitazone
4

5. Situation in 1999
ACARBOSE SULFONYLUREAS
• Slow Carbohydrate • Directly ↑ Insulin
digestion secretion
• GI incomfort INSULIN • ↑ Body Weight
• Subcutaneous
injection
• ↓ Hepatic glucose
METFORMIN output MEGLITINIDES
• ↓ Insulin resistance • Directly ↑ Insulin
• ↓ Hepatic glucose secretion
output • ↑ Body Weight
• ≈ Weight neutral
5

6. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 6

7. A new perspective:
Thiazolidinediones
New mechanism of
action
THIAZOLIDINEDIONES
• PPARγ Agonists
• ↑ Insulin action
• ↑ Adipogenesis
TZDs and diabetes: testing the waters, Katie Ris Nature Medicine 11, 822 - 824 (2005) .
7

8. Rosiglitazone’s efficacy
Studies Design
Primary endpoint: HbA1c
monotherapy
+metformin
A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with T2DM, St John Sutton M and All
Effect of Metformin and Rosiglitazone Combination Therapy in Patients With T2DM. Fonseca V, Rosenstock J
8

9. FDA Approval
ADA : « These drugs offer new options to health care
professionals who treat people with type 2 diabetes
and represent important advances in drug therapy »
May 1999
FDA Approval
Precautions on patients at risk of heart failure
Rosiglitazone, What went wrong? BMJ | 11 SEPTEMBER 2010 | VOLUME 341
9

10. Mechanism of action
EMA APPROVAL
INITIAL REJECTION IN OCTOBER 1999
Increase in Plasma Volume
Edema
Patients with NYHA class III or
IV status excluded from clinical
trials.
↑ Body Weight
Lipid Alteration
Rosiglitazone in the Treatment of Type 2 Diabetes Mellitus: A Critical Review, Jennifer M. Malinowski & Scott Bolesta
10

11. Situation in 1999
(UKPDS) «[…] The majority of patients need multiple
therapies to attain these glycemic target levels in the
longer term.»
(EASD) «Rosiglitazone works in a novel way to reduce
insulin resistance »
July 2000
Market Authorisation in Europe
Warning on heart failure
Post-marketing trial with CV safety as primary endpoint
Turner RC, Cull CA, Frighi V, Holman RR, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or
insulini n patients with T2DM.JAMA. 1999;281:2005-2012.
11

12. Several Warnings
Safety Signals about CV events
Approval 2007
Black Box Warning : Avandia may cause
1999 heart attack
12

13. New Reglementation
CV guidelines
2008
Approval 2007
Black Box Warning : Avandia may cause
1999 heart attack
http://www.qcclick.com/infarctus-myocarde.html
13

14. Situation in 1999
METFORMIN
MEGLITINIDES SULFONYLUREAS
ACARBOSE
Clinical trials focus
INSULIN
on HbA1c 14

15. Situation in 2008
METFORMIN
MEGLITINIDES SULFONYLUREAS
GLIPTINS (DPP-4 GLP-1 receptor
inhibitors) agonist
THIAZOLIDINEDIONE ACARBOSE
Clinical trials Independent endpoint
INSULIN
focus on HbA1c to evaluate CV risk 15

16. Avandia®’s end
Suspension of the MA in 2010
CV guidelines
Europe
2008
Approval Safety Concern :
CV risk
1999 Restricted-access Program
in USA
11 years 16

17. An other thiazolidinedione?
Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus, A Meta-analysis of Randomized Trials, 2007
17

18. Adapted from testimony by David Graham at the July 13, 2010, EMDAC meeting 18

19. But…
2002
Ten-year epidemiological study about Actos®
2007
Interim results: increased risk of bladder cancer for use
> 12 months (+ 40%)
BlackBoxWarning
2011
Meta-analysis using data from the French National Health
Insurance Plan : HR = 1.22 (95% CI 1.03 to 1.43)
Withdrawal
in France
Supplement approvals letter from FDA to Takeda about bladder cancer risk, July, 8 2011
19

20. Let’s be prudent...
Victoza®: Liraglutide
20

21. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 21

22. Victoza® : Liraglutide once a day
Liraglutide : GLP-1 analog
Lipid chain =>
Prolonged duration of action
May 23rd, 2008 : NDA filed with the FDA and EMA
22

23. Victoza® timeline
August 20th: Liragutide improves glucose control and lowers body weight
2007 2008
May 23rd: NDA filed with the FDA and Europe
23

24. Clinical efficacy
(glimepiride)
24
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

25. Clinical efficacy
(glimepiride)
HbA1c, FPG
Still primary
endpoints
Before CV guideline
25
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

26. Clinical efficacy
(glimepiride)
26
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

27. Clinical efficacy
(glimepiride)
Correction of a risk factor
27
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

28. Victoza® timeline
August 20th: Liragutide improves glucose control and lowers body weight
April 2nd: FDA Advisory Committee Meeting
December 17th:
CV guidance
2007 2008 2009
May 23rd: NDA filed with the FDA and Europe
28

29. Cardiovascular Safety
-Qualitatively similar to total comparator
-No relation dose/CV events
-Upper bound of the 95% CI exceeded 1.3
Not designed for meta-analysis, or evaluation of
Data of previous CV events
clinical trials No patients with significant CV disease
→Few major cardiovascular events
http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf
29

30. Thyroid cancers
Thyroid C-cell Male rats : mid- and high-dose groups
adenomas Female rats : all dose groups
Thyroid C-cell Male rats : all dose groups
carcinomas Female rats : mid- and high-dose groups
A NOAEL for occurrence of C-cell tumors was not identifield in rats
30
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

31. GLP-1 Receptor
(A) Saturation binding with fluorescence labeled GLP-1. (B) Saturation binding with iodinated GLP-1. (C) Western blotting.
(D)Semi-quantitative PCR. Rat C-cell lines: CA-77 and MTC-23. Human C-cell line: TT. Rat beta-cell line: INS-1E
31
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

32. Thyroid adverse events
32
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

33. All Thyroid adverse events
Total Liraglutide Placebo Active Comparator
% N % N % N
4257 907 1474
All Thyroid
Adverse 1,9 80 1,4 13 1,4 21
Events
33
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

34. Thyroid adverse events
34
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

35. Goitres
Total Liraglutide Placebo Active Comparator
% N % N % N
4257 907 1474
All Thyroid
1,9 80 1,4 13 1,4 21
Adverse Events
Goitres 0,4 17 0,1 1 0,1 2
35
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

36. Pancreatitis
9 Cases 8 with Liraglutide
7 acute 2 chronic All pancreatitis events were
reported in the intermediate
and long-term trials
Predisposing etiological factors
Alcohol abuse
Biliary tract disease or gall stones
Abdominal surgery or family history of pancreatitis
Recent abdominal trauma
Weight loss
36
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

37. Pancreatitis
37
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

38. Risk Management Plan
Post-approval safety surveillance
-Focus on thyroid neoplasms, pancreatitis and CV events
-3 to 5 years
-Reporting to regulatory authorities at 6-months
Post-approval CV trials
-Submitted to FDA and EMA
-Beginning: End of 2009 – beginning of 2010
38
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009

39. Victoza® timeline
August 20th: Liragutide improves glucose control and lowers body weight
April 2nd: FDA Advisory Committee Meeting
December 17th:
CV guidance January 20th: Approval for Victoza® in Japan
2007 2008 2009 2010 2011
January 25th: FDA approved Victoza®
with REMS
July 3rd: Marketing authorisation in Europe
May 23rd: NDA filed with the FDA and Europe
39

40. Risk Evaluation & Mitigation Strategy
Communication Plan
- Reminder Dear HCP Letter for Primary Care Providers
- Direct Mail Letter
Timetable for the Submission of Assessments to the
FDA
On March 24th, at 1, 2, 3 and 7 years from the date of the
initial REMS approval
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
40

41. Risk Evaluation & Mitigation Strategy
Thyroid nodules Patients should refer to an
endocrinologist for futher
Elevated serum calcitonin evaluation
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
41

42. Risk of Acute Pancreatitis
Pancreatitis : VICTOZA® > comparators
Observe patients carefully for signs and symptoms of pancreatitis
Pancreatitis VICTOZA® : Confirmatory Appropriate
suspected discontinue promptly tests management
Pancreatitis
VICTOZA® : not restarted
confirmed
Use with caution in patients with a history of pancreatitis
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
42

43. A QT story...
Bydureon® : Exenatide
once a week
43

44. Oral Pharmacological Agents for Type 2 Diabetes, Diabetes manager, pbworks.com 44

45. Bydureon® : exenatide once a week
Exenatide : GLP-1 analog
Twice a day
Once weekly
Once monthly In Phase II
45

46. Medisorb® Microspheres Technology
Small molecules/Peptides encapsulated in Microspheres
1/10 mm
CO2 + H20
Polylactide co-glycolide polymer (PLG)
Medical Devices industry : bioabsorbable sutures
- Versatile degradation kinetics
- Established safety Shield from
Extended release
enzymatic attack
- Biocompatibility
Mahesh Chaubal. Polyactides/Glycolides – Excipients for Injectable Drug Delivery & Beyond, Drug Delivery Technology; 2002; 2(5), 34-36
Alkermes Fact Sheet Medisorb® Microspheres Technology (2009)
Rajan K. Verma, Sanjay Garg. Current Status of Drug Delivery Technologies and Future Directions, Pharmaceutical Technology On-Line; 2001; 25 (2), 1-14
46

47. Bydureon®/Byetta® : PK profile
Vanita R. Aroda, Mary Beth DeYoung. Clinical Implications of Exenatide as a Twice-Daily or Once-Weekly Therapy for Type 2 Diabetes. Postgrad Med;
2011;123(5):228-38.
47

48. Bydureon®/Byetta® : PK profile
Vanita R. Aroda, Mary Beth DeYoung. Clinical Implications of Exenatide as a Twice-Daily or Once-Weekly Therapy for Type 2 Diabetes. Postgrad Med;
2011;123(5):228-38.
48

49. Bydureon® : exenatide twice a week
April : Byetta® approval in the US
2005
October : FDA/ICH guidance
tQT study
BC October 2010
49

50. FDA/ICH Guidances for industry, october 2005 50

51. QT interval and hERG channel
51

52. Bydureon® : exenatide twice a week
April : Byetta® approval in the US
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
July : DURATION-1 results
2005 2006 2007 2008
March : DURATION-1 – QT assessment (148 patients)
October : FDA/ICH guidance
tQT study
BC October 2010
52

53. July 2008 : DURATION 1 QT Data : No Relationship Between Baseline-
adjusted Change in QTcF Interval and Exenatide Concentrations
148 patients ECG
- 56 : mild renal impairment - At baseline
- 10 : moderate renal impairment - At steady state
71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,
Amylin Pharmaceuticals, Inc. June 26, 2011 53

54. 71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,
Amylin Pharmaceuticals, Inc. June 26, 2011 54

55. Bydureon® : exenatide twice a week
April : Byetta® approval in the US
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
June : Byetta® tQT study’s results presented at
ADA annual meeting
2005 2006 2007 2008 2009
May : Application submission
March : DURATION-1 – QT assessment (148 patients)
October : FDA/ICH guidance
tQT study
BC October 2010
55

56. June 2009 : Byetta® QT study, ADA annual meeting
Scatterplot of Changes from Predose in QTcF Interval Versus Plasma Exenatide
Concentrations Following a Single 10 µg Dose
71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,
Amylin Pharmaceuticals, Inc. June 26, 2011
ADA 2009 56

57. June 2009 : Byetta® QT study, ADA annual meeting
Scatterplot of Changes from Predose in QTcF Interval Versus Plasma Exenatide
Concentrations Following a Single 10 µg Dose
71st Scientific Sessions of the American Diabetes Association. Amylin Investor Reception. Daniel M. Bradbury , President and Chief Executive Officer,
Amylin Pharmaceuticals, Inc. June 26, 2011
ADA 2009 57

58. Action of exenatide on hERG?
Towards a hERG channel Tyr652
inhibitors pharmacophore Phe656 Intracellular
Thr623
Ser624
interaction
Mouse, Rat,
Monkey models
In vitro data
No inhibition of hERG channel
At concentrations 1.8 million
times higher than human peak
concentration
Andrea Cavalli et al. Towards a Pharmacophore for Drugs Inducing the Long QT Syndrome : Insights from a CoMFA Study of HERG K+ Channel Blockers.
J. Med. Chem. 2002, 45. 3844-3853
58

59. Bydureon® : exenatide twice a week
April : Byetta® approval in the US
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
June : Byetta® tQT study’s results presented at
ADA annual meeting
October : 2d CRL : tQT study for
Bydureon®
2005 2006 2007 2008 2009 2010
April : answer
March : CRL : manufacturing processes,
REMS program, product labelling
May : Application submission
March : DURATION-1 – QT assessment (148 patients)
October : FDA/ICH guidance
tQT study
BC October 2010
59

60. FDA Experts’ opinion
Impact of hypoglycemia and hyperglycemia on hERG channel
Hypo/Hyperglycemia =>
Impairment of hERG K+
channel
QT interval prolongation
Torsades de pointe
Yiqiang Zhang et al. Impairment of human ether-à-go-go-related gene (HERG) K+ channel function by hypoglycemia and hyperglycemia. The journal of
biological chemistry, 2003;278(12):10417-10426.
60

61. FDA Experts’ opinion
Impact of hypoglycemia and hyperglycemia on hERG channel
Trials : hypoglycemia under exenatide
Once a week => less control of its concentration
Excreted via the kidney => ! renal impairment
Need a tQT study
BC, October 2010
61

62. Bydureon® : exenatide twice a week
April : Byetta® approval in the US
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
June : Byetta® tQT study’s results presented at
ADA annual meeting
October : 2d CRL : tQT study for
Bydureon® July : answer
2005 2006 2007 2008 2009 2010 2011
April : answer
March : CRL : manufacturing processes,
REMS program, product labelling
May : Application submission
March : DURATION-1 – QT assessment (148 patients)
October : FDA/ICH guidance
tQT study
BC October 2010
62

63. And finally...
January 27th, 2012
63

64. http://www.bydureon.com/content/pdfs/Highlighted__Information_Prescribers.pdf 64

65. A new strategy
Dapagliflozin
65

66. Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com 66

67. Discovery
1835 : Phlorizin (root bark of the apple tree)
Inhibition of Sodium Glucose Cotransporter (SGLT)
SGLT-1 : Enterocytes of the small intestine
Proximal tubule of the nephron (10%)
SGLT-2 : Proximal tubule of the nephron (90%)
Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter． Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008
，J. Med. Chem.， Vol. 51，pp.1145-1149
67

68. Mechanism
SGLT2 inhibition — a novel strategy for diabetes treatment． Chao E.C., Henry R.R. July 2010，Nature Reviews， Vol. 9，pp.551-559
68

69. Mechanism
Paradox
SGLT2 inhibition — a novel strategy for diabetes treatment． Chao E.C., Henry R.R. July 2010，Nature Reviews， Vol. 9，pp.551-559
69

70. Phlorizin : Non selective SGLT inhibitor – Not suitable
drug candidate
- Inhibits SGLT-1 → Absorption problems
- Cleaved by β-glucosidase → Poor metabolic stability
SAR → New entities
Sergliflozin (GSK) Dapagliflozin (BMS/AZ)
Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter． Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008
，J. Med. Chem.， Vol. 51，pp.1145-1149 70

71. SGLT2 and SGLT1 inhibitory activity
SGLT2 EC50 (nM) SGLT1 EC50 (nM) Selectivity vs SGLT1 (fold)
Phlorizin 35.6+/-4.2 330+/-50 10
Sergliflozin 9.2+/-0.8 211+/-29 >90
Dapagliflozin 1.1+/-0.06 1390+/-7 1200
Discovery of Dapagliflozin: A Potent, Selective Renal Sodium-Dependent Glucose Cotransporter． Meng W., Ellsworth B.A., Nirschl A.A., McCann P.J. 2008
，J. Med. Chem.， Vol. 51，pp.1145-1149 71

72. Preclinical data
Acute in vivo activity
Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats ． Han S., HaganD.L., Taylor J.R., Xin L., Meng W.,
Biller S.A., Wetterau J.R., Washburn W.N., Whaley J.M.June 2008，Diabetes，Vol. 57，pp.1723-1729
72

73. Preclinical data
Chronic in vivo efficacy
• Lowering FPG maintained over a 2-week once-daily treatment regimen.
• No bodyweight changes noted, no abnormal behavior observed.
• No liver or renal toxicity measured.
Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats ． Han S., HaganD.L., Taylor J.R., Xin L., Meng W.,
Biller S.A., Wetterau J.R., Washburn W.N., Whaley J.M.June 2008，Diabetes，Vol. 57，pp.1723-1729
73

74. Clinical data
Patients with inadequate glycaemic control
Dapagliflozin 2.5mg/day 137
with metformin Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-
controlled trial． Bailey C., Gross J., Pieters A., Bastien A., List J.2010，Lancet，Num. 375，pp.2223-2233
74

75. Clinical data
Patients with inadequate glycaemic control
Dapagliflozin 2.5mg/day 137
with metformin Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-
controlled trial． Bailey C., Gross J., Pieters A., Bastien A., List J.2010，Lancet，Num. 375，pp.2223-2233
75

76. Clinical data
Patients with inadequate glycaemic control
Dapagliflozin 2.5mg/day 137
with metformin Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-
controlled trial． Bailey C., Gross J., Pieters A., Bastien A., List J.2010，Lancet，Num. 375，pp.2223-2233 76

77. Expectations
BENEFITS RISKS
• Hypoglycemia
• Insulin-independent • Renal function
• HbA1c lowering • Diuretic effect:
• Reduction in: - Hypovolemia
- Fasting Plasma Glucose - Hypotension
- Weight - Dehydration
• Reduction in Blood Pressure • Urinary tract infections,
genital tract infections
• Oral bioavailability: 84%
• Serum free fraction: 3-4%
• T1/2: 17.3h
Endocrinologic and Metabolic Drugs Advisory Committee Meeting: Dapagliflozin BMS-512148 (BMS/AZ presentation)
Drug report from Thomson Reuters: Dapagliflozin
77

78. Patients with insulin treatment
Vital signs and laboratory outcomes at week 12
Placebo + Insulin Dapagliflozin 10 mg + Insulin Dapagliflozin 20 mg + Insulin
Number of patients 23 24 24
Systolic/diastolic blood pressure Slight increase - 7.2/- 1.2 mm Hg - 6.1/- 3.9 mm Hg
Urinary glucose excretion - 1.5 mg/24 h 83.5 mg/24 h 85.2 mg/24 h
24h urinary volume + 255 mL + 365 mL + 444 mL
FPG + 17.8 mg/dL + 2.4 mg/dL - 9.6 mg/dL
Total daily dose of insulin + 1.7 UI - 1.4UI - 0.8UI
Adverse events of special interest
Placebo + Insulin Dapagliflozin 10 mg + Insulin Dapagliflozin 20 mg + Insulin
Urinary tract infection - - 1
Genital tract infection 1 - 5
Events of hypoglycemia 3 (1 severe) 7 6
A Study of Dapagliflozin in Patients with Type 2 Diabetes Receiving High Doses of Insulin Plus Insulin Sensitizers ． Wilding J., Norwood P., T'joen C.,
Bastien A., List J., Fiedorek F.，September 2009，Diabetes Care，Vol. 32，pp.1656-1662． 78

79. Urinary tract infections
Placebo Dapagliflozin 2.5mg Dapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin Total
N= 1393 N=814 N=1145 N=1193 N=3291
Total subjects with an event 63 (4.5%) 34 (4.2%) 84 (7.3%) 77 (6.5%) 209 (6.4%)
Females 52 (7.7%) 165 (10.0%)
Males 11 (1.5%) 44 (2.7%)
Not dose related
Common adverse event
One serious AE: pyelonephritis
Included in proposed labeling
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMS
Advisory Committee meeting July 19, 2011
79

80. Genital tract infections
Placebo Dapagliflozin 2.5mg Dapagliflozin 5mg Dapagliflozin 10mg Dapagliflozin Total
N= 1393 N=814 N=1145 N=1193 N=3291
Total subjects with an event 29 (2.3%) 47 (5.8%) 80 (7%) 83 (7%) 223 (6.8%)
Females 23 (3.4%) 165 (10.0%)
Males 6 (0.8%) 58 (3.5%)
Appears dose related
None of these infections are
serious
Included in proposed labeling
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMS
Advisory Committee meeting July 19, 2011
80

81. Future
FDA Advisory Committee: July 19th, 2011
Vote: 9 against and 6 for
Action date: October 26th, 2011
Delayed action date: January 28th, 2012
81

82. Bladder cancers
Cases Dapagliflo Control SEER
zin (Surveillance, Epidemiology
and End Result) program
Total 4310 1962
Including:
•Adjustment for smoking and BMI
•Epidemiology of bladder cancer in
Expected 2.05 1 the US population
Downward-adjusted hazard ratio
Effective 9 1 of 1.40 calculated for the diabetic
population
Limits
•Concerns US population: only 20% of patients
•Literature-based factor: subject to uncertainty
•Incidence may be underestimated
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMS
Advisory Committee meeting July 19, 2011 82

83. Further more...
Age Sex Dapagliflozin Cancer Diagnosis day Smoking Baseline
dose (mg) grade hematuria
75 M 2,5 2 43 Former 2+
48 M 10 Low 74 Former -
67 M 5 (+ Pio) High 144 Never Trace
55 M 10 Low 169 Current Trace
63 M 5 (+ Ins) 2 393 (tumor 358) Current -
67 M 10 (+ Ins) 2 399 Never 3+
60 M 5 (+ Met) Low 512 Former 2+
66 M 10 (+ Ins) Low 581 Former -
76 M 2,5-10 (+ Met) High 727 Former -
67 M Placebo High 136 Current 3+
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMS
Advisory Committee meeting July 19, 2011 83

84. Both sides arguments
FDA BMS/AZ
Trials not powered to distinguish
the incidence of bladder cancer Bladder cancer
Increased surveillance of urinary
Dapagliflozin may be associated symptoms with dapagliflozin =
with increased risk a bladder increased detection of cancer
cancer
Continued follow-up of all participants in the dapagliflozin clinical trials
and further analysis should be done to evaluate the relative risk of
cancer associated with dapagliflozin treatment.
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMS
Advisory Committee meeting July 19, 2011 84

85. Future
Action date: October 26th, 2011
Delayed action date: January 28th, 2012
Complete Response Letter: January 19th, 2012
Additional clinical data for a better benefit-risk assessment
85

86. New requirements
Unexpected
effects
Pharmacological risks
Clinical data
data
benefits
Reducing risk Improving benefit
86