getting drugs to reach the market becomes harder and harder
DESCRIPTION
TRANSCRIPT
Getting drugs to reach the
market becomes
harder and harder...
Antidiabetic drugs
Mélanie TiltePauline Flipo Florent ZoonekyndNicolas Bernard
2WHO
Diabetes worldwide
Raised fasting blood glucose, 2008 Fasting blood glucose ≥ 7,0 mmol/L or medication for raised blood glucose
Prevalence (%)
3American Diabetes Association
T2DM complications
Eye complications
GlaucomaCataracts
Retinopathy
Foot complications
NeuropathyCalluses
Foot ulcersPoor circulation
Amputation
Skin complications
Bacterial & fungal infectionsDiabetic
dermopathy
Cardiovascular diseases
Myocardial infarction
Stroke
KetoacidosisNeuropathy
Nephropathy
Hypertension
Hearing loss
Gastroparesis
Hyperosmolar hyperglycemic
nonketotic syndrome
Peripheral arterial disease
4
What was the situation in the early 2000s ?Avandia®: Rosiglitazone
5
Situation in 1999
• Slow Carbohydrate digestion• GI incomfort
• Directly ↑ Insulin secretion• ↑ Body Weight
SULFONYLUREASACARBOSE
• ↓ Insulin resistance• ↓ Hepatic glucose output• ≈ Weight neutral
METFORMIN• Directly ↑ Insulin secretion• ↑ Body Weight
MEGLITINIDES
• Subcutaneous injection• ↓ Hepatic glucose output
INSULIN
6Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com
7
A new perspective:Thiazolidinediones
• PPARγ Agonists• ↑ Insulin action• ↑ Adipogenesis
THIAZOLIDINEDIONES
TZDs and diabetes: testing the waters, Katie Ris Nature Medicine 11, 822 - 824 (2005) .
New mechanism of action
8
Rosiglitazone’s efficacy
Primary endpoint: HbA1cStudies Design
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 AllEffect of Metformin and Rosiglitazone Combination Therapy in Patients With T2DM. Fonseca V, Rosenstock J
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 »
Rosiglitazone, What went wrong? BMJ | 11 SEPTEMBER 2010 | VOLUME 341
FDA ApprovalMay 1999
Precautions on patients at risk of heart failure
10
Mechanism of action
Edema
Increase in Plasma Volume
Patients with NYHA class III or IV status excluded from clinical trials.
Rosiglitazone in the Treatment of Type 2 Diabetes Mellitus: A Critical Review, Jennifer M. Malinowski & Scott Bolesta
↑ Body Weight
Lipid Alteration
EMA APPROVAL
INITIAL REJECTION IN OCTOBER 1999
11Turner 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.
(UKPDS) «[…] The majority of patients need multiple therapies to attain these glycemic target levels in the longer term.»
Situation in 1999
(EASD) «Rosiglitazone works in a novel way to reduce insulin resistance »
Market Authorisation in EuropeJuly 2000
Warning on heart failure
Post-marketing trial with CV safety as primary endpoint
12
Several Warnings
Safety Signals about CV events
Approval
1999
2007
Black Box Warning : Avandia may cause heart attack
13
New Reglementation
Approval
1999
2008
CV guidelines
2007
http://www.qcclick.com/infarctus-myocarde.html
Black Box Warning : Avandia may cause heart attack
14
Situation in 1999
METFORMIN
INSULIN
SULFONYLUREAS
ACARBOSE
MEGLITINIDES
Clinical trials fo
cus on
HbA1c
15
Situation in 2008
METFORMIN
SULFONYLUREAS
ACARBOSE
INSULIN
MEGLITINIDES
GLIPTINS (DPP-4 inhibitors)
GLP-1 receptor agonist
THIAZOLIDINEDIONE Clinical tri
als focus on
HbA1c
Independent endpoint
to evaluate CV risk
16
Avandia®’s end
Approval
1999
2010
Safety Concern : CV risk
11 years
Suspension of the MA in Europe
Restricted-access Program in USA
2008
CV guidelines
17
An other thiazolidinedione?
Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus, A Meta-analysis of Randomized Trials, 2007
MORE FAVORABLE EFFECT ON RISK OF CARDIOVASCULAR
EVENTS
18Adapted from testimony by David Graham at the July 13, 2010, EMDAC meeting
19
Meta-analysis using data from the French National Health Insurance Plan : HR = 1.22 (95% CI 1.03 to 1.43)
2011
But…
Supplement approvals letter from FDA to Takeda about bladder cancer risk, July, 8 2011
Ten-year epidemiological study about Actos®2002
Interim results: increased risk of bladder cancer for use > 12 months (+ 40%)
2007
BlackBoxWarning
Withdrawal in France
20
Victoza®: LiraglutideLet’s be prudent...
21Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com
22
Victoza® : Liraglutide once a day
Liraglutide : GLP-1 analog
May 23rd, 2008 : NDA filed with the FDA and EMA
Lipid chain => Prolonged duration of action
23
Victoza® timeline
2007
August 20th: Liragutide improves glucose control and lowers body weight
2008
May 23rd: NDA filed with the FDA and Europe
24
Clinical efficacy
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
(glimepiride)
25
Clinical efficacy
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
Still primary endpoints
HbA1c, FPG
(glimepiride)
Before CV guideline
26
Clinical efficacy
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
(glimepiride)
27
Clinical efficacy
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
(glimepiride)
Correction of a risk factor
28
Victoza® timeline
2007 2008 2009
August 20th: Liragutide improves glucose control and lowers body weight
May 23rd: NDA filed with the FDA and Europe
April 2nd: FDA Advisory Committee MeetingDecember 17th:
CV guidance
29http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4422b2-01-FDA.pdf
Cardiovascular Safety
Data of previous
clinical trials
Not designed for meta-analysis, or evaluation of CV events
No patients with significant CV disease→Few major cardiovascular events
-Qualitatively similar to total comparator-No relation dose/CV events
-Upper bound of the 95% CI exceeded 1.3
30
Male rats : mid- and high-dose groupsFemale rats : all dose groups
Male rats : all dose groupsFemale rats : mid- and high-dose groups
Thyroid cancers
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
Thyroid C-cell adenomas
Thyroid C-cell carcinomas
A NOAEL for occurrence of C-cell tumors was not identifield in rats
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-1ENovo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
32
Thyroid adverse events
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
33
Total Liraglutide Placebo Active Comparator
% N % N % N
4257 907 1474
All ThyroidAdverse Events
1,9 80 1,4 13 1,4 21
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
All Thyroid adverse events
34
Thyroid adverse events
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 1474All Thyroid
Adverse Events 1,9 80 1,4 13 1,4 21
Goitres 0,4 17 0,1 1 0,1 2
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
36
Alcohol abuseBiliary tract disease or gall stones Abdominal surgery or family history of pancreatitisRecent abdominal traumaWeight loss
8 with Liraglutide
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
9 Cases
All pancreatitis events were reported in the intermediate
and long-term trials
Predisposing etiological factors
Pancreatitis
7 acute 2 chronic
37
Pancreatitis
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
38
-Focus on thyroid neoplasms, pancreatitis and CV events-3 to 5 years -Reporting to regulatory authorities at 6-months
-Submitted to FDA and EMA-Beginning: End of 2009 – beginning of 2010
Risk Management Plan
Post-approval safety surveillance
Post-approval CV trials
Novo Nordisk Briefing document Endocrine and Metabolic Drug Advisory Committee 2 April 2009
39
Victoza® timeline
2007 2008 2009 2010 2011
August 20th: Liragutide improves glucose control and lowers body weight
May 23rd: NDA filed with the FDA and Europe
April 2nd: FDA Advisory Committee Meeting
January 25th: FDA approved Victoza® with REMS
July 3rd: Marketing authorisation in Europe
January 20th: Approval for Victoza® in JapanDecember 17th:
CV guidance
40http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
On March 24th, at 1, 2, 3 and 7 years from the date of the initial REMS approval
- Reminder Dear HCP Letter for Primary Care Providers- Direct Mail Letter
Risk Evaluation & Mitigation Strategy
Communication Plan
Timetable for the Submission of Assessments to the FDA
41http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
Risk Evaluation & Mitigation Strategy
Thyroid nodules
Elevated serum calcitonin
Patients should refer to an endocrinologist for futher
evaluation
42
Risk of Acute Pancreatitis
Pancreatitis : VICTOZA® > comparators
Observe patients carefully for signs and symptoms of pancreatitis
Use with caution in patients with a history of pancreatitis
http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM202063.pdf
Pancreatitis suspected
VICTOZA® : discontinue promptly
Confirmatory tests
Appropriate management
Pancreatitis confirmed VICTOZA® : not restarted
43
Bydureon® : Exenatide once a week
A QT story...
44Oral Pharmacological Agents for Type 2 Diabetes, Diabetes manager, pbworks.com
45
Bydureon® : exenatide once a week
Exenatide : GLP-1 analog
Once monthly In Phase II
Once weekly
Twice a day
46
Medical Devices industry : bioabsorbable sutures
- Versatile degradation kinetics
- Established safety
- Biocompatibility
Medisorb® Microspheres Technology
Mahesh Chaubal. Polyactides/Glycolides – Excipients for Injectable Drug Delivery & Beyond, Drug Delivery Technology; 2002; 2(5), 34-36Alkermes 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
Small molecules/Peptides encapsulated in Microspheres
1/10
mm
CO2 + H20
Polylactide co-glycolide polymer (PLG)
Extended release Shield from enzymatic attack
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.
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.
49BC October 2010
Bydureon® : exenatide twice a week
2005
April : Byetta® approval in the US
October : FDA/ICH guidancetQT study
50FDA/ICH Guidances for industry, october 2005
51
QT interval and hERG channel
52BC October 2010
Bydureon® : exenatide twice a week
2005 2006 2007 2008
April : Byetta® approval in the US
October : FDA/ICH guidancetQT study
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
March : DURATION-1 – QT assessment (148 patients)
July : DURATION-1 results
53
ECG - At baseline- At steady state
148 patients- 56 : mild renal impairment- 10 : moderate renal impairment
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
July 2008 : DURATION 1 QT Data : No Relationship Between Baseline-adjusted Change in QTcF Interval and Exenatide Concentrations
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
55BC October 2010
Bydureon® : exenatide twice a week
2005 2006 2007 2008 2009
April : Byetta® approval in the US
October : FDA/ICH guidancetQT study
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
March : DURATION-1 – QT assessment (148 patients)
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
May : Application submission
June : Byetta® tQT study’s results presented at ADA annual meeting
56 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
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
57
Action of exenatide on hERG?
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
Towards a hERG channel inhibitors pharmacophore
Tyr652Phe656Thr623Ser624
Intracellular interaction
No inhibition of hERG channel
At concentrations 1.8 million times higher than human peak
concentration
Mouse, Rat, Monkey modelsIn vitro data
58BC October 2010
Bydureon® : exenatide twice a week
2005 2006 2007 2008 2009 2010
April : Byetta® approval in the US
October : FDA/ICH guidancetQT study
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
March : DURATION-1 – QT assessment (148 patients)
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
May : Application submission
June : Byetta® tQT study’s results presented at ADA annual meeting
March : CRL : manufacturing processes, REMS program, product labelling
April : answer
October : 2d CRL : tQT study for Bydureon®
59
FDA Experts’ opinion
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.
Impact of hypoglycemia and hyperglycemia on hERG channel
Hypo/Hyperglycemia =>
Impairment of hERG K+ channel
QT interval prolongation
Torsades de pointe
60
FDA Experts’ opinion
BC, October 2010
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
61BC October 2010
Bydureon® : exenatide twice a week
2005 2006 2007 2008 2009 2010 2011
April : Byetta® approval in the US
October : FDA/ICH guidancetQT study
End-of-Phase II meeting : Simple process for Bydureon®’s QT profile
March : DURATION-1 – QT assessment (148 patients)
July : DURATION-1 results : “no clinically meaningful changes in QTc” – “acceptable”
May : Application submission
June : Byetta® tQT study’s results presented at ADA annual meeting
March : CRL : manufacturing processes, REMS program, product labelling
April : answer
October : 2d CRL : tQT study for Bydureon® July : answer
62
And finally...January 27th, 2012
63http://www.bydureon.com/content/pdfs/Highlighted__Information_Prescribers.pdf
64
DapagliflozinA new strategy
65Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com
66
Discovery
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
1835 : Phlorizin (root bark of the apple tree)
Inhibition of Sodium Glucose Cotransporter (SGLT)
SGLT-1 : Enterocytes of the small intestineProximal tubule of the nephron (10%)
SGLT-2 : Proximal tubule of the nephron (90%)
67
Mechanism
SGLT2 inhibition — a novel strategy for diabetes treatment. Chao E.C., Henry R.R. July 2010, Nature Reviews , Vol. 9, pp.551-559
Paradox
68
Sergliflozin (GSK) Dapagliflozin (BMS/AZ)
- Inhibits SGLT-1 → Absorption problems- Cleaved by β-glucosidase → Poor metabolic stability
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
Phlorizin : Non selective SGLT inhibitor – Not suitable drug candidate
SAR → New entities
69Discovery 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
SGLT2 and SGLT1 inhibitory activity SGLT2 EC50 (nM) SGLT1 EC50 (nM) Selectivity vs SGLT1 (fold)
Phlorizin 35.6+/-4.2 330+/-50 10Sergliflozin 9.2+/-0.8 211+/-29 >90
Dapagliflozin 1.1+/-0.06 1390+/-7 1200
70
Preclinical data
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
Acute in vivo activity
71
Preclinical data
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
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.
72
Clinical data
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
Dapagliflozin 2.5mg/day 137
Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Patients with inadequate glycaemic control with metformin
73
Clinical data
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
Dapagliflozin 2.5mg/day 137
Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Patients with inadequate glycaemic control with metformin
74
Clinical data
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
Dapagliflozin 2.5mg/day 137
Dapagliflozin 5mg/day 137
Dapagliflozin 10mg/day 135
Placebo/day 137
Total 546
Patients with inadequate glycaemic control with metformin
75
• Oral bioavailability: 84%• Serum free fraction: 3-4%• T1/2: 17.3h
• Hypoglycemia• Renal function• Diuretic effect:
- Hypovolemia- Hypotension- Dehydration
• Urinary tract infections, genital tract infections
• Insulin-independent• HbA1c lowering• Reduction in:
- Fasting Plasma Glucose- Weight
• Reduction in Blood Pressure
Expectations
75Endocrinologic and Metabolic Drugs Advisory Committee Meeting: Dapagliflozin BMS-512148 (BMS/AZ presentation)Drug report from Thomson Reuters: Dapagliflozin
BENEFITS RISKS
76
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
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
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.
Patients with insulin treatment
Vital signs and laboratory outcomes at week 12
Adverse events of special interest
77FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011
Urinary tract infectionsPlacebo 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
7878FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011
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
Genital tract infections
79
Vote: 9 against and 6 for
Future
Action date: October 26th, 2011
Delayed action date: January 28th, 2012
FDA Advisory Committee: July 19th, 2011
80
Including:•Adjustment for smoking and BMI •Epidemiology of bladder cancer in the US population
Downward-adjusted hazard ratio of 1.40 calculated for the diabetic population
SEER (Surveillance, Epidemiology
and End Result) program
FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011
•Concerns US population: only 20% of patients•Literature-based factor: subject to uncertainty •Incidence may be underestimated
Limits
Cases Dapagliflozin
Control
Total 4310 1962
Expected 2.05 1
Effective 9 1
Bladder cancers
81FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011
Further more...
Age Sex Dapagliflozin dose (mg)
Cancer grade
Diagnosis day Smoking Baseline 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+
82FDA briefing document: NDA 202293 Dapagliflozin tablets, 5 and 10mg Sponsor: BMSAdvisory Committee meeting July 19, 2011
Both sides arguments
FDA BMS/AZ
Trials not powered to distinguish the incidence of bladder cancer
Dapagliflozin may be associated with increased risk a bladder cancer
Bladder cancerIncreased surveillance of urinary symptoms with dapagliflozin = increased detection of 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.
83
Additional clinical data for a better benefit-risk assessment
Future
Action date: October 26th, 2011
Delayed action date: January 28th, 2012
Complete Response Letter: January 19th, 2012
Unexpected effects
84
New requirements
benefits
risksClinical data Pharmacological data
Reducing risk Improving benefit
Thanks for your attention