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

Nov 22, 2014

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Page 1: Getting drugs to reach the market becomes harder and harder...

Getting drugs to reach the

market becomes

harder and harder...

Antidiabetic drugs

Mélanie TiltePauline Flipo Florent ZoonekyndNicolas Bernard

Page 2: Getting drugs to reach the market becomes harder and harder...

2WHO

Diabetes worldwide

Raised fasting blood glucose, 2008 Fasting blood glucose ≥ 7,0 mmol/L or medication for raised blood glucose

Prevalence (%)

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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

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4

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

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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

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

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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

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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

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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

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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

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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

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12

Several Warnings

Safety Signals about CV events

Approval

1999

2007

Black Box Warning : Avandia may cause heart attack

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13

New Reglementation

Approval

1999

2008

CV guidelines

2007

http://www.qcclick.com/infarctus-myocarde.html

Black Box Warning : Avandia may cause heart attack

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14

Situation in 1999

METFORMIN

INSULIN

SULFONYLUREAS

ACARBOSE

MEGLITINIDES

Clinical trials fo

cus on

HbA1c

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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

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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

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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

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

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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

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20

Victoza®: LiraglutideLet’s be prudent...

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

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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

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23

Victoza® timeline

2007

August 20th: Liragutide improves glucose control and lowers body weight

2008

May 23rd: NDA filed with the FDA and Europe

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24

Clinical efficacy

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

(glimepiride)

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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

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26

Clinical efficacy

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

(glimepiride)

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27

Clinical efficacy

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

(glimepiride)

Correction of a risk factor

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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

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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

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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

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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

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32

Thyroid adverse events

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

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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

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34

Thyroid adverse events

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

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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

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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

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37

Pancreatitis

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

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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

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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

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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

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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

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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

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43

Bydureon® : Exenatide once a week

A QT story...

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

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45

Bydureon® : exenatide once a week

Exenatide : GLP-1 analog

Once monthly In Phase II

Once weekly

Twice a day

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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

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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.

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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.

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49BC October 2010

Bydureon® : exenatide twice a week

2005

April : Byetta® approval in the US

October : FDA/ICH guidancetQT study

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50FDA/ICH Guidances for industry, october 2005

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51

QT interval and hERG channel

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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

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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

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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

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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

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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

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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

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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®

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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

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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

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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

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62

And finally...January 27th, 2012

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63http://www.bydureon.com/content/pdfs/Highlighted__Information_Prescribers.pdf

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64

DapagliflozinA new strategy

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65Oral Pharmacological Agents for Type 2 Diabetes, Diabetesmanager, pbworks.com

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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%)

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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

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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+

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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.

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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

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Unexpected effects

84

New requirements

benefits

risksClinical data Pharmacological data

Reducing risk Improving benefit

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Thanks for your attention