Life Cycle Strategic Plan for Rosiglitazone (Avandia)

Life Cycle Strategic Plan

ROSIGLITAZONESubmitted for course

Drug Discovery Development amp Commercialization at UC San Diego via Coursera

December 13 2014

Role PharmD MD PhD MBA ESQLuis Fernando Duarte

de Carvalho Veronika Valdova Nir Arbel Simon Blythe

LIFE CYCLE STRATEGIC PLAN ndash PARTs 3 3459 2 1678

THE TEAM

THE TEAMPart

TITLE Author Team Role

I The Market Simon Blythe MBA

II Preclinical Development Nir Arbel PhD

III Early Clinical Development Luis Fernando Duarte de Carvalho Veronika Valdova

PharmD

IV Late Clinical Development Veronika Valdova MD

V Regulatory Strategy Veronika Valdova MD

VI Intellectual Property Strategy Simon Blythe ESQ

VII Marketing Strategy Simon Blythe MBA

VIII Sales Strategy amp Managed Markets Simon Blythe MBA

IX Final Remarks Veronika Valdova PhD

bull Insulin resistance results in increased blood glucose and development of type II diabetes

bullRosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs It works as an insulin sensitizer by binding to the peroxisome proliferator responsive elements (PPARs) receptors in fat cells DNA and making the cells more responsive to insulin

bull In turn specific genes have increased and decreased transcription with the outcome being better glucose usage by the cells

bullThe results are better Glycemic control and increased endogenous insulin production

LCSP I ndash The MARKETINTRODUCTION

DIABETES MELLITUS IS A SERIOUS DISEASEbull its complications affect about 20 million Americansbull Prediabetes affects about 86 million Americans bull Diabetes remains the 7th leading cause of death in the US

COMPLICATIONS OF DIABETESbull Hypoglycemia Hypertension Dyslipidemia Cardiovascular conditions including heart

attack and stroke kidney disease and amputationsbull Advanced glycosylation end products play a role in damaging blood vessels which can

lead to diabetes complications like neuropathy nephropathy and retinopathybull Glycosylated Hemoglobin is used as surrogate endpoint in diabetes medications studiesBiguanides and Thiazolidinediones improve insulin sensitivity as their primary effectbull Troglitazone (Rezulin) was the first drug in this class to be marketed but was removed

from the market in both the US and UK because of hepatotoxicitybull Two thiazolidinediones rosiglitazone (Avandia GSK) and pioglitazone (Actos Takeda)

are currently available in the US used as monotherapy or with sulfonylureas (SFU) metformin (MET) or insulin (INS)

LCSP I ndash The MARKETUNMET MEDICAL NEED

bull Market opportunitybull Benchmarking analysisbull Medical need -gt Burden of Disease and Competitive landscape

LCSP I ndash The MARKETMARKET ANALYSIS

Market opportunitybullType 2 Diabetes specificallybullType 2 diabetes is up to 6 times more common in people of

South Asian descentbullEstimated to be 3 times more common among those of

African and African-Caribbean originbullBMI over 25 has been estimated to account for between 60

ndash 80 of new casesbullType 2 Diabetes affects 90-95 of the 26 million Americans

affected by Diabetes Risk is said to increase in those over 45 and with overweight lack of exercise high blood pressure and family history

Benchmarking analysis

Other Thiazolidinedone members arebullPioglitazone (Actos) heart and bladder side effectsbullTroglitazone (Rezulin) withdrawn from the market due to an increased occurrence of drug-induced hepatitis

bullLobeglitazone (Duvie) approved for use in South Korea with weight gain as the main side effect

withdrawn 1997 in Europe and 2000 in the US because of hepatotoxicityInsulins not included in this overview

HYPOGLYCEMICS IN 1999GENERIC NAME LICENSE BRAND NAME APPROVA

L DATEBIGUANIDES

Metformin Bristol-Myers Squibb Glucophage 1994SECOND-GENERATION SULFONYLUREAS (SU)

Glimepiride Hoechst Marion Roussel Inc Amaryl 1999

Glyburide (Glibenclamide) Sanofi Aventis 1984Glipizide Pfizer Glucotrol 1984

MEGLITINIDESRepaglinide (Rep) NovoNordisk Prandin 1997

ALPHA-GLUCOSIDASE INHIBITORMiglitol Bayer Glyset 1996

THIAZOLIDINEDIONES (TZD)Pioglitazone (Pio) Takeda Actos 1999Rosiglitazone (RSG) GlaxoSmithKline Avandia 1999Troglitazone Daiichi Sankyo Rezulin 1997

HYPOGLYCEMICS IN 2014GENERIC NAME LICENSE BRAND NAME APPROVAL DATE

Biguanides MetforminSecond-generation sulfonylureas Glimepiride Glyburide (glibenclamide) Glipizide Meglitinides Repaglinide Nateglinide (2000)Alpha-glucosidase inhibitor MiglitolThiazolidinediones Pioglitazone Rosiglitazone Troglitazone (1997 1997 (EU) and 2000 (US)

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Vildagliptin Novartis Galvus Zomelis Jalra2007 (EU) US not approved

Sitagliptin Merck Januvia 2006Saxagliptin AstraZeneca Onglyza 2009Linagliptin Eli Lilly Co and Boehringer Ingelheim Tradjenta Trajenta 2011

Anagliptin Sanwa Kagaku Kenkyusho Co Ltd and Kowa Company Ltd Suiny Beskoa 2012 (Japan)

Teneligliptin Daiichi Sankyo Tenelia 2012 (Japan)Alogliptin Takeda Nesina 2013

Glucagon-like peptide-1 (GLP-1) receptor agonistsExenatide injection AstraZeneca Byetta 2005Liraglutide injection NovoNordisk Victoza 2009 EU 2010 US

Sodium-glucose transport proteins (SGLT2)

DapagliflozinBristol-Myers Squibb in partnership with AstraZeneca Farxiga Forxiga

2014 (NDA submitted 2011)

Canagliflozin Mitsubishi Tanabe Pharma Invokana 2013

LCSP II PRECLINICAL DEVELOPMENT Rosiglitazone PRODUCT PROFILE

bull Rosiglitazone is a Thiazolidinedione(TZD) a group of compound which are well known for their use in treating Type 2 diabetes

bull Rosiglitazone was discovered in the 1993bull Has been extensively researched in the past two decades

with over 5000 scientific publications

LCSP II PRECLINICAL DEVELOPMENT Peroxisome proliferator-activated receptor

Chandra et al 2008 Nature

Effects of TZD on PPARbull Insulin resistance is decreasedbull Adipocyte differentiation is modifiedbull VEGF-induced angiogenesis is inhibitedbull Leptin levels decreasebull Decrease in triglyceridesbull Decrease in HDL and LDL

PPAR g and RXR complex with DNA strand

bullRosiglitazone activates PPAR gamma 1 and 2 specific does not activate PPAR a

bullAssay also shows direct binding

bullHigh AffinitykD 43 nM

Lehmann et al 1995

LCSP II PRECLINICAL DEVELOPMENT MECHANISM OF ACTION

Lehmaan et al 1995

Rosiglitazone promotes differntiation of Stem cells to adipocytesTreatment with Rosiglitazone for 7 days induced expression of PPAR gand also aP2 a marker for PPAR g activity indicating Rosiglitazone as a direct Ligand

LCSP II PRECLINICAL DEVELOPMENT EFFICACY

Gao et al 2012

Simulated profiles of insulin sensitivity in GK rats For various dosing regimens

In vivo model of Control C57 mice vs KKAy diabetic mice for Insulin Sensitization

Improvement in insulin sensitivity as compared to the activation of PPAR gMice vehicle control or maximal single dose of Rosiglitazone or PNU-91325 effect of insulin sensitivity (decrease in insulinglucose) and PPAR activation indicated by ap2 expression

Antihyperglyemic activities of Rosiglitazone Trogiltazone and Pioglitazone in KK-Ay mice (BRL049653100RXE1)

bull Study was conducted on a diabetic mouse model

bull Treatment was by oral administration for 10 days at 3 dose levels

bull Statistically significant results were only indicated at highest dose levels

PTP is inhibits insulin receptor activity Although PTP1B is an appealing target for Insulin senititization Rosiglitzone showed no effect on PTP indicating that the mechanism of action is not via the Insulin receptor

LCSP II PRECLINICAL DEVELOPMENT EFFICACYTOXICOLOGY

Effects on Rosiglitazone on insulin receptor Phosphotyrosine phosphatase(PTP) actvity on liver and muscle in Diabetic mice (PF-1007BRL0496532)

LCSP II PRECLINICAL DEVELOPMENT PKPD

10 major metabolites

Conclusion CYP2C8 is primarily responsible for the hydroxylation and N-demethylation of Rosiglitazone in human liver with minor contributions from CYP2C9

17 metabolites for Rosiglitazone

No significant difference in metabolism of Rosiglitazone either via Oral dosing or IV

2 major pathways and 1 minor pathway in liver microsomes

Binding affinity of Rosiglitazone and metabolites to PPAR g Binding Affinity Agonistic potency and antidiabetic potency

bull 998 of Rosiglitazone binds to Albumin

bull Although usually a limitation quite a few approved drugs have similar availability ratio

Pharmacokinetic data for Rosiglitazone in the mouse following dietary administration for 14 days

bull Parameters indicated are dose dependant

bull Clearance and human is slowest

LCSP II PRECLINICAL DEVELOPMENT TOXICOLOGY

13 week Dose range finding (TF-1037BRL-0496531)

bull Doses were 0 04210 and 20 mgkgdaybull Mortality and clinical observation No mortality bull High dosed animals gt10 mgkgday has swelling in the scalpar areabull No effect in body weightbull Increase in brown adipose tissue in high doses for female micebull Renal and Heart weight increase at 2mgkg and 10 mgkg respectively

Conclusion Lowest observed adverse effect level is 2mgkg

Experiment was done on HealthyControl mice More significant adverse effects were usually observed on diabetic animal models

One year study of dietary Rosiglitzaone in mice (Protocol195653RSD-100HKX1)bull Mortality and clinical signs 14 mice died or were killed during treatment All deaths were claimed to be non-related to treatmentbull Body weight and food consumptionNo indication for a change in food intake however there was a slight increase of bodyweight 6-13 higher than controlbull Hematologybull Hemoglobin concentration was decreased by 13bull Organ weight Myocardial weight was increased significantly by 36 with a high

correlation between cardiac volume and cardiac wet weight indicating cardiac atrophy

bull Rosiglitazone highest potency to reduces blood glucose was in KK-Ay mice and was also active in Zucker rats and

bull Also reduces cholesterol bull No effect on Insulin receptor phosphotyrosine phosphatasebull Pharmacokinetics and pharmacodynamics were good bull Toxicology main adverse effect

ndashMinor liver toxicity ndashIndications for cardiac atrophy which in some cases were extremendashGenotoxicity assay was goodndashCarcinogenic 2 year long assay had to be repeated for a very high mortality rate due

to cardiac atrophy at high dosesndashhERG assay which test for inhibition of certain potassium channel was not required however

later publications did indicate Rosiglitazone may inhibit these channels

LCSP II PRECLINICAL DEVELOPMENT Summary of Preclinical development

LCSP III EARLY CLINICAL DEVELOPMENT Early Stage Development in Humans

IND for BRL-49653 WAS FILED in the US in 1996 PHASE 0 STUDIES No GSK sponsored Phase 0 diabetes-related studies in the GSK registry and CTgov

PHASE I STUDIES 7 Phase I GSK-sponsored studies identified in the GSK registrybull none publicly available prior to 1999bull other indications Alzheimer disease asthmabull 1 Study of CYP450 for Drug Interaction Evaluation (2009)bull 1 Study to Assess the Utility of Biomarkers to measure pharmacodynamics (2007)bull 2 Studies to assess PK of new formulationsbull 1 Study to evaluate the effect of XR Rosiglitazone on cardiac conduction (2009)

PHASE II STUDIESbull 4 Phase II studies were identified in the GSK registry none prior to 1999bull 3 of them studied Alzheimer disease and 1 rheumatoid arthritis

Source of information on Mechanism of Action and PKPD Avandia Package InsertVV

LCSP III EARLY CLINICAL DEVELOPMENT GSK SPONSORED PHASE I STUDIES

GSK SPONSORED PHASE III STUDIES LCSP III EARLY CLINICAL DEVELOPMENT

GSK SPONSORED PHASE II STUDIES

LCSP III EARLY CLINICAL DEVELOPMENT Mechanism of Action

bull Rosiglitazone improves glycemic control by improving insulin sensitivity

bull Rosiglitazone is a highly selective agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ)

bull Rosiglitazone reduces blood glucose concentrations and hyperinsulinemia in obese mouse diabetic mouse and fatty Zucker rat

bull Antidiabetic activity of rosiglitazone is mediated by increased sensitivity to insulinrsquos action in the liver muscle and adipose tissues

bull rosiglitazone inhibits hepatic gluconeogenesis The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue

bull Rosiglitazone did not induce hypoglycemia in animal models

LCSP III EARLY CLINICAL DEVELOPMENT Pharmacodynamics

AVANDIA was associated with increases in total cholesterol LDL and HDL and decreases in free fatty acids

The changes in triglycerides during therapy with AVANDIA were variable and were generally not statistically different from placebo or glyburide controls

LCSP III EARLY CLINICAL DEVELOPMENT Pharmacokinetics

bull Maximum plasma concentration increases in a dose-proportional manner over the therapeutic dose range The elimination half-life is 3 to 4 hours

bull Absorption Bioavailability is 99 with highest concentration 1 hour after oral administration AVANDIA may be administered with or without food

bull Distribution Rosiglitazone is 998 bound to plasma proteins primarily albuminbull Metabolism Rosiglitazone is extensively metabolized via N-demethylation and

hydroxylation and then conjugation with sulfate and glucuronic acid RSG is mainly metabolized by Cytochrome P450 isoenzyme 2C8 Alternative pathway is 2C9

bull Excretion 64 of the dose is eliminated in the urine and 23 in the feces

bull Therapy with AVANDIA should not be initiated in patients with liver impairment bull PK of rosiglitazone is not affected in patients with renal impairment including heodialysisbull Race has no influence on the pharmacokinetics of rosiglitazone

bull No clinically relevant effect on PK of drugs metabolized by CYP3A4 (nifedipine)bull CYP2C8 inhibitors (gemfibrozil) increase levels of RSGbull CYP2C8 inducers (rifampin) decrease levels of RSG VV

bull Databases registries librariesbull Pivotal studiesbull Overview of Rosiglitazone clinical trials

ndash Interventional studies by phase and sponsor (ClinicalTrialsgov)ndash Observational studies by phase and sponsor (ClinicalTrialsgov) (ClinicalTrialsgov)ndash All RSG studies by phase and sponsor (ClinicalTrialsgov)ndash All RSG studies by location (ClinicalTrialsgov)ndash GSK sponsored Phase III studies for T2DM (ClinicalTrialsgov)ndash Phase III studies for T2DM (GSK registry)ndash Phase III interventional studies for T2DM conducted by other industry sponsorsndash Number of subjects enrolled in clinical trials by condition

bull Clinical studies ndash 10000 ft perspective (global context)ndash Clinical trials sponsored by Industry ndash Clinical trials by sponsor and locationndash Clinical trials sponsored by NIH ndash Clinical trials sponsored by other federal agencies

LCSP IV LATE CLINICAL DEVELOPMENT

DATABASES REGISTRIES LIBRARIES

178738 studies in all 50 states and in 187 countriesFunctional since 1999

ROSIGLITAZONE231 studies identified 217 interventional trials 14 observational trials 56 sponsored by GSKTime period April 1998 to 11112014

GALE Cengage Academic OneFileACADEMIC PAPERSTime period 01011998 to 21102014no hits prior to 01011998ldquoRosiglitazonerdquo 401 papersldquoBRL 49653rdquo 19 papers PubMed Over 5000 hitsTotal hits in PubMed gt5000

GSK sponsored studies 45 studies identified Phase I 7Phase II 4Phase III 16 Phase IV 14na 4

24297 clinical trials with a EudraCT protocol

All CTs in EEA since 52004

65 studies identified

Time period 52004 to 112014

bull Content overlaps no database can be used as a single sourcebull Results often not posted bull Publications not clearly linked to clinical studies bull Wide variety of designs and biases makes population projections challenging bull No pre-approval studies in the registries bull No or minimum records before 1999 GSK registry contains summaries

ICTRP contains CT data from CTgov EU and major national registries (India China Japan Brazil Africa the Netherlands etc)381 records for 281 trials found for rosiglitazoneNo trials prior to 1999First record 12000

bull Pivotal studies (vs placebo comparator) bull Long term safety studies for registrationbull Local registration studiesbull Phase IIIA extension studiesbull Post marketing study commitments

bull Studies intended to support publication claims or to prepare launch which start before approval but are not intended for Regulatory submissions

PIVOTAL STUDIES

Phase IIIAA Pivotal study that is a trial designed amp executed to get statistically significant evidence of efficacy and safety as required by HAs for NDA approval - Studies aimed to include claims into the

label - Post-marketing commitments

Phase IIIBA study started prior to approval and whose primary intention is support of publications rather than registration or label changes The results are not intended to be included in the submission dossier

PIVOTAL STUDIES NDA submission

ROSIGLITAZONEmonotherapy

ROSIGLITAZONE + METFORMIN MEDICAL REVIEW 011 CV SAFETY

AVANDIA Group CONTROL Group Studies from the GSK registry Study ID Patients CV Death Patients CV Death MEDS Study Period Publications49653011 357 1 176 0 RSG v PBO 91996 ndash 91997 2049653015 395 2 198 0 RSG v PBO 81996 ndash 31998 7

49653020 391 0 207 0 RSG v glibenclamide 101996 ndash 51998 14

49653024 196 0 RSG v PBO 011997 -021998 1149653079 203 1 106 1 RSG PBO SFU 41997 ndash 31998 049653093 213 0 109 0 RSG+MET PBO MET 61997 ndash 41998 349653094 232 1 116 0 RSG+MET PBO MET 41997 ndash 31998 849653095 196 1 96 0 RSGINS PBO 81997 ndash 121998 Not stated

Ethical concerns during NDA review ndash Consent form

PIVOTAL STUDIES

Study submitted with the NDA

Widely publicized studies

2mg-4mg-8mgodbdDaily dose 4-8mgFilm-coated tablet

26-WeekR - DB - SET - PBO-controlled Non-insulin Dependent DMRSG 2mg bd RSG 4mg bd PBOE1 HbA1c after 26 weeksE2 FPG fructosamine serum lipids immunoreactive insulin urinary albumincreatinine HbA1c and FPG respondersRESULTS HbA1c FPGRSG takes about 12 weeks to show full effectInclusion FPG 140-300mgdl after withdrawal from previous therapyExclusion liver chemistry over 25 x ULN Dr Fiddes (FDA probe)Demographic 75 Caucasians 65 65+ yr Male 74 BMIgt27Ethical concern informed consent for previously treated DM patients

52-WeekR ndash DB ndash PKSET ndash active controlType 2 DMRSG 2mg-4mg bd glibenclamide

PK week 4 26 and 52E1 HbA1c after 52 weeks E2 same as Study 011

RESULTS HbA1c levels fell in all groups

glyburide works quicker than RSG Insulin and proinsulin levels rose

in glyburide patients but fell in RSGLipids Total cholesterol LDLHDL

and Apo B rose in patients on RSGBody weight increase on RSGHypoglycemia more common

with glyburide ndash led to drop outs Anemia Drop in Hb Ht on RSG

Population 65 60+ yrs M BMIgt27 DM duration 6 years

26-WeekR ndash DB ndashSET ndash PBO-controlledNIDDMPBO v RSG 4mg od 2mg bid 8mg od 4 mg bid (5 arms)

E1 HbA1c after 26 weeks E2 same as Study 011

RESULTS 8 mg RSG is approximately as

effective as monotherapy4 mg RSG appears somewhat less

effective (HbA1c and FPG) RSG increased body weight and

lipids

Safety issue Cardiovascular events Myocardial infarction coronary artery disorder (RSG group)

ROSIGLITAZONE MONOTHERAPY

STUDY 011 STUDY 020 STUDY 024

26-Week R ndash SBDB ndash EST ndash Active controlTreatment RSG+MET MET RSGSB MET RSG+PBODB RSG-PBO + 10 cps MET 250mg RSG 4mg bd + 10 cps MET-PBO RSG 4mg bd + 10 cps Met 250 mg

NIDDM inadequately controlled on MET 25mgdayE1 HbA1c after 26 weeks E2 the same as 011 Population imbalance ndash white obese males Results RSG+MET superior to either monotherapy MET was better than RSG monotherapy Patients on RSG gained weight Lipids LDLHDL and VLDL increased more on RSGSafety Anemia more on RSG+MET than RSG

26-WeekR ndash DB ndash EST - Parallel ndash PBO-controlledRSG 4mg od +MET 5x500mg MET RSG 8mg od MET 5x500mg MET PBO+METTreatment RSG+MET MET+PBO NIDDM inadequately controlled on MET 25mgdayE1 HbA1c after 26 weeksE2 Same as Study 011

Population 80 Caucasian 78 75 Male BMI gt 27 low risk

Results Greatest reduction of HbA1c in patients who were previously on diet only Weight gain in patients on RSG Safety The combination of RSG + MET is better than MET alone for hyperglycemia but is associated with weight gain and rise in LDL cholesterol and VLDL

Anemia more prominent with RSG+MET

ROSIGLITAZONE + METFORMIN

STUDY 093 STUDY 094

Phase 4 commitment to conduct a long-term (4-year) safety and efficacy study ADOPT compared to MET or glipizide in drug-naiumlve patients with recent onset of diabetesbull beta-cell insulin secretion bull Long-term safety ALT profile CV and hematologic events body weight serum lipids The final draft protocol is due by 91999 and the study will be initiated by 32000

Validation of the regulatory methods not yet completed Policy is not to withhold approval

RSG RSG+MET is a safe and effective treatment for HYPERGLYCAEMIAbull Efficacy persists for at least 12 months wo deterioration bull Long-term improvement in HbA1c reduces risk of retinopathy nephropathy and neuropathybull Pediatric studies were not part of the application and shall be submitted by 122000

MAJOR SAFETY ISSUES Liver toxicity No evidence of hepatotoxicity reason for caution TroglitazoneEdema RSG 2673172 patients (2-3x higher than other groups) Class effect Contributes to CHF Hematologic disorders Anemia myelodysplastic syndrome after 60 days Cardiovascular disorders

Acute Myocardial infarction chronic heart failureCardiomegaly in animal trials

Serum lipids Consistent increase in total HDL and LDL cholesterol VLDLIncreased body weight CV risk factorUpper respiratory infections injury Ethical issues Consent form in Study 011

PIVOTAL STUDIES ndash MEDICAL REVIEW

Low risk populationSAEs unrelated to study medication

011 Exclusion criteria bull Renal disease bull Hepatic disease bull Anginabull NYHA class IIIIV cardiac

insufficiency

CV side effects The signal was picked up by FDA medical reviewer PM safety study was demanded as condition of approval ADOPT study shall answer questions about Avandia CV safety

SAEs from study 49653011

ADOPT study completed in 82006 submitted to FDA together with preliminary results from RECORD no elevated risk

RECORD requested by EU regulators design limitations

STUDY 011 CARDIOVASCULAR SAFETY

Interventional studies by phase and sponsor

ClinicalTrialsgov

Observational studies by phase and sponsor

ClinicalTrialsgov

All RSG studies by phase and sponsorClinicalTrialsgov

All RSG studies by location

ClinicalTrialsgov

GSK sponsored Phase III studies for T2DMClinicalTrialsgov

Phase III studies for T2DM

GSK registry

Phase III interventional studies for T2DM

Conducted by other industry sponsors

Number of subjects enrolled in clinical trials by condition

OVERVIEW OF ROSIGLITAZONE CLINICAL TRIALS

Source ClinicalTrialsgov (11112014)

AVANDIA INTERVENTIONAL STUDIES BY PHASE amp SPONSOR

SPONSOR PHASE 0 I II III IV naIndustry 0 0 0 0 6 0Other 0 0 0 0 1 2NIH 0 0 0 0 0 2Other Industry 0 0 0 0 0 1

US Federal 0 0 0 0 0 1US Federal Other 0 0 0 0 0 1

Number of subjects by condition and number of enrolled subjects

AVANDIA OBSERVATIONAL STUDIES BY PHASE amp SPONSOR

LOCATION OF CLINICAL STUDIES FOR ROSIGLITAZONE

Source Condition T2DM Sponsored by

GLP = glimepirideRSG = rosiglitazoneGZ = glipizideSU = sulfonylureaGLY = glyburideGBC = glibenclamidePBO = placeboPGZ = pioglitazoneINS = insulin

R = randomizationSE = SafetyEfficacy studyE = Efficacy studyS = Safety studyPA = Parallel AssignmentSG = Single Group AssignmentCO = Cross Over AssignmentOL = Open labelDB = Double blind

RECORD

GSK SPONSORED PHASE III STUDIES

PHASE III STUDIES ndash GSK REGISTRY

PHASE III STUDIES CONDUCTED BY OTHER SPONSORS

Safety concern

NUMBER OF STUDY SUBJECTS BY CONDITION

Clinical trials sponsored by Industry Clinical trials sponsored by NIH

Clinical trials sponsored by other federal agenciesClinical trials by sponsor and location

Source of data ClinicalTrialsgov

CLINICAL STUDIESndash10000 ft PERSPECTIVE

LCSP V REGULATORY STRATEGY

bull Summarybull Timelinebull NDA filing bull US labelling bull EU labellingbull National essential medicines listsbull New indications testedbull Post-market studies and publicationsbull Phase IV safety and efficacy bull Comparative safety and efficacy (WHO)bull Large Phase IV trials of RSG

ndash DREAMndash ADOPTndash RECORD ndash BARI 2D ndash 113332ndash TIDE

bull Pharmacoeconomics bull Important meta-analysesbull Epidemiological studies bull Signal detection in pharmacovigilancebull Dr Nissenrsquos meta-analysis bull Congressional hearing bull US Senate Finance Committee report bull GSK pled guilty paid criminal fine bull FDA restrictionsbull REMSbull GSK risk mitigation strategybull Post-market surveillance 2014

SUMMARYAVANDIA (rosiglitazone) was approved in the US for the treatment of diabetes in 51999

Another drug from the same class REZULIN (troglitazone) was already withdrawn from the market because of liver toxicity in 2000

In May 2007 concerns over AVANDIA cardiovascular safety caused public scandal- Dr Steve Nissen published meta-analysis of available studies in NEJM- The manuscript was leaked to the drugrsquos manufacturer GlaxoSmithKline- Congressional hearing on FDArsquos role in Avandia safety evaluation - US Senate Finance Committee launched extensive investigation FDA demanded

inclusion of numerous warnings on the drug label later that yearIn 22010 US Senate Finance Committee released report on GSK actions In 92010 the FDA severely restricted Avandia use requested independent review of RECORD trial and demanded GSK to amend REMS EMA suspended Avandia saleIn 62011 French and German Agencies suspended the use of ACTOS (pioglitazone)In 112011 Avandia-Rosiglitazone Medicines Access Program implemented as part of REMSIn 72012 GSK agreed to plead guilty and pay $3 billion to settle criminal and civil liabilityIn 2012 GSK agreed to pay $700 million to settle more than 15000 patientsrsquo claimsIn 2013 the FDA restrictions on Avandia were lifted

111998 NDA

FDA Approval

FDA Restrictions on Avandia prescription and dispensingregulatory decisions on RECORD and TIDE trials

PATENT EXPIRATION

Nissenrsquos Meta-analysis published in NEJM

Congressional hearing on FDArsquos role in evaluation of safety of Avandia

US Senate Finance Committee Investigation

FDA requires removal of the

2010 prescribing and dispensing

restrictions

GSK pled guilty to criminal misconduct paid a $3 billion fine

1996 IND

LABELLING

TIMELINE

STUDIES

Dr Buse voiced concerns over Avandiarsquos CV safety

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

NDA FILINGUSACanadaEurope

bull At initial filing over 4327 patients and 500 volunteers were exposed to RSG RSG+MET or RSG+SFU for period up to 18 months

bull gt2600 patients for +6 monthsbull 1005 patients for +12 monthsbull 222 patients exposed to RSG in long-term echocardiography studies

bull Priority review requested based on excellent efficacy and safety profile grantedbull Indication T2DM

INDICATION bull Monotherapy for the treatment of hyperglycemia in patients with type 2 diabetes

who are inadequately controlled by diet and exercisebull As combination therapy with metformin for the treatment of hyperglycemia in

patients with type 2 diabetes who are inadequately controlled by metformin monotherapy

APPROVED in the US on May 25 1999

NDA FILED on November 24 1998

Boxed Warning Congestive heart failure myocardial ischemiaIndications RSG + insulin and nitrates not recommendedContraindications NYHA IIIIV heart failureWarnings Cardiac Failure Myocardial Ischemia Fractures

Boxed Warning myocardial infarction (instead of ischaemia)Indications RSG + with insulin and nitrates not recommendedContraindications NYHA IIIIV heart failureWarnings Cardiac Failure Myocardial Ischemia Fractures

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Proposed For the treatment of T2DM as monotherapy and in combination with metforminApproved Monotherapy as an adjunct to diet and exercise in combination with metformin

+ combination with sulfonylurea

+ combination with insulin Warning can cause fluid retention which may exacerbate or lead to heart failure

+ combination with metformin plus sulfonylurea

Patients who are already taking AVANDIA or are unable to achieve adequate glycemic control on other diabetes medications and have decided not to take pioglitazone for medical reasons Patient counseling information and medication guide

REMS Access program

Boxed Warning AVANDIA-Rosiglitazone Medicines Access Program removal Indications patient population restrictions removalWarnings Cardiac Failure MACE Rosiglitazone REMS Program removal

NDA 111998 Phase IIIIIbull 4598 patientsbull 3673 patient years of exposure

AVANDIA US LABELLING CHANGES 1999-2014

AVANDIA CURRENT US LABELLING

EU SAFETY UPDATES Product name AVANDIAProduct no EMEAHC000268II0023

REJECTED IN the EU 1999 APPROVED in the EU on July 11 2000

EU LABEL UPDATES Product name AVANDIAProduct no EMEAHC000268II0023

TRIPLE THERAPY STUDIES (2005 review)

MA suspended in September 2010VV

Source Comparative Review of Oral Hypoglycemic Agents in Adults Section 185 Harinder Chahal for WHO Secretariat

NATIONAL ESSENTIAL MEDICINES LISTS (NEML)

RESPIRATORY (4 trials phases 0 I II IIIII) bull Asthma (3) lung inflammation (1)

MUSCULOSKELETAL (4 trials phase II) bull Bone density (3) rheumatoid arthritis (1)

ONCOLOGY (11 trials phases I II III) bull Prostate AC bladder cancer RCCbull Head and neck cancer thyroid cancerbull T-Cell lymphoma mycosis fungoidesbull Solid tumors sarcoma breast cancerbull Brain and CNS tumors

CNS (11 trials phases I II III) bull Alzheimer disease cognitive impairment (15)bull Schizophrenia (1) depressionbipolar (1)

Uro-genital (11 trials phases I II IIIII III) bull Glomerulosclerosis (2) nephropathy (4)bull Kidney transplant (1)bull Polycystic ovary syndrome (3) bull Endometriosis (2)

GIT (7 trials phases III II III IV) bull IBD ulcerative colitis (3)bull Fatty liver (4)INFECTIONS (16 trials phases I III II IV) bull HIV associated mtb syndrome (11)bull Malaria (2) Hepatitis C (3)

OTHER (5 trials phases I II III) bull Cushingrsquos disease (1)bull Cystic fibrosis (1)bull Erectile dysfunction (1)bull Chemotherapy-induced nausea (1)bull Multiple organ failure (1)

HEALTHY VOLUNTEERS (11 trials phase I)

NEW INDICATIONS TESTED 1999 Type 2 Diabetes Mellitus

SmithKline Beecham (2000) GlaxoSmithKline

bull At least 165 articles in scientific journals

bull 23 studies ndash number of publications by the company not stated

bull 9 studies not published at allbull 3 studies published extensively

STUDY ID Publications49653011 2049653020 1449653080 1249653024 1149653094 849653015 749653048 (ADOPT) 649653127 6BRL-049653231 (RECORD) 5AVD107642 (DREAM) 5

bull Extensive selective publication of some studies models PERCEPTION within the scientific community

bull Aggressive marketing in popular press drives demand

bull Off-label marketing and direct to consumer advertising were important topics in the 62007 Congressional hearing as one of the key issues addressed via False Claims Act

bull Corporate free speech (US v Caronia 2012) blurs the issue

bull Dr Buse and Dr Nissen both intimidated by GSK for publishing their concerns threatened by lawsuits

bull Federal state and civil lawsuits against GSK regarding illegal marketing failure to report certain safety information and pricing issues

BLURRED LINE BETWEEN SCIENCE amp MARKETING

POST-MARKET STUDIES amp PUBLICATIONS

Refinement of target population for the treatment of T2DM amp Metabolic Syndrome

Cardiovascular safety amp efficacy studies

bull Angina pectoris amp Metabolic syndrome bull Congestive heart failurebull Coronary artery diseasebull Dilated cardiomyopathybull Inhibition of Platelet Aggregation bull Atherosclerosisbull Strokebull Hypercholesterolemiabull Ischemia-Reperfusion Injurybull Hypertension

bull T2DMbull Impaired Glucose Tolerancebull Type 1 Diabetes in teenagersbull Dyslipidemiabull Diabetic nephropathybull Pre-diabetesbull Metabolic Syndromebull Non-alcoholic Fatty Liver Diseasebull Obesity Adipose Cell Turn Overbull Insulin Resistancebull Latent Autoimmune Diabetes in Adults

PHASE IV SAFETY amp EFFICACY

COMPARATIVE EFFICACY amp SAFETY OF ORAL HYPOGLYCEMICS

LARGE PHASE IV TRIALS OF RSG ADOPT and DREAM do not support the CV mortality trend AMI shows trend RECORD (4447 patients with T2DM)bull EMA request Open-label comparison of RSG v MET+SFU + Other drugs bull SAEsSUSARs identified by a CRO ndash Quintiles sent to a blinded adjudication committeebull bias toward the desired finding of ldquono differencerdquobull Many CV deaths ldquounattributedrdquo to case under-referral in RSGbull There is a reduction in stroke No suggestion of any excess mortalitybull AMI criteria not sensitive enough To evaluate the AMI finding properly we will need to

adjudicate essentially all hospitalizations NFMI would remain a concernUnblinded studies with MACE endpoints are common in devices surgery and oncologyBARI 2D was a comparison of insulin sensitization (IS) approaches (MET glitazones) with insulin provision (IP) approaches (INS SFU) Slightly favorable result of the IS group vs IPLarge studies at worst a very modest effect on AMI and a favorable trend on MACE

BARI 2D113332

ADOPT RECORD

TIDEVV

The DREAM study evaluated the likelihood of progression to T2DM over a 3-year median follow-up period among 5269 people with impaired fasting glucose or impaired glucose tolerance

SPONSOR Gerstein Hertzel MD CONDUCTED BY the Population Health Research Institute at the Michael G DeGroote School of Medicine at McMaster University and Hamilton Health Sciences in Hamilton Ontario CanadaFUNDING Canadian Institutes of Health Research GlaxoSmithKline Sanofi-Aventis amp King Pharmaceuticals (Pfizer)TREATMENT RSG PBO RAMIPRILbull Primary Outcome Measures DIABETES DEATHbull Secondary Outcome Measures Myocardial infarction (MI) Stroke Congestive Heart Failure Angina

Revascularization procedures Ventricular Arrhythmia Renal Events

RESULTS bull Participants on RSG were significantly less likely to have developed diabetes compared with PBO bull No significant reduction in the incidence of death was observed RSG had beneficial effect on blood pressure

bull RSG group showed increased incidence of heart failure and other CVS events heart attacks (15 on RSG v 9 on PBO) ndash did not reach statistical significance but trending in the wrong direction

PRACTICE POINT Rosiglitazone is not recommended for diabetes prevention as it is not superior to evidence-based lifestyle intervention there are also concerns about the high costs and long-term safety of this pharmacologic treatment (Tuomilehto 2007)

DREAM Start Date July 2001 Completion Date September 2006 NCT00095654 Gerstein Hertzel MD

Diabetes REduction Assessment With Ramipril and Rosiglitazone Medication

ADOPTStart 92000 Completion

82006Observational study | Study No BRL 49653048|NCT00279045

A Diabetes Outcome Progression Trial Diabetes Study With Rosiglitazone Monotherapy Versus Metformin Or

GlyburideGlibenclamide

A Randomized Double-Blind Study to Compare the Durability of Glucose Lowering and Preservation of Pancreatic Beta-Cell Function of Rosiglitazone Monotherapy Compared to Metformin or GlyburideGlibenclamide in Patients with Drug-Naive Recently Diagnosed T2DM

Study Design Multicenter international randomized double-blind active control

Treatment RSG GLYGLIB or MET - 473 centers Enrollment 4100 SPONSOR GlaxoSmithKlineRequested by the FDA as condition of approvalLong term efficacy compared to other drugs ES including hepatic (Troglitazone had liver toxicity issues) CHF CV hematological changes of weightOutcome Measures Time from randomization to monotherapy failure Fractures were not one of the pre-defined categories aFINDINGS RSG improved diabetes CVS events trending in the wrong direction Heart attacks ndash 33 greater no statistical significance a higher risk of fractures in diabetic women randomized to RSGnd were summarized on a post-hoc basis

A long term open label randomised parallel group study in patients with T2DM comparing the combination of RSG and either MET or SFU with MET plus SFU on cardiovascular endpoints and glycaemia

Treatment 6 yearsEnrollment 4 447 SPONSOR GlaxoSmithKline

Study requested by EMAbull Primary Outcome Measures CV DEATH DEATH MI (fatal and non-fatal) CV hospitalization MACE strokebull Secondary Outcome Measures CRP cholesterol and lipid profile HOMA Beta cell function insulin sensitivity CV

hospitalizations and deaths insulin therapy all-cause deaths cancer-related event and death blood pressure (SBPDBP) bone fractures glycemic failure events Hb1A1c ALT insulin and pro-insulin urinary albumincreatinine FPG fibrinogen change in body weight plasminogen activator inhibitor-1 Ag

Safety issues NoneRECORD Follow-up (2008-2012) Blinded Re-adjudication of Mortality and MACE from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of glycaemia in Diabetes trial (RECORD)bull Start January 2011bull Completion February 2012 bull Primary Outcome Measures CV Mortality and All cause mortalitybull Secondary Outcome Measures MACE MI Stroke

RECORD

Start April 2001 Completion December 2008

BRL-049653231 | NCT00379769| Overseen by MHRA

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes

SAFETY ISSUE NO

Study Design Multicenter international randomized double-blind active control The primary aim to test the treatment efficacy in patients with T2DM and documented stable CAD in the setting of uniform glycemic control and intensive management of all other risk factors

bull Coronary Revascularization Hypothesis a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone

bull Method of Glycemic Control Hypothesis with a target HbA1c level of less than 70 a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year and mortality compared to a strategy of insulin provision

bull SPONSOR University of Pittsburgh | COLLABORATORS NIH (NHLBI NIDDK) |Enrollment 2368bull FINDINGS Mortality risk is the same for patients with T2DM and stable ischemic heart

disease whether they are managed with optimal medical therapy CABG surgery or PCI bull 45 Publications

BARI 2DStart 92000 Completion 32009 NCT00006305

Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes

Trials DREAM ADOPT RECORD and BARI 2D were closely examined at the Joint meeting of the EMDAC and DSRMAC on July 30 2007 on Avandia with respect to cardiac ischemic risk identified in the meta-analysis

It is hypothesized that spironolactone reduces the risk of fracture in TZD treated patients Amiloride was included as a comparator in an attempt to explore if the beneficial effect of spironolactone on fractures is unique to its steroid receptor binding properties or if it is related to the common effect on ENaC which is a ubiquitous channel found in a variety of tissues including the kidney and bone cells

Study Design Case-control study nested within a T2DM cohort exposed to TZD for 6 or 12 months compared to data from the US health claims database the INGENIX Impact National Managed Care Database

Enrollment 98483 SPONSOR GlaxoSmithKline

EXPOSURE MEASURES TZD only (RSG PIO or troglitazone) TZD + spironolactone TZD + amiloride Other

Start May 2009 Completion March 2010 Observational study | Study No 113332 | NCT01055223

The association between exposure to SPIRONOLACTONE or AMILORIDE and FRACTURE RISK among subjects treated with THIAZOLIDINEDIONES

Outcome Measures Insurance claims - low impact fractures fractures of hand foot upper arm amp wrist hip fractures

FINDINGS SPIRONOLACTONE DOES NOT REDUCE THE RISK OF FRACTURE IN TZD TREATED PATIENTS NO CONSISTENT TREND IN FRACTURE RISK WAS OBSERVED FOR TZD+SPIRONOLACTONE COMPARED TO TZD

STUDY TITLE Type Enrolled Start Completion

Fracture Risk With Thiazolidinediones OBS 98483 52009 32010Study In Postmenopausal Women With Type 2 Diabetes Looking At Approved Diabetes Drugs And How They Affect Bone Health

INT 226 42008 92010Bone Turnover in Type 2 Diabetes Patients INT 20 82008 82010The Effect of Glitazone Treatment on Bone Marrow and Bone Marrow Cells INT 57 12008 112009Effect of Diabetic Medications on Bone Metabolism OBS 280 102006 92009Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women INT 82 62005 22007Insulin Resistance Polycystic Ovary Syndrome and Bone Research Study

INT 75 32005 122015

A Multicenter Randomized Double-Blind Placebo Controlled Trial of a Thiazolidinedione or Placebo and of Vitamin D or Placebo In People With Type 2 Diabetes at Risk For Cardiovascular Disease Study Design Long-term CV outcomes trial to assess if the addition of TZD to the therapeutic regimen of a T2DM patient would reduce the risk of CV outcomes and if the addition of vitamin D would reduce total mortality andor serious cancer in people with T2DM who are at high risk for CV disease

Primary outcomes TZD CV death non-fatal MI non-fatal stroke | Vitamin D death or serious cancer Secondary outcomes All-cause mortality components of the composite outcomes retinopathy vitrectomy renal and liver impairment any hospitalization for CHF shortness of breath pneumonia or angina revascularization fracture cancer cognitive decline erectile dysfunction and quality of life

On 9232010 the FDA placed the TIDE trial on full clinical hold The study was terminated in 112010

TIDEStart May 2009 Completion TERMINATED 92010 NCT00879970 | 111960

Thiazolidinedione Intervention with vitamin D Evaluation

Treatment TZD (RSG 8mg PIO 45mg) or PBO and vitamin D or PBO for up to 55 years for TZDs and for up to 10 years for vitamin D RSG PIO and PBO allocated in 303040 ratios

bull Rosiglitazone was suspended in the EU and restricted in the US and Canada in 2010 bull In 2013 FDA lifted the restrictions on Avandiabull Pioglitazone suspended in the EU because of risk of bladder cancer

PHARMACOECONOMICS

ORIGIN - Outcome Reduction With Initial Glargine InterventionDrs Hamid and Simmons comment on two positive aspects that favor the use of insulin glargine over rosiglitazone as add-on therapy in T2DM patients who are inadequately controlled on SFU+MET

bull SFU+MET+RSGbull SFU+MET+Insulin Glargine

bull Neutral effect on LDL levels (+14 with insulin glargine v +131 with rosiglitazone) bull Reduction in triglyceride levels (-19 with insulin glargine v +46 with RSGbull ORIGIN A large (n = 12612) ongoing cardiovascular outcomes trial will assess whether

insulin glargine can reduce CV risk in people with early dysglycemia lipid levels will be assessed in conjunction with the primary end point of cardiovascular outcomes

Costs of both rosiglitazone and insulin glargine were based on actual study medication usage by all patients during the trial average wholesale price for insulin glargine was $4699 at the time of the study analysis resulting in actual cost of $21600 per patient as reported

Robert Temple in response to the FDA Action Committee meeting on RSG July 13 2010Endpoints of interest MACE and its components ndash CV death NFMI non-fatal stroke

Nissen Meta-analysis pooled 42 relatively small studies with ADOPT and DREAM bull Small studies higher CV mortality with a trend on NFMI The finding occurs early bull MACE CV death and AMI were not considered (could not tell patients from events)

FDA meta-analysis (42 trials 2007 52 trials 2010 ndash 17000 patients)bull AMI (significant) mortality - CV and overall (trending) bull MACE (not statistically significant) CV and overall mortality (not close)bull Stroke trends favorably for RSGbull Survival (no significant effect)bull Increased LDL caused by RSG a long-term concernFDA does not use meta-analyses as a proof of efficacy but use them to assess safety

Meta-analysis by Mannucci (164 short-term RSG trials 43000 patients) bull OR CV death 093 total death 094 NFMI of 114 similar to RECORD bull ADOPT and DREAM 2 largest studies to date did not find excess CV death+AMI WHO comparison

IMPORTANT META-ANALYSES ON RSG

bull Apparent advantage of PIO over RSG for important endpoints (CV mortality stroke heart failure) in 3 epidemiologic studies

bull Fourth study (WellPoint) shows no advantage for PIObull Uncertain meaning of studies reporting very small differences (less than 15)bull RSG v other anti-diabetics ndash AMI and all-cause mortality do not appear worsened by

RSG For CHF RSG is inferior to other drugs bull RSG v PIO no controlled trial only epidemiologic No significant increase of AMI for

RSG Epidemiological methods have long history of incorrect conclusions so the results shall be interpreted with caution

bull Adverse trend regarding increase AMI persists CV and total mortality seems no worse than other treatments

EPIDEMIOLOGIC STUDIES

bull AVANDIA False Negative v Correct Rejection v False Alarm v HITbull Weak signal on high noise background + lot of confounding factors (no clearimmediate link) bull -- gt Different methods comparison of data from large populations

X1 = Background risk due to Disease (and comorbidities)X2 = Risk resulting from combination of X1 and InterventionX1 ndash X2 = increasedecrease in relative risk

HIT = Correct detection (signal present detected)FN = False negative (miss) (Signal present undetected)FA = False Alarm (Signal detected although not present)Correct rejection (noise signal absent)

Quantification of risk requires pharmaco-epidemiological tools

Signal + Noise

Criterion x

CORRECTREJECTION

hellipREAL TIME RESULTS NEEDED

bull Well-designed large post-market studiesbull Pharmaco-Epidemiological studiesbull Data from target population (high risk) bull Data from patients with multiple comorbidities

SIGNAL DETECTION IN PHARMACOVIGILANCE

Published in May 2007 triggered by publication of DREAM which showed increased CV events Examined data from GSK studies registry at study level not patient levelIdentified increased potential risk of heart attack with Avandia CV Safety not a new concern

ndash FDA required post-market study as condition of approval worried about CHF and hepatotoxicityndash Dr Buse (2000) worried about Avandia effects on cholesterol and lipid profilendash WHO issued a warning on CV safety of TZDs in 22003ndash In 2005 GSK conducted internal review of CV safety found increased risk of myocardial ischemia

CONSEQUENCESbull The issue was widely publicized in both scientific and popular press popular demand to withdraw the drug bull Attacks against Dr Nissen and Dr Buse questioning their motivations and professional integritybull 62007 Congressional hearing both Dr Buse and Dr Nissen testified just like FDA officialsbull Both FDA and GSK both performed their own patient-level meta-analyses Very similar findings not

published communicated to the HR Committee under Oath in 62007 bull US Senate Finance Committee investigation (report 22010)

DR NISSENrsquoS META-ANALYSIS

Committee on oversight and government reformHouse of Representatives 110th Congress First Session | June 6 2007 | Serial No 110-76

WITNESS STATEMENTS Steven Nissen Department of Cardiovascular Medicine Cleveland Clinic John B Buse University of North Carolina School of Medicine Bruce M Psaty CV Health Research Unit University of WA Center for Health Studies WAMoncef M Slaoui chairman research and development GlaxoSmithKlineAndrew von Eschenbach John K Jenkins Gerald Dal Pan Food and Drug Administration

KEY POINTS bull DM is a serious disease false alarm would cause harm to patientsbull Avandia lowers blood glucose but there are concerns about CV safety (CHF MI lipids)bull Large PM study a condition of FDA approval but did not insist on it (ADOPT TIDE)bull CV safety repeatedly questioned (Dr Buse WHO DREAM trial Dr Nissen)bull RECORD study required by EMA Results inconclusive completed 2009bull AVANDIA case study for reform of post-market surveillance bull FDA needs more resources preferably from public funds rather than PDUFAbull Post-market surveillance should be moved to a different groupbull How effective is FDA in collecting and analyzing data how sensitive these tools arebull Direct to consumer advertising a serious issue not enough resources to address that

Intimidation of Dr Buse ndash ldquoAvandia Renegaderdquo by GSK in relation with Avandia CV safety was brought to the US Senate Finance Committee in November 2007

FDArsquoS ROLE IN THE EVALUATION OF AVANDIA SAFETY

ldquoAmericans have a right to know there are serious health risks associated with Avandia and GlaxoSmithKline had a responsibility to tell them Patients trust drug companies with their health and their lives and GlaxoSmithKline abused that trustrdquo Senator Baucus

Both the FDA and Congress need to take every step possible to establish independence for post-market surveillance The Institute of Medicine has made recommendations Itrsquos a matter of sound science and public safetyrdquo Senator Grassley

US SENATE FINANCE COMMITTEE REPORT

The totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public Several years prior to Nissenrsquos study it can be argued that GSK was on notice that Avandia may have problems Based on this knowledge GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner Instead GSK executives intimidated independent physicians focused on strategies to minimize findings that Avandia may increase cardiovascular risk and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk

Conclusion from Staff Report on GlaxoSmithKline and the Diabetes Drug Avandia February 2010VV

bull For the past 4 years the staff of the Senate Committee on Finance (Committee) has been examining allegations that pharmaceutical companies attempt to manipulate science to improve the marketability of drugs potentially at the expense of public safety

bull These allegations include intimidating scientists ghostwriting studies for academic researchers suppressing studies that may show that a drug could be dangerous and selecting data to publish results that favor one product over another

bull Investigators reviewed 250000 pages of documents provided by GSK FDA and othersbull Investigation was triggered by Dr Nissenrsquos meta-analysis which linked Avandia to heart

attacksbull GSK executives attempted to intimidate independent physicians like Dr Nissen and Dr

Buse and sought ways to downplay cardiovascular risks of Avandiabull GSK also sought to counter the studyrsquos findings by quickly releasing preliminary results

from RECORDbull Despite attempts to highlight the RECORD study it appears that GSK knew for years that

the study was lsquolsquounderpoweredrsquorsquo ie the study did not provide sufficient data to test for cardiovascular safety And executives appeared more concerned about designing a study to limit competition from ACTOS

bull Company was aware of the potential cardiovascular risks associated with Avandia since at least late 2004 or early 2005 VV

Extensive investigation by special agents HHS-OIG FDA DOD VA DOL TRICARE and FBIbull GSK agreed to plead guilty and to pay $3 billion to resolve its criminal and civil liability

bull unlawful promotion of Rx drugs Paxil Wellbutrin and Avdairbull failure to report certain safety data on CV risks of Avandiabull civil liability for alleged false price reporting practices

bull Corporate integrity agreement with HHS-OIG to increase accountability and transparency

Criminal Plea Agreementbull Between 2001 and 2007 GSK failed to report certain safety data about Avandia to

the FDA including data regarding PM studies about CV safety of Avandia bull GSK pled guilty and paid $242612800 for its unlawful conduct concerning Avandia

Civil Settlement Agreementbull False and misleading statements concerning the safety of Avandiabull Reporting false best prices under the Medicaid Drug Rebate Programbull This settlement resolves 4 federal lawsuits under whistleblower provisions of the FCA

Health Care Fraud Prevention and Enforcement Action Team (HEAT) Initiative was announced in May 2009 by Attorney General Eric Holder and Kathleen Sebelius

DOJ release July 2 2012

GSK PLED GUILTY PAID $3 BILLION

Restrictions imposed 23-Sep-2010

GSK will work with FDA to update rosiglitazonersquos label and implement REMS for Avandia Avandaryl and Avandamet

GSK will immediately cease promotion of rosiglitazone in all global markets

Significant restriction of the use of Avandia to patients with T2DM who cannot be controlled on other medicationsClinical trial RECORD which studied the cardiovascular safety of Avandia compared to standard diabetes drugs to be reviewed by independent group of scientists because of questions about bias (DUKE)

Clinical trial TIDE which compares Avandia to Actos and to standard diabetes drugs was halted

FDA RESTRICTIONS Restrictions lifted 25-Nov-2013

Recent data for rosiglitazone-containing drugs such as Avandia Avandamet Avandaryl and generics do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea

As a result FDA is requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010

This decision is based on our review of data from a large long-term clinical trial RECORD and is supported by a comprehensive outside expert re-evaluation of the data conducted by the Duke Clinical Research Institute (DCRI)

RISK EVALUTION AND MITIGATION STRATEGY

2008 2009 2010 2011 2012 2013 2014

1222008AVANDARYL AVANDAMETMedication Guide and a timetable for submission of REMS assessments

5182011AVANDIAAVANDARYL AVANDAMETProposed modified REMS Rev Medication GuidesRisk of ischemic cardiovascular eventslisted in the labelingCommunication planETASUImplementation system Timetable for submission of REMS assessments

1252013Conversion to a single shared REMS program that includes generics

11132011AVANDIAAVANDARYL AVANDAMETModified REMS Communication plan REMS website - requirement for patients to be enrolled in the REMS Program

572014Most restrictions removed

9162013Modified REMS Package insert Medication Guide Description of tablets from ldquoSBrdquo to ldquoGSKrdquo

AVANDIA (rosiglitazone maleate)NDA 21-071

5302012 Modified REMS Medication Guide ETASUImplementation system Timetable for REMS assessments

2392010 Restrictions imposedInitial REMS with ETASU Approval 05182011 REMS launched 11042011Avandia-Rosiglitazone Medicines Access Program

bull Healthcare providers must enroll in the if they wish to prescribe rosiglitazone medicines to outpatients or patients in long-term care facilities after November 18 2011

bull After November 18 2011 rosiglitazone medicine will only be available from specialized pharmacies

bull Enrollment in the Avandia-Rosiglitazone Medicines Access Program will be required for patients who wish to receive this medicine

572014 Restrictions liftedThe FDA has determined that recent data for rosiglitazone-containing drugs such as Avandia Avandamet Avandaryl and generics do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea As a result we are requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010 This decision is based on our review of data from a large long-term clinical trial and is supported by a comprehensive outside expert re-evaluation of the data conducted by the Duke Clinical Research Institute (DCRI)

NDA 21-071 AVANDIA (rosiglitazone maleate) NDA 21-410 AVANDAMET (rosiglitazone maleate and metformin hydrochloride) NDA 21-700 AVANDARYL (rosiglitazone maleate and glimepiride)

ldquoRISKrdquo has different meaning for different people

CORPORATE PERSPECTIVE PUBLIC PERSPECTIVE

Definition and perception of risk depends on definition of vital interest

Intellectual property Limited access and cost

Criminal and civil liabilities

Public scandals

Regulatory limitations

Control over information flow

Adverse findings

Side effects and declared risks

Undetected hazards

Limitations on liability for injury

Delays in regulatory action

Cost of injury left to victims

PROFIT ACCESS TO SAFE AND EFFECTIVE DRUGSREGULATORS

Curbed fundingLimits on staffing Public scandals

Oversight failures Lost legal casesLoss of control

Corruption Loss of credibility

RISK EVALUATION amp MITIGATION

SBGSK STRATEGY bull Initial indication covers new DM patients who require life-long treatmentbull Inclusion of combinations with SFU and INSbull High-risk groups (CHF NYHA IIIIV) excluded from CTs not excluded on label bull Warnings and Precautions included with long delaybull Restrictions on target population only implemented in 112011 (REMS)bull Eventual removal of the restrictions on patient access (2013)

MEANS amp TOOLS bull Clinical trials delayed underpowered not designed to address concerns over

cardiovascular safety bull Extensive and selective publication of the findings in medical journals bull Intimidation of scientists who voiced concerns (US Senate investigation)

CONSEQUENCES bull Disputed design of some of the studies (RECORD ndash led to EMA withdrawal)bull ADOPT study requested by the FDA could not answer CV safety questionsbull Undisclosed CV risks which led to a series of restrictions and criminal chargesbull Concerns over CV safety led to thousands of lawsuits Outcome Avandia remained on the market for almost the entire period covered by

patents without serious restrictions

GSK RISK MITIGATION STRATEGY

POST-MARKET SURVEILLANCE 2014Primary suspect cases 47023Data complete through 01242014

FAERS DATABASE Data provided by AdverseEvents

CV adverse events associated with RSG (FAERS data from 11011997 to 12312012)bull 27928 serious Cardiovascular adverse events (RSG primary suspect)

o 15947 patient hospitalizationso 4685 patient deaths

bull 2220 cases where RSG was primary and MET secondaryinteractingconcomitantbull 50 cases which listed exenatide (Byetta Bydureon) as secondaryinteractingconcomitant

bull 54976 serious adverse events (RSG RSG+MET RSG+GLIM primary suspect)o 22788 hospitalizations o 7102 patient deaths

bull The most commonly reported side effects o myocardial infarctiono cardiac failure congestiveo cerebrovascular accident

CV adverse events associated with RSG RSG+MET RSG+GLIM

Patent history for rosiglitazone

LCSP VI INTELLECTUAL PROPERTY STRATEGY

PATENT HISTORY

bull 1988 ndash Initial patent filed for the Rosiglitazone compoundbull 1995 ndash Patent for administrating the drugbull 1998 ndash Initial Patents granted to Avandiabull 2003 ndash GSK awarded the drug compound patent for 2-8mg

Rosiglitazone and its pharmacologically useful salts bull 2012 ndash Pioglitazone patent expirybull 2013 ndash Generic version patent grantedbull 2015 ndash Avandia and Avandia combinations with Sulfonylurea and

Metformin patent expiry

Patent time line US amp Europe

PATENT HISTORY

Bio-markers filed as a companion that reinforce the patent

PATENT HISTORY

httpwwwslidesharenetmromanosBiomarker-Discovery-for-Early-Clin-Dev-Dublin-Oct-2008 SB

Unique strategies that the company developed to protect their asset

PATENT HISTORY

bull A high number of salt and polymorph patents were introduced

bull The result is only the most proactive generic competitors can try to replicate

bull Companies may be forced to hold back launch until the maleate salt patent expires

Patent cliff

PATENT HISTORY

US Patent Number

Expiry date Description

5741803 2015 Maleate salt form of Rosiglitazone

6288095 2017 Avandia to treat Type 2 Diabetes

7358366 2020 Polymorphic form of Rosiglitazone

Chinese patent dispute

bullPatent law different in Chinabull3 Patents

ndash Formulation (conceded by GSK as the patent was a compound patent)

ndash Compound ndash Manufacturing

bullLack of harmonization resulted in the USPTO sending an attorney advisor to China

LITIGATION

LCSP VII MARKETING STRATEGY

MARKET ANALYSIS

MARKET AT TIME OF IND MARKET AT TIME OF LAUNCHbull In April 1999 Avandia was initially

promoted for its safety and efficacy while it was still in the investigational stage

bull Mild side effects stated to be as Anemia Edema and decreased hemoglobin

bull In March 2000 competitor Troglitazone was withdrawn from the market due to over 60 patients dying with liver problems

bull Metformin mainly used as a medication to lower blood sugar

bull Little knowledge of Thiazolidinediones

bull Treatment focused on weight loss diet changes and smoking cessation

LCSP VII MARKETING STRATEGYIMPACT OF WITHDRAWAL RESTRICTIONS

US before restrictionbull Could be prescribed with little focus

on side effects

US after restriction

bull Usage reduced due to concerns raised ndash 120000 to 3000

bull After 2010 only Type 2 patients who could not manage their blood sugar levels with other medicine could use

bull Enrollment required in FDArsquos Risk Evaluation and Mitigation Strategy (REMS) program

EUbull Withdrawn in EU (2010)bull Manufacturer has no intentions to

sell the drug in EU going forward

ROWbull Withdrawn in New Zealand South

Africa (both 2011) and India (2010)

LCSP VII MARKETING STRATEGYSWOT ANALYSIS

bull Drug value propositionThe primary effect is decreasing blood glucose followed by a very mild reduction in blood pressure improved insulin sensitivity and anti-inflammatory effectsbull Positioning statementThe drug was positioned as needing no dose adjustments for elderly renally impaired or hemodialysis It was used as an additional treatment to other therapies such as metformin and only occasionally as a single therapybull Pricing strategyMarketed as the most economic Thiazolidinedione in comparison to Rezulin and Actos A 30 lower cost was stated in comparison to Actos based on the most commonly prescribed doses

LCSP VII MARKETING STRATEGYMARKETING STRATEGY

LCSP VII MARKETING STRATEGYPRE-APPROVAL MARKETING

Describe Sales strategybull Before September 2010 sales in the US were unrestrictedbull After this time there was a restricted access program in the US and marketing was suspended by the European Medicines Agencybull FDA has approved a generic product to be sold from 2015Family practitioners vs specialistsbull Control of dispensing the drug was tightened by a Risk Evaluation and Mitigation Strategy created by the FDA bull Practitioners needed to be aware of cardiovascular risks and specialise more in potential side effects of the drugHospital vs Primary careMost commonly used in Primary care

LCSP VIII SALES STRATEGY amp MANAGED MARKETS

SALES STRATEGY

SALES STRATEGY AdvertisingFocus on glycemic control once a day dosing for 75 of patients and hepatitis safety compared to rival Rezulin

SALES STRATEGY

Advertising by market differencesNo efforts made to advertise in Europe since restrictions

What are the unique tools used by the company to differentiate their drugGSK were focused on portraying an image of safety versus Rezulin which was withdrawn in 2000 3 years after launch

Are there any innovative uses of social media or technologyIn 2004 Della Reese the jazz singer and actress helped market the drug especially to African American consumers to create a niche

What sales volume have they achieved$2 billion in annual revenue by 2006

What is the stage of the life of the productPatent expired in 2012

SALES STRATEGY

LCSP IX FINAL REMARKS

bull SBGSK attempted to satisfy unmet medical need which they identified in large population of people with diabetes These patients typically require life-long treatment

bull Most patients with diabetes at that time were on metformin and sulfonylurea In pivotal trials GSK compared their drug AVANDIA against long-available generics rather than other glitazones which were only starting to emerge

bull The highest potential would be in the population of people with prediabetes who would never develop diabetes on AVANDIA

bull Mechanism of Action was exciting to the professional public With a drug which affects DNA it is possible to modify expression of genes and hence indirectly influence own genetic heritage

bull Cardiomegaly which was identified in animal studies did not stop the drug from moving to human studies

bull Priority approval improved AVANDIArsquos odds against ACTOS bull Marketing campaign highlighted high hopes in genetic cure and suppressed

concerns and uncertainties bull Focus on liver toxicity caused by previous withdrawal of Rezulin sidelined other

safety issues namely cardiovascular or effect of the drug on metabolism of lipids

bull GSK did all it could to disprove concerns about cardiovascular safety of Avandia This includes several large clinical trials and extensive publication activity

bull Despite all efforts the sales never recovered to levels before the scandal bull Rosiglitazone still has its place on the market in several countries it is even on the

list o essential medicines The restrictions were lifted bull The investigation resulted in the highest fine in pharmaceutical industry on record

and signing a corporate integrity agreement in July 2012 bull The outcome shall be measured in both monetary and non-monetary terms bull Recovery of RampD investment from a potentially blockbuster drug is certainly

important Loss of trust among physicians and consumers is much more difficult to measure

bull The scandal had an impact on the whole industry and led to numerous reforms and changes of procedures

bull The FDA can now demand post-market safety studies (v mere recommendation)bull According to the US Senate Finance Committee (2010) Avandia scandal became a

case for the reform of post-market surveillance

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Role PharmD MD PhD MBA ESQLuis Fernando Duarte

de Carvalho Veronika Valdova Nir Arbel Simon Blythe

LIFE CYCLE STRATEGIC PLAN ndash PARTs 3 3459 2 1678

THE TEAM

THE TEAMPart

PharmD

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

THE TEAMPart

PharmD

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

L DATEBIGUANIDES

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Lehmann et al 1995

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Lehmaan et al 1995

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Gao et al 2012

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PIVOTAL STUDIES

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

lipids

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

STUDY 093 STUDY 094

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

insufficiency

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

ClinicalTrialsgov

GSK registry

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Safety concern

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

111998 NDA

FDA Approval

PATENT EXPIRATION

restrictions

1996 IND

LABELLING

TIMELINE

STUDIES

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 201

4ADOPTDREAMBARI 2D

RECORD113332

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

REMS Access program

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

BARI 2D113332

ADOPT RECORD

TIDEVV

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

RECORD

SAFETY ISSUE NO

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

INT 75 32005 122015

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PHARMACOECONOMICS

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Signal + Noise

Criterion x

CORRECTREJECTION

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

2008 2009 2010 2011 2012 2013 2014

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Public scandals

Adverse findings

Undetected hazards

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

PATENT HISTORY

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Patent cliff

PATENT HISTORY

US Patent Number

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

LITIGATION

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

MARKET ANALYSIS

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

on side effects

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

SALES STRATEGY

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

THANK YOUQUESTIONS

THE TEAM

THE TEAM (2)

INTRODUCTION

UNMET MEDICAL NEED

MARKET ANALYSIS

MARKET ANALYSIS (2)

MARKET ANALYSIS (3)

Health & Medicine

Life Cycle Strategic Plan for Rosiglitazone (Avandia)