Diabetes Product-Value: Stakeholders Changing Expectations and the Role of Real-World Evidence

Today s Presenters Dr. Anthony Abruzzini Vice President, Global Strategic Drug Development Dr. Abruzzini has 3 years of drug discovery and animal research experience, 6 years of entrepreneurial biotechnology company experience in clinical development and regulatory affairs, and 18 years of CRO experience in regulatory affairs, clinical development, and project management, including 15 years at Quintiles. In his current role, he provides strategic guidance to partner companies in the planning and design of development pathways for new drugs and biologics. His responsibilities include development of registration strategies for new drug and biologics license applications (NDAs, BLAs, MAAs, etc.). Karen Fraser Vice President, Global Marketing and Brand Solutions Ms. Fraser has over 25 years experience in the industry, with expertise in commercial brand marketing. Prior to joining Quintiles 12 years ago, she was responsible for a number of industry brands in different therapy areas, before going on to establish and run a profitable marketing consultancy, introducing the concept of outsourced brand management and successfully co-ordinating the UK launch of 4 brands for 3 international companies. During her time at Quintiles, she has provided marketing insight and support to many partnership opportunities spanning the US, UK, Europe and the Far East in numerous therapeutic areas. Dr. Frederick Gale, MD, FACS Vice President and Medical Director, Real-World and Late Phase Research Dr. Gale has 25 years of experience in consulting support for the biopharma and biotech industries, including strategic research on the many drivers underlying decision-making behaviors of healthcare stakeholders. In his current role, he leverages that experience to advise on evidence optimization, in order for results to be compelling to the decision-makers that lie beyond regulatory approval. Frederick trained in the subspecialty of Infectious Diseases, is Board certified in General Surgery, and has won awards for teaching excellence in both of these disciplines. He is a Fellow of the American College of Surgeons, and serves on the Value Proposition team of Quintiles Center of Excellence in Diabetes.. Quintiles Confidential 2

Overview Diabetes drug development environment Evolving expectations of regulators, prescribers, patients, and payers Case examples Preview of future trends 3

Today s Webinar Audience 4% 6% 24% Academia Biostatistician Clinical Operations 3% 4% 35% Epidemiology Health Economics/Health Outcomes Medical Affairs 7% Market Access Regulatory Affairs 8% 9% Other 4

Polling Questions A small number of polling questions have been added to today s webinar to make the session more interactive? 5

Diabetes Drug Development Environment 6

Diabetes: The Global Burden Environment for Diabetes Drug Development, by the numbers Worldwide > 366 million people had diabetes in 2011* > 552 million people are expected to have diabetes by 2030 > 50% are undiagnosed > 78,000 children develop type 1 diabetes every year > 4.6 million deaths resulted from diabetes in 2011** > Diabetes caused > 465 B USD healthcare expenditures in 2011 * 80% with diabetes live in low- and middle-income countries ** WHO projects diabetes will be the 7 th leading cause of death in 2030 United States > 25 million people had diabetes in 2011 > 33 million people are expected to have diabetes by 2030 > 27% are undiagnosed > 1/400 children (<20 y) have type 1 diabetes > 180,000 million deaths resulted from diabetes in 2011 > Diabetes caused > 176 B USD healthcare expenditures in 2011 (6,800 USD diabetes related expenditure per person with diabetes) 7

Success Rates by Phase Bunnage ME: Nature Chemical Biology 7:335-339, 2011 8

Diabetes Research Today IMPACT Over 230 drugs in clinical development for treatment of diabetes and related conditions This growing pipeline is driving initiation of many large and complex phase II and Phase III trials The sheer number of drugs in development requires higher efficiency in the conduct of clinical trials Diabetes epidemic drives a critical need to focus on product value Source: 2012 Phrma Medicines in Development for Diabetes Report http://www.phrma.org/research/medicines-development-diabetes 9

Unique Challenges in Diabetes Drug Development Diabetes Phase 3 programs have 2 discrete goals > Demonstration of glycemic efficacy: Clinical program typically requires 3,000 4,500 patients > Demonstration of cardiovascular safety: CV Outcome Study (CVOT) typically requires 4,500 10,000 patients Regulatory guidance for demonstration of CV Safety: US & EU > Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), December 2008 > Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus, Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency, 14 May 2012 In order to satisfy FDA 2008 requirements > Time: Typically 3-5 years (additional) > Cost: ~ $200M to $350M higher than prior FDA CV safety requirement 10

Challenges in Demonstrating Cardiovascular Safety 11

CVO Trial Landscape: Populations and MACE Definitions MACE-primary endpoint Start Drug Size Population NCT ORIGIN CV mort 9/2003 Insulin Glargine 12,500 At risk CVD prior MI,stroke, revasc 00069784 TECOS (M4) UA-hosp 12/2008 Sitagliptin 14,000 Preexisting CV D 00790205 ACE (M3) 02/2009 Acarbose 7,500 Prev MI, ACS, UA, stable Angina 00829660 EXAMINE (M3) 09/2009 Alogliptin 5,400 ACS within 15 to 90 days 00968708 CANVAS (M3) 11/2009 Canagliflozin 4,300 History of or a high risk CVD 01032629 AleCardio (M3) 02/2010 Aleglitazar 7,000 ACS 2-6 w prior to randomization 01042769 SAVOR TIMI-53 (M3) 04/2010 Saxagliptin 16,500 EstablCVD and/or multiple RF 01107886 ELIXA (M4) UA-hosp 06/2010 Lixisenatide 6,000 ACS within 180 days 01147250 EXSCEL (ND) 06/2010 Exenatide LAR 9,500 No CV Inclusion listed 01144338 C-SCADE 8 (M3) 07/2010 Empagliflozin 7,000 Prior MI, UA, revasc 01131676 CAROLINA (M4) UA-hosp 10/2010 Linagliptin 6,000 Pre-existing CVD 01243424 LEADER (M3) 11/2010 Liraglutide 8,750 Concomitant CVD 01179048 REWIND (M3) 07/2011 Dulaglutide 9,600 Established CVD 01394952 ITCA 650 (M4) UA-hosp 01/2012 Exenatide ITCA650 2,000 Hx of CVD, Stroke or PAD 01455896 Selected populations vary, as does MACE definition Adapted from Gore O, McGuire D. Diabetes & Vascular Disease Research. 9(2) 85-888. 2012 12

CVOT Endpoint Considerations MACE or MACE+? MACE (CV Mortality, MI, Stroke) > Attainment of a given level of statistical significance is afforded more gravitas than MACE + > Accruing sufficient events will be more challenging than MACE+ > MACE+ > Inclusion of revascularization has value to clinicians as reason to use > Unstable angina may require core-lab validation of angiography > Hospitalization for Acute Coronary Syndrome FAVORED POSITION > Dependent on MOA of drug candidate and concurrence with regulatory authorities RESULT(S) > Trade-off on time-tocompletion of CVOT versus evaluation on target patient population for marketed product 13

CVOT Design Considerations Non-Inferiority versus Superiority Designs Non-inferiority [NI] > Risk Ratio: <1.8 pre-nda and <1.3 post NDA (2-sided, 95% CI) > Meta-analysis or stand-alone study > Precedents for MACE, or MACE+ exists Superiority [S] > Risk Ratio: <1.0 > Stand-alone study > Ability of sponsor to propose MACE+ is desired FAVORED POSITION > [NI] satisfies regulatory requirements, but requires more subject events > [S] may be difficult to demonstrate in target population 14

Polling Questions What is your experience in conducting cardiovascular outcomes studies for antidiabetic drugs?? >No experience >1 study >2 or more studies Quintiles Confidential 15

Diabetes Insights KOLs / Primary Care Clinicians / Patients 16

Insulin + GLP-1 Insulin FFAR1 / GPR40 agonist SGLT-2 GLP-1 PPAR DPP-4 The diabetes pipeline is extremely crowded Alogliptin (Takeda) Alogliptin+ Metformin (Takeda) Alogliptin+ Pioglitazone (Takeda) Omarigliptin MK-3102 (Merck) Melogliptin (Glenmark) Aleglitazar (Roche) KRP-104 (Kyorin) Lixisenatide (Sanofi) Dulaglutide (Lilly) Albiglutide (GSK) Semaglutide (Novo Nordisk) 2013 2014 2015 2016 2017 LLX4211 Lexicon Forxiga (BMS / AZ) Canagliflozin (J&J) Dapagliflozin + Metformin (BMS / AZ) Empagliflozin (BIL) Canagliflozin + Metformin (J&J) Empagliflozin +Linagliptin (BIL) Fasiglifam (TAK-875) (Takeda) Empagliflozin +Linagliptin (BIL) BI 4487 BIL Tofogliflozin Chugai PF-04971729 - Pfizer TS-071 Taisho ISIS-SGLT2RX - Isis Ryzodeg (Novo Nordisk) Degludec (Novo Nordisk) LY2963016 (Lilly / BI) U300 New Lantus (Sanofi) LY2605541 (Lilly) IDegLira Degludec + Victoza (Novo Nordisk) LixiLan Lantus+ Lyxumia (Sanofi) Launched in some EU markets 17

Pipeline Marketed KOL Insights*: Newer classes in diabetes DPPIVs have high utility and are seen as extremely safe, no hypos, weight neutral but have only moderate efficacy (eg sitagliptin, vildagliptin, saxagliptin) > Used post metformin and instead of /after sulphonylureas > Class seen as similar - many choices but sitagliptin continues to dominate GLP1s are effective, no hypoglycaemia, cause weight loss (eg exenatide, liraglutide) > Used pre insulin (or earlier in obese patients) cost and route of administration limit use > Main differences are dosing/formulations Byetta (BD), Victoza (OD) and Bydureon (OW) SGLT-2s are seen as an important new class by KOLs (eg dapagliflozin, canagliflozin) > Important new class with attractive and novel mode of action, independent of insulin > Moderate reduction in HbA1c (~1.1%), weight loss - seen as a potential challenge to the DPP-IV class > High levels of thrush/uti in female patients may limit Newer Insulins (eg degludec/tresiba) > Tresiba rejected by FDA - require CV outcomes studies > Truly flat profile very attractive - additional benefit vs Lantus tbd > Benefit in reducing nocturnal hypoglycaemia > Sanofi s Lixilan (lixisenatide/lantus) may compete directly as there is a high level of confidence with Lantus PPAR α/γ co-agonist s profile similar to the glitazones (eg aleglitazar, Roche) > Effective HbA1c reduction, no hypoglycaemia, HDL increase,tg reduction > S/E s incl weight increase, oedema, fractures, CHF, BP, > Two dual PPARs discontinued in late clinical development * KOL qualitative interviews conducted with 8 specialists in Germany, Italy, Spain & UK 18

Primary Care Insights* Diabetes is a significant & increasing workload The Classic New Patient Frequency of HbA1c Measurement Age: 50-60 yrs Employed HbA1c = 7-9% BMI = 25-35 59% 36% 1x per year 2x per year 4 x per Year 12x per year Burden of T2D in primary care is growing Consultation patterns > Almost 80% GPs say T2D patients are now presenting younger > Half of GPs say the number of new T2D patients has increased in the last year > 86% believe the aging population and increasing obesity will result in a dramatic rise in T2D patients Genuine concerns for T2D patients > 80% of GPs are very concerned for the future of their diabetic patients unless they take more responsibility for their condition > 70% of GPs require patients to re-present following routine HbA1c tests Support would be welcomed > Improved communication and support amongst the care team would be of high value to GPs > Better patient support & education is desirable > Improved patient compliance is a genuine need > Over 30% of GPs consider an remote monitoring system would be appropriate in T2D * GP online survey conducted in France, Germany, Italy, Spain & UK (n=75) 19

Primary Care Insights* Treatment & Management National Guidelines are viewed as most important and useful > Local Guidelines also important > A greater emphasis on individual patient type targets would be helpful Metformin, is the clear 1 st line choice for newly diagnosed patients > DPP- IVs are becoming the established the 2 nd line add-on therapy > The GLP-1s are increasingly the 3 rd line choice > The addition of a 2 nd therapy is often within 24 months of diagnosis The GP involves a variety of other specialities in the care of T2D patients > Key specialities included are Practice Nurses, Diabetologists, Ophthalmologists and Chiropodists - Trigger for referral to 2 Care is usually lack of HbA1c control - Ophthalmologists and Chiropodists generally included when complications arise > Most GP s see themselves as having the greatest impact on treatment Relatively high awareness exists of the new / emerging treatments > ~ 30% of GPs are aware of the new SGLT-2 drugs in the pipeline > Real concerns about future cost of effectively managing Diabetes population * GP online survey conducted in France, Germany, Italy, Spain & UK (n=75) 20

Patient Insights* Disease views Most patients do believe their condition is serious Many patients are taking > 1 medication 7% 65% Extremely serious Serious No feeling either way A little serious Not at all serious 100% 80% 60% 40% 20% 0% 89% 64% Taking medication More than one medication Patients have a fatalistic view of their condition > Patients have discussed the risk of complications with their GP > Approx 30% have been warned of the risk of premature death > There is a strong sense of resignation Additional Insights Most patients: > were aware of Diabetes and how common it is prior to their diagnosis > had not been warned about potentially developing diabetes > feel they have acted on dietary and lifestyle advice given on diagnosis > are asked to take a regular reading of their blood sugar levels * Patient online market research conducted in France, Germany, Spain & UK (n=114) 21

The diabetes patient is complicated Remote monitoring would be welcomed Quarterly HCP visits is usual Over 30% feel it will impact on ability to work in future Breaking established patterns of behaviour (i.e. the potential background causes to the disease) is inherently difficult As with many chronic conditions, in the absence of life impacting symptoms, the patient can remain in a state of resignation regarding the diagnosis. Compliance to treatment programmes is a major issue The patient can be living with the condition for as long 10 years before diagnosis It has been established that people with diabetes often have inadequate knowledge of their condition, risk factors and associated complications Many believe Diabetes is Hereditary with Lifestyle contributors Preferred Info sources: Internet Pharmacists Other HCPs Patients have insight into their own impact on course of disease 22

Polling Question Which Diabetes patient focused activities do you think is most important for the future?? Diet & Lifestyle Education Self Help Groups Patient Adherence Programmes Monitoring and PRO Collection 23

Payer Perspective 24

Payer Highlights for Diabetes HTA Watch: reports and analysis from 90 agencies in 32 countries In a recent six-month period, over 40 HTA reports published for diabetes: Diabetes HTAs per Country in 6 Months Most Common Reasons for Rejection 12 10 8 6 11 10 Less than 1 yr follow-up No compelling data on incremental benefits vs SOC (e.g., weight loss, lipids) 4 2 4 4 4 2 2 2 1 1 1 No controlled studies v. SOC Insufficient economic data 0 Insufficient QOL data 25

Principles and Case Studies for Real World and Late Phase Study Design 26

Late Phase Interventional Trials: Challenges and take-home principles from across several studies Recurring Challenges Temptations for maximizing power at the expense of being less compelling to decision-makers: o Excluding non-compliant patients; giving special attention to those remaining o Stipulating highly restrictive exclusion criteria in efficacy studies o Stipulating highly restrictive inclusion criteria in safety studies Decision-maker assumptions can differ from those of the manufacturing team s about: o Unmet needs (e.g., hypoglycemia) o A compound s comparative strengths Stakeholder demands for economic evaluation (e.g., CVZ, NICE, PBAC, and SMC) Deliver new products that not only appear to be safe, but are safe Delivering Stakeholder-Oriented Results Plan for later phase randomized trials to be as naturalistic as possible real-world interventional Learn stakeholders priorities for a compelling value-story o Discuss optimal thresholds for patient inclusion / exclusion o Instead of excluding data in a way that sacrifices real-world projectability, consider sub-analysis and stratification o Consider a sampling plan that includes un- and under-studied patients (elderly, renal insufficient, AA, pediatric) o Consider fielding tandem studies from the same protocol o Ask what they see as the unmet needs in diabetes within their healthcare system o Ask their perceptions about relative strengths / weaknesses of products and categories o Get help understanding the economic evidence demands of all intended markets Run ROI analysis to guide evidence optimization First, make the most out of pre-marketing safety data: interrogate multiple safety analysis datasets Learn from diabetes Clinical Project Managers 27

Case Study: DM in Primary Care Evolving landscape of North American treatment patterns of HCPs initiating diabetes care Challenges Clarify Practice Patterns/Outcomes in NA Clarify care patterns at sites initiating Rx for T2D Describe referral patterns, and care at those sites Relate practice and referral patterns to outcomes 10,000 patients, 388 sites, North America PIs are frontline PCPs, not trialists Deliver meaningful comparisons across settings and over time Solution Handling Operations and Data Issues De-identification of study data through tokens Single-site submission to central IRB; waiver of formal informed consent EMRs identify patients per inclusion criteria, and invite patient directly Patients self-register and give Authorization to Participate; EMR pre-populates database Data supplemented by site surveys, patient surveys, and per visit clinician thinking Timeline Overview 1 year 18 months to 4 years Baseline epro & HRU 1 y 2 y 3 y 4 y 28

Staggered Enrollment Allows observation of practice patterns over time 12 months FPI LPI Study End 30 months 18 months 48 months 29

Sources of Insights Site, physician, and patient characteristics; patient observations; medications, labs, and special exams; clinical decision-making; and outcomes 2 EMR Data Merges directly with patient survey data 1 Survey Data o Patient o Site Admin o HCP 3 Clinical Reasoning Sites enter rationale for med changes & referrals Data Warehouse 30

Preview of Future in Diabetes Diabetes product-value trends Increasing emphasis on evidentiary sufficiency, including real-world value > Better comparisons to SOC > Longer-term follow-up > Deeper analysis of all safety data > More pediatric trials in T2D > Use of anti-diabetic agents for pre-diabetes > Metabolic surgery; diabetes remission > The need to develop ethical excellence in recruiting indigent and low-literacy patients Increased investment in digital and nurse-led patient education and support Potential game-changers > Proof of macrovascular end-organ protection in T2D > Beta cell preservation or restoration 31

Conclusion: multiple drivers for increased efficiency and evidence-value in diabetes Diabetes prevalence greatly increasing globally The pipeline is crowded Payers, providers, and patients are all under pressure to make good decisions they now join regulators as empowered decision-makers For both efficiency and sufficiency of evidence, their voices must be sought early and often, leading to the idea of late phase thinking, starting early Giving stakeholders the evidence support they need means evolving from traditional clinical development planning to product-value planning A product s real-world performance helps define its real-world value 32

Upcoming Events Upcoming Webinar Title: AHRQ Registry of Patient Registries (RoPR): An Introduction Date: July 23, 2013, 11am-12pm EDT Register: https://www1.gotomeeting.com/register/159106832 33