Copyright © 2013 Quintiles

Diabetes Product-Value: Stakeholders’ Changing

Expectations and the Role of Real-World Evidence

Dr. Anthony Abruzzini

Karen Fraser

Dr. Frederick Gale

2

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.).

Quintiles Confidential

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.

.

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.

3

Overview

• Diabetes drug development environment

• Evolving expectations of regulators, prescribers,

patients, and payers

• Case examples

• Preview of future trends

4

Today’s Webinar Audience

4%

6%

35%

9%

8%

7%

4%

3%

24% Academia

Biostatistician

Clinical Operations

Epidemiology

Health Economics/Health Outcomes

Medical Affairs

Market Access

Regulatory Affairs

Other

5

Polling Questions

A small number of

polling questions

have been added to

today’s webinar to

make the session

more interactive

?

6

Diabetes Drug Development Environment

7

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 7th 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)

8

Success Rates by Phase

Bunnage ME: Nature Chemical Biology 7:335-339, 2011

9

Diabetes Research Today

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

IMPACT

10

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

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Challenges in Demonstrating Cardiovascular Safety

12

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

Adapted from Gore O, McGuire D. Diabetes & Vascular Disease Research. 9(2) 85-888. 2012

Selected populations vary, as does MACE definition

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CVOT Endpoint Considerations

MACE (CV Mortality, MI, Stroke)

MACE+

> Attainment of a given level of statistical

significance is afforded more gravitas

than MACE +

> Accruing sufficient events will be more

challenging than 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-to-

completion of CVOT versus

evaluation on target patient

population for marketed

product

MACE or MACE+ ?

14

Non-Inferiority versus Superiority Designs

Non-inferiority [NI]

Superiority [S]

> 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

> 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

CVOT Design Considerations

15

Polling Questions

What is your experience in

conducting cardiovascular

outcomes studies for

antidiabetic drugs?

>No experience

>1 study

>2 or more studies

Quintiles Confidential

?

16

Diabetes Insights KOLs / Primary Care Clinicians / Patients

17

The diabetes pipeline is extremely

crowded

DP

P-4

G

LP

-1

Insu

lin

Insu

lin +

GL

P-1

2013 2014 2015 2016 2017

SG

LT

-2

Albiglutide

(GSK)

PP

AR

Aleglitazar

(Roche)

Degludec (Novo Nordisk)

Semaglutide (Novo Nordisk)

Lixisenatide

(Sanofi)

Canagliflozin

(J&J)

Empagliflozin

(BIL)

Forxiga

(BMS / AZ)

Dulaglutide

(Lilly)

Alogliptin

(Takeda)

Melogliptin

(Glenmark)

Omarigliptin

MK-3102

(Merck)

Empagliflozin

+Linagliptin

(BIL)

Canagliflozin

+ Metformin

(J&J)

LY2605541 (Lilly)

Empagliflozin

+Linagliptin

(BIL)

Launched in some EU markets

KRP-104

(Kyorin)

LLX4211 – Lexicon

BI 4487 – BIL

Tofogliflozin – Chugai

PF-04971729 - Pfizer

TS-071 – Taisho

ISIS-SGLT2RX - Isis

Alogliptin+

Metformin

(Takeda)

Alogliptin+

Pioglitazone

(Takeda)

Dapagliflozin

+ Metformin

(BMS / AZ)

LixiLan Lantus+ Lyxumia

(Sanofi)

FF

AR

1 /

GP

R40

ag

on

ist Fasiglifam

(TAK-875)

(Takeda)

IDegLira

Degludec +

Victoza (Novo Nordisk)

U300 New Lantus

(Sanofi)

LY2963016 (Lilly / BI)

Ryzodeg (Novo Nordisk)

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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

Mark

ete

d

Pip

elin

e

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Primary Care Insights* Diabetes is a significant & increasing workload

* GP online survey conducted in France, Germany, Italy, Spain & UK (n=75)

> 80% of GPs are very concerned for the future of their

diabetic patients unless they take more responsibility for

their condition

Genuine concerns for T2D patients

> 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

Burden of T2D in primary care is growing

36%

59%

Frequency of HbA1c Measurement

1x per year

2x per year

4 x per Year

12x per year

> 70% of GPs require patients to re-present following

routine HbA1c tests

Consultation patterns

> 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

Support would be welcomed

The Classic “New” Patient

• Age: 50 -60 yrs

• Employed

• HbA1c = 7-9%

• BMI = 25-35

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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 1st line choice for newly diagnosed patients

> DPP- IVs are becoming the established the 2nd line add-on therapy

> The GLP-1s are increasingly the 3rd line choice

> The addition of a 2nd 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)

21

Patient Insights* Disease views

7%

65%

Extremely serious

Serious

No feeling either way

A little serious

Not at all serious

* Patient online market research conducted in France, Germany, Spain & UK (n=114)

> 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

Patients have a fatalistic view of their condition

Most patients do believe their condition is serious

89%

64%

0%

20%

40%

60%

80%

100%

Taking medication

More than one medication

Many patients are taking > 1 medication

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

Additional Insights

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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.

The diabetes patient is complicated

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

Compliance to treatment

programmes is a major issue

Remote monitoring would be welcomed

Many believe Diabetes is Hereditary

with Lifestyle contributors

Patients have insight into their own impact on course of disease

Preferred Info sources:

Internet Pharmacists Other HCPs

Over 30% feel it will impact on ability to

work in future

Quarterly HCP visits is usual

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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

?

24

Payer Perspective

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Diabetes HTAs per Country in 6 Months

Payer Highlights for Diabetes HTA Watch: reports and analysis from 90 agencies in 32 countries

Most Common Reasons for Rejection

• Less than 1 yr follow-up

• No compelling data on incremental

benefits vs SOC

(e.g., weight loss, lipids)

• No controlled studies v. SOC

• Insufficient economic data

• Insufficient QOL data

In a recent six-month period, over 40 HTA reports published for diabetes:

11

10

4 4 4

2 2 2

1 1 1

0

2

4

6

8

10

12

26

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

27

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

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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

Baseline

1 year 18 months to 4 years

1 y 2 y 3 y 4 y

ePRO

& HRU

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Staggered Enrollment Allows observation of practice patterns over time

48 months

18 months

LPI Study End FPI

30 months

12 months

30

Sources of Insights Site, physician, and patient characteristics; patient observations;

medications, labs, and special exams; clinical decision-making; and outcomes

1 Survey Data

o Patient

o Site Admin

o HCP

2 EMR Data

Merges directly with patient survey data

3 Clinical Reasoning

Sites enter rationale for med changes

& referrals

Data Warehouse

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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

32

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

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