Emerging Strategies for More Cost-Effective Clinical ... Strategies for More Cost-Effective Clinical Development in the NASH Indication Randy L. Anderson, PhD SVP, Scientific and Regulatory

Emerging Strategies for More Cost-Effective

Clinical Development in the NASH Indication

Randy L. Anderson, PhD

SVP, Scientific and Regulatory Affairs

Therapeutic Area Leader for Endocrinology and Metabolism

22 February 2017

Overview

2 Proprietary & Confidential. © 2016 Chiltern

● A brief review of the epidemiology, etiology, morbidity, and mortality associated with nonalcoholic steatohepatitis (NASH)

● A review of the circumstances leading to the rapid increase of investigative products intended to treat NASH

● An experiential survey of strategic and logistical issues to consider in clinical development planning and program execution in NASH

Chronically

excess caloric

intake, sedentary

lifestyle

Causal Etiology of Lifestyle Metabolic Diseases

• Overweight, obesity

• Muscle atrophy

• Abdominal obesity

• Waist-hip ratio > 1

• Genetic predispositions may accelerate specific progression paths


Metabolic

Syndrome

(Reaven, 1980)

Metabolic

Complications

• Elevated CVD risk

• Chronic inflammation

• Insulin resistance

• Hyperinsulinemia

• Dysglycemia

• Dyslipidemia

• Hypertension

• Organ-specific adiposity

• CVD events

• Type 2 diabetes

• Vascular disease

• Nephropathy

• Neuropathy

• Retinopathy

• NASH

Stages of Fatty Liver Disease


● Fatty liver

● Liver inflammation

● Steatohepatitis (Fibrosis)

● Cirrhosis

Ectopic Liver Fat

(Steatosis)

Inflammation

(Steatohepatitis)

Reversible

Scar tissue

(Fibrosis)

Permanent Scaring

(fibro-connective

tissue hypertrophy

and pseudo-lobule

formation)

Cellular Changes Oxidative stress Moderate injury Severe injury

Clinical Changes ALT, AST

elevation

ALT, AST

elevation

Liver deformed and

rigid

Fibrosis Staging S0 S0 S1-S3 S4

Central Obesity √

Metabolic

syndrome

√

Fatty Liver √

NASH √ √ √

Cirrhosis √ √ √ √

Prevalence and Mortality Risk by Region


US Western Europe Central Europe Asia

Metabolic

syndrome

Fatty Liver 20%-30%

NASH 2%-5%

Cirrhosis

A Summary of NASH Products in Development


MOA Preclinical Phase 1 Phase 2 Phase 3 Approved

Anorectic 0

Anti-

inflammatory

0

0

0

Why NASH?

T2D Program Considerations with Cardiovascular Safety


● December 2008 FDA guidance (Evaluating CV risk in new antidiabetic therapies to treat T2DM) requires demonstrated Major Cardiovascular Events (MACE) noninferiority (vs standard-of-care) in marketing application

• MACE includes myocardial infarction, stroke, and CV death

• MACE hazard ratio (HR) significantly less than 1.8 (two-sided, α=0.05)

• Approx 125 MACE events to have 90% power at HR criterion of 1.8 assuming no CV risk difference between treatment and SOC

• Expected MACE rate in monotherapy, add-on studies: 0.75% (0.75 events per 100 patient-years observation)

● Phase II-III program of about 3,600 subjects needs to accrue about 66 MACE events, assuming 12 months accrual, total treatment duration of 36 months, and 1:1 active:comparator treatment assignment.

● Program will need another 60 events in marketing application

T2D Program Considerations with Cardiovascular Safety


● FDA CV safety guidance requires meeting an even more stringent noninferiority criterion before full marketing approval (i.e. “clean” label)

● Cumulative Phase III data must demonstrate statistical significance of noninferiority at an HR criterion of 1.3 (2-sided, α=0.05)

• FDA allows only one meta-analysis to meet this criterion

• Otherwise, product must meet this criterion within a stand-alone CV safety study

● This more stringent criterion requires observing a total of about 625 MACE events, or another 500 beyond those accrued for marketing application

● Since releasing CV Safety guidance, FDA has applied it to products intended for chronic use in following indications:

• Obesity

• Gout

• Prostate cancer

Cardiovascular Safety Implications for T2D Treatments


True Magnitude of

Product’s CV Relative Risk (relative to standard-of-

care)

Alternative Hypotheses of CV Risk Reduction

HR <1.8a HR<1.3b HR<1.0c

Pt-yrsd MACEe Pt-yrsd MACEe Pt-yrsd MACEe

CV Risk Neutral (HR=1.0) 12,200 122 61,200 612

5% Reduction 10,400 104 42,900 429 1,598,600 15,986

10% Reduction (HR=0.90) 8,900 89 31,200 312 379,800 3,798

15% Reduction 7,600 76 23,500 235 160,200 1,602

20% Reduction 6,500 65 18,200 182 85,500 855

25% Reduction 5,700 57 14,200 142 51,900 519 30% Reduction (HR=0.70) 5,000 50 11,400 114 34,100 341

a FDA December 2008 Guidance for Cardiovascular Safety in T2DM requires statistically significant evidence in marketing application that product CV safety is no

more than 80% worse than standard-of-care treatments (i.e. HR<1.8). MACE counts assume 90% statistical power using a one-sided log rank tests with α=0.025. b Before marketing, guidance requires statistical significance that product’s CV safety is no more than 30% worse than standard-of-care treatments (i.e. HR<1.3). c A claim of superiority requires that product’s CV safety is statistically significantly better than standard-of-care treatments (i.e. HR<1.0).

d Patient-years of complete follow-up required to accrue indicated number of MACE assumes an overall 1.0% MACE rate. To use a higher MACE rate, divide

tabulated patient-years value by anticipated annualized MACE rate. For example, with a 2.0% MACE rate, tabulated patient-years value is divided by 2.0.

Typical T2D Program-wide MACE Accrual


Protocol N Accrual/

FU

Time

(mos)

MACE

Rate

(%)

RR 24 Months 30 Months

Patient-

Years

MACE Patient-

Years

MACE

Monotherapy 250 12/12 0.75 0.75 318 2.6 425 3.4

Metformin 250 12/12 0.75 0.75 318 2.6 425 3.4

H2H 400 12/12 0.75 0.75 557 4.1 750 5.4

DPP-IV 750 12/12 0.75 0.75 1025 7.7 1425 10.4

Sulfonylurea 250 12/12 1.00 0.80 318 3.4 425 4.5

Insulin 350 12/12 1.50 0.85 495 7.7 645 9.9

CKD 300 18/18 5.00 0.95 334 16.5 485 23.1

Subtotals 3,377 45.5 4,580 60.1

CV Study 6,200 24/12 3.00 0.87 5,251 157.5 8,219 246.6

Totals 8,628 203.0 12,799 306.7

Cost Implications of T2D Product Development


● 16 products have met FDA Guidance CVD safety requirements for T2D

● No product has shown evidence of increased CVD risk

● Estimated cost per product to meet CVD safety requirements is $400 million

● Two products have shown statistically significant CVD risk reduction

• Empagliflozin estimated cost

• Liraglutide estimated cost

● How could requirements be changed to “fix” disincentive for T2D or obesity product development

• Not a viable argument to be against demonstration of CVD safety

• Instead, shift CVD safety requirement to a post-approval requirement

• Estimate that 70% of products pursuing NASH indication would change (back) to T2D or obesity indication

Current Challenges for NASH Product Development


● Epidemiology of NASH

• 30% prevalence of NASH among T2D patients (1/3 the market size of T2D)

• 20%-30% prevalence of NASH among patients with high abdominal obesity

● Regulatory requirement of biopsy-confirmed inflammation and fibrosis

• Patient aversion to multiple liver biopsies for asymptomatic disease

• Insufficient screening biomarkers to detect fibrosis with high probability

● Treatment duration sufficient to observe fibrosis reversal or stopped progression

● Competition for investigators and patients relative to NASH prevalence

• Too many products chasing too few patients

● Estimated cost per patient of $XX,XXX (with screening costs averaged in)

Anticipated Program-wide NASH Accrual with Biopsy Endpoint


Protocol N Accrual/

FU

Time

(mos)

PBC

Rate

(%)

RR 24 Months 30 Months

Patient-

Years

PBC Patient-

Years

PBC

Phase 2 250 12/12 5.00 0.75

Phase 3 2300 30/24 5.00 0.75

Totals

PBC=Primary Biliary Cirrhosis

Cost and Investment Return Potential by Indication


NASH

(current)

Type 2 Diabetes Obesity

Estimated clinical cost

to marketing

application

$200 million $650 million $600 million

Global Market Size

Global Market Sales

Potential

Clinical Development Cost Reduction Strategies

for NASH Indication

Candidate Biomarkers of NAFLD, NASH


Multiparameter MRI as Alternative to Liver Biopsy for Disease Severity


● Current Standard: Liver biopsy screening and at least one additional biopsy in 100% of participants

● Alternative 1: MP-MRI screening, with 100% liver biopsy endpoints (i.e. eliminate screen-failure biopsies)

● Alternative 2: MP-MRI screening and endpoints, and biopsy reduced to 50% of participants

● Alternative 3: MP-MRI screening and endpoints, and biopsy reduced to 20% of participants

● Alternative 4: MP-MRI screening and endpoints, replacing all liver biopsy

Cost and Time to Marketing Application


MP-MRI + no

biopsy

MP-MRI + 20%

Biopsy

MP-MRI + 50%

Biopsy

MP-MRI screen

+ 100% Biopsy

100% Biopsy

Cost per

patient

Time to

Marketing

Application

Cost and Investment Return Potential by Indication


NASH

(innovative)

NASH

(current)

Type 2 Diabetes Obesity

Estimated Clinical

Cost to Marketing

Application

$170 million $200 million $650 million $600 million

Global Market Size 85 million 85 million 250 million 500 million

Estimated Annual

Rx Cost per Patient $4000 $4000 $2500 $1250

Estimated Global

Annual Market

Sales Potential at

5% of Market Size

$17.0 billion $17.0 billion $31.3 billion $31.3 billion

Annual Gross

Revenue Multiple of

Clinical Cost

100 85 48 52

Time to Market

Application (years) 5 6 8 8


When you are seeking people, processes and technology in the right locations, Chiltern

has the right resources Designed Around You.

23

NORTH AMERICA Canada

United States

LATIN AMERICA Argentina

Brazil

Chile

Mexico

WESTERN EUROPE Austria

Belgium

Cyprus

Denmark

Finland

France

Germany

Greece

Ireland

Italy

Netherlands

Norway

Portugal

Spain

Sweden

Switzerland

Turkey

United Kingdom

CENTRAL EUROPE Bulgaria

Croatia

Czech Republic

Hungary

Poland

Romania

Russia

Slovakia

Ukraine

MIDDLE EAST

AND AFRICA Israel

South Africa

ASIA-PACIFIC Australia

China

Hong Kong

India

Japan

Malaysia

New Zealand

Philippines

Singapore

South Korea

Taiwan

Thailand

Endocrinology & Metabolism


INVESTIGATORS

1,744 PATIENTS

19,360 COUNTRIES

32

TOTAL BIOPHARMACEUTICAL

STUDIES

84

TOTAL MEDICAL DEVICE &

DIAGNOSTICS STUDIES

8

Over the last five years, Chiltern has conducted a total of 92 endocrine & metabolic studies.

Endocrinology & Metabolism Experience


Biopharmaceutical Experience

● Diabetes complications • Diabetic foot ulcers

• Diabetic nephropathy

• Diabetic neuropathy

• Macular edema

● Diabetes type 1

● Diabetes type 2

● Hyponatremia

● Hypophosphatasia

● Male hypogonadism

● Molybdenum cofactor deficiency

● Obesity

● Renal disease (CKD and ESRD)

Medical Device & Diagnostics Experience

● Diabetes companion devices

● Diabetes diagnostic

● Diabetic neuropathy

● Diabetic nephropathy

● Diabetes type 1

● Diabetes type 2

Gastroenterology


INVESTIGATORS

2,638 PATIENTS

22,799 COUNTRIES

39 TOTAL STUDIES

71

Over the last five years, Chiltern has conducted 71 gastroenterology studies.

Gastroenterology Experience


● Anal fissure

● Clostridium difficile infection

● Constipation

● Crohn’s disease

● Gastroesophageal reflux disease (GERD)

● Inflammatory bowel disease

● Irritable bowel syndrome

● Liver disorder

● Liver fibrosis

● Oral mucositis

● Parenteral nutrition

● Primary biliary cirrhosis

● Steatohepatitis

● Ulcerative colitis

Clinical Supplies Strategic Regulatory

MEDICAL AFFAIRS SCIENTIFIC AFFAIRS

DATA , ANALYSIS & REPORTING

PHARMACOVIGILANCE

REGULATORY AFFAIRS

CLINICAL SUPPLIES

The Only Resource You Need


PROGRAM MANAGEMENT

SITE SERVICES & CLINICAL MONITORING

● 24/7 medical monitoring

● CSR review

● Medical coding review

● Medical data review and trend analysis

● Medical monitoring plan

● Medical writing

● Patient eligibility and withdrawal

● Protocol deviation review

● Protocol review

● Project training

● Review of laboratory/ECG alert reports

● SAE/AE review and assessment

● Study design and feasibility

Medical Affairs Services


Our expert physicians in Medical Affairs provide product development planning, product-level safety

surveillance, and medical monitoring services Designed Around You.

● Product development strategy

● Clinical development planning

● Product target label formulation

● Literature review and trend analysis

● Discerning unmet medical need

● Publications writing

● Scientific presentations

● Precedence in indication

● Study design and feasibility

● Protocol writing or review

● Team training

Scientific Affairs Services


When you need therapeutic area clinical scientists, Chiltern has experienced leaders to assist in program

design and oversight, from clinical development planning through marketing applications.

Designed Around You.

Regulatory Affairs Services

● Clinical trial authorizations (CTA)

● Competent authority meetings

● Due diligence

● IND/IDE/BLA applications

● Local representative

● Pediatric investigation plans (PIP)

● Product labeling

● Regulatory consultancy

● Reimbursement

● Safety risk minimization plan

● Scientific advice, protocol assistance

● Suitability for registration


When you need to stay informed of evolving regulatory requirements, Chiltern has seasoned

professionals with an understanding of global regulations and standards Designed Around You.

Program Outsourcing With a Chiltern Shared Leadership Team

Program

● Client: “Help me get my product through marketing approval sooner, more efficiently, and with a more complete label”

● Provider: “Hire me to get your product through marketing approval sooner, more efficiently, and with a more complete label”

● Program milestones can be part of contract terms

o Intentionally more collaborative

o Client and provider share interests in same outcomes

● Client workload reduced; Provider workload more predictable

● Overhead reduced for both parties

Transactional

● Client: “Which provider will do next study at lowest price?”

● Provider: Hire me to do your next study” ● Contractual workscope is more discrete –

Provider much less involved in what happened before, what happens after

● Client: Dramatic swings in staff workload; extra overhead in repeat cycles of bid-award-execute

● Provider: Low predictability in staff workload; extra overhead on repeat cycles of bid-award-execute

33 Proprietary & Confidential. © 2016 Chiltern, 11 February 2016

Client-Provider Relationships in Program versus Transactional Outsourcing


Clinical Development Shared Leadership Roles for Programs

• Deep knowledge of current standard-of-care and evolving treatment paradigms in disease and indication

• Expertise in medical and safety surveillance from first-in-human to global confirmatory trials

• Deep knowledge of regulatory guidance and precedence in indication and aggressive development planning

• Expert understanding of regulatory strategy options

Regulatory Affairs

Program Management

• Deep knowledge of disease etiology, mechanisms of available treatments, and potential treatment targets

• Well-versed in strategic use of clinical trials scientific methods to accomplish desired labeling objectives

Scientific Affairs

Medical Affairs

Hands-on Strategic Development Support of Client and Project Teams

• Deep knowledge of logistical contingencies and development milestones across trials

• Indication-specific experience

• Expert expressive and receptive communication and coordination skills

Clinical Development Planning Outline

● Review of unmet medical need of intended indication

● Review of product, preclinical findings, and current understanding of mechanism(s) of action

● Review of product development precedence and regulatory guidance in intended indication

● Review of market competition within intended indication

● Clinical development program summary

o Phase 1: Broad determination of therapeutic dose range, toxicities, pharmacokinetics, maximum tolerated dose

o Phase 2: Refined estimation of dose-response relationship in patients for optimal efficacy and safety

o Phase 3: Confirmation and generalization of clinically-meaningful efficacy and safety in intended indication

o Synopsis for each component trial

o Estimated cost of each component trial

o Logistical timing and contingencies between trials

● Pre-specification of program decision points and decision criteria

36 Proprietary & Confidential. © 2016 Chiltern, 11 February 2016

The Hub & Spoke Approach to Accrual and Follow-up

Hub Site

Satellite Site

Satellite Site

Satellite Site Satellite

Site

Satellite Site


• Hub & Spoke Approach provides • “More hooks in the water” • Matches prevalent referral paths

• Satellite sites activities • Referral • Screening • Interim follow-up visits • Enhance compliance and follow-up

• Hub sites activities • KOL expertise in rare disease • Randomization qualification • More complex assessments

• Important considerations • Ameliorate satellite concerns about

losing patients • Follow existing physician referral

patterns • Work within large group practices,

where feasible

Site Engagement


When communication with your study sites is vital to your trial’s success, Chiltern has a site engagement team that provides study startup, feasibility and site training services Designed Around You.

Working Toward Better Days for Everyone


Looking for an experienced and collaborative research partner?

Chiltern is Designed Around You®.

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Looking for an experienced and collaborative research partner?

Chiltern is Designed Around You®.


Europe

171 Bath Road Slough, Berkshire, SL1 4AA UK Tel: +44 0 1753 512 000

North America

3147 S. 17th St., Suite 300 Wilmington, NC 28412

USA Tel: +1 910 338 4760

Documents

Emerging Strategies for More Cost-Effective Clinical ... Strategies for More Cost-Effective Clinical Development in the NASH Indication Randy L. Anderson, PhD SVP, Scientific and Regulatory