Ironwood 2017 R&D Day · 2019. 1. 14. · Sources: 1) ElSerag, Hashem "Update on the epidemiology...

A COMMERCIAL BIOTECHNOLOGY COMPANY

– March 9, 2017 –

Ironwood R&D Day

Introduction

Meredith Kaya Director, Investor Relations

“In large part, companies obtain the shareholder constituency that

they seek and deserve. If they focus their thinking and communications

on short-term results or short-term stock market consequences they

will, in large part, attract shareholders who focus on the same factors.

And if they are cynical in their treatment of investors, eventually that

cynicism is highly likely to be returned by the investment community.”

Warren Buffett (1979 Chairman’s Letter)

Safe Harbor Statement

This presentation contains forward-looking statements. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the development,

launch, introduction and commercial potential of linaclotide, lesinurad, our product candidates and the other products that we promote and the drivers, timing, impact and results thereof

(including near-term value-creating catalysts); reduction of a significant risk from IW-3718, if Phase IIb data is positive; market size, prevalence, growth and opportunity, including peak sales and

the potential demand for linaclotide, lesinurad and our product candidates, as well as their potential impact on applicable markets; the potential indications for, and benefits of, linaclotide,

lesinurad and our product candidates; the anticipated timing of preclinical, clinical and regulatory developments and the design, timing and results of clinical and preclinical studies; the potential

for, and timing of, regulatory submissions and approvals for linaclotide, lesinurad and our product candidates, and the level of risk associated with the path to approval; expected periods of

patent exclusivity; the strength of the intellectual property protection for linaclotide, lesinurad and our product candidates and our intentions and efforts to protect such intellectual property;

our potential for sustainable, high-margin growth and shareholder returns; consensus expectations related to revenue growth for certain commercial biotech companies; expectations concerning

if and when we will become cash flow positive; and our financial performance and results, and guidance and expectations related thereto (including the drivers and timing thereof), including

expectations related to Ironwood revenue CAGR, cash flow accretion, margin expansion and revenue growth, LINZESS U.S. net sales and growth, commercial margin and commercial costs,

LINZESS profitability and Ironwood revenues. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or

implied in such statement. Applicable risks and uncertainties include those related to the effectiveness of development and commercialization efforts by us and our partners; preclinical and

clinical development, manufacturing and formulation development; our reliance on AstraZeneca to provide critical support services related to lesinurad; the risk that findings from our completed

nonclinical and clinical studies may not be replicated in later studies; efficacy, safety and tolerability of linaclotide, lesinurad and our product candidates; decisions by regulatory authorities; the

risk that we are unable to successfully integrate lesinurad into our existing business, commercialize lesinurad or realize the anticipated benefits of the lesinurad transaction; the risk that we may

never get sufficient patent protection for linaclotide and our product candidates or that we are not able to successfully protect such patents; the outcomes in legal proceedings to protect or

enforce the patents relating to our products and product candidates, including ANDA litigation; developments in the intellectual property landscape; challenges from and rights of competitors or

potential competitors; the risk that our planned investments do not have the anticipated effect on our company revenues, linaclotide, lesinurad or our product candidates; the risk that we are

unable to manage our operating expenses or cash use for operations, or are unable to commercialize our products, within the guided ranges or otherwise as expected; and the risks listed under

the heading "Risk Factors" and elsewhere in Ironwood's Annual Report on Form 10-K for the year ended December 31, 2016, and in our subsequent SEC filings. These forward-looking statements

(except as otherwise noted) speak only as of the date of this presentation, and Ironwood undertakes no obligation to update these forward-looking statements.

4

Welcome and Introduction Meredith Kaya

Building a Top-Performing Commercial Biotech: 3 Provocative Questions Peter Hecht

IW-3718 for Uncontrolled GERD

Physician Perspective: Uncontrolled GERD and Bile Acid Hypothesis Michael Vaezi

IW-3718: When PPIs Alone Aren’t Enough Cheryl Gault + Michael Hall

Q&A

IW-1973 for Vascular Diseases

Leveraging Pharmacology to Harness Ubiquitous cGMP Pathway Mark Currie

Physician Perspective: Potential for sGC Stimulators to Treat Heart Failure, Resistant Hypertension and Diabetic Nephropathy

James Udelson

IW-1973: Tackling Big Problems in the Vascular Disease Field Cheryl Gault + Todd Milne

Q&A / Break

LINZESS® and Linaclotide Delayed Release-1 for IBS-C

Physician Perspective: Treating Visceral Pain in Lower GI Disorders Michael Camilleri

LINZESS, Abdominal Pain Relief and Linaclotide Delayed Release-1 Mark Rossetti + Carolyn Higgins

Focused U.S. Commercial Model Delivers Innovation to Patients Tom McCourt

Strategy to Deliver Sustainable, High-Margin Growth Tom Graney + Harriet Winter

Q&A / Closing

Today’s Agenda

5

Building a Top-Performing Commercial Biotech Company: Three Provocative Questions

Peter Hecht, Ph.D. Chief Executive Officer

Our Mission – Why We Are Here!

Create and commercialize

medicines that make a

difference for patients.

Build outstanding value

to earn the support of our

fellow owners.

Empower our passionate

team in its pursuit of

excellence.

7

Rapid growth Expect >25% Ironwood revenue CAGR (2016-2020)1

8

Grounded in

Innovation

Two innovative,

marketed products Multiple commercial

launches and pipeline catalysts

expected in 2017

1) The >25% Ironwood revenue CAGR calculation excludes any current or future revenue recognized in the period related to milestone payments to Ironwood, including approximately $39 million recognized in 2016.

Ironwood: A Successful Commercial Biotech Creating outstanding value for patients and our fellow shareholders

9

1

2

3

Does positive IW-3718 Phase IIb data reduce a significant risk for a >$2B drug for uGERD patients1?

Can IW-1973 be a >$5B drug2?

Can our current commercial products generate >25% revenue CAGR (2016-2020)3?

1) Peak annual U.S. sales estimates by Ironwood 2) Peak annual global sales estimates by Ironwood 3) The >25% Ironwood revenue CAGR calculation excludes any current or future revenue recognized in the period related to milestone payments to Ironwood, including approximately $39 million recognized in 2016.

Today’s Presenters

IRONWOOD TEAM • Meredith Kaya

Director, Investor Relations

• Peter Hecht, Ph.D. Chief Executive Officer

• Machelle Manuel, Ph.D. Vice President, Medical Scientific Affairs

• Cheryl Gault VP, Commercial Strategy & New Product Planning

• Michael Hall, M.B. B.Ch. SVP, Clinical Affairs

• Mark Currie, Ph.D. Chief Scientific Officer

• Todd Milne, Ph.D. Founder & VP, sGC R&D

• Mark Rossetti Sr Director, U.S. Brand Lead, LINZESS

• Carolyn Higgins Sr Scientist, GC-C R&D Program Leader

• Tom McCourt Chief Commercial Officer

• Harriet Winter VP, Corporate Strategy

• Tom Graney Chief Financial Officer

EXTERNAL MEDICAL EXPERTS

• Michael Vaezi, M.D., Ph.D. Vanderbilt University Medical Center

• James Udelson, M.D. Tufts University School of Medicine

• Michael Camilleri, M.D. Mayo Clinic

10

Uncontrolled GERD and the Bile Acid Hypothesis

Michael Vaezi, M.D., Ph.D. Professor of Medicine and Otolaryngology and Clinical

Director of the Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center

Extra-esophageal

Syndromes

Symptomatic

Syndromes

• Typical reflux

syndrome

• Reflux chest pain

syndrome

Syndromes with

Esophageal Injury

• Reflux esophagitis

• Reflux stricture

• Barrett's esophagus

• Adenocarcinoma

Established

Association

• Reflux cough

• Reflux laryngitis

• Reflux asthma

• Reflux dental

erosions

Proposed

Association

• Sinusitis

• Pulmonary

fibrosis

• Pharyngitis

• Recurrent otitis

media

Esophageal

Syndromes

GERD

GERD Common in the USA

• Heartburn and regurgitation

10%- daily 40%- weekly

• 100 million Americans

PPI Trial

H2RA’s - BID

H2RA’s-q day

Antacids

Life Style Modification

PPI’s - q day

PPI Trial

H2RA’s - BID

H2RA’s-q day

Antacids

Life Style Modification

PPI - BID

PPI’s - q day

Ignores the bigger issue of

Uncontrolled GERD

CASE

• 46 year old female presents with Hb and

regurgitation for the past several years

• Tried antacids then H2RA and now is

taking PPI’s

• Hb is better but not resolved and

regurgitation persists

• Endoscopy showed esophagitis and widely

patent GE jxn with hiatal hernia and bile

stained esophagus and stomach.

pH monitoring in symptomatic patients

on PPI therapy

Vaezi. Am J Gastroenterol 2005;100:283-289.

% D

ista

l To

tal T

ime

pH

< 4

0

5

10

15

20

25

30

Upper limit of normal

QD

ATYPICAL GERD (n = 115)

BID QD BID

TYPICAL GERD (n = 135)

(69%) (93%) (70%) (99%)

5.5

Vaezi. Am J Gastroenterol 2005;100:283-289.

% D

ista

l To

tal T

ime

pH

< 4

0

5

10

15

20

25

30

Upper limit of normal

QD

ATYPICAL GERD (n = 115)

BID QD BID

TYPICAL GERD (n = 135)

(69%) (93%) (70%) (99%)

5.5

ACID IS NOT THE PROBLEM

in

Uncontrolled GERD

Uncontrolled GERD

Referred to Specialists

Encountered by GI

Primary MD

Figure 1. Comparison of estimated economic burden of extraesophageal reflux (EER) initial evaluation to typical GERD, cancer and heart

disease.

0 12 35 58 90

Typical GERD

Cancer

Heart Disease

EER

$ (Billions)

Estimated Economic Burden of

GERD

Francis and Vaezi, AJG 2013

0 12 35 58 90

GERD

Non-Erosive Esophagitis Barrett’s

Pathophysiology

Defensive Aggressive

Factors

Acid

Pepsin

Bile acids

Trypsin

Alcohol

Acidic foods

LES

UES

Peristalsis

Saliva

Bicarbonate

Obesity

DGE

Hernia

PPI

H2RA

Lifestyle

UNMET NEED

• Bile reflux despite PPI therapy

– Uncontrolled GERD

– Progression of Barrett’s/dysplasia/CA

– Recurrence of BE post ablative therapy

– Bile aspiration chronic lung injury

– Bile damage in laryngitis/sinusitis

– Bile induced rejection of lung tx

– Bile regurgitation post-gastric bypass.

IW-3718: When PPIs Alone Aren’t Enough

Cheryl Gault VP, Commercial Strategy & New Product Planning

1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

H2 ANTAGONISTS PROTON PUMP INHIBITORS (PPIs)

GERD Proven to be Extremely Important Therapeutic Category

Improving symptom relief in millions of suffering patients resulted in multiple blockbuster brands

Despite efficacy of PPIs, millions of patients on PPIs still suffering symptoms3,4

Source: 1) QuintilesIMS Dec-2009 2) QuintilesIMS Dec 2009 3) Lieberman GI Patients Landscape survey, 2010 4) U.S. Census, 2015

U.S. Peak H2 Sales ~$4B1

U.S. Peak PPI Sales ~$14B2

33

Approximately Ten Million U.S. Adult Patients Suffer from Uncontrolled GERD1

Despite PPI use, these patients still suffering heartburn and other symptoms

• Tens of millions of U.S. adults suffer from GERD1

• Despite PPI treatment, ~10M continue to suffer2,3

• Patients identifiable; no Rx treatment options available

• Global opportunity to reach 60M+ potential uGERD adult patients1,4

Sources: 1) ElSerag, Hashem "Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review", Gut, 2014 2) Lieberman GI Patients Landscape survey, 2010 3) U.S. Census, 2015 4) Wang, Hai-Yun “Prevalence of gastro-esophageal reflux disease and its risk factors in a community-based population in southern India”

34

IW-3718 for Uncontrolled GERD: When PPIs Alone Are Not Enough

Offers potential for complementary mechanism to treat symptoms

DISEASED GI IW-3718 + PPI

IW-3718 utilizes gastric-retentive

formulation, may reduce bile exposure in

esophagus

35

IW-3718 Represents Greater than $2 Billion U.S. Annual Peak Sales Opportunity

36 Strong commercial fit; patent protection expected into mid-2030s

PHYSICIAN PAYER PATIENT

• Appreciate level of patient suffering

• Potential for broad access & reimbursement

• Recognize unmet need

• Willingness to adopt

• Minimal market preparation required

• Actively looking for relief

• Strong adherence based on high days on therapy with PPIs

36

IW-3718: When PPIs Alone Aren’t Enough

Michael Hall, M.B. B.Ch. SVP, Clinical Affairs

Bile Acid Pathogenesis: Reasons to Believe

• GERD patients had higher esophageal bile acid concentrations than controls1

• Bile acid infusions triggered GERD symptoms alone, and in combination with acid1

• Bile acids induced inflammation and cell injury in squamous epithelial cells1

• In preclinical studies2, bile acid induced:

– Esophageal mucosal nerve fiber activation

– Lower esophageal sphincter relaxation

• Effect was inhibited by coincubation with bile acid sequestrant

Supported by both preclinical and clinical data

Source: 1) McQuaid et al., Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment Pharmacol Ther 2011; 34: 146–165 2) Ironwood data 38

IW-3718 Phase IIa Trial Helped to Reduce Program Risk and Enable Phase IIb Trial Optimization

High frequency of bile reflux

Key Phase IIa Learnings

Improvements in GERD-related symptoms (heartburn, regurgitation)

Generally well-tolerated, constipation most common AE

39

PATHOLOGICAL BILE REFLUX STATUS

Consistent with published literature1

Approximately 2/3 of Patients in Phase IIa Trial who Underwent Bile Reflux Monitoring Tested Positive for Bile Reflux into the Esophagus

PBR = Pathological Bile Reflux: Data based on 52 Phase IIa patients tested for bile reflux using 24-h ambulatory Bilitec monitoring

Source: 1) Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett’s esophagus: acid reflux, bile reflux, or both? Am J Gastroenterol 2004;99:981-8.

36% PBR Negative

64% PBR Positive

40

IW-3718 Phase IIa Data Suggest Decrease in Heartburn Severity Most Pronounced in Patients with Confirmed Acid Reflux

Patients experiencing heartburn ≥2 episodes/week and confirmed acid reflux based on existing erosive esophagitis (EE); p values: pairwise comparison based on ANCOVA model w/ treatment and bile reflux status as factors and baseline as covariate. Confirmed ongoing esophagitis based on screening EGD or history of esophagitis at screening described as continuing at BL. Analysis based on ITT Population. Daytime heartburn was assessed on a 0-10 NRS (0= none; 10=very severe). BL = Baseline value

0

0.5

1

1.5

2H

eart

bu

rn S

ever

ity

Imp

rove

men

t

Treatment Period (p=0.007) BL=3.6; ∆=1.35; N=34

PPI Alone

IW-3718 + PPI

41

IW-3718 Phase IIa Data Showed Greater Decrease in Heartburn Severity in Patients with Confirmed Bile Acid Reflux

0.3

0.7

0.9

1.2

0

1.0 1.1

1.4

1.8

0

0.5

1

1.5

2

2.5

BLPb=3.22IW=3.82ave=3.52

Wk 1D=0.70p=0.02

Wk 2D=0.46p=0.20

Wk 3D=0.52p=0.13

Wk 4D=0.54p=0.12

LS M

ean

Ch

ange

PPI Alone

IW-3718 + PPI

Subgroup analyses support a trend to greater heartburn relief in patients more severe at baseline

PBR: pathologic bile reflux as assessed by 24-h ambulatory Bilitec monitoring BL= baseline; Ave is mean BL value; D= LS Mean difference IW3718+PPI vs. PPI Alone p values: comparison based on ANCOVA model w/ treatment and bile reflux status as factors and baseline as covariate Daytime Heartburn was assessed at its worst on a 0-10 NRS (0= none; 10=very severe)

0

0.4

0.6 0.7

1.1

0

0.7

1.3

1.6

2.2

0

0.5

1

1.5

2

2.5

BLPb=3.85IW=3.80Ave=3.83

Wk 1D=0.34p=0.54

Wk 2D=0.74p=0.18

Wk 3D=0.91p=0.21

Wk 4D=1.02p=0.13

LS M

ean

Ch

ange

PPI Alone

IW-3718 + PPI

All Patients N=88

Pathological Bile Reflux N=32

42

IW-3718 Phase IIa Data Leveraged to Optimize Phase IIb Trial Design

• Enhanced rigor of inclusion criteria aimed to:

– Ensure high likelihood of enrolling patients with bile reflux1

– Enroll patients with increased heartburn or regurgitation frequency at screening

– Randomize patients based on higher baseline heartburn severity

• Revised patient-reported outcome (PRO) instrument, based on FDA feedback

Sources: 1) Vaezi et al., Role of Acid and Duodenogastroesophageal Reflux in Gastroesophgeal Reflux Disease 1996 Gastroenterology 43

Phase IIb Study Designed to Provide Clear Go/No Go Decision

• 260 uGERD patients with positive reflux test, 4-arms

• Placebo and IW-3718 administered BID

• Primary endpoint: % change from baseline heartburn severity at week 8

• PRO instrument being validated in this study for potential Phase III trial

Double-blind, placebo-controlled, dose-ranging Phase IIb trial

2 WEEKS

Pretreatment Period

8 WEEKS

Treatment Period

PPI ONGOING

Placebo

IW-3718 500 mg

IW-3718 1000 mg

IW-3718 1500 mg

44

Major Phase IIb Objectives: Evaluate Improvement in Heartburn Severity with IW-3718 (+ PPI) vs PPI Alone and Define Clinically Meaningful Response Market Research Suggests Physicians Willing to Adopt if IW-3718 Demonstrates Even Modest Effect vs PPI Alone, Due to Marked Symptom Burden1

% C

ha

ng

e in

Hea

rtb

urn

Se

ve

rity

Baseline

(2 weeks)

Treatment

(8 weeks)

Illustrative only

IW-3718

+ PPI

PPI

Alone

Powered to detect >15% difference

Evaluate Improvement in Heartburn Severity

Source: 1) Ironwood 2015 Physician Survey

Patient-reported outcome data expected to:

• Define clinically meaningful response for

first time in this category

• Correlate with treatment effect

- Inform Phase III go/no go decision

- Advise Phase III endpoints, pending

FDA discussions and Phase IIb data

Define Clinically Meaningful Response

45

Positive IW-3718 Phase IIb Data Expected to Reduce a Significant Program Risk

• We believe demonstration of efficacy and clinical meaningfulness will substantially reduce one of the more significant risks in IW-3718 program

• Modest improvement in IW-3718 effect over PPIs alone is expected to lead to physician adoption (if approved)

• IW-3718 Phase IIa data demonstrated high frequency of bile reflux and supported further development of gastric-retentive bile acid sequestrant in uncontrolled GERD patients

• Uncontrolled GERD is a distinct population of ~10 million patients1,2; no existing prescription treatment options

– Opportunity for U.S. annual peak sales of >$2 billion

Source: 1) Lieberman GI Patients Landscape survey, 2010 2) U.S. Census, 2015 46

Leveraging Pharmacology to Harness the Ubiquitous

cGMP Pathway

Mark Currie, Ph.D. Chief Scientific Officer

• Therapeutic effects independent of disease mechanism (e.g. beta agonists for asthma)

• Our guanylate cyclase drugs use an agonist approach AND have the potential to treat underlying pathologies

The Beauty and Power of the Therapeutic Agonist Approach

Ironwood’s Guanylate Cyclase Agonists

cGMP

Intestinal

Characteristics: Decrease Visceral

Hypersensitivity

Increase Fluid Secretion & Transit

IW-1973 sGC

Linaclotide GC-C

Potential Characteristics:

Improve Vascular Function

Anti-Fibrotic

Anti-Inflammatory

Lower Glucose/Cholesterol

Systemic

IBS-C

CIC

Non-constipation subtypes of IBS

Non-GI Pain

DR1 (IBS-C only) LINZESS*

DR2

DRUG CANDIDATES POTENTIAL INDICATIONS

*FDA Approved

POTENTIAL INDICATIONS DRUG CANDIDATES

Diabetic Nephropathy

Heart Failure (pEF)

Resistant Hypertension

Specialty Diseases

Dementias (VaD, AD)

IW-1973

IW-6463

IW-1701

sGC Stimulator Video

Todd Milne, Ph.D. Founder and VP, sGC R&D

Potential for sGC Stimulators to Treat Heart Failure, Resistant Hypertension

and Diabetic Nephropathy

James Udelson, M.D. Chief, Division of Cardiology and Director,

Nuclear Cardiology Laboratory

Tufts University School of Medicine

52

Heart failure occurs when the heart is unable to

maintain blood flow to meet the body’s needs

• Left ventricle is the main pumping chamber

• Systole = the period of cardiac contraction

• Diastole = the period of cardiac relaxation

53

Heart failure occurs when the heart is unable to

maintain blood flow to meet the body’s needs

• Left ventricle is the main pumping chamber

• Systole = the period of cardiac contraction

• Diastole = the period of cardiac relaxation HFpEF HFrEF

54

Source: Decision Resources, Center for Disease Control, Harrison’s Principles of Internal Medicine, American Heart Association, Curr Heart Fail Rep,

Circ Heart Fail, L.E.K. analysis

The HFpEF patient population is projected to grow

at ~2.8% CAGR to reach ~4.8M patients by 2040

2

4

6

0

U.S. diagnosed prevalent HFpEF population

(2016-40F)

Millions of patients

4.8

2.1

0.5

35F

4.2

0.4

25F

3.2

1.4

0.4

20F

2.8

1.2

0.3

NYHA II

NYHA I

40F 2016

2.5

1.1

0.3

0.9

0.3

NYHA III

NYHA IV

1.0

0.4

1.3

0.3

1.1

0.3

2.8

1.8

0.5

30F

3.7

1.6

1.7

0.4 0.5

1.5

• The increasing prevalence

of HFpEF is largely

attributed to:

- Increased population

life expectancy

- Population aging

- Epidemic of cardiac and

non-cardiac

comorbidities (e.g.,

diabetes, obesity)

HFpEF prevalence

is expected to

increase by 2.8%

CAGR by 2040

Clinical Outcome Trials in HFpEF

DIG-pEF CHARM

Preserved

PEP-CHF I-PRESERVE TOPCAT SENIORS

N 988 3,023 850 4,133 3,445 752

Therapy Digoxin Candesartan Perindopril Irbesartan Spiro Nebivolol

Age (y) 67 67 75 72 69 76

LVEF (%) >45 54 64 59 56 >35

1’ Outcome HF Death/HF

Hosp

CV death/HF

Hosp

Death/HF

hosp

Death/CV

hosp

CV death/HF

hosp/aborted

arrest

Death/CV

hosp

Hazard Ratio 0.82

(0.63-1.07)

0.89

(0.77-1.03)

0.92

(0.70-1.21)

0.95

(0.86-1.05)

0.89

(0.77-1.04)

0.82

(0.63 – 1.05)

Ahmed et al. Circulation 2006

Pfeffer et al. Lancet 2003

Massie et al. N Engl J Med 2008

Pitt et al. N Engl J Med 2014 Flather et al. Eur Heart J 2005

Cleland et al. Eur Heart J 2006

55

Clinical Outcome Trials in HFpEF

DIG-pEF CHARM

Preserved

PEP-CHF I-PRESERVE TOPCAT SENIORS

N 988 3,023 850 4,133 3,445 752

Therapy Digoxin Candesartan Perindopril Irbesartan Spiro Nebivolol

Age (y) 67 67 75 72 69 76

LVEF (%) >45 54 64 59 56 >35

1’ Outcome HF Death/HF

Hosp

CV death/HF

Hosp

Death/HF

hosp

Death/CV

hosp

CV death/HF

hosp/aborted

arrest

Death/CV

hosp

Hazard Ratio 0.82

(0.63-1.07)

0.89

(0.77-1.03)

0.92

(0.70-1.21)

0.95

(0.86-1.05)

0.89

(0.77-1.04)

0.82

(0.63 – 1.05)

Ahmed et al. Circulation 2006

Pfeffer et al. Lancet 2003

Massie et al. N Engl J Med 2008

Pitt et al. N Engl J Med 2014 Flather et al. Eur Heart J 2005

Cleland et al. Eur Heart J 2006

56

HFpEF: Patient Profiles

57

JACC 2013

HFpEF: Patient Profiles

58

JACC 2013

59

Shah et al, Circulation 2016

59

60

Shah et al, Circulation 2016

60

61

Potential Benefit for sGC Stimulators in HFpEF

• Direct vascular effects

• Effects on LV & RV systolic and diastolic dysfunction

• Anti-inflammatory effects

• Anti-fibrotic effects

• Improve oxygen utilization/energetic efficiency (skeletal muscle)

Shah et al. Phenotypic Spectrum of HFpEF: Heart Fail Clin. 2014

62







O = potential effects

of sGC stimulation


63







O = potential effects

of sGC stimulation


↑ Exercise

Tolerance

Trial Program Design in HFpEF

64

Circ Heart Failure 2016

Trial Program Design in HFpEF

65

Circ Heart Failure 2016

Going forward, potential for primary emphasis on functional capacity

(as captured by exercise or walk testing) and QoL (as captured by

validated questionnaires reflecting everyday symptoms) rather than

traditional long-term morbidity and mortality…

HFpEF: Needs and Opportunities

• Large and growing population

• Currently barren therapeutic landscape – no evidence based therapies from RCTs

• Growing understanding of pathophysiology, involving multiple organs and signaling pathways…possible strike zone for sGC signaling

• Evolving regulatory thinking, enabling trial designs better targeted to the patient population and their everyday symptoms

• Development focus on function capacity +/- QoL may allow path to approval w smaller sample sizes and shorter follow-up than traditional M&M trials

66

67


Resistant hypertension is the failure to achieve goal BP (<140 ⁄ 90 mm

Hg in the general hypertensive population and <130 ⁄ 80 mm Hg in

patients with diabetes or CKD) when patients adhere to full doses of

an appropriate regimen of 3 antihypertensive drugs, including a

diuretic.

Not = Uncontrolled HTN:

• Receiving an inadequate treatment regimen

• With poor adherence

• With undetected secondary hypertension

68

Treatment paradigm for HTN

Prehypertension

120-130/80-89 mm Hg Hypertension

≥ 140/90 mm Hg

Lifestyle

Modifications

Works Fails

ACEi, ARB, or

diuretic

ACEi + diuretic or CCB

ARB + diuretic

ACEi + diuretic + CCB

ARB + diuretic + CCB

Resistant hypertension; try

aldosterone antagonist, beta

blocker, vasodilator, centrally

active agent, switch from ACEi or

ARB to renin inhibitor

Ineffective

Ineffective

Ineffective

Prevalence of Resistant HTN

69

Adapted from: Daugherty et al, Circulation 2012

3 classes of HTN meds

prescribed concurrently N = 24,499

BP controlled at BL N = 6,228 (25%)

BP uncontrolled at BL N = 18,271 (74.6%)

BP controlled at 1 yr N = 10,154 (41.4%)

BP uncontrolled at 1 yr N = 8,117 (33.1%)

Resistant HTN

(≥3 meds) N = 3,061 (12.5%)

Indeterminate N = 516 (2.1%)

Non-resistant HTN

(≤3 meds) N = 4,540 (18.5%)

Resistant HTN

(adherent) N = 2,692 (11.0%)

Pseudoresistant

(non-adherent) N = 369 (1.5%)

Increased Event Risk Among RH vs non-RH

Risk comparisons for outcomes among 60,327 resistant hypertension

patients vs 410,059 non-resistant hypertension patients (Sim et al 2015)

Ischemic Heart

Event

CHF

Cerebrovascular

Accident

End-Stage Renal

Disease

Mortality

70

https://www.ncbi.nlm.nih.gov/pubmed/25945406

71

Patients with uncontrolled HTN have high likelihood

of developing comorbid complications

• rHTN patients are usually affected by comorbid conditions

• sGC stimulation could have additional effects in comorbid conditions

Chronic Kidney

Disease

45% of patients

Diabetes

48% of patients

Ischemic Heart

Disease

41% of patients

Cerebrovascular

Disease

20% of patients

Sim, et al. Kidney International (2015)

Resistant HTN: Needs and Opportunities

• Large population

• Older, often w co-morbidities

• Currently frustrating therapeutic landscape for specialists and PCPs

• Consistent and well-known association with poor outcomes create urgency for physicians and payers alike to keep hypertension under control

• Recent trials provide guidance on recruitment and patient selection

72

Diabetic Nephropathy (DN) Overview

• Progressive kidney disease resulting from microvascular complications of diabetes

– Characterized by diffuse glomerulosclerosis

– Leads to HTN, proteinuria, ↓ GFR

– Associated with increased CV risk

• Epidemiology

– 20-30% of diabetics develop DN

7.4 million US diabetics have signs of nephropathy

– Higher prevalence in African Americans and Hispanics

– Most common cause of chronic kidney disease and end-stage renal disease (ESRD) in the US, representing a huge burden to the healthcare system (annual cost of ESRD ≈ $40 billion)

– Prevalence expected to increase with aging population

73

http://en.wikipedia.org/wiki/File:Nodular_glomerulosclerosis.jpeg

74

GFR and albuminuria contribute to the risk and

progression of CKD in DN patients

Risk and progression of CKD

Low risk Moderate risk High risk

Harrison's Principles of Internal Medicine

Prognosis of diabetic nephropathy by GFR and albuminuria levels

75

GFR and albuminuria contribute to the risk and

progression of CKD in DN patients

Risk and progression of CKD

Low risk Moderate risk High risk

Harrison's Principles of Internal Medicine

Prognosis of diabetic nephropathy by GFR and albuminuria levels

Contemporary DN Treatment Paradigm

Pharmacologic

therapy

Lifestyle

considerations

ACE or ARB Strict glucose

control

Try other class

(ACE or ARB) Restrict protein

Dialysis

Renal

transplant

1st line

2nd line

Last line

Diagnosed DN patients In

cre

asin

g s

everi

ty

Rx HTN

76

77

Rationale for Treating DN with an

sGC Stimulator

• NO deficiency is believed to be a key factor in the pathogenesis of DN

– Boosting NO-sGC-cGMP signaling could compensate for reduced NO levels

• Stimulation of sGC could have effects at multiple points in the DN disease process

– Systemic and glomerular hypertension

– Mitochondrial dysregulation/oxidative stress

– Mesangial matrix expansion/fibrosis

– Podocyte loss

Diabetic Nephropathy:

Needs and Opportunities

• Large population, significant % of diabetics

• Often with co-morbidities

• Currently frustrating therapeutic landscape for specialists and PCPs

• Markers of effect (albuminuria etc) as signals in early phase trials

• Aspects of pathophysiology well-suited for Rx with sGC stimulator

• Compelling rationale for treatment well understood by PCPs and specialists

78

Unmet Needs and Opportunities

• Heart Failure w Preserved EF

• Resistant HTN

• Diabetic Nephropathy

79

IW-1973: Tackling Big Problems in the Vascular

Disease Field

Cheryl Gault VP, Commercial Strategy & New Product Planning

Once-daily oral sGC stimulator has potential to offer much needed innovation via new mechanism

IW-1973 has Potential to Help Millions of Patients with Serious Diseases

• Large and growing patient populations

• Well established long term consequences; high unmet medical need


~7M patients1

Heart Failure preserved EF

~3M

patients2


~8M

patients3

Sources: 1) Apparent and true resistant hypertension: definition, prevalence and outcomes, J Hum Hypertens. 2014 August ; 28(8): 463–468. doi:10.1038/jhh.2013.140. 2) Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma, Curr Cardiovasc Risk Rep. 2011 October ; 5(5): 440–449. doi:10.1007/s12170-011-0184-2 3) Epidemiology of Diabetic Nephropathy, E.V. Lerma and V. Batuman (eds.), Diabetes and Kidney Disease, 9 DOI 10.1007/978-1-4939-0793-9_2.

$

$2,000,000,000

$4,000,000,000

$6,000,000,000

$8,000,000,000

$10,000,000,000

$12,000,000,000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

ARB class

Opportunity to Unlock Significant Commercial Potential across Heterogeneous Populations with Single Mechanism

Potentially analogous to angiotensin II receptor blocker (ARBs) order of entry

Source: 1) QuintilesIMS Dec-2010 2) Approval date, www.fda.gov

U.S. peak sales ~$10.8B1 Diabetic

Nephropathy indication2

Heart Failure indication2

Hypertension indication2

IW-1973 Order of Entry Designed to Maximize Commercial Success Resistant hypertension provides opportunity for initial physician education


Heart Failure preserved Ejection Fraction


• Most established aspect

of the mechanism

• Builds on vascular function • Adds potential anti-inflammatory

and anti-fibrotic effects

• Continues to build on vascular

function, potential anti-inflammatory

and anti-fibrotic effects

• Adds end-organ protection

Vascular function

Anti-inflammatory

Anti-fibrotic

IW-1973 Represents >$5 Billion Global Annual Peak Sales Opportunity

• Large and growing patient populations; significant morbidity and mortality

• Physicians and patients motivated to embrace efficacious new treatments

• Strong value proposition based on clinical profile and costs to the system

• Limited competition; potentially space for multiple brands and mechanisms


Heart Failure preserved EF


IW-1973: Tackling Big Problems in the Vascular

Disease Field

Todd Milne, Ph.D. Founder and VP, sGC R&D

Focused, Staged Clinical Development Program for IW-1973 Expect to initiate 3 Phase II Proof-of-Concept Clinical Studies in 2H 2017:


KEY ENDPOINT: urinary albumin

Heart Failure (preserved ejection fraction)

KEY ENDPOINT: exercise tolerance (cardiopulmonary exercise test and 6 minute walk test)


KEY ENDPOINT: blood pressure (on top of standard of care)

IW-1973 Clinical Demonstration of Pharmacology Phase I study in healthy subjects

TARGET ENGAGEMENT REDUCTION OF SYSTEMIC BLOOD PRESSURE

P la c e b o 3 0 m g

-8

-6

-4

-2

0

M e a n A r te r ia l P re s s u r e

mm

Hg

P la c e b o 3 0 m g

-2 0

0

2 0

4 0

6 0

P la s m a c G M P

% c

ha

ng

e c

GM

P

Plasma cGMP Mean Arterial Pressure

• No serious adverse events, adverse events generally mild to moderate

• Resolved upon repeat dosing

• Most common were headache and mild, transient symptoms and most related to lowered blood pressure

Attractive Tissue Distribution and Pharmacokinetics

Positive Safety and Tolerability Profile

• Dose-proportional and consistent exposure

• Large volume of distribution

• Long half life

IW-1973: Pharmacokinetic and Tolerability Profile

Phase I study in healthy subjects

30 mg

Steady-state Exposure of IW-1973

Ongoing IW-1973 Phase IIa Studies to Provide Clinical Experience in Relevant Patient Population

OBJECTIVES: Understand pharmaco-dynamics and tolerability and optimize dosing regimen

Data expected 2H 2017

ENDPOINTS:

Blood pressure, endothelial function, biomarkers, tolerability

PATIENTS:

Diabetics with hypertension

Study 1: Open-label, dose-

escalating

Study 2: Placebo-controlled,

14 day, 2 dosing regimens

Preclinical IW-1973 Data Support Advancement in Resistant Hypertension

• Tested in combination with major classes of anti-hypertensive medications

– ARBs

– Calcium channel blockers (CCB)

– Beta-blockers

– Diuretics

• Additive effects observed in each case

0 6 1 2 1 8 2 4

1 0 0

1 2 0

1 4 0

V e h ic le (n = 6 )

1 m g /k g (n = 6 )

3 m g /k g (n = 6 )

1 0 m g /k g (n = 6 )

T im e (h o u rs )

MA

P (m

mH

g)

IW-1973 Alone IW-1973 with Anti-hypertensives

Preclinical IW-1973 Data Support Advancement in Resistant Hypertension

• Tested in combination with major classes of anti-hypertensive medications

– ARBs

– Calcium channel blockers (CCB)

– Beta-blockers

– Diuretics

• Additive effects observed in each case

IW-1973 + Losartan (ARB) IW-1973 with Anti-hypertensives

IW -1 9 7 3 L o s a r ta n C o m b in a t io n

-1 5 0

-1 0 0

-5 0

0

hr*m

mH

g

* * *

IW-1973: Evaluating for the Treatment of Resistant Hypertension (rHTN)

Expected Phase II study design

RATIONALE: Complementary anti-hypertensive mechanism may enable rHTN patients to achieve blood pressure control

ENDPOINTS:

Blood pressure

PATIENTS:

Hypertensive patients not at goal despite treatment with 3 or more anti-hypertensives

IW-1973 Mediated Four Key Pharmacological Effects in Preclinical Models

93

V e h ic le V e h ic le H S + 1 m p k 1 9 7 3H S + 3 m p k 1 9 7 3IW -1 9 7 3 (1 0 )

0

1 0

2 0

3 0

4 0

5 0

IL -6

IL-6

(p

g/m

L)

* *

* *

Treatment

Ch

ange

in B

P

Time (h)

Pla

sma

IL-6

S M A R N A

V e h ic le V e h ic le IW -1 9 7 3 1 u M IW -1 9 7 3 3 u M IW -1 9 7 3 1 0 u M

0 .0

0 .1

0 .2

0 .3

0 .4

0 .5

T G F a t 1 0 n g /m L

S

MA

mR

NA

Re

lati

ve

Ex

pre

ss

ion

vs

GA

PD

H

Fibrosis

αSM

A

Treatment

0

1 0 0

2 0 0

3 0 0

4 0 0

***

**

Treatment

Blo

od

glu

cose

Decreased Blood Pressure

Lowered Glucose Anti-inflammatory

Anti-fibrotic

Preclinical IW-1973 Data Support Advancement in HFpEF

Dahl salt-sensitive rat model

Inflammation Fibrosis Cardiac Function

Treatment group is 10 mg/kg IW-1973

V e h ic le V e h ic le IW -1 9 7 3

0

1 0

2 0

3 0

4 0

5 0

IL-6

(p

g/m

L)

* *

* *

IL-6 (plasma)

High salt

K id n e y : T G F 1


0 .0

0 .2

0 .4

0 .6

0 .8

Ge

ne

ex

pre

ss

ion

***

***

TGF (kidney)

High salt


1 . 0

1 . 5

2 . 0

2 . 5

3 . 0

3 . 5

4 . 0

4 . 5

5 . 0

He

art W

eig

ht (

g)/B

od

y W

eig

ht (

Kg

)

***

***

Heart Hypertrophy

High salt

IW-1973: Evaluating for the Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF)


RATIONALE: Symptoms and physical activity in HFpEF patients may be improved by increasing blood flow and reducing inflammation, fibrosis and vascular stiffness

ENDPOINTS:

Exercise Tolerance (Cardiopulmonary exercise test and 6 min walk test)

PATIENTS:

Adult patients with HFpEF

Preclinical IW-1973 Data Support Advancement in Diabetic Nephropathy

Dahl salt-sensitive rat model


0

1

2

3

In te rs t it ia l In f la m m a tio n

Sc

ore

*** ***

High Salt


0 .0

0 .5

1 .0

1 .5

In te rs t it ia l F ib ro s isS

co

re

*** ***

M ic ro a lb u m in u r ia


0 .0

0 .5

1 .0

1 .5

2 .0

***

**

MA

LB

/Cr/B

W (

g/g

/kg

)

High Salt High Salt

Interstitial Inflammation Interstitial Fibrosis Microalbuminuria

Histology Kidney Function

Treatment group is 10 mg/kg IW-1973

IW-1973 for the Treatment of Diabetic Nephropathy


RATIONALE: Renal function may be protected by improving renal blood flow regulation and reducing inflammation and fibrosis

ENDPOINTS:

Urinary protein (albumin)

PATIENTS:

Adults with Type 2 diabetes, overt nephropathy

cGMP

IW-1973 sGC

Potential Characteristics:

Improve Vascular Function

Anti-Fibrotic

Anti-Inflammatory

Lower Glucose/Cholesterol

Systemic

IW-1973

Expected Phase II Initiations (2017):

• Diabetic nephropathy

• HFpEF

• Resistant hypertension

LARGE MARKET INDICATIONS

IW-1701

Expected Phase II Initiations (2017):

• Phase II in achalasia ongoing (data expected 2H 2017)

• Phase II in sickle cell (expected initiation 2018)

SPECIALTY INDICATIONS

IW-6463

• IND-enabling studies ongoing

• Penetrates blood-brain barrier preclinically (potential in vascular dementia, Alzheimer’s)

CNS INDICATIONS

Treating Visceral Pain in Lower GI Disorders

Michael Camilleri, M.D. Atherton and Winifred W. Bean Professor

Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic College of Medicine and Science Consultant in Gastroenterology, Mayo Clinic

©2012 MFMER | slide-102

Mechanisms Underlying the Irritable Bowel Syndrome

A variety of peripheral

mechanisms initiate perturbation of GI motor and sensory functions

and lead to IBS symptoms.

Identification of the peripheral mechanisms provides an

opportunity to prevent or reverse symptoms.

Declared “A Renaissance”…..

IBS is not one disease: Diverse GI pathobiological

mechanisms

Camilleri M N Engl J Med. 2012; 367:1626-35


IBS-C and CIC Pathophysiology

Decreased secretion

and GI motility

IBS-C and CIC are

characterized by decreased

fluid secretion and motility

which results in infrequent,

hard, and lumpy stools that

may be difficult to pass

Increased visceral

hypersensitivity

IBS-C is characterized by

visceral hypersensitivity,

which can present as

abdominal pain

Image reference: https://medlineplus.gov/ency/imagepages/9790.htm

https://medlineplus.gov/ency/imagepages/9790.htm


Symptom Spectrum in Functional Bowel Disorders (FBDs)

Lacy 2016


Constipation Predominant FBDs are Common

CIC IBS-C

~8 million No abdominal

discomfort,

bloating

~32 million Abdominal pain, discomfort and bloating

Straining, decreased stool frequency, hard stool

TOTAL PREVALENCE ~40 MILLION

Source: 1) Lieberman GI Patient Landscape survey, 2010. 2) IFFGD

2007, IBS Patients: Their illness experience and unmet needs


Visceral sensory innervation of the GI tract

CG, coeliac ganglion; IMG, inferior mesenteric ganglion;

NTS, nucleus of the solitary tract; SMG, superior mesenteric ganglion

Tortora & Grabowski 2000

Hypogastric nerve

Lumbar colonic

nerve

Greater splanchnic nerve

Paravertebral ganglia Vagus nerve

Pelvic nerve

Parasympathetic pathway Sympathetic

pathway

1

2

3

4

5

6

7

8

9

10

11

12

1

2

3

4

5

1

2

3

4

5

NTS

CG

SMG

IMG


afferent

efferent Sensation

brain

brainstem

prevertebral ganglia

reflex modulation

Pacinian

Corpuscle

in mesentery Naked nerve

ending in wall

of viscus

Enteroendocrine cells responsive to chemical and

mechanical stimuli

Luminal stimuli and

changes in wall tension

activate afferents

IGLE

PHYSIOLOGY OF GUT SENSATION


Integration Effect Input

Sight Sound Smell

Somatosensory

Viscerosensory Motility

Secretion Blood Flow

Cognition

Affect

Integration of CNS-Gl Function: Brain-Gut axis

Mayer EA Gastro 1990:99, 1688


Pain

Control


Bowel of IBS patient is HYPERSENSITIVE: higher sensation with stimuli

that are not-painful to healthy, and higher pain score when stimuli

induce pain in healthy people

Pain sensation

Hyperalgesia

Allodynia

Innocuous Noxious

Stimulus intensity

Normal

Insult

Sensitization


“Altered rectal perception is a biological marker of

patients with irritable bowel syndrome”.

Mertz H et al Gastroenterology 1995; 109:45-52

Hypersensitivity

Low pressure thresholds

Normal

thresholds:

median 50 mm

Hg Low thresholds:

median 20 mm Hg

Hyperalgesia at normal pressure thresholds

REFERRAL of SENSATION

Pts with IBS referred sensations

during rectal distention to sacral

and thoracolumbar dermatomes


Visceral Hypersensitivity

End Organ Sensitivity

• “Silent” nociceptors

Endogenous Modulation • Cortex

• Brainstem

Spinal Hyperexcitability

• Nitric oxide activation

Long-term Hyperalgesia

• Tonic cortical

regulation

Hyperalgesia

Allodynia

• Neuroplasticity

IBS – Hypersensitivity is associated with change in

sensory functions in the gut, nerves, spinal cord and brain

Mayer EA et al Gastroenterology 1994; 107:271


Guanylate

Cyclase-C

agonists:

Mechanism of action

On Visceral Sensation

Layer and Stanghellini

APT 2014; 39: 371–384


Effect of 5 Days linaclotide on Transit and Bowel Function in Females With IBS-C

Andresen, Camilleri et al Gastroenterology 133:761-768, 2007


cGMP Increases Pain Thresholds in a Model of Colonic Hypersensitivity and Inhibits Firing of Pain Afferents

Castro et al. Gastroenterology, 2013

CVH nociceptors

0

20

40

60

Dis

ten

sio

n T

hre

sh

old

(m

m H

g)

Naive 0.3 0 3 30 1

cGMP (mg/kg) Morphine

(mg/kg)

TNBS

** ***

***

Silos-Santiago et al. Pain, 2013


Johnston JM et al Gastro 2010; 139:1877-1886

Linaclotide Phase 2 IBS-C Trial Abdominal Symptoms over 12 week treatment


% C

ha

ng

e A

b.

Pa

in

-60

-50

-40

-30

-20

-10

0

Trial Week

BL 2 4 6 8 10 12 14 16 18 20 22 24 26

ITT Population, Observed Cases, LS-Means presented, p-values based on ANCOVA at each week. Bars

represent 95% confidence intervals.

Linaclotide Phase 3 IBS-C Trial

Abdominal Pain Over 26 Weeks

p = 0.0007 for Week 1

p < 0.0001 for Weeks 2-26

Treatment Groups

Lin 290 µg Placebo

Chey et al., Am. J. Gastroenterol. 2012, 107, 1702-1712.


Effects of linaclotide in patients with IBS-C or chronic constipation: a meta-analysis.

Videlock EJ, Cheng V, Cremonini F, CGH 2013;11:1084-1092


Linaclotide:

Mechanism of Action

Layer and Stanghellini APT 2014; 39: 371–384

Bryant, et al. Life Sciences, Volume 86, Issues 19–20, 8 May

2010, Pages 760–765

LINACLOTIDE

GUANYLIN

UROGUANYLIN


Gastrointestinal Physiology is Regulated by Peptides with pH-Dependent Activity

• Uroguanylin, a naturally

occurring peptide hormone,

binds to the GC-C receptor,

which helps to regulate fluid

secretion and intestinal

transit

• Uroguanylin is primarily

expressed in the small

intestine

• Low pH (pH 5-6)

environment where

uroguanylin is most active

Small Intestine Colon

• Guanylin, a naturally occurring peptide hormone, binds to GC-C receptors, primarily in the large intestine, which may help to regulate visceral sensation

• Guanylin is primarily expressed in the large intestine

• Higher pH (pH 8) environment where guanylin is most active


Linaclotide Works in the Small Intestine and Colon

Fluid secretion

primarily occurs in

the small intestine

Visceral sensitivity

in the colon is a

marker of IBS


Summary

• Over the last 25 years IBS has become recognized as a real disease

• Greatly expanded understanding of the pathophysiology of visceral hypersensitivity and motility

• GC-C agonists represent a probe to further understanding of abdominal pain and function in IBS

• Emerging science and new therapies will lead to a deeper understanding of science behind IBS


Guanylate Cyclase C Agonists: Emerging Gastrointestinal Therapies and Actions

Camilleri M Gastroenterology, 148:483-7, 2015

LINZESS, Abdominal Pain Relief and Linaclotide Delayed Release-1 (DR1)

Mark Rossetti Senior Director, U.S. Brand Lead, LINZESS

LINZESS on Track to Exceed $1 Billion in U.S. Net Sales by 2020; Opportunity for Continued Growth

• Nearly 1.5M patients treated;

only ~3% of suffering patients1

• >180K HCPs have prescribed

LINZESS3

• ~80% of patients have

unrestricted payer access4

3 Dosage strengths

#1 Prescribed brand1

2 Indications 4 Years on the market

126

TRx

Vo

lum

e

200,000

300,000

400,000

500,000

600,000

700,000

800,000

2Q14 3Q14 4Q14 1Q15 2Q15 3Q15 4Q15 1Q16 2Q16 3Q16 4Q16

Strong Rx Growth2

Sources: 1) QuintilesIMS Total Patient Tracker Jan-2017 2) QuintilesIMS NPA Dec-2016 3) QuintilesIMS Xponent Feb-2017 4) Fingertip Formulary Jan-2017

Estimated 40 Million U.S. Adult IBS-C & CIC Patients; 80% Experience Abdominal Symptoms with Constipation1

• >75% of surveyed IBS sufferers reported having continuous or frequently recurring abdominal pain during the last six months2

• >85% of surveyed IBS-C and CIC sufferers with abdominal symptoms rate their symptoms as bothersome1

• ~70% of surveyed IBS-C and CIC sufferers are dissatisfied with OTC treatments1

127

CIC IBS-C

~8 million No abdominal

discomfort, bloating

~32 million Abdominal pain, discomfort and bloating

Straining, decreased stool frequency, hard stool

TOTAL PREVALENCE ~40 MILLION

Source: 1) Lieberman GI Patient Landscape survey, 2010. 2) IFFGD 2007, IBS Patients: Their illness experience and unmet needs

Assumptions • Branded medication

priced $11.78/day • TRx (30 day) priced

$353/TRx

128

Converting OTC Treated Patients Expected to Fuel Continued Growth of LINZESS

Rx Lax ~11M TRxs2,4

OTC Lax ~22M units3,4

(unit=30 days)

>$4.0B

LINZESS2

2/3 of new LINZESS Rxs come from OTC1

$7.5B+ OTC Lax Market

Sources: 1) QuintilesIMS Custom Source of Business Dec-2016; 2) QuintilesIMS NPA Jan-2017; 3) QuintilesIMS/IRI June 2016; 4) Chey, W. et al “Frequency and Bothersomeness of Symptoms, Health Care Seeking Behavior and Satisfaction with Therapy in IBS-C Patients Meeting ROME II Criteria: Results of a Population Based Survey”; Hoch, R, et al "Title: Symptom Frequency, Health Care Seeking Behavior, and Satisfaction with Therapy among Chronic Constipation Patients with Both Constipation and Abdominal Symptoms: Results of a Population-Based Survey“;

Surveyed Physicians Ranked LINZESS Higher Than OTC Laxatives on Key Product Attributes

0

10

20

30

40

50

60

Abdominal pain relief Bloating relief* Predictableconstipation relief

Low out of pocketcost

Low incidence ofsevere diarrhea

Surveyed Physicians Rated LINZESS vs OTC Laxatives

LINZESS OTC LAX

Top 5 most important product attributes for IBS-C/CIC patients, as reported by 273 surveyed targeted HCPs

% o

f H

IGH

rat

ing

wit

h M

Ds

C1. Below is a list of attributes related to products used to treat IBS-C and/or CIC symptoms. Please rate how important each attribute is in the selection of a treatment for IBS-C and/or CIC. C2. Now considering the same attributes, please indicate how well you feel each of the following IBS-C and/or CIC medications performs on those attributes. HIGH rating (6 or 7) on 7 point scale

129 Source: 1) SRI IBS HCP Tracker-Wave 4, August 30, 2016.

*Data from physician survey; not a claim of efficacy or safety.

Physician Satisfaction for LINZESS Increased with Experience

50

55

60

65

70

75

80

2013 2014 2015 2016

Gastroenterologists

>70% of surveyed physicians reported to be highly to extremely satisfied with LINZESS

50

55

60

65

70

75

80

2013 2014 2015 2016

Primary Care Physicians

S9. Please enter the names of all the Prescription products used to treat the symptoms of IBS-C and/or CIC that you are aware of (whether you use them or not). S9a. Please enter the names of all the Over-the-Counter (OTC) products used to treat the symptoms of IBS-C and/or CIC you are aware of (whether you use them or not). S10. Regardless of your answers in the previous question, please indicate whether or not you are aware of the following products used to treat the symptoms of IBS-C and/or CIC. A4. Please rate your level of knowledge of each of the following product(s) used to treat the symptoms of IBS-C and/or CIC on a 1 to 7 scale, where 1 = “Not at all Knowledgeable” and 7 = “Extremely Knowledgeable”. A5. Thinking of your experience with each of the following product(s) used to treat IBS-C and/or CIC symptoms, please indicate how satisfied you are with the overall performance of each product used for the treatment of IBS-C and/or CIC.

% H

igh

ly/

Extr

emel

y Sa

tisf

ied

130

Outstanding Payer Access is Foundational for Continued Growth of LINZESS

Strong value proposition supports broad access

• Indicated in adults for both IBS-C and CIC

• 3 doses to tailor treatment to individual patient need (IBS-C: 290mcg; CIC: 145mcg and 72mcg)

• Price intended to ensure patient access and maintain payer coverage

>90% Unrestricted access for Medicare Part D lives1

>75% Unrestricted

access for commercial

lives2

Affordable for patients

• ~$30 copay for up to 90-day supply

• Daily cost is less than many OTC laxatives

Sources: 1) Finger Tip Formulary Feb 2017 2) Analysource Feb 2017 131

Source: 1) QuintilesIMS 2016

LINZESS Provides Effective Abdominal Pain Relief for IBS-C Patients

LINZESS reaches maximum relief of abdominal pain in 6-9 weeks

1 6 7 8 9 12 Baseline

Effe

ct

Trial Period (weeks)

Max Abdominal Pain Improvement Achieved

WKS 6-9 For Illustrative Purposes Only

Abdominal Pain

170

119

0

50

100

150

200

New to Brand 30 Day

New to Brand 90 Day

Day

s o

f Th

erap

y

+43%

Patients are more adherent to treatment if their initial trial is

longer than 30 days1

132

LINZESS patients more adherent to treatment if trial >30 days

Patient Funnel Continues to Expand; Increases Opportunity to Drive the Growth of LINZESS

2014 2016

HCPs honor patient request for LINZESS3

# of HCPs Rx LINZESS2

Consumer awareness1

Prescriptions Rejected by Payer4

1% Unaided Awareness

~70K

~75%

~9%

8% Unaided Awareness

>180K

>90%

~12%

8x increase

>2.5x increase

20% increase

133 Sources: 1) ComScore Linzess Brand Monitor Report – Dec-2016 2) QuintilesIMS Xponent Dec-2016 3) Direct to Consumer Advertising Survey Wave 15, Princeton Survey Research Associates; comScore Patient Pathway – Dec-2016 4) Symphony Health DCA Q4 2015

25% decrease

Linaclotide Franchise Positioned for Strong Growth

Grow the Market

Capture Market Share

Raise the Bar

134

Outstanding Access

LINZESS, Abdominal Pain Relief and Linaclotide Delayed Release-1 (DR1)

Carolyn Higgins Senior Scientist, GC-C R&D Program Leader

Linaclotide Believed to Work on Visceral Hypersensitivity and GI Motility Through cGMP

136

Hypothesis Building: Leveraging Scientific Knowledge to Help Patients

• Delivering more linaclotide to the colon may enhance abdominal pain relief

• Drug release at the mid-ileum could achieve this while retaining the favorable effects on constipation of LINZESS

137

Abdominal Pain in IBS-C is Believed to Be Driven by Hypersensitivity in the Colon

Linaclotide reduced the activity of colonic pain nerves that have been hypersensitized (in ex vivo experiments)

138

Colonic visceral hypersensitivity is a marker of IBS

0

Mec

han

ose

nso

ry r

esp

on

se (

spik

es/s

ec)

0

6

12

18

24

1 30 100 300 1,000

n = 10

Linaclotide (nM)

***

***

*** ***

Castro et al. Gastroenterology (2013)

Linaclotide increased fluid secretion along the small intestine of rats

Linaclotide is Believed to Work on Constipation By Increasing Secretion in the Small Intestine

139

Wei

ght

/ Le

ngt

h R

atio

0

0.05

0.1

0.15

0.25

n = 10

Duodenum

0.2 ***

Jejunum Ileum

***

**

Vehicle

Linaclotide (5 ug)

Busby et al. European Journal of Pharmacology (2010)

Linaclotide Delayed-Release (DR1) Designed to Deliver More Drug to the Colon

DR1: Mid-Ileum Release LINZESS: Immediate Release in Stomach

140

Effective Relief of Abdominal Pain

Potential For Even MORE Abdominal Pain Relief

Testing the DR Hypothesis Clinically in a Phase IIb Study in IBS-C Patients

• Randomized, placebo-controlled, double-blind study

• 532 IBS-C patients (66-67 per treatment group)

– Placebo

– LINZESS 290 μg (immediate-release linaclotide)

– DR1 (30, 100, 300 μg)

– DR2 (30, 100, 300 μg)

• Treated for 12 weeks (after 2-week baseline period)

– Daily diary collections of IBS-C symptoms

– Comparison before (baseline) and after treatment

141

DR1 Phase IIb Data on FDA-Recommended Endpoint

Proportion of Combined Responders (Pain + Constipation)

21.2

31.8

38.8

0

5

10

15

20

25

30

35

40

45

Placebo(N=66)

IR 290 ug(N=66)

p=0.167

DR1 300 ug(N=67)

p=0.026

Perc

ent

Res

po

nd

ers

142 P-values vs. placebo based on CMH test controlling for geographic region; not corrected for multiplicity

DR1 Phase IIb Data Demonstrated Improvement in Abdominal Pain Relief1

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

0 1 2 3 4 5 6 7 8 9 10 11 12

LS M

ean

% C

han

ge f

rom

Bas

elin

e

Treatment Week

Abdominal Pain % Change from Baseline by Week

LSMeans based on an ANCOVA with treatment and region as fixed effect and baseline as a covariate.

P-values vs. placebo and LSMeans based on an ANCOVA with treatment and region as fixed effect and baseline as a covariate. P-values are not corrected for multiplicity

IR 290 ug -40.6% p=0.0429

Placebo -26.2%

DR1 300 ug -49.5% p=0.0011

1) Double-blind, placebo-controlled, dose-ranging, exploratory 8-arm Phase IIb trial in 532 IBS-C patients. Differences cited above were numerical. The trial was designed to evaluate the safety and efficacy of each linaclotide colonic release formulation relative to placebo; the statistical power was based on a linear dose response 2) Lieberman GI Patient Landscape survey, 2010 143

0

5

10

15

20

25

30

35

40

Placebo(N=66)

IR 290 ug(N=66)

p=0.1439

DR1 300 ug(N=66)

p=0.0263

Perc

ent

Res

po

nd

ers

DR1 Phase IIb Data Demonstrated Improvement in 50% Abdominal Pain Responders1

18.2

28.8

35.8

144

1) Double-blind, placebo-controlled, dose-ranging, exploratory 8-arm Phase IIb trial in 532 IBS-C patients. Differences cited above were numerical. The trial was designed to evaluate the safety and efficacy of each linaclotide colonic release formulation relative to placebo; the statistical power was based on a linear dose response

P-values vs. placebo based on CMH test controlling for geographic region; not corrected for multiplicity.

DR1 Phase IIb Data Demonstrated Constipation Relief

CSBM Responder Rate (6 of 12 weeks)

34.8

52.2

0

10

20

30

40

50

60

Placebo(N=66)

IR 290 ug(N=66)

p=0.040

DR1 300 ug(N=67)

p=0.032

Perc

ent

Res

po

nd

ers

P-values vs. placebo based on CMH test controlling for geographic region; not corrected for multiplicity.

53.0

145

DR1 is an Exciting Opportunity

• DR1 could advance IBS-C care even further

– Potential for improvement in pain relief

– Potential for better benefit/side effect profile

– Possible new endpoint claims on additional symptoms of great importance to patients (abdominal bloating, discomfort, and pain)

• DR1 next steps

– Execution of a successful Phase III program is a top priority

– FDA meetings are planned to align with agency

– Anticipating Phase III study start by 2H 2017

LINZESS and Linaclotide Delayed Release Poised for Strong Growth

• LINZESS shows strong growth and momentum driven by demand for effective relief of abdominal pain and constipation in IBS-C and multiple symptoms in CIC

• Linaclotide delayed release, if approved, is expected to accelerate growth in the IBS-C category

• If approved, potential for:

– Abdominal pain relief with good tolerability driving choice

– Increased adherence to treatment

– Formerly treated patients who experienced inadequate relief

– Communicating relief of abdominal pain and other symptoms, such as bloating, discomfort or fullness

147

If Approved, DR1 Growth Expected to Accelerate as Physicians & Patients Choose More Effective Treatment

Prescrip

tion

s

DR1 Expected Growth Drivers • Motivate NEW OTC patients with

pain, bloating & discomfort message

• Discontinued patients due to inadequate pain relief

• Better adherence to treatment

Time

148

• Prescription refills

• High patient awareness of LINZESS

• MD experience

Expected LINZESS Momentum Drivers:

Focused U.S. Commercial

Model Delivers Innovation

to Patients

Tom McCourt Chief Commercial Officer

Ironwood’s Commercial Model Expected to Drive Productive, High-Margin Business

150

Innovative products treating motivated patients with

highly symptomatic disorders in underserved markets

INNOVATIVE PRODUCTS

UNDERSERVED MARKETS/ MINIMAL COMPETITION

FOCUSED SELLING EFFORT

MOTIVATED PATIENTS

HIGHLY SYMPTOMATIC DISORDERS

VALUE RECOGNIZED BY PAYER

Opportunity for LINZESS to Address High Unmet Needs Enables Favorable Market Dynamics to Drive Growth

Millions of symptomatic patients2

Underserved patients

First in category

Advancement in care

Limited competition

151

TRx

Vo

lum

e

1) QuintilesIMS NPA December 2016 2) Lieberman GI Patient Landscape survey, 2010

200,000

300,000

400,000

500,000

600,000

700,000

2Q14 3Q14 4Q14 1Q15 2Q15 3Q15 4Q15 1Q16 2Q16 3Q16 4Q16

Strong Rx Growth1

Drive High Productivity and Growth While Leveraging Efficiency and Synergies With Customers and Patients

Ironwood has demonstrated ability to impact behavior and demand with potential for expansion across multiple therapeutic areas

Productivity Drivers for Brand Growth

High prescribing primary care physicians

Early adopters

Physicians treat multiple therapeutic categories

Highly promotionally sensitive

Several cost synergies

25-35k PCPs

IBS-C & CIC

IBS-D & M

uGout uGERD

Other symptomatic

diseases IBD

152

ZURAMPIC® (lesinurad) and DUZALLO™ (lesinurad + allopurinol FDC) are Aligned with IRWD Commercial Model

Innovative Advancement In Care

Underserved Market/ Minimal Competition

Overlapping Prescribers

Motivated Patients

Highly Symptomatic Disorders

Recognized By Payers

Little innovation for over 30 years

Nearly 2X as many patients on ZURAMPIC + allo (vs allo alone) reached goal1,2

>2 million Americans suffer from ~5 painful flares / year3

Strong physician and patient desire to gain control of gout

Strong value proposition

>80% of gout prescriptions written by PCPs4

MARKET DRIVERS BRAND SOLUTIONS

Sources: 1) Allopurinol PI 2) Zurampic PI 3) 2010 NHANES Study estimate, grown at 3% AGR; Juraschek SP etal, Arthritis Care, 2015; Zhu Y al, Arthritis Rheumatol, 2012; Wood Retal, J Rheumatol, 2016; Khanna Petal, Postgrad/Med, 2016: Meyer M et al, Am J Pharmacy Ben 2015; PrimatestalP et al, BMC Musculoskeletal Dis. 2010; Singh J A Etal, Arthritis Res & Ther, 2015 AZ/Decision Resources Market Research. 4) QuintilesIMS NPA December 2016

153

XOI and Acute Treatment

30+ years

Estimated annual peak sales opportunity for uncontrolled gout franchise >$300M

ZURAMPIC and DUZALLO: Simple Solution to Get More Uncontrolled Gout Patients to Goal Up to 2M Americans not reaching targeted sUA levels of <6mg/dL1

Building a Gout Franchise

ZURAMPIC + XOI DUZALLO

(lesinurad + allo FDC)

TODAY Expected late 2017 →

Stagnant Advancement Acceleration

154 1) 2010 NHANES study estimate, grown at 3% AGR; Juraschek SP et al, Arthritis Care, 2015; Zhu Y et al, Arthritis Rheumatol, 2012; Wood R et al, J Rheumatol, 2016; Khanna P et al, Postgrad Med, 2016; Meyer M et al, Am. J Pharmacy Ben 2015; Primatesta P et al, BMC Musculoskeletal Dis. 2010; Singh JA et al, Arthritis Res & Ther, 2015; AZN/Decision Resource Market Research

Source: 1) 2010 NHANES study estimate, grown at 3% AGR; Juraschek SP et al, Arthritis Care, 2015; Zhu Y et al, Arthritis Rheumatol, 2012; Wood R et al, J Rheumatol, 2016; Khanna P et al, Postgrad Med, 2016; Meyer M et al, Am. J Pharmacy Ben 2015; Primatesta P et al, BMC Musculoskeletal Dis. 2010; Singh JA et al, Arthritis Res & Ther, 2015; AZN/Decision Resource Market Research

XOI and Acute Treatment

30+ years

Estimated peak sales opportunity for uncontrolled gout franchise >$300M

ZURAMPIC and DUZALLO: Simple Solution to Get More Uncontrolled Gout Patients to Goal Up to 2M Americans not reaching targeted sUA levels of <6mg/dL

Building a Gout Franchise

ZURAMPIC + XOI DUZALLO

(lesinurad + allo FDC)

TODAY Expected late 2017 →

Stagnant Advancement Acceleration

DUZALLO (lesinurad + allo FDC)

Expected late 2017 →

Acceleration

• 2 products, 1 pill, once a day

• 1 copay for patients

Ironwood Model Expected to Drive

Expansion of Commercial Margin

Commercial

Expenses

Commercial

Net Sales

Mid-2030s

• Patient need & adherence

• Increasing product demand

• MD prescribing productivity

• Target selling effort & synergy

• Shared Expenses

156

(illustrative)

Strategy to Deliver Sustainable, High-Margin Growth

Tom Graney Chief Financial Officer

Harriet Winter VP, Corporate Strategy

IW-3718

Key Takeaways from Earlier Presentations

158

• Bile acid sequestration is an innovative investigational approach to major unmet clinical need of uncontrolled GERD

• Attractive commercial market with opportunity for U.S. annual peak sales of >$2 billion

• Upcoming Phase IIb trial data expected to substantially reduce one of the more significant risks to program

IW-1973


159

• IW-1973 has potential to generate global annual peak sales of >$5 billion

• Pharmacology may address pathophysiology underlying resistant hypertension, HFpEF and diabetic nephropathy

• Multiple Phase II studies expected to begin in 2017

• Additional sGC stimulators IW-1701 and IW-6463 also have potential to be multi-billion dollar peak sales opportunities

Linaclotide Delayed Release-1 (DR1)


160

• LINZESS expected to generate >$1 billion in U.S. annual net sales by 2020

• DR1 Phase IIb data showed improvement in abdominal pain relief in IBS-C, #1 motivator for patients seeking treatment

• DR1, if approved, expected to expand IBS-C market and together with LINZESS, drive U.S. annual peak sales of >$2 billion

Delivering on Innovation: Ironwood is a Fast-Growing Biotech with a Strong Pipeline

LINZESS, ZURAMPIC and DUZALLO (if approved) expected to drive first wave of sustainable growth and expanding margins; expect to achieve positive cash flow during 2018

161

Innovative mid- and late-stage pipeline is increasingly de-risked

and aims to deliver a series of important launches beginning in 20201

- IW-3718, DR1, IW-1973

- IW-1701, DR2, IW-6463

Multiple major catalysts expected over next 12 to 24 moths

1) If investigational drug is FDA-approved

Current Commercial Products Driving Sustainable Growth and Expanding Margins

Mid 2030’s (illustrative)

162

Expect >25% Ironwood revenue CAGR (2016-2020)1

2019 Expect ZURAMPIC & DUZALLO cash flow accretive

2020 Expect >$1B LINZESS U.S. Net Sales

LINZESS, ZURAMPIC & DUZALLO (if approved) U.S. Net Sales

Commercial Expenses

Source: 1) The >25% Ironwood revenue CAGR calculation excludes any current or future revenue recognized in the period related to milestone payments to Ironwood, including approximately $39 million recognized in 2016.

Ironwood Expected Revenue Growth is Among Highest for Commercial Biotech Companies

Source: 1) Factset Feb 22, 2017. Ironwood consensus forecast, adjusted to exclude any current or future revenue recognized in the period related to milestone payments to Ironwood, including approximately $39M recognized in 2016. Excludes companies without commercial products and those with 2016 revenue <$100M. 4-year CAGR calculated between full year revenue actuals for 2016 and analyst consensus revenue estimates for 2020, as reported in FactSet on 22 Feb 2017

163

Company Consensus

Expected Rev Growth '16-'201

Seattle Genetics 32%

Ironwood Pharmaceuticals 25%

Alkermes 24%

Incyte 23%

Vertex Pharmaceuticals 23%

Pacira Pharmaceuticals 21%

BioMarin Pharmaceuticals 19%

Alexion Pharmaceuticals 17%

Celgene 17%

Acorda Therapeutics 13%

Shire 13%

Regeneron Pharmaceuticals 12%

Jazz Pharmaceuticals 12%

Actelion 11%

Grifols 5%

UCB 5%

Biogen 4%

Amgen 1%

Endo International (0%)

United Therapeutics (2%)

Gilead Sciences (7%)



164



- IW-3718, DR1, IW-1973

- IW-1701, DR2, IW-6463

Multiple major catalysts expected over next 12 to 24 months

1) If FDA-approved

Innovative Pipeline Programs are Risk-Reduced Opportunities in Large, Uncrowded Markets

165

Unmet Need

Clinical Validation

Safety Experience

Manufacturing

Regulatory Clarity

IW-1973 IW-3718

?

Delayed Release (DR1)



166



- IW-3718, DR1, IW-1973

- IW-1701, DR2, IW-6463


1) If FDA-approved

Potential upside through value-creating acquisitions and in-licensing

Future High-Margin Growth Expected to be Driven By Series of Important Launches from Innovative Pipeline

167

Continuing momentum driven by growth of LINZESS,

ZURAMPIC & DUZALLO1 – long-lived, high margin

assets

+ Growth of delayed release products and

IW-37181

+ Growth of IW-1973 and other sGC stimulators1

Ironwood Expected Revenue Over Time

2017

1) If FDA-approved



168



- IW-3718, DR1, IW-1973

- IW-1701, DR2, IW-6463


1) If FDA-approved

Key Catalysts Expected in Next 12 to 24 Months

169

EVENT / METRIC EXPECTED TIMING

IMPACT IF DATA ARE POSITIVE

IW-3718 uGERD Phase IIb data

Mid 2017 Reduces a significant risk to >$2B U.S annual peak sales opportunity

DUZALLO launch (if approved) 2H17 Significant catalyst for uncontrolled gout franchise

DR1 Phase III initiation in IBS-C 2H17 Clearer view on timeline to potential approval and anticipated labeling

IW-1973 Phase IIa results in diabetics with hypertension

2H17 Emerging data on vascular effects and tolerability in diabetic population

IW-1973 Phase II initiations 2H17 Study data expected to establish dose(s) and safety/tolerability profile to enable pivotal studies

IW-1701 Phase IIa results in achalasia

2H17 Establish proof-of-principle for 2nd sGC stimulator in GI neuromuscular disorder

DR2 Phase IIb initiation 2017/2018 Study data expected to establish potential for new linaclotide brand in non-constipation subtypes of IBS

IW-1701 Phase II initiation in sickle cell disease

2018 Advance 2nd sGC stimulator in additional disease space

IW-3718 Phase III initiation 2018 Clearer view on timeline to potential approval and anticipated labeling

An R&D-driven innovation engine delivering outstanding value to our shareholders by creating and commercializing medicines that

make a meaningful difference in patients’ lives

Ironwood Vision

170

• Executing on a robust portfolio of marketed and development-stage products, derived from internally-discovered and externally-acquired assets

• Commercializing medicines ourselves in the U.S. whenever value-maximizing; partnering to access capabilities when advantageous

• Fostering a culture where exceptional, high-performing employees love coming to work and are passionate about what they do

• Delivering outstanding returns and growth in cash flow per share, earning the right to remain an independent company for the long-term

Rapid growth Expect >25% Ironwood revenue CAGR (2016-2020)1

172

Grounded in

Innovation

Two innovative,

marketed products Multiple commercial

launches and pipeline catalysts

expected in 2017

1) The >25% Ironwood revenue CAGR calculation excludes any current or future revenue recognized in the period related to milestone payments to Ironwood, including approximately $39 million recognized in 2016.

Ironwood: A Successful Commercial Biotech Creating outstanding value for patients and our fellow shareholders

Ironwood 2017 R&D Day · 2019. 1. 14. · Sources: 1) ElSerag, Hashem "Update on the epidemiology...

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