Ironwood Pharmaceuticals, Inc. · NASDAQ:IRWD
Ironwood Pharmaceuticals — Investor Day (March 2017)
172 slides from Ironwood Pharmaceuticals's investor day presentation, Mar 9, 2017
Slide 1: Ironwood R&D Day
A COMMERCIAL BIOTECHNOLOGY COMPANY Ironwood R&D Day – March 9, 2017 –
Slide 2: Introduction
Introduction Meredith Kaya Director, Investor Relations
Slide 3: Warren Buffett quote on shareholder constituency
“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 cynica
Slide 4: Safe Harbor Statement
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 candi
Slide 5: Today's Agenda
Today’s Agenda 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 +
Slide 6: Building a Top-Performing Commercial Biotech Company: Three Provocative Questions
Building a Top-Performing Commercial Biotech Company: Three Provocative Questions Peter Hecht, Ph.D. Chief Executive Officer
Slide 7: Our Mission – Why We Are Here
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
Slide 8: Ironwood: A Successful Commercial Biotech
Ironwood: A Successful Commercial Biotech Creating outstanding value for patients and our fellow shareholders Rapid growth Grounded in Expect >25% Ironwood revenue Innovation CAGR (2016-2020)1 Two innovative, Multiple commercial marketed products launches and pipeline catalysts expected in 2017 1) T
Slide 9: Three Questions: IW-3718, IW-1973, Commercial Products
Does positive IW-3718 Phase IIb data 1 reduce a significant risk for a >$2B drug for uGERD patients1? 2 Can IW-1973 be a >$5B drug2? Can our current commercial products 3 generate >25% revenue CAGR (2016-2020)3? 1) Peak annual U.S. sales estimates by Ironwood 2) Peak annual global sales estimates by
Slide 10: Today's Presenters
Today’s Presenters IRONWOOD TEAM • Mark Rossetti Sr Director, U.S. Brand Lead, LINZESS • Meredith Kaya Director, Investor Relations • Carolyn Higgins Sr Scientist, GC-C R&D Program Leader • Peter Hecht, Ph.D. Chief Executive Officer • Tom McCourt Chief Commercial Officer • Machelle Manuel, Ph.D. • H
Slide 11: Uncontrolled GERD and the Bile Acid Hypothesis
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
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Slide 14: GERD syndromes
GERD Esophageal Extra-esophageal Syndromes Syndromes Symptomatic Syndromes with Established Proposed Syndromes Esophageal Injury Association Association • Typical reflux • Reflux esophagitis • Sinusitis • Reflux cough syndrome • Reflux stricture • Pulmonary • Reflux laryngitis • Reflux chest pain •
Slide 15: GERD common in the USA
GERD Common in the USA • Heartburn and regurgitation 10%- daily 40%- weekly • 100 million Americans
Slide 16: Quality of Life in GERD Patients
QUALITY OF LIFE IN GERD PATIENTS Psychiatric Patients GERD, Untreated Duodenal Ulcer, Untreated Angina Pectoris Heart Failure (mild); Climacteric Woman Normal Female Normal Male Untreated Hypertensives Population 1 | | | | ! a | i ] 60 65 70 75 80 85 90 95 100 105 110 Psychological General Well-Bein
Slide 17: PPI Trial
PPI Trial PPI’s - q day H2RA’s - BID H2RA’s-q day Antacids Life Style Modification
Slide 18: PPIs ignore bigger issue of uncontrolled GERD
PPI Trial PPI - BID Ignores the PPI’sbigger - q day issue of Uncontrolled H2RA’s - BIDGERD H2RA’s-q day Antacids Life Style Modification
Slide 19: Case: 46-year-old female with heartburn
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
Slide 20: pH monitoring in symptomatic patients on PPI therapy
pH monitoring in symptomatic patients on PPI therapy 30 % Distal Total Time pH < 4 25 20 15 10 5.5 Upper limit of normal 5 (69%) (93%) (70%) (99%) 0 QD BID QD BID TYPICAL GERD ATYPICAL GERD (n = 135) (n = 115) Vaezi. Am J Gastroenterol 2005;100:283-289.
Slide 21: Acid is not the problem in uncontrolled GERD
30 % Distal Total Time pH < 4 25 20 15 ACID IS NOT THE PROBLEM 10 in 5.5 5 Uncontrolled GERD Upper limit of normal (69%) (93%) (70%) (99%) 0 QD BID QD BID TYPICAL GERD ATYPICAL GERD (n = 135) (n = 115) Vaezi. Am J Gastroenterol 2005;100:283-289.
Slide 22: Uncontrolled GERD
Uncontrolled GERD Referred to Specialists Encountered by GI Primary MD
Slide 23: Estimated Economic Burden of GERD
Estimated Economic Burden of GERD Figure 1. Comparison of estimated economic burden of extraesophageal reflux (EER) initial evaluation to typical GERD, cancer and heart disease. Typical GERD Cancer Heart Disease EER 0 12 35 58 90 0 12 35 58 90 $ (Billions) Francis and Vaezi, AJG 2013
Slide 24: GERD: Non-Erosive, Esophagitis, Barrett's
GERD Non-Erosive Esophagitis Barrett’s
Slide 25: Pathophysiology
Pathophysiology Defensive Aggressive Factors PPI LES Acid H2RA Pepsin Obesity UES Bile acids DGE Peristalsis Hernia Trypsin Saliva Bicarbonate Alcohol Lifestyle Acidic foods
Slide 26: Pathophysiology of GERD
Pathophysiology of GERD Salivary HCO, Impaired mucosal defense <4—_ paired esophageal clearance Impaired LES e }basal tone e {transient LES rn relaxations Hiatus hernia enzymes Delayed gastric emptying
Slide 27: Postulated Agents Responsible for Esophageal Mucosal Injury
POSTULATED AGENTS RESPONSIBLE FOR ESOPHAGEAL MUCOSAL INJURY x Acid Alone Pepsin Conjugated Lysolecithin Unconjugated Trypsin Ble Acids Bile Ns a ee —
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Slide 29: % Total Time Bilirubin Absorbance > 0.14
% Total Time Bilirubin Absorbance > 0.14 DGER 60-4 10- Controls No Esophagitis Uncomplicated Complicated Esophagitis Barrett's l iL JL Jl p<.01 NS NS p<.05 [|
Slide 30: Refluxate Characteristics in GERD Patients by Subgroups
Refluxate Characteristics in GERD Patients by Subgroups 100: we mAcid Only © Acid+/Bile+ \ Bile Only & Acid-/Bile-
Slide 31: Unmet Need: Bile reflux despite PPI therapy
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.
Slide 32: IW-3718: When PPIs Alone Aren't Enough
IW-3718: When PPIs Alone Aren’t Enough Cheryl Gault VP, Commercial Strategy & New Product Planning
Slide 33: GERD Proven to be Extremely Important Therapeutic Category
GERD Proven to be Extremely Important Therapeutic Category Improving symptom relief in millions of U.S. Peak PPI Sales ~$14B2 suffering patients resulted in multiple blockbuster brands U.S. Peak H2 Sales ~$4B1 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Slide 34: Ten Million U.S. Adults Suffer from Uncontrolled GERD
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 o
Slide 35: IW-3718 for Uncontrolled GERD
IW-3718 for Uncontrolled GERD: When PPIs Alone Are Not Enough Offers potential for complementary mechanism to treat symptoms IW-3718 utilizes gastric-retentive formulation, may reduce bile exposure in esophagus DISEASED GI IW-3718 + PPI 35
Slide 36: IW-3718 Greater than $2 Billion U.S. Peak Sales Opportunity
IW-3718 Represents Greater than $2 Billion U.S. Annual Peak Sales Opportunity PATIENT PHYSICIAN PAYER • Actively looking for relief • Recognize unmet need • Appreciate level of patient suffering • Strong adherence based • Willingness to adopt on high days on therapy • Potential for broad access & wi
Slide 37: IW-3718: When PPIs Alone Aren't Enough
IW-3718: When PPIs Alone Aren’t Enough Michael Hall, M.B. B.Ch. SVP, Clinical Affairs
Slide 38: Bile Acid Pathogenesis: Reasons to Believe
Bile Acid Pathogenesis: Reasons to Believe Supported by both preclinical and clinical data • 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 injur
Slide 39: Phase IIa Trial Helped Reduce Program Risk
IW-3718 Phase IIa Trial Helped to Reduce Program Risk and Enable Phase IIb Trial Optimization Key Phase IIa Learnings High frequency Improvements in Generally of bile reflux GERD-related well-tolerated, symptoms constipation most (heartburn, common AE regurgitation) 39
Slide 40: Two-thirds of Phase IIa patients tested positive for bile reflux
Approximately 2/3 of Patients in Phase IIa Trial who Underwent Bile Reflux Monitoring Tested Positive for Bile Reflux into the Esophagus Consistent with published literature1 PATHOLOGICAL BILE REFLUX STATUS 36% 64% PBR Negative PBR Positive PBR = Pathological Bile Reflux: Data based on 52 Phase IIa
Slide 41: Heartburn Severity Improvement in Confirmed Acid Reflux
IW-3718 Phase IIa Data Suggest Decrease in Heartburn Severity Most Pronounced in Patients with Confirmed Acid Reflux 2 IW-3718 + PPI Heartburn Severity Improvement 1.5 1 0.5 PPI Alone 0 Treatment Period (p=0.007) BL=3.6; ∆=1.35; N=34 Patients experiencing heartburn ≥2 episodes/week and confirmed aci
Slide 42: Greater Heartburn Decrease in Confirmed Bile Acid Reflux
IW-3718 Phase IIa Data Showed Greater Decrease in Heartburn Severity in Patients with Confirmed Bile Acid Reflux Pathological Bile Reflux All Patients N=32 N=88 2.5 2.5 PPI Alone 2.2 PPI Alone 2 2 IW-3718 + PPI IW-3718 + PPI LS Mean Change 1.8 LS Mean Change 1.6 1.5 1.5 1.3 1.4 1.1 1.1 1.2 1 1 1.0 0
Slide 43: Phase IIa Data Leveraged to Optimize Phase IIb Design
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 highe
Slide 44: Phase IIb Study Designed for Clear Go/No Go Decision
Phase IIb Study Designed to Provide Clear Go/No Go Decision Double-blind, placebo-controlled, dose-ranging Phase IIb trial 2 WEEKS 8 WEEKS Treatment Period Pretreatment Period Placebo IW-3718 IW-3718 IW-3718 500 mg 1000 mg 1500 mg PPI ONGOING • 260 uGERD patients with positive reflux test, 4-arms •
Slide 45: Major Phase IIb Objectives
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 Evaluate Impr
Slide 46: Positive Phase IIb Data Expected to Reduce Program Risk
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 t
Slide 47: Leveraging Pharmacology to Harness the cGMP Pathway
Leveraging Pharmacology to Harness the Ubiquitous cGMP Pathway Mark Currie, Ph.D. Chief Scientific Officer
Slide 48: The Beauty and Power of the Therapeutic Agonist Approach
The Beauty and Power of the Therapeutic Agonist Approach Ironwood’s Guanylate Cyclase Agonists • 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
Slide 49: cGMP pathway: GC-C and sGC
Linaclotide GC-C sGC IW-1973 Intestinal Systemic Characteristics: cGMP Potential Characteristics: Decrease Visceral Improve Vascular Function Hypersensitivity Anti-Fibrotic Increase Fluid Anti-Inflammatory Secretion & Transit Lower Glucose/Cholesterol POTENTIAL INDICATIONS DRUG CANDIDATES POTENTIAL
Slide 50: sGC Stimulator Video
sGC Stimulator Video Todd Milne, Ph.D. Founder and VP, sGC R&D
Slide 51: Potential for sGC Stimulators in Heart Failure, Hypertension, Nephropathy
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
Slide 52: Heart failure definition
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 52
Slide 53: HFrEF and HFpEF
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 HFrEF HFpEF 53
Slide 54: HFpEF patient population projected to grow
The HFpEF patient population is projected to grow at ~2.8% CAGR to reach ~4.8M patients by 2040 U.S. diagnosed prevalent HFpEF population (2016-40F) Millions of patients 6 HFpEF prevalence • The increasing prevalence is expected to increase by 2.8% of HFpEF is largely CAGR by 2040 4.8 attributed to:
Slide 55: Clinical Outcome Trials in HFpEF
Clinical Outcome Trials in HFpEF DIG-pEF CHARM PEP-CHF I-PRESERVE TOPCAT SENIORS Preserved 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 CV death/HF Death/HF Death/CV CV
Slide 56: Clinical Outcome Trials in HFpEF
Clinical Outcome Trials in HFpEF DIG-pEF CHARM PEP-CHF I-PRESERVE TOPCAT SENIORS Preserved 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 CV death/HF Death/HF Death/CV CV
Slide 57: HFpEF: Patient Profiles
HFpEF: Patient Profiles JACC 2013 57
Slide 58: HFpEF: Patient Profiles
HFpEF: Patient Profiles JACC 2013 58
Slide 59: Shah et al, Circulation 2016
Shah et al, Circulation 2016 59 59
Slide 60: Shah et al, Circulation 2016
Shah et al, Circulation 2016 60 60
Slide 61: Potential Benefit for sGC Stimulators in HFpEF
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 Fai
Slide 62: Potential Benefit for sGC Stimulators in HFpEF
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) O = potential effects of sGC stimulation Shah et al
Slide 63: Potential Benefit for sGC Stimulators in HFpEF
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) ↑ Exercise Tolerance O = potential effects of sGC s
Slide 64: Trial Program Design in HFpEF
Trial Program Design in HFpEF Circ Heart Failure 2016 64
Slide 65: Trial Program Design in HFpEF
Trial Program Design in HFpEF 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… Circ Heart Failure 20
Slide 66: HFpEF: Needs and Opportunities
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 thi
Slide 67: Resistant Hypertension
Resistant Hypertension 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
Slide 68: Treatment paradigm for HTN
Treatment paradigm for HTN Prehypertension Hypertension 120-130/80-89 mm Hg ≥ 140/90 mm Hg Lifestyle Modifications Works Fails ACEi, ARB, or diuretic Ineffective ACEi + diuretic or CCB ARB + diuretic Ineffective ACEi + diuretic + CCB ARB + diuretic + CCB Ineffective Resistant hypertension; try aldos
Slide 69: Prevalence of Resistant HTN
Prevalence of Resistant HTN 3 classes of HTN meds prescribed concurrently N = 24,499 BP controlled at BL BP uncontrolled at BL N = 6,228 (25%) N = 18,271 (74.6%) BP controlled at 1 yr BP uncontrolled at 1 yr N = 10,154 (41.4%) N = 8,117 (33.1%) Non-resistant HTN Indeterminate Resistant HTN (≤3 meds)
Slide 70: Increased Event Risk Among RH vs non-RH
Increased Event Risk Among RH vs non-RH Ischemic Heart Event CHF Cerebrovascular Accident End-Stage Renal Disease Mortality Risk comparisons for outcomes among 60,327 resistant hypertension patients vs 410,059 non-resistant hypertension patients (Sim et al 2015) 70
Slide 71: Uncontrolled HTN patients likely to develop comorbid complications
Patients with uncontrolled HTN have high likelihood of developing comorbid complications • rHTN patients are Chronic Kidney Diabetes usually affected by Disease 48% of patients 45% of patients comorbid conditions • sGC stimulation could Ischemic Heart Cerebrovascular have additional effects in Disea
Slide 72: Resistant HTN: Needs and Opportunities
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 contro
Slide 73: Diabetic Nephropathy Overview
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 d
Slide 74: GFR and albuminuria in DN patients
GFR and albuminuria contribute to the risk and progression of CKD in DN patients Prognosis of diabetic nephropathy by GFR and albuminuria levels Risk and progression of CKD Low risk Moderate risk High risk Harrison's Principles of Internal Medicine 74
Slide 75: GFR and albuminuria in DN patients
GFR and albuminuria contribute to the risk and progression of CKD in DN patients Prognosis of diabetic nephropathy by GFR and albuminuria levels Risk and progression of CKD Low risk Moderate risk High risk Harrison's Principles of Internal Medicine 75
Slide 76: Contemporary DN Treatment Paradigm
Contemporary DN Treatment Paradigm Diagnosed DN patients Pharmacologic Lifestyle therapy considerations Increasing severity Rx HTN 1st line Strict glucose ACE or ARB control 2nd line Try other class Restrict protein (ACE or ARB) Last line Dialysis Renal transplant 76
Slide 77: Rationale for Treating DN with an sGC Stimulator
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 glomer
Slide 78: Diabetic Nephropathy: Needs and Opportunities
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-sui
Slide 79: Unmet Needs and Opportunities
Unmet Needs and Opportunities • Heart Failure w Preserved EF • Resistant HTN • Diabetic Nephropathy 79
Slide 80: IW-1973: Tackling Big Problems in Vascular Disease
IW-1973: Tackling Big Problems in the Vascular Disease Field Cheryl Gault VP, Commercial Strategy & New Product Planning
Slide 81: IW-1973 Potential to Help Millions of Patients
IW-1973 has Potential to Help Millions of Patients with Serious Diseases Resistant Heart Failure Diabetic Hypertension preserved EF Nephropathy ~7M ~3M ~8M patients1 patients2 patients3 • Large and growing patient populations • Well established long term consequences; high unmet medical need Once-da
Slide 82: Significant Commercial Potential with Single Mechanism
Opportunity to Unlock Significant Commercial Potential across Heterogeneous Populations with Single Mechanism Potentially analogous to angiotensin II receptor blocker (ARBs) order of entry U.S. peak sales Diabetic 1 $12,000,000,000 Heart Failure Nephropathy ~$10.8B indication2 $10,000,000,000 indica
Slide 83: IW-1973 Order of Entry
IW-1973 Order of Entry Designed to Maximize Commercial Success Resistant hypertension provides opportunity for initial physician education Diabetic Nephropathy • Continues to build on vascular Heart Failure preserved function, potential anti-inflammatory Ejection Fraction and anti-fibrotic effects •
Slide 84: IW-1973 >$5 Billion Global Peak Sales Opportunity
IW-1973 Represents >$5 Billion Global Annual Peak Sales Opportunity Resistant Heart Failure Diabetic Hypertension preserved EF Nephropathy • Large and growing patient populations; significant morbidity and mortality • Physicians and patients motivated to embrace efficacious new treatments • Strong v
Slide 85: IW-1973: Tackling Big Problems in Vascular Disease
IW-1973: Tackling Big Problems in the Vascular Disease Field Todd Milne, Ph.D. Founder and VP, sGC R&D
Slide 86: Focused, Staged Clinical Development Program for IW-1973
Focused, Staged Clinical Development Program for IW-1973 Expect to initiate 3 Phase II Proof-of-Concept Clinical Studies in 2H 2017: Resistant Heart Failure (preserved Diabetic Hypertension ejection fraction) Nephropathy KEY ENDPOINT: KEY ENDPOINT: KEY ENDPOINT: blood pressure (on top exercise toler
Slide 87: IW-1973 Clinical Demonstration of Pharmacology
IW-1973 Clinical Demonstration of Pharmacology Phase I study in healthy subjects TARGET ENGAGEMENT REDUCTION OF SYSTEMIC BLOOD PRESSURE Plasma P la s m acGMP cG M P Mean M e a n Arterial A r t e r ia l Pressure P re s s u re 60 0 % change cG M P 40 -2 m m Hg 20 -4 0 -6 -2 0 -8 P la c e b o 30mg P la
Slide 88: IW-1973: Pharmacokinetic and Tolerability Profile
IW-1973: Pharmacokinetic and Tolerability Profile Phase I study in healthy subjects Attractive Tissue Distribution Steady-state Exposure of IW-1973 and Pharmacokinetics • Dose-proportional and consistent exposure • Large volume of distribution • Long half life 30 mg Positive Safety and Tolerability
Slide 89: Ongoing IW-1973 Phase IIa Studies
Ongoing IW-1973 Phase IIa Studies to Provide Clinical Experience in Relevant Patient Population Data expected 2H 2017 Study 1: Study 2: Open-label, dose- Placebo-controlled, escalating 14 day, 2 dosing regimens OBJECTIVES: PATIENTS: ENDPOINTS: Understand pharmaco- Diabetics with Blood pressure, dyna
Slide 90: Preclinical Data in Resistant Hypertension
Preclinical IW-1973 Data Support Advancement in Resistant Hypertension IW-1973 Alone IW-1973 with Anti-hypertensives • Tested in combination with major 140 classes of anti-hypertensive medications M A P (m m H g ) – ARBs 120 V e h ic le (n = 6 ) – Calcium channel blockers (CCB) 1 m g /k g (n = 6 ) –
Slide 91: Preclinical Data in Resistant Hypertension
Preclinical IW-1973 Data Support Advancement in Resistant Hypertension IW-1973 + Losartan (ARB) IW-1973 with Anti-hypertensives 0 • Tested in combination with major classes of anti-hypertensive medications -5 0 h r*m m H g – ARBs – Calcium channel blockers (CCB) -1 0 0 – Beta-blockers – Diuretics -1
Slide 92: IW-1973 in Resistant Hypertension
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 PATIENTS: Hypertensive patients not at goal despite treatment with 3 or more anti-hype
Slide 93: Four Key Pharmacological Effects in Preclinical Models
IW-1973 Mediated Four Key Pharmacological Effects in Preclinical Models Decreased Blood Pressure Anti-fibrotic Fibrosis SMA RNA S M A m R N A R e la t iv e E x p r e s s io n v s G A P D H 0 .5 0 .4 Change in BP 0 .3 αSMA 0 .2 0 .1 0 .0 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
Slide 94: Preclinical Data Support Advancement in HFpEF
Preclinical IW-1973 Data Support Advancement in HFpEF Dahl salt-sensitive rat model Inflammation Fibrosis Cardiac Function IL-6 (plasma) 50 TGF (kidney) TG F 1 K id n e y : Heart Hypertrophy 0 .8 H e a r t W e ig h t ( g ) /B o d y W e ig h t ( K g ) 40 5.0 G e n e e x p re s s io n 4.5 IL -6 (p g
Slide 95: IW-1973 in HFpEF
IW-1973: Evaluating for the Treatment of Heart Failure with Preserved Ejection Fraction (HFpEF) Expected Phase II study design RATIONALE: Symptoms and physical activity in HFpEF patients may be improved by increasing blood flow and reducing inflammation, fibrosis and vascular stiffness PATIENTS: Adu
Slide 96: Preclinical Data in Diabetic Nephropathy
Preclinical IW-1973 Data Support Advancement in Diabetic Nephropathy Dahl salt-sensitive rat model Histology Kidney Function In te r s titia l F ib r o s is M icMicroalbuminuria r o a lb u m in u r ia Interstitial In t e r s t itia l In flaInflammation m m a t io n Interstitial Fibrosis 1 .5 2 .0 3
Slide 97: IW-1973 for Diabetic Nephropathy
IW-1973 for the Treatment of Diabetic Nephropathy Expected Phase II study design RATIONALE: Renal function may be protected by improving renal blood flow regulation and reducing inflammation and fibrosis PATIENTS: Adults with Type 2 diabetes, overt nephropathy ENDPOINTS: Urinary protein (albumin)
Slide 98: sGC Franchise: IW-1973, IW-1701, IW-6463
sGC IW-1973 Systemic cGMP Potential Characteristics: Improve Vascular Function Anti-Fibrotic Anti-Inflammatory Lower Glucose/Cholesterol IW-1973 IW-1701 IW-6463 LARGE MARKET INDICATIONS SPECIALTY INDICATIONS CNS INDICATIONS Expected Phase II Expected Phase II • IND-enabling studies Initiations (2017
Slide 99: Q&A
Q&A A Ironwood’
Slide 100: Break
Break A Ironwood’
Slide 101: Treating Visceral Pain in Lower GI Disorders
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
Slide 102: Mechanisms Underlying Irritable Bowel Syndrome
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
Slide 103: IBS-C and CIC Pathophysiology
IBS-C and CIC Pathophysiology Decreased secretion Increased visceral and GI motility hypersensitivity IBS-C and CIC are IBS-C is characterized by characterized by decreased visceral hypersensitivity, fluid secretion and motility which can present as which results in infrequent, abdominal pain hard,
Slide 104: Symptom Spectrum in Functional Bowel Disorders
Symptom Spectrum in Functional Bowel Disorders (FBDs) Lacy 2016 ©2012 MFMER | slide-104
Slide 105: Constipation Predominant FBDs are Common
Constipation Predominant FBDs are Common CIC IBS-C TOTAL PREVALENCE ~40 MILLION ~8 million No abdominal ~32 million discomfort, Abdominal pain, discomfort and bloating bloating Straining, decreased stool frequency, hard stool Source: 1) Lieberman GI Patient Landscape survey, 2010. 2) IFFGD 2007, IBS
Slide 106: Visceral sensory innervation of the GI tract
Visceral sensory innervation of the GI tract NTS Vagus nerve Paravertebral ganglia 1 2 3 4 5 Greater splanchnic nerve 6 7 8 9 10 Lumbar colonic CG 11 nerve 12 1 SMG 2 3 4 IMG 5 1 2 Hypogastric nerve 3 4 5 Pelvic nerve Sympathetic Parasympathetic pathway pathway CG, coeliac ganglion; IMG, inferior me
Slide 107: Physiology of Gut Sensation
PHYSIOLOGY OF GUT SENSATION brain Enteroendocrine cells responsive to chemical and mechanical stimuli brainstem Pacinian Naked nerve Corpuscle afferent ending in wall in mesentery of viscus prevertebral ganglia Luminal stimuli and changes in wall tension reflex modulation activate afferents Sensatio
Slide 108: Integration of CNS-GI Function: Brain-Gut Axis
Integration of CNS-Gl Function: Brain-Gut axis Input Integration Effect Cognition Affect Sight Sound Smell Somatosensory Motility Viscerosensory Secretion Blood Flow Mayer EA Gastro 1990:99, 1688 ©2012 MFMER | slide-108
Slide 109: Pain Control
Pain Control ©2012 MFMER | slide-109
Slide 110: Bowel of IBS patient is hypersensitive
Bowel of IBS patient is HYPERSENSITIVE: higher sensation with stimuli Sensitization that are not-painful to healthy, and higher pain score when stimuli induce pain in healthy people Hyperalgesia Pain sensation Insult Allodynia Normal Innocuous Noxious Stimulus intensity ©2012 MFMER | slide-110
Slide 111: Altered rectal perception is a biological marker of IBS
“Altered rectal perception is a biological marker of patients with irritable bowel syndrome”. Hyperalgesia at normal pressure thresholds Hypersensitivity Low pressure thresholds Normal thresholds: median 50 mm Low thresholds: Hg median 20 mm Hg REFERRAL of SENSATION Pts with IBS referred sensations
Slide 112: Visceral Hypersensitivity
IBS – Hypersensitivity is associated with change in sensory functions in the gut, nerves, spinal cord and brain End Organ Endogenous Sensitivity Modulation • “Silent” • Cortex nociceptors • Brainstem Visceral Hypersensitivity Hyperalgesia Allodynia Spinal Long-term Hyperexcitability Hyperalgesia • N
Slide 113: Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain
Gastroenterolog www.gastrojoumnalorg Volume 145 Number6 December 2013 GASTROENTEROLOGY 2013;145:1334-1346 Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3',5'-Monophosphate JOEL CASTRO,’ ANDREA M. HARRINGTON, '” PATRICK
Slide 114: Guanylate Cyclase-C agonists: Mechanism of action
Guanylate Cyclase-C agonists: Mechanism of action On Visceral Sensation Layer and Stanghellini APT 2014; 39: 371–384 ©2012 MFMER | slide-114
Slide 115: Effect of linaclotide on Transit and Bowel Function in IBS-C
Effect of 5 Days linaclotide on Transit and Bowel Function in Females With IBS-C Andresen, Camilleri et al Gastroenterology 133:761-768, 2007 ©2012 MFMER | slide-115
Slide 116: cGMP Increases Pain Thresholds and Inhibits Pain Afferents
cGMP Increases Pain Thresholds in a Model of Colonic Hypersensitivity and Inhibits Firing of Pain Afferents CVH nociceptors 60 Distension Threshold (mm Hg) *** 40 *** ** 20 0 Naive 0 0.3 3 30 1 cGMP (mg/kg) Morphine (mg/kg) TNBS Silos-Santiago et al. Pain, 2013 Castro et al. Gastroenterology, 2013 ©
Slide 117: Linaclotide Phase 2 IBS-C Trial
Linaclotide Phase 2 IBS-C Trial Abdominal Symptoms over 12 week treatment Johnston JM et al Gastro 2010; 139:1877-1886 ©2012 MFMER | slide-117
Slide 118: Linaclotide Phase 3 IBS-C Trial Abdominal Pain
Linaclotide Phase 3 IBS-C Trial Abdominal Pain Over 26 Weeks 0 % Change Ab. Pain -10 -20 -30 -40 -50 -60 BL 2 4 6 8 10 12 14 16 18 20 22 24 26 p = 0.0007 for Week 1 Trial Week Treatment Groups Lin 290 µg Placebo p < 0.0001 for Weeks 2-26 ITT Population, Observed Cases, LS-Means presented, p-valu
Slide 119: Linaclotide meta-analysis in IBS-C or chronic constipation
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 ©2012 MFMER | slide-119
Slide 120: Linaclotide: Mechanism of Action
Linaclotide: Mechanism of Action LINACLOTIDE GUANYLIN UROGUANYLIN Layer and Stanghellini APT 2014; 39: 371–384 Bryant, et al. Life Sciences, Volume 86, Issues 19–20, 8 May 2010, Pages 760–765 ©2012 MFMER | slide-120
Slide 121: GI Physiology Regulated by Peptides with pH-Dependent Activity
Gastrointestinal Physiology is Regulated by Peptides with pH-Dependent Activity Small Intestine Colon • Uroguanylin, a naturally • Guanylin, a naturally occurring peptide hormone, occurring peptide hormone, binds to GC-C receptors, binds to the GC-C receptor, primarily in the large which helps to re
Slide 122: Linaclotide Works in the Small Intestine and Colon
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 ©2012 MFMER | slide-122
Slide 123: Summary
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 t
Slide 124: Guanylate Cyclase C Agonists: Emerging Gastrointestinal Therapies
Guanylate Cyclase C Agonists: Emerging Gastrointestinal Therapies and Actions Camilleri M Gastroenterology, 148:483-7, 2015 ©2012 MFMER | slide-124
Slide 125: LINZESS, Abdominal Pain Relief and Linaclotide DR1
LINZESS, Abdominal Pain Relief and Linaclotide Delayed Release-1 (DR1) Mark Rossetti Senior Director, U.S. Brand Lead, LINZESS
Slide 126: LINZESS on Track to Exceed $1 Billion U.S. Net Sales
LINZESS on Track to Exceed $1 Billion in U.S. Net Sales by 2020; Opportunity for Continued Growth #1 Prescribed brand1 2 Indications 3 Dosage strengths 4 Years on the market Strong Rx Growth2 800,000 700,000 • Nearly 1.5M patients treated; only ~3% of suffering patients1 600,000 • >180K HCPs have pr
Slide 127: 40 Million U.S. Adult IBS-C & CIC Patients
Estimated 40 Million U.S. Adult IBS-C & CIC Patients; 80% Experience Abdominal Symptoms with Constipation1 CIC IBS-C TOTAL PREVALENCE ~40 MILLION ~8 million ~32 million No abdominal Abdominal pain, discomfort and bloating discomfort, bloating Straining, decreased stool frequency, hard stool • >75% o
Slide 128: Converting OTC Treated Patients to Fuel LINZESS Growth
Converting OTC Treated Patients Expected to Fuel Continued Growth of LINZESS LINZESS2 $7.5B+ OTC Lax Market >$4.0B 2/3 of new Rx Lax ~11M TRxs2,4 LINZESS Rxs come from OTC1 OTC Lax ~22M units3,4 (unit=30 days) Assumptions • Branded medication priced $11.78/day • TRx (30 day) priced $353/TRx Sources:
Slide 129: Physicians Ranked LINZESS Higher Than OTC Laxatives
Surveyed Physicians Ranked LINZESS Higher Than OTC Laxatives on Key Product Attributes Top 5 most important product attributes for IBS-C/CIC patients, as reported by 273 surveyed targeted HCPs Surveyed Physicians Rated LINZESS vs OTC Laxatives 60 50 % of HIGH rating with MDs 40 30 20 10 0 Abdominal
Slide 130: Physician Satisfaction for LINZESS Increased with Experience
Physician Satisfaction for LINZESS Increased with Experience >70% of surveyed physicians reported to be highly to extremely satisfied with LINZESS Gastroenterologists Primary Care Physicians 80 80 % Highly/ Extremely Satisfied 75 75 70 70 65 65 60 60 55 55 50 50 2013 2014 2015 2016 2013 2014 2015 20
Slide 131: Outstanding Payer Access Foundational for LINZESS Growth
Outstanding Payer Access is Foundational for Continued Growth of LINZESS Affordable for patients • ~$30 copay for up to >90% 90-day supply >75% Unrestricted • Daily cost is less than Unrestricted access for many OTC laxatives access for Medicare commercial Part D lives1 lives2 Strong value propositi
Slide 132: LINZESS Provides Effective Abdominal Pain Relief
LINZESS Provides Effective Abdominal Pain Relief for IBS-C Patients LINZESS patients more adherent to treatment if trial >30 days LINZESS reaches maximum relief of Patients are more adherent to abdominal pain in 6-9 weeks treatment if their initial trial is longer than 30 days1 Max Abdominal Pain Im
Slide 133: Patient Funnel Continues to Expand
Patient Funnel Continues to Expand; Increases Opportunity to Drive the Growth of LINZESS 2014 2016 Consumer 1% Unaided 8% Unaided awareness1 Awareness Awareness 8x increase # of HCPs ~70K >180K Rx LINZESS2 >2.5x increase HCPs honor patient request for LINZESS3 ~75% >90% 20% increase Prescriptions Re
Slide 134: Linaclotide Franchise Positioned for Strong Growth
Linaclotide Franchise Positioned for Strong Growth Grow Capture Outstanding Raise the Bar the Market Market Share Access 134
Slide 135: LINZESS, Abdominal Pain Relief and Linaclotide DR1
LINZESS, Abdominal Pain Relief and Linaclotide Delayed Release-1 (DR1) Carolyn Higgins Senior Scientist, GC-C R&D Program Leader
Slide 136: Linaclotide Works on Visceral Hypersensitivity and GI Motility Through cGMP
Linaclotide Believed to Work on Visceral Hypersensitivity and GI Motility Through cGMP 136
Slide 137: Hypothesis Building
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
Slide 138: Abdominal Pain in IBS-C Driven by Colon Hypersensitivity
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) 24 Mechanosensory response (spikes/sec) 18 *** 12 Colonic visceral *** *** hypersensitivity *** is a marke
Slide 139: Linaclotide Increases Secretion in the Small Intestine
Linaclotide is Believed to Work on Constipation By Increasing Secretion in the Small Intestine Linaclotide increased fluid secretion along the small intestine of rats 0.25 0.2 ** ** * Weight / Length Ratio ** Vehicle 0.15 * Linaclotide (5 ug) 0.1 n = 10 0.05 0 Duodenum Jejunum Ileum Busby et al. Eur
Slide 140: Linaclotide DR1 Designed to Deliver More Drug to the Colon
Linaclotide Delayed-Release (DR1) Designed to Deliver More Drug to the Colon LINZESS: Immediate Release in Stomach DR1: Mid-Ileum Release Effective Relief of Potential For Even MORE Abdominal Pain Abdominal Pain Relief 140
Slide 141: Phase IIb Study in IBS-C Patients
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 1
Slide 142: DR1 Phase IIb Data on FDA-Recommended Endpoint
DR1 Phase IIb Data on FDA-Recommended Endpoint Proportion of Combined Responders (Pain + Constipation) 45 40 38.8 35 31.8 Percent Responders 30 25 21.2 20 15 10 5 0 Placebo IR 290 ug DR1 300 ug (N=66) (N=66) (N=67) p=0.167 p=0.026 P-values vs. placebo based on CMH test controlling for geographic reg
Slide 143: DR1 Phase IIb Abdominal Pain Relief
DR1 Phase IIb Data Demonstrated Improvement in Abdominal Pain Relief1 Abdominal Pain % Change from Baseline by Week 0 -5 LS Mean % Change from Baseline -10 -15 -20 -25 Placebo -26.2% -30 -35 IR 290 ug -40 -40.6% p=0.0429 -45 DR1 300 ug -50 -49.5% 0 1 2 3 4 5 6 7 8 9 10 11 12 p=0.0011 Treatment Week
Slide 144: DR1 Phase IIb 50% Abdominal Pain Responders
DR1 Phase IIb Data Demonstrated Improvement in 50% Abdominal Pain Responders1 40 35.8 35 30 28.8 Percent Responders 25 20 18.2 15 10 5 0 Placebo IR 290 ug DR1 300 ug (N=66) (N=66) (N=66) p=0.1439 p=0.0263 P-values vs. placebo based on CMH test controlling for geographic region; not corrected for mul
Slide 145: DR1 Phase IIb Constipation Relief
DR1 Phase IIb Data Demonstrated Constipation Relief CSBM Responder Rate (6 of 12 weeks) 60 53.0 52.2 50 Percent Responders 40 34.8 30 20 10 0 Placebo IR 290 ug DR1 300 ug (N=66) (N=66) (N=67) p=0.040 p=0.032 P-values vs. placebo based on CMH test controlling for geographic region; not corrected for
Slide 146: DR1 is an Exciting Opportunity
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) •
Slide 147: LINZESS and DR Poised for Strong Growth
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 t
Slide 148: DR1 Growth Expected to Accelerate if Approved
If Approved, DR1 Growth Expected to Accelerate as Physicians & Patients Choose More Effective Treatment DR1 Expected Growth Drivers • Motivate NEW OTC patients with pain, bloating & discomfort message • Discontinued patients due to inadequate pain relief Prescriptions • Better adherence to treatment
Slide 149: Focused U.S. Commercial Model Delivers Innovation to Patients
Focused U.S. Commercial Model Delivers Innovation to Patients Tom McCourt Chief Commercial Officer
Slide 150: Commercial Model Expected to Drive High-Margin Business
Ironwood’s Commercial Model Expected to Drive Productive, High-Margin Business Innovative products treating motivated patients with highly symptomatic disorders in underserved markets INNOVATIVE PRODUCTS UNDERSERVED MARKETS/ MINIMAL COMPETITION HIGHLY SYMPTOMATIC DISORDERS MOTIVATED PATIENTS VALUE R
Slide 151: LINZESS Addresses High Unmet Needs
Opportunity for LINZESS to Address High Unmet Needs Enables Favorable Market Dynamics to Drive Growth Strong Rx Growth1 700,000 Millions of 600,000 symptomatic patients2 Underserved patients TRx Volume 500,000 First in category 400,000 Advancement in care 300,000 Limited competition 200,00
Slide 152: High Productivity and Growth Leveraging Efficiency and Synergies
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 IBS-C IBS-D for Brand Growth & CIC &M High pr
Slide 153: ZURAMPIC and DUZALLO Aligned with Commercial Model
ZURAMPIC® (lesinurad) and DUZALLO™ (lesinurad + allopurinol FDC) are Aligned with IRWD Commercial Model MARKET DRIVERS BRAND SOLUTIONS Innovative Nearly 2X as many patients on ZURAMPIC Advancement In Care + allo (vs allo alone) reached goal1,2 Underserved Market/ Little innovation for over 30 years
Slide 154: ZURAMPIC and DUZALLO: Get More Gout Patients to Goal
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 >$300M Estimated annual peak sales opportunity for uncontrolled gout franchise Building a Gout Franchise XOI and DUZALLO Acute Treatment ZURAMPIC + XOI
Slide 155: ZURAMPIC and DUZALLO: Get More Gout Patients to Goal
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 DUZALLO >$300M Estimated peak sales opportunity (lesinurad + allo FDC) for uncontrolled gout franchise Expected late 2017 → Building a Gout Franchise XO
Slide 156: Model Expected to Drive Expansion of Commercial Margin
Ironwood Model Expected to Drive Expansion of Commercial Margin Commercial Net Sales • Patient need & adherence • Increasing product demand • MD prescribing productivity • Target selling effort & synergy • Shared Expenses Commercial Expenses Mid-2030s (illustrative) 156
Slide 157: Strategy to Deliver Sustainable, High-Margin Growth
Strategy to Deliver Sustainable, High-Margin Growth Tom Graney Chief Financial Officer Harriet Winter VP, Corporate Strategy
Slide 158: Key Takeaways: IW-3718
Key Takeaways from Earlier Presentations IW-3718 • 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
Slide 159: Key Takeaways: IW-1973
Key Takeaways from Earlier Presentations IW-1973 • 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
Slide 160: Key Takeaways: Linaclotide DR1
Key Takeaways from Earlier Presentations Linaclotide Delayed Release-1 (DR1) • 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
Slide 161: Ironwood: Fast-Growing Biotech with a Strong Pipeline
Delivering on Innovation: Ironwood is a Fast-Growing Biotech with a Strong Pipeline LINZESS, ZURAMPIC and Innovative mid- and Multiple major DUZALLO (if approved) late-stage pipeline is catalysts expected expected to drive first increasingly de-risked over next 12 to 24 wave of sustainable and aims
Slide 162: Current Commercial Products Driving Growth and Margins
Current Commercial Products Driving Sustainable Growth and Expanding Margins Expect >25% Ironwood revenue CAGR (2016-2020)1 LINZESS, ZURAMPIC & DUZALLO (if approved) 2019 U.S. Net Sales Expect ZURAMPIC & DUZALLO cash flow accretive 2020 Expect >$1B LINZESS U.S. Net Sales Commercial Expenses Mid (ill
Slide 163: Ironwood Expected Revenue Growth Among Highest for Commercial Biotechs
Consensus Ironwood Expected Company Expected Rev Growth '16-'201 Revenue Growth is Seattle Genetics 32% Among Highest for Ironwood Pharmaceuticals Alkermes 25% 24% Commercial Biotech Incyte 23% Vertex Pharmaceuticals 23% Companies Pacira Pharmaceuticals 21% BioMarin Pharmaceuticals 19% Alexion Pharm
Slide 164: Ironwood: Fast-Growing Biotech with a Strong Pipeline
Delivering on Innovation: Ironwood is a Fast-Growing Biotech with a Strong Pipeline LINZESS, ZURAMPIC and Innovative mid- and Multiple major DUZALLO (if approved) late-stage pipeline is catalysts expected expected to drive first increasingly de-risked over next 12 to 24 wave of sustainable and aims
Slide 165: Pipeline Programs are Risk-Reduced Opportunities
Innovative Pipeline Programs are Risk-Reduced Opportunities in Large, Uncrowded Markets IW-3718 Delayed Release (DR1) IW-1973 Unmet Need Clinical Validation ? Safety Experience Regulatory Clarity Manufacturing 165
Slide 166: Ironwood: Fast-Growing Biotech with a Strong Pipeline
Delivering on Innovation: Ironwood is a Fast-Growing Biotech with a Strong Pipeline LINZESS, ZURAMPIC and Innovative mid- and Multiple major DUZALLO (if approved) late-stage pipeline is catalysts expected expected to drive first increasingly de-risked over next 12 to 24 wave of sustainable and aims
Slide 167: Future High-Margin Growth from Launches of Innovative Pipeline
Future High-Margin Growth Expected to be Driven By Series of Important Launches from Innovative Pipeline Ironwood Expected Revenue Over Time + Growth of IW-1973 and other sGC stimulators1 + Growth of delayed release products and IW-37181 Continuing momentum driven by growth of LINZESS, ZURAMPIC & DU
Slide 168: Ironwood: Fast-Growing Biotech with a Strong Pipeline
Delivering on Innovation: Ironwood is a Fast-Growing Biotech with a Strong Pipeline LINZESS, ZURAMPIC and Innovative mid- and Multiple major DUZALLO (if approved) late-stage pipeline is catalysts expected expected to drive first increasingly de-risked over next 12 to 24 wave of sustainable and aims
Slide 169: Key Catalysts Expected in Next 12 to 24 Months
Key Catalysts Expected in Next 12 to 24 Months EVENT / METRIC EXPECTED IMPACT IF DATA ARE POSITIVE TIMING IW-3718 Reduces a significant risk to >$2B U.S annual peak sales Mid 2017 uGERD Phase IIb data opportunity DUZALLO launch (if approved) 2H17 Significant catalyst for uncontrolled gout franchise
Slide 170: Ironwood Vision
Ironwood Vision 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 • Executing on a robust portfolio of marketed and development-stage products, derived from internally-discov
Slide 171: A Ironwood’
A Ironwood’
Slide 172: Ironwood: A Successful Commercial Biotech
Ironwood: A Successful Commercial Biotech Creating outstanding value for patients and our fellow shareholders Rapid growth Grounded in Expect >25% Ironwood revenue Innovation CAGR (2016-2020)1 Two innovative, Multiple commercial marketed products launches and pipeline catalysts expected in 2017 1) T