Ironwood Pharmaceuticals, Inc. · NASDAQ:IRWD
Ironwood Pharmaceuticals — Investor Day (December 2013)
136 slides from Ironwood Pharmaceuticals's investor day presentation, Dec 12, 2013
Slide 1: Ironwood Investor Day
Ironwood Investor Day December 12, 2013 1
Slide 2: Introduction
Introduction Meredith Kaya Director, Investor Relations 2
Slide 3: 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, but not limited to, statements about our development and commercialization plans, and the investments associated with those
Slide 4: Today’s Agenda
Today’s Agenda • Building a Leading GI Company ………..…..………. Peter Hecht • Maximizing LINZESS® (linaclotide) Driving Continued Growth of LINZESS..………………. Abe Ceesay Activating the Patient ……………………….………...… Sharon DeBacco • Leveraging Commercial Capabilities …………..…… Tom McCourt • Burden of Illness fo
Slide 5: Building a Leading GI Company
Building a Leading GI Company Peter Hecht, Ph.D. Chief Executive Officer 5
Slide 6: Ironwood Mission: Patients, Shareholders, Team
Ironwood Mission: Patients, Shareholders, Team 6
Slide 7: Building a Leading GI Company
Building a Leading GI Company We will: • Maximize LINZESS® • Advance robust GI pipeline • Leverage commercial capabilities • Prioritize investments in key value drivers 7
Slide 8: LINZESS: Company-building Asset and Foundation to Our Strategy
LINZESS®: Company-building Asset and Foundation to Our Strategy • Launched December 2012: Strong Uptake – 50/50 partnership with Forest • Treatment option for millions of adults with IBS-C or CIC • First in new class of medicines: GC-C agonists • Strong global partnerships bringing linaclotide to pa
Slide 9: Focused Strategy, Prioritized Investments, Near-Term Value
Focused Strategy, Prioritized Investments, Near-Term Value • Maximizing LINZESS® – Transforming physician-patient dialog through launch of LINZESS direct-to-consumer campaign in 1H 2014 • Progressing pipeline of therapeutics targeting significant unmet needs – Includes 7 GI clinical development prog
Slide 10: Financial Strength to Execute Strategy and Deliver Shareholder Value
Financial Strength to Execute Strategy and Deliver Shareholder Value • Strong balance sheet: ended Q3 2013 with $242M in cash1 • LINZESS® revenue growing – LINZESS net product sales of ~$87M from launch through Q3 20132 – >190K unique patients filled Rx through October 2013; >500K TRx since launch t
Slide 11: Today’s Presenters
Today’s Presenters Ironwood Team • Peter Hecht, Ph.D. Chief Executive Officer • Brian Cali, Ph.D. SVP, Preclinical R&D • Michael Higgins • Abe Ceesay Chief Operating Officer VP, Marketing • Tom McCourt Chief Commercial Officer • Mark Currie, Ph.D. President of R&D, SVP, Chief External Medical Expert
Slide 12: Driving Continued Growth of LINZESS
Driving Continued Growth of LINZESS® Abe Ceesay Vice President, Marketing 12
Slide 13: LINZESS Provides Treatment Option for Millions of Adults with IBS-C or CIC
LINZESS® Provides Treatment Option for Millions of Adults with IBS-C or CIC Addressing a Demonstrated efficacy significant unmet need and safety profile • ~30M patients not satisfied with • Differentiated mechanism of current treatments action; works two ways – abdominal pain and transit • Improveme
Slide 14: Initial Launch of LINZESS Strong with Significant Opportunity Ahead
Initial Launch of LINZESS Strong with Significant Opportunity Ahead 800,000 700,000 600,000 500,000 TRx 400,000 Prilosec® Zelnorm® 300,000 200,000 LINZESS® 100,000 0 – 18- actual 18 – (10/89) 36 36 – 60 LINZESS Prilosec Zelnorm (8/02) Time (months) Source: IMS NPA October-2013 LINZESS Month 1: Jan 2
Slide 15: Solid Fundamentals Driving Growth of LINZESS
Solid Fundamentals Driving Growth of LINZESS® • Broad and growing prescribing base of >48k physicians1 • Physicians consistently increasing productivity over time1 PHYSICIAN • ~75% Commercial and ~50% Medicare Part D unrestricted2 • ~75% of LINZESS claims being paid3 PAYER • Patient persistency rate
Slide 16: Broad and Growing Prescribing Base Continues to Support LINZESS Uptake
Broad and Growing Prescribing Base Continues to Support LINZESS® Uptake >48,000 Total Prescribers and Majority of Highest Potential Target Currently Adding >900 Each Week Physicians have Prescribed LINZESS 7,000 Total Weekly Prescribers: 6,015 6,000 74% of decile 8-10 HCPs Weekly Prescribers 5,000 4
Slide 17: Physician Prescribing Consistently Increasing Across High Potential Physicians
Physician Prescribing Consistently Increasing Across High Potential Physicians Highest Potential GI Prescribing Highest Potential PCP/Other Prescribing Increases Over Time (N=5,219) Increases Over Time (N=4,017) 90.0 90.0 Dec ’12 80.0 n=368 80.0 Dec ’12 n=115 70.0 70.0 TRx/HCP Cumulative TRx/HCP Cum
Slide 18: Physician Prescribing Consistently Increasing Across All Physician Segments
Physician Prescribing Consistently Increasing Across All Physician Segments All Potential GI Prescribing Increases All Potential PCP/Other Prescribing Over Time (N=6,807) Increases Over Time (N=18,490) 60.0 Dec ’12 25.0 n=434 Dec ’12 n=427 50.0 Jan ’13 20.0 TRx/HCP Cumulative TRx/HCP Cumulative n=1,
Slide 19: 74% of Responding Physicians Reported to be Satisfied with LINZESS
74% of Responding Physicians Reported to be Satisfied with LINZESS®; Abdominal Pain Main Reason To Choose LINZESS for IBS-C Ranking of reasons for prescribing LINZESS for IBS-C Provides effective relief of 50% abdominal pain 74% of responding physicians are moderately to highly 34% 29% Increases bow
Slide 20: Solid Fundamentals Driving Growth of LINZESS
Solid Fundamentals Driving Growth of LINZESS® • Broad and growing prescribing base of >48k physicians1 • Physicians consistently increasing productivity over time1 PHYSICIAN • ~75% Commercial and ~50% Medicare Part D unrestricted2 • ~75% of LINZESS claims being paid3 PAYER • Patient persistency rate
Slide 21: 75% of LINZESS Claims are Paid Today
75% of LINZESS® Claims are Paid Today Resulting from Efforts with Payers and Co-pay Solutions LINZESS Total Claims 100% 90% 20.6% 18.9% Rejection 80% Reversal 6.1% 70% 13.3% Paid 60% 50% 40% 75.1% 30% 66.1% 20% 10% 0% Jan-2013 Oct-2013 Source: IMS PlanTrax Oct-2013 21
Slide 22: Solid Fundamentals Driving Growth of LINZESS
Solid Fundamentals Driving Growth of LINZESS® • Broad and growing prescribing base of >48k physicians1 • Physicians consistently increasing productivity over time1 PHYSICIAN • ~75% Commercial and ~50% Medicare Part D unrestricted2 • ~75% of LINZESS claims being paid3 PAYER • Patient persistency rate
Slide 23: LINZESS Patient Persistency Rates Tracking ~40%–57% Above Zelnorm
LINZESS® Patient Persistency Rates Tracking ~40% – 57% Above Zelnorm, Launch Aligned LINZESS Amitiza Zelnorm April, Launch Aligned July, Launch Aligned January, Launch Aligned 40% 40% 40% 38.5% +52.2% 37.6% % Persistent and Restart Patients % Persistant and Restart Patients 34.3% 35% 35% +56.6% 35%
Slide 24: LINZESS Growth Supported by Strong Refill Rate
LINZESS® Growth Supported by Strong Refill Rate Current Month % Refills = 45% 80,000 TOTAL 70,000 60,000 Rx Volume 50,000 40,000 NEW REFILL 30,000 20,000 10,000 Nov 2012 Dec 2012 Jan 2013 Mar 2013 May 2013 Jun 2013 Aug 2013 Oct 2013 Feb 2013 Apr 2013 Jul 2013 Sep 2013 Monthly Source: IMS NPA October
Slide 25: LINZESS Commercialization Focused on Driving Greater Demand
LINZESS® Commercialization Focused on Driving Greater Demand LINZESS Today LINZESS Future • Broad prescribing base of >48k • Physician state a 40%-50% increase physicians1 in future prescribing4 • Prescribing rates consistently • ~60%-70% are willing to honor a increase across all physicians PHYSICI
Slide 26: LINZESS 2014 Commercial Investment
LINZESS® 2014 Commercial Investment • Actively working with Forest on LINZESS commercial investment to drive future brand growth • Ironwood and Forest sales & marketing expense expected to be $250-$300M – Implement broad-based patient marketing initiatives in 1H 2014 – Focus selling effort on highes
Slide 27: Activating the Patient
Activating the Patient Sharon DeBacco Senior Director, Customer Communications 27
Slide 28: Consumer Advertising Continues to Generate Patient-Initiated Discussions
Consumer Advertising Continues to Generate Patient-Initiated Discussions Overall, in 2012 across all prescription brands and categories, 26% of US adults (~46M) spoke to a doctor about a 14% of US adults (~25M) spoke about a condition never before discussed with their brand they saw advertised, and…
Slide 29: Initial Digital Efforts Reveal Strong Interest Among Adult IBS-C & CIC Sufferers
Initial Digital Efforts Reveal Strong Interest Among Adult IBS-C & CIC Sufferers In the 12 months 2,100,000 Engagements with LINZESS online, and since digital campaign launch: 100,000/month Unique visitors to linzess.com Source: Internal Digital Tracking Data, 2013 29
Slide 30: Significant Opportunity to Generate Awareness and Action Among Sufferers
Significant Opportunity to Generate Awareness and Action Among Sufferers Low current awareness of LINZESS® and its strong clinical profile 9.4% of IBS-C sufferers are aware of LINZESS - only 2.5% of CIC sufferers are aware1 (Physician awareness is >90%2) Aware Unaware Source: 1) LINZESS Custom Patie
Slide 31: Significant Opportunity to Generate Awareness and Action Among Sufferers
Significant Opportunity to Generate Awareness and Action Among Sufferers Low current awareness of LINZESS® and its strong clinical profile 9.4% of IBS-C sufferers are aware of LINZESS - only 2.5% of CIC sufferers are aware1 (Physician awareness is >90%2) Aware Unaware But awareness alone doesn’t gua
Slide 32: Successful DTC Brands Share Common Hallmarks
Successful DTC Brands Share Common Hallmarks Highly symptomatic, easily identifiable High unmet need More important to patient than physician Patient believes it’s their fault Highly differentiated Brings news to category 32
Slide 33: LINZESS is Ideal Candidate for Successful Consumer Advertising
LINZESS® is Ideal Candidate for Successful Consumer Advertising Highly symptomatic, easily identifiable Multiple, chronic symptoms, on average 110 days per year1 High unmet need 70-80% of sufferers have low2 levels of satisfaction with current therapy More important to patient than physician S
Slide 34: Campaign Designed to Help Patient Navigate Pathway to Relief
Campaign Designed to Help Patient Navigate Pathway to Relief Ironwood and Forest understanding of the patient informs campaign messaging, addresses barriers and supports patient Enable Self Generate News Facilitate the Differentiate Identification & Awareness Dialogue Brand • Validate patients’ • El
Slide 35: Multi-Channel Plan Designed to Reach Patients at Key Moments of Consideration
Multi-Channel Plan Designed to Reach Patients at Key Moments of Consideration In-Pharmacy TV • Targeted awareness • Efficient mass reach In- • OTC point-of-purchase TV • Rapid awareness builder Pharmacy • Influence pharmacist • Competitive presence discussions • Drives online PR Print • Broad reach
Slide 36: DTC Had Clear Effect on Zelnorm Uptake
DTC Had Clear Effect on Zelnorm® Uptake Measureable impact of DTC on Zelnorm NRx growth 100,000 National DTC Launch 75,000 Disease Awareness Campaign NRx 50,000 25,000 0 Aug-02 Sep-02 Oct-02 Nov-02 Dec-02 Jan-03 Feb-03 Mar-03 Apr-03 May-03 Jun-03 Jul-03 Aug-03 Sep-03 Oct-03 Source: IMS New Product S
Slide 37: LINZESS Positioned for DTC Success
LINZESS® Positioned for DTC Success • Digital response indicates significant, untapped potential1 • Brand meets hallmarks of DTC success • Physicians demonstrate confidence in LINZESS2 • Patients find LINZESS profile and experience appealing3 • LINZESS TV ad exceeded key performance benchmark in qua
Slide 38: Leveraging Commercial Capabilities
Leveraging Commercial Capabilities Thomas McCourt Chief Commercial Officer, SVP, Sales & Marketing 38
Slide 39: Industry-Leading Commercial Capability Maximizing LINZESS and Building a GI Franchise
Industry-Leading Commercial Capability Maximizing LINZESS® and Building a GI Franchise Brand Leadership & Management • Extensive GI and primary care experience Physician & Patient Forest Laboratories • Multiple successful Education launches • Created new categories and grew Business Analytics Global
Slide 40: Establish Brand Strategy to Drive Blockbuster Growth
Establish Brand Strategy to Drive Blockbuster Growth Positioning LINZESS® as solution for abdominal pain and constipation symptoms in labeled indications Abdominal Pain & Constipation 40
Slide 41: Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS Sales
Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS® • Proven selling skills and track record of success Sales • Expertise in both GI and primary care Excellence • Highly collaborative, co-promotion experience • Ensure the RIGHT price point for entry Payer & • Create a strong va
Slide 42: Collaborative Selling Effort is Increasing GI and Primary Care Prescribing
Collaborative Selling Effort is Increasing GI and Primary Care Prescribing Gastroenterologists Primary Care Physicians 8 3 7 2.5 6 25% 59% 2 # of TRx per GI # of TRx per PCP 5 4 1.5 3 1 2 0.5 1 0 0 Single Sales Force Combined Selling Single Sales Force Combined Selling 50/50 50/50 Controlled for tot
Slide 43: Over 90% of Top Prescriber Base Report Being Knowledgeable of LINZESS
Over 90% of Top Prescriber Base Report Being Knowledgeable of LINZESS® Access to Key Physicians1 Knowledge of LINZESS2 100 100 90 95% 95% % of Physicians 93% 80 80 70 71% % of Physicians 60 60 50 40 40 30 20 20 10 0 0 GE (n=81) PCP (n=82) Launch to Date Monthly (October) Extremely/Very Moderately Lo
Slide 44: Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS Sales
Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS® • Proven selling skills and track record of success Sales • Expertise in both GI and primary care Excellence • Highly collaborative, co-promotion experience • Ensure the RIGHT price point for entry Payer & • Create a strong va
Slide 45: Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS Sales
Our Commercial Capability is Focused and Dedicated to Maximizing LINZESS® • Proven selling skills and track record of success Sales • Expertise in both GI and primary care Excellence • Highly collaborative, co-promotion experience • Ensure the RIGHT price point for entry Payer & • Create a strong va
Slide 46: GI Diseases Present Significant Commercial Opportunity
GI Diseases Present Significant Commercial Opportunity Millions of highly symptomatic patients and billions in potential sales ABDOMINAL PAIN Refractory GERD Gastroparesis Dyspepsia IBS-M & IBS-D CONSTIPATION IBS-C * *CIC Opioid Induced Constipation * Currently Approved for LINZESS ® 0 10 20 30 Mill
Slide 47: Deep Understanding of Patients Combined with Novel Science to Unlock Multiple GI Opportunities
Deep Understanding of Patients Combined with Novel Science to Unlock Multiple GI Opportunities GI Patient Insight Data Base ABDOMINAL PAIN Refractory GERD Gastroparesis Dyspepsia IBS-D GC-C & GI Platform IBS-M *IBS-C CONSTIPATION *CIC Opioid Induced Constipation Understanding of Patients Across ® *C
Slide 48: Our Commercial Capabilities are Platform for Future Growth
Our Commercial Capabilities are Platform for Future Growth Poised to attract and build future GI brands ⃝ Proven track record for success, demonstrated ability to commercialize multiple blockbuster GI brands ⃝ Highly collaborative, effectively maximizing joint selling effort and payer coverage ⃝ Ind
Slide 49: Burden of Illness for Functional GI Disorders
Burden of Illness for Functional GI Disorders Philip Schoenfeld, MD, MEd, MSc (Epi) Professor of Medicine and Director of GI Epidemiology Training Program, Department of Gastroenterology, University of Michigan The views expressed in this portion of the presentation are those of Dr. Schoenfeld and d
Slide 50: Functional GI Disorders
Functional GI Disorders Confidential | 50
Slide 51: Functional GI Disorders
Functional GI Disorders Refractory GERD Functional Dyspepsia Gastroparesis IBS-C, IBS-D, IBS-M, Chronic Constipation, Opioid-Induced Constipation, Diverticulitis Confidential | 51
Slide 52: Functional GI Disorders = Large Burden of Illness
Functional GI Disorders = Large Burden of Illness • Functional GI Disorders Are Very Prevalent • Morbidity is High • Health Care Utilization = $$$ Confidential | 52
Slide 53: Millions of Functional GI Disorder Patients Seek Care
Millions of Functional GI Disorder Patients Seek Care Refractory GERD Gastroparesis Pain Dyspepsia IBS-D IBS-M IBS-C Chronic Constipation Opioid Induced Constipation 0 5 10 15 Million of Patients Sources: Lieberman GPLS, 2010; Qual Research, Nov 2008; Intagliata and Koch; Abeel et al., Hasler WL; El
Slide 54: Patients Suffer
Patients Suffer • Although functional GI disorders are not life-threatening, my patients truly suffer from frequent and very “bothersome” symptoms. Days/Year Very/Extremely Bothersome • IBS-C: Constipation 135 81% Abdominal Discomfort 102 74% Bloating 97 70% • CC: Constipation 99 69% Hard stools 87
Slide 55: Leading GI Symptoms Prompting Outpatient Visits
Leading GI Symptoms Prompting Outpatient Visits • Abdominal Pain/Bloating: 16.5 million/year • Constipation: 3.2 million/year • “Indigestion”: 2.0 million/year Peery A, et al. Burden of GI Disease In US: 2012 Update. Gastroenterology 2012: 143: 1179. From 2009 National Ambulatory Medical Care Survey
Slide 56: Functional GI Disorders = Large Burden of Illness
Functional GI Disorders = Large Burden of Illness • Functional GI Disorders Are Very Prevalent • Morbidity is High • Health Care Utilization is Substantial Confidential | 56
Slide 57: Functional GI Disorders = Large Burden of Illness
Functional GI Disorders = Large Burden of Illness • Functional GI Disorders Are Very Prevalent • Morbidity is High • Health Care Utilization is Substantial Unmet medical need: Available treatments are limited. Confidential | 57
Slide 58: Functional GI Disorders Are Associated with Symptoms of Dysmotility and Hypersensitivity
Functional GI Disorders Are Associated with Symptoms of Dysmotility and Hypersensitivity Symptoms of GI Symptoms of dysmotility: Visceral impaired Hypersensitivity: coordination of discomfort/bloating/ the muscular pain in the GI tract contractions in the GI tract. that is more intense than normal M
Slide 59: Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract
Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract Gas/Air Intestinal wall Gas/Air Nutrients, Nutrients, water, stool Pain Sensing water, stool nerves Signals to Signals to Brain Brain Normal IBS GI tract stretches or distends which is sensed In IBS, pain fibe
Slide 60: Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract
Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract Gas/Air Intestinal wall Gas/Air Nutrients, Nutrients, water, stool Pain Sensing water, stool nerves Signals to Signals to Brain Brain Normal IBS GI tract stretches or distends which is sensed In IBS, pain fibe
Slide 61: Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract
Visceral Hypersensitivity in IBS: Pain fibers are hypersensitive to distention of GI tract Gas/Air Intestinal wall Gas/Air Nutrients, Nutrients, water, stool Pain Sensing water, stool nerves Signals to Signals to Brain Brain Normal IBS GI tract stretches or distends which is sensed In IBS, pain fibe
Slide 62: Functional GI Disorders Are Associated with Symptoms of Dysmotility and Hypersensitivity
Functional GI Disorders Are Associated with Symptoms of Dysmotility and Hypersensitivity Symptoms of GI Symptoms of dysmotility: Visceral impaired Hypersensitivity: coordination of discomfort/bloating/ the muscular pain in the GI tract contractions in the GI tract. that is more intense than normal M
Slide 63: There may be multiple causes of visceral hypersensitivity & GI dysmotility
There may be multiple causes of visceral hypersensitivity & GI dysmotility Altered serotonin Post-infectious signaling in gut (enteric) nervous system Visceral Hypersensitivity GI Dysmotility Mucosal Altered brain-gut inflammation communication Small Intestinal Bacterial Overgrowth Confidential | 63
Slide 64: Visceral hypersensitivity is not limited to one segment of the GI tract
Visceral hypersensitivity is not limited to one segment of the GI tract = FGIDs overlap Frissora C and Koch K. Cur Gastroenterol Rep 2005 Confidential | 64
Slide 65: Overlap Between Conditions
Overlap Between Conditions IBS-C CC FD GERD IBS-C 100% -- 23% 17% CC -- 100% 53% 40% FD 70% 51% 100% 46% GERD 52% 42% 47% 100% NOTE: IBS-C and CC are mutually exclusive as defined by ROME II definitions FD as defined by ROME III definition Confidential | 65 65
Slide 66: Overlap Between Conditions
Overlap Between Conditions IBS-C CC FD GERD IBS-C 100% -- 23% 17% CC -- 100% 53% 40% FD 70% 51% 100% 46% GERD 52% 42% 47% 100% NOTE: IBS-C and CC are mutually exclusive as defined by ROME II definitions FD as defined by ROME III definition Confidential | 66 66
Slide 67: Overlap Between Conditions
Overlap Between Conditions IBS-C CC FD GERD IBS-C 100% -- 23% 17% CC -- 100% 53% 40% FD 70% 51% 100% 46% GERD 52% 42% 47% 100% NOTE: IBS-C and CC are mutually exclusive as defined by ROME II definitions FD as defined by ROME III definition Confidential | 67 67
Slide 68: American College of Gastroenterology: Evidence-Based Management Position Statements
American College of Gastroenterology: Evidence-Based Management Position Statements • No FDA-approved treatments for Functional Dyspepsia, Refractory GERD, or Gastroparesis • Effective treatment of IBS-C (2009, 2nd ed): Lubiprostone (Amitiza®) • Effective treatment of Chronic Constipation (2005, 1st
Slide 69: Visceral hypersensitivity is the holy grail of treatment
• “Visceral hypersensitivity is currently the holy grail [of treatment]....it is widely regarded as the reason for the development of [pain] in functional GI disorders”* • GI Dysmotility: Use Laxatives (e.g., Miralax®) for Constipation & Anti-diarrheals (Imodium®) for Diarrhea…. *Camilleri M. Gut 20
Slide 70: Need therapy that reduces abdominal pain due to visceral hypersensitivity
• “Visceral hypersensitivity is currently the holy grail [of treatment]....it is widely regarded as the reason for the development of [pain] in functional GI disorders”* • GI Dysmotility: Use Laxatives (e.g., Miralax®) for Constipation & Anti-diarrheals (Imodium®) for Diarrhea…. • Need therapy that
Slide 71: Pharmacology: Linaclotide Works in Two Ways
Pharmacology: Linaclotide Works in Two Ways — *Decreased activity of pain-sensing nerves is believed to occur as a result of elevation in extracellular cGMP — Increased intestinal transit is believed to occur as a result of elevation in intracellular cGMP, which stimulates secretion of chloride & bi
Slide 72: Pharmacology: Linaclotide Works in Two Ways
Pharmacology: Linaclotide Works in Two Ways — *Decreased activity of pain-sensing nerves is believed to occur as a result of elevation in extracellular cGMP — Increased intestinal transit is believed to occur as a result of elevation in intracellular cGMP, which stimulates secretion of chloride & bi
Slide 73: Linaclotide: My Experience
Linaclotide: My Experience • A potent treatment for constipation* • Abdominal discomfort improves gradually over 6-8 weeks • My experience with linaclotide-associated diarrhea. *No head-to-head trials comparing linaclotide to other constipation treatments Confidential | 73
Slide 74: Finding Effective Treatments for Functional GI Disorders
Finding Effective Treatments for Functional GI Disorders Refractory GERD Functional Dyspepsia Gastroparesis IBS-C, IBS-D, IBS-M, Chronic Constipation, Opioid-Induced Constipation, Diverticulitis Confidential | 74
Slide 75: BREAK
BREAK LY, 75 lronwood
Slide 76: Leveraging Pharmacologic Expertise
Leveraging Pharmacologic Expertise Mark Currie, Ph.D. President of R&D, SVP, Chief Scientific Officer 76
Slide 77: Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy
Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy NEW PRODUCTS NEW INDICATIONS Linaclotide IBS-C / CIC Adults GC-C 77
Slide 78: Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy
Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy NEW PRODUCTS NEW INDICATIONS Gastro- intestinal (GI) Linaclotide IBS-C / CIC Adults GC-C 78
Slide 79: Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy
Leveraging Therapeutic and Pharmacologic Expertise Core to Strategy NEW PRODUCTS NEW INDICATIONS Gastro- Guanylate intestinal Cyclases (GI) (GC) Linaclotide IBS-C / CIC Adults GC-C 79
Slide 80: Expect to Advance Multiple Product Opportunities
Expect to Advance Multiple Product Opportunities Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention P
Slide 81: Robust R&D Platform with Multiple Near-Term Value Opportunities
Robust R&D Platform with Multiple Near-Term Value Opportunities • Opportunity for up to 7 GI clinical development programs over next 24 months – Linaclotide new indications – New product opportunities – Multiple opportunities to generate proof-of-concept data • Advancing sGC platform with first clin
Slide 82: Linaclotide Mechanism of Action
Linaclotide Mechanism of Action • Minimally absorbed peptide • Guanylate cyclase-C (GC-C) agonist, results in increase of cyclic guanosine monophosphate (cGMP) • Based upon available nonclinical data, cGMP is proposed to work in two ways: 1. Intracellular – increases fluid secretion and accelerates
Slide 83: GC-C Intestinal Expression Provides Possibility for Upper and Lower GI-Targeted Therapies
GC-C Intestinal Expression Provides Possibility for Upper and Lower GI-Targeted Therapies • GC-C expression throughout small and large intestine • Stimulation of GC-C elicits intestinal analgesia in non-clinical models GC-C • Opportunity for targeted delivery of linaclotide and design of novel GC-C
Slide 84: Linaclotide Relieved Multiple Abdominal Symptoms in Phase III IBS-C Trials
Linaclotide Relieved Multiple Abdominal Symptoms in Phase III IBS-C Trials Abdominal Pain Bloating 0 0 Ab. Pain -10 -10 Change -20 -20 % Change % Change -30 -30 % Change -40 -40 % -50 -50 -60 -60 BL 2 4 6 8 10 12 14 16 18 20 22 24 26 BL 2 4 6 8 10 12 14 16 18 20 22 24 26 Trial Week Trial Week Treatm
Slide 85: Multiple Scientific Publications Characterizing Breakthrough Discovery of Linaclotide Actions
Multiple Scientific Publications Characterizing Breakthrough Discovery of the Actions of Linaclotide to Decrease Intestinal Pain in Non-Clinical Models 85
Slide 86: Recognition of Growing Excitement around Mechanism of Action for Linaclotide
Recognition of Growing Excitement around Mechanism of Action for Linaclotide 86
Slide 87: Linaclotide and cGMP Reduce Firing of Pain-Sensing Nerves
Linaclotide and cGMP Reduce Firing of Pain-Sensing Nerves Recordings from pain fibers in non-clinical colonic model Colonic Segment ** Linaclotide (nM) cGMP (uM) Source: Castro J., et al. Gastroenterology. 2013 Dec;145(6):1334-1346.e11. doi: 10.1053/j.gastro.2013.08.017. Epub 2013 Aug 16. 87
Slide 88: Insights into GC-C Regulation of Pain-Sensing Nerves Enable New Product Opportunities
Insights into GC-C Regulation of Pain-Sensing Nerves Enable New Product Opportunities • Targeted colonic delivery of linaclotide with potential to improve treatment of lower abdominal pain with two product opportunities across multiple indications – IBS-C, CIC – IBS-M, IBS-D, Ulcerative Colitis, Div
Slide 89: Growing GI Clinical Development Opportunities
Growing GI Clinical Development Opportunities Michael Hall, M.D. SVP, Clinical Development 89
Slide 90: Linaclotide Colonic Delivery: Advancing Phase II in 2015
Linaclotide Colonic Delivery: Advancing Phase II in 2015 Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prev
Slide 91: Linaclotide Colonic Delivery: Potential for Enhanced Lower Abdominal Pain Relief
Linaclotide Colonic Delivery: Potential for Enhanced Lower Abdominal Pain Relief Opportunities for two products Opportunity to enhance abdominal pain relief in IBS-C and CIC patients Opportunity to extend lower abdominal pain relief in non- constipated patients that suffer GI conditions with lower C
Slide 92: Targeting Lower Abdominal Pain Relief with Colonic Delivery of Linaclotide
Targeting Lower Abdominal Pain Relief with Colonic Delivery of Linaclotide LINZESS® COLONIC DELIVERY Stomach Small More Less Intestine Fluid Fluid GC-C More Colon Pain Relief Pain Relief = linaclotide 92
Slide 93: Optimizing Therapeutic Profile of Targeted Delivery Products by Titrating Dose
Optimizing Therapeutic Profile of Targeted Delivery Products by Titrating Dose Higher Dose Pharmacological Goal Potential Benefits Patient Population • Pain relief in colon • Enhanced • IBS-C • Modulated effect on fluid abdominal pain • CIC w/abdominal secretion relief symptoms • Relief of constipat
Slide 94: Addressing Two Opportunities in One Program
Addressing Two Opportunities in One Program • Plan to initiate Phase II dose-ranging study in IBS-C mid- 2015 – Titrate doses to compare effects on abdominal pain and constipation relief to enable the two product opportunities • Anticipate proof-of-concept data in 2016 • Partnered 50/50 with Forest
Slide 95: IW-9179: Phase II for Upper GI Disorders
IW-9179: Phase II for Upper GI Disorders Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention Phase II
Slide 96: Opportunity for GC-C Agonist with Potential to Treat Gastroparesis and Functional Dyspepsia
Opportunity for GC-C Agonist with Potential to Treat Gastroparesis and Functional Dyspepsia Current Unmet Need • ~5-12M U.S. gastroparetic Gastroparesis patients (diabetic and idiopathic) • Suffer from nausea, vomiting, bloating, early satiety, and pain • Limited treatments available Current Unmet N
Slide 97: Linaclotide Data Suggest Potential for Upper GI-Targeted GC-C Agonist
Linaclotide Data Suggest Potential for Potent Upper GI-Targeted GC-C Agonist in Gastroparesis and FD Symptoms Data from linaclotide Phase IIIb CIC Study Pain or Ache in Upper Abdomen Discomfort in Upper Abdomen Placebo 145 µg 290µg Placebo 145 µg 290µg (N=138) (N=129) (N=126) (N=138) (N=129) (N=126)
Slide 98: Targeting GC-C Agonist Designed to Maximize Relief of Upper GI Symptoms
Targeting GC-C Agonist Designed to Maximize Relief of Upper GI Symptoms LINZESS® IW-9179: UPPER GI TARGETED Stomach Small Intestine GC-C Colon = linaclotide = IW-9179 98
Slide 99: IW-9179: A Potent GC-C Agonist Designed to Selectively Target Upper GI Disorders
IW-9179: A Potent GC-C Agonist Designed to Selectively Target the Upper GI Disorders Linaclotide CCEYCCNPACTGCY IW-9179 CCSLCCNPACTGC Metabolic Handle PO4 • Phosphate group mediates upper GI targeting – Potent when phosphorylated – Enzyme in upper GI removes phosphate – Phosphate removal reduces pot
Slide 100: IW-9179 Promoted Gastric Emptying in Non-Clinical Model of Gastroparesis
IW-9179 Promoted Gastric Emptying in Non-Clinical Model of Gastroparesis 100 90 80 % Liquid Retained in Stomach 70 60 * * * 50 40 30 20 10 0 Vehicle Vehicle IW-9179 IW-9179 IW-9179 0.1 mpk 0.3 mpk 1 mpk Healthy Diabetic Study conducted in collaboration with Drs. Niaz Sahibzada and Richard Gillis, Ge
Slide 101: IW-9179 Phase I Clinical Trial Results
IW-9179 Phase I Clinical Trial Results Early evidence of strong pharmacological profile • Demonstration of pharmacodynamic activity in both single and multi-dose studies • Minimally absorbed • Generally well tolerated – Diarrhea most common AE • Substantial non-clinical safety package with large the
Slide 102: Strategy to Develop IW-9179 for Both Functional Dyspepsia and Gastroparesis
Strategy to Develop IW-9179 for Both Functional Dyspepsia and Gastroparesis • Refine regulatory paths for both gastroparesis and FD – Define appropriate population and endpoints with FDA – Leverage prior success developing PROs in GI • Ongoing Phase IIa clinical trial in FD – Data from a small patie
Slide 103: IW-9179 Designed to Address Unmet Need in Two Large Patient Populations
IW-9179 Designed to Address Unmet Need in Two Large Patient Populations • Learnings from LINZESS® clinical studies provide strong rationale for developing a potent upper GI-targeted GC-C agonist • Emerging pharmacology and tolerability profile • Composition of matter patent coverage through 2030 – P
Slide 104: Building on our Expertise in GI Disorders and Guanylate Cyclases
Building on our Expertise in GI Disorders and Guanylate Cyclases Brian Cali, Ph.D. SVP, Preclinical R&D 104
Slide 105: IW-3718: Advancing to Phase II in 2014
IW-3718: Advancing to Phase II in 2014 Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention Phase II Li
Slide 106: IW-3718: Exploring Potential Utility for Treatment of Refractory GERD and Barrett’s Esophagus
IW-3718: Exploring Potential Utility for Treatment of Refractory GERD and Barrett’s Esophagus Refractory GERD Current Unmet Need • ~40M patients in US suffer regularly from GERD • ~7M do not get relief from current standard of care • Bile acid reflux may be driver of symptoms in refractory patients
Slide 107: Esophageal Pathology Resulting from Bile Acid Reflux
Esophageal Pathology Resulting from Bile Acid Reflux Lower Esophageal Sphincter Pyloric Sphincter HEALTHY GI BILE REFLUX Bile is released into the small Bile acids reflux into stomach and intestine: not present in eventually to the esophagus, causing stomach or esophagus pain, inflammation and poten
Slide 108: Role of Bile in Refractory GERD, Barrett’s Esophagus and Adenocarcinoma
Role of Bile in Refractory GERD, Barrett’s Esophagus and Adenocarcinoma: Some Relevant Literature Bile acids can induce heartburn symptoms, including nausea and epigastric pain, as well as physical changes in esophageal mucosa that would drive development of heartburn symptoms (Siddiqui A et al, D
Slide 109: Bile Acid Sequestrant Prevents Bile-induced Relaxation of Lower Esophageal Sphincter
Bile Acid Sequestrant Prevents Bile-induced Relaxation of Lower Esophageal Sphincter Data from non-clinical ex vivo system 100 *** *** Percent Relaxation 80 60 40 20 0 M M M M EH 1m 1m V 0 0 30 50 DCA Bile Acid Bile Acid Sequestrant (2mg/mL) 109
Slide 110: Bile Acid Sequestrant Prevents Bile-induced Activation of Esophageal Nerve Fibers
Bile Acid Sequestrant Prevents Bile-induced Activation of Esophageal Nerve Fibers Data from non-clinical ex vivo system Bile Acid Induces Nerve Fiber Activation Bile acid (1mM) Activations/5 sec. 12 0 1 minute Bile Acid Sequestrant Blocks Bile Acid Effect Activations/5sec. Bile acid (1mM) + Bile Aci
Slide 111: IW-3718 Utilizes Gastric Retentive Technology
IW-3718 Utilizes Gastric Retentive Technology; Designed to Protect Esophagus by Intercepting Bile Acids in Stomach • IW-3718 combines a bile acid sequestrant with Depomed’s gastric retentive polymer Tablet expands in stomach, causing technology Acuform® gastric retention and extending release time –
Slide 112: IW-3718: Non-clinical Profile Suggests Gastric Retentive Product
IW-3718: Non-clinical Profile Suggests Gastric Retentive Product In vitro Performance In vivo Performance 10 100 90 8 80 Mean Erosion Time (hrs) % Drug Released 70 6 60 50 4 40 30 2 20 Immediate Release 10 IW‐3718 (Extended Release) 0 0 Immediate IW‐3718 0 5 10 15 20 Release Time (hr) 112
Slide 113: IW-3718 Phase II Trial Design
IW-3718 Phase II Trial Design • Phase II proof-of-concept study in ~90 refractory GERD patients currently on PPIs • 28 day, double-blind, placebo-controlled, parallel groups • Key endpoints: symptom relief, reduction in esophageal bile acids, and tolerability – To support proof-of-mechanism and symp
Slide 114: IW-3718: Novel Bile Acid Sequestrant Formulation
IW-3718: Novel Bile Acid Sequestrant Formulation • Gastric retentive bile acid sequestrant designed to prevent esophageal reflux of bile acids – Novel approach being evaluated for the treatment of refractory GERD and Barrett’s esophagus – Significant unmet need and easy to identify patients • Develo
Slide 115: sGC Platform: Advancing First Candidate
sGC Platform: Advancing First Candidate Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention Phase II L
Slide 116: Pharmacologic Expertise in Guanylate Cyclases and cGMP Lays Foundation for sGC Platform
Pharmacologic Expertise in Guanylate Cyclases and cGMP Lays Foundation for sGC Platform NEW PRODUCTS Linaclotide Colonic Delivery • Linaclotide/PPI • IW-9179 NEW INDICATIONS Gastro-inte Pediatrics • OIC Guanylate stinal (GI) Additional Symptoms Cyclases (GC) IW-3718 sGC Stimulators Linaclotide IBS-C
Slide 117: Building on GC-C/cGMP Pharmacology
Building on GC-C/cGMP Pharmacology Guanylate Soluble Cyclase C Guanylate (GC-C) Cyclase (sGC) Guanylin, Uroguanylin, Nitric Oxide, Linaclotide sGC stimulators GTP cGMP GTP cGMP Diverse and compelling pharmacology of cGMP 117 117
Slide 118: cGMP: Ongoing Legacy of Solutions for Patients
cGMP: Ongoing Legacy of Solutions for Patients Angina— NO Heart Failure— PAH, Donor Natriuretic CTEPH—sGC (1875) Peptide (2001) stimulator (2013) What next? Erectile CIC, IBS-C— Dysfunction, GC-C Agonist PAH, BPH— (2012) PDE5 inhibitors (1998) 118
Slide 119: Diverse Functions of sGC in Different Body Systems Creates Potential for New Product Opportunities
Diverse Functions of sGC in Different Body Systems Creates Potential for New Product Opportunities Illustrative Examples Therapeutic Body System sGC Function Opportunity Smooth muscle relaxation PAH, CTEPH, resistant Cardiovascular and vasodilation hypertension, heart failure Central Nervous Long-te
Slide 120: Novel sGC Stimulators Set Stage for Multiple Product Opportunities
Novel sGC Stimulators Set Stage for Multiple Product Opportunities 120
Slide 121: Adempas (riociguat): Breakthrough Treatment for Severe CV Diseases
Adempas® (riociguat): Breakthrough Treatment for Severe CV Diseases • Strong evidence of improvement in function in PAH and Chronic Thromboembolic Pulmonary Hypertension (CTEPH) patients • Delayed time to clinical worsening • Three times a day dosing • Hypotension a limiting side effect 121
Slide 122: Robust PK/PD Profile for Lead sGC Stimulator in Non-clinical Models
Robust PK/PD Profile for Lead sGC Stimulator in Non-clinical Models PK Profile of Ironwood Lead Compound IV, 1 mg/kg 1000 PK profile consistent with once Concentration (ng/mL) daily dosing in humans 100 Elimination half-life:425 min 10 1 0 500 1000 1500 2000 Time (min) Blood Pressure Effect after Or
Slide 123: sGC Platform Provides Opportunity for Multiple Product Candidates
sGC Platform Provides Opportunity for Multiple Product Candidates • Lead sGC candidate for PAH and other CV diseases – Expect proof-of-mechanism and PK/PD profile data in 2015 • Rich and competitive area with numerous therapeutic product opportunities – Opportunity for early strategic partnerships t
Slide 124: Summary
Summary Mark Currie, Ph.D. President of R&D, SVP, Chief Scientific Officer 124
Slide 125: Exploring Linaclotide in Colon Cancer Prevention
Exploring Linaclotide in Colon Cancer Prevention Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention P
Slide 126: Exploring Linaclotide in Colon Cancer Prevention
Exploring Linaclotide in Colon Cancer Prevention Ongoing collaborative biomarker study1 • Loss of expression of guanylin and uroguanylin in colon cancer cells2, 3 • GC-C agonist replacement therapy results in marked reduction of intestinal polyps and dysplasia in non-clinical studies3, 4 • GC-C agon
Slide 127: Multiple Value-Creating Product Opportunities
Multiple Value-Creating Product Opportunities Discovery Formulation & Stability / Phase I Phase II Pivotal Approved GI LINZESS® IBS-C or CIC in adults Approved 8/12 & Launched 12/12 Platform (linaclotide) Phase II Opioid-induced Constipation 1H’14 IBS-C/CIC in Pediatrics Colon Cancer Prevention Phas
Slide 128: Multiple Value-Creating Product Opportunities
Multiple Value-Creating Product Opportunities 2014 2015 2016 GI Platform Obtain Ph II data Linaclotide in Japan 1H 2014 Phase III Linaclotide in China ongoing Phase II Linaclotide OIC 2H ‘15 1H’14 Establishing path Linaclotide in Pediatrics with FDA Linaclotide in Colon Cancer Biomarker study ongoin
Slide 129: Robust R&D Platform with Multiple Near-Term Value Opportunities
Robust R&D Platform with Multiple Near-Term Value Opportunities • Opportunity for up to 7 GI clinical development programs over next 24 months – Linaclotide new indications – New product opportunities – Multiple opportunities to generate proof-of-concept data • Advancing sGC platform with first clin
Slide 130: Closing
Closing Peter Hecht, Ph.D. Chief Executive Officer 130
Slide 131: Building a Leading GI Company
Building a Leading GI Company We will: • Maximize LINZESS® • Advance robust GI pipeline and GC research • Leverage commercial capabilities • Prioritize investments in key value drivers 131
Slide 132: Q&A
Q&A LY, 132 lronwood
Slide 133: lronwood
LY, lronwood
Slide 134: Appendix
Appendix LY, 134 lronwood
Slide 135: Linaclotide Phase II OIC Study Design
Linaclotide Phase II OIC Study Design • Phase II dose-ranging in patients with OIC • Double-blind, parallel group, 3 arm study • Placebo, linaclotide 145ug & 290ug • ~80 patients per arm 135
Slide 136: IW-3718 Phase IIa Study Design – Refractory GERD
IW-3718 Phase IIa Study Design – Refractory GERD Purpose: To evaluate the safety and effects of IW-3718 on symptoms and esophageal bile reflux in GERD patients not completely responsive to PPI therapy Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group Patients to be st
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