Insmed Incorporated · NASDAQ:INSM
Insmed — Investor Day (July 2017)
149 slides from Insmed's investor day presentation, Jul 19, 2017
Slide 1: Insmed Analyst and Investor Day July 19, 2017
Insmed Analyst and Investor Day July 19, 2017
Slide 2: Safe Harbor Statement & Disclaimer
Safe Harbor Statement & Disclaimer This presentation contains forward-looking statements that are based on management’s current expectations regarding, among other things, the status, results and timing of our clinical trials and clinical data, the anticipated benefits of our product candidates, and
Slide 3: Welcome and Opening Remarks
Welcome and Opening Remarks Will Lewis President and Chief Executive Officer
Slide 4: The Cornerstones of Insmed's Success
The Cornerstones of Insmed’s Success MISSION To improve the lives of patients battling serious rare diseases VALUES Respect Passion Integrity Collaboration Accountability STRATEGY Growth International Additional products Financial responsibility • • • • • • • • • 4
Slide 5: Current Efforts Underway
Current Efforts Underway • • CONVERT Phase 3 data – Top line results expected September +/-a month Non-branded disease education efforts for non-tuberculous mycobacteria (NTM) diagnosis and guideline based treatment • INS1007 expected to enter Phase 2 study in 2H 2017 - The Willow Study in Non-CF Br
Slide 6: New Information Today
New Information Today • • • Amikacin Liposome Inhalation Suspension (ALIS) CONVERT Phase 3 study status ALIS market opportunity and commercialization approach • • • • • Sizing the addressable market Specifics of US sales force NTM cost burden Local understanding of the patient landscape New life cyc
Slide 7: NTM Lung Disease Caused by MAC: Unmet Medical Need
NTMLUNGDISEASECAUSEDBY MYCOBACTERIAL AVIUM COMPLEX Unmet Medical Need Kevin L. Winthrop M.D., M.P.H. Associate Professor Divisions of Infectious Diseases, Public Health and Preventive Medicine Oregon Health and Science University
Slide 8: Disclosures
Disclosures Consultant and/or research support: • • • • • • • • Bayer Insmed Raptor FDA NIH PCORI American NTMir Lung Association 8
Slide 9: NTM Lung Disease Caused by Mycobacterial Avium Complex
NTM Lung Disease Caused Complex (MAC) by Mycobacterial Avium • • • • • Epidemiology and disease overview Understanding the disease Identifying Treatment Treatment and treating patients – the guidelines clinical experience challenges and unmet needs 9
Slide 10: What is NTM?
What is NTM? • • NTM stands for non-tuberculous mycobacteria Environmental organisms - - - - soils, lakes, rivers municipal water (yes, including your tap at home) ability to form biofilms where water flows (live with amoeba, NTM are able to shield themselves within the airway biofilm cells like the
Slide 11: NTM Lung Disease Overview
NTM Lung Disease Overview US rate of NTM lung disease increased 1997-20071 Guidelines for treatment include therapies that have poor efficacy, safety, and adherence (i.e. macrolide, ethambutol, and rifampin)2 Refractory and cavitary patients often require IV aminoglycosides which • • • are known to
Slide 12: Prevalence of NTM Lung Disease is Rising
Prevalence of NTM Lung Disease is Rising Estimated prevalence of NTM lung disease in patients > 65 years in the USA*1 N T M P D 60 50 40 P R E V A L E N C E Increase in the annual estimated prevalence by 8.2% per year1 30 20 10 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Over the last d
Slide 13: Incidence of Pulmonary NTM Disease in Oregon
Annual Age-and Sex-specific Incidence of Pulmonary NTM Disease in Oregon, 2007-2012 35.0 30.0 25.0 20.0 Males Females 15.0 10.0 5.0 0.0 0-49 50-59 60-69 70-79 80+ Age group (years) 13 Incidence per 100,000
Slide 14: Why are the Rates of NTM Lung Infections Increasing?
Why are the Rates of Increasing? NTM Lung Infections Improved quality of diagnostic methods e.g. microbiological detection techniques1 Aging population2,3 with an increase morbidities1 in the prevalence of COPD2 and other co-Increased disease awareness1 Further research on the epidemiology of NTM lu
Slide 15: Risk Factors for and Transmission of NTM
Risk Factors for and Transmission of NTM Inhalation of NTM-laden aerosols from shower heads; hot tubs; heated pools Ingestion of soil or water1 followed by gastric Contamination of hospital water supplies and medical equipment2 Person-to-person transmission extremely rare CF, cystic fibrosis; NTM, n
Slide 16: NTM Lung Disease can be Progressive
NTM Lung Disease can be Progressive If left untreated, MAC lung disease NTMPD can become a Ifclaenftruensutrlet ainteedx, tMenAsCivleuncgavditiasreyase can result in extensive lung destruction adnedsrteruscptiiroantoarynd respiratory failure2 failure2 cavitary lung lung disease1,2 progressive Declin
Slide 17: NTM Lung Disease can be Progressive
NTM Lung Disease can be Progressive NTMPD can become a progressive lung disease’? If left untreated, MAC lung disease can result in extensive cavitary lung destruction and respiratory failure? Decline in lung function among NTMPD patients (n=68)** + Mean reduction in FEV, was 48 mL/year + Normal ran
Slide 18: I
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Slide 19: Treatment Guidelines
Treatment Guidelines • Treatment guidelines for patients with Mycobacterium avium complex (MAC) lung disease were published in 2007 by the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) -based primarily on observational, small uncontrolled or non-comparative studies in
Slide 20: Treatment of MAC Pulmonary Disease
Treatment of MAC Pulmonary Disease • For most patients with nodular/bronchiectatic disease, regimen of a three-times-weekly - - - clarithromycin (1,000 mg) or azithromycin (500mg) rifampin (600 mg) ethambutol (25 mg/kg) is recommended • For patients with fibrocavitary MAC lung disease or severe nodu
Slide 21: Therapeutic Unmet Need
Therapeutic Unmet Need • Efficacy -“cure” is unusual -relapse and reinfection is common (approx. Chest 2014 50% in 3 years) – Wallace & Griffith • Tolerability - - - high degree of non-serious adverse events often “lose” at least 1 drug during initial therapy serious adverse events (e.g. optic neuri
Slide 22: Need Paradigm
Need Paradigm • First-line therapeutic for MDR -“Refractory” patients -all patients Can we shorten treatment? -tolerability New treatment strategies regimen • • - - suppressive post-treatment suppressive/preventive 23
Slide 23: Summary
Summary • • NTM lung disease prevalence is increasing worldwide Patients typically have at least one additional lung disease, bronchiectasis or COPD (or both) NTM treatment guidelines are currently being rewritten, but based upon expert opinions and observational studies -Current multi drug regimens
Slide 24: ALIS Clinical Development Strategy
ALIS Clinical Development Strategy Gina Eagle, MD Vice President, Clinical Development
Slide 25: Overview of ALIS Clinical Development Strategy
Overview of ALIS Clinical Development Strategy • • • Addressing an unmet medical need Leveraged insights from Phase 2 results to optimize CONVERT Phase 3 study for success Incorporated discussions with US Food and Drug Administration (FDA) to support accelerated path to potential approval in refract
Slide 26: In vitro Susceptibilities to Amikacin for Slow-growing NTM
In vitro Susceptibilities to Amikacin for Slow-growing NTM For the slow-growing NTM, >89% of isolates for each slowly growing NTM species, and 92% of isolates for the slowly growing MAC NTM species, are susceptible to Amikacin 27
Slide 27: Amikacin Liposome Inhalation Suspension (ALIS)
Amikacin Liposome Inhalation Suspension (ALIS) • • • • Amikacin: established in vitro evidence against NTM Nebulized liposome particles directly target the lung Liposomes facilitate intra-cellular uptake by lung macrophages Low serum levels of amikacin reduce the potential for systemic toxicity 28
Slide 28: Regulatory Landscape
Regulatory Landscape granted June 2014 *Dmitri Iarikov, MD PhD (Deputy Director, Division of Anti-infective Products) 29 FDA has granted multiple designations for ALIS in NTM lung disease •Orphan Indication Designation – granted March 2013 •Qualified Infectious Disease Product (QIDP) – granted June
Slide 29: ALIS Development Program: Phase 2 Study
ALIS Development Program: Phase 12 Week Treatment Phase 2 Study 12 Week Treatment Phase 4 Week Off Treatment* R No Treatment Primary Endpoint: Efficacy • Change on Semi-Quantitative Scale for mycobacterial density at Day 84 • ALIS did not meet statistical significance for the primary efficacy endpoi
Slide 30: Consistency of Beneficial Effect in Phase 2
Consistency of Beneficial Effect in Phase 2: Three Consecutive Negative Cultures in Non-CF MAC Sub-Population(“Culture Conversion” as Defined in Phase 3)* Percentage of patients who achieved three consecutive negative cultures at each time point (ITT population in Phase 2) 50% 40% 37.0 30% 20% 18.5
Slide 31: Phase 2 Safety Data
• 32 Phase 2 Safety Data • • Adverse events reported at >5% frequency in either arm.
Slide 32: Phase 3 Study Design Based on Phase 2 Results
Phase 3 Study Design Based on Phase 2 Results Insmed discussed protocol with FDA for potential accelerated approval under Sub-part H for the primary endpoint of sputum culture conversion by Month 6 More homogeneous population based on subgroup of non-CF MAC that showed greatest efficacy signal Prima
Slide 33: Phase 3 INS212 CONVERT Study
Phase 3 INS212 CONVERT Study A Randomized, Open-Label, Multicenter Study of Amikacin Liposome Inhalation Suspension (ALIS) in Adult Patients with Nontuberculous Mycobacterial (NTM) Lung Disease caused by Mycobacterium avium complex (MAC) that are refractory to treatment • • Global 127 Clinical Trial
Slide 34: CONVERT Study Design
CONVERT Study Design Treatment Phase (Up to Month 16) Off Treatment Phase (Up to Month 28) Baseline Adult patients with Period longer than 12 6 Months on Treatment* Primary Endpoint: Percentage of Patients who Achieve Culture Conversion by 6 Months 3 Months off Treatment Efficacy Data Readouts Durab
Slide 35: CONVERT Study: Key Study Criteria
CONVERT Study: Key Study Criteria • Amikacin-resistant (MIC>64mcg/mL) 36 Exclusion: •Patients with cystic fibrosis •Active pulmonary tuberculosis requiring treatment at screening •History of lung transplantation Inclusion: •Continually MAC+ on sputum culture while adhering to SOC for >6 months •Diag
Slide 36: CONVERT Study: Key Study Endpoints for Potential Accelerated Approval
CONVERT Study: Key Study Endpoints for Potential Accelerated Approval* 1° Primary Efficacy Endpoint • Proportion of patients achieving culture conversion (three consecutive negative sputum cultures collected monthly) at Month 6 in the ALIS arm compared to multi-drug regimen alone 90% powered to show
Slide 37: CONVERT Study: Status
CONVERT Study: Status • The last subject has exited Month 6 • Primary endpoint evaluated at Month 6 • Discontinuation rate slightly lower than expected • Based on original assumption of 25% • Data Monitoring Committee has met seven times to date • Recommend no changes to study conduct 38
Slide 38: Phase 3 INS312 CONVERT Extension Study
Phase 3 INS312 CONVERT Extension Study An Open-Label Safety Extension Study to a Multicenter Study of ALIS in Adult Patients with NTM Lung Disease Caused by MAC That are Refractory to Treatment • • Global 62 Clinical Trial Sites – – – – United States/Canada Europe/UK/Israel Australia/NZ Japan/South
Slide 39: CONVERT Extension Study: Key Study Endpoints
CONVERT Extension Study: Key Study Endpoints 1° Primary Safety Endpoint • To evaluate the long term safety and tolerability of ALIS in combination with standard multi-drug regimen 2° Key Secondary Efficacy Endpoints • • • • Proportion of patients achieving culture conversion at Month 6* and Month 12
Slide 40: Scenario Planning Around Topline Results
Scenario Planning Around Topline Results* 02 Submission under but misses one or more secondary endpoints 04 The basis for Sub-part H approval is a surrogate endpoint (21 CFR 314.510) consistent with FDA guidance. The approval relies on the effect of the surrogate endpoint being reasonably likely to
Slide 41: Future Study Strategies: Focusing on MAC Disease
Future Study Strategies: Focusing on MAC Disease Treatment Pathway Complete treatment Initiate multi-drug regimen Month 6 review Treatment Pathway for MAC Lung Disease Potential ALIS Label Indications in MAC Lung Disease 42 ALIS indicated as add-on treatment for non-converters after 6 months of mult
Slide 42: Conclusions
Conclusions • • • ALIS has potential to address unmet medical needs in NTM lung disease CONVERT Phase 3 study optimized for success Positive data from CONVERT Phase 3 study may support accelerated path to potential approval in the refractory population Additional future opportunities for ALIS may in
Slide 43: ALIS Market Opportunity and Commercialization Approach
ALIS Market Opportunity and Commercialization Approach Roger Adsett Chief Commercial Officer
Slide 44: Discussion Topics
Discussion Topics • • Global addressable market for ALIS US market opportunity and go-to-market strategy • • • • • • Where do the NTM patients reside? Who is managing these patients for NTM? How are we going to reach the NTM treating healthcare providers (HCPs)? What is our approach towards disease
Slide 45: US and Japan Account for Majority of Global Addressable Market
US and Japan Account for Majority Addressable Market for ALIS of the Estimated Global Total Estimated NTM Patients by Country/Region 22 Source: Internal analysis of published NTM epidemiology, primary market research with treating HCPs, and anonymized patient level claims data in US 46 (2018E) ‘000s
Slide 46: Refining the NTM MAC Opportunity in the US
Refining the NTM MAC Opportunity in the US (2018 estimates) 250,000-300,0001 Patients w/ NTM Isolate Diagnosis Rate (30-35%)1 Patients w/ Diagnosed NTM Lung Disease 75,000-105,000 Rate of MAC NTMLD (~80%)2 Patients w/ NTMLD Caused by MAC 65,000-80,000 Treatment Rate (~60%)3 40,000-50,000 Patients w/
Slide 47: Initial ALIS Opportunity in the US
Initial ALIS Opportunity in the US 250,000-300,0001 Diagnosis Rate (30-35%)1 75,000-105,000 Rate of MAC NTMLD (~80%)2 65,000-80,000 Treatment Rate (~60%)3 40,000-50,000 48 “Refractory” Rate (25-30%)4 Patients w/ Non-responding NTMLD Caused by MAC 10,000-15,000
Slide 48: NTM Cases are Primarily Concentrated in Southeastern and Coastal Regions
NTM Cases are Primarily Concentrated in Southeastern •• • Annual NTM Case Numbers c=J <500 c=J 500-1000 c=J 1001-2000 • and Coastal Regions 2001-3000 >3000 . . .. ... _.... ••• Source: Strollo,et al, The Burden of Pulmonary Nontuberculous Mycobacterial Disease in the United States, Ann Am Thorac Soc
Slide 49: Understanding the Patient Population
Understanding the Patient Population Drayton Wise General Manager - ALIS
Slide 50: Two 'NTM Likely' Patients for Each Diagnosed Patient in the US
We Estimate That There are Two ‘NTM Likely’ Patients for Each Currently Diagnosed NTM Patient in the US Counties with 100+ ‘NTM Likely’ patients journey of NTM patients patients amongst national patient claims database (‘NTM Likely’ patients with a predictive likelihood score of 0.9 or above) Source
Slide 51: Local Market Execution of National Strategy is Key to Success
Local Market Execution of National Strategy is Key to Success Hillsborough County, FL Los Angeles County, CA NTM Diagnosed NTM Likely 1.5% 1.5% % of Total US Diagnosed Patients (approx.) 1:1 4:1 Ratio of ‘NTM-Likely’ to Diagnosed Patients ~70 HCP Targets IDN dominated market (e.g. Kaiser) ~100 HCP T
Slide 52: NTM Treatment is Concentrated Among Providers
NTM Treatment is Concentrated Among Providers • ~5K physicians manage 70% of NTM patients 8 in 10 diagnosed NTM patients managed by Pulmonologist or Infectious Disease Specialist 52% of HCPs considered themselves “aggressive treaters” • • Cumulative % of Physicians Source: Symphony Health, PatientSo
Slide 53: Targeted US Go-to-Market Approach
Targeted US Go-to-Market Approach Designed Launch Success to Maximize • • • Targeted go-to-market approach with 70-75 sales representatives Vice President of US Sales hired Core requirements for sales representatives: • • • • • • Scientific aptitude Orphan Pulmonary and Infectious Disease experience
Slide 54: Disease Awareness and Patient Experience
Disease Awareness and Patient Experience Colleen Silk Senior Director, US Marketing - ALIS
Slide 55: Patients' Journey to NTM Diagnosis is Challenging
Patients’ Journey to NTM Diagnosis is Challenging The symptoms of NTM pulmonary disease are variable and nonspecific…Physical findings are nonspecific and reflect underlying pulmonary pathology, such as bronchiectasis and COPD - ATS/IDSA Statement on NTM 85% have a pre-existing lung condition at tim
Slide 56: Helping NTM Patients to Diagnosis through Disease Awareness
Helping NTM Patients to Diagnosis through Disease Awareness “1,000 Words about NTM” NTMFacts.com Healthcare Professional Disease Awareness Campaign: Educate on the importance of timely NTM diagnosis Communicate the importance of guideline-based treatment for NTM lung disease • • “Over & Over” AboutN
Slide 57: Patient Disease Awareness Activities
Patient Disease Awareness Activities Designed to Engage ‘NTM-Likely’ Patients gardening, swimming, traveling 59 Campaign Target Profile: •Age 65+ •Majority female •Diagnosed with one or more respiratory conditions: i.e. bronchiectasis, COPD, asthma •Suffering from one or more symptoms: Fatigue, coug
Slide 58: Patient Experience
Patient Experience Rahul Bhatia Senior Director, Commercial Strategy & Operations
Slide 59: Designing a Patient Support Program from a Patient's Perspective
Designing a Patient Support Program from a Patient’s Perspective As a non-responding NTM patient, I have … …. not achieved success in getting rid of my NTM lung disease … been on a long journey, before I got the right diagnosis (NTM), and found the right specialist …. limited income, since I retired
Slide 60: Appropriate Patient Support Aligned to Approved Label
Appropriate Patient Patient Needs Support Aligned to Approved Label and What to expect? (Physician office) Treatment initiation (Patient’s home) Patient off-boarding Ongoing reinforcement and adherence support Payer reimbursement & financial assistance 62
Slide 61: Plan to Deliver a Differentiated Patient Experience
Plan to Deliver a Differentiated Patient Experience Insmed ownership of patient interface, with back-office support from our partners Simple, flawless execution In-depth understanding of NTM patient journey Collaboration with NTM patients Predictive analytics with real-time view of each patient’s tr
Slide 62: Collaboration with Patients to Create Convenient Packaging
Collaboration with Patients to Create Convenient Innovative Packaging and Packaging design incorporated “voice of patient” and revealed key considerations for ALIS packaging Storage and Distribution Head 64 Tracking ProgressTravel and Mobility Replacing Aerosol Instructional MaterialsEnvironmental C
Slide 63: Voice of the Payer, Manufacturing, Future Opportunities and Conclusion
Voice of the Payer, Manufacturing, Future Opportunities and Conclusion Roger Adsett Chief Commercial Officer
Slide 64: Payer Voice
Payer Voice Source: Insmed Data on File: September 2016 Payer in-depth interviews (n=20); and April 2017 HEOR Advisors Panel (n=9) Combined organizations represent >150,000,000 lives covered 66 “CONVERT Study:Focus on Efficacy” “Do not anticipate overly restrictive management of ALIS utilization” “I
Slide 65: First-Year Insurance/Payer Spending in NTMLD
First-Year Insurance/Payer Spending in NTMLD and Patient Groups of COPD, IPF, PAH, and Lung Cancer without NTMLD $48,169 $44,313 $22,901 $51,753 $69,005 COPD IPF PAH Lung Cancer NTMLD *Cost burden is calculated as first-year insurance spending after NTMLD diagnosis between 2008 and 2013, and standar
Slide 66: Payer Value Framework: First Year Payer Cost
Burden* Payer Value Framework – First Year Payer Cost in Patient Subgroups $211,096 $80,486 $91,599 $55,120 $69,005 $51,753 $22,901 $44,313 *Cost burden is calculated as first-year insurance spending after NTMLD diagnosis between 2008 and 2013, and standardized using RBRVS (Resource Based Relative V
Slide 67: Payer Value Framework for Urgency of Decision
Payer Value Framework for Urgency of Decision Up to 33% years of diagnosis² Disease Severity/ Unmet Need ¹ 2017 US national managed care insurance claims database (Insmed Data on File); ²Marras, TK, Pulmonary Nontuberculous Mycobacteria–Associated Deaths, Ontario, Canada, 2001–2013 Emerging Infectio
Slide 68: Supply Chain in Place for Commercial Requirements
Supply Chain in Place for Commercial Requirements Multi-sourced drug supply chain for ALIS Expanding commercial-scale manufacturing capabilities 70 50L 200L
Slide 69: Initial ALIS Opportunity
Initial ALIS Opportunity 250,000-300,0001 Diagnosis Rate (30-35%)1 75,000-105,000 Rate of MAC NTMLD (~80%)2 65,000-80,000 Treatment Rate (~60%)3 40,000-50,000 71 “Refractory” Rate (25-30%)4 Patients w/ Non-responding NTMLD Caused by MAC 10,000-15,000
Slide 70: Tip of the Iceberg: Life-cycle Opportunities
Tip of the Iceberg: Unmet Needs Present Potential Life-cycle Opportunities to Conduct Additional Clinical Trials Potential Initial Indication 40,000-50,000 Patients w/ Treated NTMLD Caused by MAC Potential First Line Therapy Patients w/ NTMLD Caused by MAC 65,000-80,000 Patients w/ Diagnosed NTM Lun
Slide 71: Tip of the Iceberg: Life-cycle Opportunities
Tip of the Iceberg: Unmet Needs Present Potential Life-cycle Opportunities to Conduct Additional Clinical Trials Initial Indication 40,000-50,000 Patients w/ treated NTMLD Caused by MAC First Line Therapy Patients w/ NTMLD Caused by MAC M. Abscessus; Increased Diagnosis 65,000-80,000 Patients w/ Dia
Slide 72: Tip of the Iceberg: Life-cycle Opportunities
Tip of the Iceberg: Unmet Needs Present Potential Life-cycle Opportunities to Conduct Additional Clinical Trials Patients w/ Non-responding NTMLD Caused by MAC Initial Indication 10,000-15,000 40,000-50,000 Patients w/ treated NTMLD Caused by MAC First Line Therapy Patients w/ NTMLD Caused by MAC M.
Slide 73: Potential Maintenance Therapy: Prevention of Re-infection
Potential Maintenance Therapy: Prevention of Re-infection Month 0 Initiate multi-drug regimen By Month 6 Month 6 review By Month 18 Complete treatment Converters continue treatment for 12 months of negative cultures Chronic Use 3x Week 75 Potential New Indication Potential ALIS Maintenance Monothera
Slide 74: Commercial Readiness to Support Global ALIS Launches
Commercial Readiness to Support Global ALIS Launches Germany, UK, France and Italy efforts underway 76 Launch Readiness • Commercial HQ leadership and teams already in place • Disease state awareness efforts underway • Go-to-market strategy and field territories defined • Account directors, field sa
Slide 75: References
References US 1. A) Adjemian, et al, Prevalence of Nontuberculous Mycobacterial Lung Disease in U.S. Medicare Beneficiaries, AJRCCM, Vol 185, Apr 15, 2012 B) Strollo, et al, The burden of pulmonary nontuberculous mycobacterial disease in the United States, Ann Am Thorac Soc Vol 12, No 10, pp 1459-14
Slide 76: References
” References US 1. A) Adjemian, etal, Prevalence of Nontuberculous Mycobacterial Lung Disease in US. Medicare Beneficas 5, AIRCCM, Vol 185, Apr 15, 2012 8) Strollo, etal, The burden of pulmonary nontuberculous mycobacterial disease inthe United States, Ann Am Thorac Soc Vol 12, No 10, pp 1459-1464,
Slide 77: Infectious Complications of Non-cystic Fibrosis Bronchiectasis
Infectious Complications of Non-cystic Fibrosis Bronchiectasis Kevin L. Winthrop M.D., M.P.H. Associate Professor Divisions of Infectious Diseases, Public Health and Preventive Medicine Oregon Health and Science University
Slide 78: Disclosures
Disclosures • Consultant and/or research support: Bayer Insmed Raptor FDA NIH PCORI American NTMir Lung Association 80
Slide 79: Non-CF Bronchiectasis
Non-CF Bronchiectasis • • • • Pathophysiology Epidemiology Patient experience and current treatments Need for treatments 81
Slide 80: What is Bronchiectasis
I What is Bronchiectasis Eu r J Resir D.is 1 9&6: 69 (Su ppl 1 47): 6-15 Ch ronic bronchial sepsis, or which brouhiectasis is an example, and chronic sinusi tis di play infotmfllion a bout c he palhogenesis or chronic inllammatory disease: or the luog. 82 Inflammation: a two-edged sword-the model of
Slide 81: What is Bronchiectasis
I What is Bronchiectasis Increased mucus Deslruclion of wall Normal Bronchus Broncnlectasls l:ormal 7lc:lindrical Cystic Varicose 83 _f( _}-f( !1; 4
Slide 82: Interrupting the Vicious Cycle
Interrupting the Vicious Cycle Airway Destruction and Distortion (Bronchiectasis) Neutrophil Inflammation (Proteases) Abnormal Mucus Clearance McShane, et al, Am J Resp Crit Care Med, 2013 Bacterial Colonization 84
Slide 83: Non-CF Bronchiectasis
Non-CF Bronchiectasis • Etiology - - - - frequently idiopathic chronic lung disease (COPD, other) prior pneumonia (e.g. tuberculosis, nontuberculous mycobacteria (NTM) ) alpha-1-antitrypsin deficiency, primary ciliary dyskinesia immunodeficiency (CVID) autoimmune disease (rheumatoid arthritis (RA))
Slide 84: Non-CF Bronchiectasis: Disease Spectrum is Wide
Non-CF Bronchiectasis Mild • Only Severe • Daily symptoms symptoms number of flares destruction 1. Chalmers JD, et al. Am J Respir Crit Care Med. 2014;189:576-85. 2. Lonni S, et al. Ann Am Thorac Soc. 2015;12:1764-70. . 86 Disease spectrum is wide Moderate • Daily cough, sputum production • Variable
Slide 85: Pathogens of Interest
Pathogens of Interest • Gram-negative organisms (Pseudomonas, Achromobacter, Stenotrophomonas, Alcaligenes,H. flu, Moraxella) Gram-positive cocci (S. aureus, S. pneumonia ) • • • • Atypical pathogens (Nontuberculous Fungal (Aspergillus) mycobacteria, Nocardia) Co-infection is common 87
Slide 86: Epidemiology
Epidemiology • • Affects up Increased to 190,000 adults >65 8.7% per year 2000-2007 Sietz et al. Chest 2012; McShane et al. AJRCCM 2013 88
Slide 87: Currently Approved Therapies in NCFB
I Currently Approved Therapies in NCFB 89
Slide 88: Current Therapy for NCFB
Current therapy for NCFB 1. Pasteur MC, et al. Thorax. 2010;65(suppl 1):i1-58. 2. Flude LJ, et al. Clin Chest Med. 2012 Jun;33(2):351-361. 90 Surgical management1 • Lung resection • Lung transplant Antibiotic therapy1 • To treat exacerbations • To reduce the frequency of exacerbations Airway drug th
Slide 89: Clinical Objectives of Therapy
Clinical Objectives of Therapy • Make patient feel better (quality of life) -decrease inflammation and sputum -eradicate Vs. control of pathogen Mitigate progression of lung damage -improves live quality and quantity • • Lower cost and potential adverse events of care - exacerbations, hospitalizatio
Slide 90: Preventive Antibiotic Studies
Preventive Antibiotic Studies • • • Most measure time to exacerbation or frequency Ideas extrapolated from CF (Cystic Fibrosis) of exacerbation No - - approved inhaled therapies Prior RCTs with colistin, aztreonam & gentamicin Macrolide suppressive therapy • Recently completed phase 3 studies - - Ne
Slide 91: Aradigm ORBIT Time to First Exacerbation
I Aradigm - ORBIT 3, 4 Figure 1. Time to First PE: (A) All Severity; (B) Required Antibiotics HR (95•;.Cl) A POOLED 0 82 (0 65-1 02) P=O 074 0 72 (0 53-0 97) P=O 032 0(0 71-1 38) P=O 97 ORBIT_. "--9 e 78 ORBIT·J I I 0 2Q 40 60 80 100 02 06 Haurd Ratlo 2 DJyl B POOLED 0 74 (0 59-0 94) P=O 0122 0 66 (
Slide 92: RESPIRE Results: Time to First Exacerbation
RESPIRE 1 Results---Time to First Exacerbation Median time to first exacerbation Ciprofloxacin DPI 14 on/off >336 days (97.5% CI [290, >336]) Ciprofloxacin DPI 28 on/off 336 days (97.5% CI [206, >336]) Pooled placebo 186 days (97.5% CI [136, 282]) 94 Adjusted HR 97.5% CI P-value Ciprofloxacin DPI 14
Slide 93: Summary
Summary • • The prevalence of non-CF bronchiectasis is increasing Patients can have repeated exacerbations, poor quality of life, and in creased mortality decline in lung function Inhalation antibiotic therapies have shown efficacy, but failed to meet primary study outcomes • • There remains inflamm
Slide 94: Introduction to INS1007: A Novel DPP1 Inhibitor
Introduction to INS1007: A Novel DPP1 Inhibitor with Inflammatory Indications Eugene J. Sullivan, MD Chief Product Strategy Officer Potential in Neutrophil-Mediated
Slide 95: INS1007
INS10071 New molecular entity in-licensed from Astra Zeneca in 2016 (AZD7986) Orally bioavailable, small molecule inhibitor of dipeptidyl peptidase 1 (DPP1; also known as Cathepsin C),2 the enzyme responsible for activating the neutrophil serine proteases in the maturing neutrophil Potential in trea
Slide 96: INS1007 Binds to DPP1 to Prevent Activation of NSPs
INS1007 Binds to DPP1 to Prevent the Activation of NSPs DPP1 INS 1007 DPP1 Inhibitor Inactive Neutrophil Serine Proteases (NSPs) Cathepsin G (CatG) Proteinase 3 (Pr3) Neutrophil Elastase (NE) 99
Slide 97: Neutrophil Serine Proteases
Neutrophil Serine Proteases A Family of Proteases Contained in Neutrophilic Granules • • • • Includes Neutrophil Elastase, Proteinase-3 and Cathepsin G Kill microbes and inactivate bacterial toxins Released alone or as a component of “neutrophil extracellular traps” (NETs) Also contribute to host ti
Slide 98: Multiple Putative Damaging Effects of NSPs
Multiple Putative Damaging Effects of NSPs with Potential Relevance in NCFBE secretion from apical surface of neutrophils by macrophages and release of stored mediators) 101 Impair efferocytosis of apoptotic (resulting in neutrophil necrosis Dysregulate constitutive neutrophil apoptosis Modify pro-i
Slide 99: Papillon-Lefèvre Syndrome Informs Potential Safety Profile
Papillon-Lefévre Syndrome Informs the Potential Safety Profile of INS1007 Very rare genetic disease caused by inactivating mutation in the DPP1 gene; provides insight into potential safety implications of DPP1 inhibition • • • Characterized by palmo-plantar keratosis and periodontitis Signs of syste
Slide 100: Data from AZ's Phase 1 Study
Data from AZ’s Phase 1 Study Completed Phase 1 Study1: • • • • Single Ascending Dose (SAD) / Multiple Ascending Dose (MAD) study in healthy volunteers Well tolerated, with no major safety concerns raised PK profile supports once-daily dosing Demonstrated proof of activity, with dose-dependent inhibi
Slide 101: Initial Target Indication: Non-CF Bronchiectasis
Initial Target Indication: Non-CF Bronchiectasis • Rare, serious, pulmonary condition with no approved therapies in the US Prominent role of the neutrophil in the “vicious cycle” of infection/inflammation/impaired mucociliary clearance and tissue destruction Extensive overlap with NTM lung disease •
Slide 102: Results from a Related Compound
Results from a Related Compound Neutrophil Elastase Inhibitor (AZ’s AZD9668) controlled trial in 38 patients with NCFBE 1Kuna P, et al. Respiratory Medicine, 2012 2Stockley R, et al. Respiratory Medicine, 2013 FEV1: Forced Expiratory Volume in first second 105 Phase 2 trial in NCFBE2 •4 week, random
Slide 103: Sputum Elastase Activity as Biomarker in NCFBE
• • Utilized data from an ongoing, large, prospective, cohort study of patients with NCFBE Elastase activity in sputum was associated with disease severity, dyspnea score, FEV1, and radiologic extent of bronchiectasis During a 3-year follow-up period, elevated sputum elastase activity was associated
Slide 104: Additional Diseases Where INS1007 Might Have an Impact
Additional Diseases Where INS1007 Might Have an Impact Cystic Fibrosis Crohn’s Disease INS1007 Uveitis Lupus Nephritis Psoriasis Rheumatoid Arthritis Granulomatosis with Polyangiitis (GPA; Wegener’s Granulomatosis) Associated with auto-antibodies to Proteinase 3 (ANCA antibodies) 107
Slide 105: INS1007: Phase 2 Development Program
INS1007: Phase 2 Development Program Paul D. Streck, MD, MBA Chief Medical Officer
Slide 106: My Track Record in Drug Development
My Track Record in Drug Development • • • • • 25 years of clinical development, management and leadership expertise M.D. from Jefferson Medical College and surgical resident at Thomas Jefferson University Hospital Board certified in oral and maxillofacial surgery Masters of Business Administration,
Slide 107: Phase 2 Program in Non-CF Bronchiectasis: The Willow Study
Phase 2 Program In Non-CF Bronchiectasis Builds on Expertise in Pulmonary Rare Disease The Willow study: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Assess the Efficacy, Safety and Tolerability, and Pharmacokinetics of INS1007 Administered Once Dail
Slide 108: INS1007 Phase 2 Study Design
INS1007 Phase 2 Study Design 32 Week Study Duration Treatment Phase Day 1 to Day 168 (24 Week Treatment Period) Off Treatment Phase Day 169 to Day 196 (4 weeks) Day -28 to Day -1 (4 weeks) N= Patients randomized *End of Treatment 111 Visit 10 Visits 3-9: Treatment weeks: 2, 4, 8, 12, 16, 20 and 24*
Slide 109: INS1007 Phase 2 Study: Key Endpoints
INS1007 Phase 2 Study: Key Endpoints Primary Endpoint • To evaluate the effect of INS1007 compared with placebo on time to first pulmonary exacerbation over the 24-week treatment period. Secondary and Key Exploratory Endpoints • Key secondary endpoints addressing FEV1, sputum neutrophil elastase, ra
Slide 110: INS1007 Phase 2 Study Overview
INS1007 Phase 2 Study Overview • Estimated ~125 sites, 16 countries across North America, EU, and Asia Pacific Estimated 240 subjects First Patient – expected in 2H 2017 • • 113
Slide 111: Financials
Financials Paolo Tombesi Chief Financial Officer
Slide 112: Financial Organization Critical to Supporting Global Product Launches
Financial Organization Critical to Supporting Successful Global Product Launches • • • • 20 years of financial leadership in biotech/pharma Successfully built financial infrastructure to support global commercial organizations and launches International experience: US, Japan and Europe Multiple laun
Slide 113: Cash-Based Operating Expenses (Non-GAAP)
Cash-Based Operating Expenses (Non-GAAP) • • Cash Balance at 3/31/17 = $125.8M Remain disciplined with spending. Our critical spend consists of: • • 212/312 trial spend, including preparation for US regulatory filing Pre-launch investments on non-branded disease awareness and medical education Relia
Slide 114: Financial Planning
Financial Planning • • • Continuing long term tax planning efforts, started in 2014 Structure supports scalable platform including Japan & EU Long term plans for manufacturing and distribution • • • Current clinical: Althea (San Diego, California, US) Current commercial launch scale: Therapure (Toro
Slide 115: Closing Remarks
Closing Remarks Will Lewis President and Chief Executive Officer
Slide 116: Closing Remarks
“998 gy ied (menageeerer pre Closing Remarks Will Lewis President and Chief Executive Officer insmed
Slide 117: Question and Answer Session
wh Al Question and Answer Session insmed
Slide 118: Non-GAAP Reconciliation Table
Non-GAAP Reconciliation Table INSMED INCORPORATED Reconci l i ati on of GAAP to Non-GAAP Resul ts (i n thousands) (Unaudi ted) Three Months Ended March 31, Si x Months Ended, 2017 2H 2016 1H 2016 2H 2015 Operati ng expenses reconci l i ati on: Total operating expenses - GAAP Stock-based compensation
Slide 119: ALIS Clinical Trials
ALIS Clinical Trials INS-212 udies 110 108 122 ONGOING COMPLETED Indication Preclinical Phase 1 Phase 2 Phase 3 Enrollment (N) Extension in CF patients with chronic Pseudomonas aeruginosa Infection – European trial TR02-206 CF patients with chronic Pseudomonas aeruginosa Infection –European trial TR
Slide 120: ALIS Delivers Much Higher Doses Compared to IV Administration
ALIS Delivers Much Higher Doses Compared to IV Administration Directly to the Lung Pharmacokinetic Data from INS112 Study: Pharmacokinetics and bronchial diffusion of single daily dose amikacin in cystic fibrosis patients1 • 35mg/kg daily dosing of IV amikacin in patients with CF1: Mean serum Cmax 1
Slide 121: Residual Amikacin in Sputum on the Growth of MAC
Residual Amikacin in Sputum on the Growth of MAC CFU=colony-forming unit; minimal inhibitory concentration (MIC) units= µg/mL; ND=not determined. 124 MAC isolates with known MIC for amikacin incubated in sputum samples at various concentrations of amikacin for 24 hours. MAC isolates with known MIC f
Slide 122: Backup slides
Backup slides Kevin L. Winthrop M.D., M.P.H. Associate Professor Divisions of Infectious Diseases, Public Health and Preventive Medicine Oregon Health and Science University
Slide 123: Nontuberculous Mycobacterium (NTM)
Nontuberculous Mycobacterium (NTM) • Slow growers -MAC, M. kansasii, M. marinum, M. xenopi Rapid growers (RGM) • -M. abscessus, M. chelonae, 100+ species and growing M. fortuitum • - - 16s Too rDNA gene sequencing many PhD candidates 126
Slide 124: NTM Disease Manifestations
I NTM Disease Manifestations Table 2. Nontuberculous mycobacterium (NTM) cases by species and disease site, Oregon 2007-2012 77% of NTM disease is pulmonary 127 Mycobacterium species Pulmonary Skin/ soft tissue Disseminated Lymph Other Total N {%) N (%) N (%) N (%) N (%) N (%) M. aviumjintracel/ ula
Slide 125: Pulmonary MAI and M. abscessus/chelonae Incidence
Pulmonary MAI and M. abscessus/chelonae Incidence 6.0 (Oregon, 2007-2012) 4.8 5.0 4.4 4.3 4.2 4.1 3.9 4.0 3.0 MAI M. abscessus 2.0 1.0 0.5 0.4 0.3 0.2 0.2 0.1 0.0 2007 2008 2009 2010 2011 2012 Year 128 Henkel E et al. Ann ATS In Press Incidence per 100,000 population
Slide 126: The Griffith Frustration Index (GFI)
The Griffith Frustration Index (GFI) Frustration Index (GFI), • NTM respiratory pathogen 1 (no problem)-10 (big problem) • • • • • • • M. M. M. kansasii szulgai xenopi • • • • • • • 1 3 5-6 5-6 5-6 8-9 10+ (MAC) M. malmoense (M. abscessus) M. simiae 129
Slide 127: MAC Therapeutic Options
MAC Therapeutic Options • Diagnosis decision to treat -Observation vs. suppression vs. cure Treatment best defined for MAC • - - - - - Macrolide, rifampin, ethambutol Amikacin (parenteral or inhaled PRN) 18-24 months (12 month culture negative) No macrolide monotherapy TIW okay if non-cavitary or no
Slide 128: Treatment Episodes with Macrolide/Azalide-Based Therapy
Treatment Episodes with Initial* Intermittent or Macrolide/Azalide-Based Therapy for Nodular-Daily Bronchiectatic (NB) MAC Lung Disease 131
Slide 129: Microbiologic Results for Clarithromycin and Azithromycin Regimens
I Microbiologic Results for All Patients with Clarithromycin and Azithromycin-Containing Regimens* Clarithromycin A.zithrmnycin To tal No. Patients 91 89 180 Spunun Corm:rsion-no. ( 0'o) 78191 (86°o) 76189 (85° o) 1541180 (86°'0) 0. 7•• Da ys to Convert 130.6 ± 149.7 123.2±109.8 Month5 _ ega ti...-e
Slide 130: Drug-Drug Interactions
Drug-Drug Interactions • Rifampin - - - Beta-blockers, Levothyroxine, CA2+ Tacrolimus,steroids, cyclosporin Azoles, Protease inhibitors, FQs blockers, warfarin • Azithromycin -Digoxin, warfarin Clarithromycin has many of the QT issue • • above -Clari/azi, FQs, Bedaquiline, Clofaz, others 133
Slide 131: M. abscessus Therapy
M. abscessus Therapy • • • “Cure” = rare (often treat off and on forever) More rapidly progressive or relentless 3-4 drugs for 18-24 months -4-6 months “induction” phase -“suppressive strategy” thereafter than MAC • Rotational parenteral based regimen 134
Slide 132: Parenteral Drugs
Parenteral Drugs • • Limited antibiotic options based upon susceptibility testing Parenteral agents - - - - Tigecycline 50mg daily Cefoxitin 2gm TID, Imipenam 500-1000mg BID Amikacin 10mg/kg TIW 135
Slide 133: Other Adverse Events
Other Adverse Events • Ethambutol – Optic neuritis, hair loss Rifampin – Hepatotoxicity, red urine/tears, thrombocytopenia, drug nephritis, cytopenias Rifabutin – Uveitis, flu-like syndrome, arthralgia, cytopenias Macrolides • interactions, interstitial • • – Foul taste, tinnitus, hearing decline, s
Slide 134: Inhaled Liposomal Amikacin Double-blind Phase
I Inhaled Liposomal Amikacin from ) Negative* (miTT Population) Double-blind Phase -Daily Treatment 1.0000 30% t.loot •LAI+ SOC •Placebo + soc L-----------9-W-J€eB-e i 25% 20% ! N ··-C-h N 0 15% i ....oot 10% !0.20ot l 5% 0% .. .. ,. Baseline lAI (3144); PBO (3145} Day28 lAI (10142); PBO (4145) -05
Slide 135: Culture Negative Results
I ;;.. .. S<N*nl"': .u.2:4 '"" ·-Mon<a ==:Culture Negative (Placebo) d medium 138 Olivier K et at. ATS 2014 Doubl E e Blind (LAVPiacebo)J!_PM Label (590 mg l.AJ)' J ... J _j ..... "SQS (See aiKMf!ig,ure, Bas:efme Myoobacteriiir Load by Number of Subjects (miTT Population), iar psj SAHlin• s 2 .u.2:4
Slide 136: Acknowledgements
Acknowledgements • Close colleagues and friends at variety of institutions including: - - NJMC, Mayo,UT Tyler, NIH, Univ. Ontario, U Florida, CDC, ATS/IDSA, OHSU, OHA Oregon Clinic, Adventist Oregon Pulmonary Associates, Vancouver Clinic, Legacy, Providence, 139
Slide 137: Non-CF Bronchiectasis
Non-CF Bronchiectasis • Etiology – – – – – – – – – frequently idiopathic chronic lung disease (COPD, other) prior pneumonia (e.g. tuberculosis, nontuberculous alpha-1-antitrypsin deficiency primary ciliary dyskinesia (PCD) common variable immunodeficiency (CVID) autoimmune disease (rheumatoid arthri
Slide 138: Frequency of Colonization
I Frequency of Colonization 10!;i1B rnrsms 1,11111231 ! 1 ,1111501 ! 2007 1!0191.! 1361 ! l'lill 141 Table 1 Bacter iology of brorKhiectasis 5t u:dr:X1Ytl!ar 1 0 1 Nkotra et a...s 1 1995PasteUJr 1lrt. aL"20010Kimtgl 1lrt. a 4Liet aL1. 2005 H influnza lll35 4.739 P ae:ruufnasa 31311111 M ca tarrha!is
Slide 139: NTM and P. aeruginosa Co-infection in NCFB
NTM and P. aeruginosa Co-infection is Observed Frequently in NCFB • In observational and retrospective studies, 23% to 52% of NCFB patients with NTM are co-infected with P. aeruginosa1-4 In the BRR, patients with NTM at baseline were significantly less likely to be colonized with P. aeruginosa than
Slide 140: Colonization and Subsequent Exacerbation
I Colonization and Subsequent Exacerbation bl . • u l lll P value Jrea men vs non bioi B .l(1 .7 3. ) i D 143
Slide 141: Chronic Colonization and Decreased QOL
Chronic Colonization and Decreased QOL UK prospective single-center cohort Colonization prevalence • • H. influenzae (29% ), P. aeruginosa (12%), M. catarrhalis (10%), S. aureus (8.4%) • Chalmers JD et al. AJRCCM 2014. 144 Colonized (n=440) Not colonized (n=168) P value 4-year mortality 11.8% 6.0% 0
Slide 142: Clinical Objectives of Antibiotic Therapy
Clinical Objectives of Antibiotic Therapy • Make patient feel better (quality of life) -Decrease inflammation and sputum -Eradicate Vs. control of pathogen Mitigate progression of lung damage -Improves live quality and quantity Lower cost and potential adverse events • • of care - Exacerbations, hos
Slide 143: Time to Need for Additional Inhaled Antipseudomonal Therapy
I Time to Need for Additional Inhaled Antipseudomonal Therapy or IV -·-·-Piacebo 1!:1: Cert Ofed data - AZLI pooled " Censored data .:e..--"-1.011 "0 aJo --til-I]} l l -----,8-_.., ..,_--r:; 0 ·..;:;. ;g 0 75 -.,_ -..._ r:; iJ) Time to moo figure? 2. for additio nal in - -, -e:z. 5 haled or intrave
Slide 144: A Randomized Controlled Trial of Nebulized Gentamicin in Non-CF Bronchiectasis
A Randomized Controlled Trial of Nebulized in Non–Cystic Fibrosis Bronchiectasis Gentamicin Less sputum purulence (8.7% vs. 38.5%; P , 0.0001); greater exercise capacity (510 [350–690]mvs. [267.5–530]m; P50.03) 415 fewer exacerbations (0 [0–1] vs. 1.5 [1–2]; P , 0.0001) increased time to first exace
Slide 145: Daily Gent Decreased Inflammation
I Daily Gent Decreased Inflammation TABLE 4. SPUTUM IN FLA.MMATORV INDI,CES, VOLUME, AN D PURULE NCE BETWEE N T HE 'GROUPS THRO. ·U-Spulum Cl\ar:acro ris.Lic Month 0 Month 3. Month 6 Monlh 9 Monh 15 Spun..rn rrryelopsrox ida.s.(!, u.nits/n'ill ntamloln groLI\p Sailoo grou,p Spun..m f1"100 as,l&(!aci
Slide 146: Inhaled Colistin in Patients with Bronchiectasis
Inhaled Colistin in Patients with Bronchiectasis and Chronic Pseudomonas aeruginosa Infection 149
Slide 147: Aztreonam for Inhalation Solution in Non-CF Bronchiectasis
Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials 150
Slide 148: The Use of Aerosol Penicillin and Streptomycin
I The Use of Aerosol Penicillin and Streptomycin Bronchopulmonary Infections in JAsoN E. FARBER, M.D., and JosEPH Ross, M.D., Oakland TABLE 2. Results with Combined Antibiotic Aerosol Therapy - - - R.eduction in Cough and Sputum Number of Cases I2 13 5 II 2 - Diagnosis 50o/o More than 75% 12 11 5 10
Slide 149: The Use of Aerosol Penicillin and Streptomycin
The Use of Aerosol Penicillin and Streptomycin in Bronchopulmonary Infections Jason E. Farber, M.D., and JosepH Ross, M.D., Oakland TasLe 2.—Results with Combined Antibiotic Aerosol Therapy Number of | ———Reduction in Cough and Sputum——\ Diagnosis Cases More than 75% = 50% Less than 25% 12 12 = oa 1