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WelcomeAdvisor Live: June 8, 2017Our Presentation:Idiopathic Pulmonary Fibrosis: Overview and Emerging TreatmentsWill Begin Shortly

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Advisor LiveIdiopathic Pulmonary Fibrosis: Overview and Emerging Treatments

June 8, 2017

Download today’s slides at www.premierinc.com/events


Logistics

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QUESTIONSUse the “Questions and Answers”

RECORDINGThis webinar is being recorded. View it later today on the event post at premierinc.com/events.

NOTESDownload today’s slides from the event post at premierinc.com/events


Faculty

Scott Palmer, MD, MHSProfessor of Medicine and Immunology Vice Chair for Research, Department of Medicine, Duke Health SystemDirector Respiratory Research, Duke Clinical Research Institute

Bimal Shah, MD, MD, FACCChief Health Information Officer, Emerging Technology, Premier Inc.

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Idiopathic Pulmonary Fibrosis

• Diagnosis and Clinical Course of IPF

• Disease Mechanisms

• Treatment options

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Idiopathic Pulmonary Fibrosis (IPF): Overview

• IPF is a chronic and progressive disorder, characterized by scar tissue formation in the lungs for no apparent reason (idiopathic)

• Distinguished from other diseases where there is a known etiology for lung fibrosis – such as:• Asbestosis • Silicosis • Coal workers pneumoconiosis • Hypersensitivity pneumonitis • Beryllium disease

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DPLD

Knowncauseorassociation

IdiopathicInterstitialPneumonia

GranulomatousDiseases

UniqueEntities

ConnectiveTissueDiseases

OccupationalEnvironmental

Iatrogenicà Drug-orradiation-induced

Inherited

IPF/UIP

NSIP

COP

AIP

DIP/RB-ILD

LIP

Sarcoidosis

HypersensitivityPneumonitis

PulmonaryAlveolarProteinosis

EosinophilicPneumonias

Vasculidities

Lymphangioleio-myomatosis(LAM)

PulmonaryLangerhansCellGranulomatosis

PulmonaryAmyloidosis

InflammatoryBowelDisease

Spectrum of Diffuse Parenchymal Lung Disease

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Idiopathic Pulmonary Fibrosis (IPF): Clinical Diagnosis

• Clinical presentation– Often insidious presentation with delays in diagnosis– Breathlessness with exertion and intermittent dry cough– Crackles on lung exam and clubbing of nails– Patients become hypoxic and have restrictive physiology

• Characteristic pattern on high-resolution chest CT scan includes honeycombing

• Characteristic pattern on surgical lung biopsy called Usual Interstitial Pneumonia (UIP)

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• Patients have reduced lung volumes

• Forced vital capacity (FVC) reduced

• Also will have reductions in TLC and DLCO

Restrictive Physiology on PFTs in IPF

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IPF: A Picture is Worth 1000 Words

https://www.lungsandyou.com/ipf/what_is_ipfDial-in: 800.678.5699

What is IPF: A PICTURE IS WORTH 1000 WORDS

Pulmonary Research

Am J Respir Crit Care Med (2011) 183:788-824

Normal HRCT View of the Lungs

Subpleural, basal honeycombing is very specific for definite IPF/UIP on biopsy

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UIP Pattern

Courtesy Lake Morrison, MDAm J Respir Crit Care Med. 2013;188:141-9

Honeycombing

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How Frequently is IPF Diagnosed? Evidence from Large Clinical Datasets

Estimated 125,000 to 200,000 Current Patients in the United States(Annual incidence up to 40,000 new diagnoses)

0

Raghu et al. AJRCCM 2006. 174:810

Prevalence/100,000Claims dataset 1996-2000, 3 million members, 20 states

Intial broad definition: ICD-9 516.3 and no codes for other ILDs

Narrow definition:Broad plus procedure code for lung biopsy or Chest CT

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IPF: Incidence and Prevalence: Trends over time in Medicare

• Incidence and prevalence substantially higher than previously reported• Several other publications suggest poor specificity for coding based definition alone• Inclusion of Chest CT, multiple instances with IPF codes improves specificity

Lancet Resp Med 2014 Rhagu et al. Esposito AJRCCM 192;10,2015. Ley Annals ATS; 2017

Medicare (>65) random 5% sample, 2000-2011

Used similar approach as previous study narrow definition to identify cases

Natural History of IPF: Dismal Survival

IPF

Other ILD

• Poor survival is consistent across multiple studies including epidemiological cohorts• Data prior to FDA approved treatments (approved Nov 2014)• Lung transplant is also a potentially life extending intervention

Roland M. du Bois European Respiratory Review 2012 21: 141-146

40,000 patients die of IPF each yearMedian Survival 3-4 years

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King TE Jr, et al. Lancet. 2011;378(9807):1949-1961.

Genetic predisposition

IPF: Genetics and Environment contribute to IPF Development/Course

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IPF and Genetics• Clear evidence of genetic

etiology for familial cohorts• Mutations in several

gene/regions implicated• Telomerase genes• Surfactant genes

• Sporadic (non familial) IPF strongest association is common allelic risk variant in muc5B gene

• Recently mutations in telomerase genes were identified in IPF

Seibold MA et al. N Engl J Med 2011;364:1503-1512

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Exome Analysis in IPFDCRI Pulmonary Research

Whole exome sequencing of IPF patients that underwent lung transplantation at Duke, providing precise phenotype including access to their explanted lung tissue

• Whole-exome data compared from the 262 IPF cases and 4,141 controls• Used methods to identify rare non-synonymous variants increased in IPF• Found rare deleterious mutations in Tert, RTEL1, and PARN all with p-

values of less than 10-6,

All 3 of which are associated with shortened telomere length and have been identified in cases of familial pulmonary fibrosis, but never in idiopathic (sporadic) pulmonary fibrosisMoves paradigm of IPF to further focus on telomere biology

Petrovski/Todd et all AJRCCM Jan 2017 Dial-in: 800.678.5699

Genetics of IPF: Whole Exome Analysis to Identify Rare Variants

• Enrichment of ultra-rare deleterious non-synonymous variants in TERT and RTEL1 and loss-of-function variants in RTEL1 and PARN in PF cases (p-values <10-6)

• Together these variants contributed to greater than 10% of the genetic risk in sporadic IPFcases

• All 3 of these genes are important in telomere maintenance and have been identified in cases offamilial PF, but never in sporadic IPF

• Muc5b mutation was more common in IPF patients similar to results in Schwartz NEJM study

Petrovski/Todd et all AJRCCM Jan 2017Dial-in: 800.678.5699

IPF: Etiology

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IPF Treatments: History of Failed agents

Agent Mechanism n OutcomeWarfarin Anticoagulant 256 Terminated harm

Bosentan Dual endothelin-receptor antag 774* No difference

Macitentan Dual endothelin-receptor antag 178 No difference

Ambrisentan ET-A receptor antag 660 No difference

Interferon-Ƴ Immunoregulatory cytokine 1156* 2: No diff, and term futile

Sildenafil PDE-5 inhibitor 180 No difference

Imatinib Tyrosine kinase inhibitor 119 No difference

Octreotide Somatostatin analog 25 No difference

Etanercept TNF-α inhibitor 87 No difference

Carlumab Anti-CCL2 antibody 126 Terminated futile

QAX576 Anti-IL-13 antibody 60 Terminated

CC-930 JNK inhibitor 28 Terminated futile

Pred/Aza/NAC Immune suppression 165 Terminated harm

NAC Antioxidant 264 No difference

* Multiple studies, Ahluwalia et al. AJRCCM 2014; 190:867Dial-in: 800.678.5699

A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

Talmadge E. King, Jr., et al for the ASCEND Study Group. N Engl J Med 370(22):2083-2092

Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

Luca Richeldi, M.D., Ph.D., et al. for the INPULSIS Trial Investigators. N Engl J Med 370(22):2071-2082

First Effective IPF Treatments: May 2014 NEJM

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.

King TE Jr et al. N Engl J Med 2014;370:2083-2092

Pirfenidone (ASCEND trial)

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.Dial-in: 800.678.5699

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

ASCEND Adverse EventsAdverse Event

Pirfenidone (%)

(N = 278)

Placebo (%)

(N = 277)Δ (%)

Nausea 36.0 13.4 22.6Rash 28.1 8.7 19.4Dyspepsia 17.6 6.1 11.5Anorexia 15.8 6.5 9.3GERD 11.9 6.5 5.4Weight Loss 12.6 7.9 4.7Insomnia 11.2 6.5 4.7Dizziness 17.6 13 4.6Vomiting 12.9 8.7 4.2Fatigue 20.9 17.3 3.6

… … … …Dyspnea 14.7 17.7 -3Cough 25.2 29.6 -4.4IPF worsening 9.4 18.1 -8.7

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Possible Mechanisms of Pirfenidone Action

Hilberg O, et al. Clin Respir J. 2012;6:131-143.

TNF-αIL-6

Pirfenidone

TGF-βIL-6

MMPsCollagenases ROIs

Collagen

• Anti-fibrotic• Molecular target

unclear• Active in several

animal models of fibrosis– Lung– Liver– kidney

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Richeldi L et al. N Engl J Med 2014;370:2071-2082

Nintedanib (IMPULSIS trials)

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Common Nintedanib Adverse Events

Event INPULSIS-1 INPULSIS-2

Nintedanib (n = 309)

Placebo (n = 204)

Nintedanib (n = 329)

Placebo (n = 219)

Any (%) 96 89 94 90Diarrhea (%) 62 19 63 18

Nausea(%) 23 6 26 7

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Possible Mechanisms of Nintedanib Action

Triple kinase inhibitorPhosphatase activatorAnti-angiogenic, antitumor activity

VEGF

Nintedanib

PDGF FGF

Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.Tai WT, et al. J Hepatol. 2014;61(1):89-97.

Pleiotropic Effects

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Identify and Treat Comorbidities:• GERD• Sleep apnea• Pulmonary

hypertension• Depression

• Smoking cessation• Exercise program• Weight loss (often)• Supplemental oxygen• Vaccinations• End-of-life planning• Lung Transplantation

Other Treatment Considerations in IPF

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• In the absence of any treatments clearly demonstrated to extend survival in IPF lung transplant should be considered in almost any patient

• Risks and benefits of transplant have to be carefully considered on individual basis

Vock etalAnnalsATS2016ISHLTDatabase

“Transplantwindow”

notsickenough--- …toosick

Lung Transplant and IPF

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Considerations in IPF and Lung Transplant• Median survival after lung transplant is 5 years

• varies by type of transplant and recipient native disease• IPF patients can receive one or two donor lungs

• Single lung lower risk operation• Bilateral lung better longer term survival

• There is no firm upper age limit for lung transplant but risks increase with older recipients

• IPF accounts for about 50% of the 2,500 lung transplant performed in the US

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Annals ATS 2016

We found that survival benefit is highest for those with restrictive lung disease (IPF) or cystic fibrosis, and especially for those with higher lung allocation scores, using novel statistical approach

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Future Research Directions• Much remains unknown about the etiology of IPF in terms of both genetics

and environmental factors (or their interactions)• Focus on telomere length and related mutations will be important• Mechanistic understanding of muc5B polymorphism area of interest• Likely other as yet undiscovered genetic factors that lead to disease

• Wide range of potential therapeutic targets and need for ongoing trials• Occurs now in the background of approved therapies • Appropriate study endpoints (FVC vs. mortality vs. patient centered?)

• Outcomes research will enable better understand diagnosis, natural history, and response to existing treatments

• Established approaches with reasonable PPV to identify IPF in claims data• Premier database provides unique opportunity to better understand IPF

patient outcomes, particularly in the inpatient setting

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Continued Need for Additional IPF Treatments

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Conclusions:

• IPF is chronic progressive disease involving scarring of the lungs

• Etiology is likely related to environmental exposures in a genetically predisposed individual

• Prevalence appears to be increasing and mortality is high• Recently approved treatments Nintedanib and Pirfenidone

are effective at reducing rate of lung function decline• IPF remains an area of very active basic/mechanistic

research and ongoing clinical trials• Studies of databases like Premier will advance our

understanding of outcomes IPF patients

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Davis HuntSenior Director, Product Marketing

Integrated Pharmacy 704.816.5994

[email protected]

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