welcome advisor live: june 8, 2017 - premieroffers.premierinc.com/rs/381-nbb-525/images/ipf... ·...
Post on 23-May-2020
1 Views
Preview:
TRANSCRIPT
© 2017 PROPRIETARY & CONFIDENTIAL | 1TRANSFORMING HEALTHCARE TOGETHER®
WelcomeAdvisor Live: June 8, 2017Our Presentation:Idiopathic Pulmonary Fibrosis: Overview and Emerging TreatmentsWill Begin Shortly
Listen to Today’s Audio: 800.678.5699
Download today’s slides at www.premierinc.com/events
© 2017 PROPRIETARY & CONFIDENTIAL | 2TRANSFORMING HEALTHCARE TOGETHER®
Advisor LiveIdiopathic Pulmonary Fibrosis: Overview and Emerging Treatments
June 8, 2017
Download today’s slides at www.premierinc.com/events
© 2017 PROPRIETARY & CONFIDENTIAL | 3TRANSFORMING HEALTHCARE TOGETHER®
Logistics
AUDIODial in to our operator assisted call, 800.678.5699
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
© 2017 PROPRIETARY & CONFIDENTIAL | 4TRANSFORMING HEALTHCARE TOGETHER®
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.
Dial-in: 800.678.5699
Idiopathic Pulmonary Fibrosis
• Diagnosis and Clinical Course of IPF
• Disease Mechanisms
• Treatment options
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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)
Dial-in: 800.678.5699
• Patients have reduced lung volumes
• Forced vital capacity (FVC) reduced
• Also will have reductions in TLC and DLCO
Restrictive Physiology on PFTs in IPF
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
UIP Pattern
Courtesy Lake Morrison, MDAm J Respir Crit Care Med. 2013;188:141-9
Honeycombing
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
Idiopathic Pulmonary Fibrosis
• Diagnosis and Clinical Course of IPF
• Disease Mechanisms
• Treatment options
Dial-in: 800.678.5699
King TE Jr, et al. Lancet. 2011;378(9807):1949-1961.
Genetic predisposition
IPF: Genetics and Environment contribute to IPF Development/Course
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
Idiopathic Pulmonary Fibrosis
• Diagnosis and Clinical Course of IPF
• Disease Mechanisms
• Treatment options
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
.
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
• 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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
Continued Need for Additional IPF Treatments
Dial-in: 800.678.5699
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
Dial-in: 800.678.5699
© 2017 PROPRIETARY & CONFIDENTIAL | 39TRANSFORMING HEALTHCARE TOGETHER®
Davis HuntSenior Director, Product Marketing
Integrated Pharmacy 704.816.5994
davis_hunt@premierinc.com
top related