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Katerina M. Antoniou, MD, PhD

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ERS Assembly 12 Head

Professor in Respiratory Medicine

Faculty of Medicine, University of Crete

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Conflict of interest disclosure

In the last 3 years, I received honorarium for speaking, travel grants or research grants from :

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GSK, Astra-Zeneca, Boehringer Ingelheim, Chiesi, Roche

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Delayed treatment initiation means poor prognosis

Lamas et al. Am J Respir Crit Care Med. 2011;184:842-847.

P for trend = 0.04

Earlier diagnosis

Can we identify those patterns of interstitial lung abnormalities that will evolve into IPF?

Can we identify & manage these patients whilst they still have preserved lung volume?

Progressive fibrotic interstitial lung abnormalities (ILAs) represent a subtype of ILAs that progress to symptomatic progressive fibrotic interstitial lung disease (PF-ILD), of which idiopathic pulmonary fibrosis (IPF) is one form. The challenge is to determine with accuracy which forms of ILA belong to the progressive fibrotic ILA subtype.

Am J Respir Crit Care Med Vol 200, Iss 2, pp 121–132, Jul 15, 2019

Pirfenidone and nintedanib reduce the hospitalisation risk and exacerbation risk and reduce mortality associated with exacerbation

Kang, Sci Rep 2020

(Propensity score matching)

3 month Mortality risk in EXAFIP if antifibrotic Tt : 0.33 [0.13-0.82]

Naccache, Lancet Respir Med 2021

Early diagnosis means early intervention and improved survival�

Strongman H et al. Adv Ther 2018

With anti-fibrotics

Without anti-fibrotics

Improve IPF management in daily practice

• Diagnosis is often late

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Emphasis must be given:

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• on early diagnosis
• risk factor modification
• the identification of phenotypes/endotypes most likely to advantage from specific therapeutic interventions

How can this be achieved?����Screening�Awareness�Education

Primary Health Care

What Is Patient-Centered Care? Definition

• Explore the definition, benefits, and examples of patient-centered care. How does patient-centered care translate to new delivery models?

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• Patient- and family-centered care encourages the active collaboration and  shared decision-making between patients, families, and providers to design and manage a  customized and comprehensive care plan.

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Patient-centred outcomes and experiences

• What measures of clinical progression do you use?
• Do you use the same measures throughout the disease course?
• Why do you use these?
• How often do you use these?
• How long do you spend collecting these data?
• What do you do with the results?
• How, and to whom, do you communicate the findings?
• What are the barriers?
• Do you use the same measures in clinical practice and research?

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Kreuter M, et al. Lancet Respir Med. 2017;5:968–980

ILD, interstitial lung disease

Tzouvelekis et al. Frontiers In Med 2017

Real-world Pirfenidone use in 162 patients in Greece

Antoniou et al. BMC Pulm Med 2018

The first intention to treat real-life study showing an increased 3 years survival rate in patients treated with Pirfenidone and a survival benefit of 30% compared to patients treated with no antifibrotic agents

The sooner the better!!!

• There are studies showing that a decline in FVC has been reliably associated with decreased survival.
• Patients with more rapidly progressive disease as defined by rate of pretreatment FVC decline, appeared to gain greater beneficial effects from PFD within 6–12months of drug initiation compared with those with slower progression.

���There may be no need to watch and wait until the disease progresses.�� Physicians should look at their patients’ early response to treatment��then switch to other drugs��take part in clinical trials �or �proceed with lung transplantation without delay if needed.

Η αξία του μοντέρνου - Do we need new treatments?�

Need to flatten the functional curve/Side effects/QoL issues

Antifibrotic Therapy in IPF

Raghu et al, AJRCCM 2022; 205: e18–e47

IPF diagnostic algorithm

2022

Improve the clinical

approach by introducing clinical probability

Living with Pulmonary Fibrosis (L-PF) questionnaire

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�Swigris JJ et al. Effects of nintedanib on dyspnea, cough and quality of life in patients with progressive fibrosing interstitial lung diseases (ILDs): findings from the INBUILD trial.

Poster developed for the American Thoracic Society International Conference, 2020.

• Assesses health status in patients with pulmonary fibrosis
• 44-item questionnaire with two modules:

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• The symptoms module has three domains:

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• Symptoms and impacts scores are used to calculate a total score

Published in Lancet Respiratory Medicine

Pirfenidone is not approved for the treatment of progressive fibrosinguILD

–7

Pirfenidone in progressive fibrosinguILD: A Phase 2 trial

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*Washout period for study participants taking prohibited medications prior to screening; patients not taking a prohibited medication

will forgo the washout period and directly enter screening. ^†Informed consent may be obtained either at the washout (if applicable) or

screening visits and must be obtained before any trial-specific screening procedure is performed. ^‡After completion of the treatment

period and follow-up visit, study participants will be given the opportunity to take part in an open-label extension of pirfenidone for up

to 12 months; a final follow-up visit will be performed 4 weeks after the last open-label dose of pirfenidone. ^§A >5% absolute decline in

percent predicted FVC or significant symptomatic worsening not due to cardiac, pulmonary (except worsening of underlying uILD),

vascular, or other causes (as determined by the investigator) within the previous 6 months

DLco, carbon monoxide diffusing capacity; ICF, informed consent form; uILD, unclassifiable interstitial lung disease

Maher TM, et al. Lancet Respir Med. 2020;8:147–157;

Maher TM, et al. BMJ Open Respir Res. 2018;5:e000289

Main inclusioncriteria:

•FVC ≥45%

•DLco≥30%

•>10% fibrosis on HRCT

•Progressive disease within

the previous 6 months^§ _{Enrolment and}

randomisation: titration

period followed by daily dose

of 2403 mg/day pirfenidone

or placebo (1:1)

Treatment period

Weeks 1 to 24

Week 0

Follow-up visit^‡

Week 28

Primary efficacy

endpoint

(home spirometry FVC)

ICF^†

–6–5–4–3–2–1 24 28

Screening

Weeks –3 to 0

Washout*

Weeks –7 to –3

ICF^†

Pirfenidone

Placebo

Pirfenidone is not approved for the treatment of progressive fibrosinguILD

Predicated FVC change from baseline to Week 24�(home spirometry)�

FVC change

frombaseline at

Week 24, mL Pirfenidone (n=124)

Placebo

(n=123)

Mean (range) ^–17.9

(–5799to 16,411)

116.6

(–7256 to 33,794)

Median (Q1, Q3) ^–87.7

(–338.1, 148.6)

–157.1

(–370.9, 70.1)

Analysis of the primary endpoint was impacted by high

intra-individual variability in home spirometry values and

issues applying linear regression to patients with a small

number of readings collected in a short period of time

Q, quartile Maher TM, et al. Lancet Respir Med. 2020;8:147–157

Pirfenidone is not approved for the treatment of progressive fibrosinguILD

Predicted FVC change from baseline to Week 24 �(site spirometry) �

Predictedmean (95% CI) change in FVC from

baseline to Week 24:

•Pirfenidone: –17.8 (–62.6, 27.0) mL

•Placebo: –113.0 (–152.5, –73.6) mL

•Pirfenidone vs. placebo:

95.3 (35.9, 154.6) mL; P=0.002

•A rank ANCOVA model for %FVC for

absolute change from baseline to last

observed measurement yielded a

P-value of 0.038

Results on FVC change measured at site visits werein favour of pirfenidone over placebo

ANCOVA, analysis of covariance; CI, confidence interval Maher TM, et al. Lancet Respir Med. 2020;8:147–157

Pirfenidone is not approved for the treatment of progressive fibrosinguILD

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, Phase IIb trial

Jürgen Behr, Antje Prasse, Michael Kreuter, Johannes Johow, Klaus F Rabe, Francesco Bonella, �Reiner Bonnet, Christian Grohe, Matthias Held, Heinrike Wilkens, Peter Hammerl, Dirk Koschel, �Stefan Blaas, Hubert Wirtz, Joachim H Ficker, Wolfgang Neumeister, Nicolaus Schönfeld, �Martin Claussen, Nikolaus Kneidinger, Marion Frankenberger, Simone Hummler, Nicolas Kahn, Silke Tello, Julia Freise, Tobias Welte, Petra Neuser, Andreas Günther, on behalf of the RELIEF investigators��Lancet Respir Med. 2020

Pirfenidone is not approved for the treatment of progressive fibrosingILD

Introduction

ALF, asbestos-induced lung fibrosis; CHP, chronic hypersensitivity pneumonitis; CTD-ILD, connective tissue disease-associated interstitial lung disease; �fNSIP, fibrotic nonspecific interstitial pneumonia; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; PF-ILD, progressive fibrotic ILD�1. Meyer KC. Transl Respir Med 2014;2:4; 2. Lederer DJ et al. N Engl J Med 2018;378:1811-1823; 3. Barnikel M et al. Respir Med 2019;154:82-85; �4. Noble PW et al. Lancet 2011;377:1760-1769; 5. King Jr TE et al. N Engl J Med 2014;370:2083-2092; 6. Maher TM et al. Lancet Respir Med 2020;8:147-157

In view of the pathomechanistic and clinical similarities with IPF, and the proven �efficacy of pirfenidone in IPF,^1,2,4-6 it also has the potential to benefit patients in this population

Rationale

There is a spectrum of ILDs, almost all of which carry the risk of developing a PF-ILD phenotype,¹ �which also share a number of clinical and pathomechanistic similarities with IPF²

The PF-ILD phenotype is mostly represented by four specific diseases³:

When this study was conducted, pirfenidone and nintedanib were approved for the treatment of IPF, �but not for other types of ILD^1,2,4-6

3. CHP
4. ALF

1. CTD-ILD

The current standard of care for non-IPF ILDs largely consists of �systemic steroids and/or immunosuppressive drugs

2. fNSIP

Pirfenidone is not approved for the treatment of progressive fibrosingILD

Results�Study duration

• The first patient was randomised on 5 April 2016
• Patient recruitment initially turned out to be difficult due to the complexity of the study, including the requirement for documented progression
• To increase the enrolment rate, the DLco inclusion criterion was extended from 25–75% predicted to �10–90% predicted; however, recruitment remained below expectation
• At this point (April 2018), an interim analysis (with blinding maintained) was requested and performed by the IDMC
• As a result of the interim analysis, the IDMC recommended to stop the study due to futility
• All patients stopped further treatment and the last patient visit was on 4 October 2018

IDMC, Independent Data Monitoring Committee

Pirfenidone is not approved for the treatment of progressive fibrosingILD

Behr J et al., Lancet Respir Med. 2020

Results�Patient disposition

• Overall, 127 patients were randomly assigned to receive pirfenidone (n=64) or placebo (n=63)
• At the time of study termination, 34% of the intended total enrolment of 374 patients was achieved
• The most frequent diagnosis of ILD was:
• CHP (n=57 [45%])
• CTD-ILD (n=37 [29%]), including:
• 17 patients (46%) with RA
• 8 patients (22%) with SSc
• 5 patients (14%) with Sjörgen’s syndrome or polymyositis/dermatomyositis
• 3 patients (8%) with MCTD
• 4 patients (11%) diagnosed with an overlap �syndrome not strictly attributable to one of �the above
• fNSIP (n=27 [21%])
• ALF (n=6 [5%])

MCTD, mixed connective tissue disease; SSc, systemic sclerosis

Pirfenidone is not approved for the treatment of progressive fibrosingILD

Behr J et al., Lancet Respir Med. 2020

IPF comorbidome

Circle size relates to prevalence. Distance from the centre of the circle relates to the strength of the association with risk of death

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• Nine comorbidities had an overall prevalence >10%

Red = CV

Green = pulmonary

Orange = others

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CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CV, cardiovascular.

Kreuter M et al, Plos One 2016; 11:e0151425

• The older age and comorbidities of IPF patients must be considered when exploring therapeutic targets that may impact biological pathways involved in cellular homeostasis or pose greater risk in association the other health problems.
• Targeting the mechanisms of age-associated cellular dysfunction may prove an effective strategy and has been reviewed extensively elsewhere.

Raghu G, et al. Comorbidities in idiopathic pulmonary Fibrosis patients: a systematic literature review

Eur Respir J. 2015

Mora AL, Rojas M, Pardo A, Selman M. Emerging therapies for idiopathic pulmonary Fibrosis, a progressive age-related disease. Nat Rev Drug Discov. 2017

Current state of therapies for the management of IPF

• Pirfenidone and nintedanib are oral antifibrotic therapies that were approved by the FDA to treat IPF in 2014 following successful phase 3 trials^1-4
• These medications slow disease progression, as measured by the rate of decline in FVC, but do not halt IPF progression^3-4
• Antifibrotic therapies do not markedly improve symptoms or quality of life^3-4
• UNMET MEDICAL NEED: Additional treatment options are needed to improve outcomes in patients with IPF

FDA, United States Food and Drug Administration; FVC, forced vital capacity; IPF, idiopathic pulmonary fibrosis.

1. Genentech, Inc.: Esbriet (pirfenidone) [package insert]: South San Francisco, CA: 2019. 2. Boehringer Ingelheim: Ofev (nintedanib) [package insert]: Ridgefield, CT: 2018. 3. King TE Jr, et al. N Engl J Med. 2014;370(22):2083–2092. 4. Richeldi L, et al. N Engl J Med. 2014;370(22):2071–2082. 5. Raghu G, et al. Am J Resp Crit Care Med. 2015;192:e3–e19.

Burden of IPF on emotional well being and quality of life

Antoniou K, et al. Curr Opin Pulm Med. 2020;26:457–463

IPF, idiopathic pulmonary fibrosis; QoL, quality of life

Respir Res 2022

Patient frailty in IPF: The need for multi-disciplinary care

Symvoulakis et al. Sarcoidosis Vasc Diffuse Lung Dis 2021;38:e2021031

HRCT Academy: One-year CME accredited online training & masterclasses

STARLINER: home monitoring �in the peri-diagnostic period

ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis

Wijsenbeek M, et al. Adv Ther. 2019;36;232–243; Wijsenbeek M, et al. Adv Ther. 2021;38:4040–4056

Survey on e-health experiences and opinions

Nakshbandi G, Moor CC, Johannson KA, et al. Worldwide experiences and opinions of healthcare providers on eHealth for patients with interstitial lung diseases in the COVID-19 era. ERJ Open Res 2021; in press (https://doi.org/10.1183/23120541.00405-2021).

eHealth survey experiences & opinions from 286 healthcare providers from 54 countries

Effect of the COVID-19 pandemic

Home monitoring brings added value

Physician-patient communication: �Perspectives from an Italian multicentre study

Tomassetti S et al. Sarcoidosis Vasc and Diffuse Lung Dis 2021;38:e2021042

Borie, Eur Respir J, 2023

1.Balint E: J Roy Coll Gen Pract 1969 2. Mead N, Bower P: Patient-centredness: a conceptual frame- work and review of the empirical literature. Soc Sci Med 2000, 51:1087 – 1110. 3.Stewart M, Brown JB, Donner A, McWhinney IR, Oates J, Weston WW, Jordan J: The impact of patient-centered care on outcomes. J Fam Pract 2000, 49:796 – 804. Werbrouck A, Swinnen E, Kerckhofs E, Buyl R, Beckwée D, De Wit L: How to empower patients? A systematic review and meta-analysis. Transl Behav Med 2018, 8:660 – 674.

100.Anhang Price R, Elliott MN: Measuring patient-centeredness of care for seriously ill individuals: challenges and opportunities for accountability initiatives. J Palliat Med 2018, 21:S28–S35. 4.Molina-Molina M, Agusti A, Crestani B, Schwartz DA, Königshoff M, Chambers RC, Maher TM, Faner R, Mora AL, Rojas M, et al.: Towards a global initiative for fibrosis treatment (GIFT). ERJ Open Res 2017, 3. 5. Spagnolo P, Cottin V: Genetics of idiopathic pulmonary fibrosis: from mechanistic pathways to personalised medi- cine. J Med Genet 2017, 54:93–99.

Advanced research, precision medicine, and patient-centeredness�

Bridging disciplines from primary to tertiary care service provision, enhancing patient- centeredness, clinical precision, optimization of service delivery, bioinformatics monitoring, and, of course, biogenomic and metabolic research output by early condensing these ingredients within pregraduate and postgraduate curricula refinements are requisites to support, through operative translational data processing, guidelines, and ‘midlines’ for effective IPF care in the future.

MDT is necessary for holistic patient-centered approaches�

O₂

Cough

Nedocromil/chromoglicate

Morphine sulfate

Ifenprodil (NMDAR Antag)

Time to replace disease patterns with patients

Transplantation

Wijsenbeek M, et al. N Engl J Med. 2020;383:958–968;�Cottin V, et al. Eur Respir Rev. 2018;27:180076

ERS & the European Lung Foundation (ELF)

• ERS & ELF ensure policies are based on science and patient needs.
• Healthy Lungs for Life: Campaign brings together patients and public with respiratory professionals to champion:
• Clean air
• Benefits of physical activity
• Smoking cessation

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ΕΥΧΑΡΙΣΤΩ ΠΟΛΥ!!!