Managing IPF: connecting the dots Pulmonary & Sleep Medicine Abdullah Alsaeedi MD, FRCPC, FACP, FCCP Pulmonary & Sleep Medicine Aljahra Hospital

Managing IPF – Treatment Goals Preventing disease progression Preventing / treating acute exacerbations Improving exercise tolerance and QoL Improving symptoms: dyspnea, cough Treating comorbidities: GERD, PH Improving survival

Forced Vital Capacity: Predictive of Clinical Outcome Managing IPF – Preventing disease Progression Forced Vital Capacity: Predictive of Clinical Outcome Correlation between: %FVC and Mortality† ∆FVC and Mortality 20 *p<0.001 8 *p<0.001 15 6 4.81* HR, 1-year Mortality HR, 1-year Mortality 10 4 7.51* 2.11* 5 4.12* 2 1.00 1.97 1.00 <50 51-65 66-79 >80 <5 5-9.9 >10 Baseline %FVC Decline in %FVC du Bois R et al, ERS Annual Congress 2010. †Based on Cox proportional hazards model du Bois RM, et al. Eur Resp J 2010;36:3632. 3

GAP Scoring Gender Age Physiology Multidimensional Index Ley et al., Ann Intern Med 2012;156:684-691 Multidimensional Index Gender Age Physiology [FVC and DLCO]) Stage I (0-3 pts.) Stage II (4-5 pts.) Stage III (6-8 pts.) Preventing disease progression (i.e. decline of lung function) is an essential treatment goal in IPF patients!

Background MUC5B status is linked to disease progression in IPF 14 x overexpression of MUC5B-Gene in IPF-lungs due to promotor polymorhism on Chromosom 11: Major Allel GG vs. Minor Allel TT Seibold et al., N Engl J Med 2011;364:1503-12 MUC5B status is linked to disease progression in IPF

Clinical Trials in IPF

Pirfenidone Oral bioavailable, small molecule Shows anti-fibrotic and anti-inflammatory activity in different in vitro- und animal models Inhibits TGF-b- and TNF-a-effects CH3 N O Orally bio-available small molecule Exhibits antifibrotic and anti-inflammatory properties in vitro and in animal models Inhibits TGF-beta- and TNF-alpha-effects

ASCEND Study: Pirfenidone in IPF King et al. , N Engl J Med, 2014 ASCEND Study: Pirfenidone in IPF King et al., N Engl J Med, 2014. 370(22): p. 2083-92. IPF-Patients 40 – 80 Yrs. FVC 50 – 90 % DLco 30 – 90 % FEV1/FVC ≥ 80 % 6MWD ≥ 150 m → 555 of 1562 enrolled ∆FVC 45,1 % p<0.001 ∆6MWD 44,2 % p=0.036 PFS: HR 0.57

ASCEND - Pirfenidon 10% 23% PLacebo Pirfenidon 32% 17% Pirfenidone, FDA Label; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022535s000lbl.pdf

INPULSIS-1 & 2 - Nintedanib An intracellular inhibitor of tyrosine kinases Targets VEGF, FGF and PDGF receptors Phase II TOMORROW study 12 months’ treatment with nintedanib 150 mg bid may reduce lung function decline and acute exacerbations in patients with IPF INPULSIS trials Two replicate 52-week, randomized, double-blind, Phase III trials Compared the efficacy and safety of nintedanib 150 mg bid with placebo in patients with IPF 1. Hilberg F, et al. Cancer Res 2008;68:4774–82; 2.Wollin L, et al. J Pharmacol Exp Ther 2014;349:209–20; 3. Richeldi L, et al. N Engl J Med 2011;365:1079–87; 4. Richeldi L, et al. N Engl J Med 2014; published online May 18, 2014

INPULSIS 1& 2 STUDIES: NINTEDANIB IN IPF RICHELDI, ET AL INPULSIS 1& 2 STUDIES: NINTEDANIB IN IPF RICHELDI, ET AL., N ENGL J MED, 2014. 370(22): P. 2071-82 POOLED ANALYSIS IPF-Patients ≥ 40 Yrs. FVC ≥ 50 % DLco 30 – 79 % Inpulsis-1 → 513 of 718 enrolled Inpulsis-2 → 548 of 794 enrolled ∆ FVC 49,2 %; p=0.001 Time to first AE HR 0,32 (adjud. events!) SGRQ -1,43 pts. p=0.09 000

INPULSIS - Nintedanib 18% Placebo 30% 43% Nintedanib 29% Nintedanib, FDA Label; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205832s000lbl.pdf

Summary of recent clinical trials in IPF ASCEND Pirfenidone ~40 % reduction 44% (26m) reduction 43% rel. risk reduction not done -19.3 reduction In UCSD SOBQ, p=0.16 45% risk reduction P=0.10 GI-tract and skin 14.4% vs. 10.8%

Summary of recent clinical trials in IPF Conclusions - I Prifenidone and Nintedanib have shown efficacy in IPF in reducing annual decline of FVC Differences in study populations preclude direct comparisons of effect sizes Pirfenidone reduces decline in 6MWD, improves PFS and overall survival, while Nintedanib prolongs time to first AE Positive trends were seen in different PROs for both drugs Side effects of both drugs are manageable There is no robust evidence that NAC is effective in IPF

Anti-oxidant therapy in IPF The issue that will not go away IFIGENIA, the first positive IPF trial, caused major debate due to issues with trial design PANTHER: Nacetylcysteine monotherapy versus placebo definitively negative? Even within the IPFnet authorship, major divisions of opinion: efficacy trends differed strikingly with “recruitment climate” Is there an anti-oxidant efficacy dichotomy?

Rationale Lung host defense is influenced by oxidative signaling Mucin 5B (MUC5B) and toll interactive protein (TOLLIP) polymorphisms influential in host defense. MUC5B status is linked to disease progression in IPF Are single nucleotide polymorphisms within TOLLIP and muc5B linked to the efficacy of trial interventions in the PANTHER cohort?

Methods Post hoc analysis of the PANTHER cohort Composite end-point of death, FVC 10% decline, transplant (+ hospitalisation in the PANTHER cohort)

On multivariate analysis CC: worse outcome with NAC HR 3.23 (0.79-13.16), p=0.10 TT: better outcome with NAC HR 0.14 (0.02-0.83), p=0.03

Summary of recent clinical trials in IPF Conclusions II IPF Patients should be treated with Pirfenidone or Nintedanib to prevent disease progression Open Questions: When should treatment be initiated? Should definite, probable and possible IPF be treated all the same? When, if at all, should treatment be stopped? What about other modalities – PR, LTOT, LTX?

Managing IPF – When to initiate therapy? ASCEND INPULSIS 1 INPULSIS 2 -164ml* vs. -280ml* -115ml vs. -240ml -114ml vs. -207 ml Δ 116ml* (41.5%)* Δ125ml (52%) Δ93ml (45%) p<0.001 *erratum NEJM, Sept. 8.2014 p<0.001 p<0.001 Baseline Characteristics ASCEND INPULSIS 1 INPULSIS 2 FVC 68 ± 11 % pred. 80 ± 17 % pred. 79 ± 18 % pred. DLco 44 ± 11 % pred. 48 ± 12 % pred. 47 ± 14 % pred. ∆FVC≤-10% 32 % (placebo) 39.5 % (placebo, pooled INPULSIS 1+2) ∆FVC≥0% 10 % (placebo) not reported

Natural history of IPF – From Placebo Arms of Clinical Trials in IPF Different types and rates of Progression ∆FVC % of risk of death (% pred.) population HR Stable or improved: ≥ 0 5 – 20 <1.0 Stable, marginal progressive: 0 to -5 20 - 30 1.0 Slowly progressive disease: -5 to -10 10 – 40 1.5 – 3.0 Rapidly progressive disease: > -10 % 20 – 50 3.0 – 12.0 Acute exacerbation*: n.a. 4 – 8 4,0 – 9,5* deterioration within 4 weeks * History of respiratory hospitalisation IPF: a progressive and fatal lung disease without approved Tx Median OS 2-5 yrs Clinical course: increasing dyspnea on exertion, progressive deterioration in lung function Strong prognostic indicator (predictor of mortality): decrease in FCV (Δ-FVC) over time Therapeutically meaningful: antifibrotic drugs that slow down the deterioration in FVC 30-40 % of the IPF population will be stable or marginal progressive on placebo after one year! 60-70 % of the IPF population shows significant progression or acute exacerbation within one year on placebo du Bois et al., Am J Respir Crit Care Med 2011; 184:1382–1389; du Bois et al., Am J Respir Crit Care Med 2011; 184: 459–466; Noble et al, Lancet 2011; 377: 1760-9; Demedts et al., NEJM 20015; 353:2229-42; Taniguchi et al., Eur Respir J 2010; 35:821-9; Richeldi et al., NEJM 2011; 365:1079-87; Richeldi et al., NEJM 2014; 370: 2071-82; King et al., NEJM 2014; 370: 2083-92; IPF-net, NEJM 2014; 370:2093-2101; 23

Managing IPF – When to initiate therapy? „Let‘s wait and see whether progression occurs - if the patient progresses let‘s start therapy!“ 100 IPF patients on placebo Decline ≥ 5 % FVC pred. After 3 months YES 35 % NO 65 % Further worsened FVC 12 months later ? YES 85 % NO 15 % YES 50 % NO 50 % FVC-stability within 3 months is not a predictor of stability but is followed by progress in 50 % of the patients! Taniguchi et al. Respiratory Research 2011, 12:93

Severity of IPF and/or rate of progression predicts response to therapy with pirfenidone? „This is a mildly affected patient, let‘s wait, he/she will respond better to active therapy when progress occurs!“ Arai et al., Respir Invest 2014; 52:136-142 Panel A) Severity grade I and II: PaO2 at rest ≥ 70 mmHg and min. SpO2 during 6MWT ≥ 90 % Panel B) Severity grade III and IV: PaO2 at rest < 70 mmHg or min. SpO2 during 6MWT < 90% IPF patients with a mild disease, diagnosis by SLB, or both showed indications of a good response to pirfenidone. In addition, acid-secretion inhibitors may reduce the frequency of anorexia, nausea, or both from pirfenidone. Less severe disease and moderate progression showed more consistent response to therapy!

Managing IPF – When to initiate therapy? Conclusions III Limited data available The overall risk of clinically relevant progression within one year is at least 50 % irrespective of diease severity in a wide range also in patients with previously stable FVC In actively progressive disease risk of further progression appears to be even higher (~ 85 %) Treating later may result in a similar treatment response, but the patient will start from a lower functional level There is no evidence that witholding therapy from stable patients will positively affect overall outcome IPF patients should be offered active therapy up front!

Definite, Probable, Possible IPF – All the Same? ASCEND IMPULSIS Surgical Lung Biopsy not available Pathology panel: Definite UIP Pathology panel: Probable UIP Pathology panel: Possible UIP Pathology panel: Inconsistent with UIP or Not Classifiable Radiology Panel: Definite UIP Radiology Panel: Possible UIP Radiology Panel: Inconsistent with UIP Despite including a significant portion of IPF patients with a „possible UIP“ pattern relative treatment effects on FVC observed in the INPUSLIS trials were comparable to ASCEND, where only „definite & probable UIP“ were included!

Definite, Probable, Possible IPF – All the Same? Travis et al., AJRRCM 2013; 188: 733-48

RELIEF-In Lung Fibrosis - Clinical Trial Titel: Exploring Efficacy and Safety of oral Pirfenidone for progressive, non-IPF Lung Fibrosis (RELIEF) Coordinating Investigators: J. Behr, Munich, A. Günther, Giessen Design: Radomized (1:1) placebo-controlled phase-2 clinical trial Intervention: Pirfenidon (2403 mg/d) vs. Placebo, 48 wk follow-up Primary Endpoint: Change in FVC from baseline to week 48 Sec. Endpoints: Time to clincal worsening; progression-free survival; et al. Sample Size: 500 pts. screened, 348 pts. (174 per arm) enrolled & analysed (ITT) Trial Duration: 36 months (18 months for recruitment, 48 wk follow-up) Centers: All 5 DZL-Centers plus at least five non-DZL centers (max. 20 ctrs.)

RELIEF-In Lung Fibrosis - Clinical Trial Key inclusion criteria: • Confident diagnosis of non-IPF lung fibrosis due to CVD-associated LF, chronic HP, idiopthic fNSIP or asbestos realted LF • Progressive disease despite preceding treatment

Treatment of IPF – Pulmonary Rehabilitation PR in ILD 402 ILD-Patients: 60 yrs. VC 52% pred. LTOT 80% acute infect. 13% RH-strain 28% pre LTx 74% >MID Intervention: Ø30 days in-patient PR OVERLALL ***p<0.001  Clinically relevant improvement of exercis tolerance Huppmann et al., Eur Respir J. 2013 Aug;42(2):444-53

Treatment of IPF – Pulmonary Rehabilitation PR in ILD +11 Pkte*** >MID +5 Pkte*** Physical score Psychol. score Without PH With PH ***p<0.001 QoL improves ∆ psychological score >> physical Score patients with right heart strain also benefit Huppmann et al., Eur Respir J. 2013 Aug;42(2):444-53

Treatment of IPF – Pulmonary Rehabilitation PR in ILD Reyerson et al., Res Med 2014; 108: 203-210

IPF - Comorbidities CVD PH DVT Depression GERD OSAS Lung cancer Emphysema Diabetes Nutrition Osteoporosis

Analyses of the three Placebo-arms of the IPFnet Studies: STEP – ACE – PANTHER re. Anti-acid therapy (PPI + H2B) STEP-IPF N=180 ACE-IPF N=145 PANTHER-IPF N=159 PLACEBO STEP N=91 ACE N=73 PANTHER N=78 IPFnet GERD Substudy N=242 Taking PPI/H2B N=124 Not Taking PPI/H2B N=118 Lee et al., Lancet Respir Med 2013; 1: 369-376

Analyses of the three Placebo-arms of the IPFnet Studies: STEP – ACE – PANTHER re. Anti-acid therapy (PPI + H2B) FVC-dcline in IPF-patients with vs. without anti-acid therapy: WK 30 Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression Lee et al., Lancet Respir Med 2013; 1: 369-376

Managing IPF – Connecting the Dots Preventing disease progression Improving exercise tolerance and QoL Improving symptoms: dyspnea, cough Treating comorbidities: GERD, PH Preventing / treating acute exacerbations Improving survival Pirfenidone, Nintedanib, Clinical Trials Pirfenidone, Nintedanib, Pulm Rehab LTOT, PPI (?), PR, (Thalidomide?) GERD: PPI, H2B, (Fundoplication) PH: PAPm > 35 mmHg? RCT! Nintedanib (+) Pirfenidone (+), Nintedanib (?), Ltx (+)

Managing IPF – Connecting the Dots IPF Patient Mild-Moderate FVC≥50% DLco≥30% 6MWD≥150m Severe Disease FVC<50% DLco<30% 6MWD<150m Evaluate eligibility for clinical trials and for lung transplantation Initiate antifibrotic therapy Symptomatic therapy Evaluate/treat GERD LTOT Severe PH et al. Pulmonary Rehabilitation Monitoring in 3-monthly intervals: PFT, BGA, 6MWT

IPF International Guideline – Update 2015 Negative Recommendation (strong): a. Anticoagulation (warfarin) (⊕⊕⊝⊝, low confidence in effect estimates). b. Imatinib (⊕⊕⊕⊝, moderate confidence in effect estimates). c. Prednisone, azathioprine, and N-acetylcysteine (⊕⊕⊝⊝, low confidence in effect estimates). d. Ambrisentan (⊕⊕⊝⊝, low confidence in effect estimates). Negative Recommendation (conditional): a. Sildenafil (⊕⊕⊕⊝, moderate confidence in effect estimates. b. Macitentan, Bosentan (⊕⊕⊝⊝, low confidence in effect estimates. Positive Recommendation (conditional): a. Nintedanib (⊕⊕⊕⊝, moderate confidence in effect estimates. b. Pirfenidone (⊕⊕⊕⊝, moderate confidence in effect estimates. Updated evidence syntheses related to N-acetylcysteine monotherapy (negative, conditional) and anti-acid therapy (positive, conditional) were presented to the panel and both recommendations were left unchanged from the 2011 guidelines. Raghu et al., ATS, 19.5.2015

A consensus document for the selection of lung transplant candidates: 2014 Weill et al., J Heart Lung Transplant 2015; 34: 1-15

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