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Managing IPF: connecting the dots

Managing IPF: connecting the dots. 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

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Managing IPF: connecting the dots

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

  2. 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

  3. Forced Vital Capacity: Predictive of Clinical Outcome Managing IPF – Preventing disease Progression Correlation between: %FVC and Mortality† ∆FVC and Mortality *p<0.001 *p<0.001 20 8 15 6 4.81* HR, 1-year Mortality HR, 1-year Mortality 10 4 7.51* 2.11* 4.12* 5 2 1.00 1.97 1.00 0 0 <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.

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

  5. Background 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

  6. Clinical Trials in IPF

  7. 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

  8. ASCEND Study: Pirfenidone in IPFKing 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 p<0.001

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

  10. INPULSIS-1 & 2 - Nintedanib • 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

  11. INPULSIS 1& 2 STUDIES: NINTEDANIB IN IPFRICHELDI, ET AL., N ENGL J MED, 2014. 370(22): P. 2071-82POOLED 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 p=0.001 (adjud. events!) SGRQ -1,43 pts. p=0.09 • 000

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

  13. 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%

  14. 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

  15. Anti-oxidant therapy in IPFThe 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?

  16. 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?

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

  18. 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

  19. 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?

  20. Managing IPF – When to initiate therapy? 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 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

  21. 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 • 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;

  22. 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

  23. 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!“ 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% Less severe disease and moderate progression showed more consistent response to therapy! Arai et al., Respir Invest 2014; 52:136-142

  24. 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!

  25. Definite, Probable, Possible IPF – All the Same? 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!

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

  27. 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.)

  28. 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

  29. 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

  30. Treatment of IPF – Pulmonary Rehabilitation PR in ILD +11 Pkte*** >MID +5 Pkte*** Physical score Psychol. score With PH Without 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

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

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

  33. 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 Not Taking PPI/H2B N=118 Taking PPI/H2B N=124 Lee et al., Lancet Respir Med 2013; 1: 369-376

  34. 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 Lee et al., Lancet Respir Med 2013; 1: 369-376

  35. 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 (+)

  36. 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 Symptomatic therapy Initiate antifibrotic therapy • Evaluate/treat • GERD • LTOT • Severe PH • et al. Pulmonary Rehabilitation Monitoring in 3-monthly intervals: PFT, BGA, 6MWT

  37. 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

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

  39. Thank You For Your Attention!

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