1 / 63

THERAPY OF IPF Venerino Poletti Ospedale GB Morgagni , Forlì

THERAPY OF IPF Venerino Poletti Ospedale GB Morgagni , Forlì. Conflicts of Interest Italian & European Intermune Advisory Board. Idiopathic P u lmonary Fibrosis. - incidence: 10/100 000 Severe UIP pattern. (Bjoraker, AJRCCM 1998;157: 199-203). Responders : -Younger

venus
Download Presentation

THERAPY OF IPF Venerino Poletti Ospedale GB Morgagni , Forlì

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. THERAPY OF IPF Venerino Poletti Ospedale GB Morgagni, Forlì

  2. Conflictsof Interest Italian & EuropeanIntermuneAdvisoryBoard

  3. Idiopathic Pulmonary Fibrosis • - incidence: 10/100 000 • Severe • UIP pattern (Bjoraker, AJRCCM 1998;157: 199-203)

  4. Responders : -Younger - Histology : Cellular N=220

  5. Responders : -Younger - Histology : Cellular

  6. Prednisone + Azathioprine p = 0,02 Prednisone (Raghu, ARRD 1991;144:291-6)

  7. IFIGENIA NAC slows the rate of decline of lung function in patients treated with prednisone + azathioprine Δ CV: 180 ml (4,8%)P = 0,017 Δ DLCO : 0,75 (5%)P = 0,003 Mortality : 9% vs 11% (Demedts, NEJM 2005)

  8. Before 2011,Prednisone + AZA + NAC=the therapeutic standard in IPF • Experts (ATS/ERS 2000 consensus) • IFIGENIA study

  9. Before 2011,Prednisone + AZA + NAC=the therapeutic standard in IPF …But No placebo study • Experts (ATS/ERS 2000 consensus) • IFIGENIA study

  10. Pred + AZA + NAC N=390 60 weeks NAC Placebo PANTHER trialIPF Network NIH • IPF mild to moderate (FVC> 50%;DLCO > 30%; Dc <4 years) Prednisone 0.50.15 mg/kg 25wks Azathioprine : 150 mg/d maxi NAC : 600 mg x3/d (IPFNet, NEJM 2012)

  11. Increased mortality in treated patients (IPFNet, NEJM 2012)

  12. Increased mortality and hospitalization rate (IPFNet, NEJM 2012)

  13. IFIGENIA Mortality : 9% vs 11% No difference in lung function (IPFNet, NEJM 2012)

  14. Before 2011,Prednisone + AZA + NAC=the therapeutic standard in IPF Not supported by placebo controlled study

  15. First lesson Avoiding the use of steroids and immunosuppressants : A simple way to improve patients survivalBut…is it always true?

  16. Second lesson Placebo controlled trials are the only way to validate a treatment (old or new…) • Need to convince patients and doctors • Do not count only on pharma companies academic trials may fill some gaps

  17. Corticosteroids and Cyclophosphamide in IIPs • methylprednisolone IV 1g/d x3d/week x 4 weeks • oral CPM : 1-2 mg/kg.d + Pred 20 mg/d 1d/2 • Mean duration: 21 months 27 IPF 12 fibrotic NSIP Improved Stabilized Worsened Bolus IPF 15% 81% 4% NSIP 33% 67% 0% 12 months IPF 15% 52% 33% NSIP 67% 33% 0% Suivi IPF 0% 26% 74% (deaths : 67%) NSIP 42% 33% 25% (Kondoh, ERJ 2005)

  18. Corticosteroidsand IS in NSIP 38% (5% change) 34% 28% N=30 N=29 6 monthly IV CPM 0.6g/m2 Prednisolone : 10±5mg/d Steroids 90% I°suppressants 79% Corte, Sarcoidosis 2009 Kinder, Lung 2010

  19. Unsolvedquestions • Are steroids/CPM alwaysuseless or dangerous in IPF patients? • Isthere a subgroupofpatientswith “inflammation” thatmighthave benefit fromsteroids/CPM? • No clinicaltrialsavailable up tonow!!!

  20. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials

  21. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials Under- powered (N=88)

  22. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials A mortality study is feasible Placebo minimal changes in FVC, 6MWT distance, …

  23. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials “The ideal treatment could fail” Validated in state of the art models Plausible pathophysiology

  24. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 Warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials Raghu (ATS 2012) Disease progression Hospitalization Mortality (trend)

  25. etanerceptRaghu, AJRCCM 2008;178:948-55 interferon-gammaKing, Lancet 2009;374:222-228 imatinib (2010)Daniels, AJRCCM 2010;181:604-10 bosentan (BUILD-2011)King AJRCCM 2011;184:92-99 macitentan (MUSIC-2011)http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1541790 ambrisentan (ARTEMIS-2010) IPF and IPF-PHThttp://www.gilead.com/pr_1510358 Warfarin (ACE-IPF)Noth, AJRCCM 2012; We have learned from the negative trials Be careful with preclinical data

  26. Finally,…One drug approved in IPF !

  27. Pirfenidone: the past • 54 IPF patients • Deterioration with steroids ± I°S • TLC 58 ± 16 % • DLCO 34 ± 17 % Pirfenidone: 40 mg/kg (maxi 3600 mg/j) Stop CS and I°S within 8 weeks (Raghu, AJRCCM 1999;159:1060)

  28. Pirfenidone, 24 months TLC FVC DLCO SpO2 O2 (Raghu, AJRCCM 1999;159:1060)

  29. Pirfenidone • Pirfenidone: • Antifibrotic, antioxidant, anti-TNF • Different experimental models :heart, lung, kidney fibrosis • A series of four randomized controlled studies: (>1100 patients)

  30. FVC decline Grouped analysis % patients with ΔFVC > 10% • Progression free survival RR=0.74 P=0.025 • Distance 6MWT Δ=24m P=0.009 • Positive trend for mortality reduction (Noble, Lancet 2011;377:1760)

  31. Not approved by FDA (ASCEND trial ongoing) • Europeanapproval 3rd March 2011 (Esbriet®) • « Mild to moderate IPF » • Commerciallyavailable in Germany sinceseptember 2011 • NPP in Italy, GB, and othereuropean countries • Available in France sinceOctober 2012

  32. The pirfenidone lessons • A trial can be positive in IPF

  33. The pirfenidone lessons • A trial can be positive in IPF • A drug without target may work

  34. The pirfenidone lessons • A trial can be positive in IPF • A drug without target may work • A drug that works in the bleomycin model can work in humans

  35. The pirfenidone lessons • A trial can be positive in IPF • A drug without target may work • A drug that works in the bleomycin model can work in humans • An IPF drug costs > 24.000 €/year

  36. The Future

  37. NAC (600 mg x3/d) N=260 60 weeks Placebo PANTHER trial – Is NAC effective ? Results expected end 2013

  38. BIBF 1120 (nintedanib, Vargatef®) : multi-target Tyrosine Kinase inhibitor Triple angiokinase Inhibitor Involved in IPF pathogenesis Hilberg, Cancer Res 2008

  39. The TOMORROW study (Richeldi, NEJM 2011;365:1079) Placebo BIBF 1120-300mg P value N=85 N=85 FVC 12 mo - 190 ml - 60 ml 0,013 Exacerbations 15,7 % 2,4 % 0,02 SGRQ +5,46 -0,66 0,0007 -68% GI side effects (drug stop) Diarrhea 11,8% vs 0% Nausea 4,7% vs 0% Vomiting 2,4% vs 1,2% Two Phase 3 trials (Inpulsis) Results expected end 2013

  40. nintedanib • If phase III studies are positive… • Target multiple pathways in IPF treatment • The bleomycin model isvalid

  41. A non exhaustive list ot targets Anti-TGFβ Fresolimumab (Sanofi-Genzyme, Phase1) Anti CTGF FG-3019 (Fibrogen, Phase2) Anti-CCL2 CNTO 888 (Phase 2) Anti-IL-13 QAX-576 (Novartis, Phase 2) Tralokinumab (AZ-MedImmune, Phase 2) Anti-IL-4, IL-13 SAR156597 (Sanofi, Phase 2) JNKi CC-930 (Celgene, Phase 2) Anti-αvβ6 STX-100 (Stromedix, Phase 2) Anti LOXL2 simtuzumab (Gilead, Phase 2) SAP PRM-151 (Promedior, Phase 2) CO inhalé Phase 2 MMPs minocycline Anti-LTs zileuton Interferon alpha Phase 1 (Thorax 2011) Aerosolized IFNγ Phase 2 Collagen V IW001 (Immuneworks, Phase 1) Octreotide FIBROSAND (Phase 2) ERJ 2012 PI3Kinase GSK2126458 (GSK, Phase 1) Sirolimus Serotonin, LPA1, losartan, …

  42. A non exhaustive list ot targets Anti-TGFβ Fresolimumab (Sanofi-Genzyme, Phase1) Anti CTGF FG-3019 (Fibrogen, Phase2) Anti-CCL2 CNTO 888 (Phase 2) Anti-IL-13 QAX-576 (Novartis, Phase 2) Tralokinumab (AZ-MedImmune, Phase 2) Anti-IL-4, IL-13 SAR156597 (Sanofi, Phase 2) JNKi CC-930 (Celgene, Phase 2) Anti-αvβ6 STX-100 (Stromedix, Phase 2) Anti LOXL2 simtuzumab (Gilead, Phase 2) SAP PRM-151 (Promedior, Phase 2) CO inhalé Phase 2 MMPs minocycline Anti-LTs zileuton Interferon alpha Phase 1 (Thorax 2011) Aerosolized IFNγ Phase 2 Collagen V IW001 (Immuneworks, Phase 1) Octreotide FIBROSAND (Phase 2) ERJ 2012 PI3Kinase GSK2126458 (GSK, Phase 1) Sirolimus Serotonin, LPA1, losartan, …

  43. Is bacterial Infection/colonization a target in IPF ? Apoptosis cotrimoxazole : 960mg x 2/j Folic acid: 5mg/j

  44. cotrimoxazole (Shulgina, Thorax 2012; on line First) • No effect on • Lung function • 6MWT • Dyspnea (MRC) • Mortality • Improvement of • the SGRQ • -6.88 (-12.06; -1.70) • p=0.009 Survie NS

  45. cotrimoxazole (Shulgina, Thorax 2012; on line First) 3/53 • Improvement of • mortality in the • per-protocol • population 14/65 HR: 0.21 (IC95%: 0.06-0.78) p=0.02 Survie

  46. cotrimoxazole (Shulgina, Thorax 2012; on line First) Infection Placebo Bactrim P (n,%) (n,%)

  47. Failure of monotargeted therapies Next step ? Others... nintedanib pirfenidone 2013

More Related