Professor Chris Denton - Emerging therapies

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<ol><li> 1. Christopher P. Denton PhD FRCP Professor of Experimental Rheumatology Royal Free Hospital and UCL Medical School, London, UK Emerging therapies for systemic sclerosis </li><li> 2. Disclosures Consultancy: Actelion, Pfizer, GSK, Sanofi Aventis, Boehringer Ingelheim, Roche, CSL Behring, Genzyme, Inventiva Research grant funding: Actelion, Novartis, CSL Behring Clinical trial investigator and steering committee : Pfizer, Actelion, Sanofi-Aventis, MedImmune, United Therapeutics, Novartis, Celgene, Bayer </li><li> 3. Overview:emergingtherapies Sclerodermaisnowtreatable Licensedtherapiesfor2majorvascularcomplica</li><li> 4. dcSSc lcSSc 0 12 24 36 48 60 50 60 70 80 90 100 93% 91% P=0.534 Disease duration (months) Survival(%) Disease onset 1990 -1993 n=234 2000 -2003 n=286 0 12 24 36 48 60 50 60 70 80 90 100 84% 69%P=0.018 Nihtyanova et al, QJM 2010; 103:109-15 Improving survival in systemic sclerosis: a historical perspective </li><li> 5. EULAR/EUSTARrecommenda</li><li> 6. Bestprac</li><li> 7. WorkstartedSeptember2012 February2015-submihedtoBSRandrststageof externalpeerreviewpresenteddragApril2015 Targetforcomple</li><li> 8. Licensed targeted therapies for PAH in systemic sclerosis Endothelin receptor antagonists Selective phosphodiesterase inhibitors Prostacyclin analogues Bosentan*(approved2001) Ambrisentan Sitaxentan(withdrawn) Macitentan(approved2013) Sildenal(approved2005) Tadalal Riociguatguanylatecyclase agonist(approved2013) Epoprostenol Trepros</li><li> 9. Denton CP, et al. Ann Rheum Dis 2008; 67: 1222-8. Pope J, et al. Presented at the ACR meeting, 2007. 100 80 90 70 60 50 40 30 20 10 0 Patientssurviving(%) Time from treatment start (weeks) 0 16 32 48 64 80 96 112 128 144 160 Patients at risk 53 51 49 47 45 40 40 32 12 3 0 82% alive at 2 years 92% alive at 48 weeks TRUST TRacleer Use in PAH associated with Scleroderma and other connective Tissue diseases 3-year survival data SSc n=42 (80%) MCTD/overlap n=6 (11%) SLE n=5 (9%) mPAP = 40 (+13) mm Hg PVR = 559.4 (+371.5) dyn/s/cm5 </li><li> 10. NHSEnglandpolicyforDUinSSc* Sildenal Prostenoids(iloprost) Bosentanaccessforseverecases Severerefractorydisease:persistentorprogressive ulcera</li><li> 11. 1Hoyles et al Arthritis Rheum 2006; 54:3962-70 Cyclophosphamide for lung fibrosis in SSc Fibrosing alveolitis in scleroderma trial (FAST)1 monthly intravenous cyclophosphamide 600mg/m2 for 6 months followed by (po) azathioprine, or placebo in 45 patients Over 12 months FVC change favoured active treatment (p=0.04, BMI corrected uncorrected p=0.08) FAST primary outcome: FVC p=0.08 2.44 2.46 2.48 2.50 2.52 2.54 2.56 2.58 2.60 2.62 2.64 baseline 3 months 6 months 9 months 12months Months from baseline AbsoluteFVC(meanateachtimepoint) ACTIVE PLACEBO Magnitude of difference 5.5% (4.8% adjusted) active arm improved (+2.5 % predicted) placebo arm worsened (-3.0 % predicted) </li><li> 12. AgreedpathwayforUKpa</li><li> 13. Concept of targeted therapy in systemic sclerosis Varga, J., Denton et al. (2015) Systemic sclerosis Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.2 Pathway Process Organ </li><li> 14. Emerging molecular therapies for SSc Candidate therapy Target pathway Bosentan, macitentan ETA/ETB receptor Ambrisentan ETA receptor Selexipag IP receptor agonist Riociguat cGMP agonist Infliximab, Adalimumab TNF ligand Etanercept TNF ligand Rituximab CD20 Basiliximab IL-2R MLM-1202 CCR2 Efalizumab LFA1/ICAM-1 Abatacept CTLA4 AIMSPRO (HCS) MSH, IL10, CCL2 Tocilizumab IL-6R ACT12339 LPA1 Imatinib, Dasatinib, Nilotinib c-Abl, c-Kit, PDGF CAT-192 TGF1 GC-1008 TGF1,-2,-3 FG-3019 CCN2 P144 TGF1 (topical) Anti-v6 integrin TGF activation Pirfenidone TNF, IL1, TGF Nintedanib (BIBF1120) VEGF,PDGF,FGF VascularInflammatoryFibrotic </li><li> 15. Targeting the IL-6 axis in diffuse systemic sclerosis 180120600 100 80 60 40 20 0 DiseaseduraNon(months) Numberat risk High Low 15531 241551 IL-6serumlevelatpresenta</li><li> 16. Conclusions Treatmentofsclerodermaisimproving Establishedtreatmentsarebeingusedinbeherways e.g.immunosuppression Licenseddrugsareavailableforspeciccomplica</li><li> 17. Many thanks to . Our patients The Scleroderma team at Royal Free Research Funders Colleagues in many institutions and organisations UKSSG colleagues International collaborators EUSTAR, SCTC and FESCA, WSF Arthritis Research UK, Raynauds and Scleroderma Association (UK), Wellcome Trust (UK), Nuffield Foundation, Scleroderma Society (UK), Rosetrees Trust, Scleroderma Research Foundation (USA), MRC, EULAR, Royal Free Charity </li></ol>

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