TNF/BiO og gastroenterologiske utfordringer. Jørgen Jahnsen

Transkript

1 TNF/BiO og gastroenterologiske utfordringer Jørgen Jahnsen

2 Interessekonflikter Foredrag, konsulent eller advisory board medlem for AbbVie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Hikma, Janssen, Meda, MSD, Napp Pharma, Norgine, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts og Sandoz.

3 Inflammatorisk tarmsykdom Prevalens: 0.5-1% Aldersdebut: år Crohns sykdom Ulcerøs kolitt

4 Suksess og fiasko i utviklingen av legemidler Ustekinumab MEDI2070 Briakinumab Rituximab Ocrelizumab Abatacept Visilizumab Tofacitinib Sagramostim Fontolizumab Infliximab Adalimumab Certolizumab pegol Golimumab Tocilizumab Etanercept Basiliximab Daclizumab Tenovil Secukinumab Vidofludimus Natalizumab Vedolizumab PF Alicaforsen Traficet Adapted from Danese S et al. Gut 2012;61:

5 Journal of Crohn s and Colitis 2013;7: Gut 2013;62:

6 Main issues of concerns Extrapolation of indication Switchability

7 Mechanism of Action of Infliximab

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9 CT-P13 INX (%) (%) (%) CI: -10.7, CI: -16.9, /111 (69.4) 81/109 (74.3) CI: -16.7, /111 (60.4) 70/109 (64.2) CI: -16.2, /109 47/111 (45.0) (42.3) 50 96/111 (86.5) 96/109 (88.1) CI: -17.7, /109 78/111 (76.1) (70.3) CI: -15.2, /111 60/109 (53.2) (55.0) 50 CI: -10.3, 12.9 CI: -13.3, /111 (76.6) 82/109 (75.2) 80/111 80/109 (72.1) (73.4) CI: -15.2, /111 (55.0) 62/109 (56.9) 0 CDAI70 CDAI100 Remission 0 CDAI70 CDAI100 Remission 0 CDAI70 CDAI100 Remission Week 6 Week 14 Week 30 Lancet Apr 27;393(10182):

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11 Disease worsening Diagnosis INX (n= 202) CT-P13 (n=206) Rate difference (95% CI) Crohns disease 14 (21.2%) 23 (36.5%) -14.3% ( %) Ulcerative colitis 3 (9.1%) 5 (11.9%) -2.6% ( %) Spondyloarthritis 17 (39.5%) 14 (33.3%) 6.3% ( %) Rhematoid arthritis 11 (36.7%) 9 (30.0%) 4.5% ( %) Psoriatic arthritis 7 (53.8%) 8 (61.5%) -8.7% ( %) Psoriasis 1 (5.9%) 2 (12.5%) -6.7% ( %) Overall 53 (26.2%) 61 (29.6%) -4.4% ( %)

12 Disease worsening

13 Switching of biologic agents and biosimilars Danese, S. et al. (2016) Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

14 Ecco Statements

15 Varighet av behandling med infliksimab for Crohns sykdom n=153 Gonzaga J. Inflamm Bowel Dis. 2009;15: Cosnes J et al., Aliment Pharmacol Ther, 2016

16 Drug survival in Crohns disease First-line biological therapy survival Second-line biological therapy survival Lirhus, SL et al. P221, ECCO 2019

17 Drug survival in ulcerative colitis First-line biological therapy survival Second-line biological therapy survival Lirhus, SL et al. P191, ECCO 2019

18 Ulike virkningsmekanismer og angrepspunkt Epithelium M cell Intestinal damage Dendritic cell Lamina propria Paneth cell IL-10 TGFβ Treg CD8+ T cell Naïve T cell TNFα TNFα Block T cell effectors Fibroblasts TNFα Block T cell differentiation CD4+ T cell Activated macrophages IL-23 IL-12 Th17 Th1 Blood vessel Rolling T cells MAdCAM-1 a4β7 integrins Block T cell influx Danese S, et al. Nat Rev Gastroenterol Hepatol. 2015;12:

19 IL- 12Rβ1 IL-23R IL- 12Rβ2 IL- 12Rβ1 Inhibition of IL-12 and IL-23 IL-12/23 inhibitors target the p40 subunit shared by both cytokines; IL-23-selective inhibitors target the p19 subunit of IL IL-12 and IL-23 influence the development of Th1 and Th17 cell responses, respectively IL-23 IL-12 IL-12/23 inhibitor (ustekinumab) p40 p19 p35 p40 IL-12/23 inhibitor (ustekinumab) Th17 stabilization Th1 development Cytoplasm Created from Teng Teng MW et al. Nat Med. 2015;21: Benson JM et al. Nat Biotechnol. 2011;29: Sands BE. Gastroenterol Hepatol. 2016;12(12):

20 IL- 12Rβ1 IL-23R IL- 12Rβ2 IL- 12Rβ1 Inhibition of IL-12 and IL-23 IL-12/23 inhibitors target the p40 subunit shared by both cytokines; IL-23-selective inhibitors target the p19 subunit of IL IL-12 and IL-23 influence the development of Th1 and Th17 cell responses, respectively IL-12/23 inhibitor (ustekinumab) p40 IL-23 p19 IL-23 inhibitors (risankizumab, mirikizumab) p35 IL-12 p40 IL-12/23 inhibitor (ustekinumab) Th17 stabilization Th1 development Cytoplasm Created from Teng Teng MW et al. Nat Med. 2015;21: Benson JM et al. Nat Biotechnol. 2011;29: Sands BE. Gastroenterol Hepatol. 2016;12(12):

21 Oral small molecules tofacitinib filgotinib upadacitinib mongersen Blocks signalling of inflammatory cytokines by blocking JAK-STAT pathway JAK SMAD7 Restores TGF-β1 signalling in gut lesions stat P-stat Smad7 Smad7 PDE4 apremilast Restores balance between proand anti-inflammatory cytokines in immune cells camp AMP Internalised S1P1R S1P1R ozanimod Reduces levels of activated T-cells circulating to the gut External S1P1R

22 Oral small molecules tofacitinib filgotinib upadacitinib mongersen Blocks signalling of inflammatory cytokines by blocking JAK-STAT pathway JAK SMAD7 Restores TGF-β1 signalling in gut lesions stat P-stat Smad7 Smad7 PDE4 apremilast Restores balance between proand anti-inflammatory cytokines in immune cells camp AMP Internalised S1P1R S1P1R ozanimod Reduces levels of activated T-cells circulating to the gut External S1P1R

23 More treatment with infliximab Monthly sales (vials) >50% increase in sales 0 14/1 14/3 14/5 14/7 14/9 14/11 15/1 15/3 15/5 15/7 15/9 15/11 16/01 16/03 16/05 16/07 16/ Farmastat

24 Behandlingsoversikt pasienter 2 dager i uken pasienter i måneden

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