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JAK Inhibitors and the Next Wave of Oral Small Molecules in the Management of IBD

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JAK Inhibitors and the Next Wave of Oral Small Molecules in the Management of IBD JAK Inhibitors and the Next Wave of Oral Small Molecules in the Management of IBD Remo Panaccione, MD Director, Inflammatory Bowel Disease Clinic Director, Gastrointestinal Research Associate Dean of MD Admissions Professor of Medicine University of Calgary Canada Canada Future Directions in IBD Saturday, November 16th Toronto, ON Date of preparation: TBA. Zinc code: TBA Disclosures: R. Panaccione . Consultant for: AbbVie, ActoGeniX, AGI Therapeutics, Alba Therapeutics Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Aptalis, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek, Cellerix, Cerimon, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle, Eisai Medical Research, Elan, EnGene, Eli Lilly, Enteromedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genentech, Genzyme, Gilead, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, KaloBios, Lexicon, Lycera, Meda, Merck & Co., Merck Research Laboratories, MerckSerono, Millennium, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb, Purgenesis Technologies, Receptos, Relypsa, Salient, Salix, Santarus, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris (a GSK company), S.L.A. Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, UCB Pharma, Vascular Biogenics, Viamet and Warner Chilcott UK. Speaker’s fees for: Abbvie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, Takeda . Advisory Board for: Abbvie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Biogen Idec, Eisai, Ferring, Genentech, Janssen, Merck, Shire, Elan, Glaxo-Smith Kline, Hospira, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene, Salix . Research/Educational Support from: Abbvie, Ferring, Janssen, Shire Takeda Increasing understanding of the immunopathogenesis of IBD has enabled the development of novel targeted therapies E-cadherin Pathogen Intestinal lumen Brazikumab Guselkumab αEβ Mirikizumab 7 Risankizumab Lamina propria IL-36 IFN-γ Dendritic cell IL-36R Ustekinumab* IL-36R IL-12 Th1 IL-12R B7 IL-23R Dendritic CD28 TGF-βRI cell IL-6 TGF-βRII Th0 IL-12 IL-6R FilgotinibTNF IL-23 Tofacitinib* Smads T T cell Peficitinib STATs E TGFβ JAKs Smad7 S1P1 IL-23 Upadacitinib Lymph node Transcriptio Antimicrobial Th17 IL-22 TNFRs Ozanimod n peptides IL-4 Estrasimod NF-kβ Target genes IL-17/A/F IL-36R Adalimumab* Nucleus Certolizumab pegol* PDE4 Th2 Golimumab* T-cells IL-36 Infliximab* IL-36R Macrophage IL-13 VCAM-1 IL-6 Etrolizumab Fibroblast TNF Endothelial cell VCAM-1 MAdCAM-1Natalizumab* S1P α4β1 α4β7 IL-12 Vedolizumab* IL-23 TLR-9 Leukocyte IL-6 vessel Blood TNF Adapted from Coskún M, et al. Trends Pharm Sci 2017;38:127–42; and Nielsen OH, et al. Expert Opin Investig Drugs 2016;25:709–18. Immunopathologic pathways: JAK-STAT pathway E-cadherin Pathogen Intestinal lumen αEβ 7 Lamina propria IL-36 IFN-γ Dendritic cell IL-36R IL-36R IL-12 IL-12R Th1 IL-12R IL-23RIL-23R Dendritic B7 CD28 TGF-βRI IL-6 cell Th0 IL-12 TGF-βRII TNF IL-6RIL-6R IL-23 Smads T cell STATs TE JAKs TGFβ Smad7 S1P1 IL-23 STATs Lymph node Transcriptio Antimicrobial Th17 IL-22 TNFRsJAKs peptides IL-4 n NF-kβ Target genes IL-17/A/F IL-36R PDE4 Nucleus Th2 T-cells IL-36 IL-36R Macrophage IL-13 VCAM-1 IL-6 Fibroblast TNF Endothelial cell VCAM-1 MAdCAM-1 S1P α4β1 α4β7 IL-12 IL-23 TLR-9 Leukocyte IL-6 vessel Blood TNF Janus Kinases (JAKs) Janus kinases are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals through several steps via the JAK-STAT pathway . In ancient Roman religion and myth, Janus is the god of beginnings and transition. Also of gates, doors, doorways, passages and endings. He is usually depicted as having two faces, since he looks to the future and to the past. Shuai K, Liu B. Nat Rev Immunol 2003;3:900−911. 5 JAK/STAT pathway: activation and inhibition Activation1 Inhibition2 1 Cytokine binds to receptor JAK JAK 2 JAK proteins binds to receptor P STAT STAT P 1 JAK inhibitor binds to JAK JAK proteins activate Competitive inhibition of 3 STAT proteins P STAT STAT P 2 STAT activation Activated STAT proteins Downstream JAK-STAT 4 translocate to nucleus 3 pathway inhibited 5 STAT dimers bind to DNA P STAT STAT P Pro-inflammatory genes Pro-inflammatory genes 6 transcribed Target genes 4 reduced Adapted from Garber K. Nat Biotechnol 2011;29:467–68 JAK, Janus kinase; STAT, signal transducer and activator of transcription 1. Rawlings JS, et al. J Cell Sci 2004;117:1281–1283; 2. Hsu L, et al. J Immunol Res 2014;14:283617. JAK inhibition suppresses inflammatory cytokines involved in the pathogenesis of Crohn’s disease γc Cytokines Type 1 IFNs, EPO, TPO, (IL-2, IL-4, IL-7 IL-10 family IL-6, IL-11, IL-13 IFNγ IL-12 GM-CSF IL-9, IL-15, IL-21) of cytokines IL-27, IL-31, IL-35 IL-23 IL-3, IL-5 Cytokines TYK2 JAK1 JAK3 JAK1 TYK2 JAK1 JAK2 JAK1 JAK2 JAK2 TYK2 JAK2 JAK2 • Growth/maturation • Antiviral • Naïve T cell • Antiviral • Innate immunity • Erythropoiesis lymphoid cells differentiation • Inflammation • Inflammation • Differentiation/ • Myelopoiesis • • Differentiation/ • Antitumor T cell homeostasis • Antimycobacterial proliferation of • Megakaryocyte/ homeostasis • Inflammation TH17 cells platelet production T cells, NK cells • • Inflammation • Function Granulopoiesis Growth • B cell class switching • Mammary • Inflammation development Clark JD, et al. J Med Chem 2014;57:5023–5038. JAK inhibitors have distinct in vitro inhibition profiles Tofacitinib Upadacitinib Filgotinib nM potency against all JAKs1 Higher selectivity for Higher selectivity for JAK1 vs JAK2 (~60) JAK1 vs JAK2 (28x)8 and JAK3 (>100x)7 JAK3 ≈JAK1 ≈ JAK2 > TYK1 JAK1 JAK1 Pan-JAK inhibition – tofacitinib1 Selective JAK1 inhibition – upadacitinib, filgotinib2–6 1. Meyer DM, et al. J Inflamm 2010;7:41; 2. Clinical trial identifier: NCT0166864; 3. Clinical trial identifier: NCT01894516 (DARWIN2); 4. Clinical trial identifier: NCT01888874 (DARWIN1); 5. Clinical trial identifier: NCT01960855; 6. Clinical trial identifier: NCT02066389; 7. Parmentier JM, et al. BMC Rheumatology 2018;2:23; 8. Van Rompaey L, et al. J Immunol. 2013;191:3568–3577. Tofacitinib (pan JAK) for Induction Therapy in CD: Phase 2b Randomized Placebo-Controlled Trial (RCT) Primary Endpoint: Clinical Remission at Wk 8 (FAS, NRI) 100 Δ 6.3% 80 NNT = 16 60 36.7 43.5 43.0 40 Pts Achieving Achieving CDAI Pts 20 Score <150, % (95% Score <150, (95% % CI) N=90 N=85 N=86 0 All subjects Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID . 51% prior anti-TNF failure . Tofacitinib had small treatment effects on the proportion of pts in remission, but the differences were not statistically significant vs placebo Panes J et al. Gut. 2017 Jun;66(6):1049-1059. Tofacitinib (pan JAK)for Maintenance Therapy in CD: Phase 2b Randomized Placebo-Controlled Trial Week 8 randomized-responders (CR-100) Placebo (N=42) 100.0 95.2 95.4 100 Tofacitinib 5 mg BID (N=43) 79.1 Tofacitinib 10 mg BID (N=x) 80 73.8 74.4 66.7 67.4 58.1 55.8 60 53.5 55.8 50.0 51.2 40.5 39.5 39.5 38.1 40 CR-100% (95%CI) 20 0 Baseline Wk 4 Wk 8 Wk 12 Wk 20 Wk 26 - After 26 wks of maintenance therapy, CR-100 or remission was observed in a higher proportion of pts receiving tofacitinib than placebo, although the difference was not statistically significant Panes J et al. Gut. 2017 Jun;66(6):1049-1059. Tofacitinib, panJAK: Phase III efficacy data in UC OCTAVE 100 Week 8 100 Week 52 OCTAVE Induction 1 OCTAVE Induction 2 OCTAVE Sustain 80 80 P<0.001 60 60 P<0.001 P=0.007 P<0.001 40.6 40 40 34.3 18.5 16.6 20 8.2 11.1 3.6 20 Patients Patients (%) Clinical 0 0 remission Placebo tofacitinib Placebo tofacitinib Placebo tofacitinib tofacitinib (n=122) 10 mg BID (n=112) 10 mg BID (n=198) 5 mg BID 10 mg BID (n=476) (n=429) (n=198) (n=197) 100 Week 8 100 Week 52 80 OCTAVE Induction 1 OCTAVE Induction 280 OCTAVE Sustain P<0.001 P<0.001 60 P<0.001 P<0.001 60 45.7 37.4 40 31.3 28.4 40 20 15.6 11.6 20 13.1 Patients Patients (%) 0 0 remission Placebo tofacitinib Placebo tofacitinib Placebo tofacitinib tofacitinib Patients (%) Patients (n=122) 10 mg BID (n=112) 10 mg BID Endoscopic (n=198) 5 mg BID 10 mg BID (n=476) (n=429) (n=198) (n=197) • Moderate-to-severe patients (Mayo score 6–12) • OCTAVE Induction 1: anti-TNF-exposed, % (placebo/tofa 10 mg): 53.3/53.4 • OCTAVE Induction 2: anti-TNF-exposed, % (placebo/tofa 10 mg): 58.0/54.5 • OCTAVE Sustain: anti-TNF-exposed, % (placebo/tofa 5 mg/tofa 10 mg): 46.5/45.5/51.3 Sandborn W, et al. N Engl J Med 2017;376:1723–1736. Tofacitinib, panJAK~Phase III efficacy data in UC: OCTAVE Sub-group analysis by TNFi exposure Tofacitinib 10 mg BID (n=476) Placebo (n=122) Tofacitinib 10 mg BID (n=429) Placebo (n=112) OCTAVE Induction 1 OCTAVE Induction 2 60 Remission Mucosal Healing 60 Remission Mucosal Healing 50 ** *** Δ15.7 50 Difference from placebo Δ16.8 *** 40 Δ10.3 40 Δ13.0 31.3 *** 28.4 30 30 18.5 15.6 16.6 20 20 11.6 8.2 10 10 Patients (%) Patients (%) 3.6 0 0 60 Overall Overall 60 Overall Overall Δ13.3 50 50 Δ17.3 39.6 Δ9.4 36.4 40 Δ17.9 40 Δ13.5 Δ15.6 30 25.2 26.3 30 Δ11.1 24.0 Δ12.0 22.1 21.8 19.1 20 15.8 20 12.6 12.0 6.2 8.5 6.2 Patients (%) 10 Patients (%) 10 1.5 0 0 0 TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- TNFi- treated naive treated naive treated naive treated naive **P<0.01 vs placebo; ***P<0.001 vs placebo.
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