Psoriasis: Therapeu.c Advances Based on Increased Understanding of Disease Pathways

Transcription

1 Psoriasis: Therapeu.c Advances Based on Increased Understanding of Disease Pathways James G. Krueger, MD PhD Professor and Laboratory Head The Rockefeller University

2 Conflicts Research support, consul.ng, or lecture fees by most pharma and biotech companies with a psoriasis product or inves.ga.onal agent during the past 20 years No patents, ownership, or financial gain from any psoriasis product or drug

3 Immune-Mediated Inflammatory Diseases affect at least 1:10 People Worldwide Skin: Psoriasis Vulgaris, Atopic Derma..s, Alopecia Areata, Vi.ligo and numerous others Diges.ve System: Crohn s Disease, Ulcera.ve Coli.s, and Type 1 Diabetes Skeletal: Rheumatoid Arthri.s, Psoria.c Arthri.s CNS: Mul.ple Sclerosis Respiratory: Asthma Mul.-organ: Systemic Lupus, Systemic Sclerosis

4 Psoriasis Vulgaris The most successful case of molecular therapeu.c targe.ng in a human immune-mediated disease With a single drug can now control psoriasis extremely well in ~80-90% of pa.ents Now have drugs that directly target elements of gene.c/genomic disease risk

5 Genera.ons of Pathogenic Models 1 st - Simple T-cell model (agnos.c of T-cell polarity) 2 nd - Polar T-cell model (IL-12/Th1 T-cells) 3 rd - Innate Immunity Model--Its TNF and not T-cells 4 th - Complex T-cell Model (Th1, Th17 & Th22 T-cells) 5 th - IL-23/T17 T-cell model-- Type 17 T-cells (Th17, Tc17, innate lymphocytes synthesize IL-17 under control of IL-23)

6 Psoriasis vulgaris An autoimmune skin disease associated with increased systemic inflamma.on that impacts overall health and lifespan

7 Phenotypes of psoriasis The cellular (histologic) disease defini.on The molecular defini.on based on gene expression How are these features created by immune-derived cytokines and how does targe.ng those cytokines with immune antagonists change the phenotypes?

8 Histopathology of normal appearing background skin and a psoriasis plaque (both at same magnifica.on). Unaffected Skin of Patient Psoriasis Lesion

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10 Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal an<bodies. Bos JD et al. Arch Dermatol Res. 1983;275(3): Predominance of "memory" T cells (CD4+, CDw29+) over "naive" T cells (CD4+, CD45R+) in both normal and diseased human skin. Bos JD et al Arch Dermatol Res. 1989;281(1): CD3+ T-cells in Psoriasis Uninvolved Skin Psoriasis Plaque

11 NON-LESIONAL LESIONAL S100A7 Psoriasin (S100A7) is a protein first isolated from scales of psoria.c lesions.

12 HBD2 (β-defensin) and lipocalin 2 (LCN2) are an.-microbial proteins HBD-2 NON-LESIONAL LESIONAL LCN-2

13 Myeloid (CD11c+) Dendri.c Cells in Psoriasis NON-LESIONAL PSORIASIS PLAQUE H&E CD11c

14 CD3 cell counts NL LS CD11c cell counts NL LS Langerin cell counts NL LS 8-fold average increase 7-fold average increase p < p < no significant change Concept of an inflammatory dendri.c cell. CD11c+ DCs in psoriasis lesions had different markers and different func.ons from normal skin

15 The evolving psoriasis transcriptome disease road maps based on study of skin biopsies 159 genes 800 genes 2800 genes 4175 genes 2001 n= n= n= n=90 Oestreicher et al Zhou et al Yao et al Suarez-Farinas et al

16 Fundamental Hypothesis: Psoriasis vulgaris is an immune-mediated disease caused by T-lymphocytes (T-cells) and associated cytokines.

17 Polar T-cell subsets IL-12 (TSLP, IL-33) IL-23 (IL-23) Th1 Tc1 Th2 Th17 Tc17 Th22 Tc22 IFN-γ IL-4, IL-13 IL-17 IL-22 Autoimmunity is caused by inappropriate activation of one or more polar T-cell subsets

18 Polar T-cell subsets IL-12 (TSLP, IL-33) IL-23 (IL-23) Th1 Tc1 Th2 Th17 Tc17 Th22 Tc22 IFN-γ IL-4, IL-13 IL-17 IL-22 An early hypothesis proposed Th1 T-cells caused psoriasis

19 Type 1 Devia<on in Psoriasis Psoriasis Type 1 (γ-interferon) Type 2 (Interleukin-4) 2-3 fold expansion of Type 1 T-cells J. Invest. Dermatology 113: (1999)

20 Top 50 genes: IFNγ treated KCs Symbol Description FCH FDR CXCL10 chemokine (C-X-C motif) ligand CXCL9 chemokine (C-X-C motif) ligand CXCL11 chemokine (C-X-C motif) ligand UBD ubiquitin D CXCL11 chemokine (C-X-C motif) ligand ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus C1S complement component 1, s subcomponent HLA-DRA major histocompatibility complex, class II, DR alpha HLA-DRB1 major histocompatibility complex, class II, DR beta HLA-DPA1 major histocompatibility complex, class II, DP alpha HLA-DRA major histocompatibility complex, class II, DR alpha C1R complement component 1, r subcomponent HLA-DRB5 major histocompatibility complex, class II, DR beta RARRES3 retinoic acid receptor responder (tazarotene induced) CCL2 chemokine (C-C motif) ligand RSAD2 radical S-adenosyl methionine domain containing CTSS cathepsin S ISG20 interferon stimulated exonuclease gene 20kDa HLA-DMA major histocompatibility complex, class II, DM alpha PSMB9 proteasome (prosome, macropain) subunit, beta type, 9 (larg APOL3 apolipoprotein L, GBP2 guanylate binding protein 2, interferon-inducible CD74 CD74 molecule, major histocompatibility complex, class II in HLA-DRB1 major histocompatibility complex, class II, DR beta ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus ISG20 interferon stimulated exonuclease gene 20kDa BST2 bone marrow stromal cell antigen IRF1 interferon regulatory factor CTSS cathepsin S SERPING1 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, AIM2 absent in melanoma INDO indoleamine-pyrrole 2,3 dioxygenase APOL1 apolipoprotein L, HLA-DPA1 major histocompatibility complex, class II, DP alpha GLDC glycine dehydrogenase (decarboxylating) IL32 interleukin RARRES1 retinoic acid receptor responder (tazarotene induced) SECTM1 secreted and transmembrane ETV7 ets variant gene 7 (TEL2 oncogene) APOL6 apolipoprotein L, IL15 interleukin GBP1 guanylate binding protein 1, interferon-inducible, 67kDa IFI35 interferon-induced protein HLA-DRB4 major histocompatibility complex, class II, DR beta IFIT3 interferon-induced protein with tetratricopeptide repeats XAF1 XIAP associated factor CCL8 chemokine (C-C motif) ligand CFB complement factor B CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 ( CFH complement factor H HCP5 HLA complex P

21 Cytokine-driven pathogenesis ϒ-IFN human kera.nocytes (in vitro) CXCL9 CXCL10 CXCL11 IL-8 ICAM-1 MHC-II Immune amplifica.on

22 Cytokine-driven pathogenesis ϒ-IFN human kera.nocytes (in vitro) CXCL9 CXCL10 CXCL11 IL-8 ICAM-1 MHC-II Immune amplifica.on

23 Polar T-cell subsets IL-12 (TSLP, IL-33) IL-23 (IL-23) Th1 Tc1 Th2 Th17 Tc17 Th22 Tc22 IFN-γ IL-4, IL-13 IL-17 IL-22 In 2005 the Th17 T-cell was identified as associated with CNS autoimmunity

24 γ-interferon (Th1) Experiments in mice clearly show that IL-23 drives ac.va.on & expansion of Th17 T-cells, IL-17 not Th1 T-cells. (Th17)

25 Consistent up-regula.on of p40 and p19 mrnas (IL-23 subunits) in psoriasis plaques, as detected by real-.me RT-PCR (normalized to HARP) Relative Gene Expression 10, , p40 Relative Gene Expression 10, , p19 p< uninvolved Lee et al JEM (2005) lesion 1.0 uninvolved lesion Dendri.c Cells established as major producers of IL-23 in psoriasis lesions

26 Gene.c Biomarkers of Increased Risk O Reilley Nat Rev Rheum (2011)

27 Lowes et. al. J. Invest. Dermatol (2008) Blood Th17 T-cells increased in psoriasis lesions Psoriasis Lesion Th1 Th17

28 Gene expression during cyclosporine treatment

29 T-cell produced cytokines act on kera.nocytes to induce specific gene products IL-17A IL-17F human kera.nocytes (in vitro) S 100 A7 (psoriasin) CXCL1,2,3,8 CCL20 β-defensin and other an.-microbial pep.des

30 IL-23/Th17 pathway in psoriasis DC IL-23 T17 IL-17 KC An.-microbial pep.des β-defensins Lipocalin LL-37 S100A7, S100A8 CXC chemokines CXCL 1, 2, 3, 5 neut IL-8 Th17 Tc17 Tgamma-delta 17 ILC 17 CCL20 T cell CCR6 + cells DC But does not explain epidermal hyperplasia

31 Polar T-cell subsets IL-12 (TSLP, IL-33) IL-23 (IL-23) Th1 Tc1 Th2 Th17 Tc17 Th22 Tc22 IFN-γ IL-4, IL-13 IL-17 IL-22 The Th22 T-cell subset is also activated in psoriasis and IL-22 is a keratinocyte mitogen

32 IL-22 promotes acanthosis and impairs terminal differen.a.on Full thickness skin rars (epidermis + fibroblasts/dermis) * Nograles KE et al, Bri<sh Journal of Dermatology, 2008 Confirms effect of IL-22 on acanthosis of epidermis (Sa et al J Immunology 2007) *Parakeratosis

33 Three immune axes are activated in psoriasis However IL-23/Type-17 axis drives the disease phenotype kera.nocyte NKT cell plasmacytoid Dendri.c cell TNF-α IFN-γ IFN-α macrophage IL-1β IL-6 TNF-α ac<va<on TIP-DC TNF-α IL-12 (p40/p35) IL-23 (p40/p19) Th/Tc1 Th/Tc22 Th/Tc17 IL-22 TNF-α IFN-γ kera.nocyte IL-17A/F IL-21 LESION FORMATION An.microbial pep.des IL-1β IL-6 TNF-α S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 Figure adapted from: Nestle FO, et al. N Engl J Med. 2009;361:

34 IL-17 Signaling Ligand/Receptor Combina3ons Ixekizumab Secukinumab IL-17A X IL-17A/F X IL-17F X X FN1 FN2 Brodalumab SEFIR TILL CBAD IL-17RA IL-17RC IL-17E/IL-25 IL-17RA IL-17RB/ IL-25R?? IL-17RA IL-17RD/ SEF IL-17RB/ IL-25R IL-17B IL-17RE IL-17C IL-17RD/ SEF IL-17D?? Gaffen. Nat Rev Immunol 2009;9(8):

35 Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial Kim A Papp, Cathy Reid, Peter Foley, Rod Sinclair, David H Salinger, Gary Williams, Hua Dong, James G Krueger, Chris B Russell and David A Martin Journal of Inves3ga3ve Dermatology (2012) 132, ; doi: /jid ; published online 24 May 2012 Data first presented at Society for Inves.ga.ve Dermatology in 2010

36 Double-blind, placebo controlled study with a single dose of AMG827 Placebo (n=4) 350mg SC (n=8) 700mg IV (n=8) Key inclusion criteria: Moderate to severe plaque PsO 6 mos, PASI score 10, BSA 10, eligible to receive phototherapy or systemic therapy Key exclusion criteria: Any prior use of biologics; recent use of systemic steroids or calcineurin inhibitors

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39 Russell CB, Rand H, Bigler J, Kerkof K, Timour M, Bau.sta E, Krueger JG, Salinger DH, Welcher AA, Mar.n DA. J Immunol Apr 15;192(8):

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41 IL-23/Th17 pathway in psoriasis DC IL-23 T17 IL-17 KC An.-microbial pep.des β-defensins Lipocalin LL-37 S100A7, S100A8 CXC chemokines CXCL 1, 2, 3, 5 neut IL-8 Th17 CCL20 T cell Tc17 Tgamma-delta 17 ILC 17 Role of IL-17A probed with ixekizumab CCR6 + cells DC

42 Expression of IL-17 Target Genes (RT-PCR) Lipocalin 2 Interleukin 8 β-defensin 2 CXCL1 log2(expression /harp)= mrna expression (RT-PCR) normalized to the housekeeping gene human acidic ribosomal protein gene (harp)

43 Genes Modulated by ixekizumab (FCH>6) very rapid effects and much faster response than etanercept LS= Lesional Skin Biopsies at Baseline NL= Non- Lesional Skin Biopsies at Baseline

44 Proportion of Patients with PASI 75 Propor.on of Pa.ents Dose Dose Dose Weeks Placebo SC (n=8) LY 150 mg SC (n=8)

45 High Efficacy of IL-17 antagonists in Phase 3 Studies Secukinumab (an.-il-17a) superior to ustekinumab in CLEAR study, 87% PASI75 in JUNCTURE study 2 Ixekizumab (an.-il-17a) superior to etanercept in UNCOVER study, 90% PASI75 in best performing dosing group 1 Brodalumab (an.-il-17 Receptor, A subunit) superior to ustekinumab in AMAGINE-3 study, 3 86% PASI75 in AMAGINE-2 Study, best performing dose group 4 Amgen has terminated brodalumab partnership with AstraZeneca. Brodalumab and ixekizumab are not currently licensed for therapeu.c use 1. Lilly's Ixekizumab Superior to Etanercept and Placebo in Phase 3 Psoriasis Studies press release available at: h{ps://investor.lilly.com/releasedetail.cfm? releaseid= Date accessed: May Paul C et al. J Eur Acad Dermatol Venereol [Epub ahead of print]. 3. Amgen and AstraZeneca announce posi.ve results from second pivotal Phase III study of Brodalumab in pa.ents with moderate-to-severe plaque psoriasis press release. Available at: h{p:// Amgen and AstraZeneca announce posi.ve results from third and final pivotal Phase III study of Brodalumab in pa.ents with moderate-to-severe plaque psoriasis press release. Available at:

46 Does IL-23 drive the Th17 pathway? kera.nocyte NKT cell plasmacytoid Dendri.c cell TNF-α IFN-γ IFN-α macrophage IL-1β IL-6 TNF-α ac<va<on TIP-DC TNF-α IL-12 (p40/p35) IL-23 (p40/p19) Th1 Th/Tc22 Th17 IL-22 TNF-α IFN-γ kera.nocyte STAT1 STAT3 CEBP/NFkB IL-17A/F IL-21 LESION FORMATION An.microbial pep.des IL-1β IL-6 TNF-α S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 Figure adapted from: Nestle FO, et al. N Engl J Med. 2009;361:

47 Guselkumab Adalimumab Blauvet et al. J. Am. Acad. Dermatol. 76: 405 (2017) Voyage 1 Study

48 Disease Profile Neutralized by CNTO 1959 (Guselkumab) Disease profile (lesional vs. non-lesional skin) 1224 transcripts High dose* brought the expression level back to normal at Week Treatment visit PASI 50 skin CNTO1959 High Day 2 yes NL CNTO1959 High Day 2 yes LS CNTO1959 High Day 7 yes LS CNTO1959 High Day 84 yes LS *High dose = combined 100 & 300 mg treatment groups Baseline Lesional Week 1 Lesional Week 12 Lesional Soren et al. J. Allergy Clin. Immunol. 133:1032 (2014) Baseline Non-Lesional

49 risankizumab ustekinumab Papp et al. NEJM 376:1551 (2017)

50 Krueger et al., J. Allergy Clin. Immunol. 136: 116 (2015).

51 Hawkes JE, Chan TC, Krueger JG. JACI (2017).

52 Take Home Message Psoriasis is driven by a polar T-cell (Th17/Tc17) axis, regulated by IL-23 Kera.nocytes amplify the response All therapies that improve psoriasis directly or indirectly lower expression or signaling of this immune-response axis