BIOLOGICS: A NEW HOPE. Alastair Denniston, University Hospitals Birmingham NHSFT & University of Birmingham

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1 BIOLOGICS: A NEW HOPE Alastair Denniston, University Hospitals Birmingham NHSFT & University of Birmingham

2 And beyond... Biologics in Uvei<s Trials

3 Biologics and Beyond The tools The targets The treatments

4 Biologics and Beyond The tools The targets The treatments

5 What is a biologic? A therapeu<c medical product produced by biological processes: 1) Therapeu<cs from recombinant DNA 2) Therapeu<cs from living systems 3) Vaccines 4) Gene therapies

6 What is a biologic? A therapeu<c medical product produced by biological processes: 1) Therapeu3cs from recombinant DNA a. Monoclonal an<bodies to known targets eg infliximab vs TNFα, rituximab vs CD20 b. Fusion proteins of a known receptor asached to an immunoglobulin segment eg etanercept = TNFR/IgG1(Fc) c. Signalling molecules replicated by biosynthesis eg interferons

7 All in the name The nomenclature has some degree of logic: Prefix: can be anything but should ensure that the whole name is dis<nct Infix rela3ng to target: e.g. - (l)im- for immune system, - tu- for miscellaneous tumour Infix rela3ng to source: e.g. - u- for human, - o- for mouse, - xi- for chimeric, - zu- for humanized Suffix: the class of medicine i.e. - mab for all monoclonal an<bodies

8 All in the name The nomenclature has some degree of logic: Ada- lim- u- mab is a fully human monoclonal an<body with an immune system target (TNFα) Ri- tu- xi- mab is a chimeric monoclonal an<body with a tumour target (originally developed for use against B cell non- Hodgkin lymphoma)

9 Biologics in the 21 st Century The tools The targets The treatments

10 The cells Th1 Macrophage Th2 B cell Plasma cell MHC : TCR Dendri<c cell Th17 Stromal <ssue itreg

11 The signals Th1 IFNγ IL- 1 IL- 6 IL- 12 TNFα Macrophage IL- 12 IL- 1 IL- 6 TNFα MHC : TCR IL- 4 Th2 IL- 4 IL- 5 IL- 13 B cell Plasma cell Dendri<c cell IL- 6 TGFβ IL- 23 Th17 IL- 17 IL- 21 Stromal <ssue TGFβ itreg TGFβ IL- 10 IL- 1 IL- 6 TNFα

12 Targeting Cells and Signals 1. Cells a. Deplete Eg Alemtuzumab (an<- CD52), rituximab (an<- CD20) b. Inhibit func<on Eg Efalizumab (an<- CD11a) c. Modulate func<on Eg Abatacept (CTLA- 4/Ig fusion protein) 2. Signalling molecules (cytokines) a. Inhibit func<on Eg Infliximab, adalimumab (an<- TNFα) b. U<lise func<on Eg Interferons

13 Biologics in the 21 st Century The tools The targets The treatments

14 Anti-TNF therapies Role of TNF Th1 TNFα Macrophage TNFα Th2 B cell Plasma cell MHC : TCR Dendri<c cell Th17 Stromal <ssue TNFα

15 Anti-TNF therapies Membrane- bound TNFα Soluble TNFα TNFα Infliximab Adalimumab TNFα Macrophage Etanercept TNFα

16 Anti-TNF therapies Etanercept Chimeric fusion protein TNFR/IgG1(Fc) 25mg sc 2-3x/wk Track- record: Extensive Level 1 evidence for benefit in rheumatoid arthri<s, JIA, psoriasis, ankylosing spondyli<s Limited Level 1 evidence for benefit in uvei<s Appears less effec<ve than other an<- TNF Rx Side- effects: TB reac<va<on, opportunis<c infec<ons, increased risk of malignancy reported

17 Anti-TNF therapies Etanercept in Uvei<s LEVEL 1 Mixed uvei3s JIA Ocular sarcoid Foster 2003; n=20; no beser than placebo in tapering MTX in controlled disease Smith JA 2005; n = 12; No beser than placebo Baughman 2005; n=18 No beser than placebo LEVEL 2 Mixed uvei<s Galor 2006; n=22 Less effec<ve than infliximab LEVEL 3 Possible pro- uvei<c role eg Kakkassery et al 2010

18 Anti-TNF therapies Infliximab Chimeric an<- TNFα mab 5-10mg/kg infusion/mth Track- record: Extensive Level 1 evidence for benefit in rheumatoid arthri<s, Crohn s disease, psoriasis, ulcera<ve coli<s, ankylosing spondyli<s Level 2 evidence for benefit in uvei<s Side- effects: TB reac<va<on, opportunis<c infec<ons, increased risk of malignancy reported

19 Anti-TNF therapies Infliximab in Uvei<s LEVEL 1 NONE LEVEL 2 Uvei3s 2 to Behcet s Yamada 2010; n = 17 vs 20 Reduced flares by 87% (Infliximab ) vs 64% (ciclosporin) at 6mths follow- up LEVEL 3 Uvei<s 2 to Behcet s Mixed uvei<s Uvei<s 2 to JIA Birdshot Okada; n=63 Reduced flares from 2.66 to 0.44 per 6mths Suhler 2009: n = 32 ; 77% success on composite score 3 drug induced lupus, 2 malignancies Foeldvari 2007; n=47 70% success on composite score Artonsombudh 2013; n=22; 89% control of inflamma<on at 1yr

20 Anti-TNF therapies Adalimumab Humanised an<- TNFα mab Fortnightly sc Track- record: Extensive Level 1 evidence for benefit in rheumatoid arthri<s, Crohn s disease, psoriasis, ulcera<ve coli<s, ankylosing spondyli<s Level 2 evidence for benefit in uvei<s Side- effects: TB reac<va<on, opportunis<c infec<ons, increased risk of malignancy reported, progression of MS

21 Anti-TNF therapies Adalimumab in Uvei<s LEVEL 1 LEVEL 2 LEVEL 3 Ank Spond associated AAU Uvei<s in JIA/other childhood uvei<s Uvei<s in JIA Mixed uvei<s Behcet s VKH Uvei<s in JIA Gao 2012; n=3022; 3.4 (adalimumab) vs 5.7 (etanercept) flares/100 person- years Simonini 2011: n = 16 vs 17 Remission in 60% (adalimumab) vs 20% (infliximab) at 40mths Zannin 2013; n = 48 vs 43 Remission in 67% (adalimumab) vs 43% (infliximab) at 12mths Suhler 2013; n=31; 68% success Murray 2007: n=1; success Perra 2012; n=8; 100% success Bawazeer 2010: n=11; 91% success Dobner 2013; n =60; 82% success

22 Anti-TNF therapies Adalimumab in Uvei<s LEVEL 1 Posterior segment uvei<s - Ac<ve - Quiescent VISUAL 1 Recrui5ng VISUAL 2 - Recrui5ng

23 Anti-TNF therapies Golimumab in Uvei<s Humanised an<- TNFα mab Monthly sc LEVEL 3 Behcet s Mixed (JIA (13), HLAB27 (4)) JIA Mixed (JIA (1), Re<nal vasculi<s (1)) Mesquida 2013; n =1; success in pt refractory to other an<- TNF Miserocchi E 2013; n = 17; success in 14/17 William M 2012; n = 3; par<al/complete success in 3/3 Cordero- Coma 2011; n= 2;

24 IL-2 blockade (Daclizumab) Role of IL- 2 Th1 Macrophage Th2 B cell Plasma cell IL- 2 Dendri<c cell Th17 Stromal <ssue TNFα

25 Anti-IL-2 therapies Daclizumab Humanised an<- CD25 mab IV and SC prepara<ons Track- record: Extensive Level 1 evidence in solid organ transplanta<on Side- effects: opportunis<c infec<ons, gastrointes<nal side- effects

26 Anti-IL-2 therapies Daclizumab in Uvei<s LEVEL 1 NONE LEVEL 2 NONE LEVEL 3 Mixed uvei<s Birdshot Uvei<s 2 to JIA/other childhood uvei<s NussenblaS 2005: n=10 80% success Sobrin 2008; n=8 100% success Gallagher 2007: n=5 80% success WITHDRAWN FROM BOTH EU AND US MARKETS

27 Anti-IL1β therapy Gevokizumab Humanised an<- IL1β IV/ SC Track- record: Level 1 evidence in type II diabetes (1 study) Side- effects: Uncertain In uvei<s: LEVEL 1 LEVEL 3 Mixed Uvei<s Uvei<s 2 to Behcet s disease Uvei<s 2 to Behcet s disease EYEGUARD- A,C - Recrui5ng EYEGUARD- B - Recrui5ng Gul 2012: n=7 100% success in treatment resistant pa<ents

28 Cell-targeted therapies Th1 Macrophage CD80/86 CTLA- 4 Th2 B cell CD20 Plasma cell Dendri<c cell Th17 Stromal <ssue TNFα

29 Anti-B cell therapies Rituximab Chimeric an<- CD20 mab IV infusion at 375mg/m 2 Track- record: Extensive Level 1 evidence in RA, ANCA- associated vasculi<s, (B cell lymphoma) Side- effects: infusion related, febrile symptoms, infec<ons, progressive mul<focal leukoencephalopathy

30 Anti-B cell therapies Rituximab In uvei<s: LEVEL 2 Uvei<s 2 to Behcet s Davatchi F 2010; n = 10 rituximab vs 10 standard Rx (cyclophos/aza/pred); significant improvement in TADAI LEVEL 3 Uvei<s 2 to JIA Uvei<s 2 to Birdshot Heiligenhaus 2011: n=10 70% success at 6mths Miserocchi 2011; n=8; 88% remission at 6mths Tomkins- Netzer O; n = 1; success

31 Anti-CD52 therapy Alemtuzumab Humanised an<- CD52 mab IV infusion Track- record: Level 1 evidence in solid organ transplanta<on, CLL, MS Side- effects: In uvei<s: LEVEL 3 lymphopenia, secondary autoimmunity (eg Grave s disease, ITP) Mixed ocular inflammatory disease Behcet s disease Dick 2000: n=10 80% success Lockwood 2003: n=18 72% success at 6mths

32 Interferons Interferon- α Biosynthesised human interferon 3-12 x10 6 units/d sc Track- record: Level 1 evidence in Behçet s disease Alpsoy 2002 (n=50) In uvei<s Level 2 evidence in uvei<s associated with Behçet s disease, some Level 3 evidence for other uvei<s condi<ons Side- effects: flu- like symptoms, depression, cytopenia, liver func<on abnormali<es

33 Interferons Interferon- α in Uvei<s LEVEL 3 Uvei<s 2 to Behcet s Pan/posterior Uvei<s Pan/posterior Uvei<s Serpiginous Uvei<c CMO Interferon- β in Uvei<s Deuter 2010: n=53 89% remission Plskova 2007: n=12 83% success ; 50% depression Bodaghi 2007: n=45 83% success in Behcet s; 59% in rest Sobaci 2005: n=5 50% part success Deuter 2006:n=8 87% resolu<on of CMO LEVEL 1 Intermediate uvei<s with CMO Mackensen 2013; n=9 vs 10MTX 100% success vs 25% success LEVEL 3 Uvei<s 2 to MS Becker 2005: n= % success

34 Antibody-based therapy Intravenous immunoglobulin Pooled human immunoglobulin 1.6g/kg IV infusion/mth Track- record: Level 1 evidence in CLL, Bone Marrow Transplanta<on, ITP In uvei<s limited Level 3 evidence Side- effects: blood- borne infec<ons, thromboembolic events LEVEL 3 Birdshot Posterior/panuvei<s LeHoang 2000: n=18 54% success Rosenbaum 1999: n=10 50% success

35 And beyond... Block T cell migra<on Fingolimod (S1P receptor blocker) Natalizumab (an<- α4 integrin) Block macrophage ac<va<on C5 inhibitors CD200 receptor agonists IL- 23 and IL- 17 Ustekinumab (an<- p40) Secukinumab (an<- IL17) Autologous regulatory T cells Selec<ve glucocor<coid receptor agonists

36 In the 21 st Century... Biologics and novel targeted immunological therapies represent a major step forward in targeted therapy Role in personalised medicine Earlier place in treatment Cost issues

37 Further Reading Barry Interferon- α RJ, Nguyen in QD, Uvei<s Lee RW, Murray PI, Denniston AK Pharmacotherapy for uvei3s: current management and emerging therapy. Clinical Ophthalmology 2014 (In Press) Interferon- β in Uvei<s

New Drugs for Uveitis. Medical Eye Unit St Thomas Hospital

New Drugs for Uveitis. Medical Eye Unit St Thomas Hospital New Drugs for Uveitis Miles Stanford Medical Eye Unit St Thomas Hospital x Epithelium x x Antigen Y Y Y Y IgG m cd4 IL-2 Y m + IL-12 Cytotoxic T B pmn Ig s PG s. LTB4 O - IL-6 TNFα IFNγγ IL-2 Th1 IL-10