BIOLOGICS: A NEW HOPE Alastair Denniston, University Hospitals Birmingham NHSFT & University of Birmingham
And beyond... Biologics in Uvei<s Trials
Biologics and Beyond The tools The targets The treatments
Biologics and Beyond The tools The targets The treatments
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
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
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
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)
Biologics in the 21 st Century The tools The targets The treatments
The cells Th1 Macrophage Th2 B cell Plasma cell MHC : TCR Dendri<c cell Th17 Stromal <ssue itreg
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
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
Biologics in the 21 st Century The tools The targets The treatments
Anti-TNF therapies Role of TNF Th1 TNFα Macrophage TNFα Th2 B cell Plasma cell MHC : TCR Dendri<c cell Th17 Stromal <ssue TNFα
Anti-TNF therapies Membrane- bound TNFα Soluble TNFα TNFα Infliximab Adalimumab TNFα Macrophage Etanercept TNFα
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
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
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
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
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
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
Anti-TNF therapies Adalimumab in Uvei<s LEVEL 1 Posterior segment uvei<s - Ac<ve - Quiescent VISUAL 1 Recrui5ng VISUAL 2 - Recrui5ng
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;
IL-2 blockade (Daclizumab) Role of IL- 2 Th1 Macrophage Th2 B cell Plasma cell IL- 2 Dendri<c cell Th17 Stromal <ssue TNFα
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
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
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
Cell-targeted therapies Th1 Macrophage CD80/86 CTLA- 4 Th2 B cell CD20 Plasma cell Dendri<c cell Th17 Stromal <ssue TNFα
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
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
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
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
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=13 65-100% success
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
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
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
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