IL-17 and IL-23 antagonists Prof. Jonathan Barker 1
Key T cell subsets and biologic therapies in psoriasis Girolomoni G, et al. JEADV 2017 2
MoA of biologics targeting T cell pathways p35 IL-12 p40 Ustekinumab Briakinumab p40 IL-23 p19 Guselkumab Tildrakizumab Brazikumab Risankizumab Mirikizumab Infliximab Adalimumab Golimumab Certolizumab Etanercept Th1 TNFα Bimekizumab ALX-0761 RG 7624 ABT-122 COVA322 ABBV-257 IL-17F IL-17A/F Th17 Secukinumab Ixekizumab Perakizumab CNTO 6785 CJM112 BCD 085 SCH-900117 IL-17A IL-17E IL-17C IL-17B IL-17D Brodalumab?? TNFR1/TNFR2 IL-17RA/C IL-17RA/B IL-17RA/E IL-17RB/? IL-17RD/? Broad inflammatory effects Neutrophil recruitment and defence against extracellular pathogens (esp. fungi) Th2 induction Th1 inhibition Th17 inhibition Undefined pro-inflammatory effects Ann Rheum Dis 2018;77:175-187 3
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Which drug to use in which patient? Efficacy: o Rapid onset or long term control? o Concomitant psoriatic arthritis Safety: o Is TB an issue? o Does the patient have associated inflammatory bowel disease? Tolerability: o Frequency of injections Issues pertaining to co-morbidities Drug acquisition costs New mode of action eg IL-17 or specific IL-23 inhibition Takes time to accumulate patient years experience RCT not powered to detect rare but severe adverse events RCT impose rules (inclusion/exclusion criteria that may not reflect real life) Risk of Serious Adverse Events Associated With Biologic and Nonbiologic Psoriasis Systemic Therapy Patient Ineligible vs Eligible for Randomized Controlled Trials Arch Dermatol 2012;148:463 29.8% of patients receiving systemic therapy for psoriasis would not have been eligible for RCTs Age >70 years Non-plaque forms of psoriasis Infection: Hep B, Hep C, HIV Cancer: excluding NMSC Chronic renal or hepatic disease o NB: prevalence NASH in severe psoriasis Risk of SAE in ineligible group: IRR = 2.7 5
Biologic therapy for Psoriasis 2017 http://www.bad.org.uk/healthcare-professionals/clinical-standards/clinical-guidelines Recommendations cover Criteria for biologic therapy Choice of biologic therapy Strategies for treatment failure Transitioning between therapies Conception and pregnancy Cancer Infection (hep B, C, HIV, TB, vaccination) Formats Executive summary (in the BJD) Full version including detail of all systematic reviews Toolkit for implementation DOI: 10.1111/bjd.15665 6
Decision aid Questions you might want to ask Adalimumab Etanercept Infliximab Ixekizumab Secukinumab Ustekinumab No active treatment How often do I need to inject the treatment? 1 injection under the skin Every other week 1 injection under the skin Once or twice a week 1 injection in the vein Every 8 weeks 1 injection under the skin Every 2 weeks for the first 3 months, every 4 weeks thereafter 2 injections under the skin Every month 1 injection under the skin Every 12 weeks Does not apply Who gives the treatment? You may choose to have the injection given to you by a nurse in your home. Alternatively, you or your carer may learn to give the injection after training. You or your carer will learn to give the injection after training. You will need to go to hospital where the injection will be given by a healthcare professional. You or your carer will learn to give the injection after training You or your carer will learn to give the injection after training. You may choose to have the injection given to you by a nurse in your home. Alternatively, you or your carer may learn to give the injection after training. Does not apply How long has this treatment been Since 2008 Since 2004 Since 2006 Since 2016 Since 2015 Since 2009 Does not apply around for? IV On average, for every 1000 people how many become clear or nearly clear of psoriasis (PASI90) because of this treatment after 3-4 months? V In U.K. clinical practice, what is the likelihood of staying on this treatment past 1 year? VI 77-81% chance 2 67-73% chance 2 54-74% chance 2 Not known at present Not known at present 86-92% chance 2 Does not apply IV First approval of the drug for moderate to severe plaque psoriasis V The evidence is drawn from clinical trials including a mixed biologic-naïve and experienced population VI The evidence is drawn from real-world UK biologic-naïve population; it may not apply to biologic choice for subsequent lines of treatment www.bad.org.uk/healthcare-professionals/clinical-standards/clinical-guidelines 7
Decision aid Questions you might want to ask Adalimumab Etanercept Infliximab Ixekizumab Secukinumab Ustekinumab No active treatment At worst, for every 1000 people how many experience unwanted effects that are serious enough to stop the treatment after 3-4 months? V, VII At worst, for every 1000 people how many experience an infection serious enough to lead to admission into hospital because of this treatment after 3-4 months? VII Cannot be estimated What conditions would make your doctor hesitant about giving you the treatment? Moderate or severe heart failure, demyelinating disorders (e.g. multiple sclerosis) Moderate or severe heart failure, demyelinating disorders (e.g. multiple sclerosis) Moderate or severe heart failure, demyelinating disorders (e.g. multiple sclerosis) Inflammatory bowel disease (i.e. Crohn s disease or ulcerative colitis), recurrent candida infection (i.e. thrush) Inflammatory bowel disease (i.e. Crohn s disease or ulcerative colitis), recurrent candida infection (i.e. thrush) No particular condition Does not apply What is known about these medicines in conception and pregnancy? Women and men have had children on this treatment. Women and men have had children on this treatment. Women and men have had children on this treatment. During pregnancy, psoriasis may get beter, stay the same, or become worse. NCE eligibility criteria, infliximab: PASI 20, DLQl >18; other biologic therapies: PASI 10, DLQl >10. Images created by iconarray.com; Risk Science Center and Center for Bioethics and Social Sciences in Medicine, University of Michigan; accessed 21 st June 2017. www.bad.org.uk/healthcare-professionals/clinical-standards/clinical-guidelines 8
Conclusions IL-23/17 mediated mechanism are defined by scientific investigation as the critical T cell pathways involved in psoriasis pathogenesis Inhibition of these cytokines by therapeutic antibodies (biologics) are highly effective in management of moderate-severe disease A significant number of patients achieve complete clearance As they are new drugs real life data are limited Very few sequential studies have been performed so the optimal way of using biologics requires further investigation 9