clinical topic updates

Interleukin-23p19 Inhibitors: Current Perspectives

by Alice B. Gottlieb, MD, PhD

Overview

Selective inhibitors of the interleukin-23p19 (IL-23p19) subunit have emerged as highly effective therapies for patients with moderate to severe plaque psoriasis. The IL-23 inhibitors offer efficacy for plaque psoriasis that is comparable to that of the IL-17 inhibitors with less frequent maintenance dosing.

Expert Commentary

Alice B. Gottlieb, MD, PhD

Clinical Professor and Medical Director
Department of Dermatology
Mount Sinai Beth Israel
Kimberly and Eric J. Waldman Department of Dermatology
Icahn School of Medicine at Mount Sinai
New York, NY 

“The high degree of efficacy of these agents for plaque psoriasis is similar to that of the IL-17 blockers, and the safety of both drug classes is excellent.” 

Alice B. Gottlieb, MD, PhD

IL-23 has been recognized as a crucial player in the pathogenesis of autoimmune diseases in general and psoriasis in particular. At this time, the IL-23p19 blockers that are available for the treatment of plaque psoriasis include guselkumab, tildrakizumab, and risankizumab. The high degree of efficacy of these agents for plaque psoriasis is similar to that of the IL-17 blockers, and the safety of both drug classes is excellent. The IL-23p19 inhibitors work reasonably fast, and the small number of injections is a big plus. Maintenance dosing with guselkumab is every 8 weeks, while tildrakizumab and risankizumab are given every 12 weeks. 

The importance of psoriatic arthritis in dermatology has been increasingly recognized since the advent of the tumor necrosis factor (TNF) blockers. An interesting but still unanswered question is whether treating psoriasis early on with effective systemic therapy will prevent the subsequent development of psoriatic arthritis in those who may be at risk. We need to improve our ability to identify those patients who are at increased risk of developing arthritis, and this continues to be an active area of research.

Inhibitors of IL-17A or TNF are efficacious in the treatment of cutaneous, peripheral, and axial inflammation. Direct IL-23 inhibition also improves outcomes in the skin and peripheral joints. However, Baeten et al found that blocking IL-23 with risankizumab was not effective in treating active ankylosing spondylitis. The specific molecular and cellular mechanisms that may underlie these observations remain poorly defined.

Favorable data with tildrakizumab were recently reported in a phase 2 trial in patients with active psoriatic arthritis, and we will be interested to see the phase 3 data. Guselkumab recently became the first IL-23 inhibitor approved for the treatment of psoriatic arthritis based on 2 phase 3 trials. TNF inhibitor agents are effective and safe for most people in the context of psoriatic arthritis, as are some IL-17 inhibitor agents (eg, secukinumab and ixekizumab) that have also been shown to prevent radiographic progression.

Another interesting aspect of the clinical development of the IL-23 blockers is that they are being investigated in the treatment of inflammatory bowel disease (IBD). This would be a significant advancement if IL-23 blockers were to become a US Food and Drug Administration–approved treatment option for IBD. Psoriasis and IBD may be present in the same patient, and one would not use an IL-17 blocker in a patient with psoriasis and a history or family history of IBD. In a similar vein, one would not use a TNF inhibitor in someone with a history or family history of demyelinating disease.

References

Baeten D, Østergaard M, Wei JC-C, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum Dis. 2018;77(9):1295-1302. doi:10.1136/annrheumdis-2018-213328

Deodhar A, Helliwell PS, Boehncke W-H, et al; DISCOVER-1 Study Group. Guselkumab in patients with active psoriatic arthritis who were biologic-naive or had previously received TNFα inhibitor treatment (DISCOVER-1): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10230):1115-1125. doi:10.1016/S0140-6736(20)30265-8

Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392(10148):650-661. doi:10.1016/S0140-6736(18)31713-6

Mease P, Husni ME, Kafka S, et al. Inhibition of radiographic progression across levels of composite index-defined disease activity in patients with active psoriatic arthritis treated with intravenous golimumab: results from a phase-3, double-blind, placebo-controlled trial. Arthritis Res Ther. 2020;22(1):43. doi:10.1186/s13075-020-2126-1

Mease PJ, Chohan S, Garcia Fructuoso FJ, et al. Efficacy and safety of tildrakizumab, a high-affinity anti-interleukin-23p19 monoclonal antibody, in patients with active psoriatic arthritis in a randomised, double-blind, placebo-controlled, multiple-dose, phase 2b study [abstract OP0230]. Abstract presented at: EULAR 2020; June 5, 2020. Accessed October 6, 2020. scientific.sparx-ip.net/archiveeular/?searchfor=Mease&view=4&c=a&item=2020OP0230

Mease PJ, Rahman P, Gottlieb AB, et al; DISCOVER-2 Study Group. Guselkumab in biologic-naive patients with active psoriatic arthritis (DISCOVER-2): a double-blind, randomised, placebo-controlled phase 3 trial [published correction appears in Lancet2020;395(10230):1114]. Lancet. 2020;395(10230):1126-1136. doi:10.1016/S0140-6736(20)30263-4

Reich K, Armstrong AW, Langley RG, et al. Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial. Lancet. 2019;394(10201):831-839. doi:10.1016/S0140-6736(19)31773-8

Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials [published correction appears in Lancet. 2017;390(10091):230]. Lancet. 2017;390(10091):276-288. doi:10.1016/S0140-6736(17)31279-5

Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol. 2019;15(3):153-166. doi:10.1038/s41584-019-0175-0

Sun R, Hedl M, Abraham C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut. 2020;69(2):264-273. doi:10.1136/gutjnl-2018-316830

Wilson FC, Icen M, Crowson CS, McEvoy MT, Gabriel SE, Kremers HM. Incidence and clinical predictors of psoriatic arthritis in patients with psoriasis: a population-based study [published correction appears in Arthritis Rheum. 2010;62(4):574]. Arthritis Rheum. 2009;61(2):233-239. doi:10.1002/art.24172

Zhang M, Brenneman SK, Carter CT, et al. Patient-reported treatment satisfaction and choice of dosing frequency with biologic treatment for moderate to severe plaque psoriasis. Patient Prefer Adherence. 2015;9:777-784. doi:10.2147/PPA.S85773

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