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Why Did IL-23P19 Inhibition Fail in AS: a Tale of Tissues, Trials Or Translation?

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Why Did IL-23P19 Inhibition Fail in AS: a Tale of Tissues, Trials Or Translation? View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Enlighten Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-213654 on 8 October 2018. Downloaded from selected based on data from a phase I study Why did IL-23p19 inhibition fail in AS: a in psoriasis and were shown to have supe- rior efficacy to the p40 IL-23 inhibitor tale of tissues, trials or translation? ustekinumab in a subsequent phase II trial in psoriasis.5 However, the current study Stefan Siebert, Neal L Millar, Iain B McInnes of risankizumab in patients with active AS failed to meet the primary endpoint (ASAS40 at week 12) and demonstrated no convincing improvements in clinical Clinical trials investigating biologic this suggestive preclinical and human data or MRI outcomes compared with placebo, immune targeting therapeutics should resource. despite a dose-dependent reduction in C deliver insight regardless of direction of In Annals of the Rheumatic Diseases, reactive protein with risankizumab. the primary clinical outcome. Given the Baeten and colleagues present a phase II While these results may initially appear remarkable specificity of the ‘molecular clinical trial evaluating risankizumab, a surprising in light of the efficacy of IL-17A scalpels’ now consequent upon the phar- humanised monoclonal antibody targeting inhibition in AS, the study by Baeten et al macologic biologic revolution, it is imper- the p19 subunit of IL-23, in patients should be more wisely considered in the ative to learn lessons, particularly from with active AS.13 The authors and editors wider context of increasingly tissue-dis- those studies whose outcomes challenge should be congratulated for bringing these crete results for IL-23/IL-17 inhibition pathogenetic wisdom. In this context, data into the public domain to advance across the SpA spectrum (figure 1). In progress in understanding and treatment our understanding of underlying disease cutaneous psoriasis, the dominant role of of the spondyloarthritides (SpA) and pathogenesis. The trial evaluated three the IL-23/IL-17 pathway is firmly estab- related extra-articular manifestations, doses of risankizumab compared with lished and has led to impressive results especially psoriasis and inflammatory placebo in biologic-naive patients with with an increasing array of inhibitors of bowel disease (IBD), has been remarkable active AS. Risankizumab doses were these cytokines reaching the clinic. In PsA, in the last decade. This group of pheno- while IL-17A and IL-23 (both p40 and typically related, but still rather heteroge- p19) inhibition has demonstrated effi- neous conditions share common genetic cacy for synovial and entheseal disease, and pathogenetic features, leading to the the results are more modest and have not notion that common clinical responses met the high hurdles seen in cutaneous across the SpA spectrum should arise from psoriasis. A study using paired biopsies of specific immune-targeted interventions. skin and synovium in patients with PsA This notion may shortly be disabused. reported a dominant IL-17 gene signature Whereas initial therapeutic advances in lesional skin compared with a stronger in SpA comprised adoption of tumour TNF signature in synovium14 perhaps necrosis factor (TNF) inhibitors from rheu- suggesting that the clinical trial data may matoid arthritis, major recent therapeutic have pathogenetic correlates. In Crohn’s breakthroughs followed identification disease, IL-23 inhibition with p40 (usteki- of a substantial role for the IL-23/IL-17 numab) and p19 (risankizumab) inhibitors pathway in pathogenesis. These studies has demonstrated efficacy in phase II/III integrated insights from a composite studies.15 16 In contrast, a phase II study http://ard.bmj.com/ of genome-wide association studies of IL-17A inhibition with secukinumab (GWASs), postfunctional genomic studies, did not meet its primary outcome and a tissue analyses and a variety of preclinical phase II study of brodalumab, an IL-17RA models. Advances have been most marked inhibitor, was prematurely stopped, with in psoriasis with ‘PASI100’ response rates numerical worsening of Crohn’s disease in of around 50%–70% following IL-17A the treatment groups for both studies.17 18 on 24 July 2019 by guest. Protected copyright. or IL-23p19 inhibition.1–5 Subsequently, Therefore, while preclinical data suggested IL-12/23p40, IL-23p19 and IL-17A inhib- a role for both IL-23 and IL-17A in the itors demonstrated efficacy in psoriatic pathogenesis of Crohn’s disease, inhibi- arthritis (PsA), although this has been tion of these cytokines led to divergent somewhat less penetrant in terms of Figure 1 Proposed notional emerging tissue results in clinical trials. Indeed, it has high-hurdle responses.6–11 The IL-17A cytokine hierarchy based on current clinical been suggested subsequently that IL-17A inhibitor, secukinumab, has recently also trial data. There is now increasing evidence may have pathogenic and protective been shown to be efficacious in patients suggesting that different cytokines may enjoy roles in the gut, with IL-23-independent with active ankylosing spondylitis (AS).12 distinct hierarchical roles in tissues across IL-17A production required for regula- Studies of IL-23 inhibition for the treat- the spondyloarthritis spectrum. This figure tion of intestinal epithelial permeability ment of AS were commenced based on highlights those pathways with demonstrable via the tight junction protein occludin.19 effects in each discrete tissues against those More recently, the IL-17F pathway has in which clinical responses were not observed. also emerged as having distinct mucosal Institute of Infection Immunity and Inflammation, 20 University of Glasgow, Glasgow, UK In the absence of formal head-to-head studies, biologic features. Interestingly, AS has these comparators should be taken as potential a strong association with IBD, with 15% Correspondence to Professor Iain B McInnes, of patients developing overt IBD and up Institute of Infection Immunity and Inflammation, rather than proven. Future analyses are now University of Glasgow, Glasgow G128QQ, UK; required to ascribe formal within-tissue to 60% exhibiting evidence of underlying iain. mcinnes@ glasgow. ac. uk hierarchies. subclinical microscopic colitis, which has Siebert S, et al. Ann Rheum Dis August 2019 Vol 78 No 8 1015 Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-213654 on 8 October 2018. Downloaded from not be readily ignored. The phase III trials in AS and non-radiographic axSpA of the IL-12/IL-23 inhibitor ustekinumab were recently terminated for not meeting key efficacy endpoints ( ClinicalTrials.gov NCT02438787 and NCT02407223), despite a small open-label study suggesting efficacy in 20 patients with AS.23 Taken together, these data suggest that, in contrast to IL-17A blockade, IL-23 inhi- bition is not an effective strategy for the treatment of AS, which raises the critical question—why? The preclinical evidence supporting IL-23p19 blockade in AS was robust per current standards of ‘a priori’ proof-of- concept (POC). As noted above, GWASs clearly implicate the IL-23R pathway in disease risk and progression. The use of minicircle DNA technology to express IL-23 in the hepatocytes of B10.RIII mice resulted in a destructive polyarthritis that was found to be independent of CD4+ T cells24 while a further animal study25 using similar technology revealed that systemic expression of IL‐23 in normal mice was sufficient to induce the major features of SpA (enthesitis, sacroiliitis and aortic root inflammation), putatively through activation of a novel population of innate CD3+, CD4−CD8− and retinoic acid receptor–related orphan nuclear receptor γt (RORγt)–positive T cells located in the entheses of these mice. While the precise source of IL-23 was not identi- fied, a further study suggested that these cells were tissue-resident Vγ6+γδ T cells26 promoting bone growth through IL-1727 and were therefore a putative patho- genic cell population linking IL-23-in- http://ard.bmj.com/ Figure 2 Potential cytokine pathways driving IL-17 responses in spondyloarthritis. duced inflammation to bone growth in the enthesis. Follow-on human studies revealed the number of γδ T cells that been proposed to contribute to the patho- IL-23 in AS rather than eliciting issues produce IL-17 and express IL-23R was genesis of AS.21 22 In light of the data from concerning study design or outcome selec- elevated in peripheral blood in people the Crohn’s disease trial programme, one tion. Baseline characteristics of this study with AS.28 Interestingly, only one study29 on 24 July 2019 by guest. Protected copyright. might even have anticipated that IL-23 population do not differ significantly from has confirmed the presence of CD4−CD8− inhibition would be more effective than those in previous studies of TNF or IL-17A T cells in human entheseal digests. Further IL-17 inhibition in AS due to underlying inhibitors in active AS. While the primary examination of T-cell subsets indicated IBD or subclinical colitis. efficacy outcome includes a significant that a high proportion of these cells were Taken together, clinical trial data have subjective component, lack of efficacy likely γ/δ T cells, but no functional anal- fundamentally challenged the notion that was also observed for most secondary ysis of these human subsets was under- the pathogenic pathways driving disease in endpoints, including MRI imaging and taken. Human tissue analysis30 revealed the tissues impacted in the SpA spectrum biomarkers of bone remodelling. The a significantly higher incidence of IL-23+ are truly common. We propose that each authors eloquently consider issues relating cells in patients with AS with the majority component tissue will comprise a specific to risankizumab dose and pharmacoki- of IL-17-producing cells comprising immunologic pathology programme that netics, suggesting that these are unlikely to myeloperoxidase-positive and CD15-posi- reflects its evolutionary imperative for account for the lack of observed efficacy.
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