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Guselkumab Induces Robust Reduction in Acute Phase Proteins and Type 17 Effector Cytokines in Active Psoriatic Arthritis: Results from Phase 3 Trials

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Guselkumab Induces Robust Reduction in Acute Phase Proteins and Type 17 Effector Cytokines in Active Psoriatic Arthritis: Results from Phase 3 Trials Psoriatic arthritis RMD Open: first published as 10.1136/rmdopen-2021-001679 on 19 May 2021. Downloaded from ORIGINAL RESEARCH Guselkumab induces robust reduction in acute phase proteins and type 17 effector cytokines in active psoriatic arthritis: results from phase 3 trials Kristen Sweet ,1 Qingxuan Song,1 Matthew J Loza,1 Iain B McInnes ,2 Keying Ma,1 Karen Leander,1 Vani Lakshminarayanan,1 Carol Franks,1 Philip Cooper,1 Stefan Siebert 2 To cite: Sweet K, Song Q, ABSTRACT Loza MJ, et al. Guselkumab Objective To investigate serum protein expression in Key messages induces robust reduction in participants with psoriatic arthritis (PsA) and changes after acute phase proteins and type guselkumab treatment. What is already known about this subject? 17 effector cytokines in active Methods Participants with PsA were treated with ► Psoriatic arthritis (PsA) is a heterogeneous chronic psoriatic arthritis: results from inflammatory disease that can be treated with bio- phase 3 trials. RMD Open guselkumab or placebo in the DISCOVER-1 and DISCOVER-2 studies. Serum levels of acute phase logical therapies, however, a better understanding of 2021;7:e001679. doi:10.1136/ the interleukin (IL)-23/T-helper cell 17 (Th17) path- rmdopen-2021-001679 reactants C reactive protein (CRP) and serum amyloid A (SAA) and inflammatory cytokines/chemokines were way in response to therapies can help identify which therapies may be the most effective. ► Additional online measured at weeks 0, 4 and 24 in 300 study participants supplemental material is and 34 healthy controls (HCs). The PSUMMIT studies What does this study add? published online only. To view, measured serum interleukin (IL)- 17A, IL- 17F and CRP ► Inhibition of IL-23 p19 with guselkumab led to a please visit the journal online after ustekinumab treatment and levels with ustekinumab high reduction of Th17 effector cytokine levels to the (http:// dx. doi. org/ 10. 1136/ versus guselkumab treatment were compared. range seen in healthy controls in PsA patients and rmdopen- 2021- 001679). Results Baseline serum levels of CRP, SAA, IL-6, IL-17A greater than the reduction seen with IL-12/IL-23 p40 http://rmdopen.bmj.com/ and IL- 17F were elevated in participants with active PsA inhibition with ustekinumab. vs HCs (p<0.05, geometric mean (GM) ≥40% higher). Received 26 March 2021 ► While IL- 17A and IL-17F levels correlated with dis- Baseline T-helper cell 17 (Th17) effector cytokines were Revised 20 April 2021 ease activity and response to therapy in cutaneous significantly associated with baseline psoriasis but not Accepted 20 April 2021 psoriasis in PsA, these levels were not associated joint disease activity. Compared with placebo, guselkumab with disease activity or response to therapy in the treatment resulted in decreases in serum CRP, SAA, IL-6, joints in PsA, suggesting that local and/or other sys- IL- 17A, IL- 17F and IL-22 as early as week 4 and continued temic factors also play a role in the musculoskeletal to decrease through week 24 (p<0.05, GM decrease from disease. baseline ≥33%). At week 24, IL- 17A and IL- 17F levels on September 26, 2021 by guest. Protected copyright. were not significantly different from HCs, suggesting How might this impact on clinical practice or normalisation of peripheral IL-23/Th17 axis effector further developments? cytokines postguselkumab treatment. Reductions in IL- ► The presence of residual joint disease in the face 17A/IL- 17F levels were greater in guselkumab- treated of apparent ‘normalisation’ of serum IL-17A and versus ustekinumab-trea ted participants, whereas effects IL- 17F levels with guselkumab treatment indicates © Author(s) (or their on CRP levels were similar. that further work is required to better elucidate the employer(s)) 2021. Re- use Conclusion Guselkumab treatment reduced serum protein kinetics and underlying biology of PsA joint disease permitted under CC BY- NC. No levels of acute phase and Th17 effector cytokines and commercial re- use. See rights to understand the additional factors that need to be achieved comparable levels to those in HCs. In participants and permissions. Published addressed to improve outcomes in the musculoskel- with PsA, reductions of IL-17A and IL-17F were of greater by BMJ. etal domain in PsA beyond those seen with current 1 magnitude after treatment with guselkumab than with Immunology Therapeutic biological therapies. Area, Janssen Research and ustekinumab. Development LLC, Spring House, Pennsylvania, USA 2Institute of Infection, Immunity in the management of PsA with the develop- and Inflammation, University of INTRODUCTION ment of biological drugs. Although the initial Glasgow, Glasgow, UK Psoriatic arthritis (PsA) is a heterogeneous biological agents target tumour necrosis Correspondence to chronic inflammatory rheumatic condition factor (TNF), the identification of the key Dr Kristen Sweet; that affects 14%–23% of adults with psori- role of the interleukin (IL)-23/T-helper cell ksweet1@ its. jnj. com asis.1 There have been significant advances 17 (Th17) pathway in psoriatic disease has Sweet K, et al. RMD Open 2021;7:e001679. doi:10.1136/rmdopen-2021-001679 1 RMD Open RMD Open: first published as 10.1136/rmdopen-2021-001679 on 19 May 2021. Downloaded from led to the successful development of several efficacious results have been reported elsewhere.8 9 Briefly, the study agents targeting various proteins in this pathway. Clinical population included participants with active PsA who trials using targeted biological therapies offer an oppor- have had inadequate response to standard therapies. tunity to identify potential biomarkers and to understand Approximately 30% of the DISCOVER-1 study popula- disease processes.2 tion could have been previously exposed to up to two Agents targeting the IL-23/Th17 pathway have led to TNF inhibitors, whereas the DISCOVER-2 population was high hurdle responses in psoriasis, in excess of those seen restricted to biological- naïve participants. Participants in with TNF inhibitors,3 4 confirming the key pathogenetic both studies were randomly assigned 1:1:1 to treatment role of IL-23/Th17 in the skin in psoriasis. By contrast, in with subcutaneous guselkumab 100 mg every 4 weeks PsA, there are limited head-to- head studies5 6 and effects (q4w) from week 0 through week 48; guselkumab 100 mg of treatment on joints appear more heterogeneous than at weeks 0 and 4, then every 8 weeks (q8w) through week in the skin.7 Furthermore, in clinical practice, treatment 48; or placebo. The primary endpoint of both studies was remains largely empirical, with many patients with PsA the proportion of participants achieving an American exhibiting no or only partial response to available ther- College of Rheumatology 20% (ACR20) response at week apies, while others exhibit dichotomous responses in 24. Participants who met one of the treatment failure the skin and musculoskeletal system. Therefore, there criteria prior to week 24 were considered as ACR20 non- remains a significant unmet need in the management of responders at week 24, regardless of the observed ACR20 the musculoskeletal component of PsA and for a better response status. understanding of the IL-23/Th17 pathway in response to therapies. Participants and biomarker analysis Currently available IL-23/Th17 therapies for psoriatic In DISCOVER-1 and DISCOVER-2, approximately 100 disease either target the effector cytokines IL- 17A and/or participants per treatment arm (n=300 participants total) IL- 17F or the upstream cytokine IL-23. IL-23 is a heterod- were randomly selected for the biomarker studies. Serum imer formed by p19 and p40 subunits, with the latter samples were collected for the analysis of potential shared with IL-12. Targeting either of these subunits biomarkers at weeks 0 (pretreatment), 4, and 24. Blood has demonstrated efficacy in both psoriasis and PsA. We samples were collected in standard serum separation have previously reported on IL- 17A and IL- 17F changes tubes as per standard protocol, prepared into aliquots, in PsA in response to the IL-12/IL-23 p40 inhibitor frozen at ≤−20°C, and then shipped frozen on dry ice to ustekinumab in the PSUMMIT phase III programme.2 Covance Central Laboratory Services. Samples were later Here, we extend this work to IL-23 p19 inhibition and sent to Janssen R&D, Spring House, PA Biobank prior to a wider range of biomarkers, using data from the phase bioanalysis. III clinical studies of guselkumab, a fully human immu- Healthy control samples (n=34) were procured inde- http://rmdopen.bmj.com/ noglobulin G1 lambda IL-23 p19 monoclonal antibody. pendently of the DISCOVER clinical studies (BioIVT, The DISCOVER-1 and DISCOVER-2 multicenter, double- Westbury, NY; Biological Specialty, Colmar, Pennsylvania, blind, placebo- controlled studies demonstrated the USA). Subjects were selected to reflect the demographics efficacy of guselkumab for the cutaneous and musculo- of the clinical study participants (matched for age, sex, skeletal domains of PsA.8 9 race/ethnicity). Subjects were considered ‘healthy’ Serum samples were collected as an opportunity to based on the criteria described in the US Food and Drug identify the potential biomarkers to better understand Administration Code of Federal Regulations Title 21, the underlying inflammatory processes that drive PsA. Part 630.10 Briefly, healthy subjects had no signs of active on September 26, 2021 by guest. Protected copyright. The aim of these biomarker analyses is several-fold, infection based on physical assessment, medical history namely to better understand the biology of PsA, to and current medication. provide a biological assessment of the response of partic- Twenty- one serum proteins were analysed: the acute ipants to treatment with guselkumab, to analyse differ- phase reactants C reactive protein (CRP) and serum ences between responders and non-responders, and to amyloid A (SAA) (Meso Scale Discovery (MSD) Plat- determine if these markers can be used to classify partici- form, Rockville, Maryland, USA) and the following pants as potential responders prior to treatment.
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