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Dual Neutralisation of Interleukin-17A

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Dual Neutralisation of Interleukin-17A Spondyloarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-216980 on 6 April 2020. Downloaded from CLINICAL SCIENCE Dual neutralisation of interleukin- 17A and interleukin- 17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48- week phase IIb, randomised, double- blind, placebo- controlled, dose- ranging study Désirée van der Heijde ,1 Lianne S Gensler,2 Atul Deodhar,3 Xenofon Baraliakos ,4 Denis Poddubnyy ,5 Alan Kivitz,6 Mary Katherine Farmer,7 Dominique Baeten,8 Nadine Goldammer,9 Jason Coarse,7 Marga Oortgiesen,7 Maxime Dougados10,11 Handling editor Josef S ABSTRact Key messages Smolen Objectives Bimekizumab selectively neutralises both interleukin (IL)- 17A and IL- 17F. We report efficacy and ► Additional material is What is already known about this subject? published online only. To view, safety in a phase IIb dose- ranging study in patients with ► There remains a need for treatment options in please visit the journal online active ankylosing spondylitis (AS). ankylosing spondylitis (AS) that can provide (http:// dx. doi. org/ 10. 1136/ Methods Adults with AS (fulfilling modified New York sustained, long- term disease control and annrheumdis- 2020- 216980). criteria) were randomised 1:1:1:1:1 to bimekizumab 16 improve patient quality of life. For numbered affiliations see mg, 64 mg, 160 mg, 320 mg or placebo every 4 weeks for 12 weeks (double- blind period). At week 12, patients end of article. What does this study add? receiving bimekizumab 16 mg, 64 mg or placebo were ► Bimekizumab, a monoclonal antibody that Correspondence to re- randomised 1:1 to bimekizumab 160 mg or 320 mg neutralises both interleukin (IL)- 17A and IL- 17F, Professor Désirée van der every 4 weeks to week 48; other patients continued on has shown clinically relevant improvements in Heijde, Department of their initial dose (dose- blind period). The primary end Rheumatology, Leiden University both psoriasis and psoriatic arthritis, leading to point was Assessment of SpondyloArthritis international Medical Center, Albinusdreef 2, its evaluation in other IL-17- mediated diseases. 2333 ZA Leiden, The Society (ASAS) 40 response at week 12 (non- responder This is the first study to assess bimekizumab in Netherlands; imputation (NRI) for missing data). ► patients with active AS. mail@ dvanderheijde. nl Results 303 patients were randomised: bimekizumab A significant dose- response was observed with 16 mg (n=61), 64 mg (n=61), 160 mg (n=60), 320 mg ► Received 14 January 2020 bimekizumab for ASAS40 at week 12 (p<0.05), http://ard.bmj.com/ (n=61) or placebo (n=60). At week 12, significantly Revised 25 February 2020 with a rapid onset and greater ASAS40 Accepted 25 February 2020 more bimekizumab- treated patients achieved ASAS40 response rates for all doses of bimekizumab vs placebo (NRI: 29.5%–46.7% vs 13.3%; p<0.05 versus placebo, which continued to increase to all comparisons; OR vs placebo 2.6–5.5 (95% CI 1.0 week 48. to 12.9)). A significant dose- response was observed A similar pattern was observed across (p<0.001). The primary end point was supported by all ► secondary outcomes, representing secondary efficacy outcomes.A t week 48, 58.6% and on September 28, 2021 by guest. Protected copyright. improvements in quality of life measures versus 62.3% of patients receiving bimekizumab 160 and 320 placebo and over time. mg throughout the study achieved ASAS40, respectively Safety was in line with previous bimekizumab (NRI); similar ASAS40 response rates were observed in ► studies and comparable with the IL- 17A re- randomised patients. During the double- blind period, inhibitor class. treatment- emergent adverse events occurred in 26/60 (43.3%) patients receiving placebo and 92/243 (37.9%) How might this impact on clinical practice or receiving bimekizumab. future developments? Conclusions Bimekizumab provided rapid and Results from this study contribute to the sustained improvements in key outcome measures in ► growing body of evidence supporting dual © Author(s) (or their patients with active AS, with no unexpected safety neutralisation of IL- 17A and IL- 17F with employer(s)) 2020. Re- use findings versus previous studies. permitted under CC BY- NC. No bimekizumab as a novel therapeutic option for Trial registration number NCT02963506. commercial re- use. See rights the treatment of AS. and permissions. Published by BMJ. ► Phase III studies in patients with AS and non- radiographic axial spondyloarthritis are To cite: van der Heijde D, ongoing. Gensler LS, Deodhar A, et al. INTRODUCTION Ann Rheum Dis Epub ahead Ankylosing spondylitis (AS) is a chronic disease, of print: [please include Day characterised by inflammation of the axial skeleton.1 by other manifestations such as peripheral enthesitis Month Year]. doi:10.1136/ It is also referred to as radiographic axial spondy- and arthritis, uveitis, inflammatory bowel disease annrheumdis-2020-216980 loarthritis (r- axSpA). AS can often be accompanied (IBD) and psoriasis.1 2 Expression of human van der Heijde D, et al. Ann Rheum Dis 2020;0:1–10. doi:10.1136/annrheumdis-2020-216980 1 Spondyloarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-216980 on 6 April 2020. Downloaded from leucocyte antigen (HLA)- B27 is strongly associated with the Participants disease, and patients often have elevated levels of inflammatory Eligible patients were ≥18 years of age with AS, as determined markers such as C reactive protein (CRP).1 Patients experience by documented radiographic sacroiliitis (X-rays were centrally chronic pain and functional impairment, impacting on sleep, read by two readers and a third in case of discrepancy), fulfilling daily activities and overall quality of life,3–5 with some patients the modified New York (mNY) criteria for AS,23 symptom dura- experiencing physical disability due to structural damage of the tion of ≥3 months, age at onset of <45 years, with active disease spine.6 as defined by Bath Ankylosing Spondylitis Disease Activity Index Non- steroidal anti- inflammatory drugs (NSAIDs) are a first- (BASDAI) score of ≥4 and spinal pain ≥4 on a 0–10 numer- line treatment to provide symptomatic relief to patients with AS.7 ical rating scale (NRS) (from BASDAI question 2). Patients However, response to NSAIDs may be inadequate or they may were required to have at least one of the following: inadequate be contraindicated. Conventional synthetic disease- modifying response to NSAIDs (defined as a lack of response for ≥4 weeks antirheumatic drugs, such as methotrexate or sulfasalazine, of continuous NSAID therapy or the lack of response to ≥2 are not efficacious in axial disease, although the latter may be NSAIDs at the maximum tolerated dose for ≥4 weeks), intol- effective for patients with peripheral arthritis.7 Tumour necrosis erance to ≥1 NSAID or contraindication(s) to NSAIDs. Prior factor (TNF) inhibitors are the first- line biologic in patients with treatment with up to one TNF inhibitor was permitted, which high disease activity, but not all patients achieve adequate disease must have been discontinued because of inadequate response, 8 9 control or tolerate treatment. Interleukin (IL)- 17A inhibitors intolerance or loss of access. 10 11 are effective second- line therapies ; however, some patients Patients with active/symptomatic Crohn’s disease or ulcerative may still experience unsatisfactory response and require alterna- colitis (UC) were excluded; previous history of Crohn’s disease tive treatments. or UC was not an exclusion criterion. Other exclusion criteria The IL-17 axis represents an established target in AS treat- were total ankylosis of the spine, a concurrent or history of malig- ment, and inflammation is associated with an increase in IL-17- nancy during the past 5 years, a diagnosis of other inflammatory 12 producing innate immune cells. Two members of the IL-17 conditions (eg, rheumatoid arthritis), active infection or infec- cytokine family, IL-17A and IL-17F , share ~50% structural tion requiring antibiotics within 2 weeks of baseline, a history homology and have similar pro-inflammatory function, signal- of chronic or recurrent infections or a serious/life-threatening 13 14 ling via the same receptor complex. Preclinical evidence infection within 6 months of baseline, presence of significant, from human in vitro assays has shown that IL-17A and IL-17F uncontrolled neuropsychiatric disorder, active suicidal ideation, cooperate with other mediators of inflammation, such as TNF, or positive suicide behaviour within the past 6 months. to amplify inflammatory responses.15 The contribution of IL-17F , in addition to IL- 17A, to pathological bone formation has been shown in a human periosteum- derived stem cell model Interventions of osteogenic differentiation, indicating that neutralisation of Initially, patients were randomised 1:1:1:1:1 to receive subcuta- both cytokines inhibits this process to a greater extent than neous bimekizumab 16 mg, 64 mg, 160 mg, 320 mg or placebo IL- 17A alone.16 17 In addition, levels of IL- 17A and IL- 17F have every 4 weeks. At the end of the double- blind period at week 12, been found to be higher in the serum of patients with AS versus following all assessments, patients were re- allocated treatment healthy controls, correlating with markers of systemic inflam- for the dose- blind period as follows: patients initially receiving mation.18 19 placebo, bimekizumab 16 mg or 64 mg were randomised 1:1 to Bimekizumab is a monoclonal antibody developed to selec- receive bimekizumab 160 or 320 mg every 4 weeks through to http://ard.bmj.com/ tively neutralise both IL-17A and IL-17F ,20 and has been previ- week 48. Patients in the bimekizumab 160 and 320 mg groups ously evaluated in a first-in- human study in patients with mild continued on the same schedule through to week 48 (figure 1; psoriasis, a proof-of - concept study in patients with moderate- see online supplementary methods for additional information on to-severe psoriatic arthritis (PsA) and a phase IIb dose- ranging interventions and randomisation and masking).
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