AB0638 DO HIGH RHEUMATOID FACTOR LEVELS IMPACT RESPONSE TO CERTOLIZUMAB PEGOL IN PATIENTS WITH INADEQUATELY CONTROLLED RHEUMATOID ARTHRITIS? A POST HOC ANALYSIS OF THE PHASE 3B REALISTIC TRIAL
Authors: J. S. Smolen, T. Mikuls, J. Galloway, U. Müller-Ladner, J. R. Curtis, M. Hashimoto, T. Takeuchi, E. Choy, Y. Tanaka, C. Cara, B. Lauwerys, N. Tilt, B. Ufuktepe, P. C. Taylor
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> In patients (pts) with rheumatoid arthritis (RA), high rheumatoid factor (RF) levels are a poor prognostic factor and associated with higher disease activity, risk of progression, and decreased response to monoclonal antibodies (mAbs) targeting tumour necrosis factor (TNF).<sup>1,2,3</sup> Recent data suggest pts with RA and high RF levels have better clinical responses to TNF inhibitors (TNFis) without a fragment crystallisable (Fc) portion, such as certolizumab pegol (CZP), compared to TNFis with an Fc.<sup>4,5</sup> However, in pts with RA and high RF levels who have had previous inadequate responses or intolerance to TNFis, data on response to CZP are limited. These pts have poorer responses to subsequent biologic or targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs).<sup>6</sup> <h3>Objectives:</h3> To assess impact of RF levels and previous therapies on CZP efficacy outcomes in pts with RA, in a post hoc analysis of the REALISTIC trial. <h3>Methods:</h3> REALISTIC (NCT00717236) was double-blind and placebo-controlled to Week (Wk) 12.<sup>7</sup> Pts with inadequately controlled RA were randomised 4:1 to receive either CZP (400 mg subcutaneous [sc] at Wks 0, 2 and 4, followed by 200 mg sc every 2 weeks) or placebo (PBO) for a 12-wk period, after which all pts received open-label CZP. We report the following outcomes to Wk 36: Disease Activity Score 28 C-reactive protein (DAS28-CRP) score, DAS28-CRP &lt;2.6, Clinical Disease Activity Index (CDAI) score, and CDAI remission (CDAI ≤2.8). Results are stratified by baseline RF level (≤ quartile 3 [Q3] vs &gt;Q3) and prior TNFi use; data are reported as observed case. <h3>Results:</h3> Overall, 751 CZP-randomised pts (RF ≤Q3 [&lt;180 kU/L]: n=560, RF &gt;Q3 [≥180 kU/L]: n=191) and 179 PBO-randomised pts (RF ≤Q3: n=135, RF &gt;Q3: n=44) were included. Baseline demographics were similar between pts with RF ≤Q3 and &gt;Q3, including number of previous DMARDs (Table 1). At Wk 12, TNFi-naïve pts treated with CZP had lower DAS28-CRP scores than PBO-receiving pts regardless of RF levels (CZP, mean [SD]: RF ≤Q3: 3.9 [1.3], RF &gt;Q3: 3.8 [1.3], PBO: RF ≤Q3: 4.9 [1.4], RF &gt;Q3: 4.9 [1.2] PBO), indicating no effect of RF on response to CZP. Interestingly, in pts with prior TNFi use (TNFi-IR), larger differences between DAS28-CRP scores were seen in pts with RF &gt;Q3 than RF ≤Q3 for PBO-randomized pts (RF ≤Q3 4.7 [1.4], RF &gt;Q3, 5.7 [1.4]) compared with CZP (RF ≤Q3: 4.2 [1.4], RF &gt;Q3: 4.2 [1.5]). Responses increased to Wk 36 in all CZP-randomised groups. At Wk 36, the proportion of CZP-randomised pts who achieved DAS28-CRP&lt;2.6 was similar across RF levels and prior TNFi use (Figure 1). At Wk 12, TNFi-naïve CZP-randomised pts also had lower CDAI scores than PBO-randomised pts, regardless of RF levels (RF ≤Q3: 18.6 [13.9] CZP vs 27.3 [15.5] PBO; RF &gt;Q3: 16.7 [12.1] CZP vs 26.9 [12.9] PBO). In TNFi-IR pts, larger differences between CDAI scores for CZP vs PBO were seen in pts with RF &gt;Q3 compared with RF ≤Q3 (RF ≤Q3, mean [SD]: 21.6 [15.4] CZP vs 26.0 [15.8] PBO; RF &gt;Q3, 20.4 [14.9] CZP vs 35.4 [18.2] PBO). Responses increased to Wk 36 in all CZP-randomised groups. The proportion of pts who achieved CDAI remission at Wk 36 was similar in CZP-randomised pts across RF levels and prior TNFi use (Figure 1). <h3>Conclusion:</h3> In PBO-randomised TNF-IR pts responses were lower in the high RF group, compared with low RF (≤Q3). In contrast, pts with RA and high RF levels who were treated with CZP had similar clinical responses to those with low RF levels, indicating that RF does not influence the response to CZP. These data expand previous notions<sup>5</sup> to a TNFi-IR population. Results may have treatment choice implications in pts with RA and high RF levels who have had inadequate responses to previous TNFi treatment. <h3>REFERENCES:</h3> [1] Vastesaeger N. et al, Rheum 2009;48:1114–21. <b>2.</b> Cuchacovich M. et al, Clin Rheumatol 2014;33(12):1707–14. <b>3.</b> Takeuchi T. et al, Arthritis Res 2017;19:194. <b>4.</b> Nakayama Y. Rheumatol Int 2022;42:1227–1234. <b>5.</b> Smolen J. Arthritis Rheumatol 2023;75(suppl 9). <b>6.</b> Pappas D.A. et al, Rheumatol Int 2021;41:585–593; <b>7.</b> Weinblatt M.E. et al, Rheum 2012;51:2204–14. <h3>Acknowledgements:</h3> Funded by UCB Pharma. Medical writing support provided by Costello Medical and funded by UCB Pharma. <h3>Disclosure of Interests:</h3> Josef S. Smolen Honoraria from: AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Eli Lilly, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, Sanofi and UCB Pharma, Research grants from: Abbvie, AstraZeneca, Eli Lilly, Novartis and Roche, Ted Mikuls Consultant for: Horizon Therapeutics; Pfizer, Sanofi and UCB Pharma. Royalties from: Wolters Kluwer Health (UpToDate) and Elsevier., Research support from: Horizon Therapeutics, James Galloway Abbvie, Galapagos, Janssen, Eli Lilly, Pfizer and UCB Pharma, GSK, Pfizer, Ulf Müller-Ladner UCB Pharma, Jeffrey R Curtis Grant/research and consultancy fees: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma., Grant/research and consultancy fees from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche and UCB Pharma., Motomu Hashimoto Speaker fees from Bristol Myers, Chugai, Eisai, Eli Lilly, Tanabe and Mitsubishi., Research grants from Abbvie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Eli Lilly, Novartis and Taisho Toyama., Tsutomu Takeuchi Received honoraria from AbbVie, Asahikasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Janssen, Mitsubishi-Tanabe and Pfizer Japan., Received grants from AbbVie, Asahikasei, AYUMI, Chugai and Mitsubishi-Tanabe., Ernest Choy Speaker fees from Abbvie, Amgen, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Fresenius Kai, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, RPharm, Roche, Sanofi and UCB Pharma., Consultancy fees from Abbvie, Amgen, Biogen, Biocon, Chugai, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm and Sanofi., Research grants from Bio-Cancer, Biogen, Novartis, Pfizer and Sanofi., Yoshiya Tanaka Speaker fees and/or honoraria from: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Gilead, GLAXOSMITHKLINE, Pfizer, Taiho Pharmaceutical and Taisho, Received grants from: Chugai, Eisai, Mitsubishi-Tanabe and Taisho, Carlos Cara UCB Pharma, UCB Pharma, Bernard Lauwerys UCB Pharma, UCB Pharma, Nicola Tilt UCB Pharma, UCB Pharma, Baran Ufuktepe UCB Pharma, Peter C. Taylor Consultancy fees from: AbbVie, Eli Lilly, UCB Pharma, Pfizer, Biogen, Janssen, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Nordic Pharma, Acelyrin Inc. Participation on a Data Safety Monitoring Board/Advisory Board for Immunovant, Sanofi and Kymab., Galapagos.