SAT0576 Biomarkers predictive of pain improvement in knee osteoarthritis subjects treated with the anti-il-1 alpha/beta dual variable domain immunoglobulin lutikizumab (ABT-981)
Authors: S. Feng, S. Chen, L. Wang, C. Peterfy, V. Kraus, R. Kamath, L. Zhang, Y. Luo, L. Cui, J. Medema, M. Levesque
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Development of disease-modifying drugs for OA has been challenging, partly due to lack of predictive biomarkers. <h3>Objectives</h3> Our primary objective was to identify baseline (BL) biomarkers predicting greater treatment effects on WOMAC pain among knee OA subjects in the lutikizumab (formerly ABT-981) ILLUSTRATE-K trial (NCT02087904). <h3>Methods</h3> Subjects (n=347) with Kellgren-Lawrence (KL) grade 2–3 knee OA, synovitis on MRI or ultrasound, and knee pain score 4–8 (range, 0–10) were randomised to placebo (PBO) or lutikizumab 25, 100, or 200 mg subcutaneously every 2 wk for 50 wk. The primary endpoints were change from BL (CFB) in WOMAC pain at wk 16 and CFB in MRI synovitis at wk 26. Demographics, patient-reported outcomes (WOMAC, ICOAP, global assessment [PGA]), x-ray joint space width, and Whole Organ MRI Score (WORMS) were determined at BL. The Patient Rule Induction Method, Sequential Batting, and the Adaptive Index Model were used to identify BL predictive biomarkers and OA subsets with greater lutikizumab treatment effects. Continuous efficacy endpoints were assessed using ANCOVA with treatment, age group, and KL grade as main factors and BL measurements as covariates with LOCF imputation for WOMAC pain. <h3>Results</h3> WORMS Global Total Osteophyte Score (GTOS), which semi-quantitatively summates osteophyte severity from 14 regions of the knee, identified a subset of subjects with a greater lutikizumab treatment effect vs PBO; the optimal GTOS cutoff for discriminating treatment effects was 14 <b>(figure 1)</b>. Among subjects with a GTOS ≥14, the PBO WOMAC pain response was markedly reduced and only marginally improved for ABT-981. At wk 16, among subjects with GTOS ≥14, the standardised mean difference (95% CI) of WOMAC pain for the lutikizumab 100 mg dose group vs PBO was −0.62 (−0.16 to −1.09) vs −0.30 (0 to −0.61) for all subjects. Compared with the total study population, the 41% of subjects with GTOS ≥14 not only had a greater ABT-981 treatment effect vs PBO on WOMAC pain, but also other measures of OA symptoms. BL systemic markers of synovitis (serum C1M and C3M) and potential markers of macrophage activation by IL-1 (serum alkaline phosphatase) were positively associated with greater lutikizumab treatment effects vs PBO but to a lesser extent than GTOS. Other data supported the robustness of the GTOS predictive marker because 1) a priori, KL grade was used to stratify subjects, 2) subject characteristics were balanced and 3) osteophyte formation is directly linked with synovial macrophage numbers in humans and OA synovial macrophages are the predominant source of IL-1, which is an important mediator of pain. <h3>Conclusions</h3> The GTOS biomarker predicted improvement of knee OA pain and other symptoms with lutikizumab treatment. We hypothesise that subjects with more severe osteophytes may have had more inflammation-dependent pain that was less responsive to PBO, suggesting that IL-1 inhibitors should be studied further as a treatment for knee OA symptoms in this subset of patients. <h3>Acknowledgements</h3> AbbVie: study sponsor, contributed to design, data collection, analysis, interpretation; and writing, reviewing, approval of final version. AbbVie Funded Medical writing: RM Edwards, MJ Theisen of CPS. <h3>Disclosure of Interest</h3> S. Feng Shareholder of: AbbVie, Employee of: AbbVie, S. Chen Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, C. Peterfy Shareholder of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Employee of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), V. Kraus Consultant for: AbbVie, R. Kamath Shareholder of: AbbVie, Employee of: AbbVie, L. Zhang Shareholder of: AbbVie, Employee of: AbbVie, Y. Luo: None declared, L. Cui Shareholder of: AbbVie, Employee of: AbbVie, J. Medema Shareholder of: AbbVie, Employee of: AbbVie, M. Levesque Shareholder of: AbbVie, Employee of: AbbVie