Sean E. Connolly

Objective: Predictive biomarkers for patients with early rheumatoid arthritis (RA) are needed. This exploratory post hoc analysis investigated inflammatory biomarkers associated with baseline disease activity and biomarkers predictive of treatment response in patients who were seropositive with early RA from a phase 3 study. Methods: The AVERT‐2 study (NCT02504268) included patients who were disease‐modifying antirheumatic drug naive and anti–citrullinated protein antibody positive randomized to abatacept and methotrexate (MTX) or placebo and MTX for 56 weeks. Correlations were assessed among biomarkers and disease activity, pharmacodynamic (PD) changes on disease‐associated biomarkers in response to treatment, and baseline biomarkers to predict treatment response at week 52. Results: In the analysis, 446 patients received abatacept and MTX and 300 received placebo and MTX. Of 103 biomarkers, 47 demonstrated a significant reduction in PD changes with abatacept and MTX versus placebo and MTX, with 18 out of 47 biomarkers showing correlations with baseline disease activity. High baseline interleukin‐10 (IL‐10) levels were associated with greater probability of achieving efficacy measures by week 52 in patients receiving abatacept and MTX versus placebo and MTX, consistent with a significant reduction in disease activity with abatacept and MTX ( P < 0.03 to P < 0.0007). Higher baseline IL‐10 levels were associated with lower bone erosive development with abatacept and MTX compared with placebo and MTX. Conclusion: Treatment with abatacept and MTX resulted in significantly greater reduction of biomarkers relevant to RA, and high baseline IL‐10 levels predicted better treatment response with abatacept and MTX versus placebo and MTX across clinical outcomes. Findings suggest a well‐suited mechanism of action for abatacept and MTX in patients with early RA and high baseline IL‐10 levels.

Abatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy–based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT.

Introduction Patients with rheumatoid arthritis (RA) may respond to treatments differently based on their underlying serology and biomarker status, but real-world data comparing treatment responses to abatacept versus other non-TNFi biologic or targeted-synthetic DMARDs by anti-citrullinated protein antibody (ACPA) status remain limited. We assessed the association between ACPA status and response to treatment in patients with RA. Methods Adults from CorEvitas’ RA Registry were identified who initiated abatacept, rituximab, tocilizumab, or tofacitinib, and had ACPA measured at/prior to treatment initiation and at the 6-month follow-up visit. Three cohorts were included: abatacept/rituximab (2006–2019), abatacept/tocilizumab (2010–2019), and abatacept/tofacitinib (2012–2019). Patient characteristics at initiation were compared by ACPA status (positive [+], anti-cyclic citrullinated peptide-2 [anti-CCP2] ≥ 20 U/ml; negative [−], anti-CCP2 < 20 U/ml). Outcomes over 6 months: changes in Clinical Disease Activity Index (CDAI), modified Health Assessment Questionnaire (mHAQ), patient global assessment (PGA) scores, and proportion of patients achieving a clinical response. Adjusted mean differences and odds ratios were estimated using mixed-effects linear regression models. Results Overall, 982 abatacept, 246 rituximab, 404 tocilizumab, and 429 tofacitinib initiators were identified. ACPA+ (vs. ACPA−) patients had longer disease duration and more erosive disease. During most time periods adjusted mean changes in CDAI, mHAQ, and PGA scores and the proportion of patients achieving a clinical response were significantly higher for ACPA+ versus ACPA− patients initiating abatacept. Adjusted mean change in PGA score and patient fatigue were significantly higher for ACPA+ versus ACPA− patients initiating rituximab. No significant differences were seen by ACPA status for patients initiating tocilizumab or tofacitinib. Conclusions Patients who initiated abatacept or rituximab and were ACPA+ had a greater clinical response at 6-month follow-up post index compared to patients who were ACPA– treated with the same biologic.

Introduction The biologics abatacept and adalimumab have different mechanisms of action (MoAs). We analyzed data from patients with rheumatoid arthritis treated in AMPLE (NCT00929864) to explore the pharmacodynamic effects of abatacept or adalimumab on anti-citrullinated protein antibodies (ACPAs) and gene expression. Methods AMPLE was a phase IIIb, 2-year, randomized, head-to-head trial of abatacept versus adalimumab. Post hoc analyses of baseline anti-cyclic citrullinated peptide-2 (anti-CCP2, an ACPA surrogate) positive (+) status and ACPA fine-specificity profiles over time, as well as transcriptional profiling (peripheral whole blood), were performed. Results Of 646 patients treated (abatacept, n = 318; adalimumab, n = 328), ACPA and gene expression data were available from 508 and 566 patients, respectively. In anti-CCP2+ patients (n = 388), baseline fine specificities for most ACPAs were highly correlated; over 2 years, levels decreased with abatacept but not adalimumab. By year 2, expression of genes associated with T cell co-stimulation and antibody production was lower for abatacept versus adalimumab; expression of genes associated with proinflammatory signaling was lower for adalimumab versus abatacept. Treatment modulated the expression of T- and B-cell gene signatures, with differences in CD8+ T cells, activated T cells, plasma cells, B cells, natural killer cells (all lower with abatacept versus adalimumab), and polymorphonuclear leukocytes (higher with abatacept versus adalimumab). Conclusions In AMPLE, despite similar clinical outcomes, data showed that pharmacodynamic/genetic changes after 2 years of abatacept or adalimumab were consistent with drug MoAs. Further assessment of the relationship between such changes and clinical outcomes, including prediction of response, is warranted. Trial Registration ClinicalTrials.gov identifier, NCT00929864.

Background: Up to 50% of patients with RA discontinue DMARD treatment within 18 months.¹ However, up to 20% of patients who fail multiple treatments may have a good treatment response to another therapy.¹ Predictive biomarkers, such as RF and anti-citrullinated protein antibodies (ACPAs), may be useful to stratify patients with RA to the most appropriate treatment.¹ ASCORE (Abatacept SubCutaneOus in Routine Clinical PracticE; NCT02090556) was a 2-year, observational, prospective, multicentre study of SC abatacept for the treatment of RA in routine clinical practice.² Objectives: To determine if RF/ACPA serostatus and treatment line impact abatacept retention in patients with RA in a post hoc analysis of ASCORE. Methods: Eligible patients, aged ≥18 years, with active moderate-to-severe RA (ACR/EULAR 2010 criteria) who were IV abatacept-naive and initiated SC abatacept 125 mg once weekly, were enrolled into two cohorts: biologic (b)DMARD-naive patients and those with ≥1 prior bDMARD treatment failure. This post hoc analysis assessed abatacept retention rate at 2 years in a subset of patients with RF/ACPA serostatus data (n=1748) from the ASCORE study (N=2892; as observed). Baseline (BL) serostatus groups examined by treatment line were: RF/ACPA double positive (+/+) RA, RF/ACPA single positive (RF+/ACPA– or RF–/ACPA+) RA (data not shown) and RF/ACPA double negative (–/–) RA. Last observation carried forward (LOCF) analyses were used to assess change from BL and measures of disease remission (DAS28 [CRP] Results: BL demographic and disease characteristics were similar across serostatus groups and treatment lines (Table 1). Mean age was 57.1 and 57.8 years for +/+ RA and –/– RA, respectively. Mean DAS28 (CRP) was 4.7 and 4.8 for +/+ RA and –/– RA, respectively. In patients with +/+ RA, abatacept retention was greater when given as first-line treatment (57% vs 48% when given as ≥ second-line) (Figure 1). Retention was similar in patients with –/– RA regardless of treatment line. After 2 years, mean (SE) change from BL (LOCF) in DAS28 (CRP) was –1.41 (0.06) and –0.97 (0.09) for patients with +/+ and –/– RA, respectively. For patients with +/+ RA, mean (SE) change from BL in DAS28 (CRP) was –1.62 (0.08) for those in whom abatacept was first-line and –1.19 (0.08) for those in whom abatacept was ≥ second-line. For patients with –/– RA, mean (SE) change from BL in DAS28 (CRP) was –1.03 (0.13) for those in whom abatacept was first-line and –0.93 (0.12) for those in whom abatacept was ≥ second-line. Remission rates (LOCF) were significantly (pConclusion: In this real-world analysis, patients with +/+ RA treated with first-line abatacept had higher retention than patients receiving abatacept as a ≥ second-line therapy. Remission rates on abatacept were higher in patients with +/+ RA versus –/– RA. These results support early treatment with abatacept and highlight the importance of further evaluating precision medicine approaches in RA. References: [1]Smolen JS, et al. Ann Rheum Dis 2020;79:685–699. [2]Alten R, et al. Ann Rheum Dis 2019;78(suppl 2):A1639. Acknowledgements: Professional medical writing and editorial assistance was provided by Lindsay Craik at Caudex and was funded by Bristol Myers Squibb. This study was funded by Bristol Myers Squibb. Disclosure of Interests: Rieke Alten Speakers bureau: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Consultant of: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Grant/research support from: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, Gilead, GlaxoSmithKline, Janssen, Pfizer, UCB, Rene-Marc Flipo Speakers bureau: AbbVie, Bristol Myers Squibb, Janssen, Lilly, Medac, Merck Sharp & Dohme, Novartis, Pfizer, Roche-Chugai, Grant/research support from: Amgen, Janssen, Novartis, Pfizer, Roberto Caporali Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Fresenius Kabi, Galapagos, Gilead, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Samsung Bioepis, Sanofi, UCB, Consultant of: Galapagos, Gilead, Janssen, Lilly, Merck Sharp & Dohme, Maya H Buch Speakers bureau: AbbVie, Consultant of: AbbVie, Eli Lilly, Gilead, Merck Serono, Pfizer, Roche, Sanofi, Grant/research support from: Gilead, Pfizer, Roche, UCB, Yusuf Patel: None declared, Raimón Sanmartí Speakers bureau: AbbVie, Bristol Myers Squibb, Gebro, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Consultant of: AbbVie, Bristol Myers Squibb, Gebro, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Grant/research support from: Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Sara Marsal Speakers bureau: Bristol Myers Squibb, Celgene, Pfizer, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol Myers Squibb, Celgene, Galapagos, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, UCB, M.T. Nurmohamed Speakers bureau: AbbVie, Bristol Myers Squibb, Eli Lilly, Roche, Sanofi, Consultant of: AbbVie, Celgene, Celltrion, Eli Lilly, Janssen, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Merck Sharp & Dohme, Mundipharma, Novartis, Pfizer, Roche, Sanofi, Hedley Griffiths Consultant of: AbbVie, Gilead, Janssen, Novartis, Peter Peichl: None declared, Bettina Bannert: None declared, Adrian Forster: None declared, Melanie Chartier Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Sean Connolly Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Yedid Elbez Consultant of: Bristol Myers Squibb, Christiane Rauch Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Vadim Khaychuk Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Karissa Lozenski Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

Favorable efficacy and safety profiles have been demonstrated for abatacept in patients with rheumatoid arthritis (RA) in randomized controlled trials, but these data require validation during long-term follow-ups in routine clinical practice. This study explored long-term safety and retention rates in RA patients treated with intravenous abatacept in the Belgian cohort of the international AbataCepT In rOutiNe clinical practice (ACTION) study (NCT02109666). This non-interventional, observational, longitudinal study included Belgian patients aged ≥ 18 years with moderate-to-severe RA who started intravenous abatacept treatment as first- or second/further-line biologic therapy in routine clinical practice. Between October 2010 and December 2012, 141 patients were enrolled in this cohort, of whom 135 evaluable patients (6 biologic-naïve; 129 previously exposed to ≥ 1 prior biologic disease modifying anti-rheumatic drugs) were eligible for the descriptive analysis; 131/135 were included in the effectiveness analysis. Mean disease duration was 10.5 years (standard deviation 9.7) before abatacept initiation. RA patients presented with high disease activity and comorbidity rate, having failed multiple previous treatment options. In this cohort, the 5-year abatacept retention rate was 34% (95% confidence interval, 23−45%) per protocol, and 51% (95% confidence interval, 40−61%) when temporary discontinuations of abatacept > 84 days (n = 24) were not considered as treatment discontinuations. After 5 years of abatacept treatment, clinical outcomes were favorable [good/moderate European League Against Rheumatism (EULAR) responses in 91.7% patients]. No new safety signals were detected for abatacept in routine clinical practice. In this difficult-to-treat Belgian RA population, high retention rates, good clinical outcomes and favorable safety profile were observed with abatacept.

Background: RA is a systemic autoimmune disease with heterogeneous manifestation. Recent advances in serum proteomics, such as the SomaScan^® platform (SomaLogic, Inc., Boulder, USA), allow for a deeper exploration of the protein biomarkers associated with RA and a better understanding of the molecular aetiology of the disease. Objectives: To characterise the differences in baseline serum proteome of patients with RA (enrolled in the Phase IIIb Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX [AMPLE] study)¹ compared with a healthy population, and to identify serum protein biomarkers associated with disease severity and radiographic progression. Methods: Patients in the AMPLE study had an inadequate response to MTX and were naïve to biologic DMARDs. Protein abundance was assessed in baseline serum samples from 440 AMPLE study patients and 123 healthy individuals with matching demographics using the SomaScan^® platform, with 5000+ slow off-rate modified aptamers and up to 8 log of dynamic range.² Differential abundance testing was performed using linear models to identify differences in protein abundance in patients with RA vs healthy individuals. A separate analysis using a linear model was conducted in only the patients with RA to identify the proteins associated with DAS28 (CRP) and TSS. Pathway analyses were performed for proteins significantly (false discovery rate-adjusted p value 2000 serum proteins were significantly differentially expressed in patients with RA, including many proteins that have been associated with RA (e.g. serum amyloid A [SAA], CRP) and complement. Most of the protein expression differences were of small magnitude (fold change Conclusion: Our study revealed that thousands of serum proteins are differentially expressed and several pathways are dysregulated between patients with RA and healthy individuals. Additional pathways were identified that reflect disease severity, including joint damage, distinct from those pathways associated with the disease. The SomaScan^® platform provides a unique proteomic tool with a wide dynamic range for the identification of serum protein biomarkers associated with RA and disease severity. Proteomic signatures should be considered in clinical trials to better understand disease pathogenesis and predict risk in response to treatment. References: [1]Schiff M, et al. Ann Rheum Dis 2014;73:86–94. [2]Gold L, et al. PLoS One 2010;5:e15004. Acknowledgments: Rachel Rankin (medical writing, Caudex; funding: Bristol-Myers Squibb) Disclosure of Interests: David Galbraith Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Minal Caliskan Employee of: Bristol-Myers Squibb, Omar Jabado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sarah Hu Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Michael Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo, Lily, Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Gilead, Horizon, Lily, Pfizer, Roche, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Michael A Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

Background: Abatacept (ABA) versus adaliMumab (ADA) comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) was a Phase IIIb clinical trial to compare the safety, efficacy and radiographic outcomes of ABA vs ADA in patients with RA who exhibited an inadequate response to MTX and who were naïve to biologic DMARDs.¹ While both therapies demonstrated similar efficacy across multiple outcomes, their mechanisms of action (MoAs) are quite different; ABA is a T-cell co-stimulation modulator and ADA is a TNFα inhibitor. Previous transcriptomic analysis of the whole blood samples showed differential pharmacodynamic (PD) effects between the treatments.^1–3 Objectives: To expand our understanding of differential PD changes in the serum proteome over time in patients treated with ABA or ADA in AMPLE using a novel proteomic platform. Methods: Serum was available from 440 patients in AMPLE at four time points (Days 1, 85, 365 and 729). Serum samples from the patients in AMPLE and 123 healthy individuals with matching demographics were subjected to proteomic quantification by a highly multiplexed DNA aptamer technology with wide dynamic ranges (SomaLogic SomaScan^® platform).⁴ A linear model analysis was used to identify protein abundance changes over time and changes specific to treatment. Other covariates included in the model were country of origin, ethnicity and sex. Additionally, patient effect was adjusted for as a random factor. Results: Both treatments exhibited a significant PD effect on serum proteome over the course of the 2-year trial, with 73 proteins modulated by ABA and 125 by ADA. There were large overlaps between the two treatments, including proteins associated with RA, such as C-X-C motif chemokine ligand 13 (CXCL13), matrix metalloproteinase-3 (MMP3) and serum amyloid A1/A2 (SAA1/2). Changes in the levels of these proteins may be indicative of general improvement of the disease. The proteins modulated by the treatments were enriched in the G-protein coupled receptor (GPCR) signalling and innate immunity pathways. Among the proteins that exhibited significantly different PD effects between the treatments were CRP, CC chemokine ligand 17 (CCL17) and β-defensin 112 (Figure). While patients showed marked improvement in their symptoms after 2 years of treatment, the overall serum proteomic profiles of the patients were still different from those of a normal healthy population. Conclusion: The SomaScan^® platform provides a robust method for quantifying the PD change in a broad portion of the serum proteome in clinical trials. In AMPLE, abatacept was more selective than adalimumab in modulating protein biomarkers in patients with RA, though there was large overlap in proteins modulated by both treatments. The treatment-specific changes may reflect the different MoAs leading to similar clinical outcomes. While patients in both groups benefited from treatments, their serum proteome remained notably different from that of a healthy population. Further analysis by responder status may provide additional links between the treatment responses and proteomic changes. Proteomic approaches as described in our study could contribute to clinical trials and help shape treatment strategies for patients with RA. References: [1]Schiff M, et al. Ann Rheum Dis 2014;73:86–94. [2]Bandyopadhyay S, et al. Arthritis Rheum 2014;66:Abstract 1520. [3]Sokolove J, et al. Ann Rheum Dis 2016;75:709–14. [4]Gold L, et al. PLoS One 2010;5:e15004. Disclosure of Interests: David Galbraith Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Minal Caliskan Employee of: Bristol-Myers Squibb, Omar Jabado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sarah Hu Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Michael Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo, Lily, Sanofi/Regeneron, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Crescendo, Gilead, Horizon, Lily, Pfizer, Roche, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Michael A Maldonado Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sheng Gao Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb