Ryan DeMasi

Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies

Objectives. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The aim of this analysis was to characterize changes in haematological parameters following tofacitinib treatment, and to compare changes in haemoglobin with markers of disease activity, fatigue and vitality. Methods. Changes in neutrophil counts, lymphocyte counts and haemoglobin levels were analysed in patients with RA from six phase 3 randomized controlled trials (n = 4271) of tofacitinib 5 or 10 mg bd, placebo or active comparators of up to 24 months’ duration, and two long-term extension (LTE) studies (n = 4858) of tofacitinib of up to 84 months’ duration. Disease activity markers included CRP and ESR. Fatigue and vitality were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Short Form Health Survey-36 vitality domain scores. Results. In phase 3 studies, mean neutrophil and lymphocyte counts decreased and mean haemoglobin levels increased in all tofacitinib treatment groups. Haemoglobin levels and neutrophil counts stabilized in the LTE studies, while lymphocyte count decreases stabilized at approximately month 48. Increased haemoglobin was associated with decreased ESR and CRP levels. Clinically meaningful reductions in haemoglobin levels (⩾3 g/dl from baseline or haemoglobin ⩽7 g/dl) occurred in <1.0% of patients in all treatment groups. FACIT-F and Short Form Health Survey-36 vitality scores were weakly correlated with haemoglobin levels. Conclusion. Small changes in haematological parameters were seen with tofacitinib treatment, which stabilized over time in the LTE studies. Changes in haemoglobin levels, although associated with changes in ESR and CRP, were not associated with fatigue or vitality.

Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. Methods MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Results Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Conclusions Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. Trial registration number NCT01039688; Results.

THU0185 Tofacitinib, An Oral JAK Inhibitor, in The Treatment of Rheumatoid Arthritis: Safety and Clinical and Radiographic Efficacy in Open-Label, Long-Term Extension Studies over 7 Years

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To report tofacitinib safety, tolerability and clinical response over 84 months (mo), and radiographic data over 12 mo, in long-term extension (LTE) studies. Methods Data were from two open-label studies (NCT00413699 [ongoing; database unlocked at March 2015 data-cut] and NCT00661661]) of patients (pts) with RA who completed randomised Phase (P)1/2/3 tofacitinib studies. Pts received tofacitinib 5 or 10 mg BID as monotherapy or with background DMARDs; data were pooled. Primary endpoints: AEs and lab safety. Confirmed data are reported for decreased Hgb, neutrophil and lymphocyte counts, and increases >50% from BL in creatinine. Secondary endpoints: DAS28-4(ESR), HAQ-DI and mTSS. Safety data were included up to 96 mo and efficacy up to Mo 84 (n≤30 post-Mo 84). Results 4867 pts were treated (mean [max] duration: 1107 [2895] days). BL data were from P1/P2/P3 index studies for 90.9% of pts. Total tofacitinib exposure was 14926 pt-years (py); 79.2% of pts maintained initial dose. In total, 2132 pts (43.8%) discontinued (AEs: 1051 [21.6%]; insufficient clinical response: 153 [3.1%]). Most common AE classes: infections and infestations (67.6%) and musculoskeletal/connective tissue disorders (37.3%). Most common AEs: nasopharyngitis (18.1%), upper respiratory tract infection (16.2%) and bronchitis (11.7%). SAEs occurred in 26.8% of pts (incidence rate [IR] 9.7/100 py [95% CI 9.2, 10.2]), and serious infection events (SIEs) in 8.4% of pts (IR 2.8/100 py [95% CI 2.5, 3.0]). Malignancies excluding NMSC were reported in 3.0% of pts (IR 1.0/100 py [95% CI 0.8, 1.1]). IRs for SIEs and malignancies through Mo 96 did not increase vs reported data through Mo 84.1 Decreased Hgb (>30% decrease from BL/Hgb <8 g/dL) occurred in <1.0% of pts. Increased aminotransferases (>3×ULN) occurred in 5.4% (ALT) and 3.1% (AST) of pts. Moderate to severe neutropenia (absolute neutrophil count [ANC] 0.5–1.5×103/mm3) was noted in 1.5% of pts; there were no confirmed cases of ANC <0.5×103/mm3. Confirmed absolute lymphocyte counts <0.5×103/mm3 occurred in 1.3% of pts. Increases >50% from BL in creatinine were seen in 2.4% of pts. Mean DAS28-4(ESR) was 6.29 at BL, 3.74 at Mo 1 and 3.20 at Mo 84. Mean HAQ-DI score was 1.42 at BL, 0.81 at Mo 1 and 0.78 at Mo 84. Radiographic data were available for 1099 pts. Mean mTSS was 24.0 at BL (last P1/P2/P3 index value), 25.1 at Mo 6 and 24.3 at Mo 12. Mean change from BL in mTSS was 0.3 at Mo 6 and 0.2 at Mo 12. Conclusions Consistent safety and sustained efficacy over 84 mo was seen in pts with RA receiving tofacitinib 5 or 10 mg BID in LTE studies. Changes in mTSS were minimal at Mo 12 in LTE studies. References Wollenhaupt J et al. Arthritis Rheumatol 2014; 66: S375. Acknowledgement Previously presented (Wollenhaupt J et al. Arthritis Rheumatol 2015; 67 (S10): 1645) and reproduced with permission. This study was funded by Pfizer Inc. Editorial support was provided by S. Johnson of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, J. Silverfield Grant/research support from: Pfizer Inc, Speakers bureau: Pfizer Inc, E. B. Lee Consultant for: Pfizer Inc, K. K. Terry Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Lazariciu Consultant for: Pfizer Inc, Employee of: Quintiles Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

THU0193 Reestablishment of efficacy of tofacitinib, an oral janus kinase inhibitor, in rheumatoid arthritis patients after temporary discontinuation

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To assess the efficacy and safety of tofacitinib after temporary discontinuation and reinitiation of therapy in RA patients (pts). Methods Data were collected from a randomised, parallel-group (grp), controlled, open label, vaccine sub-study in RA pts participating in a long-term extension (LTE) study (NCT00413699). Pts were ≥18 years of age with active RA and had received tofacitinib 10 mg BID for ≥3 months. The sub-study included 2 treatment (tx) grps: “continuous tx” (tofacitinib 10 mg twice daily [BID] as monotherapy or with methotrexate [MTX]) and “interrupted tx” (tofacitinib withdrawn for 2 weeks post-randomisation [Day 1–Day 15; Visits 1–3], then tofacitinib 10 mg BID reinitiated as monotherapy or with MTX at Visit 3); randomisation was stratified by MTX use. Pneumococcal and influenza vaccines were administered to all pts on Day 8 (Visit 2; vaccine titers reported previously1). Blood samples were taken on Days 8, 15 (Visit 3) and 43 (Visit 4). Efficacy endpoints included change from baseline in C-reactive protein (CRP), Health Assessment Questionnaire Disability Index (HAQ-DI) and Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) at each visit. A mixed-effects model with repeated measures was used to evaluate treatment effect at each visit. Analyses for efficacy were exploratory, with no multiplicity adjustment for comparisons. Results Of the 199 pts in this analysis (continuous, n=100; interrupted, n=99), 117 received concomitant MTX. At LTE study baseline (BL) in the continuous and interrupted grps, respectively: 81.8/83.8% of pts were white, 84.8/86.9% were female and mean age was 55.0/53.9 years. BL (Day 1) values for CRP, HAQ-DI and DAS28-4(ESR) were generally similar between groups. At Day 8, mean CRP and DAS28-4(ESR) significantly increased from BL for interrupted vs continuous tx; HAQ-DI values were similar between grps (Figure). As expected at Day 15, mean CRP, HAQ-DI and DAS28-4(ESR) significantly increased from BL for interrupted vs continuous tx. After tofacitinib reinitiation for 28 days (Day 43), changes in CRP, HAQ-DI and DAS28-4(ESR) were similar between grps and approached BL levels. Adverse events (AEs) were experienced by 35.4% and 49.5% of pts receiving interrupted and continuous tx, respectively. The most frequent treatment-emergent AEs were bronchitis and upper respiratory tract infection (each AE: 6 pts) and vaccination-related immunisation reaction, myalgia and rash (each AE: 5 pts). Serious AEs occurred in 3 pts (3%) in each grp. In total, 1 pt (1%), in the interrupted tx grp, discontinued due to a study-drug related AE; no pts discontinued due to disease flare. Conclusions Efficacy of tofacitinib 10 mg BID can be reestablished following loss of efficacy during temporary (2 weeks) tx discontinuation in pts with RA. Pts receiving continuous tx maintained efficacy throughout the study. Further investigations are required. References Winthrop KL et al. Ann Rheum Dis 2016; 75: 687–695. Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by K Haines of CMC and was funded by Pfizer Inc. Disclosure of Interest J. Kaine Speakers bureau: Bristol-Myers Squibb, Pfizer Inc, J. Tesser Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Snyder Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Fan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc

The Impact of Biologics and Tofacitinib on Cardiovascular Risk Factors and Outcomes in Patients with Rheumatic Disease: A Systematic Literature Review

IntroductionRheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients.MethodsA systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events.ResultsOf the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated.ConclusionsTreatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.

Tofacitinib in Rheumatoid Arthritis: Lack of Early Change in Disease Activity Predicts a Low Probability of Achieving Low Disease Activity at Month 6

Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib.

OP0037 Efficacy of tofacitinib after temporary discontinuation in patients with rheumatoid arthritis: analysis of data from open-label long-term extension studies

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Given the chronic nature of RA, there may be situations when therapy is temporarily discontinued. It is important to understand loss of response during temporary discontinuation and the ability to regain disease control following treatment reinitiation. Re-establishment of tofacitinib efficacy following temporary discontinuation/reinitiation has been previously demonstrated in patients (pts) with RA participating in the vaccine sub-study of the long-term extension (LTE) study ORAL Sequel.1 Objectives To further assess tofacitinib efficacy and safety after temporary discontinuation and reinitiation in pts with RA in LTE studies. Methods Data were pooled from two open-label LTE studies (NCT00413699 [database lock: March 2017] and NCT00661661) of pts with RA who had completed qualifying Phase 1/2/3 index studies. Pts received tofacitinib 5 or 10 mg twice daily as monotherapy or with conventional synthetic disease-modifying antirheumatic drugs. Pts who received continuous tofacitinib for ≥4 months, temporarily discontinued tofacitinib for 14–30 days and then resumed treatment were included in the analysis. Efficacy outcomes were analysed at the pre-interruption visit (≤90 days before discontinuation) and at the post-interruption visit (within 14–42 days of resuming treatment); data from the interruption period were not analysed. Efficacy outcomes included: ACR20/50/70 response rates, mean tender and swollen joint counts, mean C-reactive protein levels and mean DAS28–4(ESR), CDAI, HAQ-DI, Patient Global Assessment of arthritis, Pain and Physician Global Assessment of arthritis scores. Safety was analysed from Day 1 of temporary discontinuation to the post-interruption visit and included adverse events (AEs), serious AEs (SAEs) and discontinuations due to AEs that occurred within the time range. Results 261 pts met the criteria for temporary discontinuation. Median (range) duration of temporary discontinuation was 1914–30 days. Pt demographics are shown in table 1. Efficacy outcomes were generally similar at pre- and post-interruption visits (table 2). From Day 1 of discontinuation to the post-interruption visit, AEs, SAEs and discontinuations due to AEs occurred in 142 (54.4%), 29 (11.1%) and 4 (1.5%) pts, respectively.Abstract OP0037 – Table 1 Patients demographics and baseline disease characteristics1 Abstract OP0037 – Table 2 Efficacy endpoints at the pre-interruption visit (≤90 days before temporary discontinuation) and post-interruption visit (within 14–42 days of resuming treatment) Conclusions In pts with RA who temporarily discontinued tofacitinib, similar efficacy responses were observed at pre– and post–interruption visits, suggesting that there is no loss of efficacy after temporary withdrawal and reinitiation of tofacitinib. The safety profile was consistent with previous tofacitinib reports in LTE studies over 9 years.2 References [1] Kaine J, et al. Arthritis Rheumatol2017;69(suppl 10):Abstract 424. [2] Wollenhaupt J, et al. Arthritis Rheumatol2017;69(suppl 10):Abstract 522. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by AG McCluskey of CMC and funded by Pfizer Inc. Disclosure of Interest J. Kaine Speakers bureau: Bristol-Myers Squibb, Pfizer Inc, J. Tesser Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Snyder Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Fan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, V. Bandi Consultant for: Pfizer Inc through Eliassen Group Inc, J. Wollenhaupt Speakers bureau: Pfizer Inc

THU0299 An integrated analysis of changes in lipid levels and incidence of cardiovascular events following tofacitinib treatment in patients with psoriatic arthritis across phase 3 and long-term extension studies

Background Cardiovascular (CV) disease and cardiometabolic syndrome are common comorbidities/causes of mortality in patients (pts) with psoriatic arthritis (PsA). Tofacitinib is an oral JAK inhibitor for the treatment of PsA. Objectives To investigate changes in lipid levels and incidence of CV events in pts with PsA treated with tofacitinib in Phase (P) 3 and long-term extension (LTE) studies. Methods Data were analysed for pts who received ≥1 dose of tofacitinib 5 or 10 mg BID or placebo (PBO), integrated across 2 P3 studies (OPAL Broaden [12 months (m); NCT01877668, including adalimumab control]; OPAL Beyond [6 m; NCT01882439]) and 1 LTE study (OPAL Balance [data cut-off May 2016; ongoing, database not locked; NCT01976364]). Lipid levels were assessed throughout P3 and LTE studies; this analysis included data from the PBO-controlled period (M0–3) of P3 studies. Blood pressure, hypertension events (standardised MedDRA query [narrow]) and adjudicated (independent/blinded to treatment) major adverse cardiovascular events (MACE) are reported for all pts who received ≥1 dose of tofacitinib (pooled across doses for hypertension and MACE). Incidence rates (IR; pts with events/100 pt-years [PY]) and 95% CI are reported. Results Overall, 783 pts (776 PY of tofacitinib exposure) were included in P3 and LTE studies; treatment duration was 1–927 days. After 3 m of tofacitinib treatment in P3 studies, dose-dependent increases in lipid levels were observed with tofacitinib; minimal changes were observed with PBO, except for triglycerides (figure 1). Concurrent increases in high-density and low-density lipoprotein (HDL/LDL) and no change in the total cholesterol/HDL ratio were shown. Across P3 and LTE studies, no clinically significant changes in mean systolic or diastolic blood pressure were seen to 24 m. Hypertension events were reported in 38 (4.9%) pts: IR 4.93 [95% CI 3.49, 6.77]. Of these events, 4 led to pt discontinuation and 2 were serious adverse events. MACE were reported for 3 (0.4%) pts receiving tofacitinib (IR 0.38 [95% CI 0.08, 1.11]) and included sudden cardiac death (57 days of exposure at time of event), myocardial infarction (197 days) and ischaemic stroke (80 days). This is within the range reported in tofacitinib studies in pts with psoriasis (IR 0.24 [0.15, 0.37]; 8,759 PY of exposure) and rheumatoid arthritis (RA) (IR 0.38 [0.30, 0.47]; 21,286 PY of exposure). No dose-dependent effects on blood pressure were apparent.Abstract THU0299 – Figure 1 Mean% change from baseline in lipid levels to Month 3 integrated across Phase 3 studies. BID, twice daily; SE, standard error Conclusions In pts with PsA, the magnitude and dose dependency of increases in lipid levels to M3 were consistent with findings in tofacitinib studies in pts with psoriasis and RA. In P3 and LTE studies, no clinically significant changes were seen in blood pressure or incidence of hypertension. Incidence of MACE was within the range reported in prior tofacitinib studies in psoriasis and RA; however, the long latency of MACE requires longer-term observation. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Gilead, Pfizer Inc, Regeneron-Sanofi, I. McInnes Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, D. Veale Grant/research support from: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, Speakers bureau: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, B. Thiers Consultant for: Pfizer Inc, Valeant Pharmaceuticals, D. Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wolk Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Efficacy of Monotherapy with Biologics and JAK Inhibitors for the Treatment of Rheumatoid Arthritis: A Systematic Review

Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE®, Embase®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010–2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA.Funding: Pfizer.Plain Language Summary: Plain language summary available on the journal website.

THU0180 Lack of Early Change in Disease Activity Score Predicts The Likelihood of Achieving Low Disease Activity at Month 6: Tofacitinib Monotherapy versus Methotrexate in Methotrexate-Naïve Patients with Rheumatoid Arthritis

Background Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Treatment guidelines recommend targeting remission or low disease activity (LDA), herein defined as Disease Activity Scores ≤3.2 based on 28 joint counts (DAS28≤3.2) and adjusting therapy after 3–6 months1 (Mos). Predicting the likelihood of clinical response may help inform early treatment decisions. Objectives To understand the relationship between timing and magnitude of early changes in DAS28, erythrocyte sedimentation rate (DAS28-4[ESR]) and the likelihood of achieving LDA at Mo 6 in RA patients (pts) naïve to methotrexate (MTX). Methods In a Phase 3 study (ORAL Start; NCT01039688), MTX-naïve RA pts were randomised 2:2:1 to the following monotherapies: tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or MTX. Conditional probability of pts achieving LDA at Mo 6 were calculated, given failure to achieve DAS28-4(ESR) improvement from baseline (range ≥0.3 to 1.8) at Mo 1 or 3. One-year data with non-responder imputation for missing values was used. Results 948 pts received treatment; tofacitinib 5 mg BID (n=370), tofacitinib 10 mg BID (n=394) or MTX (n=184); results previously reported.2 In this post-hoc analysis, of those patients who failed to achieve DAS28-4(ESR) improvement from baseline ≥1.2 at Mo 3, 6.8% for tofacitinib 5 mg BID, 11.3% for tofacitinib 10 mg BID and 6.2% for MTX achieved LDA at Mo 6 (Table). A minority of pts (74/353 [20.9%]) receiving tofacitinib 5 mg BID failed to achieve DAS28-4(ESR) improvement ≥1.2 from baseline at Mo 3, while a greater proportion failed for MTX (65/171 [38.0%]). Failure to achieve DAS28-4(ESR) improvement from baseline at Mo 3 (range ≥0.30–1.8) for tofacitinib 5 mg BID and MTX was associated with a low probability (≤10%) of achieving LDA at Mo 6. For tofacitinib 5 mg BID, failure to achieve lower thresholds of DAS28-4(ESR) improvement (range ≥0.3 to 0.9) at Mo 1 was associated with lower probability of LDA at Mo 6 than higher DAS28-4(ESR) thresholds (≥1.2–1.8) (Table). Conclusions Failure to achieve DAS28-4(ESR) improvement ≥1.2 from baseline at Mo 3 was associated with a low probability of achieving LDA at Mo 6 (≤6.8%) for tofacitinib 5 mg BID and MTX. For the minority of MTX-naïve RA pts treated with tofacitinib 5 mg BID or MTX who failed to achieve a minimal clinical response (DAS28-4[ESR] improvement ≥1.2) by Mo 3, another treatment option can be considered at Mo 3, as there is a low probability of reaching LDA at Mo 6. References Smolen J et al. Ann Rheum Dis 2016;75(1):3–15. Lee EB et al. N Engl J Med 2014;370:2377–2386. Acknowledgement This study was sponsored by Pfizer Inc. Editorial support was provided by Rebecca Bright, PhD, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest E. Keystone Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, R. F. van Vollenhoven Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L.-J. Hwang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Chapman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. B. Lee Consultant for: Pfizer Inc