BackgroundTofacitinib is an oral Janus kinase inhibitor under investigation for psoriatic arthritis (PsA).ObjectivesTo describe the safety profile of tofacitinib from integrated Phase (P)3 and long-term extension (LTE) studies.MethodsData were analysed for patients (pts) who received ≥1 dose of tofacitinib 5 or 10 mg BID or placebo (PBO), integrated across 2 P3 studies (OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]) and 1 LTE study (OPAL Balance [ongoing, database not locked; NCT01976364]). Common adverse events (AEs; occurring in ≥2% of tofacitinib pts in any group) were analysed in the PBO-controlled portion (Months 0–3) of the P3 studies (Cohort 1 [C1]). Serious AEs (SAEs) and discontinuations due to AEs were analysed over 12 months in pts randomised to tofacitinib 5 or 10 mg BID in P3 studies (Cohort 2a [C2a]); pts randomised to PBO were excluded from this analysis. Deaths and AEs of special interest (serious infections [SI], herpes zoster [HZ], opportunistic infections [OI] including HZ, major adverse cardiac events [MACE], malignancies, non-melanoma skin cancer [NMSC]) were evaluated in all tofacitinib-treated pts in the P3 and LTE studies (Cohort 3 [C3]). Incidence rates (IR; pts with events/100 pt-years [PY] and 95% confidence intervals) are reported. Laboratory results will be reported in future publications.ResultsC1 included 474 tofacitinib- and 236 PBO-treated pts; C2a included 474 tofacitinib-treated pts; and C3 included 783 tofacitinib-treated pts (exposure: 776 PY). Nasopharyngitis (5.9%) and headache (8.5%) were the most commonly reported AEs at Month 3 in pts receiving tofacitinib 5 and 10 mg BID, respectively (Table). In pts randomised to tofacitinib 5 or 10 mg BID, over 12 months (C2a), the IRs for SAEs were 7.92 (4.09, 13.84) and 8.11 (4.19, 14.17), respectively. Discontinuation due to AEs occurred in 11 (4.6%) and 11 (4.7%) pts randomised to tofacitinib 5 and 10 mg BID, respectively, with IRs of 7.16 (3.58, 12.82) and 7.31 (3.65, 13.08), respectively, over 12 months (C2a). Across all tofacitinib-treated pts in the P3 and LTE studies (C3), SIs occurred in 11 pts (1.4%; IR 1.40 [0.70, 2.50]). HZ was reported in 16 pts (2.0%; IR 2.05 [1.17, 3.33]) receiving tofacitinib. All 3 cases of multidermatomal HZ were adjudicated as OIs; these were the only OIs (0.4%; IR 0.38 [0.08, 1.11]). In C3, 2 deaths occurred (0.3%; IR 0.25 [0.03, 0.91]); all were considered unrelated to the study drug. MACE were reported in 3 pts (0.4%; IR 0.38 [0.08, 1.11]), malignancies (excluding NMSC) in 5 pts (0.6%; IR 0.63 [0.21, 1.48]) and NMSC in 4 pts (0.5%; IR 0.51 [0.14, 1.30]).ConclusionsTofacitinib was well tolerated in pts with PsA, with a safety profile consistent to that seen in RA; no new risks were identified. Longer-term follow-up and larger pt populations will provide further information on the safety profile of tofacitinib in pts with PsA.AcknowledgementsThese studies were sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc.Disc...

BackgroundMethotrexate (MTX) is frequently administered in combination with biologics for the treatment of rheumatoid arthritis (RA). MTX may be subsequently discontinued due to intolerance or nonadherence, and/or to reduce medication burden once disease control is achieved. Previous studies have established the efficacy of tocilizumab (TCZ) initiated as monotherapy (MONO), but the impact of MTX withdrawal in patients achieving good clinical response to TCZ+MTX (COMBO) has not been evaluated.ObjectivesTo evaluate whether TCZ-MONO is non-inferior to TCZ-COMBO in maintaining clinical response in patients who achieve low disease activity with TCZ-COMBO.MethodsUS patients with RA who were inadequate responders to MTX were enrolled: initial combination therapy included MTX (15 mg/week orally) plus TCZ 162 mg subcutaneous (SC) either weekly (qw; for patients ≥100 kg) or every 2 weeks (q2w; for patients <100 kg). Dose escalation from q2w to qw was allowed at week 12 in patients who had not achieved low disease activity (DAS28 ≤3.2). If patients achieved DAS28-ESR ≤3.2 at week 24, they were randomized (double-blind) 1:1 to receive either TCZ-MONO or continue TCZ-COMBO until week 52. Patients who did not achieve DAS28 ≤3.2 were assigned to an open-label arm and continued TCZ-COMBO until week 52. The primary outcome measured was the comparison of mean change in DAS28-ESR score in the randomized cohort between weeks 24 and 40, between the TCZ-MONO or TCZ-COMBO arms (noninferiority margin of 0.6). Secondary outcomes included the proportion of patients achieving DAS28 <2.6, DAS28 ≤3.2 and American College of Rheumatology 20%/50%/70% (ACR20/50/70) responses at weeks 40 and 52, and safety. Trial registration number: NCT01855789.ResultsOf 718 patients enrolled, 296 were randomized at week 24 (TCZ-MONO, n=148; TCZ-COMBO, n=148). Early discontinuation in the randomized cohort occurred in 12.2% of patients in the TCZ-MONO group and 10.2% in the TCZ-COMBO group. Baseline characteristics were balanced between treatment groups (mean age 55.5 years; 74.8% female; mean RA duration 6.8 years; mean DAS28-ESR 6.3). At week 24, DAS28 scores were similar in both groups, but ACR responses were ∼8–11% lower in the TCZ-MONO group prior to MTX withdrawal (randomization). The mean change in DAS28 was similar between the randomized treatment groups (Table 1). For the primary efficacy analysis, the mean changes in DAS28 from week 24 to week 40 were 0.46 and 0.14 in the TCZ-MONO and TCZ-COMBO groups, respectively (95% CI: 0.045–0.592). This study met the primary endpoint by demonstrating that discontinuing MTX in TCZ responders was noninferior to continuing MTX. The safety of TCZ-SC in this study was consistent with the known safety profile with no new safety signals observed (Table 2). The most common SAE was infection, occurring in 4.1% of patients. TCZ-COMBO had greater frequency of AEs, SAEs and serious infections than TCZ-MONO.ConclusionsThese results demonstrate that patients receiving TCZ-COMBO who achieve low disease activity can discontinue ...

Background Tabalumab is a monoclonal antibody that neutralizes membrane-bound and soluble B cell activating factor (BAFF). Objectives Evaluate efficacy and safety of tabalumab, in RA pts who had an inadequate response to methotrexate (MTX) therapy, in a randomized, double-blind, placebo-controlled study. Methods 1041 RA pts (ITT population) were enrolled in this 52-wk study evaluating 2 subcutaneous (SQ) tabalumab doses (120mg every 4 wks [120/Q4W] or 90mg every 2 wks [90/Q2W]) vs placebo (PBO). At wk 0, pts received a SQ loading dose that was 2 times the treatment dose (240mg, 180mg, or PBO). Eligible pts had moderate-severely active RA despite ongoing MTX. Primary endpoints included ACR20 and HAQ-DI at 24 wks, and change in mTSS at 52 wks. This study was terminated early due to futility. Results The ITT population was mostly female (84.2%), and seropositive (RF and/or anti-CCP, 95%) with a mean age of 53.2 yrs, mean RA diagnosis of 6.8 yrs, and DAS28-CRP of 5.6±1.0 (mean ± SD). At wk 24 in the efficacy population (ITT population excluding pts on <10 mg/wk of MTX, n=997), there were no significant differences among the 120/Q4W, 90/Q2W, and PBO groups in the percentage of pts achieving ACR20 (NRI; 29.7%, 32.8%, 25.1%). There was no significant difference among the 120/Q4W, 90/Q2W, and PBO groups in structural progression defined as change from baseline in mTSS (mean ± SD) at wk 52 (1.5±4.9, 0.9±3.8, 1.7±5.3). A modest difference was observed in wk 24 HAQ-DI results (mean ± SD) in the 90/Q2W group (mBOCF; 1.2±0.6) vs PBO (mBOCF; 1.3±0.7) [p=0.005]; no difference was observed in the 120/Q4W group (mBOCF; 1.3±0.6). After 52 wks, changes in CD3-CD20+ B cells in the 120/Q4W, 90/Q2W, and PBO groups were −15.0%, −18.8%, and 5.3%. Changes in immunoglobulin levels in the 120/Q4W, 90/Q2W, and PBO groups were: IgM (−16.3%, −19.4%, −0.1%), IgA (−11.4%, −4.7%, 1.2%), and IgG (−8.6%, −7.8%, 0.1%). Safety was evaluated in all randomized pts who received ≥1 dose of study treatment (n=1038). Discontinuations due to an AE were similar across the 120/Q4W, 90/Q2W, and PBO groups (4.3%, 3.5%, 2.9%) as were TEAEs (54.2%, 50.7%, 53.7%) and SAEs (5.2%, 5.2%, 4.9%). For the 120/Q4W, 90/Q2W, and PBO groups, there was no difference in reports of AEs of interest: infections (24%, 23%, 26%); injection-site reactions (2.3%, 4.3%, 2.3%); and allergic/hypersensitivity events (4.3%, 3.5%, 4.6%). Three deaths occurred: 2 120/Q4W pts (sepsis, MI) and 1 PBO pt (MI). Conclusions In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity. There were no differences in reports of AEs of interest and no new or unexpected safety findings for RA pts receiving tabalumab. Disclosure of Interest J. Smolen Grant/research support: Pfizer, Consultant for: Pfizer, Eli Lilly and Company, M. Weinblatt Consultant for: Eli Lilly and Company, Pfizer, Vertex, D. van der Heijde Consultant for: Eli Lilly and Company, AbbVie, Amgen, AstraZeneca, Augurex, BMS, Celgene, Centocor, Chugai, Covagen, Daiichi Sankyo Ltd, ...

BackgroundTofacitinib is an oral Janus kinase inhibitor under investigation for treatment of PsA.ObjectivesEvaluation of efficacy and safety of tofacitinib vs placebo (PBO) in adult patients (pts) with active PsA and an inadequate response (IR) to TNF inhibitors (TNFi).MethodsEligible pts in this 6-month, randomised, PBO-controlled, double-blind, multicentre, Phase 3 study had ≥6 months' PsA diagnosis, met CASPAR criteria, had active arthritis (≥3 tender/painful and ≥3 swollen joints) at screening and baseline, active plaque psoriasis at screening and IR to ≥1 TNFi (discontinued due to inadequate efficacy or adverse event [AE]). Pts were randomised 2:2:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or PBO (advancing to tofacitinib 5 or 10 mg BID in a blinded manner at Month [M]3). Ongoing treatment with 1 conventional synthetic DMARD was required. Pts were followed through M6. Primary endpoints were ACR20 response rate and change (Δ) from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at M3.ResultsPts were 92.1% white, 55.3% female and mean age was 50.0 years. At baseline, mean swollen and tender/painful joint counts were 22.0 and 11.8 respectively; mean HAQ-DI score was 1.3; 69.8% of pts had LEI >0; 49.2% had Dactylitis Severity Score (DSS) >0. Most patients (62.7%) had ≥3% BSA affected by psoriasis, for whom median PASI score was 7.9. Discontinuation rate at M3 was 7.6%, and 87.6% completed M6. ACR20 response and ΔHAQ-DI significantly improved with both tofacitinib doses vs PBO at M3 (Fig 1A,B) and were maintained to M6 (Fig 1C,D). Tofacitinib 5 mg and 10 mg BID demonstrated superior ACR20 response vs PBO as early as Week 2 (26.7% [p≤0.05] and 28.8% [p≤0.05] vs 13.0%). Secondary endpoints at M3 for tofacitinib 5 mg and 10 mg respectively were: ACR50 response, 29.8% (p≤0.05), 28.0% (p≤0.05); ACR70 response, 16.8% (not significant [NS]), 14.4% (NS); ≥75% improvement of PASI in pts with baseline BSA ≥3% and PASI >0, 21.3% (NS), 43.2% (p<0.0001); ΔLEI and ΔDSS in pts with baseline score >0: ΔLEI, -1.3 (p≤0.05) and -1.3 (p≤0.05) (least squares mean [LSM]); ΔDSS, -5.2 (p≤0.05) and -5.4 (p≤0.05) (LSM). Effects were maintained to M6. Frequency of serious AEs and discontinuations due to AEs was low and similar across treatment groups (Fig 1E). The most common AEs were upper respiratory tract infection (5.3–10.8%), nasopharyngitis (1.5–10.7%) and headache (4.5–9.1%).ConclusionsIn this study restricted to PsA pts with TNFi-IR, both tofacitinib doses appeared efficacious on musculoskeletal endpoints for treatment of PsA. No new safety risks were identified vs previous studies in other indications.AcknowledgementsPreviously presented at ACR 2016, to be presented at AAD 2017 and reproduced with permissions. This study was sponsored by Pfizer Inc. Editorial support was provided by AG McCluskey of CMC and was funded by Pfizer Inc.Disclosure of InterestD. Gladman Grant/research support from: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, Consu...

BackgroundTofacitinib is an oral JAK inhibitor for the treatment of RA. Clinical guidelines recommend live zoster vaccine (LZV) to prevent shingles in RA, but this has not been studied in RA patients (pts) and the effect of tofacitinib on humoral or cell-mediated responses to LZV is unknown.ObjectivesTo evaluate the effect of tofacitinib upon the immune response (IR) and safety of LZV.MethodsPts were aged ≥50 years with active RA (≥4 tender/painful joints and ≥4 swollen joints) despite methotrexate (MTX) ≥4 months (15–25 mg/wk before screening) (study NCT02147587). Pts with prior history of zoster vaccination were excluded, as were those receiving any vaccine in the 6 wks prior to randomisation. After screening, eligible pts on background MTX received LZV and then either tofacitinib 5 mg BID or placebo (PBO) starting 2–3 wks post-vaccination. Both humoral (varicella-zoster virus [VZV]-specific IgG via gpELISA) and cell-mediated responses (VZV-specific T cell enumeration via ELISPOT) before vaccination (baseline [BL], day of vaccination), and then at 2, 6 and 14 wks post-vaccination were measured. Primary endpoint: geometric mean fold rise (GMFR) in VZV-specific IgG titre at 6 wks post-vaccination. Secondary endpoint: proportion of pts achieving a ≥1.5 fold rise in VZV-specific IgG titre 6 wks post-vaccination. Exploratory endpoint: GMFR in VZV-specific T cells (spot-forming cells/106 peripheral blood mononuclear cells) by ELISPOT between BL and 6 wks post-vaccination. Pts were followed for 12 wks after randomisation for safety.Results112 pts were randomised to PBO (n=57) and tofacitinib (n=55). Most PBO (93%) and tofacitinib (98%) pts were evaluable for IR endpoints. Pts were similar with regard to sex, age, baseline disease activity and baseline VZV immune measures (i.e. IgG, ELISPOT). The GMFR in VZV-specific IgG titre at 6 wks was 2.11 for tofacitinib and 1.74 for PBO. GMFRs in tofacitinib and PBO pts were comparable with GMFRs in healthy people ≥50 years as indicated in the LZV labels. The proportion of pts with a 1.5 fold rise in IgG titre at 6 wks post-vaccination rise trended higher for tofacitinib (57.4%) vs PBO (43.4%). The VZV-specific T cell GMFR at 6 wks increased similarly for tofacitinib (1.50) and PBO (1.29). SAEs occurred in 0 and 3 (5.5%) of PBO and tofacitinib arms respectively. One pt had cutaneous dissemination with vaccine-strain VZV (Oka strain virus) 2 days after starting tofacitinib (16 days post-vaccination). This pt was found to lack pre-existing immunity to VZV, consistent with vaccine-induced disease. The event resolved after tofacitinib discontinuation and antiviral therapy.ConclusionsPts starting tofacitinib had similar VZV-specific humoral and cell-mediated IRs to LZV as compared to PBO-treated pts. Vaccination appeared safe in pts subsequently treated with tofacitinib; however, one patient who lacked pre-existing VZV immunity developed vaccine-induced disease.AcknowledgementPreviously presented (Winthrop K et al. Arthritis Rheumatol 2015; 67 (S10): Abstr 12L) and reproduced with per...

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BackgroundRheumatoid arthritis (RA) patients (pts) are at increased risk of herpes zoster (HZ). The most recent ACR guidelines of 2015 recommend vaccination in pts aged ≥50 years prior to starting biologic DMARDs or tofacitinib,1 an oral Janus kinase inhibitor for the treatment of RA. Live zoster vaccine (LZV) has shown 70% efficacy in immunocompetent adults aged 50–59 years and 51% efficacy in those aged ≥60 years.2 We previously reported that pts with RA on background methotrexate who started 3 months of treatment with tofacitinib after LZV had similar varicella zoster virus (VZV)-specific immunity to placebo (PBO) pts, and their VZV immunity at Week 6 post-vaccination was comparable with healthy individuals aged ≥50 years.3ObjectivesTo evaluate the long-term effectiveness of LZV in pts with RA via the incidence of HZ after treatment with tofacitinib for up to 27 months.MethodsData were analysed from a prior cohort of pts (n=100) given LZV and then randomised 2–3 weeks later to tofacitinib 5 mg twice daily (BID) or PBO for 12 weeks (A3921237 [NCT02147587]). At 14 weeks post-vaccination, pts joining the long-term extension (LTE) study ORAL Sequel (NCT00413699; study ongoing; database not locked) initiated open-label treatment with tofacitinib 5 or 10 mg BID. The incidence of HZ post-vaccination after tofacitinib exposure up to 27 months (based on an extended follow-up beyond January 2016 data snapshot) was evaluated. Among HZ cases, we analysed measures of VZV-specific immunity with average immunity after LZV.Results112 pts were randomised to PBO (n=57) or tofacitinib 5 mg BID (n=55). 100 pts continued to receive tofacitinib in ORAL Sequel. Five cases (not adjudicated) of HZ occurred (#1: 202 days [219 days post-LZV], #2: 267 days [281 days post-LZV], #3: 702 days [748 days post-LZV], #4: 699 days [741 days post-LZV], #5: 446 days [544 days post-LZV] after initiation of tofacitinib. Cases #1, #2, #3 and #4 were monodermatomal; #5 involved 5 dermatomes. All cases resolved with treatment. Cases #1, #4 and #5 had undetectable ELISPOT measures at baseline and Week 6 post-vaccination, indicating a lack of VZV-specific immunity. Cases #2 and #3 responded adequately to vaccination by both immunoglobulin G (IgG) and ELISPOT measures, but had lower than average VZV IgG levels, both at baseline and at Week 6. (Table).ConclusionsLZV prior to treatment with tofacitinib is effective at boosting IgG levels and cell-mediated immunity towards VZV. No pts who developed both strong cell-mediated and humoral immunity against VZV developed HZ. Of the 5 pts who developed HZ, 3 did not have any cell-mediated response and 2 had a low humoral response.References Singh JA et al. Arthritis Care Res (Hoboken) 2016; 68: 1–25.Hales CM et al. MMWR Morb Mortal Wkly Rep 2014; 63: 729–731.Winthrop K et al. Arthritis Rheumatol 2015; 67: Abstract 12L. AcknowledgementsThis study was sponsored by Pfizer Inc. The authors would like to acknowledge Lisa McNeil. Editorial support was provided by K Haines and C Evans of CMC and was funded by Pfizer Inc.D...

Background:Although previous studies have established the efficacy of tocilizumab (TCZ) initiated as monotherapy (MONO) for the treatment of rheumatoid arthritis (RA),1,2 changes in active intra-articular inflammation after discontinuation of methotrexate (MTX) in patients achieving good clinical control with TCZ + MTX have not been evaluated. Magnetic resonance imaging (MRI) effectively images synovitis and osteitis and can detect changes in bone erosion with greater sensitivity than radiography.3 Objectives:This study used MRI to assess differences in joint damage between patients with RA who achieved low disease activity with TCZ + MTX and then continued or discontinued MTX in the COMP-ACT trial (NCT01855789).Methods:US patients with RA who were inadequate responders to MTX were enrolled; initial combination therapy included MTX (≥15 mg/week orally) plus TCZ 162 mg subcutaneous (SC) either weekly or every 2 weeks. Patients who achieved DAS28-ESR ≤3.2 at week 24 were randomized 1:1 to receive TCZ-MONO or continue TCZ + MTX until week 52 (double blind). A subset of these patients was included in this MRI substudy; 1.5 Tesla MRI was used to obtain images of bilateral hands and wrists at Weeks 24 and 40. Two independent radiologists evaluated images at a central reading facility using RAMRIS (synovitis, osteitis, erosion) and CARLOS (cartilage loss). Outcomes included changes in MRI scores from Week 24 to 40 and the proportion of patients with progression of each score.Results:Of the 296 patients who achieved DAS28 ≤3.2 at Week 24 and were randomized to TCZ + MTX or TCZ-MONO, 79 were enrolled in the MRI substudy (n = 41 and 38, respectively); 74.7% were women, and the mean (SD) age was 56.3 (12.8) years. Patient demographics in the MRI substudy were similar to overall study demographics. Mean changes from Week 24 to 40 in bone erosion, synovitis, osteitis and cartilage loss scores were not significantly different between the TCZ + MTX and TCZ-MONO groups for both bilateral hands and the dominant hand (table 1). There were no significant differences between the groups in the proportion of patients with no progression in each outcome measure (range, 89.7% to 97.4% with TCZ + MTX and 87.9% to 100.0% with TCZ-MONO).Table 1MRI Changes in Patients Receiving TCZ in Combination With MTX or TCZ as MonotherapyConclusions:In patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal and showed no difference in the response of active intra-articular inflammation in patients who discontinued MTX vs those who continued TCZ + MTX within the period of observation, consistent with the result of similar mean change in DAS28 between the groups in the primary analysis.References[1]Jones G, et al. J Rheumatol2017;44(2):142–146.[2]Dougados M, et al. Ann Rheum Dis2013;72(1):43–50.[3]Strand V, et al. Arthritis Rheum2013;65(10):2513–2523.Acknowledgements:This study was funded by Genentech, Inc.Disclosure of Interest:C. Peterfy Consultant for: Roche, Employee of: Spire Sciences, Inc., J. Kremer Shareholder of: Corro...