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Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). Tofacitinib is approved for rheumatoid arthritis and psoriatic arthritis, where it has been shown to increase herpes zoster (HZ) risk. We evaluated HZ risk among UC patients using tofacitinib. Methods HZ cases were identified in tofacitinib phase II/III/ongoing, open-label, long-term extension (OLE) UC trials. We calculated HZ incidence rates (IRs) per 100 patient-years of tofacitinib exposure within phase III maintenance (Maintenance Cohort) and phase II/III/OLE (Overall Cohort) studies, stratified by baseline demographics and other factors. HZ risk factors were evaluated in the Overall Cohort using Cox proportional hazard models. Results Overall, 65 (5.6%) patients developed HZ. Eleven patients had multidermatomal involvement (2 nonadjacent or 3-6 adjacent dermatomes), and 1 developed encephalitis (resolved upon standard treatment). Five (7.7%) events led to treatment discontinuation. HZ IR (95% confidence interval [CI]) in the Overall Cohort was 4.07 (3.14-5.19) over a mean (range) of 509.1 (1-1606) days, with no increased risk observed with increasing tofacitinib exposure. IRs (95% CI) were highest in patients age ≥65 years, 9.55 (4.77-17.08); Asian patients, 6.49 (3.55-10.89); patients with prior tumor necrosis factor inhibitor (TNFi) failure, 5.38 (3.86-7.29); and patients using tofacitinib 10 mg twice daily, 4.25 (3.18-5.56). Multivariate analysis identified older age and prior TNFi failure as independent risk factors. Conclusions In tofacitinib-treated UC patients, there was an elevated risk of HZ, although complicated HZ was infrequent. Increased HZ rates occurred in patients who were older, Asian, or had prior TNFi failure (NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612).

Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept. 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3–24 months were randomly assigned to receive either methotrexate alone titrated up from 7·5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494). 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44–56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23–33%) taking methotrexate alone (effect difference 22·05%, 95%CI 13·96–30·15%, p<0·0001). 487 evaluable patients had severe disease (DAS28>5·1). 196 of 246 (80%, 75–85%) and 135 of 230 (59%, 53–65%), respectively, achieved radiographic non-progression (20·98%, 12·97–29·09%, p<0·0001). Serious adverse events were similar between groups. Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate. Wyeth Research.

Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease. In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3·2 and ≤5·1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15–25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409. 604 (72·4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82·6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42·6%) of 197 who had received placebo (mean difference 40·8%, 95% CI 32·5–49·1%; p<0·0001). Additionally, 159 (79·1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35·9%, 27·0–44·8%; p<0·0001). Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept. Pfizer.

Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CL inical Study I n P ediatric P atients of E tanercept for Treatment of E R A, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [ n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741 , registered 20 August, 2009, CLIPPER2, NCT01421069 , registered 22 August, 2011.

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]). Methods Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated. Results The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46–1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time. Conclusions In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

INTRODUCTION:Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated integrated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical program as of Sep 2018.METHODS:NMSC events were evaluated from 4 randomized, placebo-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], a maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612).1–3 Three cohorts were analyzed: Induction (P2/P3 induction studies); Maintenance (P3 maintenance study); Overall (patients [pts] receiving ≥1 dose of tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or ongoing OLE studies). For P3 studies, a blinded independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.RESULTS:1124 pts were evaluated for NMSC (P3 studies only), with 2399 PY of tofacitinib exposure and up to 6.1 years of treatment. NMSC occurred in 2 Induction tofacitinib-treated pts, 1 Maintenance placebo-treated pt (IR 0.97), 3 Maintenance 10 mg BID pts (IR 1.91), and 19 Overall Cohort pts (IR 0.78). 10 pts had squamous cell carcinoma (SCC) and 12 pts had basal cell carcinoma (BCC); 3 pts had both SCC and BCC (Table). No NMSC was metastatic or led to discontinuation. The Overall Cohort showed higher IRs for pts aged ≥50 years vs other subgroups and for pts with prior tumor necrosis factor inhibitor treatment, or prior immunosuppressant use vs those without (Table 1). Prior NMSC (hazard ratio [HR] 10.95; 95% CI 3.72, 32.24; P < 0.0001) and age (HR per 10-year increase 2.10; 95% CI 1.41, 3.13; P = 0.0003) were significant risk factors for NMSC.CONCLUSION:NMSC events were infrequent in the tofacitinib UC program, and were more likely to occur in pts with prior NMSC, and with increasing age – known NMSC risk factors.4 NMSC IRs were similar to those reported for tofacitinib in rheumatoid arthritis5 and for biologic UC treatments.6

INTRODUCTION:Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of adjudicated malignancies in the UC clinical development program as of Sep 2018.METHODS:Malignancies were evaluated from 4 randomized placebo (PBO)-controlled studies (Phase [P] 2 and P3 induction studies [NCT00787202; NCT01465763; NCT01458951], 1 maintenance P3 study [NCT01458574]), and an ongoing, open-label, long-term extension (OLE) study (NCT01470612).1–3 Three cohorts were analyzed: Induction (P2/P3 induction studies), Maintenance (P3 maintenance study), and Overall (patients [pts] receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, or OLE studies). Proportions and incidence rates (IRs; unique pts with events per 100 pt-years [PY] of exposure) were evaluated for malignancies (excl. non-melanoma skin cancer [NMSC]) and NMSC. For Overall Cohort analysis, pts were categorized based on the average daily tofacitinib dose: predominant dose (PD) 5 or 10 mg BID. For P3 studies, an independent adjudication committee reviewed all potential malignancies.RESULTS:1157 pts were evaluated for malignancies (2404 PY of tofacitinib exposure; up to 6.1 years of treatment). Malignancies (excl. NMSC) occurred in 0 Induction Cohort pts, 1 PBO-treated Maintenance Cohort pt, and 17 Overall Cohort pts (IR 0.69; 3 received a PD of tofacitinib 5 mg BID [IR 0.49] and 14 a PD of 10 mg BID [IR 0.75]; Table 1). NMSC occurred in 2 tofacitinib-treated Induction Cohort pts, 4 Maintenance Cohort pts (3 with 10 mg BID-treated pts, IR 1.91; and 1 PBO-treated pt, IR 0.97), and 19 Overall Cohort pts (IR 0.78; 4 had received a PD of 5 mg BID and 15 a PD of 10 mg BID).CONCLUSION:Malignancies (incl. NMSC) were observed with tofacitinib in UC. There was no malignancy type clustering (excl. NMSC). The IR of malignancies (excl. NMSC) reported here is similar to those previously reported for UC [4] – suggesting no treatment duration impact on the IR – and for tofacitinib in pts with rheumatoid arthritis and in pts with UC treated with biologics.5–7

BACKGROUND:Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Safety and efficacy of tofacitinib were demonstrated in Phase (P) 2/3 induction studies (NCT00787202; NCT01465763; NCT01458951), a 52-week, P3 maintenance study (NCT01458574), and are being further investigated in an ongoing, open-label, long-term extension (OLE) study (NCT01470612). This analysis assessed age as a risk factor for adverse events (AEs) in the tofacitinib UC clinical program.METHODS:Analyses of AEs were performed for 2 cohorts: the Maintenance Cohort (patients who received placebo or tofacitinib 5 or 10 mg twice daily in the maintenance study) and the Overall Cohort (all tofacitinib-treated patients in the P2/P3/OLE studies [as of December 2016]), stratified by age (≥65 years vs <65 years). AEs of special interest included serious infections (SIs), opportunistic infections (OIs), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE), and gastrointestinal perforations. Risk factors (based on baseline characteristics) for SIs, OIs, HZ, and NMSC in the Overall Cohort were evaluated using multivariate Cox proportional regression models.RESULTS:AEs occurred in 75.3% (placebo) and 75.9% (tofacitinib) of patients in the Maintenance Cohort, and 82.1% in the Overall Cohort (in which 83.9% received predominantly tofacitinib 10 mg twice daily). Most patients (Maintenance Cohort: 180/198 [90.9%] and 364/394 [92.4%] receiving placebo and tofacitinib, respectively; Overall Cohort: 1,080/1,157 [93.3%]) were aged <65 years. In both the placebo and tofacitinib groups of the Maintenance Cohort, rates of AEs, serious AEs, severe AEs, and discontinuations due to AEs were numerically higher in patients aged ≥65 years (placebo: 83.3%, 11.1%, 11.1%, and 22.2%; tofacitinib: 80.0%, 16.7%, 10.0%, and 16.7%) vs <65 years (placebo: 74.4%, 6.1%, 9.4%, and 18.3%; tofacitinib: 75.5%, 4.4%, 7.1%, and 8.8%). AEs of special interest were generally infrequent in both the placebo and tofacitinib groups of the Maintenance Cohort. In the Overall Cohort, AE, serious AE, and severe AE rates were numerically higher in patients aged ≥65 years (88.3%, 19.5%, and 15.6%) vs <65 years (81.7%, 14.3%, and 12.2%). OI, HZ, malignancies (excluding NMSC), NMSC, and MACE rates were numerically higher in patients aged ≥65 years (3.9%, 14.3%, 2.6%, 5.3%, and 2.6%) vs <65 years (1.7%, 5.0%, 0.6%, 0.7%, and 0.2%); SI and gastrointestinal perforation rates were similar between age groups (≥65 years: 2.6% and 0.0%; <65 years: 2.9% and 0.4%). In multivariate modeling in the Overall Cohort, increasing age (every 10 years) was associated with increased risk of OIs (hazard ratio [95% confidence interval] 1.54 [1.15, 2.08]) and HZ (1.58 [1.34, 1.87]), but not SIs or NMSC (univariate modeling: 1.0 [0.78, 1.27] and 2.31 [1.46, 3.66]).CONCLUSION(S):In the tofacitinib UC program, AE rates were higher among patients aged ≥65 years vs those aged <65 years, regardless of whether they received tofacitinib or placebo. In multivariate analyses, older age was associated with increased OI and HZ risk. Although this is consistent with the general population, due to the small number of patients aged ≥65 years (<10% of the total), these findings should be interpreted with caution.

INTRODUCTION:Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in patients (pts) with UC was evaluated in an 8-week induction Phase (P) 2 study (NCT00787202),1 2 8-week induction P3 studies (OCTAVE Induction 1 & 2; NCT01465763 & NCT01458951),2 a 52-week maintenance P3 study (NCT01458574), and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612).3 We present updated infections data (Sep 2018) from the tofacitinib UC clinical program.4,5METHODS:Pts receiving placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as Induction (P2 & P3, n = 1220), Maintenance (P3, N = 592), and Overall (pts in P2, P3 & OLE receiving tofacitinib 5 or 10 mg BID, N = 1157 [Sep 2018]) Cohorts. Proportions and incidence rates (IRs; pts with events per 100 pt-years [PY] of exposure) were evaluated for infections of special interest (incl. serious infections [SIs], opportunistic infections [OIs; independently adjudicated], and herpes zoster [HZ]).RESULTS:A total of 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID (83% predominantly 10 mg BID [avg. daily dose ≥15 mg]), with 2403.6 PY of exposure (median 623 days, up to 6.1 years of treatment). The Table 1 shows infection IRs by Cohort. In the Overall Cohort, nasopharyngitis was the most frequent infection. For SIs, the Overall Cohort “Tofacitinib All” IR (1.75 [95% CI 1.27, 2.36]) was similar to the Maintenance Cohort IRs for tofacitinib 5 and 10 mg BID. No SIs resulted in death. OIs were infrequent (28 pts) and most were HZ (24 pts; IR 0.99 [95% CI 0.63, 1.47]), mostly cutaneous. Not all HZ events were OIs; 83 pts overall had HZ events (IR 3.57 [95% CI 2.84, 4.43]; 6 serious).CONCLUSION:In induction, SIs and OIs occurred with tofacitinib but not with placebo. Overall, SIs were generally infrequent and Overall Cohort IRs did not suggest increased risk with longer tofacitinib treatment vs the Maintenance Cohort. Non-HZ OIs were rare. SI incidence was similar in the UC and rheumatoid arthritis programs (incl. increased HZ risk)6 and to other UC therapies incl. biologics.7

BACKGROUND:Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The tofacitinib UC program comprises Phase (P)2 and P3 induction studies, a P3 maintenance study, and an ongoing open-label extension study (1). We report efficacy and safety of tofacitinib in the UC program in patients with/without prior tumor necrosis factor inhibitor (TNFi) failure and/or immunosuppressant failure.METHODS:Efficacy data are reported from OCTAVE Induction 1 and 2 (NCT01465763 and NCT01458951; pooled data), and OCTAVE Sustain (NCT01458574). We evaluated rates of remission stratified by prior TNFi failure (yes/no) and prior immunosuppressant failure (yes/no). Where there were sufficient adverse events (AEs) to analyze, effects of prior TNFi failure, and prior immunosuppressant exposure on AEs of special interest (herpes zoster [HZ], serious infections, and adjudicated non-melanoma skin cancer [NMSC]), were evaluated using Cox regression analysis in tofacitinib-treated patients in the UC program (December 2016 data cut; N = 1,157; 1,613 patient-years' exposure).RESULTS:Among 1,139 patients (placebo: n = 234; tofacitinib 10 mg BID: n = 905) treated in OCTAVE Induction 1 and 2, 51.7% had prior TNFi failure and 71.9% had prior immunosuppressant failure. For patients with TNFi failure, Week (Wk) 8 remission rates were: placebo: 0.8%; 10 mg BID: 11.4% (difference from placebo [Δ] = 10.6%); rates for patients without TNFi failure were 11.8% and 24.1%, respectively (Δ = 12.3%). In patients with immunosuppressant failure, Wk8 remission rates were: placebo 3.2%; 10 mg BID: 15.6% (Δ = 12.4%); rates in patients without immunosuppressant failure were 11.8% and 23.0%, respectively (Δ = 11.1%). Among 593 patients treated in OCTAVE Sustain (placebo: n = 198; 5 mg BID: n = 198; 10 mg BID: n = 197), 44.7% had prior TNFi failure and 69.6% prior immunosuppressant failure at induction baseline. For patients with TNFi failure, Wk52 remission rates were: placebo: 11.2%; 5 mg BID: 24.1% (Δ = 12.9%); 10 mg BID: 36.6% (Δ = 25.3%); rates for patients without TNFi failure were: placebo: 11.0%; 5 mg BID: 41.7% (Δ = 30.7%); 10 mg BID: 44.2% (Δ = 33.2%). For patients with immunosuppressant failure, Wk52 remission rates were: placebo: 7.8%; 5 mg BID: 29.4% (Δ = 21.6%); 10 mg BID: 37.6% (Δ = 29.8%); rates for patients without immunosuppressant failure were: placebo 17.4%; 5 mg BID: 47.3% (Δ = 29.9%); 10 mg BID: 48.2% (Δ = 30.8%). Among all tofacitinib-treated patients in the UC program with prior TNFi failure, 505/583 (86.6%) had AEs and 92/583 (15.8%) had serious AEs. For patients without prior TNFi failure, 431/541 (79.7%) had AEs and 75/541 (13.9%) had serious AEs. Prior TNFi failure (hazard ratio [95% confidence interval]: 1.9 [1.2–3.2]) was identified as a significant risk factor for HZ, and for NMSC (11.3 [1.4–88.3]). Prior immunosuppressant exposure was not identified as a significant risk factor for AEs of special interest in Cox regression analyses.CONCLUSION(S):In patients with UC, prior TNFi/immunosuppressant failure did not preclude benefit from tofacitinib induction or maintenance therapy. Prior TNFi failure was associated with greater risk for HZ and NMSC. HZ cases in the UC program were typically non-complicated and manageable with standard antiviral therapy (2).