B. Benda

Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

BACKGROUND Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. METHODS We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28<2·6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440. FINDINGS At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06-28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45-34·92]; p<0·0001) for tofacitinib 10 mg twice a day versus 24·4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0·43 ([-0·36 to -0·15]; p<0·0001) for 5 mg twice a day and -0·46 ([-0·38 to -0·17]; p<0·0001) for 10 mg twice a day tofacitinib versus -0·18 for placebo; DAS28<2·6 rates were 6·7% (eight of 119; [0-10·10]; p=0·0496) for 5 mg twice a day tofacitinib and 8·8% (11 of 125 [1·66-12·60]; p=0·0105) for 10 mg twice a day tofacitinib versus 1·7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4·9%), nasopharyngitis (11 of 267; 4·1%), headache (11 of 267; 4·1%), and urinary tract infection (eight of 267; 3·0%) across tofacitinib groups, and nausea (nine of 132; 6·8%) in the placebo group. INTERPRETATION In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. FUNDING Pfizer.

Tofacitinib (CP‐690,550) in patients with rheumatoid arthritis receiving methotrexate: Twelve‐month data from a twenty‐four–month phase III randomized radiographic study

OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.

Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

Objective. To describe the longterm safety and efficacy profile of tofacitinib in patients with moderate to severe active rheumatoid arthritis (RA). Methods. Data were pooled from 2 open-label studies (NCT00413699, NCT00661661) involving patients who had participated in qualifying phase I, II, or III index studies of tofacitinib. Safety data included over 60 months of observation; efficacy data are reported up to Month 48. Treatment was initiated with tofacitinib 5 or 10 mg twice daily. Primary endpoints were adverse events (AE) and laboratory safety data. Secondary endpoints included American College of Rheumatology (ACR) response rates, and Disease Activity Score (28 joints) (DAS28)-4[erythrocyte sedimentation rate (ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) assessments. Results. Overall, 4102 patients were treated for 5963 patient-years; mean (maximum) treatment duration was 531 (1844) days; 20.8% of patients discontinued treatment over 60 months. The most common AE were nasopharyngitis (12.7%) and upper respiratory tract infection (10.5%). Serious AE were reported in 15.4% of patients with an exposure-estimated incidence rate of 11.1 events/100 patient-years. Serious infections were reported in 4.5% of patients with an exposure-estimated incidence rate of 3.1 events/100 patient-years (95% CI: 2.66–3.55). Mean values for laboratory variables were stable over time and consistent with phase II and III studies. Persistent efficacy was demonstrated through Month 48, as measured by ACR response rate (ACR20/50/70) DAS28-4-ESR, and HAQ-DI. Safety and efficacy were similar for patients receiving tofacitinib as monotherapy or with background nonbiologic disease-modifying antirheumatic drugs. Conclusion. Tofacitinib demonstrated consistent safety and persistent efficacy over 48 months in patients with RA.

Analysis of Infections and All-Cause Mortality in Phase II, Phase III, and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis†

To determine the rate of infection and all‐cause mortality across tofacitinib phase II, phase III, and long‐term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).

Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme

Objectives Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. Methods Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. Results Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. Conclusions The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

Tofacitinib for rheumatoid arthritis - Authors' reply.

1812 www.thelancet.com Vol 381 May 25, 2013 same chance of getting results as those with BMI <30, since BMI can aff ect the effi cacy of some TNFi. Additionally, we need to know whether a poor response to other biological drugs used as fi rstline therapy, such as abatacept or tocilizumab, will be rescued to the same extent with tofacitinib. This will be particularly important for tocilizumab because tofacitinib seems to have biological eff ects comparable to those of tocilizumab–rapid onset of pharmacological eff ect and adverse events, such as dislipidaemia.

THU0147 Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancies across the Rheumatoid Arthritis Clinical Programme

Background Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives An evaluation of malignancies in the tofacitinib RA programme from the Phase (P) 2, P3, and long-term extension (LTE) studies based on data up to April 2013. Methods Data were pooled from 6 P2 and 6 P3 randomised studies and 2 open-label LTE studies (ongoing at time of analysis; databases not locked). Patients (pts) in P3 and LTE studies (LTE pts rolled over from the P2 and P3 studies) were treated with tofacitinib 5 or 10 mg twice daily (BID); P2 included additional doses. Results A total of 5,671 pts (12,664 pt-yrs) received tofacitinib in the P2, P3 and LTE studies. 107 receiving tofacitinib (all doses) reported malignancies (excluding non-melanoma skin cancer [NMSC]); the most common types were lung and breast cancer. There were 10 lymphoma cases. The overall incidence rate (IR, events per 100 pt-yrs) for all malignancies (excluding NMSC) and lymphomas were 0.85 (95% CI: 0.70, 1.02) and 0.08 (0.04, 0.14), respectively. The IRs (95% CI) for all malignancies (excluding NMSC) for P3 were 0.55 (0.27, 1.09) for 5 mg BID and 0.87 (0.50, 1.49) for 10 mg BID. In the LTE the IRs were 1.02 (0.75, 1.39) for 5 mg BID and 0.81 (0.60, 1.10) for 10 mg BID. The IRs (95% CI) for all malignancies (excluding NMSC) broken down into 0–6, 6–12, 12–18, 18–24, 24–30, 30–36, 36–42, and >42 months based on exposure to study drug were 0.70 (0.44, 1.11), 0.66 (0.40, 1.10), 0.94 (0.59, 1.49), 1.04 (0.64, 1.67), 0.83 (0.47, 1.46), 1.00 (0.57, 1.76), 0.79 (0.36, 1.76), and 1.04 (0.54, 2.0), respectively. The standardised incidence ratios (SIRs) (95% CI) (as compared with the US Surveillance Epidemiology and End Result database) for all malignancies (excluding NMSC) and lymphomas were 1.08 (0.89, 1.31) and 2.58 (1.24, 4.74), respectively. The SIRs (95% CI) for lung and breast cancer were 1.91 (1.22, 2.84) and 0.77 (0.46, 1.20), respectively. Overall, 66 pts experienced NMSCs, for an IR of 0.53 (95% CI 0.41, 0.67). The IRs (95% CI) for NMSC in P3 were 0.41 (0.19, 0.92) for 5 mg BID and 0.53 (0.27, 1.07) for 10 mg BID. In the LTE studies the IRs were 0.35 (0.21, 0.59) for 5 mg BID and 0.84 (0.62, 1.13) for 10 mg BID. By comparison, the IR of NMSC in pts treated with anti-TNF was 0.47 in a meta-analysis of randomised controlled trials [1] and ranged from 0.23–0.35 in a meta-analysis of registries [2]. Conclusions The malignancies that occurred in the tofacitinib RA programme, including more than 12,000 pt-yrs of drug exposure, are consistent with the type and distribution of malignancies expected for pts with moderately to severely active RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer, and lymphomas are stable over time and consistent with published estimates in RA pts treated with biologic and non-biologic DMARDs [3–6]. References Askling J, et al. Pharmacoepidemiol Drug Saf 2011; 20: 119-30. Mariette X, et al. Ann Rheum Dis 2011; 70: 1895-904. Carmona L, et al. Semin Arthritis Rheum 2011; 41: 71-80. Pallavicini FB, et al. Autoimmun Rev 2010; 9: 175-80. Simon TA, et al. Ann Rheum Dis 2009; 68: 1819-26. Wolfe F, Michaud K. Arthritis Rheum 2007; 56: 2886-95. Acknowledgements This study was sponsored by Pfizer Inc. Pfizer personnel were involved in protocol development and data analysis. Editorial assistance was provided by Claire Cridland, of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest : X. Mariette Grant/research support: Pfizer Inc, J. Curtis Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, B. Benda Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Kaplan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.2139

THU0241 Haemoglobin Changes and Relationship between Anaemia and Fatigue or Vitality in Rheumatoid Arthritis Patients Treated with Tofacitinib

Background Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib inhibits JAK3 and/or JAK1 with functional selectivity over JAK2. Objectives To characterise changes in haemoglobin (Hb) and incidence of anaemia following tofacitinib treatment and evaluate the relationship between anaemia and fatigue or vitality. Methods Changes in Hb and incidence of anaemia as defined by the OMERACT criteria were analysed from five randomised controlled Phase (P) 3 (N=3314) and two open-label long-term extension (LTE) (N=3515) studies in patients (pts) with RA. Fatigue and vitality were assessed in pts with and without anaemia using the Functional Assessment of Chronic Illness Therapy (FACIT) and the Short Form Health Survey (SF)-36 Vitality scores, respectively. Results In the P3 studies, mean increases in Hb were seen in pts on tofacitinib 5 mg twice daily (BID), with little change in pts on tofacitinib 10 mg BID or placebo. Similar rates of decreased Hb, including anaemia, were observed between tofacitinib and placebo pts. Most cases of anaemia were mild to moderate. Clinically significant Hb changes (change ≥3 g/dL from baseline or Hb ≤7 g/dL) were seen in 0.1% of pts in the tofacitinib 10 mg BID and placebo groups and in no pts in the tofacitinib 5 mg BID group during Month 0-3, and in <0.1% of pts in the tofacitinib 10 mg BID and in no pts in the tofacitinib 5 mg BID groups (no placebo after Month 6) over 12 months. Changes from baseline in Hb and incidence of anaemia were stable over 4 years in LTE. FACIT-fatigue scores were improved following tofacitinib treatment with no numerical differences between pts with or without anaemia in P3 or LTE. Correlations between fatigue and anaemia were small and not significant with a correlation coefficient of 0.18 and 0.06 with tofacitinib 5 and 10 mg BID, respectively, at Month 12 in P3 and 0.15 in tofacitinib 5 and 10 mg BID doses combined at Month 24 in LTE. Similar results were seen with the SF-36 Vitality scores including tiredness/worn out. Image/graph Conclusions Rates of decreased haemoglobin and incidence of anaemia were low and similar across treatment groups in the tofacitinib RA development programme. Fatigue and vitality improved with tofacitinib treatment and there was no observable association between fatigue or vitality and anaemia in pts treated with tofacitinib. Disclosure of Interest H. Schulze-Koops Grant/research support from: Abbot, BMS, Novartis, MSD, Consultant for: Abbott, Actelion, AstraZeneca, Biotest, BMS, Celgene, Chugai, GSK, Hoffmann-La Roche, MSD, Medac, Merck, Mundi Pharma, Novartis, Nycomed, Pfizer, Roche, Savient, UCB, 4SC, B. Benda Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., G. Wallenstein Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Kwok Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., L. Wang Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

THU0225 Tofacitinib Monotherapy is Effective in Methotrexate-NaÏVe Patients with Disease Duration Less Than 6 Months: a Post-HOC Analysis of Early Rheumatoid Arthritis Subjects in a Phase 3 Trial

Background Tofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To assess the efficacy of tofacitinib monotherapy in patients (pts) with early RA (eRA), as defined by disease duration (i.e., time since diagnosis) <6 months, in a Phase 3, 24-month (Mo) study (ORAL Start, NCT01039688) of tofacitinib vs methotrexate (MTX) in MTX-naïve pts with active RA. Primary analyses have been reported.1 Methods Pts were randomised 2:2:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, or MTX. Post-hoc subgroup analyses from the planned 12-Mo interim analyses of signs and symptoms (rates of ACR20, 50 and 70; DAS28-4[ESR] [DAS]-defined remission and low disease activity [LDA] [DAS <2.6 and ≤3.2, respectively]), physical function (mean change from baseline [BL] in HAQ-DI) and structure preservation (mean change from BL in modified Total Sharp Score [mTSS] and rates of no radiographic progression [mTSS change ≤0.5]) in pts with eRA are presented. Results 409 of 952 pts receiving treatment had a disease duration <6 Mo. In this eRA subpopulation, ACR (20/50/70) response rates, rates of DAS-defined remission and LDA and mean HAQ-DI improvement were significantly better with tofacitinib vs MTX at Mo 3 and inhibition of structural damage at Mo 6 and 12. Results by disease duration <6 Mo or ≥6 Mo are summarised in Figure 1. Image/graph Conclusions Tofacitinib monotherapy significantly inhibited progression of structural damage and improved RA signs and symptoms and physical functioning vs MTX, in MTX-naïve pts with early as well as established disease. References Lee EB et al Arthritis Rheum 20;64(10[supplement]):S1049. Disclosure of Interest T. J. Huizinga Grant/research support from: Dutch Arthritis Foundation, The Dutch NIH en the EU, Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boeringher, Takeda, Eli Lilly, Employee of: LUMC, Paid instructor for: Roche, Pfizer, Speakers bureau: Roche, Pfizer, R. Fleischmann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, MSD, Pfizer, Roche, UCB, D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Wilkinson Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., T. Koncz Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Benda Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.