Tamas Koncz

Tofacitinib or Adalimumab versus Placebo in Rheumatoid Arthritis

BACKGROUND Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. METHODS In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). RESULTS At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. CONCLUSIONS In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).

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 versus Methotrexate in Rheumatoid Arthritis

BACKGROUND Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. METHODS We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patients assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). RESULTS Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. CONCLUSIONS In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).

Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis: A Randomized Trial

BACKGROUND Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING 114 centers in 19 countries. PATIENTS 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE Pfizer.

Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors

IntroductionThe long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. The response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of different therapeutic sequences is of particular importance in the evaluation of long-term RA treatment strategies. The objective of this study was to systematically review and quantitatively evaluate the relationship between the clinical response to biologic treatments and the number of previous treatments with tumor necrosis factor α (TNF-α) inhibitors.MethodsA systematic search was undertaken to identify published, peer-reviewed articles that reported clinical outcomes of biologic treatment among RA patients with an inadequate response to TNF-α inhibitors. Data were systematically abstracted. Efficacy rates were estimated for groups of patients who differed in the number of prior TNF-α inhibitors used. End points included American College of Rheumatology (ACR)-, European League Against Rheumatism (EULAR)- and Disease Activity Score 28 (DAS28)-based response criteria.ResultsThe literature search identified 41 publications, of which 28 reported biologic treatment outcomes for RA patients with prior exposure to TNF-α inhibitors. Seven publications reported outcomes obtained in randomized clinical trials, while the remaining consisted of observational studies. The likelihood of responding to a subsequent biologic treatment decreased as the number of previous treatments with TNF-α inhibitors increased for six of the seven response criteria examined.ConclusionsFor patients with prior exposure to TNF-α inhibitors, the likelihood of response to subsequent treatment with biologic agents declines with the increasing number of previous treatments with TNF-α inhibitors.

Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis

Objective. To evaluate effects of tofacitinib or adalimumab on patient-reported outcomes (PROs) in patients with moderate to severe RA and inadequate responses to MTX. Methods. In this 12-month, phase 3, randomized controlled trial (ORAL Standard), patients (n = 717) receiving background MTX were randomized to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks or placebo. PROs included HAQ-Disability Index, Patient Global Assessment of Arthritis, Patient Assessment of Arthritis Pain, health-related quality of life (Short Form-36 [SF-36]), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) and sleep (Medical Outcomes Study-Sleep). Results. At month 3, tofacitinib 10 mg BID treatment resulted in significant changes from baseline vs placebo across all PROs, sustained to month 12, with the highest number of patients reporting improvements ⩾minimum clinically important differences vs placebo (P < 0.05). Changes from baseline at month 3 with tofacitinib 5 mg BID and adalimumab were similar and statistically significant vs placebo across most PROs, excluding SF-36 Mental Component Score and Social Functioning, Role Emotional, and Mental Health domains, with significantly more patients reporting improvements ⩾minimum clinically important differences. Numbers Needed to Treat were lowest for tofacitinib 10 mg BID and similar between tofacitinib 5 mg BID and adalimumab. Conclusion. Patients with moderate to severe RA and inadequate responses to MTX reported improvements across a broad range of PROs with tofacitinib 5 and 10 mg BID and adalimumab that were significantly superior to placebo.

Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial

Objectives To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX. Methods In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]). Results PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F. Conclusions Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier. Trial registration number NCT01039688.

Efficacy and safety of tofacitinib in patients with active rheumatoid arthritis: review of key Phase 2 studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here, the safety and efficacy data from five Phase 2 studies of tofacitinib in patients with RA are summarized. Tofacitinib 1–30 mg twice daily was investigated, as monotherapy and in combination with methotrexate, in patients with RA. Tofacitinib 20 mg once daily was investigated in one study. Tofacitinib 5 and 10 mg twice daily were selected for investigation in Phase 3 studies; therefore, the efficacy and safety of tofacitinib 5 and 10 mg twice daily in Phase 2 studies are the focus of this review. Tofacitinib ≥ 5 mg twice daily was efficacious in a dose‐dependent manner, with statistically significant and clinically meaningful reductions in the signs and symptoms of RA and patient‐reported outcomes. The safety profile was consistent across studies. The efficacy and safety profile of tofacitinib in Phase 2 studies supported its further investigation and the selection of tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily for evaluation in Phase 3 studies.

OP0152 Effects of Tofacitinib Monotherapy versus Methotrexate on Patient-Reported Outcomes in the 2-Year Phase 3 Oral Start TRIAL in Methotrexate-NaÏVe Patients with Rheumatoid Arthritis

Background Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To compare the effects of twice daily (BID) tofacitinib 5 mg and 10 mg monotherapy versus methotrexate (MTX) on patient-reported outcomes (PROs) in the 24-month Phase 3, randomised, double-blind, parallel-group ORAL Start study (NCT01039688) in MTX-naïve patients. Results from a 12-month interim analysis have been presented previously [1,2] here we present the final analysis at 24 months. Methods MTX-naïve patients with moderate-to-severe active RA were randomised 2:2:1 to receive tofacitinib 5 mg (n=373) or 10 mg BID (n=397), or MTX (n=186) titrated from 10 mg per week to 20 mg per week by Week 8. Secondary PRO endpoints included the mean change from baseline in: Patient Global Assessment of arthritis (PtGA; Visual Analogue Scale [VAS]), pain (VAS), physical function (Health Assessment Questionnaire-Disability Index; HAQ-DI), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale; FACIT-F), and health-related quality of life (HR-QoL; Short Form 36 version 2, acute; SF-36). Analyses used a linear mixed-effect model with baseline values as covariates in the full analysis set (all randomised patients who received ≥1 dose of study drug and had ≥1 post-baseline measurement). Least squares (LS) mean changes from baseline (±standard error [SE]) and proportions of patients reporting improvements ≥minimum clinically important differences (MCID; no imputation for missing data) in PROs at Month 24 are presented. P-values presented here are with no correction for type I error inflation. Results A total of 658 patients completed the 24-month study (266, 286, and 106 in the tofacitinib 10 mg and 5 mg and MTX groups, respectively). Over 24 months, significantly (p<0.05) greater improvements from baseline were observed with both tofacitinib 5 and 10 mg BID compared with MTX across the PROs analysed, with the exception of the SF-36 mental component summary score, which was significant at Month 3 but not later (Table 1). Compared with MTX, significantly greater proportions of patients receiving tofacitinib 10 mg BID reported changes ≥MCID in all PROs at Month 3, and all PROs, except HAQ-DI, at Months 12 and 24 and FACIT-F at Month 12. Numerically more patients administered tofacitinib 5 mg BID reported changes ≥MCID across PROs versus MTX. Table 1. PROs at Months 3, 12 and 24 Conclusions In this Phase 3 trial in MTX-naïve patients with RA, tofacitinib 5 and 10 mg BID monotherapy significantly improved multiple PROs over 24 months compared with MTX. References Lee EB et al. Arthritis Rheum 2012; 64 (Suppl 10): S1049. Strand V et al. Ann Rheum Dis 2013; 72: 252-253. Acknowledgements Writing support was provided by Erin Bekes PhD, of Complete Medical Communications and funded by Pfizer Inc. Disclosure of Interest R. Alten Grant/research support: Pfizer Inc, Speakers bureau: Pfizer Inc, V. Strand Consultant for: Pfizer Inc, R. Fleischmann Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, T. Koncz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Zwillich Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, B. Wilkinson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, G. Wallenstein Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.3168

THU0258 Oral Start: Effects of the Oral JAK Inhibitor Tofacitinib Monotherapy Versus Methotrexate on Patient-Reported Outcomes in the Phase 3 Oral Start Trial of Active Rheumatoid Arthritis

Background Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Objectives To compare the effects of tofacitinib 5 mg and 10 mg twice daily (BID) monotherapy versus methotrexate (MTX) on patient-reported outcomes in a 12-month interim analysis of a randomised, double-blind, parallel group Phase 3 study (NCT01039688).1 Methods MTX-naïve patients with RA (≥6 tender/swollen joints; erythrocyte sedimentation rate [ESR] >28 mm/hr and/or C-reactive protein [CRP) >7mg/L]) were randomised 2:2:1 to tofacitinib 5 mg BID, 10 mg BID, or MTX titrated from 10 mg/week to 20 mg/week. PROs were secondary endpoints, including mean changes from baseline in: patient-reported pain (Visual Analogue Scale; VAS), Patient Global Assessment (PtGA) of disease activity (VAS), physical function (Health Assessment Questionnaire-Disability Index; HAQ-DI), health-related quality of life (HR-QoL) (Short Form 36 version 2, acute; SF-36), and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue; FACIT-F). Analyses used a linear mixed-effect model, with baseline values as covariates, on all patients who received ≥1 study drug dose (full analysis set) and had both a baseline and ≥1 post-baseline value. Least squares mean changes from baseline at Month 12 are presented; non-responder imputation for minimum clinically important differences (MCID) of PROs. Results At the 12-month cut-off (24 May 2012), 769 patients who received treatment were ongoing; 307 with tofacitinib 5 mg BID, 328 with tofacitinib 10 mg BID, 134 with MTX. Tofacitinib treatment resulted in statistically significant improvements versus MTX in all PROs except SF-36 mental component score for the 5 mg BID dose (Table 1). Changes in values for all PROs were numerically greater in patients receiving tofacitinib 10 mg BID than those receiving 5 mg BID. A significantly greater proportion of pts achieved at least MCID with tofacitinib 10 mg BID vs MTX for all PROs (FACIT-F data not available) (Table 1). Conclusions In this Phase 3 study, MTX-naive patients receiving tofacitinib monotherapy generally reported significant improvements in PROs compared with MTX over 12 months’ treatment. References Lee EB, et al. Arthritis Rheum 2012; 64(S10): S1049 Disclosure of Interest V. Strand Consultant for: Pfizer Inc., R. Fleischmann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., R. Alten Grant/research support from: Pfizer Inc., Speakers bureau: Pfizer Inc., T. Koncz Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., B. Wilkinson Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Krishaswami Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., G. Wallenstein Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.