Sujatha Menon

Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study

Objectives To compare efficacy and safety of various doses of tofacitinib, an oral Janus kinase inhibitor, with placebo in patients with active ankylosing spondylitis (AS, radiographic axial spondyloarthritis). Methods In this 16-week (12-week treatment, 4-week washout), phase II, multicentre, dose-ranging trial, adult patients with active AS were randomised (N=51, 52, 52, 52, respectively) to placebo or tofacitinib 2, 5 or 10 mg twice daily. The primary efficacy endpoint was Assessment of SpondyloArthritis International Society 20% improvement (ASAS20) response rate at week 12. Secondary endpoints included objective measures of disease activity, patient-reported outcomes and MRI of sacroiliac joints and spine. Safety was monitored. Results Emax model analysis of the primary endpoint predicted a tofacitinib 10 mg twice daily ASAS20 response rate of 67.4%, 27.3% higher than placebo. Supportive normal approximation analysis demonstrated tofacitinib 5 mg twice daily ASAS20 response rate significantly higher than placebo (80.8% vs 41.2%; p<0.001); tofacitinib 2 and 10 mg twice daily demonstrated greater response rate than placebo (51.9% and 55.8%, respectively; not significant). Secondary endpoints generally demonstrated greater improvements with tofacitinib 5 and 10 mg twice daily than placebo. Objective (including MRI) endpoints demonstrated clear dose response. Adverse events were similar across treatment groups with no unexpected safety findings. Dose-dependent laboratory outcome changes returned close to baseline by week 16. Conclusions Tofacitinib 5 and 10 mg twice daily demonstrated greater clinical efficacy versus placebo in reducing signs, symptoms and objective endpoints of active AS in adult patients with a similar 12-week safety profile as reported in other indications. Trial registration number NCT01786668.

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial

IntroductionThe purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).MethodsThis phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.ResultsSixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).ConclusionsMaraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.Trial RegistrationClinicalTrials.gov: NCT00427934

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs (DMARDs). Methods In this 12‐month, double‐blind, active‐controlled and placebo‐controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5‐mg dose taken orally twice daily (107 patients), tofacitinib at a 10‐mg dose taken orally twice daily (104), adalimumab at a 40‐mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5‐mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10‐mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ‐DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. Results ACR20 response rates at month 3 were 50% in the 5‐mg tofacitinib group and 61% in the 10‐mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ‐DI score was ‐0.35 in the 5‐mg tofacitinib group and ‐0.40 in the 10‐mg tofacitinib group, as compared with ‐0.18 in the placebo group (P=0.006 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the score change was ‐0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5‐mg tofacitinib group, 71% in the 10‐mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5‐mg tofacitinib dose, and 64% in the placebo group that switched to the 10‐mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. Conclusions The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668.)

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. Methods In this 6‐month randomized, placebo‐controlled, double‐blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire–Disability Index (HAQ‐DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. Results At 3 months, the rates of ACR20 response were 50% with the 5‐mg dose of tofacitinib and 47% with the 10‐mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ‐DI score were ‐0.39 and ‐0.35, as compared with ‐0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5‐mg dose of tofacitinib continuously and in 6% who received the 10‐mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. Conclusions In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439.)

Estimating transformations for repeated measures modeling of continuous bounded outcome data

Continuous bounded outcome data are unlikely to meet the usual assumptions for mixed-effects models of normally distributed and independent subject-specific and residual random effects. Additionally, overly complicated model structures might be necessary to account adequately for non-drug (time-dependent) and drug treatment effects. A transformation strategy with a likelihood component for censoring is developed to promote the simplicity of model structures and to improve the plausibility of assumptions on the random effects. The approach is motivated by Health Assessment Questionnaire Disability Index (HAQ-DI) data from a study in subjects with rheumatoid arthritis and is evaluated using a simulation study.

Lack of Interaction Between the Peptidomimetic Substrates Captopril and Cephradine

Intestinal peptide transporters, including hPEPT1, facilitate the absorption of cephalosporins and angiotensin‐converting enzyme inhibitors, and have been investigated as a means to improve oral drug absorption. Renal peptide transporters including hPEPT2, may also facilitate renal reabsorption of such compounds. In vitro and animal studies suggest that co‐administration of peptidomimetic compounds may alter oral pharmacokinetics, although this has not been well studied in humans. The purpose of this study was to determine whether co‐administration of the hPEPT substrates captopril and cephradine alters the oral pharmacokinetics of either agent. Nine healthy male volunteers received a single oral 25‐mg dose of captopril, a single oral 500‐mg dose of cephradine, or concurrent ingestion of captopril and cephradine in a cross‐over manner. Venous blood samples were taken and captopril and cephradine pharmacokinetics were determined using noncompartmental analyses. No significant differences were observed in captopril or cephradine pharmacokinetics when administered together as compared to each agent alone (a marginal decrease in Cmax was observed for both captopril and cephradine during co‐administration [5–15%]; however, differences were not statistically significant). The results of our study suggest that hPEPT1 and hPEPT2 are unlikely to contribute to clinically important drug interactions in humans.

OP0024 Safety and efficacy of SBI-087 in subjects with active rheumatoid arthritis in a phase 2 randomized, double-blind, placebo-controlled study

Background SBI-087 is a humanized CD20-directed SMIP™ (mono-specific protein therapeutic) that has been shown to deplete B cells in a dose dependent manner in Phase 1 studies in subjects with stable rheumatoid arthritis (RA). Objectives The objective of this study was to evaluate the safety and efficacy of four 200 mg subcutaneous (SC) dosing regimens versus placebo in seropositive subjects with active RA on a stable background of methotrexate (MTX). Methods Subjects with active RA (≥5 tender joints, ≥5 swollen joints, and either C-reactive protein ≥7 mg/L or erythrocyte sedimentation rate ≥28 mm/h) were randomized to either placebo or 1 of 4 active treatment arms receiving 200 mg SBI-087 as follows: (1) Day 1; (2) Day 1, 15; (3) Day 1, Week 12; (4) Day 1, 15, and Week 12. SBI-087 was administered as two 100 mg SC injections in combination with 40 mg oral prednisone or equivalent, acetaminophen, and an antihistamine prior to dosing and 20 mg oral prednisone or equivalent 4 hours post dose. The study consisted of 2 parts: a 24 week initial phase evaluating safety and efficacy and a follow-up phase after week 24 to monitor for safety and B cell recovery. The primary outcome measure was ACR20 at week 16. Secondary outcome measures included ACR50/70 and DAS28 at week 16 and also ACR20/50/70 and DAS28 at week 24. Improvements in individual parameters such as the HAQ-DI and acute phase reactants were also assessed. All subjects were evaluated for safety. Results 209 subjects were randomized into the study. 40 (19.1%) subjects discontinued during the initial phase of the study primarily due to adverse events (15, 7.2%) or lack of efficacy (13, 6.2%). Improvement in the ACR20 primary endpoint was seen in the Day 1, 15, and Week 12 treatment arm (relative to placebo) at week 16 (p<0.05). The ACR20/50/70 rates at week 16 were 71%/39%/12% in the Day 1, 15, and Week 12 arm versus 50%/26%/8% in the placebo arm. The DAS28 mean changes from baseline at week 16 were -2.12 in the Day 1, 15, and Week 12 arm versus -1.52 in the placebo arm (p<0.05). B cell depletion showed a clear biological response in relation to the different SBI-087 regimens engaged. The most frequently occurring adverse events in SBI-087 treated subjects (≥5 subjects), excluding infections, through the first 24 Weeks, were headache, leukopenia, pyrexia, RA exacerbation, diarrhea, nausea, and increased ALT. Most infections were mild to moderate in severity. There were no opportunistic infections. During the first 24 weeks, 11 subjects who received SBI-087 experienced serious adverse events. Only 5 subjects experienced mild to moderate injection site reactions. Conclusions SBI-087 administered subcutaneously was generally well tolerated. The 200 mg SBI-087 Day 1, 15, and Week 12 treatment arm achieved significant improvement in RA disease activity by week 16 compared to placebo. Disclosure of Interest N. Damjanov: None Declared, M. Tlustochowicz: None Declared, J. Aelion Grant/Research support from: Abbott, BMS, Celgene, Eli Lilly, Novartis, Pfizer, Takeda, Vertex, and UCB, Consultant for: Abbott, Amgen, Takeda, and UCB, A. Dimic: None Declared, M. Greenwald: None Declared, A. Diehl Employee of: Pfizer Inc., I. Bhattacharya Employee of: Pfizer Inc., S. Menon Employee of: Pfizer Inc., I. Gourley Employee of: Pfizer Inc.

SAT0439 Integrated safety summary of tofacitinib in psoriatic arthritis clinical studies

Background Tofacitinib is an oral Janus kinase inhibitor under investigation for psoriatic arthritis (PsA). Objectives To describe the safety profile of tofacitinib from integrated Phase (P)3 and long-term extension (LTE) studies. Methods Data 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. Results C1 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]). Conclusions Tofacitinib 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. Acknowledgements These studies were sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc. Disclosure of Interest G. Burmester Grant/research support from: UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Hexal, Janssen, MSD, MedImmune, Novartis, Pfizer Inc, Sanofi, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Hexal, MSD, Novartis, Pfizer Inc, Roche, O. FitzGerald Grant/research support from: AbbVie, Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Speakers bureau: Celgene, Janssen, Novartis, K. Winthrop Grant/research support from: Bristol-Myers Squibb, Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Pfizer Inc, UCB, G. Williams Consultant for: Pfizer Inc, V. Azevedo Grant/research support from: Bristol-Myers Squibb, GSK, Pfizer Inc, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Merck Novartis, Pfizer Inc, Serono, W. F. Rigby Grant/research support from: Amgen, Pfizer Inc, Roche, Consultant for: Bristol-Myers Squibb, Eli Lilly, Pfizer Inc, Roche, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, P. Biswas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Palmetto Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Rojo Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Evaluation of the Effect of Tofacitinib on the Pharmacokinetics of Oral Contraceptive Steroids in Healthy Female Volunteers

Tofacitinib is an oral Janus kinase inhibitor. Tofacitinib metabolism is primarily mediated by cytochrome P450 3A4. This phase 1 randomized, open‐label, 2‐way crossover study (NCT01137708) evaluated the effect of tofacitinib 30 mg twice daily on the single‐dose pharmacokinetics of combination oral contraceptives ethinylestradiol (EE) and levonorgestrel (LN). EE and LN were administered as a single Microgynon 30® tablet (30 μg EE and 150 μg LN) to 19 healthy women. In the presence of tofacitinib, the area under the curve from time zero to infinity (AUC∞) increased by 6.6% and 0.9% for EE and LN, respectively. Maximal plasma concentrations decreased by 10.4% for EE and increased by 12.2% for LN when coadministered with tofacitinib. The 90% confidence intervals for the adjusted geometric mean ratios for AUC∞ fell within the 80%–125% region for both EE and LN. Mean half‐life was similar in the presence and absence of tofacitinib: 13.8 and 13.3 hours, respectively, for EE; 25.9 and 25.4 hours, respectively, for LN. Tofacitinib had no clinically relevant net inhibitory or inductive effect on the pharmacokinetics of EE and LN. Therefore, there is no evidence to suggest dose adjustments of oral contraceptive drugs containing EE or LN when coadministered with tofacitinib.

THU0145 Association of Mean Changes in Laboratory Safety Parameters with C-Reactive Protein at Baseline and Week 12 in Rheumatoid Arthritis Patients Treated with Tofacitinib

Background Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Changes in laboratory parameters observed during tofacitinib treatment included mean increases in low (LDL) and high (HDL) density lipoproteins, serum creatinine (SCr) and mean decreases in neutrophils (ANC). It was of interest to understand the inter-relationship between drug and disease effects on these parameters [1]. Objectives To investigate potential explanatory mechanisms for these changes in laboratory parameters. Methods Baseline and Week 12 data from five Phase 3 (P3) nonbiologic or biologic disease-modifying anti-rheumatic drug-inadequate responder trials were pooled for each treatment arm: placebo, tofacitinib 5 mg and 10 mg twice daily (BID), and adalimumab 40 mg every other week (EOW). The defined laboratory parameters were explored with C-reactive protein (CRP) as a marker of inflammation. Mean changes at Week 12 were compared with quartile levels of CRP at baseline and quartiles of change in CRP at Week 12. Results Across the defined laboratory parameters, the smallest mean changes from baseline were observed in the quartile of patients with the smallest reductions in CRP (Figure, 1st quartile) and the greatest changes were observed with the greatest reductions in CRP (Figure, 4th quartile). A similar pattern of association was evident with baseline CRP, where the greatest mean changes in laboratory parameters occurred in patients with highest levels of baseline CRP. Numerical differences in the magnitude of changes across the treatment arms were observed, but no statistical comparisons were performed. Conclusions A consistent pattern of association between mean changes in each of the laboratory parameters and CRP was observed. The precise mechanism behind these laboratory changes is unknown. Based upon these analyses, the lowering of inflammation, as measured by CRP, may partly explain some of the observed mean changes in laboratory parameters during clinical studies. References Genovese MC et al. Arthritis and Rheumatism 2013; 65: S193 Acknowledgements Editorial support was provided by AM Reid, PhD, of CMC and funded by Pfizer Inc. Disclosure of Interest : V. Strand Consultant for: Pfizer Inc, J. Isaacs Consultant for: Pfizer Inc, J. Beal Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Nduaka Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Boy Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.4361