Irina Kaplan

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Objective Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. Methods A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). Results Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. Conclusions Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. Trial registration number NCT00976599.

Potential Mechanisms Leading to the Abnormal Lipid Profile in Patients With Rheumatoid Arthritis Versus Healthy Volunteers and Reversal by Tofacitinib

Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers.

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.

Effects of tofacitinib and other DMARDs on lipid profiles in rheumatoid arthritis: implications for the rheumatologist

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

THU0131 Tofacitinib (CP-690,550), an oral janus kinase inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical programme

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA). Objectives To evaluate the malignancies that occurred in the tofacitinib RA programme from the Phase (P) 2, 3, and long-term extension (LTE) studies up to 29 March 2011. Methods Data were pooled from 6 randomized P2, 5 randomized P3 studies and 2 open-label LTE studies. Patients (pts) in P3 and LTE studies were treated with tofacitinib 5 or 10 mg twice daily. Analyses included malignancy data from 1608 pts in P2, 3315 pts in P3, and 3227 pts in LTE studies (LTE pts rolled over from the P2 and P3 studies). Results A total of 4789 patients (5651 pt-yr) received tofacitinib in the P2, P3 and LTE studies. Fifty pts receiving tofacitinib (all doses) reported malignancies (excluding non-melanoma skin cancer [NMSC]); the most common were lung (12 cases) and breast cancer (9 cases). There were 3 lymphoma cases. The overall incidence rate (IR, events per 100 pt-yr) for all malignancies (excluding NMSC) was 0.89 (95% confidence interval [CI]: 0.67,1.17). The IRs (95% CI) of all malignancies (excluding NMSC) broken down into 0-6, 6-12, 12-18, 18-24 and >24 months based on exposure to study drug were 0.75 (0.46,1.23), 0.73 (0.41,1.28), 0.97 (0.48,1.94), 1.28 (0.53,3.08), and 1.37 (0.71,2.63), respectively. The number of cases in each time interval was small, with resultant wide CIs. The standardised incidence ratio (SIR) (95% CI) (as compared with the Surveillance Epidemiology and End Result database covering the general population) for all malignancies (excluding NMSC), lung, breast cancer and lymphomas in the tofacitinib group were 1.11 (0.82-1.47), 2.16 (1.12,3.77), 0.82 (0.38,1.56) and 1.74 (0.36,5.10), respectively. Twenty-one pts experienced NMSCs, for an IR of 0.37 (95% CI: 0.24,0.57). By comparison, the IR of NMSC in patients treated with anti-TNF was 0.47 (0.37-0.59) in a meta-analysis of randomized controlled trials and ranged from 0.23 to 0.35 in a meta-analysis of registries.1,2 Conclusions The malignancies that occurred in the tofacitinib RA programme are consistent with the type and distribution of malignancies expected for patients with moderate to severe RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer and lymphomas are consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs.3-6 Longer follow-up is necessary to further evaluate the potential risk of malignancies in the CP RA programme. 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. Disclosure of Interest X. Mariette Consultant for: Pfizer Inc, J. Curtis Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Kaplan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Chew 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, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Evaluation of the effect of fluconazole and ketoconazole on the pharmacokinetics of tofacitinib in healthy adult subjects

Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Two Phase 1, randomized, open‐label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2–7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1–3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed‐effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co‐administration and by 103% and 16%, respectively, with ketoconazole co‐administration. Tofacitinib half‐life increased by approximately 1 hour during co‐administration with fluconazole or ketoconazole. Co‐administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.

Evaluation of the potential interaction between tofacitinib and drugs that undergo renal tubular secretion using metformin, an in vivo marker of renal organic cation transporter 2

Tofacitinib is a novel, oral Janus kinase inhibitor. The potential for drug–drug interactions (DDIs) between tofacitinib and drugs that undergo renal tubular secretion was evaluated using metformin as a probe transporter substrate, and genotyping for organic cation transporter (OCT) 1, OCT2 and multidrug and toxin extrusion 1 polymorphisms.

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