M. Boy

Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Pharmacologic Effect of CP-690,550 in Patients With Psoriasis

CONFLICT OF INTEREST The authors state no conflict of interest. Penkanok Sriwiriyanont, Akira Hachiya, William L. Pickens, Shigeru Moriwaki, Atsushi Ohuchi, Takashi Kitahara, Yoshinori Takema, William J. Kitzmiller, Marty O. Visscher, Alexander Bello, Ryoji Tsuboi and Gary P. Kobinger Skin Sciences Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Kao Biological Science Laboratories, Haga, Tochigi, Japan; Department of Dermatology, Tokyo Medical University, Tokyo, Japan; Department of Surgery, University of Cincinnati, Cincinnati, OH, USA; Special Pathogens Program, Department of Medical Microbiology, National Microbiology Laboratory, Public Health Agency of Canada, University of Manitoba, Winnipeg, Canada E-mail: gary_kobinger@phac-aspc.gc.ca

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.

Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.

OBJECTIVES Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. METHODS Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. RESULTS Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). CONCLUSIONS Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Pharmacokinetics of tofacitinib, a janus kinase inhibitor, in patients with impaired renal function and end‐stage renal disease

The pharmacokinetics (PK) of tofacitinib were assessed in patients with mild (Cockcroft–Gault creatinine clearance >50 and ≤80 mL/min), moderate (≥30 and ≤50 mL/min), and severe (<30 mL/min) renal impairment, and end‐stage renal disease (ESRD) requiring dialysis. Six patients each with normal, mild, moderate, or severely impaired renal function, and 12 patients with ESRD, received single tofacitinib doses of 10 mg. PK data were obtained from blood and dialyzate (patients with ESRD only) samples prior and subsequent to dosing and/or hemodialysis (patients with ESRD only). Relative to patients with normal renal function, mean (90% CI) AUC(0–∞) ratios were 137% (97–195), 143% (101–202), and 223% (157–316) in patients with mild, moderate, and severe renal impairment, respectively. Maximum plasma concentrations (Cmax) were similar across the four treatment groups. Terminal phase half‐life (t1/2) increased with severity of renal impairment. Mean AUC(0–∞) in patients with ESRD on a non‐dialysis day was similar to that in patients with moderate renal impairment and approximately 40% greater than healthy volunteer data. Mean (SD) dialyzer efficiency (ratio of dialyzer clearance/blood flow entering the dialyzer) was 0.73 (0.15). However, due to extensive non‐renal clearance, dialysis procedure is unlikely to result in significant elimination of tofacitinib.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double‐blind, parallel‐group, placebo‐controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7–9 subjects were randomized to tofacitinib and 3–5 subjects to placebo. Ninety‐five males and females (age range 19–45) completed the study. Forty‐nine treatment‐emergent all‐causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax] 0.5–1 hour), rapid elimination (mean terminal half‐lives 2.3–3.1 hours), and dose‐proportional systemic exposures (peak serum concentration [Cmax] and area under the serum concentration‐time curve from time zero to infinity [AUC0–∞]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single‐dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs.

THU0136 Cardiovascular safety findings in rheumatoid arthritis patients treated with tofacitinib (CP-690,550), a novel, oral jak inhibitor

Background Tofacitinib is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA). Objectives To evaluate the cardiovascular (CV) event rates and changes in blood pressure (BP) in the tofacitinib Phase 3 (P3) and long-term open-label extension (LTE) studies. Methods Five P3 studies in patients (pts) with inadequate response to nonbiologic/biologic disease-modifying anti-rheumatic drugs (DMARDs) and 2 LTE studies were included. Tofacitinib was administered as monotherapy or with background nonbiologic DMARDs, predominantly methotrexate. One P3 study included adalimumab (ADA) as active control. An independent CV Safety Endpoint Adjudication Committee performed blinded adjudication of deaths, potential major adverse CV events (MACE), and events of congestive heart failure (CHF). MACE was defined as CV death and non-fatal CV events. Results: Table 1 All P3 Studies (0-12 Months) LTE Studies PBO *All Dose tofacitinib (5 and 10 mg BID) ADA 40 mg SC q2w All Dose tofacitinib (5 and 10 mg BID) (N=681) (N=3030) (N=204) (N=3227) Exposure 202.6 pt-y 2098.2 pt-y 178.9 pt-y 2622.2 pt-y MACE  Events (n) 2 14 3 5  IR per 100 pt-y (95% CI) 0.99 (0.25, 3.95) 0.57 (0.33, 1.01) 1.68 (0.54, 5.20) 0.19 (0.08, 0.46) CV Mortality  Events (n) 0 2 1 1  IR per 100 pt-y (95% CI) 0 0.10 (0.02, 0.38) 0.56 (0.08, 3.97) 0.04 (0.01, 0.27) Non-fatal myocardial infarction  Events (n) 0 4 2 1  IR per 100 pt-y (95% CI) 0 0.19 (0.07, 0.51) 1.12 (0.28, 4.47) 0.04 (0.01, 0.27) Non-fatal cerebrovascular accidents  Events (n) 2 8 0 3  IR per 100 pt-y (95% CI) 0.99 (0.25, 3.95) 0.33 (0.16, 0.70) 0 0.11 (0.04, 0.36) CHF  Events (n) 0 7 0 3  IR per 100 pt-y (95% CI) 0 0.29 (0.13, 0.64) 0 0.08 (0.02, 0.31) *Pts advanced from PBO to tofacitinib are “PBO” until advanced and only in “All Dose” post-advancement. MACE IRs (per 100 pt-y) in placebo (PBO) and tofacitinib groups in P3 were low. IR in the LTE studies in the tofacitinib All Dose group (0.19) was lower than in P3 (0.57). IRs of CHF in tofacitinib were low. In P3, mean changes from baseline at Month 3 for systolic and diastolic BP, respectively, were -0.1 mmHg and -0.8 mmHg for PBO and -0.2 and 0.3 mmHg for tofacitinib. Mean BP changes at Months 6 and 12 and in the LTE studies remained stable. Conclusions Incidence rates of MACE were similar across groups in P3 with lower rates in LTE, suggesting no increased risk over 3 years of follow up. Tofacitinib was not associated with clinically meaningful increases in BP. Although the number of events have been fewand longer observation periods are warranted, CV risk does not appear to be increased with tofacitinib treatment and rates of CV events are consistent with those observed among patients with RA of similar disease severity.1-3 References Solomon DH et al. Circulation 2003; 107: 1303-1307; Solomon DH et al. Ann Rheum Dis 2006; 65: 1608-1612; 3. Nicola PJ et al. Arthritis Rheum 2006; 54: 60-67. Disclosure of Interest C. Charles-Schoeman Grant/Research support from: Pfizer Inc., Consultant for: Pfizer Inc., P. Wicker Consultant for: Pfizer Inc., U. Sechtem Consultant for: Pfizer Inc., M. Gonzalez-Gay Consultant for: Pfizer Inc., S. Wood Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., M. Boy Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Geier Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., D. Gruben Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Soma Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., J. Bradley Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RA clinical development program.

THU0140 Tofacitinib (CP-690,550), an oral janus kinase inhibitor: Analysis of gastrointestinal adverse events across the rheumatoid arthritis clinical programme

Background Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator in rheumatoid arthritis (RA). Objectives To describe and report the incidence of gastrointestinal (GI) adverse events (AEs) that occurred in the tofacitinib RA programme up to 29 March 2011. Methods Data from 5 randomised Phase 3 (P3) studies or 2 open-label long-term extension (LTE) studies were pooled. Patients (pts) were treated with tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID, placebo (PBO; P3 only), or adalimumab (ADA; P3 only). Analyses of integrated safety data were from 3315 (P3; 2480 pt-y) and 3227 pts (LTE; 3118 pt-y) (LTE pts rolled over from P2 and P3). GI perforation data were analysed from P2 (1608 pts), P3, and LTE studies. Results In P3 studies, exposure-adjusted event rates (EAER) (per 100 pt-y) of AEs (regardless of causality) coding to the GI System Organ Class and MedDRA preferred term, Month (Mo) 0-12, was numerically lower in pts receiving tofacitinib 5 mg BID (33.48), 10 mg BID (31.03) and ADA (21.23) vs PBO (49.87). In LTE, EAERs of GI AEs were 17.52 and 25.26 in the 5 and 10 mg BID groups, respectively. GI AEs included gastritis, constipation, diarrhoea, abdominal pain, dyspepsia, nausea and vomiting; diarrhoea (3.4%) and nausea (2.3%) were the most frequently reported with tofacitinib. EAERs for discontinuations (DCs) due to GI AEs in P3 (Mo 0-3, PBO-controlled period) were similar for tofacitinib (doses combined) (1.52) and PBO (1.93); EAER for ADA was 4.26. EAERs for DCs due to GI AEs for Mo 3-6 and > Mo 6 were similar to Mo 0-3. EAERs for DCs due to GI AEs in LTE were numerically lower vs P3: 0.72 (5 mg) and 0.34 (10 mg). Abdominal pain was the most common GI cause leading to DC (0.1%) with tofacitinib. Serious adverse events (SAEs) (all causality) due to GI disorders were uncommon in P3 and LTE. In P3, no GI SAE occurred in more than one pt in any dose group during Mo 0-3, 3-6 and >6. In LTE the most common abdominal SAEs were pancreatitis (4 pts, 0.12%) and cholecystitis (5 pts, 0.15%). To assess the occurrence of GI perforations, potential cases were retrospectively reviewed by Pfizer gastroenterologists based on pre-specified criteria. Ten cases of probable or definite perforation occurred in tofacitinib-treated pts; one resulted in death associated with appendicitis and sepsis. The overall GI perforation incidence rate was 0.18 (95% CI 0.095, 0.329) events per 100 pt-y. GI perforations primarily involved the lower GI tract (9 pts), and generally occurred in pts with other underlying risk factors, eg non-steroidal anti-inflammatory drugs (7 pts), glucocorticoid use (8 pts), or comorbidity of diverticulitis (3 pts). Conclusions GI AEs occurred commonly in all treatment groups including PBO, but were uncommon causes for DCs. Serious GI AEs were uncommon. The rate of GI perforation falls between the rates reported for pts treated with tocilizumab (0.19) and TNF inhibitors (0.13).1 References Gout T et al. Clin Rheumatol 2011; 30: 1471-1474. Disclosure of Interest E. B. Lee Consultant for: Pfizer Inc., J. Curtis Grant/Research support from: Pfizer Inc., Consultant for: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., C. Connell Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Chew Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., M. Boy Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., E. Maller Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., C. Su 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.

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