Safety and efficacy of long-term tofacitinib treatment in East Asian patients with ulcerative colitis in OCTAVE Open.

BACKGROUND AND AIM: Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present safety and efficacy data from patients from East Asia (Japan, Korea, and Taiwan) in OCTAVE Open, an open-label, long-term extension study. METHODS: Patients in remission at OCTAVE Open baseline received tofacitinib 5 mg twice daily (BID); all others received tofacitinib 10 mg BID. Proportions and IRs (unique patients with events/100 patient-years) were calculated for adverse events (AEs) of special interest. Efficacy endpoints were evaluated up to 36 months. RESULTS: In OCTAVE Open, 105/944 patients were from East Asia (tofacitinib 5 mg BID, n = 22; tofacitinib 10 mg BID, n = 83). Overall, 87.6% and 24.8% of patients had AEs and serious AEs, respectively; IRs (95% CI) for AEs of special interest were herpes zoster (HZ; non-serious and serious), 6.07 (3.40-10.02); serious infections, 1.47 (0.40-3.76); opportunistic infections, 1.91 (0.62-4.45); major cardiovascular adverse events, 0.37 (0.01-2.04); malignancies (excluding non-melanoma skin cancer [NMSC]), 0.37 (0.01-2.04); and NMSC, 0.00 (0.00-1.35). No deaths, venous thromboembolic events, or gastrointestinal perforations occurred. At month 36, 68.2% and 54.2% of patients had a clinical response, 68.2% and 53.0% had endoscopic improvement, and 63.6% and 49.4% were in remission with tofacitinib 5 and 10 mg BID, respectively. CONCLUSIONS: The HZ IR in East Asian patients was numerically higher versus the global study population; excluding HZ, tofacitinib safety and efficacy were consistent with the global study population.

Tofacitinib as Induction and Maintenance Therapy in Japanese Patients with Active Ulcerative Colitis.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor approved in Japan for the treatment of ulcerative colitis (UC). Differences in the safety profile of tofacitinib in Japanese patients versus the global population, such as a higher risk of herpes zoster, have been reported. OBJECTIVES: We conducted post hoc analyses of tofacitinib treatment in Japanese patients with moderate-to-severe UC in two global phase III studies. METHODS: In OCTAVE Induction 1 (NCT01465763), 62 patients were randomized to placebo or tofacitinib 10 mg twice daily (b.i.d.). In OCTAVE Sustain (NCT01458574), 39 patients with clinical response in OCTAVE Induction 1 were re-randomized to placebo, tofacitinib 5 mg, or 10 mg b.i.d. Efficacy endpoints included: remission (primary endpoint; total Mayo score ≤2; no individual subscore >1; rectal bleeding subscore 0); mucosal healing (Mayo endoscopic subscore ≤1); clinical response (≥30% and ≥3-point decrease from induction study baseline total Mayo score; decrease in rectal bleeding subscore ≥1 or absolute subscore ≤1). Adverse events (AEs) and clinical laboratory parameters were recorded. RESULTS: At week 8 of OCTAVE Induction 1, 22.4% of patients achieved remission with tofacitinib (placebo, 7.7%). At week 52 of OCTAVE Sustain, 31.3% and 66.7% of patients receiving tofacitinib 5 and 10 mg b.i.d., respectively, achieved remission (placebo, 9.1%). The occurrence of AEs or serious AEs in Japanese patients was generally similar to that in the global study population, with no new or unexpected safety risks observed. CONCLUSIONS: Although patient numbers were small, tofacitinib demonstrated numerically greater efficacy versus placebo among Japanese patients in OCTAVE Induction 1 and OCTAVE Sustain, with a safety profile consistent with that of the global study population.

Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study.

Objective: Tofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX. Methods: Phase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was <0.6. Results: At week 12, with tofacitinib MR 11 mg QD and IR 5 mg BID, respectively, the change from baseline in least squares mean DAS28-4(CRP) was -2.43 and -2.85; the mean difference was 0.43 (95% CI 0.17, 0.69). Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met. Improvement of DAS28-4(CRP) ⩾1.2 was observed in 89 and 85% of patients, respectively, corresponding to a clinically important, significant change in both groups. The frequency of adverse events (52.9 and 51.4%, respectively) and serious adverse events (4.8 and 3.8%, respectively) was generally similar between treatments. No deaths were reported. Conclusion: Non-inferiority of MR 11 mg QD to IR 5 mg BID was not met in this study. However, clinically meaningful improvements in RA were observed with both tofacitinib formulations in Japanese patients. The safety profile was similar with both formulations. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02281552.

Corrigendum: Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies.

[This corrects the article on p. 233 in vol. 16, PMID: 29743836.].

Tofacitinib induction and maintenance therapy in East Asian patients with active ulcerative colitis: subgroup analyses from three phase 3 multinational studies.

BACKGROUND/AIMS: Tofacitinib is an oral, small-molecule Janus kinase inhibitor being investigated for ulcerative colitis (UC). In OCTAVE Induction 1 and 2, patients with moderately to severely active UC received placebo or tofacitinib 10 mg twice daily (BID) for 8 weeks. Clinical responders in OCTAVE Induction were re-randomized to 52 weeks' therapy with placebo, tofacitinib 5 mg BID, or tofacitinib 10 mg BID. METHODS: We conducted post-hoc efficacy and safety analyses of East Asian patients in OCTAVE Induction 1 and 2 and OCTAVE Sustain. RESULTS: A total of 121 East Asian (Japan, Korea, and Taiwan) patients were randomized in OCTAVE Induction 1 and 2 (placebo, n=26; tofacitinib 10 mg BID, n=95), and 63 in OCTAVE Sustain (placebo, n=20; tofacitinib 5 mg BID, n=22; tofacitinib 10 mg BID, n=21). At week 8 of OCTAVE Induction 1 and 2, 18.9% of patients (18/95) achieved remission with tofacitinib 10 mg BID versus 3.8% (1/26) with placebo. In OCTAVE Sustain, the week 52 remission rates were 45.5% (10/22), 47.6% (10/21), and 15.0% (3/20) with 5 mg BID, 10 mg BID, and placebo, respectively. Adverse event rates were similar between groups in OCTAVE Induction and numerically higher with tofacitinib in OCTAVE Sustain. Serious adverse event rates were similar across groups in all studies. Infections were numerically more frequent with tofacitinib than placebo. Increases in serum lipid levels were observed with tofacitinib. CONCLUSIONS: In East Asian patients with UC, tofacitinib demonstrated numerically greater efficacy versus placebo as induction and maintenance therapy, with a safety profile consistent with the global study population. ClinicalTrials.gov: NCT01465763; NCT01458951; NCT01458574.

Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented. METHODS: Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study. RESULTS: A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion. CONCLUSIONS: Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population. TRIAL REGISTRATION: Clinicaltrials.gov NCT00661661 . Registered 7 February 2008.

Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials.

Abstract Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.

A Comparison of the Pharmacokinetics and Drug Safety Among East Asian Populations.

Global clinical studies conducted in various countries and regions are increasing. Race and extrinsic ethnic factors are key covariates that may affect the pharmacokinetics (PK), efficacy, and safety of the drug. Genetic similarity among East Asian populations has been confirmed; thus, PK, efficacy, and safety in these populations are expected to be similar, but this has not been confirmed. This study presents a comparison of PK and safety among East Asians from clinical studies sponsored by Pfizer. Four compounds with different characteristics, including mechanism of actions and PK profiles, were selected, and retrospective PK and safety comparisons in East Asians were conducted. No distinct differences were observed in PK and safety across the 4 compounds. These results are consistent with previous reports on PK comparisons and meet the expectations based on genetic similarity among East Asians. Extrapolation of these findings to other compounds should be done with caution, but these results should support the consideration of mutual use of clinical data among East Asian countries.

A phase 3 randomized, double-blind, multicenter comparative study evaluating the effect of etanercept versus methotrexate on radiographic outcomes, disease activity, and safety in Japanese subjects with active rheumatoid arthritis.

OBJECTIVES: The aim of this phase 3, double-blind study was to compare the radiographic and clinical effects of etanercept (ETN) versus methotrexate (MTX) over 52 weeks in Japanese subjects with active rheumatoid arthritis. METHODS: The study population comprised 550 subjects with inadequate response to ≥1 disease-modifying anti-rheumatic drugs who were randomized to treatment groups of ETN 25 mg twice weekly (BIW; n = 182), ETN 10 mg BIW (n = 192), or MTX (≤8.0 mg/week; n = 176). RESULTS: Of the 550 subjects initially enrolled in the three treatment groups, 21.6% discontinued the study; a significantly higher proportion of those who withdrew from the study due to lack of efficacy were in the MTX (21.6%) group compared with the ETN 25 mg (3.3%) and ETN 10 mg (6.8%) groups (P < 0.001). Mean change from baseline in the modified total Sharp score at week 52 (primary endpoint) was significantly lower in the ETN 25 mg [3.33; standard error (SE), 0.73] and ETN 10 mg (5.19; SE 0.93) groups than in the MTX group (9.82; SE 1.16; P < 0.0001 vs. either ETN group). Compared with subjects receiving MTX, significantly higher percentages of subjects treated with ETN 25 and 10 mg achieved American College of Rheumatology (ACR) ACR20 and ACR50 response rates at all time points (P < 0.01). ETN was well-tolerated, with no unexpected safety findings. CONCLUSIONS: ETN 25 mg BIW and ETN 10 mg BIW slowed radiographic progression and improved clinical outcomes more effectively than MTX in this Japanese population.

Safety and efficacy of long-term etanercept in the treatment of methotrexate-refractory polyarticular-course juvenile idiopathic arthritis in Japan.

OBJECTIVES: Previous short-term trials found etanercept (0.2 or 0.4 mg/kg) to be effective and well tolerated in Japanese children with juvenile idiopathic arthritis (JIA) who were intolerant/resistant to methotrexate. The aim of this study was to evaluate the long-term safety and efficacy of etanercept in Japanese children with JIA. METHODS: Patients (4-19 years) who received etanercept in one of three short-term studies continued onto this long-term open-label study. RESULTS: Of the 32 patients enrolled, 18 (56.3%) completed 192 weeks of the study and 14 (43.8%) were discontinued; 7 (21.9%) for patient refusal, 2 (6.3%) for adverse events (AEs), and 5 (15.6%) for lack of efficacy. All patients reported AEs; 31 (96.9%) reported infections and 6 (18.8%) reported serious AEs. Main efficacy assessments included change from baseline in the American College of Rheumatology Pediatric core components, including mean improvements from baseline in the physician global assessment (90.7%), patient/guardian global assessments (54.1%), Childhood Health Assessment Questionnaire (84.6%), and median improvements in C-reactive protein levels (92.7%). No unexpected safety results were reported, and early efficacy responses were sustained in the long term. CONCLUSIONS: This study provides further evidence that etanercept is an effective therapeutic option for Japanese children with polyarticular-course JIA.

Etanercept in the treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory polyarticular course juvenile idiopathic arthritis: experience from Japanese clinical trials.

Efficacy, safety, and pharmacokinetics results from 4 studies-3 open-label (OL) and 1 randomized double-blind (DB)-have provided data for approval of etanercept for treatment of disease-modifying anti-rheumatic drug (DMARD)-refractory juvenile idiopathic arthritis (JIA) in Japan. Results from the 3 shorter-term (2 OL and 1 DB) studies are reported here. Subjects (4-17 years) enrolled in the OL studies had active JIA, i.e. ≥5 swollen joints and ≥3 joints with limitation of motion and pain or tenderness. Subjects enrolled in the primary OL study received etanercept 0.4 mg/kg subcutaneously twice weekly; in the lower-dose OL study subjects received etanercept 0.2 mg/kg. Subjects in the primary OL study who completed ≥48 weeks could continue into a 12-week DB dose-down extension study in which subjects received etanercept 0.4 or 0.2 mg/kg twice weekly. The primary endpoint in all 3 studies, i.e. 30% improvement in the American College of Rheumatology criteria for JIA (ACR Pedi 30) at 12 weeks, was achieved by ≥80% of subjects by week 2 and sustained to week 12. Common adverse events reported were injection site reactions, nasopharyngitis, and gastroenteritis. These results provide further evidence that etanercept is effective therapy for DMARD-refractory polyarticular JIA patients.