Efficacy and safety of etrasimod in patients with ulcerative colitis in Japan: data from the phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN trials.

INTRODUCTION: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. METHODS: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at Week 12 and Week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. RESULTS: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at Week 12 (etrasimod: 14.3%; placebo: 7.1%) and Week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. CONCLUSION: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations. CLINICALTRIALS: gov: NCT03945188; NCT03996369; NCT04706793.

Cost-Effectiveness Analysis of Tofacitinib Compared with Biologics in Biologic-Naïve Patients with Moderate-to-Severe Ulcerative Colitis in Japan.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). The objective of this study was to evaluate the long-term cost-effectiveness of tofacitinib versus current biologics, considering combinations of first-line (1L) and second-line (2L) therapies, from a Japanese payer's perspective in patients with moderate-to-severe active UC following an inadequate response to conventional therapy and in those who were naïve to biologics. METHODS: A cost-effectiveness analysis was conducted during the time horizon specified in the Markov model, which considers a patient's lifetime as 60 years and an annual discount rate of 2% on costs and effects. The model compared tofacitinib with vedolizumab, infliximab, adalimumab, golimumab, and ustekinumab. The time of active treatment was divided into induction and maintenance phases. Patients not responding to their biologic treatment after induction or during the maintenance phase were switched to a subsequent line of therapy. Treatment response and remission probabilities (for induction and maintenance phases) were obtained through a systematic literature review and a network meta-analysis that employed a multinomial analysis with fixed effects. Patient characteristics were sourced from the OCTAVE Induction trials. Mean utilities associated with UC health states and adverse events (AEs) were obtained from published sources. Direct medical costs related to drug acquisition, administration, surgery, patient management, and AEs were derived from the JMDC database analysis, which corresponded with the medical procedure fees from 2021. The drug prices were adjusted to April 2021. Further validation through all processes by clinical experts in Japan was conducted to fit the costs to real-world practices. Scenario and sensitivity analyses were also performed to confirm the accuracy and robustness of the base-case results. RESULTS: In the base-case, the treatment pattern including 1L tofacitinib was more cost-effective than vedolizumab, infliximab, golimumab, and ustekinumab for 1L therapies in terms of cost per quality-adjusted life year (QALY) gained (based on the Japanese threshold of 5,000,000 yen/QALY [38,023 United States dollars {USD}/QALY]). The base-case results demonstrated that the incremental costs would be reduced for all biologics, and decreases in incremental QALYs were observed for all biologics other than adalimumab. The incremental cost-effectiveness ratio (ICER) was found to be dominant for adalimumab; for the other biologics, it was found to be less costly and less efficacious. The efficiency frontier on the cost-effectiveness plane indicated that tofacitinib-infliximab and infliximab-tofacitinib were more cost-effective than the other treatment patterns. When infliximab-tofacitinib was compared with tofacitinib-infliximab, the ICER was 282,609,856 yen/QALY (2,149,157 USD/QALY) and the net monetary benefit (NMB) was -12,741,342 yen (-96,894 USD) with a threshold of 5,000,000 yen (38,023 USD) in Japan. Therefore, infliximab-tofacitinib was not acceptable by this threshold, and tofacitinib-infliximab was the cost-effective treatment pattern. CONCLUSION: The current analysis suggests that the treatment pattern including 1L tofacitinib is a cost-effective alternative to the biologics for patients with moderate-to-severe UC from a Japanese payer's perspective.

Incidence rates for hospitalized infections, herpes zoster, and malignancies in patients with ulcerative colitis in Japan: an administrative health claims database analysis.

BACKGROUND/AIMS: Patients with ulcerative colitis (UC) are at an increased risk of certain infections and malignancies compared with the general population. Incidence rates (IRs) of hospitalized infections, herpes zoster (HZ), and malignancies in patients with UC, stratified by treatment, in Japan were estimated. METHODS: This retrospective study identified patients with UC treated with corticosteroids, immunosuppressants, or tumor necrosis factor inhibitors (TNFi) from 2 administrative databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). IRs (unique patients with events per 100 patient-years) were estimated for hospitalized infections, HZ, and malignancies, between June 2010 and May 2018. RESULTS: Among 6,033 MDV patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: hospitalized infections, 1.73 (1.52-1.93); HZ, 1.00 (0.85-1.16), and malignancies, 1.48 (1.29-1.66). Among 958 JMDC patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: HZ, 1.82 (1.27-2.37) and malignancies, 1.35 (0.87-1.82). In both cohorts, IRs of malignancies were generally similar among patients receiving immunosuppressants, TNFi, or combination therapy (immunosuppressants and TNFi); this was also true for IRs of hospitalized infections and HZ in the MDV cohort. IRs of hospitalized infections, HZ, and malignancies were higher in patients receiving calcineurin inhibitors compared with immunosuppressants or TNFi, in both cohorts. CONCLUSIONS: IRs of hospitalized infections, HZ, and malignancies among patients with UC were generally similar regardless of UC treatment, except for calcineurin inhibitors.

Notable gaps between patients' and physicians' perspectives on communication and disease management in Japan: multifaceted ad hoc analyses of the global Ulcerative Colitis Narrative Survey for further optimal care.

Introduction: The patient-physician relationship is important in implementing appropriate management strategies. The Ulcerative Colitis (UC) Narrative Global Surveys examined patient and physician views on multiple aspects of living with UC. However, there are many other important undiscovered aspects of UC to consider for patients in Japan. Aim: The aim of these ad hoc analyses was to identify detailed practical issues for further optimal care. Methods: Patient and physician questionnaires covered broad aspects of living with UC and practical care. Results were compared to identify gaps. We conducted multifaceted ad hoc analyses on the responses from Japan. Results: In Japan, 210 patients with UC and 151 physicians were surveyed. Most (64%) patients felt they would be more successful if they did not have UC. Physicians were more likely to discuss treatment-related topics, including side effects as a proxy for medication satisfaction, than quality of life-related topics. Physicians underestimated the importance to patients of toileting accidents (28% vs 54%) and overestimated the importance of mucosal healing (59% vs 29%). Although 72% of patients felt comfortable raising concerns with their physician, 53% worried about asking too many questions, as they thought they would be seen as a difficult patient, and 66% wished they had talked more about medication fears. The majority (83%) of patients said they were honest with their physician when discussing their experiences with UC, although 45% regretted not telling them more. Some (26%) patients believed, and some (20%) were not sure, that if their symptoms were under control then their UC was not active. More positively, 65% of patients agreed that UC had made them more appreciative of the important things in life. Conclusion: This survey revealed notable gaps between patients' and physicians' perspectives. Consequently, the importance of patient-physician communication remains constant, even in the era of biologics and treat-to-target strategies. Plain Language Summary: Overlap and differences in views around communication and management of ulcerative colitis between patients and doctors It is important to discover the different ways that ulcerative colitis (UC) can impact individual patients, and to identify differences in views between people with UC and the doctors treating them, to improve patient care. The UC Narrative is a global survey (containing two questionnaires, one for patients, and one for doctors) that gathers information on how UC impacts patients. The survey aims to identify differences between patients' and doctors' views on communication and disease management.In this analysis, we report the results from 210 patients with UC and 151 doctors who completed the UC Narrative survey in Japan, between November 2017 and January 2018. Most patients (85%) were satisfied with their communication with their doctor. However, doctors underestimated patient satisfaction, as they believed that about 71% of their patients were satisfied with communication. Around two-thirds of patients (65%), and most doctors (82%), wanted more discussion about goals for managing or treating UC. Most patients (83%) said they were honest with their doctor when discussing their experiences with UC, although almost half of patients (45%) said they regretted not telling their doctor more. Three-quarters of doctors (75%) felt that their patients were honest with them. Doctors underestimated the importance of toileting accidents to patients and thought that healing the patients' intestine would be more important to the patients than toileting accidents. Some patients had misconceptions about treatment. For example, only 69% of patients knew that it was not OK to stop taking their UC medications once they felt better. This survey shows that even though treatment options for UC have developed, sufficient communication between patients and doctors is very important for overall patient care.

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.

Real-World Insurance Claims Analysis of Venous Thromboembolism in Japanese Patients with Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD), which encompasses both ulcerative colitis (UC) and Crohn's disease (CD), is a risk factor for venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). AIM: To investigate the incidence of, and risk factors for, VTE in patients with IBD in Japan. METHODS: This was a retrospective, non-interventional study in patients with IBD from the Japan Medical Data Center claims database. Incidence rates (IRs; unique patients with events per 100 patient-years) were calculated for VTE, DVT, and PE among the IBD, UC, and CD cohorts. Odds ratios of potential risk factors were calculated by univariate and multivariate analyses in a nested case-control design. RESULTS: Overall, 16 273 patients with IBD were included: 13 585 with UC and 3443 with CD. VTE events occurred in 1.3%, 1.2%, and 1.9% of patients with IBD, UC, and CD, respectively. In patients with IBD, UC, and CD, IRs of VTE were 0.45, 0.40, and 0.64, respectively, IRs of DVT were 0.42, 0.38, and 0.61, respectively, and IRs of PE were 0.07, 0.07, and 0.11, respectively. In patients with IBD, treatment history (immunomodulators), cardiovascular risk (hypertension, high-density lipoprotein or diabetes mellitus, and history of coronary artery disease or heart failure), malignancy, and undergoing major surgery were identified as potential risk factors for VTE in the multivariate analysis, with similar risk factors reported for patients with UC and CD. CONCLUSIONS: This large study provides insight into the incidence and risk factors for VTE in patients with IBD from Japan.

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.

Serotonin syndrome triggered by postoperative administration of serotonin noradrenaline reuptake inhibitor (SNRI).

BACKGROUND: Serotonin syndrome is a rare but potentially severe disease, which is caused by hyperstimulation of serotonin receptors in the central nervous system. Several antidepressants exert their effect by modulating intrasynaptic serotonin concentration and anesthetics may affect the metabolism of serotonin, implicating to induce serotonin syndrome in patients taking those antidepressants. We present a case which provoked serotonin syndrome immediately after taking serotonin noradrenaline reuptake inhibitor (SNRI) in the postoperative period. CASE PRESENTATION: A 31-year-old female underwent laparoscopic ovarian cystectomy under general anesthesia with propofol, fentanyl, and remifentanil. She has been taking duloxetine, a SNRI for depression. She developed myoclonus seizure with an increase of blood pressure and heart rate after taking duloxetine on the day after the surgery, which was subsided by a non-selective serotonin receptor antagonist. CONCLUSIONS: Anesthesiologists should be aware of the risk of perioperative serotonin syndrome in patients taking antidepressants affecting serotonin metabolism.

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data.

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients. Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3 mg), 5 mg, 10 mg) twice daily (BID) or placebo, with low-dose (>0 to 8 mg/week) or high-dose (>8 mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3. Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5 mg BID, 56.5%/64.3%; 10 mg BID, 73.8%/67.7%. Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5 mg BID, but not 10 mg BID, with no apparent differences across system organ class/laboratory parameters.

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.

Fear memory consolidation in sleep requires protein kinase A.

It is well established that protein kinase A (PKA) is involved in hippocampal dependent memory consolidation. Sleep is also known to play an important role in this process. However, whether sleep-dependent memory consolidation involves PKA activation has not been clearly determined. Using behavioral observation, animals were categorized into sleep and awake groups. We show that intrahippocampal injections of the PKA inhibitor Rp-cAMPs in post-contextual fear conditioning sleep produced a suppression of long-term fear memory, while injections of Rp-cAMPs during an awake state, at a similar time point, had no effect. In contrast, injections of the PKA activator Sp-cAMPs in awake state, rescued sleep deprivation-induced memory impairments. These results suggest that following learning, PKA activation specifically in sleep is required for the consolidation of long-term memory.

An international validation study of a Bhas 42 cell transformation assay for the prediction of chemical carcinogenicity.

The Bhas 42 cell transformation assay is a sensitive short-term system for predicting chemical carcinogenicity. Bhas 42 cells were established from BALB/c 3T3 cells by the transfection of v-Ha-ras gene and postulated to have acquired an initiated state in the two-stage carcinogenesis theory. The Bhas 42 cell transformation assay is capable of detecting both tumor-initiating and tumor-promoting activities of chemical carcinogens. The full assay protocol consists of two components, the initiation assay and the promotion assay, to detect the initiating activity and the promoting activity, respectively. An international study was carried out to validate this cell transformation assay in which six laboratories from three countries participated. Twelve coded chemicals were examined in total and each chemical was tested by three laboratories. In the initiation assay, concordant results were obtained by three laboratories for eight out of ten chemicals and in the promotion assay, concordant results were achieved for ten of twelve chemicals. The positive results were obtained in all three laboratories with the following chemicals: 2-acetylaminofluorene was positive in both initiation and promotion assays; dibenz[a,h]anthracene was positive in the initiation assay; sodium arsenite, lithocholic acid, cadmium chloride, mezerein and methapyrilene hydrochloride were positive in the promotion assay. o-Toluidin hydrochloride was positive in the both assays in two of the three laboratories. d-Mannitol, caffeine and l-ascorbic acid were negative in both assays in all the laboratories, and anthracene was negative in both assays in two of the three laboratories except one laboratory obtaining positive result in the promotion assay. Consequently, the Bhas 42 cell transformation assay correctly discriminated all six carcinogens and two tumor promoters from four non-carcinogens. Thus, the present study demonstrated that the Bhas 42 cell transformation assay is transferable and reproducible between laboratories and applicable to the prediction of chemical carcinogenicity. In addition, by comparison of the present results with intra-laboratory data previously published, within-laboratory reproducibility using the Bhas 42 cell transformation assay was also confirmed.

A Bhas 42 cell transformation assay on 98 chemicals: the characteristics and performance for the prediction of chemical carcinogenicity.

The Bhas 42 cell transformation assay is a short-term system using a clone of the BALB/c 3T3 cells transfected with an oncogenic murine ras gene (v-Ha-ras). The assay has previously been reported to be capable of detecting the tumor-initiating and tumor-promoting activities of chemical carcinogens according to the different protocols, an initiation assay and a promotion assay, respectively. We applied this short-term assay to 98 chemicals to characterize the assay and evaluate its performance for the detection of chemical carcinogenicity. When the assay results were compared with the existing genotoxicity data, the Bhas 42 cell transformation assay could detect a considerable number of Ames-negative and Ames-discordant carcinogens: and the promotion assay detected most of those Ames-negative and -discordant carcinogens. This fact suggested that the Bhas 42 cells behaved as initiated cells in the transformation assay. The performance indices were calculated from the assay results of 52 carcinogens and 37 non-carcinogens. The concordance was 78%, sensitivity 73%, specificity 84%, positive predictivity 86%, negative predictivity 69%, false negative 27% and false positive 16%. Of these values, the concordance, specificity, negative predictivity and false positive were superior and the other performance indices were equivalent to those of conventional genotoxicity tests. From overall results, we concluded that the accuracy of prediction of chemical carcinogenicity would be improved by introducing the Bhas 42 cell transformation assay into the battery of in vitro assays.