Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: 2-Year Interim Results from the Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. METHODS: Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). RESULTS: A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. CONCLUSION: UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

Growth analysis among adolescents with moderate-to-severe atopic dermatitis receiving upadacitinib in combination with topical corticosteroids in Japan: A case study series from a phase 3, randomized, controlled trial (Rising Up).

Background: Treatment options for adolescents with moderate-to-severe atopic dermatitis (AD) are limited. Oral corticosteroid therapies are used to treat children and adolescents with moderate-to-severe AD; however, long-term use is not recommended because of potential growth impairment. Upadacitinib, an oral Janus kinase inhibitor, is approved to treat moderate-to-severe AD in the United States, Japan, and Europe. To investigate potential effects of upadacitinib on growth, we analyzed height and height velocity in 6 adolescent patients in the phase 3 Rising Up study who were in the decline phase of pubertal growth at the time of study entry. Methods: The randomized, double-blind, Rising Up (NCT03661138) study compared upadacitinib plus topical corticosteroids (TCS) to placebo plus TCS in adolescents and adults with moderate-to-severe AD in Japan. Eligible adolescents (aged 12-17 years) were randomized 1:1:1 to receive once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo in combination with TCS for 16 weeks. After 16 weeks, patients randomized to receive placebo were rerandomized 1:1 to receive upadacitinib 15 mg or upadacitinib 30 mg. Historical height measurements were obtained when available. Individual growth and growth velocity curves were compared with standard curves for Japanese youths. This non-prespecified analysis used 52-week data. Results: Of the 29 adolescents enrolled, 6 were in the decline phase of pubertal growth at enrollment. Growth curves and growth velocity curves for these 6 patients remained within the normal range for Japanese adolescents throughout the study. Biomarkers of bone metabolism generally remained stable over the course of the study. No musculoskeletal adverse events were reported. Conclusions: No cases suggested that upadacitinib negatively affected adolescent growth. Ongoing studies will continue to assess height and adverse effects related to bone growth to further inform on this patient group. Trial registration: ClinicalTrials.gov Identifier NCT03661138.

A phase 3 randomized, multicenter, double-blind study to evaluate the safety of upadacitinib in combination with topical corticosteroids in adolescent and adult patients with moderate-to-severe atopic dermatitis in Japan (Rising Up): An interim 24-week analysis.

BACKGROUND: Systemic atopic dermatitis treatments that have acceptable safety are needed. OBJECTIVE: To evaluate the safety of the oral Janus kinase inhibitor upadacitinib in combination with topical corticosteroids (TCSs) for the treatment of atopic dermatitis. METHODS: In this phase 3, double-blind study (Rising Up), Japanese patients (12-75 years) with moderate-to-severe atopic dermatitis were randomized in a 1:1:1 ratio to receive 15 mg of upadacitinib + TCS, 30 mg of upadacitinib + TCS, or a placebo + TCS (rerandomized in a 1:1 ratio to receive either 15 or 30 mg of upadacitinib + TCS at week 16). Adverse events and laboratory data were assessed for safety. RESULTS: In 272 treated patients, the serious adverse event rates were similar for 15- and 30-mg upadacitinib + TCS at week 24 (15 mg, 56%; 30 mg, 64%) but greater than those for placebo + TCS (42%). Acne (all mild or moderate; none leading to discontinuation) occurred more frequently with upadacitinib + TCS (15 mg, 13.2%; 30 mg, 19.8%) than with placebo + TCS (5.6%). Furthermore, herpes zoster infection (4.4% vs 0%), anemia (1.1% vs 0%), neutropenia (4.4% vs 1.1%), and creatine phosphokinase elevations (2.2% vs 1.1%) occurred more frequently with 30-mg upadacitinib + TCS than with 15-mg upadacitinib + TCS; none of these events were reported with placebo + TCS. No thromboembolic events, malignancies, gastrointestinal perforations, active tuberculosis, or deaths occurred. LIMITATIONS: The limitations included a small sample size and short observation period as well as nongeneralizability of the results beyond Japanese populations. CONCLUSIONS: The results were generally consistent with those of previous reports; no new safety risks were detected.

Sample size and proportion of Japanese patients in multi-regional trials.

In recent years, multi-regional trials have received increasing attention by pharmaceutical companies carrying out global drug development programs. In Japan, new drugs are often approved several years after market release in other countries. The recently published guidance on 'Basic Principles on Global Clinical Trials' addresses specifically this time lag. A multi-regional trial has at least two main objectives. First, it is necessary to show a significant benefit in effect of a new drug in the entire population. Second, one needs to demonstrate that the results for a particular region are consistent with those from the entire population. In this paper, we discuss the methods proposed in the Japanese regulatory guidance document and derive closed form expressions for the resulting probabilities, which require the evaluation of multivariate normal or t probabilities. In addition, we propose an alternative method with better operating characteristics than the current approaches. Moreover, we examine the performance of our suggested method by simulating the probability of achieving the objectives and calculating the false-positive error rate.

One year treatment with omalizumab is effective and well tolerated in Japanese Patients with moderate-to-severe persistent asthma.

BACKGROUND: We have previously demonstrated that addition of omalizumab to standard therapy improved asthma control by significantly improving lung function and reducing asthma exacerbations in Japanese patients with moderate-to-severe asthma. The aim of this study was to evaluate the effects of omalizumab on long-term disease control in Japanese patients with moderate-to-severe persistent asthma. METHODS: An open-label, 48-week study was conducted in 133 Japanese patients with moderate-to-severe persistent asthma. Omalizumab was administered subcutaneously every 2 or 4 weeks based on serum IgE level and body weight in each patient. RESULTS: Treatment with omalizumab significantly improved lung function. A subgroup of patients with inadequately controlled severe persistent asthma, despite high dose inhaled corticosteroids and other multiple controller therapies, which corresponds to the Japanese label (label population), showed greater improvements in morning PEF and FEV(1) than the whole study population (full Analysis Set). Serum free IgE levels decreased to below the target and were maintained during the treatment period in almost all patients. The majority of adverse events were mild-to-moderate in severity and there was no trend toward an increase in incidence of adverse events with increase in duration of omalizumab. In addition, the profile of adverse events in this study was similar to that in a 16-week, placebo-controlled study which the present authors had conducted previously in Japan. There were no anaphylactic reactions and no anti-omalizumab antibodies were detected. CONCLUSIONS: Long-term treatment with omalizumab is effective and well tolerated in Japanese patients with moderate-to-severe persistent asthma.

Efficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: a subgroup analysis from the SHINE study.

BACKGROUND: COPD-related deaths are increasing in Japan, with ~5.3 million people at risk. METHODS: The SHINE was a 26-week, multicenter, randomized, double-blind, parallel-group study that evaluated safety and efficacy of indacaterol (IND)/glycopyrronium (GLY) 110/50 µg once daily (od) compared with GLY 50 µg od, IND 150 µg od, open-label tiotropium (TIO) 18 µg od, and placebo. The primary end point was trough forced expiratory volume in 1 second (FEV1) at Week 26. Other key end points included peak FEV1, area under the curve for FEV1 from 5 minutes to 4 hours (FEV1 AUC5 min-4 h), Transition Dyspnea Index focal score, St George's Respiratory Questionnaire total score, and safety. Here, we present efficacy and safety of IND/GLY in the Japanese subgroup. RESULTS: Of 2,144 patients from the SHINE study, 182 (8.5%) were Japanese and randomized to IND/GLY (n=42), IND (n=41), GLY (n=40), TIO (n=40), or placebo (n=19). Improvement in trough FEV1 from baseline was 190 mL with IND/GLY and treatment differences versus IND (90 mL), GLY (100 mL), TIO (90 mL), and placebo (280 mL) along with a rapid onset of action at Week 26. IND/GLY showed an improvement in FEV1 AUC5 min-4 h versus all comparators (all P<0.05). All the treatments were well tolerated and showed comparable effect on Transition Dyspnea Index focal score and St George's Respiratory Questionnaire total score. The effect of IND/GLY in the Japanese subgroup was consistent to overall SHINE study population. CONCLUSION: IND/GLY demonstrated superior efficacy and comparable safety compared with its monocomponents, open-label TIO, and placebo and may be used as a treatment option for the management of moderate-to-severe COPD in Japanese patients.

Efficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: Pooled analysis of SHINE and ARISE.

BACKGROUND: To better evaluate the efficacy and safety of the indacaterol/glycopyrronium (IND/GLY) fixed-dose combination versus tiotropium in Japanese patients, a pooled data analysis was conducted from the SHINE and ARISE studies, which were part of the IND/GLY clinical trial program. METHODS: Japanese patients with moderate-to-severe COPD were included in the analysis. Efficacy in terms of pre-dose forced expiratory volume in one second (FEV1) at Week 12 and Week 24/26 (ARISE/SHINE) and FEV1 at 30min and 60min post-dose at Day 1, Week 12, and Week 24/26 was evaluated. Health status using the St. George׳s Respiratory Questionnaire (SGRQ) score, rescue medication use (number of puffs/day), safety, and tolerability were also assessed. RESULTS: In total, 340 patients (IND/GLY, n=161; IND, n=41; GLY, n=40; tiotropium, n=79; and placebo, n=19) were included in the analysis that focused on comparing IND/GLY versus tiotropium since they were included in both studies. At Week 12 and Week 24/26, pre-dose FEV1 was significantly improved with IND/GLY compared with tiotropium (treatment differences=70mL and 80mL, respectively; both P≤0.001). FEV1 at 30min and 60min post-dose, the SGRQ total score, and rescue medication use were more statistically significant with IND/GLY than with tiotropium for all assessed time-points. The overall incidence of adverse events (AEs) and serious AEs was similar between the IND/GLY- and tiotropium-treated groups. CONCLUSIONS: Compared to tiotropium, IND/GLY provided significant improvements in lung function, health status, and rescue medication use, while having a good safety profile in Japanese patients with moderate-to-severe COPD.