A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Evaluate the Safety, Reactogenicity, and Immunogenicity of Single Vaccination of Ad26.RSV.preF-Based Regimen in Japanese Adults Aged 60 Years and Older.

BACKGROUND: Respiratory syncytial virus (RSV) is increasingly recognized as a significant cause of lower respiratory tract disease (LRTD) in older adults. The Ad26.RSV.preF/RSV preF protein vaccine demonstrated protective efficacy against RSV related LRTD in a Phase 2b study in the United States. Hence, Ad26.RSV.preF/RSV preF protein vaccine candidate was evaluated in the Japanese older adult population. METHODS: This Phase 1 study evaluated safety, reactogenicity, and immunogenicity of Ad26.RSV.preF/RSV preF protein vaccine at dose level of 1 × 1011 vp/150 µg in Japanese healthy adult aged ≥60 years. The study included a screening Phase, vaccination, 28-day follow up Phase, a 182-day follow-up period, and final visit on Day 183. A total of 36 participants were randomized in a 2:1 ratio to receive Ad26.RSV.preF/RSV preF protein vaccine (n = 24) or placebo (n = 12). After study intervention administration, the safety and immunogenicity analysis were performed as per planned schedule. Immune responses including virus-neutralizing and preF-specific binding antibodies were measured on Days 1, 15, 29, and 183. RESULTS: There were no deaths, SAEs, or AEs leading to discontinuation reported during the study. The Ad26.RSV.preF/RSV preF protein vaccine had acceptable safety and tolerability profile with no safety concern in Japanese older adults. The Ad26.RSV.preF/RSV preF protein vaccine induced RSV-specific humoral immunity, with increase in antibody titers on Days 15 and 29 compared with baseline which was well maintained until Day 183. CONCLUSIONS: A single dose of Ad26.RSV.preF/RSV preF protein vaccine had an acceptable safety and tolerability profile and induced RSV-specific humoral immunity in Japanese healthy adults. TRIAL REGISTRATION: NCT number: NCT04354480; Clinical Registry number: CR108768.

Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study of ustekinumab in Japanese patients with active polymyositis and dermatomyositis who have not adequately responded to one or more standard-of-care treatments.

OBJECTIVES: To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM). METHODS: Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24. RESULTS: No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis. CONCLUSIONS: UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study. TRIAL REGISTRATION NUMBER: NCT03981744.

Design and implementation of an adaptive confirmatory trial in Japanese patients with palmoplantar pustulosis.

Background/Aims: More and more literature describes how to overcome challenges in the implementation of adaptive designs for trials for drug approval process. Most adaptive trials were conducted in Western Europe or USA for Phase II or Phase II/III settings; however, examples of non-oncology pivotal adaptive trials used for regulatory approval in Japan are rare. This article elaborates on our experience with designing and implementing a Phase III adaptive confirmatory trial permitting unblinded sample size re-estimation and futility analysis after a single interim analysis in Japanese patients with palmoplantar pustulosis (PPP) receiving guselkumab. Methods: We provide insights into consideration at the design stage of an adaptive study, including design options, development duration, operational risks, and statistical methods. We also share our experience from two aspects of implementation: conducting an adaptive clinical trial in Japan and setting up a Japanese domestic independent data monitoring committee. Results: Final analysis results of this study successfully demonstrated the effectiveness of guselkumab for the treatment of PPP. Based on the interim analysis results, it was recommended to continue the study without sample size adjustment. Conclusion: We discuss results versus design assumptions and advantages to the conduct of the study with the adaptive design approach. Significant cost savings were gained and development time was reduced compared to the alternative option of a fixed conservative design. Several limitations of our study are also discussed.

Occurrence and disease burden of respiratory syncytial virus and other respiratory pathogens in adults aged ≥65 years in community: A prospective cohort study in Japan.

BACKGROUND: The frequency and clinical profile of respiratory syncytial virus (RSV)-acute respiratory disease (ARD) in older adults in Japan has not been well-characterized. METHODS: This was a multicenter prospective observational cohort study to evaluate the occurrence rate of ARD in 1000 older adult participants (≥65 years) for 52 weeks during the 2019 to 2020 season. A multiplex polymerase chain reaction panel was used for pathogen detection in nasopharyngeal swab from participants diagnosed with ARD. Symptoms and impact of ARD was assessed using the Respiratory Infection Intensity and Impact Questionnaire (RiiQ™). The study was registered at UMIN (https://www.umin.ac.jp/ctr/): UMIN000037891. RESULTS: RSV-ARD was detected in 24/1000 (2.4%) participants and RSV-lower respiratory tract disease in 8/1000 (0.8%) participants. The median duration of RSV-ARD was 18 days. All 24 participants had utilized the medical services of outpatient visits and only 1 (4.2%) participant was hospitalized for RSV-ARD. The most common viruses other than RSV that caused ARD (detected in >10 participants) were human rhinovirus/enterovirus, parainfluenza 3, coronavirus OC43, human metapneumovirus, and influenza A/H1. The most frequent symptoms of RSV-ARD were cough, sore throat, nasal congestion, and expectoration. CONCLUSIONS: RSV was reported as a major pathogen for respiratory infections in older adults in Japan.

Sustained efficacy and safety of guselkumab in patients with palmoplantar pustulosis through 1.5 years in a randomized phase 3 study.

The safety and efficacy of guselkumab for palmoplantar pustulosis (PPP) have been established through week (W)52; however, no sufficient information is available beyond 1 year. This study was conducted to assess the efficacy and safety of guselkumab through W84, and to explore factors associated with the sustainability of its efficacy in Japanese PPP patients. Patients received guselkumab 100 or 200 mg at W0, W4, W12, and every 8 weeks (q8w) until W60, or placebo at W0, W4, and W12. At W16, patients receiving placebo were re-randomized to receive guselkumab 100/200 mg at W16, W20, and q8w until W60. Efficacy end-points included PPP Area and Severity Index (PPPASI), PPP Severity Index (PPSI), Physician's Global Assessment scores, and patient reported outcomes (PRO) (Dermatology Life Quality Index, EuroQoL-5 Dimensions, and 36-item Short Form Health Survey). Post-hoc comparison of patient characteristics was performed between PPPASI-75/90 responders and non-responders at W60, and sustained responders and non-responders at W84. Safety was evaluated through W84. A total of 45, 43, 21, and 24 patients from the guselkumab 100 mg, guselkumab 200 mg, placebo→guselkumab 100 mg, and placebo→guselkumab 200 mg groups, respectively, completed the study through W84. Overall, the mean improvement in the guselkumab groups from baseline in the PPPASI and PPSI total scores at W84 was ~79% and ~66%, respectively. All PRO improved through W84. The proportion of responders through W60 was higher in patients who had not received prior phototherapy and non-biologic systemic therapy for PPP. Non-smokers and patients with no prior non-biologic systemic treatment tended numerically towards sustained efficacy through W84. The majority of treatment-emergent adverse events (TEAE) were mild to moderate (~88%) with low incidence of serious TEAE (7.6%). Overall, guselkumab showed sustained efficacy and safety with improvement in the health-related quality of life through W84 in Japanese PPP patients.

Efficacy and safety of ustekinumab in East Asian patients with moderately to severely active ulcerative colitis: a subpopulation analysis of global phase 3 induction and maintenance studies (UNIFI).

BACKGROUND/AIMS: We aimed to evaluate the efficacy and safety of ustekinumab (UST) in the East-Asian population with moderate to severely active ulcerative colitis (UC). METHODS: This sub-analysis was conducted on data from East-Asian patients included in the UNIFI program (NCT02407236). UNIFI consisted of two double-blind, placebo-controlled trials: an 8-week induction study and a 44-week randomized withdrawal maintenance study. RESULTS: Of 133 East-Asian patients (Japanese: 107, Korean: 26) who underwent randomization, 131 completed induction study and 111 entered maintenance study. In the maintenance study, 78 patients were randomized. Patients who received UST 130 mg and UST 6 mg/kg showed numerically higher clinical remission at week 8 in the induction study (5/44 [11.4%] and 5/45 [11.1%], respectively) compared with those who received placebo (0/44, 0%). The proportion of patients achieved clinical remission at week 44 was numerically higher in the UST 90 mg q12w group (10/21, 47.6%), but similar in the UST 90 mg q8w group (5/26, 19.2%) compared to placebo (7/31, 22.6%). Serious adverse events were reported in 1 patient in UST 130 mg group, but no patient in UST 6 mg/kg group through week 8 in the induction study, and 1 patient in UST 90 mg q12w group and 5 patients in the UST 90 mg q8w group in the maintenance study. No deaths were reported in East-Asian patients throughout the study. CONCLUSIONS: UST induction and maintenance treatments were effective in East-Asian patients with moderate to severe UC; the efficacy and safety profiles were consistent with the overall population.

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Palmoplantar pustulosis (PPP) causes erythematous, scaly plaques with recurrent sterile pustules refractory to treatment and with few randomized clinical trials conducted. Evidence points to involvement of interleukin 23 in the pathogenesis of PPP. OBJECTIVE: To determine the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized clinical trial was conducted from December 15, 2015, to December 12, 2017. A total of 159 enrolled patients (aged ≥20 years) had an inadequate response to conventional therapies, with a diagnosis of PPP for 24 or more weeks before screening. Intention-to-treat analysis was performed. INTERVENTIONS: Subcutaneous injections of guselkumab, 100 or 200 mg, at weeks 0, 4, and 12, and every 8 weeks thereafter were administered; placebo was given at weeks 0, 4, and 12. MAIN OUTCOMES AND MEASURES: Changes from baseline in PPP Area and Severity Index (PPPASI) score (possible score range, 0-72, with higher scores indicating greater area and severity), PPP severity index (PPSI) score (possible score range, 0-12, with higher scores indicating greater severity), and proportion of PPPASI-50 (≥50% reduction) responders at weeks 16 and 52 were assessed. Safety was monitored through week 52. RESULTS: A total of 159 patients (mean [SD] age at diagnosis, 46.8 [11.9] years; 126 women [79.2%]) were enrolled. Treatment groups comprised guselkumab, 100 mg (n = 54), guselkumab, 200 mg (n = 52), or placebo (n = 53). Both guselkumab groups demonstrated significant improvement in least-squares mean changes in PPPASI score compared with placebo: -15.3 and -11.7 in the guselkumab 100-mg and 200-mg groups, respectively, and -7.6 in the placebo group (difference [SE] vs placebo: -7.7 [1.7] in the 100-mg group, P < .001; 95% CI, -11.00 to -4.38; and -4.1 [1.7] in the 200-mg group, P < .017; 95% CI, -7.47 to -0.75]). Least-squares mean changes in PPSI score showed significant improvement in both guselkumab groups (100 mg: -2.0 [0.5]; P < .001; 95% CI, -2.96 to -0.95; 200 mg: -1.0 [0.5; P = .04; 95% CI, -2.06 to -0.03). A significantly higher proportion of patients in the guselkumab 100-mg group (31 [57.4%]) achieved a PPPASI-50 response at week 16 vs placebo (18 [34.0%]; P = .02); however, the result was not significant for the guselkumab 200-mg group (19 [36.5%]) vs placebo; P = .78). Each efficacy end point improved consistently through week 52. Health-related quality of life improved significantly as indicated by a reduction in the Dermatology Life Quality Index score (100 mg: -2.6; 95% CI, -4.0 to -1.2; P < .001; 200 mg: -1.6; 95% CI, -3.1 to -0.2; P = .03). Serious treatment-emergent adverse events were observed in 8 patients (placebo group, 2 of 53 [3.8%]; combined guselkumab group, 6/157≠10.5%). No serious infections were reported. CONCLUSIONS AND RELEVANCE: Targeting interleukin 23 with guselkumab may be an effective and safe treatment option for a recalcitrant disease such as PPP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02641730.

Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study.

Previous global studies of guselkumab have demonstrated clinical benefits in patients with psoriasis. The aim of this 52-week, phase 3 study was to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque-type psoriasis. Patients randomly received guselkumab 50 mg or 100 mg at weeks 0, 4 and every 8 weeks, or placebo with cross-over to guselkumab 50 mg or 100 mg at week 16. Co-primary end-points were the proportion of patients achieving Investigator's Global Assessment (IGA) cleared/minimal (0/1) and 90% or more improvement in Psoriasis Area and Severity Index (PASI-90) at week 16. Overall, 192 patients were randomized to placebo, guselkumab 50 mg or 100 mg. At week 16, patients in the placebo group were crossed over to guselkumab 50 mg or 100 mg. At week 16, a significantly (P < 0.001) higher proportion of patients receiving guselkumab 50 mg and 100 mg versus placebo achieved IGA 0/1 (92.3% and 88.9% vs 7.8%) and PASI-90 (70.8% and 69.8% vs 0%). Patients in guselkumab 50 mg and 100 mg groups achieved significant improvement versus placebo in PASI-75 (89.2% and 84.1% vs 6.3%, P < 0.001) at week 16; improvement was maintained through week 52. Incidences of treatment-emergent adverse events were comparable among the groups through week 16; the most commonly reported was nasopharyngitis. No new safety concerns were observed until week 52. In conclusion, guselkumab treatment demonstrated superior efficacy over placebo and was well tolerated in Japanese patients with moderate to severe plaque-type psoriasis.

Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study.

Generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP) are the rare and severe subtypes of psoriasis, which are often difficult to treat. The aim of this phase 3, open-label study was to evaluate efficacy and safety of guselkumab, a human interleukin-23 monoclonal antibody, in Japanese patients with GPP and EP. Guselkumab 50 mg was administrated to GPP (n = 10) and EP (n = 11) patients at weeks 0, 4 and thereafter every 8 weeks (q8w). Beginning at week 20, patients were escalated to 100 mg q8w if they met the dose escalation criteria. The primary end-point was the proportion of patients achieving treatment success (Clinical Global Impression score of "very much improved", "much improved" or "minimally improved") at week 16. Safety evaluations included assessment of treatment-emergent adverse events (TEAE) through week 52. At week 16, the proportions of GPP and EP patients achieving treatment success were 77.8% (7/9) and 90.9% (10/11), respectively. Furthermore, guselkumab treatment consistently showed improvement in responses of secondary end-points such as Psoriasis Area and Severity Index, Investigator's Global Assessment, Japanese Dermatological Association severity index and improvement in body surface area involvement. Improvements in quality of life, as assessed by the Dermatology Life Quality Index, were also observed through week 52. The most commonly reported TEAE was nasopharyngitis (28.6%, 6/21). Safety findings were consistent with those observed previously in other studies. In conclusion, guselkumab treatment demonstrated efficacy and showed no safety concerns in Japanese patients with GPP and EP through week 52.

Efficacy and safety of ustekinumab in Japanese patients with moderately to severely active Crohn's disease: a subpopulation analysis of phase 3 induction and maintenance studies.

BACKGROUND/AIMS: Efficacy and safety of ustekinumab were evaluated in a Japanese subpopulation with moderately to severely active Crohn's disease (CD) in UNITI-1, UNITI-2 and IM-UNITI studies and results were compared with the overall population. METHODS: Overall, patients in UNITI-1 (Japan, n=56; failed response to tumor necrosis factor antagonist) and UNITI-2 (Japan, n=26; failed response to prior conventional therapy) were randomized to placebo or ustekinumab intravenous induction (130 mg or ~6 mg/kg) at week 0. Responders to ustekinumab induction therapy (Japan, n=21) were randomized to placebo or ustekinumab (90 mg, subcutaneous) maintenance (every 12 weeks [q12w] or 8 weeks [q8w]) in IM-UNITI. The primary endpoint was clinical response at week 6 for induction studies and clinical remission at week 44 for maintenance study. RESULTS: Percentage of patients achieving clinical response at week 6 was greater in ustekinumab 130 mg and ~6 mg/kg groups than in the placebo group (UNITI-1: 36.8% and 31.6% vs. 27.8%, respectively, for Japanese; 34.3% and 33.7% vs. 21.5%, respectively, for overall; UNITI-2: 37.5% and 55.6% vs. 11.1%, respectively, for Japanese; 51.7% and 55.5% vs. 28.7%, respectively, for overall). Clinical remission rate at week 44 during maintenance was greater in the ustekinumab 90 mg SC q12w and q8w groups than in the placebo group (50.0% and 55.6% vs. 25.0%, respectively, for Japanese; 48.8% and 53.1% vs. 35.9%, respectively, for overall). Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Ustekinumab could be considered as a new therapeutic option for moderately to severely active CD in Japanese patients. Both ustekinumab induction and maintenance treatments were generally well tolerated (Clinical Trial Registration: NCT01369329, NCT01369342, NCT01369355).