Post-marketing Surveillance In Japan Research Articles

#550 Characteristics of patients with aHUS who discontinued dialysis after eculizumab treatment: sub-analysis of post-marketing surveillance in Japan

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS), a type of thrombotic microangiopathy (TMA), is a disease accompanied by acute kidney injury which typically requires dialysis in half of the patients. Eculizumab is the first complement C5 inhibitor approved for aHUS in Japan. Early treatment initiation with eculizumab is associated with better renal outcomes, and dialysis withdrawal has been observed in some of patients on dialysis after treatment with eculizumab. However, patient characteristics relating to dialysis continuation or withdrawal after treatment with C5 inhibitors have not been investigated. Method Paediatric and adult patients with aHUS who were enrolled in Japanese post-marketing surveillance (PMS) for eculizumab and who were on dialysis at the initiation of eculizumab treatment were included in this analysis. Characteristics and clinical courses were compared in two groups: patients who discontinued dialysis within 26 weeks from initiation of eculizumab (Group A) and those who stayed on dialysis for 26 weeks (Group B). Results Among 38 patients included in this analysis, 21 patients (55%) discontinued dialysis (Group A) and 17 patients (45%) stayed on dialysis (Group B). The proportion of paediatrics/adults (7/14 vs. 2/15, P = 0.148), median age (6 vs. 8 years old, P = 0.88 and 54.5 vs. 62 years old, P = 0.47), and the proportion of patients with/without complement-related gene variants or anti-CFH antibody (9/8 vs. 6/5, P = 1.000) were comparable between the two groups. Meanwhile, the proportion of patients with hypertension at baseline was significantly lower in Group A than in Group B (6/21 vs. 11/17, P = 0.022). The median duration of dialysis before initiation of eculizumab (6.0 days vs. 17.0 days, P = 0.011) and the median time from TMA onset to eculizumab initiation (9.0 days vs. 25.0 days, P = 0.008) were significantly shorter in Group A than in Group B, respectively. In contrast, there was no significant difference in the median time from TMA onset to initiation of plasma therapy between the two groups (3.5 days vs. 8.0 days, P = 0.154). No significant difference was also observed in the median (range) duration of eculizumab treatment [75 (13-241) weeks vs. 40 (12-256) weeks, P = 0.167]. Stepwise multivariate logistic regression analysis showed that the time from TMA onset to eculizumab initiation (<15 days/≥15 days) was an independent factor associated with the withdrawal of dialysis (P = 0.013), but the existence of hypertension at baseline as a complication and patients age (paediatrics/adults) were not (P = 0.157 and P = 0.869). No patients in Group A restarted dialysis after dialysis discontinuation. Five out of 17 patients in Group B discontinued dialysis after 27 weeks; their median (range) time to dialysis withdrawal was 63 (27-184) weeks. Conclusion These results demonstrate that early initiation of C5 inhibitors can offer the chance of renal recovery and no further need for dialysis. Continuing treatment with C5 inhibitor beyond 26 weeks may also offer the chance to discontinue dialysis for some patients.

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) < 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr < 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin >4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Safety and Effectiveness of Molnupiravir in Japanese Patients with COVID-19: Final Report of Post-marketing Surveillance in Japan.

Molnupiravir is an orally available prodrug of N-hydroxycytidine that received special approval for emergency treatment of coronavirus disease 2019 (COVID-19) in Japan in December 2021 and full approval in April 2023. To assess the real-world safety and effectiveness of molnupiravir in Japanese patients with COVID-19, we conducted nationwide post-marketing surveillance to collect data at registered institutions in Japan. The surveillance data were collected from December 27, 2021, to May 2, 2023. All reported adverse events were collected for safety analysis. Adverse drug reactions (ADRs) were assessed by the treating physicians. Effectiveness was assessed by the composite of hospitalization or all-cause death in outpatients and the composite of oxygen/mechanical ventilation initiation or all-cause death in inpatients. The observation period was from molnupiravir initiation through day 29. Of 3214 patients enrolled in the survey, 3179 were analyzed for safety. At baseline, 52.31% (1663/3179) of patients were male, the median (range) age was 69.0 (18-107) years, 82.38% (2619/3179) received COVID-19 vaccines, and 95.72% (3043/3179) had risk factors for severe COVID-19 illness. COVID-19 severity at baseline was mild in 86.44% (2748/3179) and moderate I in 10.22% (325/3179). A total of 205 ADRs occurred in 5.50% (175/3179) of patients; ADRs that occurred in > 0.5% of patients were diarrhea (1.86% [59/3179]) and rash (0.69% [22/3179]). Seven serious ADRs were reported in seven patients. In the effectiveness analysis population, the incidence of all-cause death through day 29 was 1.14% (34/2988), and the incidence of death through day 29 related to COVID-19 was 0.40% (12/2988). The cumulative incidence of the composite endpoint was 2.34% (47/2006) in outpatients and 4.60% (38/826) in inpatients. This large-scale survey showed that molnupiravir was safe and effective in real-world settings in highly vaccinated Japanese patients with COVID-19, including older patients and those with comorbidities.

Eculizumab treatment in paediatric patients diagnosed with aHUS after haematopoietic stem cell transplantation: a HSCT-TMA case series from Japanese aHUS post-marketing surveillance

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21–58) and the median doses of eculizumab was three (IQR;2–5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95–555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

Real-World Evidence for the Safety and Effectiveness of Naldemedine in the Management of Opioid-Induced Constipation in Patients With Cancer Pain: Post-hoc Subgroup Analysis of Post-marketing Surveillance in Japan.

Opioid-induced constipation is common and greatly affects the quality of life but is often under-recognised and undertreated. This study aimed to investigate the safety and effectiveness of naldemedine for opioid-induced constipation with cancer pain according to specific subgroups of clinical interest. In this exploratory post-hoc subgroup analysis of post-marketing surveillance from Japan (UMIN: 000042851), data were investigated by the subgroups: age (≥75, <75 years), Eastern Cooperative Oncology Group performance status (PS 0-2, 3-4), constipation severity (mild, moderate, severe), brain metastasis (yes, no), anticancer drug treatment (yes, no), opioid at naldemedine initiation (fentanyl only, only strong opioids other than fentanyl, weak opioids only, other), and prior or concomitant use of laxative (only osmotic/saline laxatives, only stimulant laxatives, other, none). Enrolled patients (n = 1184) received naldemedine (0.2 mg once daily) orally for up to 12 weeks. Regarding safety endpoints, the incidence of adverse drug reactions, including diarrhoea, was determined within each subgroup. Regarding effectiveness endpoints, improvement rates in the frequency and condition of bowel movements were investigated by subgroups. The incidence of adverse drug reactions, including diarrhoea, among subgroups ranged from 7.74% to 16.08% (diarrhoea: 5.95% to 13.19%), compared to 11.30% (diarrhoea: 9.09%) in the total population. Through week two to week 12, improvement rates in the frequency and condition of bowel movement among subgroups ranged from 63.6% to 89.7% and 67.6% to 94.9%, compared to 75.0% to 83.2% and 80.0% to 88.0% in the total population, respectively. Naldemedine was well tolerated and effective in patients with opioid-induced constipation and cancer pain regardless of the subgroups investigated.

Safety and effectiveness of a 300 IR house dust mite sublingual tablet: descriptive 4-year final analysis of a post-marketing surveillance in Japan.

Background: Data are limited for clinical outcomes with house dust mite (HDM) allergen immunotherapy beyond 2years' observation. Materials & methods: A post-marketing drug-use survey assessed the safety and effectiveness of the 300 index of reactivity (IR) HDM tablet during use forup to 4years in Japan. Results: 538 patients were evaluable for safety and 383 for effectiveness. Most adverse drug reactions (ADRs) occurred early and were local reactions; 5.6% of 249 total events were reported during years 2 to 4 as new ADRs after the interim analysis. The CAP-RAST score was identified as a potential risk factor for ADRs. The proportion of evaluable patients with severe allergic rhinitis symptoms decreased from 46.4% at baseline (n= 317) to 1.0% at 4years (n=104). Patients (n=16) who discontinued 300 IR HDM tablet due to symptomatic improvement had sustained improvement relative to baseline 1 to 2years later. Conclusion: Long-term use of the300 IR HDM tablet is safe and effective.

Safety and effectiveness of nusinersen, a treatment for spinal muscular atrophy, in 524 patients: results from an interim analysis of post-marketing surveillance in Japan

ABSTRACT Purpose Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy (SMA). A post-marketing surveillance (PMS) has been ongoing (August 2017–August 2025) in all patients in Japan who were administered nusinersen intrathecally in real-world clinical settings. We report the interim analysis results for safety and effectiveness. Methods This interim analysis was conducted using data collected from 524 patients whose case report forms were obtained at least once by May 30, 2022. Collected data included patient demographics and adverse events (AEs) for safety, and motor function assessments and Clinical Global Impressions of Improvement (CGI-I) for effectiveness. Results Of the 524 patients in the safety analysis set, 522 patients who were diagnosed with SMA were included in the effectiveness analysis (infantile-onset SMA [n = 153, 29.3%], later-onset SMA [n = 369, 70.7%]). The median duration of treatment was 785.0 (range 1–1549) days. AEs occurred in 35.9% of patients (49.0% in infantile-onset SMA and 30.6% in later-onset SMA). Nusinersen treatment significantly improved Hammersmith Infant Neurological Examination scores in patients with infantile-onset SMA and Hammersmith Functional Motor Scale-Expanded scores in patients with later-onset SMA for up to nearly 3 years. Based on CGI-I assessments, 98.5–100% of patients receiving nusinersen "improved" or remain "unchanged". Conclusions This interim analysis of the large-scale, all-case PMS in patients who were administered nusinersen in Japan supports the safety and effectiveness of nusinersen. The benefit–risk balance of nusinersen treatment remains favorable.

Safety and effectiveness of lusutrombopag in patients who have chronic liver disease with thrombocytopenia and undergoing invasive procedures: Real-world post-marketing surveillance in Japan.

Lustrombopag has been approved for the treatment of thrombocytopenia in patients with chronic liver diseases (CLD) who are scheduled to undergo an invasive procedure. Here we report the final results of a post-marketing surveillance assessing the safety and effectiveness of lusutrombopag in Japan. This multicenter, prospective, real-world surveillance collected data from case report forms between October 2016 and May 2021. The observation period was 2 months after the first day of lusutrombopag treatment. Safety and effectiveness (proportion of patients avoiding preoperative platelet transfusion and responders who achieved platelet count increase from baseline) were assessed. The safety analysis set included 1033 (100.0%), 130 (12.6%), and 14 (1.4%) patients received ≥1, ≥2, and ≥3 treatment cycle(s), and 482 (48.9%), 457 (46.3%), and 43 (4.4%) patients were Child-Pugh (CP) class A, B, and C, respectively. The most common serious adverse drug reactions (ADRs) were portal vein thrombosis (PVT), pancytopenia, and white blood cell count decreased, reported in 14 (1.36%), 3 (0.29%), and 2 (0.19%) patients, respectively. The incidence of ADRs was not higher in patients with CP class C or those undergoing retreatment cycles compared with other CP classes or the first treatment cycle, respectively. During the observation period of the first treatment cycle, 94.7% (889/939) of patients avoided preoperative platelet transfusion and 82.8% (741/895) of the patients met the responder criteria. This surveillance further supports the safety and effectiveness of lusutrombopag in a broad range of patients with CLD undergoing planned invasive procedures. This article is protected by copyright. All rights reserved.

Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan

BackgroundThe CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial.MethodsThis was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS).ResultsOf the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8–10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94–128) days for cabazitaxel and 58 (57–66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279–0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258–0.402) favouring cabazitaxel.ConclusionsConsistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

Safety and Effectiveness of Molnupiravir (LAGEVRIO®) Capsules in Japanese Patients with COVID-19: Interim Report of Post-marketing Surveillance in Japan.

Molnupiravir is an oral antiviral drug that received special approval for emergency use in Japan on December 24 2021 for infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This post-marketing surveillance (PMS) is underway to investigate the safety and effectiveness of molnupiravir in daily clinical practice in Japan. The interim PMS data collected from December 27 2021 to June 15 2022 are reported in this publication. This survey included adult Japanese patients treated with molnupiravir. For safety, adverse drug reactions (ADR) were assessed by physicians. Effectiveness was assessed by the composite endpoint of (1) hospitalization or (2) death in outpatients and by the composite endpoint of (3) death or (4) initiation of oxygen administration/mechanical ventilation in inpatients hospitalized for any reasons and without oxygen administration at the start of molnupiravir administration. The observation period was through 29days from the start of molnupiravir administration. Of the 1031 patients in the safety analysis set, 68 (6.60%) patients reported ADRs and four (0.39%) patients reported serious ADRs. The main ADRs observed were diarrhoea [26 patients (2.52%)], rash [six patients (0.58%)], dizziness [five patients (0.48%)], and faecessoft [four patients (0.39%)]. In the effectiveness analysis from the start date of molnupiravir administration to day 29, there were 16/612 (2.61%) hospitalizations and no deaths. Oxygen administration was newly initiated in 9/199 (4.52%) inpatients after the initiation of molnupiravir administration; 2/199 (1.01%) inpatients died. This interim analysis of molnupiravir in daily clinical practice use in Japan supports the safety and effectiveness profile of molnupiravir under pandemic conditions in which Omicron was the dominant SARS-CoV-2 variant. The results of this PMS will provide valuable information for daily clinical practice use.

Safety and Effectiveness Analyses of Dolutegravir/Lamivudine in Patients with HIV: 2-Year Report of Post-Marketing Surveillance in Japan.

Since 2019, for the first time, a two-drug regimen with dolutegravir/lamivudine (DTG/3TC) has been recommended for HIV treatment as initial and subsequent therapy in the international guidelines. However, safety and efficacy data of DTG/3TC in Japanese people living with HIV (PLHIV) in clinical trials are limited and have not been evaluated in clinical practice. In this report, we evaluated safety and effectiveness of DTG/3TC in Japanese PLHIV through post-marketing surveillance. Post-marketing surveillance was conducted to evaluate the real-world safety and effectiveness of DTG/3TC in Japanese PLHIV. One hundred ninety-seven patients who received oral DTG 50mg/3TC 300mg as a single-tablet fixed-dose combination regimen (STR) were registered in clinical practice. The safety was evaluated by incidence of adverse drug reactions (ADRs). The effectiveness was evaluated by plasma HIV RNA and peripheral CD4+ cell counts. This is a 2-year (from 2020 to 2022) report of approximately 6years of survey, and 187 patients were registered from 21 Japanese sites. The number of antiretroviral therapy (ART)-experienced patients was 178, and > 60% of their previous antiretrovirals (ARVs) were DTG/abacavir (ABC)/3TC. There were only nine ART-naïve patients. Four of 178 ART-experienced patients (2.25%) reported ADRs, and 1 serious ADR of syphilis was reported. There was no clear causal relationship between DTG/3TC and the ADRs. Plasma HIV RNA and peripheral CD4+ cell counts maintained the pre-DTG/3TC level in ART-experienced patients. No new clinical concerns of safety and effectiveness were identified in Japanese ART-experienced PLHIV treated with DTG/3TC. We could not discuss the safety and effectiveness in ART-naïve patients because of the small sample size.

Real-World Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Interim Report of a Post-Marketing Surveillance in Japan.

Nintedanib is recommended for the treatment of idiopathic pulmonary fibrosis (IPF); however, treatment discontinuation due to adverse events (AEs) is common. A large-scale post-marketing surveillance study is investigating the real-world tolerability/safety of nintedanib in Japanese patients with IPF in routine clinical practice. Here, we report a 12-month interim analysis of this study. The study included Japanese patients with IPF who started nintedanib between 31 August 2015 and 25 December 2018. The primary outcome was the frequency of adverse drug reactions (ADRs), defined as AEs for which a causal relationship with nintedanib could not be excluded. The secondary outcome was change from baseline in forced vital capacity (FVC). Outcomes were analysed in patients who stopped ('discontinued' subgroup) and continued ('continued' subgroup) nintedanib after 12months. A multivariate analysis was performed to determine potential risk factors for treatment discontinuation. Of 5578 patients in the safety analysis set, 2795 (50.1%) discontinued nintedanib within 12months of treatment initiation. Overall, 3767 patients (67.5%) had ADRs, with 1356 (24.3%) discontinuing nintedanib because of an ADR. Among patients in the 'discontinued' subgroup (n = 2795), 1442 (51.6%) discontinued because of an ADR. The most common ADRs causing discontinuation within 3 and 12months were hepatic function abnormal (n = 137/730; 18.8%) and diarrhoea (n = 190/1442; 13.2%), respectively. At 12months, the decrease in FVC from baseline was smaller in the 'continued' versus the 'discontinued' subgroup (adjusted mean ± standard error change -104.4 ± 10.9ml vs. -311.2 ± 29.2ml). Stage III/IV IPF and FVC < 70% predicted at baseline were risk factors for early treatment discontinuation. About 50% of Japanese patients with IPF discontinued nintedanib within the first year of treatment, with worse lung function being associated with an increased risk of early treatment discontinuation. ClinicalTrials.gov: NCT02607722; European Union electronic register of Post-Authorisation Studies: EUPAS10891.

Long-term safety and effectiveness of eculizumab in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a 2-year interim analysis of post-marketing surveillance in Japan.

The terminal complement C5 inhibitor eculizumab is approved in Japan for relapse prevention in aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and is undergoing mandatory post-marketing surveillance (PMS) of clinical use. The objective of the study is to assess the real-world, long-term safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD. Regulatory-mandated PMS analysis implemented as an all-case surveillance of all patients with AQP4+ NMOSD who have been treated with eculizumab in Japan since its approval in November 2019. This PMS interim analysis assessed the safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD from November 2019 to April 2022. Of 147 patients treated with eculizumab who consented to publication, 71 had at least one case report form collected and locked at the interim analysis data cut-off, constituting the safety analysis set; three patients from PREVENT (NCT01892345) were excluded from the effectiveness analysis set. Twelve and 10 patients in the safety and effectiveness analysis sets discontinued, respectively. In the safety analysis set, 67/71 patients (94.4%) were female, mean illness duration was 6.8 [standard deviation (SD): 6.2] years, mean age at eculizumab initiation was 50.7 (SD: 13.3) years, and mean eculizumab treatment duration was 44.6 (SD: 23.7) weeks. At diagnosis of NMOSD, 34/71 patients (47.9%) and 35/71 patients (49.3%) in the safety analysis set had symptoms of optic neuritis and transverse myelitis, respectively. In the safety analysis set, 19/71 patients (26.8%) reported adverse events, 10/71 (14.1%) reported adverse drug reactions (ADRs), and 7/71 (9.9%) reported serious ADRs; no meningococcal infections were observed. In the effectiveness analysis set, 64/68 patients (94.1%) were female, mean disease duration was 6.9 (SD: 6.3) years, mean age at eculizumab initiation was 50.6 (SD: 13.2) years, and 27/68 (39.7%) were tested for C5 genetic polymorphism (all negative). In the 2 years before eculizumab, 51/68 patients (75.0%) experienced relapse. Relapse rate was 0.02/patient-year after eculizumab initiation versus 0.74/patient-year in the 2 years before eculizumab. Overall, 37/68 patients (54.4%) were prescribed immunosuppressants in the 6 months before and 19/40 (47.5%) in the 6-12 months after starting eculizumab treatment. The proportion of patients taking >10 mg/day of prednisolone decreased from 45.6% at 24-20 weeks before to 23.1% and 0% at 48-52 and 100-104 weeks after eculizumab, respectively. This article reports interim PMS data for Japanese patients and provides updated real-world evidence for the safety of eculizumab and its effectiveness at preventing relapses in patients with AQP4+ NMOSD. Safety and effectiveness results are consistent with those from PREVENT.

Intravenous immunoglobulin in patients with bullous pemphigoid insufficient response to corticosteroids: Nationwide post-marketing surveillance in Japan

BackgroundIn Japan, intravenous immunoglobulin (IVIG) has been approved for corticosteroid-unresponsive bullous pemphigoid (BP); however, its usage, efficacy, and safety in clinical settings remain unclear. ObjectiveTo elucidate IVIG efficacy, we examined the improvement in disease severity based on the Bullous Pemphigoid Disease Area Index (BPDAI). MethodsIn this 3-year (April 2016–March 2019), prospective, post-marketing, observational surveillance study, we enrolled 379 patients (51.3 % men; mean age, 74.5 years) with corticosteroid-unresponsive BP treated with IVIG from 143 institutions in Japan (720 treatment cycles). The percentage of patients who improved by at least one severity stage or whose symptoms completely resolved based on the BPDAI score was evaluated at 15, 30, and 60–90 days. ResultsThe improvement rates at 15, 30, and 60–90 days after initial treatment in the 328 IVIG-naïve patients were 70.7 %, 83.5 %, and 84.3 %, respectively. The BPDAI score decreased rapidly and significantly by 15 days compared with that observed during pre-treatment. Further improvement was observed at 30 and 60–90 days. The corticosteroid dose and anti-BP180 antibody titers decreased significantly post-treatment (both, p < .001). Approximately 25 % of IVIG-naïve patients underwent multiple treatment cycles. The improvement rate at 30 days after the final dose was 88 %, and the symptoms completely resolved in 44 % of patients. The incidence of adverse drug reactions per cycle was 8.34 %; the most common reaction was transient thrombocytopenia. ConclusionMost patients showed improvement in severity and decrease in corticosteroid dose and anti-BP180 antibody levels post-treatment, indicating that IVIG is useful for corticosteroid-unresponsive BP treatment.

Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: Analysis of 1‐year postmarketing surveillance

AbstractIntroductionEculizumab, a terminal complement protein C5 inhibitor, is approved in Japan for the treatment of patients with anti‐acetylcholine receptor antibody‐positive (AChR Ab+) generalized myasthenia gravis (gMG) that is difficult to control with plasmapheresis or high‐dose intravenous immunoglobulin therapy.MethodsThis analysis of mandatory postmarketing surveillance in Japan assessed the safety and effectiveness of eculizumab in patients with AChR Ab+ gMG who had completed case‐report forms at 26 wk after eculizumab initiation up to the cutoff date of April 2021. Changes from baseline were assessed for Myasthenia Gravis‐Activities of Daily Living (MG‐ADL) and Quantitative Myasthenia Gravis (QMG) total scores overall, and MG‐ADL scores in patient subgroups according to sex, age at diagnosis and baseline, and baseline disease severity. The change in concomitant corticosteroid use was also evaluated.ResultsData were available for 134 adults (67.2% female; mean age 51.9 y); the effectiveness‐analysis set comprised 126 patients. After 26 wk, 78% of patients were continuing eculizumab treatment. Adverse drug reactions were reported by 49 patients (37%) (most frequently headache [n = 10]). Improvements in MG‐ADL scores were seen regardless of sex; age at diagnosis (&lt;50/≥50 y); baseline age (18 to &lt;40/≥40 to &lt;65/≥65 y); Myasthenia Gravis Foundation of America disease classification (IIa/IIb/IIIa/IIIb/IVa/IVb/V); or baseline MG‐ADL score (&lt;6/≥6). Of patients receiving corticosteroids, the proportion receiving low doses (average ≤5 mg/d) increased from 7.0% before eculizumab initiation to 26.4% by Week 52.ConclusionEculizumab was well tolerated and effective in treating AChR Ab+ gMG across a broad spectrum of adult Japanese patients with difficult‐to‐control gMG.

Safety and effectiveness of avelumab in patients with curatively unresectable merkel cell carcinoma (MCC) in a real-world setting: A post-marketing surveillance in Japan.

e21528 Background: Avelumab is an anti–PD-L1 monoclonal antibody that was approved in Japan for the treatment of patients with curatively unresectable MCC in Sept 2017. Because the number of Japanese patients with MCC participating in the global Phase II JAVELIN Merkel 200 study was limited (3 patients), Japan was mandated to conduct an all-case surveillance as a post-marketing surveillance (PMS) study. In the all-case surveillance, safety and efficacy information is accumulated with respect to a defined period of time or a defined number of post-approval prescription cases and is provided as real-world data. This report summarizes the results of the final analysis of this MCC PMS. Methods: This PMS is a multicenter, non-comparative, prospective, observational study. Since Nov 2017 (following approval in Japan), all patients with MCC who received at least one dose of avelumab in Japan were enrolled, and case report forms (CRF) were collected for all patients who started treatment through Oct 2019. Results: As of Sept 22, 2021, 152 patients from 86 sites were enrolled, and CRFs were collected from 77 patients. Of the 75 patients (53 sites) who met the analysis adequacy criteria, 48% were female, and the median age at the start of avelumab treatment was 77.0 years (42-95 years). Of the treatment lines in which avelumab was administered, 93.3% (70/75) were prescribed as first-line therapy. The incidence of adverse reactions was 61.3% (46/75), and 9.3% (7/75) discontinued treatment due to adverse reactions. Grade 3 and 4 adverse reactions occurred in 12.0% (9/75) and 4.0% (3/75), respectively; no grade 5 adverse reactions were reported. Infusion reactions were reported in 28.0% (21/75). The objective response rate (proportion of patients whose best response was assessed by the investigator as a complete or partial response) up to 1 year after the start of avelumab treatment was 45.3% (95% CI: 33.8, 57.3). The 1-year overall survival rate was 59.6% (95% CI: 47.0, 70.1). Conclusions: This study report is the first real-world evidence collected and analyzed from actual clinical use of avelumab in patients with curatively unresectable MCC in the East Asia region. Despite the different baseline patient characteristics, avelumab therapy in clinical practice had a manageable safety profile with no new safety concerns and has shown similar efficacy to that observed in the JAVELIN Merkel 200 trial.

Real-world safety and effectiveness of canakinumab in patients with tumour necrosis factor receptor-associated periodic syndrome or hyperimmunoglobulinaemia D syndrome: Interim results from post-marketing surveillance in Japan.

To assess the real-world safety and effectiveness of canakinumab in patients in Japan with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate kinase deficiency/hyperimmunoglobulinaemia D with periodic fever syndrome (MKD/HIDS). All patients with TRAPS or MKD/HIDS who received canakinumab following drug approval in Japan were registered in a post-marketing all-patient surveillance with a 2-year observation period. Herein, the interim results are reported. Fifteen patients with TRAPS and seven with MKD/HIDS were included in the safety and effectiveness analysis set. Adverse drug reactions were reported in 26.67% (n = 4) and 42.86% (n = 3) of TRAPS and MKD/HIDS patients, respectively. Most common adverse drug reactions were upper respiratory tract inflammation (13.33%, n = 2) and pyrexia (42.86%, n = 3) in TRAPS and MKD/HIDS patients, respectively. No serious adverse drug reactions were observed in either TRAPS or MKD/HIDS patients. The proportion of responders was 46.67% and 14.29% in the TRAPS and MKD/HIDS groups, respectively; 72.73% and 66.67% achieved clinical remission, while 90.91% and 66.67% achieved serological remission by Week 4 in the TRAPS and MKD/HIDS groups, respectively. These interim results provide the first evidence of the real-world effectiveness of canakinumab in patients with TRAPS or MKD/HIDS in Japan. No new safety concerns were identified.

MO316: Eculizumab for Adult Patients With Atypical Haemolytic-Uremic Syndrome: Full Dataset Analysis of Post-Marketing Surveillance in Japan

Abstract BACKGROUND AND AIMS Atypical haemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) associated with dysregulation of the alternative complement pathway [1]. It is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute kidney injury [1]. In the USA, two adults per million develop aHUS each year, whereas 1 to 2 patients per million are estimated in Japan [2, 3]. Eculizumab has been approved for aHUS in Japan since 2013. A regulatory-mandated post-marketing surveillance (PMS) was conducted in a real-world setting from September 2013 to July 2018, for which an interim analysis has been published [3]. Here, we report the findings from the full data set analysis of the data from the PMS. METHOD The PMS enrolled adult patients diagnosed with aHUS and treated with at least one dose of eculizumab. The patients without underlying diseases, i.e. autoimmune diseases, drugs, infection, malignant tumours, metabolic disorders or transplantation, were evaluated for serious adverse events (SAE) and clinical effectiveness endpoints, i.e. haematologic normalization, platelet count (PLT) normalization, lactic dehydrogenase (LDH) normalization, a decrease of ≥ 25% in serum creatinine (sCr) levels, TMA event-free status and a complete TMA response (haematologic normalization and a ≥ 25% decrease in sCr that persisted for ≥ 4 weeks during eculizumab treatment). In addition, the difference of baseline (i.e. at treatment initiation of eculizumab) patient characteristics between patients who met and did not meet effectiveness endpoints was evaluated. RESULTS In this analysis, 79 adult patients were included; the median age was 54.0 years. Median eculizumab treatment duration was 30 weeks. The total exposure time of eculizumab was 75.51 person-years and 94 SAEs (1.24 per person-years) were reported in 39 patients. No unexpected safety signals were identified in this population by the end of observation. No meningococcal infection was reported throughout the observation period. Mean PLT (P &amp;lt; .001), LDH (P &amp;lt; .05) and estimated glomerular filtration rate (P &amp;lt; .01) were significantly improved after 7 days. Complete TMA response, haematologic normalization, PLT normalization, LDH normalization, improvement of sCr levels, and TMA event-free status were met by 35.3%, 40.4%, 49.2%, 50.0%, 51.3% and 50.0% of patients, respectively. Median treatment duration was shorter in patients who did not meet complete TMA response than in patients who met (6 weeks versus 114 weeks; P &amp;lt; .001). Multivariate analysis suggested that the time from most recent TMA to eculizumab treatment (OR 0.899; P = .007) and the days of plasma therapy (OR 0.807; P = .008) were negatively associated with improvement of sCr levels. CONCLUSION The percentages of patients who met effectiveness endpoints were similar to the interim analysis [3], yet the percentages of patients who met complete TMA responses were lower than in clinical trials [4]; the disparity in these outcomes could be attributed to the differences between clinical and real-world studies. This PMS analysis further demonstrated the safety and effectiveness of eculizumab in Japanese patients with aHUS in a real-world setting.