Sanofi (Japan)

Alemtuzumab is a monoclonal antibody directed against CD52 on T and B lymphocytes and is used to treat lymphoproliferative disorders including chronic lymphocytic leukaemia (CLL). This postmarketing surveillance, as mandated by the Japanese health authorities, investigated the safety and effectiveness of alemtuzumab in Japanese patients receiving alemtuzumab for relapsed/refractory CLL. This was an observational, prospective study conducted in patients with lymphoproliferative disorders who received alemtuzumab in routine clinical practice in Japan between March 2015 and June 2023. Follow-up was for 24weeks after alemtuzumab administration. Endpoints were adverse drug reactions (ADRs), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), and factors associated with safety and effectiveness. Safety was evaluated in 179 patients with lymphoproliferative disorders (112 males and 67 females; median age 68years) and effectiveness in 95 with relapsed/refractory CLL. Overall, 138 patients (77.1%) developed an ADR (most commonly cytomegalovirus [CMV]-related events [37.4%]), 100 (55.9%) developed serious ADRs (most commonly CMV-related events [31.3%]), and 93 (52.0%) developed grade≥3 ADRs (most commonly decreased platelet count [13.4%]). Of 95 patients with relapsed/refractory CLL, 39 (41.1%) had an ORR (15 complete and 24 partial responses). At 24weeks, PFS and OS rates were 55.5% and 70.0%, respectively. The ORR was significantly associated with Rai classification, performance status, and treatment days or duration. This prospective postmarketing surveillance study confirms the effectiveness and manageable safety profile of alemtuzumab for Japanese patients with relapsed/refractory CLL.

Background/Objectives: Prurigo nodularis (PN) is associated with considerable disease burden. Limited information exists about the epidemiology, treatment patterns, and impact of PN. This retrospective study used Japanese health insurance claims data to investigate the prevalence and incidence of PN from 2006 to 2021. Methods: A cross-sectional study design was used to estimate prevalence and incidence longitudinally; a cohort design was used to assess comorbidities, treatment patterns, and healthcare resource utilization (HCRU). Results: Over the study period, data from 297,545 to 10,081,414 individuals were available annually; in 2020, 1946 individuals were diagnosed with PN. The prevalence and incidence of PN showed little variation over the study period; in 2021, the prevalence was 41 per 100,000 persons. Although there was a tendency for a higher prevalence of PN in childhood, the prevalence and incidence were similar in other age groups and were slightly higher in females. Inflammatory skin diseases and atopic diathesis were common comorbidities. The most prescribed treatments for adults with PN were topical steroids (78%), oral antihistamines (68%), and moisturizers (54%). Oral steroids, macrolides, and psychotropics were prescribed to >10% of patients. Individuals with PN who also had atopic dermatitis (AD) received higher cumulative doses of stronger potency topical steroids, local steroid injections, and oral steroids than those without concomitant AD. Additionally, HCRU was higher in individuals with AD. Conclusions: Although patients are usually treated according to the guidelines, there is an unmet need for more effective treatments for PN due to the frequent use of intensive and late-line treatments.

This post-marketing surveillance assessed the safety and effectiveness of isatuximab plus pomalidomide and dexamethasone (Isa-Pd) for relapsed or refractory multiple myeloma (RRMM) during real-world use in Japan. Data from 211 individuals with RRMM treated with Isa-Pd in Japan between October 2020 and October 2021 were collected, with follow-up for up to 12 months after initiation of Isa-Pd or until treatment discontinuation. The incidence of adverse drug reactions (ADRs), ADRs of special interest (infusion reactions, bone marrow suppression, infections, cardiac disorders, other ADRs of Grade ≥ 3), and serious ADRs was assessed. Best overall response and overall response rate (ORR) were determined. In the safety analysis set (n = 120), ADR incidence was 57.5%. Most ADRs were hematologic, and serious ADRs occurred in 28.3%. Bone marrow suppression occurred in 46.7% of participants (19.2% serious), infusion reactions in 18.3% (6.7% serious), infections in 11.7% (8.3% serious), and a serious cardiac disorder in one participant; other Grade ≥ 3 ADRs were reported in 3.3% (1.7% serious). In the effectiveness analysis set (n = 108), the most common best overall response was very good partial response (24.1%), and ORR was 51.9%. These findings support the safety and effectiveness of Isa-Pd for RRMM in real-life settings in Japan.

BackgroundThe Phase 3 IKEMA study (NCT03275285) demonstrated isatuximab (Isa) in combination with carfilzomib (K) and dexamethasone (d) significantly improved progression-free survival (PFS) in patients with relapsed multiple myeloma (MM) compared with Kd. A post-hoc analysis of East Asian patients in IKEMA evaluated the efficacy and safety of Isa-Kd versus Kd in this population and was previously published. Patients and methodsPatients with relapsed MM who had received 1 to 3 prior lines of therapy were randomized 3:2 to receive Isa-Kd or Kd. The primary endpoint was PFS, and key secondary endpoints included rate of very good partial response or better (≥VGPR), complete response (CR) rate, and minimal residual disease (MRD) negativity. Of the IKEMA overall population, 46 patients were of East Asian descent. This is an updated analysis of the efficacy and safety of Isa-Kd in East Asian patients, including data through 14 January 2022. ResultsIsa-Kd continued to demonstrate improved efficacy and safety versus Kd in East Asian patients with relapsed MM, with improved PFS, rate of ≥VGPR, CR rate, and MRD negativity, that was consistent with the overall IKEMA population. The rate of Grade ≥3 treatment-emergent adverse events was also consistent with the prior analysis and overall IKEMA population. ConclusionBased on the results of this analysis, Isa-Kd is a novel treatment option for East Asian patients with relapsed MM.

Caplacizumab is an anti-von Willebrand factor humanized single-variable-domain immunoglobulin fragment whose efficacy and safety in immune-mediated thrombotic thrombocytopenia purpura (iTTP) have been demonstrated in international studies. This prospective, open-label phase 2/3 study evaluated caplacizumab 10 mg administered daily during plasma exchange and for 30 days afterward, in combination with immunosuppressive treatment, in Japanese adults with a clinical diagnosis of iTTP (new or recurrent). The primary endpoint was prevention of iTTP recurrence; key secondary endpoints included time to platelet count response, time to organ damage normalization, and safety. Among 21 treated patients, 1 of 15 (6.7%) evaluable patients developed iTTP recurrence. Median time to normalization was 2.79 days for platelet count and 2.65 days for organ damage markers (n = 15). Treatment-emergent adverse events (TEAEs) were mostly mild to moderate in severity; the most frequently reported caplacizumab-related TEAEs were increased alanine aminotransferase, epistaxis, and gastrointestinal hemorrhage (all in 9.5% of patients). At least one bleeding event was reported in 7 of 21 patients (33%). Caplacizumab was effective in Japanese patients with iTTP, with a low rate of iTTP recurrence, rapid normalization of platelet counts and organ damage markers, and no unexpected TEAEs. Trial registration: ClinicalTrials.gov identifier, NCT04074187.

BackgroundSafety and effectiveness of aflibercept with 5‐fluorouracil/levofolinate/irinotecan have not been reported in Japanese patients with metastatic colorectal cancer (mCRC) in a real-world clinical setting.MethodsThis post-marketing surveillance enrolled patients with un-resectable advanced or recurrent mCRC who were prescribed aflibercept from December 2017 to June 2019 in Japan. Data, collected up to 1 year from starting treatment, included patient background, safety, and effectiveness assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or physician’s evaluation.ResultsOf 261 patients registered from 64 centers, 235 [53.2% male with a median age of 67 years (range 28–84)] received treatment and were included in the safety analysis. Aflibercept was received at 1st, 2nd, and ≥ 3rd line in 1.3%, 48.1%, and 50.2% of patients, respectively. Median number of treatment cycles was 6 (range 1–22) and relative dose intensity was 75.4% (range 14.3–101.8%). Adverse events (all grades) were reported in 88.5% of patients, including neutropenia (34.5%), proteinuria (24.7%), hypertension (17.0%), diarrhea (17.0%), and decreased appetite (15.3%). Three treatment-related deaths occurred by perforation of the digestive tract, pneumonia and gastrointestinal bleeding, and sudden death. The effectiveness analysis included 198 patients. Overall response rate was 6.1% (1st line, 0%; 2nd line, 10.1%; ≥ 3rd line, 2.1%) and disease control rate was 47.5% (1st line, 100%; 2nd line, 58.6%; ≥ 3rd line, 34.4%).ConclusionNo new risks of aflibercept were identified in real clinical practice. Effectiveness in patients at the 2nd line was consistent with previous reports.

Urinary tract infection (UTI) and pyelonephritis cause urosepsis, which can become life threating. Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors, a class of oral anti-diabetic drugs, may increase the risk of UTI and pyelonephritis, as observed from their mechanism of action. Patients with diabetes receiving SGLT2 inhibitors are often concomitantly administered other antidiabetic, antidyslipidemic, or antihypertensive drugs. To determine if drug-drug interactions (DDIs) between SGLT2 inhibitors and these medications increased the risk of UTI and pyelonephritis, we analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We applied Norén's and Gosho's methods for detecting DDIs. FAERS contains records describing 14 526 398 patient characteristics, 54 290 663 drug properties, and 47 252 416 reactions/events. We found 23 drug combinations that could induce UTI and pyelonephritis, such as SGLT2 inhibitors administered with dipeptidyl peptidase-4 inhibitors, thiazolidinediones, glinides, statins, angiotensin II receptor blockers, and calcium channel blockers. Combination therapy with the drugs detected in our analyses would show potential interactions that could result in UTI and pyelonephritis in patients with diabetes mellitus. However, owing to various limitations, these results must be confirmed by additional analyses.

ABSTRACTBackgroundExercise training is an accepted evidence-based adjunct treatment modality for patients with chronic heart failure. However, the influence of medications or conditions on exercise has not been fully explored.MethodsThe patient records of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study were obtained from the National Heart, Lung, and Blood Institute, and analyzed by medications used at baseline (renin-angiotensin system inhibitors [RASIs], beta-blockers [BBs], and combination of both) with multivariable Cox regression models focusing on the interactions with exercise effects, and a score to indicate exercise training suitability was proposed accordingly.ResultsMedication type strongly influenced the exercise effect on all-cause death (AD) (P = 0.007) even though medication itself did not change prognosis significantly in HF-ACTION trial. In patients taking both BBs and RASIs at baseline, exercise reduced the AD risk (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), whereas in patients not taking BBs, exercise increased the risk (HR, 4.58; 95% CI, 2.90–6.86). The exercise on AD was also influenced by pulse pressure, hemoglobin level, electrocardiography conditions, body mass index, and history of stroke. Accordingly, we constructed the Score for Eligibility of Exercise on Mortality (SEEM). When exercise training was chosen based on SEEM score, both AD and AD and hospitalization (ADH) risks were expected to reduce significantly (HR, 0.54; 95% CI, 0.44–0.68; HR, 0.83; 95% CI, 0.75–0.93, respectively).ConclusionsExercise training in patients with heart failure should be recommended carefully with consideration of patient background.Clinical Trial RegistrationClinicaltrials.govidentifier:NCT00047437. Trial registration date: 4 October 2002.

Background Asthma is a common, chronic inflammatory airway disorder, with up to 1,177,000 people receiving asthma treatment in Japan. Dupilumab is a first-in-class, monoclonal antibody for the treatment of atopic diseases, including persistent asthma. The objective of this study was to assess the cost-effectiveness of dupilumab, compared with other biologics, as add-on treatment to background therapy in patients aged ≥12 years with uncontrolled, persistent asthma in Japan. Methods A life-time Markov cohort model was used to conduct cost-effectiveness analysis from the Japanese healthcare payer perspective with an annual discount rate of 2%. Dupilumab was compared with benralizumab and mepolizumab, and against omalizumab (as a hypothetical scenario). Inputs were informed by dupilumab clinical trials (VENTURE [NCT02528214] and QUEST [NCT02414854] trials), the literature, official Japanese sources and expert opinions. Results The base case results suggest that treatment with dupilumab leads to fewer severe exacerbations and increased life-years (LYs) and quality-adjusted LYs (QALYs) than benralizumab and mepolizumab. At a willingness-to-pay (WTP) threshold of ¥5,000,000 per QALY gained, dupilumab was the dominant strategy (lower cost, increased QALYs) versus benralizumab, and cost-effective versus mepolizumab with an incremental cost-effectiveness ratio (ICER) of ¥1,010,921 (US$9,190, US$1 = ¥110). Versus omalizumab, dupilumab was not cost-effective (ICER of ¥10,802,368 [US$98,203]). Conclusions In Japan, dupilumab, as an add-on to background therapy, is economically dominant compared with benralizumab, and cost-effective versus mepolizumab.