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Objective: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small‐molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD. Methods: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition. Results: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up‐regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis. Conclusion: We highlight key biologic effects of apremilast on neutrophils in BD. [ABSTRACT FROM AUTHOR]

Background: Although expanded access is an increasingly used pathway for patients to access investigational medicine, little is known on the magnitude and content of published scientific research collected via expanded access. Methods: We performed a review of all peer-reviewed expanded access publications between January 1, 2000 and January 1, 2022. We analyzed the publications for drugs, diseases, disease area, patient numbers, time, geographical location, subject, and research methodology (single center/multicenter, international/national, prospective/retrospective). We additionally analyzed endpoints reported in all COVID-19-related expanded access publications. Results: We screened 3810 articles and included 1231, describing 523 drugs for 354 diseases for 507,481 patients. The number of publications significantly increased over time ( p < 0.001 ). Large geographical disparities existed as Europe and the Americas accounted for 87.4% of all publications, whereas Africa only accounted for 0.6%. Oncology and hematology accounted for 53% of all publications. Twenty-nine percent of all expanded access patients (N = 197,187) reported on in 2020 and 2021 were treated in the context of COVID-19. Conclusions: By summarizing characteristics of patients, diseases, and research methods described in all scientific literature published on expanded access, we provide a unique dataset for future research. We show that published scientific research on expanded access has surged over the past decades, partly due to COVID-19. However, international collaboration and equity in geographic access remain an issue of concern. Lastly, we stress the need for harmonization of research legislation and guidance on the value of expanded access data within real-world data frameworks to improve equity in patient access and streamline future expanded access research. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795 [ABSTRACT FROM AUTHOR]

Summary: Background: Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production. Methods: In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18–60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT). Findings: Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43–1·74; 75 mg, 0·79, 0·40–1·58; 150 mg, 0·98, 0·52–1·81; placebo, 0·38, 0·17–0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97–5·27; 75 mg, 2·30, 1·08–4·92; 150 mg, 2·49, 1·18–5·27; placebo, 3·07, 1·40–6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group Interpretation: Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted. Funding: Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA). [Copyright &y& Elsevier]

ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT. [ABSTRACT FROM AUTHOR]