Cts-Clinical and Translational Science最新文献

Ruzotolimod (Toll-like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno-modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug-related adverse events of flu-like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu-like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC-suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu-like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu-like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN-α, neopterin, IP-10, and the transcriptional expression of ISG15, OAS-1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu-like symptoms occurrence increases with PD responses (IFN-α and IP-10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug-related flu-like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu-like symptoms.

The OPRM1 gene codes for the mu opioid receptor (MOR) and polymorphisms are associated with complex patient clinical responses. The most studied single nucleotide polymorphism (SNP) in OPRM1 is adenine (A) substituted by guanine (G) at position 118 (118A>G, rs1799971) leading to a substitution of asparagine (Asn) for aspartic acid (Asp) at position 40 in the N terminus of the resulting protein. To date, no structural explanation for the associated clinical responses resulting from the 118A>G polymorphism has been proposed. We utilized computational modeling paired with functional cellular assays to predict unstructured N- and C-terminal regions of MOR-1. Using molecular docking and post-docking energy minimizations with morphine, we show that the extracellular substitution of Asn at position 40 alters the cytoplasmic C-terminal conformation, while leaving the G-protein binding interface unaffected. A real-time BRET assay measuring G-protein and β-arrestin association with MOR r generated data that tested this prediction. Consistent with this in silico prediction, we show changes in morphine-mediated β-arrestin association with receptor variants with little change in morphine-mediated G-protein association comparing MOR-1 wild type (WT) to MOR-1_118A>G. We tested the system with different opioid agonists, the OPRM1 118A>G SNP, and different MOR splice variants (MOR-1 and MOR-1O). These results are consistent with the observation that patients with the 118A>G OPRM1 allele respond more readily to fentanyl than to morphine. In conclusion, the 118A>G substitution alters receptor responses to opioids through variable C-terminal domain movements that are agonist and splice variant dependent.

With advances in medical technology, extracellular vesicles, also known as exosomes, are gaining widespread attention because of their potential therapeutic applications. However, their regulatory landscape is complex and varies across countries because of their unique intracellular mechanisms of action. The diversity of manufacturing techniques renders their standardization challenging, leading to a fragmented regulatory landscape. The current global regulatory framework of exosomes can be broadly classified into two strategies: one involves elucidating constituent components within exosomes and the other involves examining the physiological repercussions of their secretion. When using exosomes as therapeutic agents, they should be governed similarly to biological medicinal products. Similar to biologics, exosomes have been analyzed to determine their particle size and protein composition. An exosome-based therapeutic agent should be clinically approved after understanding its molecular composition and structure and demonstrating its pharmacokinetics and therapeutic efficacy. However, demonstrating the pharmacokinetics and therapeutic efficacy of exosomes is challenging for regulatory agencies. This article reviews the technical characteristics of exosomes, analyzes the trends in regulatory laws in various countries, and discusses the chemistry, manufacturing, and control requirements of clinical applications.

The potential of real-world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on reproducing control arm outcomes by matching real-world patient cohorts to clinical trial baseline populations. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. In this article, we propose a novel approach that aims to explore and examine these discrepancies by concomitantly investigating the impact of selection criteria and operations on the measurements of outcomes from the patient data. We tested the approach on a dataset consisting of small-cell lung cancer patients receiving platinum-based chemotherapy regimens from a real-world data cohort (n = 223) and six clinical trial control arms (n = 1224). The results showed that the discrepancy between real-world and clinical trial data potentially depends on differences in both patient populations and operational conditions (e.g., frequency of assessments, and censoring), for which further investigation is required. Discovering and accounting for confounders, including hidden effects of differences in operations related to the treatment process and clinical trial study protocol, would potentially allow for improved translation between clinical trials and real-world data. Continued development of the method presented here to systematically explore and account for these differences could pave the way for transferring learning across clinical studies and developing mutual translation between the real-world and clinical trials to inform clinical study design.

Inflammation may contribute to postoperative cardiac complications and ketorolac, an anti-inflammatory agent inhibiting cyclooxygenase (COX), shows promise in enhancing cardiac graft patency by suppressing endothelial cell proliferation in animal studies. However, the safety of postoperative ketorolac use remains controversial. This study investigates the association between early ketorolac application and complications following cardiac surgery. Data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database fueled this retrospective cohort study. The primary outcome is a composite of mortality, pulmonary insufficiency, severe acute kidney injury (AKI), hemorrhage or hematoma, infection, cardiogenic shock, and cerebrovascular infarction postcardiac surgery. Propensity score matching (PSM; 1:1 match, caliper 0.2), multivariate logistic regression, interaction stratification analysis, pairwise algorithmic, and overlap weight model analyses were employed. Following inclusion and exclusion criteria, 7143 patients who underwent valvular surgery or coronary artery bypass grafting (CABG) were included. PSM created a balanced cohort of 3270 individuals (1635 in the ketorolac group). The matched cohort exhibited an 8.1% overall rate of postoperative complications, with a lower composite outcome rate in patients receiving ketorolac within 48 h of surgery compared with those without (PSM, OR 0.70 [95% CI, 0.54–0.90]). Consistent associations were observed in total cohort analyses, sensitivity, and subgroup analyses. Early ketorolac use within 48 h post-CABG or valvular procedures in adults is independently associated with a lower incidence of composite postoperative adverse events. Prospective trials are warranted to assess causality.

Real-world evidence (RWE) has an increasing role in preapproval settings to support the approval of new medicines and indications. The main objectives of this study were to identify and characterize regulatory use cases that utilized RWE and other related observational approaches through targeted review of publications and regulatory review documents. After screening and inclusion/exclusion, the review characterized 85 regulatory applications with RWE. A total of 31 were in oncology and 54 were in non-oncology therapeutic areas. Most were for indications in adults only (N = 42, 49.4%), while 13 were in pediatrics only (15.3%), and 30 were in both (35.3%). In terms of regulatory context, 59 cases (69.4%) were for an original marketing application, 24 (28.2%) were for label expansion, and 2 (2.4%) were for label modification. Most also received special regulatory designations (e.g., orphan indication, breakthrough therapy, fast track, conditional, and accelerated approvals). There were 42 cases that utilized RWE to support single-arm trials. External data to support single-arm trials were utilized in various ways across use cases, including direct matching, benchmarking, natural history studies as well as literature or previous trials. A variety of data sources were utilized, including electronic health records, claims, registries, site-based charts. Endpoints in oncology use cases commonly included overall survival, progression-free survival. In 13 use cases, RWE was not considered supportive/definitive in regulatory decision-making due to design issues (e.g., small sample size, selection bias, missing data). Overall, RWE is utilized in regulatory approval processes for new indications/label expansion across various therapeutic areas with wide range of approaches. Multifaceted cross-sector efforts are needed to further improve the quality and utility of RWE in regulatory decision-making.

Prior research highlights that rural populations have been historically underrepresented/excluded from clinical research. The primary objective of this study was to describe the inclusion of rural populations within our research enterprise using Clinical Research Management System demographic information at a large academic medical center in the Southeast. This was a cross-sectional study using participant demographic information for all protocols entered into our Clinical Research Management System between May 2018 and March 2021. Descriptive statistics were used to analyze the representation of rural and non-rural participants and demographic breakdown by age, sex, race, and ethnicity for our entire enterprise and at the state level. We also compared Material Community Deprivation Index levels between urban and rural participants. Results indicated that 19% of the research population was classified as rural and 81% as non-rural for our entire sample, and 17.5% rural and 82.5% urban for our state-level sample. There were significant differences in race, sex, and age between rural and non-rural participants and Material Community Deprivation Indices between rural and non-rural participants. Lessons learned and recommendations for increasing the inclusion of rural populations in research are discussed.

There is an unmet clinical need for effective anticoagulant therapies for the management of thromboembolic diseases that are not associated with a relevant risk of bleeding. Asundexian (BAY 2433334) is an oral, direct, small-molecule inhibitor of activated factor XI (FXIa). Phase I data from healthy Caucasian male participants indicated predictable pharmacokinetic (PK) and pharmacodynamic (PD) profiles and no clinically relevant bleeding-related adverse events (AEs). Reported here are data from two phase I, randomized, placebo-controlled, single- and multiple-dose escalation studies of asundexian conducted in 60 healthy men: 24 Japanese and 36 Chinese. Baseline characteristics were comparable between the treatment groups. All treatment-emergent AEs were mild, with no serious AEs or AEs of special interest reported. Systemic exposure to asundexian increased dose proportionally after single or multiple dosing, with relatively low accumulation following multiple once-daily dosing in both Chinese and Japanese volunteers. Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants.

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.