Cts-Clinical and Translational Science最新文献

GM1 and GM2 gangliosidosis are inherited, progressive, neurodegenerative lysosomal disorders of variable onset and disease progression. GM1 gangliosidosis is a result of biallelic pathogenic variants in the GLB1 gene, which confer absent or reduced β-galactosidase enzyme activity and lead to the accumulation of glycoconjugates such as glycosphingolipid GM1-gangliosides. GM2 is caused by biallelic pathogenic variants in one of the three genes (HEXA, HEXB, and GM2A) which confer deficiency of β-hexosaminidase or the GM2 ganglioside activator protein, responsible for the catabolism of GM2 gangliosides. In both gangliosidoses, glycosphingolipids accumulate primarily in neurons, with subsequent neuronal death, which translates to early mortality for patients. The clinical course is commonly differentiated by age of symptom onset. To date, no disease-modifying therapy has been approved globally, and treatment is typically supportive. The lack of mature biomarker development in these diseases contributes to challenges associated with quantifying treatment response. However, recent advancements in the detection of neurodegenerative biomarkers and treatment innovation have spurred interest in biomarker identification in plasma and cerebrospinal fluid in patients with GM1 and GM2 gangliosidosis as pharmacodynamic endpoints to support clinical trials and regulatory decision-making. In this review, we assess the landscape of lipid and protein biomarkers, the extent of evidence, and propose considerations for future biomarker development to measure treatment response and support drug development in GM1 and GM2 gangliosidosis.

In vitro cell culture experiments play an important role in medical research. Various cellular mechanisms and signaling pathways have been identified with in vitro experimental techniques. Unfortunately, the clinical and translational impact of these studies is often limited due to their inability to closely resemble physiological or pathophysiological milieus in cell culture and the use of unrealistic experimental conditions. Thus, further developments must be made to improve the translation of in vitro cell culture work. The application of human plasma or serum as a stimulus for cells, human or otherwise, is a relatively new approach that ultimately overcomes many of the in vitro limitations and provides a more physiologically relevant model. While this technique has been used for the investigation of various diseases and pharmacological mechanisms, discrepancies remain regarding the appropriate methodologies. This review provides insight into recent findings through the application of human plasma or serum as stimuli, as well as an analysis of methodological considerations and suggestions for future directions.

E7777 is a therapeutic recombinant fusion protein comprised of diphtheria toxin fragments and human interleukin-2 (IL-2). Treatment with E7777 generates anti-drug antibodies (ADA). E7777-G000-302 assessed the efficacy and safety of E7777 in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Here, we describe the association between E7777 (at 9 μg/kg) and ADAs, and its effect on pharmacokinetics (PK), efficacy, and safety. Of 91 patients with immunogenicity results at baseline, 78.0% and 5.5% had preexisting anti-E7777 (E-ADAs) and anti-IL-2 antibodies (I-ADAs), respectively. The prevalence of E-ADAs and I-ADAs peaked at C3D1 (median titer 650,175) and C8D1 (median titer 32,805), respectively. However, I-ADA fold increases (1312-fold) were higher than E-ADA increases (181-fold). ADAs' effect on PK was assessed after treatment. E7777 reached C_max at 60 min after infusion, with clearance of 44.6 mL/min at C1D1 and 133 mL/min at C5D1. C_max and AUC_(0–t) decreased by 60% and 84%, respectively, at C5D1 compared with C1D1. Of patients in the safety analysis set (n = 84) evaluated for treatment-emergent (TE) ADAs, 92.9% were considered TE E-ADA positive and 82.1% were TE I-ADA positive. The objective response rate was 39.0% in TE E-ADA-positive patients and 42.6% in TE I-ADA-positive patients. Serious TE adverse events were reported by 32.1% of TE E-ADA-positive patients, 29.0% of TE I-ADA-positive patients, 100% of E-ADA-negative patients, and 73.3% of I-ADA-negative patients. These results indicate that the presence of ADAs decreased E7777 exposure over time but did not adversely impact efficacy and safety in patients with CTCL.

The use of model-informed precision dosing to personalize infliximab has been shown to improve both the acquisition of concentration targets and clinical outcomes during maintenance. Current iterations of infliximab pharmacokinetic models include time-varying covariates of drug clearance, however, not accounting for the expected improvements in the covariates can lead to indiscriminate use of higher infliximab doses and imprecise drug exposure. The aim was to identify changes in the four biomarkers associated with infliximab clearance (Xiong et al. model) and determine if integration of these dynamic changes would improve model performance during induction and early maintenance. We analyzed two cohorts of children receiving infliximab for Crohn's Disease. The E_max method was used to assess time-varying changes in covariates. Model performance (observed vs. predicted infliximab concentrations) was evaluated using median percentage error (bias) and median absolute percentage error (precision). The combined cohorts included 239 Crohn's disease patients. We found from baseline to dose 4, the maximum changes in weight, albumin, erythrocyte sedimentation rate, and neutrophil CD64 were 4.7%, +11.7%, −62.4%, and −26.5%, respectively. We also found the use of baseline covariates alone to forecast future trough concentration was inferior to the E_max time-varying method with a significant improvement observed in bias (doses 2, 3, and 4) and precision (doses 2 and 4). The integration of the four time-varying biomarkers of drug clearance with pharmacokinetic modeling improved the accuracy and precision of the predictions. This novel strategy may be key to improving drug exposure, minimizing indiscriminate dosing strategies, and reducing healthcare costs.

Since its initial discovery, HIV has infected more than 70 million individuals globally, leading to the deaths of 35 million. At present, the annual number of deaths has significantly decreased due to 75% of HIV-positive individuals being on antiretroviral therapy. Although there is no cure yet, available treatments extend life expectancy, enhance quality of life, and reduce transmission by maintaining viral load below the detection limit of 50 copies/mL, making the individual's levels undetectable and untransmittable. HIV has attracted considerable attention in the computational modeling area, with various models having been developed with different degrees of complexity in an attempt to explain the viral dynamics of the disease. It is important to note that no single model can fully incorporate and predict all the critical factors influencing the dynamics of the disease and its response to treatments. Since the number of published models is large, the purpose of this article is to review several relevant models found in the literature that describe biologically plausible scenarios of HIV infection, including key features of disease progression with or without treatment. A total of 15 models are described, with some implemented in the mrgsolve package in R Studio and shared for the benefit of the scientific community. The modeling framework concerning HIV infection aids in identifying the most impactful parameters within the system and their implications in the model outcomes. Insights provided by these models may help in confirming targets for current and novel therapies, thereby contributing to the exploration of new strategies.

Evaluation of the proarrhythmic potential of imetelstat, a novel oligonucleotide telomerase inhibitor, in nonclinical and clinical studies is presented. In vitro, imetelstat sodium ≤ 750 μg/mL and negative (vehicle) and positive (cisapride) controls were evaluated for hERG channel current inhibition. In vivo, cynomolgus monkeys received a single vehicle control or imetelstat sodium (5 mg/kg [2-h infusion], 10 mg/kg [6-h infusion], or 15 mg/kg [6- or 24-h infusion]); cardiovascular parameters were collected before and after drug administration. A ventricular repolarization substudy of the IMerge phase III study evaluated patients with lower-risk myelodysplastic syndromes administered imetelstat 7.1 mg/kg active dose every 4 weeks; intensive electrocardiograms and pharmacokinetic samples were collected for concentration-QTc and by-time point analyses after a single dose. In vitro, imetelstat did not inhibit the hERG channel (IC₅₀ > 750 μg/mL). In monkeys, imetelstat demonstrated no treatment-related changes in cardiac parameters, including QTc using Fridericia correction (QTcF). In the IMerge QTc substudy, 45 patients received imetelstat (n = 29) or placebo (n = 16). The concentration-QTc relationship was described by a linear mixed-effects model; at the geometric mean maximum plasma concentration (C_max) for imetelstat 7.1 mg/kg of 89.5 μg/mL, the predicted effect on placebo-corrected change from baseline QTcF was 2.36 ms (90% confidence interval, −3.04 to 7.76), supporting no evidence of QTcF prolongation. By-time point analysis demonstrated no clinically significant effect of imetelstat on QTc. Nonclinical studies demonstrated no proarrhythmic risk at > 140× (in vitro) and > 2.6× (in vivo) imetelstat 7.1 mg/kg C_max. Clinical evaluations showed no significant effects on QTcF or other electrocardiogram parameters at 7.1 mg/kg. Collectively, this integrated risk assessment supports the low proarrhythmic potential of imetelstat.

Omaveloxolone is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥ 16 years at a dose of 150 mg once daily. This double-blind, randomized, placebo- and active-controlled, three-way crossover, thorough corrected QT interval (QTc) study (NCT05927649) evaluated the effect of supratherapeutic omaveloxolone exposure on QTc to exclude a clinically significant prolongation (defined as > 10 ms). Healthy adults were randomized to one of six sequences of three single oral doses (omaveloxolone 450 mg, placebo, or moxifloxacin 400 mg [open-label positive control]) administered with an FDA high-fat meal. Serial pharmacokinetic blood sampling and time-matched electrocardiogram assessments were performed. The primary endpoint was placebo-corrected change from baseline in QTcF (ΔΔQTcF) following omaveloxolone administration. Secondary endpoints included pharmacokinetic parameters of omaveloxolone and its major plasma metabolites (M17 and M22) and safety. All 30 enrolled participants completed the study. The mean omaveloxolone C_max was 319 ng/mL in this study (4.5-fold the mean steady-state C_max [71.5 ng/mL] with the approved dose). The mean QTcF intervals were < 450 ms, and mean changes from baseline were < 10 ms at all timepoints following all doses. The upper limit of the 90% CIs of ΔΔQTcF following omaveloxolone administration was < 10 ms at all timepoints. At the C_max of omaveloxolone, M17, and M22, alone or combined, the upper limits of the 90% CIs of the model-predicted ΔΔQTcF were all < 10 ms. No safety concerns were identified. Supratherapeutic omaveloxolone exposure that covers the worst-case clinical exposure did not cause a clinically significant QTc prolongation and was generally well tolerated.

There has been a growing trend that activities relating to clinical trials take place at locations other than traditional trial sites (hence decentralized clinical trials or DCTs), some of which are at settings of real-world clinical practice. Although there are numerous benefits of DCTs, this also brings some implications on a number of issues relating to the design, conduct, and analysis of DCTs. The Real-World Evidence Scientific Working Group of the American Statistical Association Biopharmaceutical Section has been reviewing the field of DCTs and provides in this paper considerations for decentralized trials from a statistical perspective. This paper first discusses selected critical decentralized elements that may have statistical implications on the trial and then summarizes regulatory guidance, framework, and initiatives on DCTs. More discussions are presented by focusing on the design (including construction of estimand), implementation, statistical analysis plan (including missing data handling), and reporting of safety events. Some additional considerations (e.g., ethical considerations, technology infrastructure, study oversight, data security and privacy, and regulatory compliance) are also briefly discussed. This paper is intended to provide statistical considerations for decentralized trials of medical products to support regulatory decision-making.

While multiple oral medications are used to treat dystonia, limited information exists on current prescribing practices. This study analyzes real-world prescribing practices for pediatric dystonia in the United States, evaluating prescription frequency, dosing, and the impact of comorbidities. Oracle electronic health record real-world data were queried from 2014 to 2019 for encounters of patients under age 18 with a dystonia diagnosis and available medication records. Information was extracted on prescriptions for dystonia medications (baclofen, clonidine, carbidopa-levodopa, gabapentin, tetrabenazine, trihexyphenidyl, and select benzodiazepines), dosing, and comorbid diagnoses of cerebral palsy (CP), epilepsy, or spasticity. A total of 4010 pediatric patients with dystonia were included. Benzodiazepines were most commonly prescribed (midazolam in 53.5% of patients, diazepam 46.7%, lorazepam 41.9%, clonazepam 28.3%). This was followed by baclofen (33.4%), clonidine (26.3%), and gabapentin (19.7%). Dystonia patients with epilepsy were more commonly prescribed benzodiazepines than patients without epilepsy (diazepam 79.1% vs. 29%; clonazepam 50.9% vs. 16%) and baclofen was more often prescribed in patients with CP (59.4%) or spasticity (63.8%) than those without (17%). All medications showed decreased milligram per kilogram dosage as patient weight increased. Benzodiazepines, baclofen, and clonidine were the most common medications prescribed to pediatric patients with dystonia in the United States, although medical comorbidities impact prescribing practices. There was significant variability in weight-based dosing of all medications. There remains a need to determine which dystonia medications are most effective for each patient and the necessary drug exposure to maximize therapeutic efficacy and minimize adverse effects.

Companion diagnostics (CDxs) are essential in personalized medicine for oncology, where specific genetic mutations drive treatment decisions. Some differences remain in the regulatory frameworks and approval processes for CDx between the United States (U.S.) and Japan. Data were collected from public databases for CDxs and anticancer drugs approved between January 1, 2014, and August 15, 2024, in both countries. The analysis included both initial drug approvals and supplemental approvals to examine the characteristics of approved CDxs and anticancer drugs, identify regional differences, compare development and approval timelines of CDxs and associated anticancer drugs in both countries, and assess the factors influencing approval timelines. CDx approval has increased significantly in both countries since 2014, driven by next-generation sequencing technologies, with 96 anticancer drug indications approved with CDx in the U.S. and 61 in Japan. In the U.S., drug approvals often preceded CDx approvals, influenced by post-marketing commitments (PMCs), whereas Japan tended to approve CDxs and drugs almost simultaneously. The median gap between CDx and drug approvals in the U.S. was 0 days (interquartile range (IQR): 0–391), indicating a broader range and often longer delay compared to 18 days (IQR: −52 to 0) in Japan, with a statistically significant difference between the two countries (p < 0.0001). Logistic regression analysis revealed orphan drug designation was significantly associated with CDx-related PMC in the U.S. (p = 0.042). These results highlight the need for greater regulatory harmonization between the U.S. and Japan to streamline approval processes and improve patient access to personalized treatments.