Cognitive decline in Parkinson's disease (PD) varies widely. While models to predict cognitive progression exist, comparing traditional probabilistic models to deep learning methods remains understudied. This study compares sequential modeling techniques to identify cognitive progression in individuals with and without PD. Using data from the Parkinson's Progression Marker Initiative, shallow Markov, deep recurrent (long short-term memory [LSTM]), and nonrecurrent (temporal fusion transformer [TFT]) models were compared to predict cognitive status over time. Cognitive status was categorized into normal cognition (NC), mild cognitive impairment (MCI), and dementia. Predictions were made annually for up to 3 years using clinical data, including demographics, cognitive assessments, PD severity, and medical history. Each approach was evaluated using inverse probability weighted (IPW-) F1 scores. An ensemble method combined outputs from the Markov, LSTM, and TFT models. The dataset included 917 individuals (53% PD; 30% at risk for PD; 17% Healthy Controls). The TFT model outperformed others across all annual periods (IPW-F1 = 0.468) compared to the Markov (IPW-F1 = 0.349) and LSTM (IPW-F1 = 0.414) models, with improved performance using an ensemble approach (IPW-F1 = 0.502). For MCI and dementia predictions, which were rarer occurrences compared to NC status (ratios: 50:8:1), the TFT model consistently outperformed competing models, achieving IPW-F1 scores of 0.496 and 0.533 for MCI and dementia, respectively. In conclusion, sequential deep learning models like TFT, which mitigate long-term memory loss and can interpret complex, high-dimensional data, perform best overall in predicting clinically important cognitive transitions. These methods should be further explored for predicting degenerative conditions.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein-cholesterol (LDL-C) by decreasing the expression of the LDL-receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long-acting LDL-C lowering effect by exclusively inhibiting PCSK9 in pre-clinical studies. Two randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty-four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15-450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non-linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half-life (t) values of 4.5-6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL-C levels by 30%-73% in healthy subjects, and repeated doses of ongericimab reduced LDL-C levels by 67%-80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL-C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long-acting LDL-C lowering effect with good safety and potential for clinical application.

Lack of pharmacogenomics knowledge among healthcare professionals is the most significant cited barrier to implementing pharmacogenomics in clinical settings. Despite the growth in research initiatives and awareness of pharmacogenomics, healthcare professionals continue to report a lack of knowledge and confidence in practicing pharmacogenomics. This study aims to assess the current pharmacogenomics knowledge gaps and learning needs of healthcare professionals in Malaysia. A modified Delphi with a multidisciplinary expert panel was conducted, and a purposive sampling method was used with predefined selection criteria. Fourteen study sites in Malaysia were included. The cut-off value to approach consensus was predefined as a threshold of 60% or higher, and a quantitative descriptive statistical analysis was performed. The study demonstrated that all experts rated the suggested educational content components as essential/important to be included in the educational intervention. Additionally, experts highlighted the significant barriers and gaps to adopting and practicing pharmacogenomics. To conclude, this multisite Delphi study enabled the development of a tailored, effective, evidence-based, competency-based educational intervention in pharmacogenomics for healthcare professionals in Malaysia. To keep up with the rapid evolution of the pharmacogenomics field, healthcare professionals should be equipped with the necessary competencies required to practice pharmacogenomics for better health outcomes. Future research is needed to determine the feasibility of the proposed educational intervention.

Bruton's tyrosine kinase (BTK) is a potential therapeutic target for allergic and autoimmune diseases. This first-in-human phase I study evaluated safety, pharmacokinetic, and pharmacodynamic profiles of sofnobrutinib (formerly AS-0871), a highly selective, orally available, non-covalent BTK inhibitor, in healthy adult subjects. Single ascending doses (SAD; 5-900 mg) and multiple ascending doses (MAD; 50-300 mg twice daily [b.i.d.] for 14 days [morning dose only on Day 14]) of sofnobrutinib were tested. In the entire study, all adverse events (AEs) were mild or moderate, and no apparent dose-proportional trend in severity or frequency was observed. No serious treatment-emergent AEs, cardiac arrythmias, or bleeding-related AEs were reported. In the SAD part, sofnobrutinib exhibited approximately dose-dependent systemic exposures up to 900 mg with rapid absorption (median time to maximum concentration of 2.50-4.00 h) and gradual decline (mean half-lives of 3.7-9.0 h). In the MAD part, sofnobrutinib showed low accumulation after multiple dosing (mean accumulation ratios of ≤1.54) and reached a steady state on ≤Day 7. Single dosing of sofnobrutinib rapidly and dose-dependently suppressed basophil and B-cell activations in ex vivo whole blood assays. Multiple dosing of sofnobrutinib achieved 50.8%-79.4%, 67.6%-93.6%, and 90.1%-98.0% inhibition of basophil activation during the dosing interval of 50, 150, and 300 mg b.i.d., respectively. Based on pharmacokinetic-pharmacodynamic analysis, half-maximal inhibitory concentration (IC) of sofnobrutinib for basophil activation was 54.06 and 57.01 ng/mL in the SAD and MAD parts, respectively. Similarly, IC for B-cell activation was 187.21 ng/mL. These data support further investigation of sofnobrutinib in allergic and autoimmune diseases.

Despite increasing interest in using Artificial Intelligence (AI) and Machine Learning (ML) models for drug development, effectively interpreting their predictions remains a challenge, which limits their impact on clinical decisions. We address this issue by providing a practical guide to SHapley Additive exPlanations (SHAP), a popular feature-based interpretability method, which can be seamlessly integrated into supervised ML models to gain a deeper understanding of their predictions, thereby enhancing their transparency and trustworthiness. This tutorial focuses on the application of SHAP analysis to standard ML black-box models for regression and classification problems. We provide an overview of various visualization plots and their interpretation, available software for implementing SHAP, and highlight best practices, as well as special considerations, when dealing with binary endpoints and time-series models. To enhance the reader's understanding for the method, we also apply it to inherently explainable regression models. Finally, we discuss the limitations and ongoing advancements aimed at tackling the current drawbacks of the method.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision-recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.

The increased use of sensor-based digital health technologies (DHTs) in clinical trials brought to light concerns about implementation practices that might introduce burden on trial participants, resulting in suboptimal compliance and become an additional complicating factor in clinical trial conduct. These concerns may contribute to the lower-than-anticipated uptake of DHT deployment and data use for regulatory decision-making, despite well-articulated benefits. The Electronic Clinical Outcome Assessment (eCOA) Consortium gathered collective experience on deploying sensor-based DHTs and supplemented this with relevant literature focusing on mechanisms that may enhance participant compliance. The process for DHT implementation starts with identifying a clinical concept of interest followed by a digital measure selection, defining active or passive data capture and their sources, the number of sensors with respective body location, plus the duration and frequency of use in the context of perceived participant burden. Roundtable discussions among patient groups, physicians, and technology providers prior to protocol development can be very impactful for optimizing trial design. While diversity and inclusion are essential for any clinical trial, patient populations should be considered carefully in the context of trial-specific aims, requirements, and anticipated patient burden. Minimizing site burden includes assessment of training, research engagement, and logistical burden which needs to be triaged differently for early and late-stage clinical trials. Additional considerations include sharing trial results with study participants and leveraging publicly available data for compliance modeling. To the best of our knowledge, this report provides holistic considerations for sensor-based DHT implementation that may optimize participant compliance.

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Multi-lineage differentiating stress-enduring (Muse) cells, identified as pluripotent surface marker SSEA-3(+) cells, are stress tolerant endogenous pluripotent-like stem cells, and are involved in tissue repair. However, the significance of Muse cells in acute myocarditis has not been evaluated. In the present study, we counted Muse cells/area in biopsied myocardial tissue samples from 17 patients with fulminant myocarditis, and 6 with non-inflammatory myocardial disease as controls. Compared with controls, patients with fulminant myocarditis had significantly more Muse cells (p = 0.00042). Patients with mechanical circulatory support (p = 0.006) and myocardial degeneration (p = 0.023) had significantly more Muse cells than those without them. The Muse cell number was correlated with acute phase CK-MB level (ρ = 0.547, p = 0.029), indicating the severity of myocardial injury, and was also correlated with acute/recovery phase ratio of CK-MB (ρ = 0.585, p = 0.023) and cardiac troponin I (ρ = 0.498, p = 0.047) levels, indicating resilience of myocardial injury. In fulminant myocarditis, the Muse cell number was associated with the severity of clinical features in the acute phase, and also with the recovery from myocardial damage in the chronic phase. Endogenous Muse cells might be mobilized and accumulate to the myocardial tissues in fulminant myocarditis, and might participate in the repair of injured myocardium.

Tofacitinib is a targeted JAK inhibitor used to treat rheumatoid arthritis. Despite some recent safety concerns, it is considered effective and safe with appropriate patient selection. Between May 2015 and May 2024, data were retrospectively analyzed from 112 patients with a diagnosis of RA in a tertiary care hospital who had received tofacitinib for at least 1 month, with or without prior biologic DMARDs. The mean disease duration was 12 years, and the median duration of tofacitinib use was 32.5 months. The p-value for all disease activity parameters evaluated for effectiveness between the 1st- and 3rd-month visits was <0.001, except CRP (p = 0.097). Adverse events occurred in 15 (13.4%) patients, with an incidence rate of 4.54 per 100 patient-years. Observed were one myocardial infarction (0.3/100 patient-years), two pulmonary embolisms (0.6/100 patient-years), three herpes zoster (HZ) (0.9/100 patient-years), and one basal cell carcinoma (BCC) (0.3/100 patient-years). Median drug-free survival was 68 (95% CI: 54.8-81.2) months. The drug was discontinued in 28 (25%) patients due to ineffectiveness and in 13 (11.6%) due to side effects. A significant difference in drug survival rates was observed between patients who had not previously used bDMARDs and those who had received at least one bDMARD before tofacitinib (p < 0.001). Drug survival was 46.35 months in the prior bDMARD group and 71.09 months in the bDMARD-naive group. This study found significant reductions in disease activity indices at 3 and 6 months after starting tofacitinib, with sustained effectiveness. Although adverse event rates were somewhat higher than reported in the literature, tofacitinib can be used effectively and safely in appropriate patient populations for RA treatment.

Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open-label adaptive dose-escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty-four participants (12 female, median age 53, IQR 35-61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, reaching maximum concentrations at 15 min. C-peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High-dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted.

Registry-based randomized controlled trials (RRCTs) can combine the advantages of registries with those of randomization. This review aimed to expand the current knowledge on RRCT utilization and implementation by providing a comprehensive overview of RRCT use cases. A targeted literature search was conducted through July 2023 to identify articles on RRCTs. Information regarding the RRCT characteristics, their utilization, and the registries' contributions and the constraints faced was extracted. Descriptive statistics were used. We identified 102 RRCTs in 110 publications. RRCTs were mostly performed for the assessment of medical devices or surgical/clinical procedures (n = 45), followed by drugs (n = 30). More than half of the RRCTs were conducted in the Nordic countries (n = 58) and the most used registry types were health service registries/administrative health data (n = 63), followed by disease registries (n = 46). Approximately half of the RRCTs (n = 53) utilized additional data sources aside from registry data. The contribution of a registry to the RRCT was mostly for data collection and study follow-up (n = 90-92), followed by patient recruitment (n = 56-61), and randomization (n = 28-38), with varying levels of transparency in reporting. We collated author-reported constraints related to the used registries into four overarching themes, that is, data availability and completeness, data quality, representativeness, and registry infrastructure and accessibility. This review shows that RRCTs are already used in different domains and geographic regions. Guidelines on structured and transparent reporting of RRCT methods and the optimal use are, however, needed to inform decision-making by health authorities and to reach their full potential.

TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. C and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median T for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (T) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 C but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

Quizartinib prolongs QT interval through inhibition of the slow delayed rectifier potassium current (I). We used non-linear mixed-effects modeling to explore the relationship between quizartinib and its pharmacologically active metabolite AC886 and the Fridericia-corrected QT interval (QTcF) in newly diagnosed acute myeloid leukemia (AML) patients. We evaluated linear and non-linear drug effect models, using triplicate QTcF measurements with available time-matched pharmacokinetic samples from the Phase 3 QuANTUM-First trial. The effect of intrinsic and extrinsic factors on model parameters was tested using stepwise covariate model building. Simulations were conducted to predict the change from baseline in QTcF (ΔQTcF) at the maximum concentration at steady-state (C) for quizartinib maintenance daily doses of 30 and 60 mg. The concentration-QTcF (C-QTcF) relationship was best described by a sigmoidal maximum effect model. After accounting for the effect of quizartinib, including AC886 concentrations did not further explain changes in QTcF. Circadian variations in QTcF were described using an empirical change from baseline based on clock times. Age and hypokalaemia were identified as statistically significant covariates on baseline QTcF; no covariates were found to impact the C-QTcF relationship. The median model-predicted ΔQTcF at C was 18.4 ms (90% confidence interval (CI): 16.3-20.5) at 30 mg and 24.1 ms (90% CI: 21.4-26.6) at 60 mg. In conclusion, in newly diagnosed AML patients, ΔQTcF increased non-linearly with increasing quizartinib concentrations. The predicted ΔQTcF increase at C supports the proposed dose adaptation based on observed QTcF and the dose reduction in case of strong cytochrome P450 3A (CYP3A) inhibitors coadministration.

Molecular targeted tyrosine kinase inhibitors (TKIs) have produced unprecedented treatment response in cancer therapy for patients harboring specific oncogenic mutations. While the TKIs are mostly well tolerated, they were reported to increase serum levels of creatine kinase (CK) and cause muscle metabolism-related toxicity. CK is an essential enzyme involved in cellular energy metabolism and muscle function. Elevated serum CK levels can arise from both physiological and pathological factors, as well as triggered by specific drug classes. The incidence of serum CK elevation induced by a few approved TKIs (brigatinib, binimetinib, cobimetinib-vemurafenib combination [Food and Drug Administration, United States]; aumolertinib, and sunvozertinib [only approved by National Medical Products Administration, China]) were over 35%. CK elevation-related symptoms include myopathy, myositis, inclusion body myositis (IBM), cardiotoxicity, rhabdomyolysis, rash, and acneiform dermatitis. High-level or severe symptomatic CK elevation may necessitate dose reduction and indirectly dampen TKI efficacy. This review presents an updated summary about the prevalence rate and recent research about mechanisms leading to TKI-induced serum CK elevation in cancer patients. The utility of monitoring serum CK levels for predicting TKI-induced adverse effects and their management will also be discussed.

SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and C of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the C by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the C did not change significantly. All treatments were well tolerated in all three studies.

Controversies regarding the benefits of statin treatment on clinical outcomes in coronary artery spasm (CAS) without obstructive coronary artery disease (CAD) persist due to limited data. In this retrospective nationwide population-based cohort study from the Taiwan National Health Insurance Research Database during the period 2000-2012, the matched cohorts consisted of 12,000 patients with CAS. After propensity score matching with 1:1 ratio, 2216 patients were eligible for outcome analysis in either statin or nonstatin group, with the mean follow-up duration of 4.8 and 4.6 years, respectively. Statin users versus nonusers had a significantly reduced risk of major adverse cardiovascular events (MACEs) (6.7% vs. 9.5%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55-0.84) and all-cause mortality (6.0% vs. 7.6%; HR 0.77; 95% CI 0.61-0.96). While the results of MACEs were mainly contributed by cardiovascular death (1.9% vs. 3.2%; HR 0.56; 95% CI 0.38-0.83) and ischemic stroke (3.8% vs. 5.4%; subdistribution HR 0.69; 95% CI 0.52-0.91), they were primarily driven by reductions in ischemic but not hemorrhagic stroke. The benefit of statins was significantly pronounced in patients with hypertension and diabetes. Nevertheless, the effect on MACEs was consistent irrespective of age, sex, dyslipidemia, and mental disorder. Statins significantly reduced the risk of MACEs and all-cause mortality in CAS patients. The benefit of statin therapy in reducing MACEs appeared to be linear, with greater risk reduction with higher doses and longer duration without upper threshold, reflecting the dose-dependent relationship of statins with MACEs in CAS patients.

Milvexian is an oral, small-molecule factor XIa inhibitor being developed to prevent thromboembolic events. This study assessed the absolute bioavailability (F) of milvexian following single doses of milvexian spray-dried dispersion (SDD) formulation under fed and fasted conditions, and milvexian solution, in healthy adult participants using an intravenous microtracer approach. This was a phase I, open-label, partially randomized, 4-sequence, 5-period crossover study. After fasting for ≥10 h, participants received milvexian 200-mg oral solution with a 100-μg C milvexian intravenous microtracer at the time of maximum observed plasma concentration. Following a 3-day washout, participants were randomized to 1 of 4 milvexian SDD treatment sequences in a crossover fashion: 25 mg fasted, 25 mg fed, 200 mg fasted, or 200 mg fed. Pharmacokinetic data were collected up to 72 h postdose. Seventeen participants were dosed, and 14 completed treatment. Under fasted conditions, milvexian F was ~100%, 58.2%, and 54.2% following administration of the oral solution, 25 mg SDD, and 200 mg SDD, respectively. Under fed conditions, milvexian F following 25 mg and 200 mg SDD was 44.3% and 75.6%, respectively. The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies.