Papers by Stephan Schwers
Journal of Thrombosis and Haemostasis, Oct 1, 2021
BackgroundCoagulation factor XI (FXI) contributes to the development of thrombosis but appears to... more BackgroundCoagulation factor XI (FXI) contributes to the development of thrombosis but appears to play a minor role in hemostasis and is, therefore, an attractive anticoagulant drug target.ObjectivesTo evaluate the safety, pharmacokinetic, and pharmacodynamic properties of BAY 2433334, an orally administered small molecule targeting activated FXI (FXIa), in healthy men.Patients/MethodsThis phase 1 study was conducted in two parts. In part 1, 70 volunteers were randomized 4:1 to receive a single oral dose of BAY 2433334 (5–150 mg as oral solution or immediate‐release tablets) or placebo. In part 2, 16 volunteers received a single oral dose of five BAY 2433334 5‐mg tablets with or without a high‐calorie breakfast in a randomized crossover study design. Adverse events, pharmacokinetic parameters, and pharmacodynamic parameters were assessed up to 72 h after drug administration. Volunteers were followed up after 7 to 14 days.ResultsBAY 2433334 demonstrated favorable safety and tolerability with a dose‐dependent increase in exposure and a terminal half‐life of 14.2 to 17.4 h. A high‐calorie breakfast reduced mean maximum plasma concentration and exposure by 31% and 12.4%, respectively. AY 2433334 was associated with a dose‐dependent inhibition of FXIa activity and an increase in activated partial thromboplastin time. Bleeding times in volunteers who had received BAY 2433334 were similar to those in volunteers who had received placebo.ConclusionsThese data indicate that BAY 2433334 is a promising development candidate for once‐daily oral anticoagulation; it is being evaluated in phase 2 dose‐finding studies in patients at risk of thrombosis.
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European Respiratory Journal, Sep 1, 2014
Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An exces... more Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases like bronchiectasis (BE) and COPD. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target. In order to assess, whether biomarkers could support clinical evaluation of this new treatment concept, a multicenter biomarker study was conducted in BE patients and healthy controls: A sputum induction and processing protocol was implemented at three study sites and collected sputum was analyzed for neutrophil cell count, HNE activity, IL-8 and other markers with a 2 week interval over six weeks. In addition, the elastin degradation product desmosine was analyzed in urine. First results from 15 patients and 5 healthy controls indicate that, based on sputum HNE activity, BE patients could be divided into HNE(low) and HNE(high) groups (>10-fold difference), whereas healthy volunteers were always found to be HNE(low). Furthermore, high sputum HNE activity often coincides with other markers of inflammation (neutrophil cell count, IL-8). Those markers may guide patient selection and contribute to identifying BE patients eligible to treatment with a novel HNE inhibitor, which is currently in clinical development. In summary, Biomarker evaluation in BE patients revealed that significant HNE activity in sputum could be detected and might be used for stratification of patients for HNE inhibitor treatment.
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European Respiratory Journal, Sep 1, 2014
Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An exces... more Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases, e.g. bronchiectasis (BE), COPD, and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target. BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models. This First-in-Man study evaluated BAY 85-8501 in a Single-Dose-Escalation (SDE) design with 0.05, 0.1, 0.2, 0.5 or 1.0 mg as oral liquid formulation in 37 healthy male subjects (27 active, 10 placebo). The single dose treatments were safe and well tolerated without serious or severe adverse events and without any hints for mode of action or drug substance related adverse effects. All clinical safety parameters (BP, HR, ECG) and clinical laboratory parameters were in the normal range for single doses up to 1 mg. Drug absorption was fast, max. concentration (C) reached after 1 h, mean drug half-life was up to 145 - 175 h, allowing once daily dosing. Max. C and Area under Curve (0-24) increased in a dose-proportional way. Renal elimination of the unchanged drug is a minor pathway of elimination ( 4%). SDE up to 1 mg BAY 85-8501 was safe and well tolerated with pharmacokinetics that allow once daily dosing. Drug candidate is adequate for further clinical evaluation in studies in chronic anti-inflammatory treatment of lung diseases.
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Scientific Reports, Jun 13, 2022
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British Journal of Clinical Pharmacology, Mar 24, 2022
AimTo evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers.MethodsPh... more AimTo evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers.MethodsPhase 1 study of healthy men at a German centre. Part A: randomized, single‐blind, multiple dose‐escalation study of BAY 2433334 (25/50/100 mg once daily [OD]) vs. placebo. Part B: similar design to Part A; evaluated BAY 2433334 25 mg twice daily. Part C: nonrandomized, open‐label study; evaluated potential interactions between BAY 2433334 (25/75 mg OD) and midazolam (7.5 mg), a CYP3A4 index substrate. Primary variables: treatment‐emergent adverse events (TEAEs; Parts A and B); area under the plasma concentration–time curve (AUC) and maximum plasma concentration of midazolam and α‐hydroxymidazolam (Part C). Study period: 18 days plus follow‐up visit.ResultsParts A and B: 36 participants randomized to BAY 2433334; 12 to placebo. Part C: 48 participants assigned to BAY 2433334 plus midazolam. BAY 2433334 was well tolerated in all study parts. AUC and maximum plasma concentration of BAY 2433334 in plasma appeared dose proportional over 25–100 mg OD, with low‐to‐moderate variability in pharmacokinetic parameters. Multiple dosing caused minor‐to‐moderate accumulation and a mean terminal half‐life (15.8–17.8 h) supporting once‐daily dosing. Dose‐dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed. BAY 2433334 appeared to have a minor effect on AUC for midazolam (ratio [90% confidence interval]: 1.1736 [1.0963–1.2564]) and α‐hydroxymidazolam (0.9864 [0.9169–1.0612]) only for BAY 2433334 75 mg OD on day 10.ConclusionMultiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.
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Journal of Thrombosis and Haemostasis, Oct 1, 2017
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Journal of Thrombosis and Haemostasis, Dec 1, 2021
Determining patient's coagulation profile, i.e. detecting a bleeding tendency or the opposite... more Determining patient's coagulation profile, i.e. detecting a bleeding tendency or the opposite, a thrombotic risk, is crucial for clinicians in many situations. Routine coagulation assays and even more specialized tests may not allow a relevant characterization of the hemostatic balance. In contrast, thrombin generation assay (TGA) is a global assay allowing the dynamic continuous and simultaneous recording of the combined effects of both thrombin generation and thrombin inactivation. TGA thus reflects the result of procoagulant and anticoagulant activities in blood and plasma. Because of this unique feature, TGA has been widely used in a wide array of settings from both research, clinical and pharmaceutical perspectives. This includes diagnosis, prognosis, prophylaxis, and treatment of inherited and acquired bleeding and thrombotic disorders. In addition, TGA has been shown to provide relevant information for the diagnosis of coagulopathies induced by infectious diseases, comprising also disturbance of the coagulation system in COVID‐19, or for the assessment of early recurrence in breast cancer. This review article aims to document most clinical applications of TGA.
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Thrombosis and Haemostasis, 2012
SummaryRivaroxaban is a direct factor Xa inhibitor, which can be monitored by anti-factor Xa chro... more SummaryRivaroxaban is a direct factor Xa inhibitor, which can be monitored by anti-factor Xa chromogenic assays. This ex vivo study evaluated different assays for accurate determination of rivaroxaban levels. Eighty plasma samples from patients receiving rivaroxaban (Xarelto®) 10 mg once daily and 20 plasma samples from healthy volunteers were investigated using one anti-factor Xa assay with the addition of exogenous antithrombin and two assays without the addition of antithrombin. Two different lyophilised rivaroxaban calibration sets were used for each assay (low concentration set: 0, 14.5, 59.6 and 97.1 ng/ml; high concentration set: 0, 48.3, 101.3, 194.2 and 433.3 ng/ml). Using a blinded study design, the rivaroxaban concentrations determined by the assays were compared with concentrations measured by HPLC-MS/MS. All assays showed a linear relationship between the rivaroxaban concentrations measured by HPLC-MS/MS and the optical density of the anti-FXa assays. However, the assay with the addition of exogenous anti-thrombin detected falsely high concentrations of rivaroxaban even in plasma samples from controls who had not taken rivaroxaban (intercept values using the high calibrator set and the low calibrator set: +26.49 ng/ml and +13.71 ng/ml, respectively). Plasma samples, initially determined by the high calibrator setting and containing rivaroxaban concentrations <25 ng/ml, had to be re-run using the low calibrator setting for precise measurement. In conclusion, anti-factor Xa chromogenic assays that use rivaroxaban calibrators at different concentration levels can be used to measure accurately a wide range of rivaroxaban concentrations ex vivo. Assays including exogenous antithrombin are unsuitable for measurement of rivaroxaban.
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Thrombosis Journal, 2013
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Immunity, Mar 1, 1997
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Journal of Thrombosis and Haemostasis, Jul 1, 2022
BackgroundBleeding is a clinically significant issue with all current anticoagulants. Safer antit... more BackgroundBleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required.ObjectivesTo investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)‐directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers.Patients/MethodsIn a first‐in‐human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single‐dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated.ResultsIn this study, no hemorrhage, or hypersensitivity or infusion‐/injection‐related reactions were reported. Drug‐related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self‐limited. Dose‐dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio‐to‐baseline: aPTT, range, 1.09–3.11 vs. 1.05 with placebo; FXI, range, 0.70–0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half‐life increased continuously with increasing i.v. dose (range, 28–208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2–73.7).ConclusionsBAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose‐dependent prolongation of aPTT and duration of FXI inhibition.
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Journal of Thrombosis and Haemostasis, Dec 1, 2021
Thrombin is the pivotal enzyme in the biochemistry of secondary hemostasis crucial to maintaining... more Thrombin is the pivotal enzyme in the biochemistry of secondary hemostasis crucial to maintaining homeostasis of hemostasis. In contrast to routine coagulation tests (PT or aPTT) or procoagulant or anticoagulant factor assays (e.g. fibrinogen, factor VIII, antithrombin or protein C), the thrombin generation assay (TGA), also named thrombin generation test (TGT) is a so‐called “global assay” that provides a picture of the hemostasis balance though a continuous and simultaneous measurement of thrombin formation and inhibition. First described in the early 1950s, as a manual assay, efforts have been made in order to standardize and automate the assay to offer researchers, clinical laboratories and the pharmaceutical industry a versatile tool covering a wide range of clinical and non‐clinical applications. This review describes technical options offered to properly run TGA, including a review of preanalytical and analytical items, performance, interpretation, and applications in physiology research and pharmacy.
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Research and practice in thrombosis and haemostasis, Apr 1, 2019
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Clinical pharmacology in drug development, May 15, 2013
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Background: Inhibition of excessive neutrophil elastase (NE) might represent a therapeutic approa... more Background: Inhibition of excessive neutrophil elastase (NE) might represent a therapeutic approach in neutrophilic airway diseases such as non-cystic fibrosis bronchiectasis (NCFB). Methods: We conducted a multicenter, phase IIa, randomized, double-blind, placebo-controlled, parallel-group study in patients with NCFB. Primary endpoint was safety and tolerability of 28-day oral administration of BAY 85-8501 (1.0 mg OD). Secondary objectives included lung function, biomarkers of inflammation and tissue damage, and health status (ClinicalTrials.gov Identifier: NCT01818544). Results: 94 patients (mean age, 66 years, 53% male) were randomized to treatment. 45 patients received BAY 85-8501. A total of 67 patients reported treatment-emergent adverse events (TEAEs); 31 patients with BAY 85-8501and 36 patients with placebo. The most frequently reported TEAEs were headache, nasopharyngitis, and cough with no difference between groups. 3 patients in the BAY 85-8501 treatment group and 1 patient in the placebo group had a serious TEAE, all not assessed to be related to study treatment. There were no clinically relevant changes in blood pressure, heart rate, ECG, and blood-laboratory parameters. Compared to placebo there were no significant changes in lung function, health status, 24 hour sputum weight, NE activity and concentration, and other biomarkers including urine desmosine. Conclusion: BAY 85-8501 1.0 mg OD was generally safe and well tolerated over 28 days in patients with non-CF BE. Further studies need to show long-term safety and potential efficacy of BAY 85-8501 in patients with non-CF BE.
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Pharmaceuticals, Feb 24, 2012
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Blood, Nov 29, 2018
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Thrombosis Research, Dec 1, 2022
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Journal of Thrombosis and Haemostasis
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SSRN Electronic Journal
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Papers by Stephan Schwers