scholarly journals First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects

2018 ◽  
Vol 84 (5) ◽  
pp. 876-887 ◽  
Author(s):  
Vidya Perera ◽  
Joseph M. Luettgen ◽  
Zhaoqing Wang ◽  
Charles E. Frost ◽  
Cynthia Yones ◽  
...  
Keyword(s):  
Small Molecule ◽  
Healthy Subjects ◽  
Human Study ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Factor Xia

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of Amg 986, a Novel Small Molecule Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients

2020 ◽  
Vol 26 (10) ◽  
pp. S68
Author(s):  
Jennifer Hellawell ◽  
Siddique Abbasi ◽  
Ashit Trivedi ◽  
Kate Tsirtsonis ◽  
Allegra Kaufman
Keyword(s):  
Heart Failure ◽  
Small Molecule ◽  
Healthy Subjects ◽  
Receptor Agonist ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Heart Failure Patients ◽  
Apelin Receptor

scholarly journals First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-986177/JNJ-70033093, a direct, reversible, small molecule Factor XIa inhibitor in healthy volunteers

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Perera ◽  
Z Wang ◽  
J Luettgen ◽  
J Wang ◽  
D Li ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Volunteers ◽  
Small Molecule ◽  
Healthy Subjects ◽  
Funding Source ◽  
Private Company ◽  
Factor Xia ◽  
Clinically Significant ◽  
Oral Doses ◽  
The Impact

Abstract Background Inhibition of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in many conditions predisposing to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits FXIa with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on therapy to current standard of care (SOC) antithrombotic agents or potentially as a replacement for current SOC. Purpose To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of BMS-177/JNJ-3093 in healthy subjects. Methods This was a 2-part, randomized, double-blind, placebo-controlled, sequential single- (Part A) and multiple- (Part B) ascending dose study to assess the safety, tolerability, PK, and PD of BMS-177/JNJ-3093 in healthy subjects. In Part A (SAD) of the study, 48 subjects were treated in 6 panels (8 subjects per panel). The 200 mg and 500 mg dose panels investigated the impact of a high fat diet on PK. In Part B (MAD), 56 subjects were treated in 7 panels (8 subjects per panel) on a once daily (QD) or twice daily (BID) regimen for a 14-day period. Within each panel in Parts A and B, subjects were randomized to receive either BMS-177/JNJ-3093 or matched placebo (3:1). Results Administration of single ascending doses of BMS-177/JNJ-3093 up to 500 mg and multiple ascending doses of BMS-177/JNJ-3093 up to 200 mg BID or 500 mg QD for 14 days were safe and well tolerated. No subjects had a clinically significant bleeding event. All treatment-emergent adverse events were mild in severity. After single doses of BMS-177/JNJ-3093 ranging from 4 to 500 mg in fasted status, BMS-177/JNJ-3093 plasma concentration reached Cmax at 3 h postdose in all panels, indicating a similar rate of absorption. The terminal half-life ranged from 8.26 to 13.8 h across SAD panels. Over 20 to 200 mg, a dose proportional increase was observed; however, saturable absorption was seen at higher doses of 300 and 500 mg. Food also increased the bioavailability of BMS-177/JNJ-3093. In the MAD portion of the study, based on visual inspection of trough plasma concentration profiles, BMS-177/JNJ-3093 plasma concentration steady state was reached between 1–3 dosing days (ie, Days 2–4) for the QD panels and 6 dosing days (ie, Day 7) for the 200 mg BID panel. Renal excretion was relatively low, ranging from 8–20%. After single oral dose or multiple oral doses, there is a clear trend that aPTT was prolonged and the magnitude of change was related to drug exposure. Conclusion BMS-177/JNJ-3093 was safe and well tolerated in healthy volunteers. The PK and PD profile demonstrates suitable dosing properties for further clinical studies. Currently, two Phase II studies are ongoing. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

scholarly journals First‐in‐human study of milvexian, an oral, direct, small molecule factor XIa inhibitor

2021 ◽  
Author(s):  
Vidya Perera ◽  
Zhaoqing Wang ◽  
Joseph Luettgen ◽  
Danshi Li ◽  
Mary DeSouza ◽  
...  
Keyword(s):  
Small Molecule ◽  
Human Study ◽  
Factor Xia

scholarly journals First evaluation of the safety, pharmacokinetics and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor Xia

2021 ◽  
Author(s):  
Dirk Thomas ◽  
Friederike Kanefendt ◽  
Stephan Schwers ◽  
Sigrun Unger ◽  
Ashraf Yassen ◽  
...  
Keyword(s):  
Small Molecule ◽  
Coagulation Factor ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Factor Xia

scholarly journals P135 A phase I, first-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of M5049, a dual antagonist of TLR7/8, in healthy subjects

2020 ◽  
Author(s):  
Andreas Port ◽  
Lena Klopp-Schulze ◽  
Jamie Shaw ◽  
Elizabeth Hussey ◽  
Nadra Mammasse ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Subjects ◽  
Human Study ◽  
Pharmacokinetics And Pharmacodynamics

scholarly journals A Single Administration of the Cytolytic CD38 Antibody TAK-079 to Healthy Subjects: Tolerability, Pharmacokinetics and Pharmacodynamics

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3249-3249 ◽  
Author(s):  
Eric Robert Fedyk ◽  
Deborah Berg ◽  
Glenda Smithson ◽  
Jose Estevam ◽  
Lachy Mclean ◽  
...  
Keyword(s):  
Nk Cells ◽  
Healthy Subjects ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Human Study ◽  
Model Systems ◽  
Controlled Study ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Limit Of Quantification ◽  
The Mean

Abstract Background: A study investigating the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-079 administered subcutaneously as a single agent in participants with relapsed/refractory multiple myeloma (RRMM) is ongoing because this investigational agent demonstrated distinct pharmacologic properties in a first in human study involving healthy volunteers. CD38 is expressed at high levels on subtypes of leukocytes which mediate immune disorders (e.g. plasma cells, activated B and T lymphocytes) and the selective removal of these cells could also restore immune homeostasis in these patients. TAK-079 is a fully human monoclonal antibody which binds to human CD38 protein with high affinity (KD = 0.7 nM) and lyses bound cells by CDC and ADCC in vitro. Methods: A randomized, double-blind, placebo-controlled study was conducted to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single intravenous (IV) infusion or subcutaneous (SC) injection of TAK-079 in escalating dose cohorts of healthy subjects. A starting single dose of 0.0003 mg/kg IV was selected, based upon modeling of responses in human and monkey model systems. Dose escalation ceased once a prespecified PD objective was achieved (i.e. ≥ 50% reduction in a leukocyte subset within peripheral blood which was sustained for ≥ 1 month). Six subjects were enrolled per dose cohort (4 receiving TAK-079; 2 receiving matching placebo). Subjects were monitored for at least 92 days post-dosing. Results: After IV (n=30) or SC (n=24) administration at all dose levels, TAK-079 was well tolerated and no safety concerns were identified. The maximum doses given were 0.06 mg/kg IV and 0.6 mg/kg SC. There were no serious adverse events (AE), severe AEs, withdrawals due to AEs, or infusion reactions. All AEs were mild or moderate. At the higher doses of TAK-079 administration, transient, mild to moderate increases in cytokine levels coincided with anticipated cell depletion; clinical symptoms primarily included mild pyrexia, headache, and postural hypotension. No remarkable findings for laboratory tests, ECGs, vital signs, or physical examinations were reported. Following a 2-hour IV infusion of 0.06 mg/kg, Cmax was observed at 5 minutes post EOI with a mean Cmax of 100.4 ng/mL. After Cmax was reached, serum concentrations decreased below the limit of quantification within 1 to 4 hours after the end of infusion. Following a single SC injection of 0.6 mg/kg TAK-079, the mean Cmax of 23.0 ng/mL was observed at approximately 24 hours post-dose and decreased gradually to below the limit of quantification by a median of 8 days (range 3-14). The mean AUClast and AUC∞ values were 90.4 and 212 ng*day/mL, respectively. Pharmacodynamic effects included a transient, dose-dependent reduction in NK cells at doses ≥0.003 mg/kg IV, approximately 167-fold less than the lowest dose reported for NK cell reduction by daratumumab administered to RRMM patients IV (≥0.5 mg/kg1). TAK-079 administered IV or SC reduced NK cells to a comparable extent (EC75 = 21 and 23 ng/mL, respectively). Greater than 90% reduction of plasmablasts was also observed in each subject dosed at 0.6 mg/kg SC, which generally peaked 2 days after injection and returned to baseline levels by 29 days. Neutrophil, lymphocyte, monocyte, red blood cell and platelet counts remained within normal ranges for all dose cohorts. Conclusion: TAK-079 may be a potent and convenient second generation anti-CD38 therapeutic, which warrants development for treatment of hematologic malignancies. Therefore, the safety, efficacy, pharmacokinetics, and pharmacodynamics of subcutaneous TAK-079 is being investigated in patients with RRMM in an ongoing study (NCT03439280; Figure 1) The starting dose in the RRMM study is fixed at 45 mg, based on the profile of the equivalent 0.6 mg/kg in healthy subjects. References Blood Adv. 2017 Oct 24;1(23):2105-2114. Disclosures Fedyk: Takeda Pharmaceuticals Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Smithson:Takeda Pharmaceuticals Inc.: Employment. Estevam:Takeda Pharmaceuticals Inc.: Employment. Mclean:Takeda Pharmaceuticals Inc.: Employment. Allikmets:Takeda Pharmaceuticals Inc.: Employment. Palumbo:Takeda Pharmaceuticals Inc.: Employment.

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