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-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

383 First-in-human study of PF-04691502, a small molecule oral dual inhibitor of PI3K and mTOR in patients with advanced cancer: Preliminary report on safety and pharmacokinetics

2010 ◽  
Vol 8 (7) ◽  
pp. 121-122 ◽  
Author(s):  
C.D. Britten ◽  
A.A. Adjei ◽  
R. Millham ◽  
B. Houk ◽  
Z.A. Wainberg ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Small Molecule ◽  
Preliminary Report ◽  
Human Study ◽  
Dual Inhibitor

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

First-in-human study of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-00299804, a small molecule irreversible panHER inhibitor in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3599-3599 ◽  
Author(s):  
J. H. Schellens ◽  
C. D. Britten ◽  
D. R. Camidge ◽  
D. Boss ◽  
S. Wong ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tyrosine Kinases ◽  
Human Study ◽  
Xenograft Model ◽  
Tumor Growth Inhibition ◽  
Her Family ◽  
Molecule Inhibitor ◽  
Hand Foot Syndrome ◽  
Fdg Pet Ct ◽  
Dose Levels

3599 Background: There are scientific rationale for inhibitors which provide combined and irreversible blockade of HER family members. PF-00299804 is an orally available, potent, irreversible small molecule inhibitor of the HER tyrosine kinases. Methods: The safety, tolerability, PK, PD, and efficacy of PF-00299804 administered orally once daily in 3-week cycles were assessed in patients with advanced solid tumors using an accelerated dose-escalation design. Safety assessments included adverse event (AE), laboratory, ECG, and LVEF assessments. PK parameters were determined after a single lead-in dose and on Day 14 by non-compartmental techniques. PD measures included assessment of HER-related signaling pathways via IHC analyses of serial skin and, in some patients, tumor biopsies. Serial 18F-FDG- PET/CT has been performed on a subset of patients with scans being classified according to modified EORTC criteria by a central reader. Results: 32 pts have been treated across 8 sequential dose levels ranging from 0.5 to 60 mg. The most common AEs were diarrhea, fatigue, nausea, and rash. 3/6 patients at 60 mg experienced a DLT [hand-foot syndrome (1), dehydration related to diarrhea(1), mucositis(1)]. Cmax and AUC of PF-00299804 increased with dose in an approximately proportional manner. Accumulation ranged from 3.3 to 6.8, suggesting a terminal t1/2>24 h. At the 30 mg dose level, mean Day 14 drug concentration was above the predicted efficacious concentration for tumor growth inhibition based on A431 xenograft model. Of 7 sets of PET data evaluated thus far, partial responses (PR) have been observed in 2 patients. A PR as assessed using RECIST criteria has been reported in 1 of 2 patients with advanced refractory NSCLC treated to date. Conclusions: Daily administration of PF-00299804 across many dose levels appears safe and tolerable. Diarrhea, fatigue, nausea, and rash are the most frequent AEs. Evaluation of 45 mg/d as the potential MTD is ongoing. Systemic exposures at doses = 30 mg exceed the threshold for efficacy as predicted from preclinical studies. Clinical and biological activity of PF-00299804 was observed including a PR in 1 of 2 patients with advanced refractory NSCLC. No significant financial relationships to disclose.

Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3099-TPS3099 ◽  
Author(s):  
James J. Lee ◽  
John D. Powderly ◽  
Manish R. Patel ◽  
Joshua Brody ◽  
Erika Paige Hamilton ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Human Study ◽  
Immune Checkpoints ◽  
Dual Inhibitor ◽  
Anti Tumor Activity

TPS3099 Background: Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that negatively regulate T-cell function and are implicated in various malignancies. Preclinical studies have demonstrated that dual blockade of these pathways is synergistic. CA-170 is a first-in-class oral small molecule that directly targets both PD-1/PD-L1 and VISTA pathways and has shown anti-tumor activity in multiple preclinical models. Methods: The dose escalation phase has a target enrollment of 50 pts with advanced solid tumors or lymphomas onto escalating doses; the first four single-pt cohorts are accelerated titration but then switch to 3+3 design. The dose expansion phase has a target enrollment of 250 pts with select tumor types known to be responsive to anti-PD-1/L1 inhibitors and/or known to express PD-L1 or VISTA. Key eligibility criteria include: age ≥ 18 years, ECOG ≤1, adequate organ function, and ineligible for/did not respond to standard therapy including anti-PD-1/L1 inhibitors, where available. Primary objectives of this first-in-human study: safety, maximum tolerated dose, and recommended phase 2 dose. Secondary objectives: pharmacokinetics (PK) and anti-tumor activity. Exploratory endpoints: biomarkers and pharmacodynamic (PD) effects, which include changes in immune cell and peripheral cytokine populations in tumor (IHC/mRNA) and blood (flow cytometry/mRNA). Oral CA-170 is administered once daily in 21-day cycles. Response will be evaluated every other cycle per RECIST (v1.1) and Immune-related Response Criteria or by Cheson criteria (2007). Patients who discontinue treatment for reasons other than progressive disease will be followed for progression-free survival. Serial plasma, blood, and tumor samples will be collected for PK and PD evaluation. Clinical trial identifier: Clinical trial information: NCT02812875.

scholarly journals Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits

2021 ◽  
Author(s):  
Pancras C. Wong ◽  
Earl J. Crain ◽  
Jeffrey M. Bozarth ◽  
Yiming Wu ◽  
Andrew K. Dilger ◽  
...  
Keyword(s):  
Small Molecule ◽  
In Vitro Studies ◽  
In Vivo Evaluation ◽  
Experimental Thrombosis ◽  
Factor Xia ◽  
Orally Bioavailable

In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa

2015 ◽  
Vol 40 (4) ◽  
pp. 416-423 ◽  
Author(s):  
Pancras C. Wong ◽  
Mimi L. Quan ◽  
Carol A. Watson ◽  
Earl J. Crain ◽  
Mark R. Harpel ◽  
...  
Keyword(s):  
Small Molecule ◽  
Bleeding Time ◽  
Factor Xia

Small Molecule, Multimodal, [18F]-PET and Fluorescence Imaging Agent Targeting Prostate-Specific Membrane Antigen: First-in-Human Study

2021 ◽  
Author(s):  
Omer Aras ◽  
Cetin Demirdag ◽  
Harikrishna Kommidi ◽  
Hua Guo ◽  
Ina Pavlova ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Small Molecule ◽  
Human Study ◽  
Imaging Agent ◽  
Prostate Specific Membrane Antigen ◽  
Specific Membrane
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