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Recent advances in clinical trials of the direct and indirect selective Factor Xa inhibitors
A R Porcari1, L Chi, R Leadley
1Information Research & Analysis, Department of Knowledge Management Services, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Anthony.Porcari@wl.com.
Abstract:
Over the years, pharmacological intervention to prevent undesired intravascular coagulation and the associated detrimental effects has been a clinical challenge. The first generation of anticoagulant agents, warfarin and unfractionated heparin (UFH), involve indirect mechanisms of inhibiting the coagulation cascade. Fractionated, or low-molecular weight, heparins (LMWHs) are more selective for coagulation Factor Xa (FXa) over thrombin (FIIa). LMWHs also utilise an indirect mechanism of inhibition and have improved pharmacokinetic, pharmacodynamic and therapeutic profiles over UFH. The success of LMWHs, along with the pivotal location of FXa in the coagulation cascade, has prompted interest in the discovery and development of selective FXa inhibitors. There are two general classes of FXa inhibitors in development, of which SR90107A/ORG31540, an antithrombin-III-dependent pentasaccharide and DX-9065a, a small molecule direct FXa inhibitor, have published clinical data. SR90107A/ORG31540 and DX-9065a offer safe, predictable pharmacokinetic and pharmacodynamic profiles when administered subcutaneously and intravenously, respectively, to healthy volunteers and appear to be progressing through clinical development. The purpose of this review is to compile and summarise the published Phase I and II clinical data for SR90107A/ORG31540 and DX-9065a.
Insights
New anticoagulants targeting Factor Xa (FXa) show promise. SR90107A/ORG31540 and DX-9065a, selective FXa inhibitors, demonstrate safe and predictable profiles in early clinical trials.
Area of Science:
- Pharmacology
- Hematology
- Drug Development
Background:
- Anticoagulant therapy faces challenges in preventing intravascular coagulation.
- Warfarin and unfractionated heparin (UFH) are first-generation agents with indirect mechanisms.
- Low-molecular-weight heparins (LMWHs) offer improved profiles by selectively inhibiting Factor Xa (FXa).
Purpose of the Study:
- To review and summarize published Phase I and II clinical data for two novel FXa inhibitors.
- To assess the safety and efficacy of SR90107A/ORG31540 and DX-9065a.
- To evaluate the pharmacokinetic and pharmacodynamic properties of these agents.
Main Methods:
- Review of published Phase I and II clinical trial data.
- Analysis of pharmacokinetic and pharmacodynamic profiles.
- Assessment of safety and tolerability in healthy volunteers.
Main Results:
- SR90107A/ORG31540 (antithrombin-III-dependent pentasaccharide) and DX-9065a (direct FXa inhibitor) have published clinical data.
- Both agents exhibit safe and predictable pharmacokinetic and pharmacodynamic profiles.
- SR90107A/ORG31540 was administered subcutaneously, while DX-9065a was administered intravenously.
Conclusions:
- Selective FXa inhibitors represent a promising advancement in anticoagulant therapy.
- SR90107A/ORG31540 and DX-9065a appear to be progressing well through clinical development.
- These agents offer potential alternatives to existing anticoagulants with improved characteristics.