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KDDF-201210-04 Development of a novel anti-coagulant Factor Xa inhibitor, GCC-4401C(Cardiovascular Diseases, Chemical) [2015-07-07]

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Ongoing Project
Section Lead
Generation
Lead
Optimization
Preclinical Phase I Phase II Phase III

Development and Market Objectives

Green Cross Corporation is developing an orally available direct Factor Xa inhibitor, GCC-4401C, which has shown an excellent safety profile during Phase I clinical study. After completion of Phase II and III studies for the prevention of venous thromboembolism (VTE) on hip or knee replacement surgery patients, we will explore additional indications for the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation.

Unmet Medical Need & Target Patients

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GCC-4401C may prove its greatest impact in providing a much-needed and attractive alternative to warfarin in various indications. Prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism in patients undergoing hip or knee arthroplasty, is considered to be a primary unmet medical need. It is the most common cause for rehospitalisation in this patient group. Each year in the United States, between 350,000 and 600,000 people experience a blood clot in the legs or in the lungs. The US and European hip and knee implant markets are the two largest, accounting for nearly 80 percent of total procedures conducted worldwide. The 2005 revenues for hip and knee implants in the US and Europe were $6.5 billion.  Demand driven by an aging population and an increasing number of younger patients are contributing to the continuous growth of hip and knee replacement procedures.
 
Thromboembolism involving arterial or venous circulation is a common cause of morbidity and mortality. As an anticoagulation therapy, heparin and Vitamin K antagonists (VKAs) such as warfarin have been used in clinical settings for more than 50 years, but both are associated with several limitations requiring frequent coagulation monitoring due to unpredictable effects of anticoagulant .  Therefore, there is an urgent need for novel, oral agents with a predictable anticoagulant action. The greatest unmet medical need in anticoagulation therapy is to find a replacement for VKAs for long-term therapy, particularly stroke prevention in patients with atrial fibrillation (a heart rhythm disorder).  Recently, Factor Xa has emerged as an attractive target for novel anticoagulants and a number of Factor Xa inhibitors are currently under development as oral anticoagulants for long-term use.
A major unmet medical need is for direct FXa inhibitors that are simpler to administer than VKAs, with fewer strokes and less intracranial bleeding compared with warfarin and less bleeding yet similar or better efficacy with a lower-dose regimen. In addition, the availability of simple, fixed-dose, unmonitored therapies should increase the use of direct FXa inhibitor therapy in patients with atrial fibrillation at risk for stroke.

Status

Phase I Clinical Study

To investigate the safety and tolerability of single doses of GCC-4401C in healthy male subjects, a Phase Ia study (GCC-4401C-101) was recently conducted at Quintiles in the United States under the conditions of randomized, double-blind, placebo-controlled, and single ascending dose. Forty eight healthy male subjects were enrolled in 6 cohorts and administered at 6 dose-escalation levels up to 80 mg/subject. GCC-4401C was well-tolerated without any significant adverse events, and was detected in blood plasma dose-proportionally across the dose range of 2.5 mg to 80 mg per patient. The pharmacodynamic variables were also statistically correlated with GCC-4401C plasma concentrations.
We plan to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of GCC-4401C in healthy male subjects based on the safety margins of the SAD study. An appropriate dose and dosing regimen of oral GCC-4401C from subsequent clinical trials on VTE patients are expected to be identified. The Phase 1b study will be completed with Global CRO in the US in 3Q, 2014.

Intellectual Property

Material patent for GCC-4401C, covering a wide range of chemical structures, was awarded in early 2008 within S. Korea, followed by its production method patent in early 2011. Moreover, patent applications for both material and production method, are in progress in 21 and 5 overseas countries including the US, respectively.
-          KR811865 : Pyrimidinone derivatives or pyridazinone derivatives for inhibition of factor VIIa activity
-          KR109594 : FXa inhibitors with cyclic amidines as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
-          KR898361 : FXa inhibitors with cyclic amidoxime or cyclic amidrazone as P4 subunit, processes for their preparations, and pharmaceutical compositions and derivatives thereof
-          KR1037051 : Method for preparing of (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
-          KR1037052 : Method for preparing 5-chloro-N-(((5S)-2-oxo-3-(4-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophen-2-carboxamide derivatives, and their intermediates
-          PCT/KR2010/004420 : Method for preparing (S)-5-chloro-N-((3-(4-(5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide derivatives
-          PCT/KR2010/004421 : Method for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(5,6-dihydro-4H-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide derivative and intermediate used therein

Competitive Advantages

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GCC-4401C has been specifically designed for chronic, once-a-day treatment. It has a half-life that supports true, once-daily dosing and a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability. Since GCC-4401C has an excellent aqueous solubility, there has been potential for the development of both po and iv formulations. Data from comparative efficacy studies in animals have also demonstrated the superiority of GCC-4401C against other direct FXa inhibitors with less bleeding effects. From the recent Phase Ia clinical study, GCC-4401C did not show any significant sign of adverse events. PK parameters and PD markers were predictable dose-proportionally across the all dose ranges. GCC-4401C is expected to show excellent safety profiles, less bleeding and less liver toxicity through human clinical studies.

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