Idraparinux

Idraparinux

Clinical data
Routes of administration	Subcutaneous
ATC code	none
Legal status
Legal status	Investigational
Pharmacokinetic data
Elimination half-life	80-130 hours
Identifiers
IUPAC name Nonasodium (2S,3S,4S,5R,6R)-6-[(2R,3R,4S,5R,6R)-6- [(2R,3S,4S,5R,6R)-2-carboxylato- 4,5-dimethoxy-6-[(2R,3R,4S,5R,6S)-6-methoxy-4,5- disulfonatooxy-2-(sulfonatooxymethyl)oxan-3-yl] oxyoxan-3-yl]oxy-4,5-disulfonatooxy- 2-(sulfonatooxymethyl)oxan-3-yl]oxy-4,5-dimethoxy- 3-[(2R,3R,4S,5R,6R)-3,4,5-trimethoxy- 6-(sulfonatooxymethyl)oxan-2-yl]oxyoxane- 2-carboxylate
CAS Number	149920-56-9
PubChem CID	3083444
ChemSpider	2340656 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C38H55Na9O49S7
Molar mass	1727.17683 g/mol
3D model (JSmol)	Interactive image
SMILES CO[C@@H]1[C@H](O[C@@H]([C@@H]([C@H]1OC)OC)O[C@H]2[C@@H]([C@H]([C@@H](O[C@@H]2C(=O)[O-])O[C@@H]3[C@H](O[C@@H]([C@@H]([C@H]3OS(=O)(=O)[O-])OS(=O)(=O)[O-])O[C@H]4[C@@H]([C@H]([C@@H](O[C@H]4C(=O)[O-])O[C@@H]5[C@H](O[C@@H]([C@@H]([C@H]5OS(=O)(=O)[O-])OS(=O)(=O)[O-])OC)COS(=O)(=O)[O-])OC)OC)COS(=O)(=O)[O-])OC)OC)COS(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]
InChI InChI=1S/C38H64O49S7.9Na/c1-64-15-12(9-72-88(43,44)45)76-35(27(68-5)18(15)65-2)80-21-19(66-3)28(69-6)37(82-25(21)32(39)40)79-17-14(11-74-90(49,50)51)77-38(31(87-94(61,62)63)24(17)85-92(55,56)57)81-22-20(67-4)29(70-7)36(83-26(22)33(41)42)78-16-13(10-73-89(46,47)48)75-34(71-8)30(86-93(58,59)60)23(16)84-91(52,53)54;;;;;;;;;/h12-31,34-38H,9-11H2,1-8H3,(H,39,40)(H,41,42)(H,43,44,45)(H,46,47,48)(H,49,50,51)(H,52,53,54)(H,55,56,57)(H,58,59,60)(H,61,62,63);;;;;;;;;/q;9*+1/p-9/t12-,13-,14-,15-,16-,17-,18+,19+,20+,21+,22+,23+,24+,25+,26-,27-,28-,29-,30-,31-,34+,35-,36-,37-,38-;;;;;;;;;/m1........./s1 Y Key:MVPQUSQUURLQKF-MCPDASDXSA-E Y
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Idraparinux sodium is a novel long-acting synthetic indirect inhibitor of coagulation factor Xa. The agent is being developed by Sanofi-Aventis. It has a similar chemical structure and mechanism of action as fondaparinux, but its elimination half-life of 80 hours is 5 to 6 times longer than that of fondaparix (17 hours). Given its long half life, it can be injected subcutaneously once a week.

Use in Atrial Fibrillation

The AMADEUS study

The phase III AMADEUS study was a randomized, open label trial designed to compare the efficacy and safety of once-a-week idraparinux versus oral VKA treatment for the long-term prevention of thromboembolic events (stroke and non-central nervous system systemic embolism) in patients with AF and at least one additional risk factor for stroke. The predefined risk factors were previous ischemic stroke, transient ischemic attack or SE, hypertension requiring drug treatment, left ventricular dysfunction, age >75 years, age between 65-75 years plus diabetes mellitus, or age between 65-75 years plus symptomatic coronary heart disease.

Patients (n=4,576) with AF who were eligible for VKA treatment were randomized to receive either subcutaneous idraparinux 2.5 mg once a week (2,283) or VKA therapy (2,293) adjusted to achieve a target international normalized ratio (INR) of 2.5 (range 2 to 3) between September 2003 and July 2005. The study was powered to show non-inferior efficacy of idraparinux, compared with standard vitamin K antagonist (VKA) treatment in patients with AF who require prolonged oral anticoagulation. The primary efficacy endpoint was the composite of all strokes (ischemic, hemorrhagic and undefined) and non-CNS SE within the planned treatment period. The principal safety endpoint was the occurrence of major bleeding or clinically relevant non-major bleeding. The other safety outcome was all cause mortality. A weekly subcutaneous administration of idraparinux was as effective as warfarin, a Vitamin K Antagonist (VKA), in reducing stroke and non Central Nervous System (CNS) systemic embolic events in patients with atrial fibrillation (AF), a population at risk of thromboembolic events (TE). The results of the AMADEUS study were presented at the XXI ISTH Congress (International Society on Thrombosis and Haemostasis) in Geneva.

The AMADEUS trial met its primary endpoint. The event rate of the composite endpoint of any strokes (ischemic, hemorrhagic, and undefined) and non-CNS systemic embolism was 0.9% with idraparinux and 1.3% with warfarin (p= 0.007), meeting the criteria for non-inferiority.

The incidence of clinically relevant bleeding, the primary safety outcome, was significantly higher in the idraparinux group than in the comparator group (19.7% vs. 11.3%, p<0.0001). There was an increase in fatal bleeds as well (13/1941 (0.7%) vs 2/2,131 (0.1%), HR =7.14, [95% CI =1.61;31.58], although, overall no difference was observed in the all causes mortality between the two treatment groups. Intracranial hemorrhage was not increased (4/1,922 (0.2%) vs 5/2,107 (0.2%), HR= 0.88, [95% CI = 0.24;3.26]). Bleeding appeared over time and was more pronounced in patients with impaired renal function and in the elderly.

Given the increased risk of bleeding, future trials will adjust the dose of a reversible form of idraparinux depending on patient age and renal function. The BOREALIS-AF study will evaluate the safety and efficacy of a new neutralizable / reversible form of idraparinux (biotinylated idraparinux) to VKA in patients with atrial fibrillation and the dose will be adjusted depending on age and renal function after 7 weeks of treatment.

Biotinylated Version of Idraparinux

Because idraparinux has a very long half life, a biotinylated version of this drug (SSR 126517) is also in clinical development. The addition of a biotin moiety to the structure allows the more rapid removal of the drug and reversal upon the addition of avidin. A bioequipotency study of biotinylated idraparinux vs. idraparinux for the treatment of DVT is ongoing.

Biotinylated idraparinux is being compared to warfarin for the treatment of pulmonary embolism in the phase III CASSIOPEA.

The BOREALIS-AF study of Biotinylated Idraparinux

Once a week idraparinux treatment could represent a convenient alternative to cumbersome VKA treatment for AF patients. The goal of BOREALIS-AF is to improve the safety profile of Idraparinux using the reversible biotinylated idraparinux and adjusting the dose to patients renal function and age.

BOREALIS-AF is a multicenter, randomized, double-blind, assessor-blind, non-inferiority study comparing the efficacy and safety of once-a-week subcutaneous biotinylated idraparinux (whichis reversible) with adjusted-dose warfarin in the prevention of stroke and systemic thromboembolic events in patients with atrial fibrillation.

Treatment will be administrated for a period of 6 months to 2 years. All patients will start with biotinylated idraparinux 3 mg (equivalent to base idraparinux 2.5 mg) once-a-week for 7 weeks, and then the dose will be reduced depending on age and renal function.

References

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