CA2645982A1 - Use of ave5026 for minimizing the incidence of bleedings during an antithrombotic treatment - Google Patents

Abstract

The invention relates to the use of AVE5026 for minimizing the incidence of bleedings during an antithrombotic treatment.

Description

DURING AN ANTITHROMBOTIC TREATMENT

The invention relates to the use of AVE5026 as an antithrombotic treatment, wherein said use involves a decreased incidence of bleedings compared to a standard antithrombotic treatment.

AVE5026 (sanofi-aventis laboratory code) belongs to a new generation of hemisynthetic heparins. It is a new ultra-low-molecular-weight heparin, with an average molecular weight of 2000-3000 Daltons and a novel antithrombotic profile resulting from high anti-Factor Xa activity and residual anti-Factor Ila activity. It is obtained by selective and controlled depolymerization of heparin, as described in the patent application WO 2004/033503.

AVE5026 is in clinical development for venous thromboembolism (VTE) prevention (see The Pink Sheet, October 1 st, 2007, Vol. 69, No. 040, page 19).

VTE is a frequent complication following total knee replacement surgery, as well as other types of surgery. Medical patients may also present increased VTE
risks, for example when they are confined to bed or if they have other risk factors, including active cancer, previous VTE, sepsis, acute neurological disease or inflammatory bowel disease. Therefore, the American College of Chest Physicians (ACCP) recommends that all patients undergoing major surgery and medical patients with risk factors of VTE
receive routine prophylaxis with either an unfractionated heparin, a low-molecular-weight heparin, fondaparinux or a vitamin K antagonist (Geerts W.H. et al., Chest, 2008, 133 (6 Suppl.), 381 S-453S).

These therapies are effective, but the antithrombotic properties of such drugs are accompanied by a risk of haemorrhage.
It has now been found that AVE5026 has an advantageous safety profile.
Therefore, the subject-matter of the invention is the use of AVE5026 for minimizing (decreasing) the incidence of bleedings during an antithrombotic treatment.
It shall be understood that the use of AVE5026 as an antithrombotic drug involves a decreased incidence of bleedings compared to a standard antithrombotic treatment.

Indeed, AVE5026 enables to improve the benefit/risk ratio during an antithrombotic treatment.

According to the instant invention, the term "bleeding" (or "any bleeding") designates any clinically relevant bleeding (or haemorrhage).

The term "treatment" as used herein refers to the administration of a therapy to an individual who has a constituted disease or condition (in the instant case, a thromboembolic pathology such as deep venous thrombosis (DVT), which may lead to pulmonary embolism (PE)), or who is considered as being at risk for a thromboembolic pathology. It shall therefore be understood that the term "treatment" as used in the instant invention refers both to a curative treatment of a constituted pathology or to a prophylactic treatment of said pathology.

According to the instant invention, the effect of minimizing the incidence of bleedings is more particularly meant in comparison with the incidence of bleedings during a treatment with enoxaparin. In an embodiment, the invention therefore relates to the use of AVE5026 for minimizing the incidence of bleedings ("any bleedings") during an antithrombotic treatment, compared with a treatment with enoxaparin.
In another embodiment, the invention relates to the use of AVE5026 for minimizing the incidence of bleedings during a prophylactic treatment for venous thromboembolism (VTE).

In another embodiment, the invention relates to the use of AVE5026 for minimizing the incidence of bleedings during a prophylactic treatment for DVT
which may lead to PE.

In another embodiment, the invention relates to the use of AVE5026 for minimizing the incidence of bleedings during an antithrombotic treatment in the following patient populations:
. in patients undergoing knee replacement surgery, hip replacement surgery, or hip fracture surgery including an extended prophylaxis;
. in patients undergoing abdominal surgery who are at risk for thromboembolic complications;
. in cancer patients undergoing chemotherapy; or in medical patients at risk for thromboembolic complications.

The use according to the instant invention is more particularly directed to minimizing the incidence of any bleedings, as defined above.
In another embodiment, the invention relates to a method for minimizing the incidence of bleedings during an antithrombotic treatment, wherein the drug administered is AVE5026.

The method according to the invention comprises the step of administering to a patient in need thereof the product AVE5026.

In the method and use according to the invention, the product AVE5026 is advantageously administered for 5 days to several months. In particular, the product AVE5026 is advantageously administered for 7 to 10 days in orthopaedic surgery or in abdominal surgery, for 1 month in hip fracture surgery, for several months for cancer patients and for 10-14 days for medical patients.

In the method and use according to the invention, the product AVE5026 is advantageously administered once-daily.

In the method and use according to the invention, the product AVE5026 is advantageously administered by the subcutaneous route.

In the method and use according to the invention, the product AVE5026 may be administered at a dose from 10 to 20 mg: a 10 mg dose may be administered to a specific patient population, however the 20 mg dose is used for most patients.

In another embodiment, the invention relates to a pharmaceutical composition comprising AVE5026, useful for minimizing the incidence of bleedings during an antithrombotic treatment. Such a pharmaceutical composition advantageously comprises AVE5026, at a daily subcutaneous dose of from 10 to 20 mg (more specifically 20 mg), as well as pharmaceutically acceptable and inert excipients. Such excipients are chosen among those known in the Art, according to the desired pharmaceutical formulation and mode of administration. An advantageous pharmaceutical composition according to the invention is an injectable formulation adapted to the subcutaneous route.

The invention will be more clearly understood by reference to the following examples of the invention, which are included herewith for purposes of illustration only and are not intended to be limiting the invention.

1) Preparation of AVE5026 AVE5026 is prepared by depolymerization of a quaternary ammonium salt of the benzyl ester of heparin in an organic medium, by means of a phosphazene base (BEMP: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,3-d iazaphosphorin e), conversion of the quaternary ammonium salt of the benzyl ester of the depolymerized heparin to a sodium salt, saponification of the residual esters and finally purification.

The depolymerization step is advantageously performed in an aprotic solvent, such as dichloromethane, containing a percentage of water of less than 0.6%.
Preferably, this percentage of water should be chosen less than 0.3% and most particularly less than 0.2%.

Advantageously, the phosphazene base/ester mol ratio is between 0.2 and 5, preferably between 0.6 and 2 and most particularly between 0.8 and 1.2. The use of the equimolar ratio is preferred.

The quaternary ammonium salt of the benzyl ester of heparin is advantageously the benzethonium salt.

The method for preparing the AVE5026 therefore comprises the following steps:
a) transalification of sodium heparin by the action of benzethonium chloride, b) esterification of benzethonium heparinate by the action of benzyl chloride, c) transalification of the heparin benzyl ester obtained to a quaternary ammonium salt, by benzethonium salts, d) depolymerization of the benzethonium salt of the benzyl ester of heparin by the method as defined above, e) conversion of the benzethonium salt to a sodium salt, f) saponification by the action of a base such as sodium hydroxide, g) purification, in particular by the action of an oxidizing agent such as hydrogen peroxide.

Step e) is generally carried out by treating the reaction medium with an alcoholic solution of sodium acetate and preferably with a 10% solution of sodium acetate in 5 methanol (weight/volume), at a temperature of between 15 and 25 C. The equivalent by weight of acetate added is preferably 3 times greater than the mass of benzethonium salt of the benzyl ester of heparin used in the depolymerization reaction.

The saponification (step f) is generally carried out by means of an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an aqueous medium, at a temperature of between 0 and 20 C and preferably between and 10 C. 1 to 5 molar equivalents of alkali metal hydroxide will be generally used.
Preferably, the saponification will be carried out in the presence of 1 to 2 molar equivalents of alkali metal hydroxide.
The purification (step g) is carried out by means of hydrogen peroxide, in an aqueous medium, at a temperature of 10 to 50 C. Preferably, this operation is carried out between 20 and 40 C.

The quaternary ammonium salt (benzethonium salt) of the benzyl ester of heparin is prepared according to the following reaction scheme:
a) conversion of the heparin to the form of a sodium salt by means of benzethonium chloride in order to obtain benzethonium heparinate (transalification), b) esterification of the benzethonium salt obtained above by means of benzyl chloride and treatment with an alcoholic solution of sodium acetate in order to obtain the sodium salt of the benzyl ester of heparin, and c) transalification of the sodium salt of the benzyl ester of heparin to a quaternary ammonium salt (benzethonium salt).

The reaction of step a) is carried out by the action of benzethonium chloride in excess, on sodium heparin, at a temperature in the region of 15 to 25 C.
Advantageously, the salt/sodium heparin molar ratio is between 3 and 4.

The starting heparin used is preferably a pig heparin. The latter may be purified beforehand in order to reduce its dermatan sulfate level according to the method described in patent FR2663639.

The esterification of step b) is preferably carried out in a chlorinated organic solvent (for example chloroform or methylene chloride), at a temperature of between 25 and 45 C and preferably between 30 and 40 C. The ester in the form of a benzethonium salt is then recovered in the form of a sodium salt by precipitation by means of sodium acetate at 10% by weight in an alcohol such as methanol. 1 to 1.2 volumes of alcohol are generally used per volume of reaction medium. The quantity of benzyl chloride and the reaction time are adjusted in order to obtain a degree of esterification of between 50 and 100% and preferably between 70 and 90%.
Preferably, 0.5 to 1.5 parts by weight of benzyl chloride are used for 1 part by weight of benzethonium salt of heparin. Likewise, preferably the reaction time will be between 10 and 35 hours.

The transalification step c) is carried out by means of benzethonium chloride in an aqueous medium, at a temperature of between 10 and 25 C. Advantageously, the quaternary ammonium chloride/sodium salt of the benzyl ester of heparin mol ratio is between 2 and 3.

This process, described in WO 2004/033503, enables to obtain a low-molecular weight heparin with an average molecular weight of 2000-3000 Daltons, an anti-Factor Xa activity of between 150-200 IU/mg (most particularly, between 150-180 IU/mg), an anti-Factor Ila activity of less than 5 IU/mg, and most particularly of 0.5 to 3.5 IU/mg, and an anti-Factor Xa/anti-Factor Ila activity ratio of greater than 30.

The anti-Xa activity is measured by the amidolytic method on a chromogenic substrate described by Teien et al., Thromb. Res., 10, 399-410 (1977), with, as standard, the first international standard for low-molecular-weight heparins.
The anti-Ila activity is measured by the technique described by Anderson L.O. et al., Thromb. Res., 15, 531-541 (1979), with, as standard, the first international standard for low-molecular-weight heparins.

2) Methods 2.1: Patients Patients were considered for inclusion in the study if they were aged ? 18 years and were undergoing elective total knee replacement surgery, or revision of a primary procedure that was performed at least 6 months before study entry. All patients provided written informed consent.

The main reasons for exclusion from the study were: any major orthopedic surgery in the previous 3 months; clinical signs or symptoms of VTE in the previous 12 months; active bleeding; a documented congenital or acquired bleeding disorder;
severe renal impairment; progressive malignant disease; uncontrolled arterial hypertension; ischemic stroke or myocardial infarction in the previous 3 months;
treatment with anticoagulants or antiplatelet drugs during the week before surgery;
recent trauma, major surgery, eye surgery, or parenchymal organ biopsy;
contraindication to heparin therapy or sensitivity to iodinated contrast medium;
thrombocytopenia; and significant anemia. Women were excluded if they were pregnant or nursing, or not using effective contraception.
2.2: Study design This was a randomized, multicentre, double-blind, double-dummy, parallel-group, dose-response study of AVE5026 (sanofi-aventis, France) with an enoxaparin (Clexane /Lovenox ) calibrator arm, in patients undergoing elective total knee replacement. Enoxaparin was included as a positive calibrator arm given that low-molecular-weight heparins are a standard therapy recommended by the ACCP for VTE
prevention in patients undergoing total knee replacement surgery (Geerts W.H.
et al., see above) and because enoxaparin has demonstrated efficacy in this population (Leclerc J.R. et al., Ann. Int. Med., 1996, 124, 619-26; Brookenthal K.R. et al., J. Arthroplasty, 2001, 16, 293-300; Fitzgerald R.H. Jr et al., J. Bone Joint Surg. Am., 2001, 83-A, 900-6; Howard A.W. et al., Thromb. Haemost., 1998, 79, 902-6).

Patients were randomly assigned to six treatment groups (see Figure 1) using centralized randomization via an interactive voice response system.
Randomization was stratified into pre- and post-operative treatment groups according to whether or not the investigator was willing to perform a pre-operative injection. Due to the risk of epidural or spinal hematoma, patients scheduled to receive loco-regional anesthesia could not be randomized into the pre-operative stratum.
The day of surgery was defined as day 1. Treatment was continued until day 5-10, and mandatory bilateral venography was performed between days 5 and 11.
Patients were followed-up after surgery for 30 3 days.

An independent Data Monitoring Committee continuously monitored safety and efficacy. The committee could recommend changes to the protocol, as well as discontinuation of study drugs to one or more of the dose groups if it considered that patients were put at undue risk.

The study was conducted in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice in the spirit of the Declaration of Helsinki. The research protocol was approved by independent local institutional review boards.

2.3: Treatment regimens AVE5026 at doses of 5, 10, 20, 40, and 60 mg (single-use vials) and enoxaparin at a dose of 40 mg (pre-filled syringes) were both administered once-daily, by the subcutaneous route. Patients in the pre-operative stratum received their first dose of the study drug 12 1 h before surgery, their second dose 8 1 h after surgery, and all subsequent doses within 24 2 h of the previous dose. Patients in the post-operative stratum received their first dose of study drug 8 1 h after surgery, and all subsequent doses within 24 2 h of the previous dose.

Throughout the treatment period the use of intermittent pneumatic compression and any other anticoagulant, thrombolytic, or antiplatelet drug was prohibited, except for low-dose aspirin in those patients with coronary artery disease. The use of non-steroidal anti-inflammatory drugs was discouraged.

2.4: Study end points Besides efficacy, which was the primary end point, safety was also assessed in this study.

The main safety outcome was the incidence of major bleeding, adjudicated by an independent committee, between the first dose of study drug and 3 days after the last dose. Major bleeding included fatal bleeding, surgical site bleeding leading to intervention, bleeding that was retroperitoneal or intracranial, or that involved any other critical organ (e.g. eye, adrenal gland, pericardium, or spine), and non-surgical site bleeding requiring surgical intervention or non-surgical site overt bleeding with a bleeding index of 2 or more. The bleeding index was calculated as the difference between pre- and post-bleeding hemoglobin plus the number of transfused blood units.
Minor bleeding was defined as clinically overt bleeding that did not meet the criteria for major bleeding.

Other adverse events were also monitored during the study, as were platelet counts and liver function tests.

2.5: Statistical analysis The primary statistical analysis was an assessment of the dose-response of AVE5026 on the primary end point. The sample size determination was based on the assumption that the incidence of the primary efficacy end point for the AVE5026 dose groups would range from 12.5% (highest dose) to 40% (lowest dose). Assuming a linear trend in the dose-response relationship and taking into account the logarithmic regression model that was to be used, it was concluded that 100 patients were needed in each of the five AVE5026 dose groups to detect a significant dose effect with 85%
power (Patel H.I., J. Biopharm. Stat., 1992, 2, 1-8). A similar number of patients were to be recruited into the enoxaparin arm. The target number of patients allowed for failure to obtain primary efficacy data was up to 30%.
The primary efficacy population included randomized patients who received at least 1 dose of study drug, who underwent total knee replacement surgery and who were eligible for the primary endpoint. The safety population included all patients who were randomized and treated. The primary analysis was planned on the pooled strata (pre-operative and post-operative).

The presence or absence of a dose-response for the primary efficacy endpoint was estimated using a two-sided Cochran-Armitage test for trend, using the logarithms of the doses as score and a logistic regression model including logarithmic dose levels as covariates. The incidence of the primary efficacy endpoint was also compared between each of the AVE5026 dose groups and the enoxaparin group, using a two-sided stratum-adjusted Cochran-Mantel-Haenszel test. Dose-response effects were estimated for secondary efficacy endpoints and safety endpoints, as described for the primary efficacy endpoint. All statistical analyses were carried out using SAS
version 8.2.

3) Results 3.1: Patients 10 A total of 690 patients were randomized to receive study drug (see Figure 1).
12 patients did not receive any study drug, leaving 678 available for the safety analysis.
28 patients prematurely stopped the study drug, 21 of these because of adverse events.
A total of 67.2% of the randomized patients were included in the primary efficacy population. Exclusions were mainly due to venograms not being performed (50 patients) or because VTE diagnostic tests were not evaluable (164 patients).

The six treatment groups were well matched with regards to baseline demographic and surgical characteristics, and VTE risk factor profiles. Most of the patients were female (76.8%) and Caucasian (78.2%). The median age of the population was 66 years (range: 27 to 85 years), with 15.0% of patients aged older than 75 years. Nearly half (45.0%) of the patients were obese (body mass index ?30 kg/m2), and 5.4% had moderate renal impairment (creatinine clearance >_30 to <50 ml/min). A
total of 28.5% of patients had a previous history of major orthopedic surgery and very few (0.7%) had a history of VTE. The characteristics of patients excluded from the primary efficacy analysis did not differ from those of patients included in the analysis.
Most of the patients received regional anesthesia (83.0%). Only 5% of patients received pre-operative treatment. The median duration of post-operative treatment was identical in all treatment groups (8 days).
3.2: Safety There was a significant dose-response effect for AVE5026 for major bleeding (P = 0.0231) and any bleeding (P = 0.0003) in the safety population.
Six patients experienced major bleedings in the AVE5026 dose groups, 4 of these were in the AVE5026 60 mg group (3 surgical bleedings and 1 gastrointestinal bleeding). One patient in the AVE5026 40 mg group experienced a surgical site bleeding leading to intervention, and 1 patient in the 20 mg group had an overt gastrointestinal bleed. No patients in the enoxaparin arm experienced major bleeding.
One patient in the pre-operative stratum who received AVE5026 60 mg experienced a major bleeding event; the remaining major bleeding events were in patients in the post-operative stratum. Post-operative major surgical bleeding warranted treatment discontinuation for 2 patients, both in the AVE5026 60 mg group. No cases of fatal bleeding or bleeding into a critical organ were observed.
Results in terms of major, minor and of any bleedings, as defined above, are presented in table 1 (N = 678).

Table 1:
AVE5026 Enoxaparin 5mg 10 mg 20 mg 40 mg 60 mg 40 mg (N = 92) (N = 87) (N = 130) (N = 133) (N= 117) (N= 119) Major bleedings n 0 0 1 1 4 0 % 0 0 0.8 0.8 3.4 0 (95% Cl) 0.0-3.9 0.0-4.2 0.0-4.2 0.0-4.1 0.9-8.5 0.0-3.1 Minor bleedings n 5 4 4 9 20 6 % 5.4 4.6 3.1 6.8 17.1 5.0 (95% Cl) (1.8-12.2) (1.3-11.4) 0.8-7.7 3.1-12.5 10.8-25.2 (1.9-10.7) Any bleedings n 5 4 5 10 24 6 % 5.4 4.6 3.8 7.5 20.5 5.0 (95% Cl) (1.8-12.2) (1.3-11.4) (1.3-8.7) (3.7-13.4) (13.6-29.0) (1.9-10.7) N: total number of patients n: number of patients having experienced bleeding events Cl: confidence interval The results in table 1 demonstrate a lower incidence of any bleedings events for AVE5026 at the 10 and 20 mg doses (especially at the 20 mg dose), compared to the enoxaparin arm. This suggests an improved safety profile for AVE5026 at these doses.

Claims (11)

1. Use of AVE5026 for minimizing the incidence of bleedings during an antithrombotic treatment.

2. The use according to claim 1, wherein the incidence of bleedings is minimized compared with a treatment with enoxaparin.

3. The use according to claim 1 or 2 for minimizing the incidence of any bleedings.

4. Use of AVE5026 for improving the benefit/risk ratio during an antithrombotic treatment.

5. The use according to claim 4, wherein the benefit/risk ratio is improved compared with a treatment with enoxaparin.

6. The use according to any of claims 1 to 5, wherein the antithrombotic treatment is a prophylactic treatment for venous thromboembolism.

7. The use according to any of claims 1 to 6, wherein the antithrombotic treatment is a prophylactic treatment for deep venous thrombosis which may lead to pulmonary embolism.

8. The use according to any of claims 1 to 7, wherein the antithrombotic treatment is administered to a patient population chosen from:
. patients undergoing knee replacement surgery, hip replacement surgery, or hip fracture surgery including an extended prophylaxis;
. patients undergoing abdominal surgery who are at risk for thromboembolic complications;
. cancer patients undergoing chemotherapy; and . medical patients at risk for thromboembolic complications.

9. The use according to any of claims 1 to 8, wherein AVE5026 is administered at a dose from 10 to 20 mg.

10. The use according to any of claims 1 to 9, wherein AVE5026 is administered at a dose of 20 mg.

11. A pharmaceutical composition comprising AVE5026, useful for minimizing the incidence of bleedings during an antithrombotic treatment.