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WO2012055843A1 - Sémuloparine pour la prévention d'une trombo-embolie veineuse majeure chez un patient subissant une chirurgie abdominale majeure - Google Patents

Sémuloparine pour la prévention d'une trombo-embolie veineuse majeure chez un patient subissant une chirurgie abdominale majeure Download PDF

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Publication number
WO2012055843A1
WO2012055843A1 PCT/EP2011/068599 EP2011068599W WO2012055843A1 WO 2012055843 A1 WO2012055843 A1 WO 2012055843A1 EP 2011068599 W EP2011068599 W EP 2011068599W WO 2012055843 A1 WO2012055843 A1 WO 2012055843A1
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WIPO (PCT)
Prior art keywords
molecular weight
ultra
low molecular
weight heparin
major
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Ceased
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PCT/EP2011/068599
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English (en)
Inventor
Dominique Destree
Fransesca Lawson
Judith Murphy
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Aventis Pharma SA
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Aventis Pharma SA
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Publication of WO2012055843A1 publication Critical patent/WO2012055843A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan

Definitions

  • the invention relates to the use of semuloparin or a pharmaceutically acceptable salt thereof for the prevention of major venous thromboembolism in a patient undergoing major abdominal surgery.
  • Semuloparin or 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 (between 145 and 180 U/mg, average value of ⁇ 160 U/mg) and residual anti-Factor I la activity (less than 5 U/mg, on average ⁇ 2 U/mg).
  • heparin in the form of its sodium salt, is in clinical development for venous thromboembolism prevention.
  • LMWHs low-molecular-weight heparins
  • the synthetic pentasaccharide fondaparinux or dose-adjusted anti-vitamin K are the primary treatments for the prevention of venous thromboembolic diseases.
  • VTE postoperative venous thromboembolism
  • CPP guidelines guidelines in thrombosis recommend the use of antithrombotic drugs for certain categories of surgical patients.
  • Enoxaparin has an average molecular weight of 3800-5000 Daltons, an anti- Factor Xa activity comprised between 90 and 125 lU/mg and an anti-Factor lla activity of 20-35 I U/mg.
  • the subject-matter of the invention is an ultra-low molecular weight heparin (ULMWH) with an average molecular weight of 2000 to 3000 Daltons, an anti-Factor Xa (anti-FXa) activity of 145 to 180 U/mg and an anti-Factor lla (anti-Flla) activity of less than 5 U/mg, for use as an antithrombotic treatment in a patient undergoing major abdominal surgery, wherein said use is effective in the prevention of major venous thromboembolism events.
  • ULMWH ultra-low molecular weight heparin
  • the anti-FXa and anti-Flla activities described above are measured using amidolytic methods on a chromogenic substrate as adapted from the monograph on LMWHs of the European Pharmacopeia in force, using as reconstitution buffer a tris-NaCI pH 7.4 buffer comprising PEG6000 (polyethylene glycol 6000) instead of albumin, and an ULMWH reference substance with an anti-FXa activity of 159 U/mg and an anti-Flla activity of 2.9 U/mg.
  • the potencies are expressed in units per mg due to the use of an internal ULMWH reference standard.
  • the above ULMWH is semuloparin and the subject-matter of the invention is therefore semuloparin for use as an antithrombotic treatment in a patient undergoing major abdominal surgery, wherein said use is effective in the prevention of major venous thromboembolism events.
  • semuloparin in the framework of the instant invention, encompasses any pharmaceutically acceptable salt thereof, in particular its sodium salt.
  • the term “semuloparin” shall therefore be understood as “semuloparin or any pharmaceutically acceptable salt thereof” throughout the instant specification. According to the instant invention, the terms below have the following meanings:
  • treatment refers to the administration of a therapy to an individual who is considered as being at risk for a thromboembolic pathology, in particular venous thromboembolism (VTE), such as deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE).
  • VTE venous thromboembolism
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • patient refers to a subject being at risk of VTE and for whom prophylaxis of venous thromboembolic events is indicated;
  • major abdominal surgery refers to open surgery in the peritoneal and/or the retroperitoneal space and/or the pelvis minor for indications other than liver (including hepatobiliary system), uterus, or prostate related, said surgery being performed under general anesthesia, and lasting more than 45 minutes;
  • VTE events excluding asymptomatic distal DVT, being therefore a composite of proximal deep vein thrombosis, symptomatic distal deep vein thrombosis, non-fatal pulmonary embolism and death.
  • the efficacy of the antithrombotic treatment refers to the occurrence of major venous thrombo-embolic events, defined as detailed above, while the safety of the antithrombotic treatment refers to the occurrence of bleeding events, more particularly clinically relevant bleedings or major bleedings.
  • the above ULMWH is used as an antithrombotic treatment in a patient undergoing major abdominal surgery, wherein said use is effective in the prevention of major VTE events, being a composite of proximal DVT, symptomatic distal DVT, non-fatal PE and death.
  • said use is effective in the prevention of proximal DVT.
  • said use is accompanied by an proved safety in terms of clinically relevant bleedings, including major bleedings, compared to a standard antithrombotic treatment.
  • said use is accompanied by an improved safety in terms of major bleedings compared to a standard antithrombotic treatment.
  • a major bleeding designates a bleeding associated with at least one of the following:
  • Symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular leading to a compartment syndrome;
  • Circulatory decompensation (related to overt bleeding leading to a systolic blood pressure [SBP] of ⁇ 90mmHg or requiring massive fluids infusion or vasopressor support to maintain SBP ⁇ 90 mmHg).
  • a clinically relevant non-major bleeding is defined as:
  • Wound hematoma requiring intervention e.g. needle aspiration
  • Wound hematoma requiring intervention is adjudicated as a major bleeding according to the definition above (bleeding leading to an invasive diagnostic or therapeutic intervention - e.g. re-operation, needle aspiration at surgical site, gastroscopy, colonoscopy, ... ).
  • an unusual wound hematoma that does not require surgical or medical intervention maybe adjudicated as a clinically relevant non-major bleeding;
  • the ULMWH as described herein is effective in the prevention of major venous thromboembolism events in patients undergoing major abdominal surgery, and is also causing less bleedings (clinically relevant bleedings, including major bleedings) in comparison to a standard antithrombotic treatment.
  • the invention therefore also relates to said ULMWH for use as an antithrombotic treatment in a patient undergoing major abdominal surgery, wherein said use is effective in the prevention of major VTE events, as described above, and simultaneously involves an improved safety in terms of bleedings compared to a standard antithrombotic treatment started pre-operatively, as it will be apparent from the clinical trial results detailed below.
  • the standard antithrombotic treatment consists in the LMWH known under the INN (International Nonproprietary Name) enoxaparin.
  • Enoxaparin is marketed under the tradenames Lovenox ® or Clexane ® .
  • phase III clinical trial refers to a multinational, multicenter, randomized, double-blinded study involving a large patients group, as defined by the Health authorities and the regulatory laws and guidelines, aiming at being the definitive assessment of how effective and safe the drug is in comparison with current standard treatment.
  • said ULMWH is administered at a 20 mg daily dose to patients with normal renal function or to patients with mild or moderate renal impairment.
  • said ULMWH is administered at a 10 mg daily dose.
  • the renal function of the patients is defined according to estimated creatinine clearance (CLcr) values calculated using the well- known Cockroft-Gault formula, and is classified according to the following characteristics :
  • the treatment with the above ULMWH is administered once daily. Said treatment is started post-operatively and is administered for 7 to 10 days.
  • the wording "ULMWH for use ... " shall be understood as being equivalent to the wording "use of the ULMWH for ... " or "use of the ULMWH for the preparation of a medicament for use
  • the invention therefore also relates to the use of the ULMWH defined above for the manufacture of a medicament useful as an antithrombotic treatment in a patient undergoing major abdominal surgery, wherein said use is effective in the prevention of major venous thromboembolism events. All of the embodiments as described above also apply to said use.
  • said use is clinically proven by a phase III clinical trial, and said use is accompanied by an improved safety in terms of clinically relevant bleedings, including major bleedings, compared to a standard antithrombotic treatment.
  • the invention also relates to an article of manufacture comprising:
  • the invention also relates to an article of manufacture comprising:
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • LMWH low molecular weight heparin
  • VTE venous thromboembolism
  • Semuloparin in the form of a sodium salt, is obtained by a chemoselective depolymerization of heparin, activated through its benzyl ester derivative, by the phosphazene base 2-tert-butylimino-2-diethylamino-1 ,3-dimethylperhydro-1 ,2,3- diazaphosphorine (BEMP).
  • BEMP phosphazene base 2-tert-butylimino-2-diethylamino-1 ,3-dimethylperhydro-1 ,2,3- diazaphosphorine
  • This procedure yields semuloparin with an average molecular weight of 2000-3000 Daltons (around 2400 Da on average), an anti-Factor Xa activity of between 145 and 180 U/mg (average value - 160 U/mg) and a residual anti-Factor I la activity of less than 5 U/mg (on average ⁇ 2 U/mg).
  • Example 2 The SAVE-ABDO study. A Multinational, Multicenter, Randomized, Double Blind Study comparing the Efficacy and Safety of AVE5026 with enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Major Abdominal Surgery.
  • the primary objective of the study was to compare the efficacy of once daily (q.d.) subcutaneous (s.c.) injections of 20 mg AVE5026 (10 mg for patients with SRI) with q.d. s.c. injections of 40 mg enoxaparin (20 mg in SRI patients) administered up to Day 7 to 10 for the prevention of venous thromboembolic events in patients undergoing major abdominal surgery.
  • the secondary objectives of this study were to evaluate the safety of AVE5026 in patients undergoing major abdominal surgery and to document AVE5026 exposures in this population.
  • Randomized treatment was allocated to eligible patients, taking into account the geographical region of the patient, the type of surgery (cancer / non-cancer) and the estimated CLcr at baseline ( ⁇ or ⁇ 30 mL/min). Randomization occured a close as possible before the first IP injection (according to the local enoxaparin labeling, but in any case prior to surgery).
  • Maximum duration of study participation was therefore 42 days, including a treatment period up to Day 7-10 and a follow-up period with a visit at Day 35-42 after randomization.
  • Patients meeting the following criteria were suitable for enrolment in the study: - Patients undergoing major surgery in the peritoneal and/or the retroperitoneal space and/or the pelvis minor (but not limited to the pelvis minor) for indications other than limited disease of the liver (including hepatobiliary system), the uterus, or the prostate; and
  • Chronic Heart Failure is defined as systolic dysfunction leading to low cardiac output.
  • Chronic heart failure functional classes are be defined according to the New
  • Class III patients with cardiac disease resulting in marked limited physical activity. These patients are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or angina.
  • Class IV patients with cardiac disease resulting in inability to carry on physical activity without discomfort.
  • Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.
  • Respiratory failure can be manifest either as hypoxemia, hypercarbia, or a combination of both types of gas exchange abnormalities.
  • Patients with chronic respiratory failure may have any of the following underlying pulmonary diseases:
  • Obstructive chronic obstructive pulmonary disease (COPD) (chronic bronchitis, emphysema).
  • COPD chronic obstructive pulmonary disease
  • Restrictive parenchymal (alveolar and interstitial lung disease) (like sarcoidosis, idiopathic pulmonary fibrosis, pneumoconiosis, connective tissue disorders, drug or radiation induced lung disease).
  • Restrictive extraparenchymal lung disease due to neuromuscular disorders like diaphragmatic paralysis, myasthenia gravis, Guillain Barre syndrome, muscular dystrophias, cervical spine injury
  • due to chest wall dysfunction like kyphoscoliosis, extreme obesity, ankylosing spondylitis.
  • vitamin K antagonists vitamin K antagonists
  • endocarditis congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery.
  • End stage renal disease (estimated creatinine clearance ⁇ 10 mL/min) or patient on dialysis.
  • contraceptive method of birth control as defined for contraception in the Informed Consent Form for the duration of the study and/or who are unwilling or unable to be tested for pregnancy.
  • Enoxaparin treatment was started pre-operatively in accordance to local enoxaparin labeling. Semuloparin treatment was started post-operatively (8 ⁇ 1 hours after the end of the surgery). Due to the different time of administration, pre-filled syringes containing placebo were used. The matching placebo syringe was strictly identical in appearance, containing the same volume but without active component.
  • AVE5026 or enoxaparin were administered subcutaneously. The entire volume of the pre-filled syringe was injected.
  • Investigational Product was administered in a blinded manner once daily during 7-10 days after surgery.
  • the day of surgery was defined as Day 1.
  • the first pre-operative injection enoxaparin for patients allocated to comparator group and placebo for patients allocated to AVE5026 group
  • the first post-operative injection (AVE5026 or placebo) was administered 8 ⁇ 1 hours after incision closure, provided that hemostasis had been established.
  • the second post-operative injection (enoxaparin or placebo) was administered 12 ⁇ 1 hours after incision closure.
  • this IP injection was performed on Day 2.
  • the primary efficacy endpoint was a composite of any VTE confirmed by a blinded Central Independent Adjudication Committee (CIAC), and deaths from any cause reported during the efficacy evaluation period, i.e. :
  • PCC Central Independent Adjudication Committee
  • any DVT (symptomatic or not) : any proximal DVT or distal DVT only,
  • the main secondary efficacy endpoint was a composite of the following events reported during the efficacy analysis period :
  • a symptomatic distal DVT was defined as :
  • the main secondary efficacy endpoint therefore differed from the primary efficacy endpoint by the exclusion of asymptomatic distal DVT events.
  • the events part of the main secondary efficacy endpoint can be defined as major VTE events.
  • the efficacy analysis period was defined as the period from randomization up to the mandatory bilateral venography or up to Day 1 1 , whichever came first (Day 1 being the day of surgery).
  • the efficacy populations included all randomized patients who received at least one IP injection (active or placebo), who underwent major abdominal surgery, and with a non missing efficacy endpoint assessment for the parameter analyzed. 6) Assessment of safety
  • the safety analysis period was defined as the period from the first IP injection up to the last IP injection plus 3 calendar days (called « on-treatment » period).
  • the safety population included all randomized patients exposed to the study treatment, regardless of the number of injections administered.
  • N number of patients in the primary efficacy population
  • n number of patients showing a given event
  • Table 2 Components of the primary efficacy endpoint
  • N number of efficacy evaluable patients
  • n number of patients showing a given event
  • N number of patients in the secondary efficacy composite endpoint population
  • n number of patients showing a given event
  • N number of patients in the safety population
  • n number of patients with any clinically relevant bleeding

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur l'utilisation de sémuloparine ou d'un sel pharmaceutiquement acceptable de celle-ci en tant que traitement antithrombotique chez un patient subissant une chirurgie abdominale majeure, ladite utilisation étant efficace et sans danger dans la prévention d'évènements de trombo-embolie veineuse majeure, tels qu'une trombose veineuse profonde proximale.
PCT/EP2011/068599 2010-10-28 2011-10-25 Sémuloparine pour la prévention d'une trombo-embolie veineuse majeure chez un patient subissant une chirurgie abdominale majeure Ceased WO2012055843A1 (fr)

Applications Claiming Priority (2)

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EP10306183.4 2010-10-28
EP10306183 2010-10-28

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WO2012055843A1 true WO2012055843A1 (fr) 2012-05-03

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PCT/EP2011/068599 Ceased WO2012055843A1 (fr) 2010-10-28 2011-10-25 Sémuloparine pour la prévention d'une trombo-embolie veineuse majeure chez un patient subissant une chirurgie abdominale majeure

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008295A1 (fr) 2000-07-21 2002-01-31 Aventis Pharma S.A. Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant
WO2004033503A1 (fr) 2002-10-10 2004-04-22 Aventis Pharma S.A. Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant
CA2645982A1 (fr) * 2008-12-05 2010-06-05 Sanofi-Aventis Utilisation de l'ave5026 pour reduire la frequence des saignements durant un traitement antithrombotique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002008295A1 (fr) 2000-07-21 2002-01-31 Aventis Pharma S.A. Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant
WO2004033503A1 (fr) 2002-10-10 2004-04-22 Aventis Pharma S.A. Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant
CA2645982A1 (fr) * 2008-12-05 2010-06-05 Sanofi-Aventis Utilisation de l'ave5026 pour reduire la frequence des saignements durant un traitement antithrombotique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol. 7, 2009, pages 1143 - 1151
LASSEN M R ET AL: "AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery - TREK: A dose-ranging study", JOURNAL OF THROMBOSIS AND HAEMOSTASIS, BLACKWELL PUBLISHING, OXFORD, GB, vol. 7, no. 4, 24 January 2009 (2009-01-24), pages 566 - 572, XP002533591, ISSN: 1538-7933, DOI: DOI:10.1111/J.1538-7836.2009.03301.X *
LASSEN MICHAEL R ET AL: "AVE5026, a new anticoagulant for the prevention of venous thromboembolism in total knee replacement surgery - TREK: A dose ranging study", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 110, no. 11, Part 1, 1 November 2007 (2007-11-01), pages 98A - 99A, XP009123808, ISSN: 0006-4971 *

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