EP3280436A1 - Novel use of von willebrand factor - Google Patents
Novel use of von willebrand factorInfo
- Publication number
- EP3280436A1 EP3280436A1 EP16719018.0A EP16719018A EP3280436A1 EP 3280436 A1 EP3280436 A1 EP 3280436A1 EP 16719018 A EP16719018 A EP 16719018A EP 3280436 A1 EP3280436 A1 EP 3280436A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- von willebrand
- willebrand factor
- pharmaceutical composition
- body weight
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the present invention relates to a new use of von Willebrand factor, and in particular the treatment and / or prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
- Mechanical circulatory assistance is an intra or extracorporeal device that can totally or partially replace the circulatory functions normally performed by the heart. Its purpose is to preserve or restore the great functions of the organism, and in particular to ensure, as the case may be, a uni or biventricular discharge, or to totally take charge of the work of the failing heart. This type of device is prescribed when the hemodynamic state of the patient requires it, especially in three particular indications:
- the first circulatory assistance systems were all pneumatic. They all consisted of a rigid outer shell inside which there is either a bag or a polyurethane diaphragm. Mechanical or biological valves provided unidirectional flow. They were connected to an activation console usually very bulky and bulky, limiting the possible movements for the patient.
- the compressed air came from a wall socket in the hospital (CardioWest ® ) with the possibility of working temporarily with compressed air bottles inside the console. All other systems were connected to consoles in which the air was compressed by a compressor.
- the operating principle of these devices is simple: a depression around the bag or under the diaphragm ensures the filling of the prosthesis.
- ventricles Conversely, during the ejection phase, pressurized air compresses the bag or pushes the diaphragm thus allowing the ejection of the blood rhythmically. All these ventricles thus provide a pulsed flow.
- these pneumatic ventricles there are paracorporeal ones that can be used for uni-ventricular (mostly left) or bi-ventricular assistance, and implanted ventricles (CardioWest ® total artificial heart). All these ventricles provide excellent hemodynamic performance and can be used over long periods, allowing to wait for a graft in the best possible conditions.
- the most used system is undoubtedly the Thoratec ® system, featuring a new activation console (TLC-II) that improves the patient's comfort and even allows for hospital discharge and a return home.
- TLC-II new activation console
- implantable pumps The latest generation of implantable pumps is rotary type. These implantable pumps can be classified into two groups:
- Centrifugal pumps such as DuraHeart ® or HeartWare ® and - Axial pumps such as HeartMate II ® , MicroMed DeBakey ® , BerlinHeart Incor ® or Jarvik 2000 ® .
- the patient received a dose of 60UI / kg body weight of a pharmaceutical composition comprising von Willebrand factor and factor VIII every eight hours at a rate of three doses while continuing the administration of aminocaproic acid.
- Treatment with the von Willebrand factor and factor VIII composition was continued for 33 days with decreasing doses. Nevertheless, the patient developed bruising around the left eye and a thrombus at the pump a few days later, resulting in discontinuation of treatment.
- the authors conclude that treatment with von Willebrand factor and factor VIII treatment has been successful in treating hemorrhage and / or gastrointestinal bleeding, but this treatment requires careful monitoring of thromboses in the pump circuit. in particular to the presence of factor VIII in the therapeutic concentrate.
- the inventors have surprisingly shown that the administration of a pharmaceutical composition comprising von Willebrand factor to a specific dose and under specific conditions prevented the risks associated with the establishment of mechanical circulatory assistance. More particularly, the inventors have shown that this preventative administration of von Willebrand factor surprisingly makes it possible to reduce by more than 60% the risks associated with setting up mechanical circulatory assistance, namely to reduce by more than 60% haemorrhage and / or bleeding in these patients. Preferably, this preventive administration of von Willebrand factor makes it possible to reduce by more than 70%, preferably 80%, preferably 90%, the occurrence of haemorrhages and / or bleeding in these patients.
- this administration of von Willebrand factor makes it possible definitely to eliminate any risk of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, including the risk of relapse.
- the administration of a pharmaceutical composition comprising von Willebrand factor according to the invention makes it possible to reduce the frequency of clinically significant bleeding in comparison with usual care.
- the invention relates to a pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
- bleeding refers to a flow of blood (internal or external) outside the small-volume natural bloodstream. When blood loss is significant and potentially life-threatening, it is called “bleeding”. Bleeding or bleeding may be externalized through the skin, or through a natural orifice, or may be internalized.
- clinical significant bleeding refers to internal or external bleeding leading to death or prolonged hospitalization, or requiring re-hospitalization, surgery or transfusion of at least 3 units of red blood cells, or resulting in elevated blood flow. hemoglobin at a rate greater than 3 g / dL, or which is refractory to conventional approaches to treatment.
- the term "pharmaceutical composition” is understood to mean both a pharmaceutical composition in liquid form, in particular in the form of a solution or a suspension, and a pharmaceutical composition in the form of a powder.
- This pharmaceutical composition comprises at least one active ingredient, von Willebrand factor and pharmaceutically acceptable excipients.
- von Willebrand Factor or "von Willebrand Factor” or “FvW” includes polypeptides comprising the von Wild-type human willebrand, or von Willebrand factor derived from another species (eg bovine, porcine, canine, murine). It further includes natural allelic variations of von Willebrand factor that may exist, and any form or degree of glycosylation or other post-translational modification.
- von Willebrand factor also includes von Willebrand factor variants which exhibit the same or a higher biological activity as compared to the activity of the wild form, these variants having in particular at least 70%, preferably 75%, of preferably 80%, preferably 85%, preferably 90%, preferably 92%, preferably 94%, preferably 95%, preferably 96%, preferably 97%, preferably 98%, preferably 99%, preferably preferably 100% homology with the nucleotide sequence of wild von Willebrand factor.
- the von Willebrand factor is a human von Willebrand factor.
- the pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of factor VIII.
- factor VIII-free means that the composition of the invention does not contain factor VIII or is present in a negligible amount.
- the inventors have found that the elimination of this coagulation factor makes it possible to reduce the risks of occurrence of thrombosis, unlike the combination pharmaceutical compositions FVIII / FvW already marketed, in particular the product consisting of a combination of 160 IU. von Willebrand factor and 66.6 IU / ml factor VIII.
- the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 10 IU / 100 IU VWF: RCo.
- This rate is measured by the von Willebrand factor ristocetin cofactor (VWF: RCo) assay method compared to the International Standard for Willebrand Factor Concentrate as defined by the World Health Organization (WHO).
- VWF von Willebrand factor ristocetin cofactor
- WHO World Health Organization
- the von Willebrand factor activity in the composition of the invention is 100 IU per 1 ml of reconstituted solution.
- the residual factor VIII content of the composition according to the invention is thus divided by a factor of at least a factor of 4 in relation to the products on the market, thus making it possible to limit the thrombotic risk by controlling and minimizing the exogenous contribution of FVIII.
- the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than 10 IU / 100 IU VWF: RCo, preferably less than 8 IU / 100 IU VWF: RCo, preferably less than 6 IU / 100 IU VWF: RCo, preferably less than 4 IU / 100 IU VWF: RCo.
- the composition comprising von factor Von Willebrand is totally free of factor VIII blood clotting.
- the pharmaceutical composition comprising von Willebrand factor also comprises factor VIII in a significant amount.
- the ratio factor VIII / von Willebrand factor is then advantageously between 1/10 and 5/10 IU / mL.
- the pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of ADAMTS13.
- ADAMTS13-free or ADAMTS13-free protein means that the composition of the invention does not contain ADAMTS13 protein or that this ADAMTS13 protein is present in a negligible amount or that ADAMTS13 activity is negligible. Indeed, the inventors have found that this protein has a tendency to weaken the von Willebrand factor, or even to degrade it, but also that the activity of this protein is potentiated by the shear forces induced by the mechanical circulatory assistance device. Thus, the absence of this protein or its presence in negligible amount reduced the risk of bleeding and / or bleeding in patients under mechanical circulatory assistance.
- the pharmaceutical composition comprising von Willebrand factor is devoid of ADAMTS13.
- the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 0.15 ⁇ g / ml.
- the residual level of ADAMTS13 is less than or equal to 0.10 ⁇ g / ml, preferably less than or equal to 0.05 ⁇ g / ml, preferably less than or equal to 0.01 ⁇ g / ml.
- the residual level of ADAMTS13 is between 0.01 ⁇ g / ml and 0.15 ⁇ g / ml.
- the pharmaceutical composition comprising von Willebrand factor does not contain ADAMTS13 activity.
- the residual level of ADAMTS13 activity in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to the detection threshold, that is less than or equal to 0.03 ADAMTS13: Act [U / mL].
- ADAMTS13 content residual of the composition according to the invention is at least 2 to 3 times lower compared to products on the market which comprise at least 0.13 ⁇ 0.07 ADAMTS13: Act [U / mL], thereby avoiding any risk of haemorrhage and / or bleeding in patients with mechanical circulatory assistance.
- the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than 0.10 ADAMTS13: Act [U / mL], preferably less than 0.05 ADAMTS13: Act [U / mL].
- the composition comprising von Willebrand factor is totally free of ADAMTS13.
- the amount of ADAMTS13 in the composition comprising von Willebrand factor of the invention is adjusted to avoid the presence of multimeric ultralarges (> 20 mers).
- the ADAMTS13 may advantageously be of plasmatic origin and copurified with the composition comprising von Willebrand factor of the invention, or else be of recombinant origin and advantageously be added to the composition comprising von Willebrand factor of the invention. invention of recombinant origin.
- the distribution of multimeric forms of von Willebrand factor is defined after analysis of an electrophoretic gel allowing the quantification of the size of the seas (subunits) in multiples of the monomeric subunit of 225 kD. Thus we describe seas of size 225x2 to 225x15.
- high molecular weight multimers of the pharmaceutical composition comprising von Willebrand factor is meant multimers from 10 monomers.
- the content of high molecular weight multimers of the pharmaceutical composition comprising von Willebrand factor is close to that of the plasma.
- the high molecular weight multimer content of the pharmaceutical composition comprising von Willebrand factor is sufficiently conserved to allow sufficient in vivo activity of the pharmaceutical composition.
- the pharmaceutical composition comprising von Willebrand factor according to the invention has a high molecular weight multimer content of at least 65%, preferably 70%, even more preferably 75%, in a very preferred manner. % of the total multimer content of von Willebrand factor contained in the pharmaceutical composition. The presence of at least 65% of multimers of high molecular weight gives the composition according to the invention a better therapeutic efficacy.
- the pharmaceutical composition according to the invention may also comprise one or more excipients, making it possible to stabilize the von Willebrand factor. and allowing the solubilization of freeze-dried forms of von Willebrand factor.
- the excipients may especially be chosen from:
- hydrophilic amino acid or having a positively charged side chain
- Hydrophilic (or polar) amino acids or amino acids carrying a positively charged side chain include Lysine, Arginine, Histidine, Glycine, Serine, Threonine, Tyrosine, Asparagine, Glutamine.
- hydrophilic amino acids or carrying a positively charged side chain it is preferable to use arginine, or a derivative salt thereof, such as arginine hydrochloride or arginine phosphate.
- Amino acids such as glycine and / or lysine or a derivative salt thereof such as lysine hydrochloride may be advantageously added.
- Hydrophobic amino acids include the following amino acids: Alanine, Valine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Proline.
- the salt may be an alkali metal salt, an alkaline earth metal salt, or a transition metal salt.
- a transition metal salt there may be mentioned in particular sodium citrate, calcium chloride, or zinc chloride.
- the salt used is preferably sodium citrate or calcium chloride.
- the protein stabilizer may be selected from known protein stabilizers, for example albumin and factor VIII.
- the preferred protein stabilizer is albumin, preferably human albumin.
- the composition comprises von Willebrand factor as active principle and the following pharmaceutically acceptable excipients: albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride. More particularly, the composition may comprise:
- albumin preferably human albumin
- arginine optionally in the form of hydrochloride
- Reconstitution from the powder in the form of an injectable preparation can be carried out by adding water for injection (water ppi).
- prevention or “prophylaxis” or “preventive treatment” or “prophylactic treatment” includes both treatment leading to the prevention of a disease and treatment that reduces and / or delays the incidence of a disease or disease. risk of it happening.
- the von Willebrand factor composition is particularly useful for preventing or reducing haemorrhage and / or bleeding associated with setting up the mechanical circulatory assistance device.
- preventive or prophylactic treatment may take place before the setting up of the mechanical circulatory assistance device in the patient or after the placement of the latter, that is to say in the days following the placement of the device, but in all cases before the occurrence of bleeding or haemorrhage.
- the pharmaceutical composition comprising von Willebrand factor is administered to the patient under mechanical circulatory assistance at a dose of at least 30 IU / kg of body weight.
- administration is meant the injection to the patient of the pharmaceutical composition according to the invention.
- This administration includes parenteral injections such as intravenous, intramuscular, subcutaneous, intraorbital, intradermal, intraspinal, intraperitoneal injections as well as direct perfusion into tissue or organ.
- parenteral injections such as intravenous, intramuscular, subcutaneous, intraorbital, intradermal, intraspinal, intraperitoneal injections as well as direct perfusion into tissue or organ.
- Oral or aerial administration for example by inhalation, are also contemplated within the scope of the present invention.
- the pharmaceutical composition comprising von Willebrand factor is administered intravenously.
- the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient at a dose of at least 40 IU / kg of body weight, preferably 45 IU / kg of body weight, preferably 50 IU / kg of weight. body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU / kg body weight.
- the dose is 50 IU / kg of body weight.
- the preferred dose administered will be 50 IU / kg body weight.
- the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a 20% increase of multimers greater than 15 mers for 1 hour after injection.
- the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with an increase of multimers greater than 15 mers for at least 30 min.
- the dosing regimen provides a modification of the von Willebrand Factor multimeric distribution with a multimer rise greater than 15 months for at least 45 min.
- the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a multimer rise greater than 15 months for at least 1 hour after injection. This temporary elevation and this modification make it possible to restore normal angiogenesis in the microcirculation.
- the dosing regimen makes it possible to restore a normal von Willebrand factor functionality measured by a VWF: Act / VWF: Ag> 0.7 result.
- the average plasma concentration of von Willebrand factor and the maximum average plasma concentration of von Willebrand factor are measured after the intravenous administration of the pharmaceutical composition comprising von Willebrand factor according to the invention.
- the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out before the appearance of the first hemorrhage or first bleeding in the patient under mechanical circulatory assistance of the patient.
- the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out four days after the establishment of the mechanical circulatory assistance of the patient.
- the first administration of the pharmaceutical composition comprising von Willebrand factor is performed five days after placement under mechanical circulatory assistance of the patient, preferably six days, preferably seven days after the establishment of mechanical circulatory assistance. of the patient.
- the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out between the 4 th and 7 th day after the establishment of the patient under mechanical circulatory assistance. No first administration is performed beyond the seventh day. Indeed, the administration must be as early as possible to observe an effect, confirming the effectiveness linked to an early blocking of angiogenesis. A later inclusion would expose to a modulation of efficiency.
- the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out four to seven days after the setting up of the mechanical circulatory assistance of the patient.
- the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly with two administrations per week.
- the first administration of factor composition VWD was performed on day 5 after the establishment in patient mechanical circulatory support, while the second administration of factor composition VWD is performed between the 6th and geme j 0u r after placement under mechanical circulatory assistance of the patient.
- the first administration of factor composition VWD was performed on the 6th day after the establishment in patient mechanical circulatory support, while the second administration of factor composition VWD is performed between the 7th and the 8th day after the establishment in patient mechanical circulatory support.
- the interval between two administrations of the pharmaceutical composition comprising von Willebrand factor according to the invention must not be less than one day, preferably 2 days.
- the interval between two administrations of the pharmaceutical composition comprising von Willebrand factor according to the invention must not be greater than six days, preferably five days, preferably four days, preferably three days.
- the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at a rate of two administrations per week, for at least 15 days.
- the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 30 days, preferably 45 days, preferably 60 days, of preferably 75 days, preferably 90 days.
- the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient under mechanical circulatory assistance, at a dose of 50 IU / kg of body weight, repeatedly at the rate of two administrations per week. , for 90 days.
- a von Willebrand factor composition as a preventive measure, considerably reduces the risk of the appearance or recurrence of haemorrhage and / or bleeding in these patients.
- the risk of haemorrhage associated with the establishment of mechanical circulatory assistance is reduced by 60%.
- this preventive administration of von Willebrand factor makes it possible to reduce by more than 70%, preferably 80%, preferably 90%, the occurrence of haemorrhages and / or bleeding in these patients.
- this administration of von Willebrand factor makes it possible definitely to eliminate any risk of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, including the risk of relapse.
- Another object of the invention relates to a method of preventive treatment of haemorrhage and / or bleeding of patients under mechanical circulatory assistance, comprising the administration to said patients of a von Willebrand factor composition.
- the present invention relates to the use of a pharmaceutical composition comprising von Willebrand factor in the manufacture of a medicament for the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance. .
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising von Willebrand factor intended to be used in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, which comprises administering to said patients at a dose of minus 30 IU / kg body weight of von Willebrand factor, at a rate of two administrations per week.
- treatment or “curative treatment” is defined as a treatment resulting in a cure or treatment that alleviates, improves and / or eliminates, reduces and / or stabilizes the symptoms of an illness or the suffering it causes.
- the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient at a dose of at least 30 IU / kg of body weight, of at least 40 IU / kg of body weight, preferably 45 IU / kg of weight. body weight, preferably 50 IU / kg body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU / kg body weight.
- the dose is 50 IU / kg of body weight.
- the dosing regime provides a modification of the multimeric distribution of von Willebrand Factor with an elevation of at least 10%, preferably at least 15%, advantageously at least 20% of the multimers greater than 15 seas. during 1 hour after the injection.
- the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with an increase of multimers greater than 15 mers for at least 30 min.
- the dosing regimen provides a modification of the von Willebrand Factor multimeric distribution with a multimer rise greater than 15 months for at least 45 min.
- the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a multimer rise greater than 15 months for at least 1 hour after injection.
- the dosing regimen makes it possible to restore a normal von Willebrand factor functionality measured by a VWF: Act / VWF: Ag> 0.7 result.
- the average plasma concentration of von Willebrand factor and the maximum average plasma concentration of von Willebrand factor are measured after the intravenous administration of the pharmaceutical composition comprising von Willebrand factor according to the invention.
- the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 15 days.
- the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 30 days, preferably 45 days, preferably 60 days, of preferably 75 days, preferably 90 days.
- the pharmaceutical composition comprising von Willebrand factor according to the invention is administered in a curative manner to the patient under mechanical circulatory assistance, at a dose of 30 IU / kg of body weight, repeatedly at the rate of two administrations per week, for 90 days.
- the pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of factor VIII.
- the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 10 IU / 100 IU VWF: RCo.
- the pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of ADAMTS13.
- the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor is less than or equal to 0.10 ADAMTS13: Act [U / mL].
- Another subject of the invention relates to a method for the curative treatment of haemorrhages and / or bleeds of patients under mechanical circulatory assistance, comprising the administration to said patients of a von Willebrand factor composition.
- the method of curative treatment of hemorrhages and / or bleeding of patients under mechanical circulatory assistance comprises the administration to said patients of a von Willebrand factor composition, free of blood coagulation factor VIII.
- the method for the curative treatment of hemorrhages and / or bleeds of patients under mechanical circulatory assistance comprises the administration to said patient of a von Willebrand factor composition at a dose of at least 30 IU / kg of weight. body weight, preferably 40 IU / kg body weight, preferably 45 IU / kg body weight, preferably 50 IU / kg body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU. / kg body weight.
- the dose is 50 IU / kg of body weight.
- the method of curative treatment of haemorrhage and / or bleeding of patients under mechanical circulatory assistance comprises the administration to said patients of a von Willebrand factor composition, repeatedly at the rate of two administrations per week.
- the method for the curative treatment of haemorrhages and / or bleeds of patients under mechanical circulatory assistance comprises the administration to said patient of a von Willebrand factor composition, the first administration of the pharmaceutical composition comprising von Willebrand factor being performed at the onset of the first hemorrhage or first bleeding in the patient under mechanical circulatory support of the patient.
- the curative treatment method comprising the administration to the patient under mechanical circulatory assistance, of the pharmaceutical composition comprising von Willebrand factor according to the invention at a dose of 50 IU / kg of body weight, so repeated twice a week for 90 days.
- the present invention relates to the use of a pharmaceutical composition comprising von Willebrand factor for use in the manufacture of a medicament for the treatment of haemorrhage and / or bleeding in patients undergoing treatment. mechanical circulatory assistance.
- the present invention relates to a process for obtaining the pharmaceutical composition comprising von Willebrand factor.
- the von Willebrand factor composition can be obtained by methods well known to those skilled in the art, for example by fractionation of plasma by expression by cell culture or by expression in the milk of transgenic animals.
- the von Willebrand factor of the invention can be obtained from human blood plasma, either a fraction of cryoprecipitated human plasma or cryoprecipitated plasma supernatant still containing von Willebrand factor or obtained by conventional methods of fractionation (Cohn et al., J. Am Chem Soc., 68, 459, 1946 and Kistler et al., Vox Sang., 7, 1962, 414-424), having optionally undergone a prepurification treatment including by adsorption on aluminum hydroxide, in which vWF is complexed with Factor VIII This is called "plasma" von Willebrand factor.
- the von Willebrand factor is obtained from a fraction of the cryoprecipitated plasma having undergone a preliminary chromatographic purification step using a DEAE-Fractogel®-TSK 650 type anion exchanger, such as described in patents EP 0 359 593 and EP 0 503 991.
- the von Willebrand factor can be obtained by genetic engineering, in particular produced by cells whose DNA has been modified by genetic recombination so as to express a molecule of FVII, and having the particular glycosylation characteristics. .
- This is called recombinant von Willebrand factor.
- the von Willebrand factor of the invention is derived from the transcription and subsequent translation of a DNA molecule encoding von Willebrand factor into a cellular host.
- the recombinant von Willebrand factor of the invention can be obtained by standard techniques, well known to those skilled in the art, allowing the expression of a protein in a biological system.
- recombinant von Willebrand factor means any von Willebrand factor obtained by genetic recombination and expressed by a cell line cultured.
- BHK Baby Hamster Kidney
- BHK tk tsl3
- tsl3 CCL 10314, Waechter and Baserga, Proc Natl Acad Sci USA 79: 1106-1110, 1982
- CHO ATCC CCL 61
- COS-I ATCC CRL 1650
- HEK293 ATCC CRL 1573, Graham et al., J. Gen.
- the von Willebrand factor can thus be isolated from a fraction enriched in FvW and / or recombinant Factor VIII / FvW complex isolated from cell culture supernatant according to known techniques.
- the von Willebrand factor is a transgenic von Willebrand factor, that is to say obtained by genetic recombination and expressed by a living tissue, animal or
- the transgenic von Willebrand factor is obtained by genetic recombination and expressed in an animal, referred to as a transgenic animal.
- the term "transgenic animal” is understood to mean an animal whose genome has been transgenically introduced into one or more genes.
- the von Willebrand factor is produced in particular in the transgenic animal milk, the formulation of the invention for retaining the von Willebrand factor satisfactory biological activity after lyophilization.
- human von Willebrand factor is produced in the milk of non-human transgenic mammalian animals genetically modified to produce this protein.
- it is the milk of a rabbit or a transgenic goat.
- the secretion of von Willebrand factor by the mammary glands, allowing its secretion into the milk of the transgenic mammal involves the control of von Willebrand factor expression in a tissue-dependent manner. Such control methods are well known to those skilled in the art.
- the control of the expression is carried out by means of sequences allowing the expression of the protein towards a particular tissue of the animal. These include the promoter sequences WAP, beta-casein, beta-lactoglobulin and signal peptide sequences.
- the method of extracting proteins of interest from the milk of transgenic animals is described in EP 0 264 166.
- the transgenic von Willebrand factor can also be isolated from a fraction enriched in VWF and / or Factor VIII / FvW complex obtained from transgenic mammalian milk as described in US Pat. No. 6,518,482.
- the von Willebrand factor fraction may be diafiltered to incorporate suitable excipients to allow dry heating.
- von Willebrand factor without risk of denaturation, concentrated by ultrafiltration, packaged in flasks and lyophilized, after a prior addition of a pharmaceutically acceptable additional stabilizer, such as albumin.
- the lyophilisates undergo a final viral inactivation step by dry heating the lyophilizate according to conventional conditions, at 80 ° C. for 72 hours, for the inactivation of non-enveloped viruses which have not been inactivated and / or eliminated by at least one of the two preceding inactivation and / or viral elimination steps.
- the dry-heated lyophilizates are then reconstituted in an aqueous medium compatible for clinical use, preferably in 10 ml of purified water for injection (PPI) to obtain an injectable formulation.
- PPI purified water for injection
- the injectable formulation may be administered parenterally, preferably intravenously, subcutaneously or intramuscularly.
- parenterally preferably intravenously, subcutaneously or intramuscularly.
- the administration of the liquid form (solution or suspension before drying) or of the powder form by any suitable route and means is not excluded.
- the injectable formulation is administered intravenously.
- a cryoprecipitate of human plasma resuspended in an aqueous solution of sodium heparin (at 2 U / ml) at a pH of 7-7.1 was used.
- This suspension of cryoprecipitate is subjected to a prepurification on aluminum hydroxide for the removal of the main contaminants, as described in patent EP 0 359 593.
- the prepurified supernatant is then recovered and is subjected to a conventional viral inactivation treatment. by solvent-detergent, in the presence of Tween®-TNBP.
- the prepurified cryoprecipitate solution is then injected onto a chromatographic column of the Fractogel® TSK-DEAE 650 (M) type 25 cm long and 1 cm in diameter, previously equilibrated in a buffer consisting of 0.01 M trisodium citrate, chloride of 0.001M calcium, 0.11M sodium chloride, 0.12M glycine and 0.016M lysine, adjusted to pH 7.01, the linear velocity of the mobile phase is fixed at 100 cm / hour.
- the von Willebrand Factor, Factor VIII and fibronectin are retained by the chromatographic medium. Proteins weakly or not retained by the support, mainly fibrinogen and immunoglobulin G (IgG), are removed in the filtrate, as well as Tween® and TNBP, by several successive washings with the same buffer.
- the protein content is monitored by measuring the absorption at 280 nm (denoted hereinafter D.O.).
- the sodium chloride concentration of the buffer is increased to 0.15 M.
- the von Willebrand factor is eluted.
- the eluate thus obtained is highly enriched in von Willebrand Factor and fibronectin and still contains Tween® and TN BP, as well as residual Factor VIII.
- the column is then washed with an acid buffer of 20 mM sodium acetate, adjusted to pH 4.35 and 80 mosmolkg-1, with a linear velocity of 150 cm / h. Under these conditions, very good elimination not only of the residues of viral inactivation agents, but also of fibronectin and especially Factor VIII which was still complexed von Willebrand factor, without observing precipitation of these proteins in the column.
- the linear rate is brought back to 100 cm / hr and then the column is rinsed and equilibrated with the same buffer as previously, containing 0.11 M NaCl.
- Elution of the fraction containing the von Willebrand factor is effected by increasing the concentration of NaCl in the equilibration buffer at 0.17 M, adjusted to a pH of 6.95 and 492 mosmolkg-1.
- the fraction eluted von Willebrand factor then undergoes the conventional treatments of sterilizing filtration on 0.22 ⁇ m filters, nanofiltration on 35 nm filters, diafiltration and ultrafiltration according to known techniques so that the concentrate of Von Willebrand factor has a specific activity (AS) of at least 90 IU RCo / mg protein.
- AS specific activity
- the von Willebrand factor concentrates thus obtained are added with albumin at 10 g / l and then lyophilized at -40 ° C. for 48 hours. Lyophilization is followed by viral inactivation heat treatment by dry heating the lyophilizate at 80 ° C for 72 hours.
- Example 2 Effect of the Administration of a von Willebrand Factor Composition on the Prevention of Hemorrhage and / or Bleeding in Patients Under Mechanical Circulatory Support
- the present study involved 136 patients over the age of 18 requiring mechanical circulatory assistance due to advanced heart failure.
- the abbreviation J 0, corresponds to the day of the intervention, called day 0.
- the abbreviation J + 4 corresponds to the 4 th day after the intervention.
- the patients underwent implantation of the mechanical circulatory assistance device, via the implantation of a HeartMate II continuous flow pump. Between D + 4 and D + 7, the patients received a first administration of the pharmaceutical composition comprising von Willebrand factor according to the invention at a dose of 50 IU / kg of body weight. The administration of this pharmaceutical composition comprising von Willebrand factor was continued at a rate of two administrations per week and at a dose of 50 IU / kg of body weight for 90 days.
- VEGF vascular endothelial growth factor
- angiopoietin 2 galectin 1 and 3
- the evolution of the pharmacological characteristics of von Willebrand factor were monitored at D + 15, D + 30, D + 45, D + 60, D + 75 and D + 90.
- the results show that the administration at 50 IU / kg of the von Willebrand factor composition according to the invention at the rate of two administrations per week, and this for 90 days, makes it possible to prevent the appearance of haemorrhages and / or bleeding in these patients.
Abstract
The present invention relates to a von Willebrand factor composition for preventing and/or treating haemorrhages and/or bleeding in patients under mechanical circulatory support.
Description
Nouvelle utilisation du Facteur von Willebrand New use of von Willebrand Factor
La présente invention se rapporte à une nouvelle utilisation du facteur von Willebrand, et en particulier le traitement et/ou la prévention des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique. The present invention relates to a new use of von Willebrand factor, and in particular the treatment and / or prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
L'assistance circulatoire mécanique est un dispositif intra ou extracorporel pouvant suppléer totalement ou partiellement les fonctions circulatoires normalement exercées par le cœur. Son objectif est de préserver ou de restaurer les grandes fonctions de l'organisme, et en particulier d'assurer, selon le cas, une décharge uni ou biventriculaire, ou de prendre en charge totalement le travail du cœur défaillant. Ce type de dispositif est prescrit lorsque l'état hémodynamique du patient le nécessite, notamment dans trois indications particulières : Mechanical circulatory assistance is an intra or extracorporeal device that can totally or partially replace the circulatory functions normally performed by the heart. Its purpose is to preserve or restore the great functions of the organism, and in particular to ensure, as the case may be, a uni or biventricular discharge, or to totally take charge of the work of the failing heart. This type of device is prescribed when the hemodynamic state of the patient requires it, especially in three particular indications:
chez des patients en attente de transplantation cardiaque pour éviter une détérioration de l'état hémodynamique du patient, dû à un allongement de l'attente sur la liste de transplantation ; in patients awaiting heart transplantation to avoid a deterioration of the patient's hemodynamic status, due to an increase in waiting on the transplant list;
chez des patients en attente de récupération, notamment chez des patients ayant subi une myocardite virale, une intoxication médicamenteuse ou ayant un débit cardiaque bas après une intervention de chirurgie cardiaque sous circulation extracorporelle ; chez des patients éventuellement candidats à une transplantation cardiaque, mais qui malheureusement présentent une contre- indication formelle à une telle intervention chirurgicale (hypertension artérielle pulmonaire, néoplasie en rémission mais non guérie, âge). in patients awaiting recovery, particularly in patients who have undergone viral myocarditis, drug poisoning or low cardiac output after cardiac surgery under extracorporeal circulation; in patients who may be candidates for a heart transplant, but who unfortunately have a formal contraindication to such a surgical procedure (pulmonary arterial hypertension, neoplasia in remission but not cured, age).
Les premiers systèmes d'assistance circulatoire étaient tous de type pneumatique. Ils étaient tous composés d'une coque externe rigide à l'intérieur de laquelle, il y a soit un sac, soit un diaphragme en polyuréthane. Des valves mécaniques ou biologiques assuraient un flux unidirectionnel . Ils étaient reliés à une console d'activation généralement très volumineuse et encombrante, limitant les déplacements possibles pour le patient. L'air comprimé provenait une prise murale à l'hôpital (CardioWest®) avec la possibilité de fonctionner temporairement avec des bouteilles d'air comprimé situées à l'intérieur de la console. Tous les autres systèmes étaient reliés à des consoles à l'intérieur desquelles l'air était comprimé par un compresseur. Le principe de fonctionnement de ces dispositifs est simple : une dépression autour du sac ou sous le diaphragme assure le remplissage de la prothèse. A l'inverse, pendant la phase d'éjection, de l'air sous pression comprime le sac ou refoule le diaphragme permettant ainsi de façon rythmique l'éjection du sang . Tous ces ventricules assurent donc un débit puisé. Parmi ces ventricules pneumatiques, il en existe des paracorporels qui peuvent être
utilisés pour une assistance uni-ventriculaire (le plus souvent gauche) ou bi- ventriculaire, et des ventricules implantés (cœur artificiel total CardioWest®). Tous ces ventricules assurent d'excellentes performances hémodynamiques et peuvent être utilisés sur des périodes longues, permettant d'attendre un greffon dans les meilleures conditions possibles. Le système le plus utilisé est sans nul doute le système Thoratec®, disposant d'une nouvelle console d'activation (TLC-II) améliorant le confort du patient et autorisant même la sortie de l'hôpital et un retour à domicile. The first circulatory assistance systems were all pneumatic. They all consisted of a rigid outer shell inside which there is either a bag or a polyurethane diaphragm. Mechanical or biological valves provided unidirectional flow. They were connected to an activation console usually very bulky and bulky, limiting the possible movements for the patient. The compressed air came from a wall socket in the hospital (CardioWest ® ) with the possibility of working temporarily with compressed air bottles inside the console. All other systems were connected to consoles in which the air was compressed by a compressor. The operating principle of these devices is simple: a depression around the bag or under the diaphragm ensures the filling of the prosthesis. Conversely, during the ejection phase, pressurized air compresses the bag or pushes the diaphragm thus allowing the ejection of the blood rhythmically. All these ventricles thus provide a pulsed flow. Among these pneumatic ventricles, there are paracorporeal ones that can be used for uni-ventricular (mostly left) or bi-ventricular assistance, and implanted ventricles (CardioWest ® total artificial heart). All these ventricles provide excellent hemodynamic performance and can be used over long periods, allowing to wait for a graft in the best possible conditions. The most used system is undoubtedly the Thoratec ® system, featuring a new activation console (TLC-II) that improves the patient's comfort and even allows for hospital discharge and a return home.
Les ventricules de dernière génération fonctionnent à l'énergie électrique. Dans les années 1980 et 1990, il existait deux ventricules électromécaniques implantés entre la pointe du ventricule gauche et l'aorte thoracique ascendante (Novacor®, HeartMate XVE®). La pompe était implantée derrière les muscles de la paroi abdominale et un câble électrique reliait cette pompe à un contrôleur et aux sources d'énergie. Le débit délivré était de type puisé. Le Novacor® n'est plus disponible et le HeartMate® pratiquement plus utilisé, du moins en Europe. The latest generation ventricles operate on electrical energy. In the 1980s and 1990s, there were two electromechanical ventricles implanted between the tip of the left ventricle and the ascending thoracic aorta (Novacor ® , HeartMate XVE ® ). The pump was implanted behind the muscles of the abdominal wall and an electric cable connected this pump to a controller and to the energy sources. The flow delivered was of the pulsed type. Novacor ® is no longer available and the HeartMate ® is practically no longer used, at least in Europe.
La dernière génération de pompes implantables est de type rotatif. Ces pompes implantables peuvent être classées en deux groupes: The latest generation of implantable pumps is rotary type. These implantable pumps can be classified into two groups:
- les pompes centrifuges telles que DuraHeart® ou HeartWare® et, - les pompes axiales telles que HeartMate II®, MicroMed DeBakey®, BerlinHeart Incor® ou Jarvik 2000®. - Centrifugal pumps such as DuraHeart ® or HeartWare ® and - Axial pumps such as HeartMate II ® , MicroMed DeBakey ® , BerlinHeart Incor ® or Jarvik 2000 ® .
Ces pompes délivrant un débit continu, non puisé, n'ont pas besoin de valves pour assurer un débit uni-directionnel. Pour la plupart de ces pompes rotatives, le rotor tourne autour d'un axe. These pumps delivering a continuous flow, not pulsed, do not need valves to ensure a uni-directional flow. For most of these rotary pumps, the rotor rotates about an axis.
Néanmoins, il a été constaté que les patients placés sous ce type de pompes implantables, délivrant un débit continu, non puisé, développent une maladie de Willebrand acquise. En effet, il a été constaté chez ces patients, une perte importante de la fraction de multimères de haut poids moléculaires du facteur von Willebrand, provoquant ainsi des saignements majoritairement gastro-intestinaux, pour lesquels les médecins sont démunis de traitement.Nevertheless, it has been found that patients placed under this type of implantable pumps, delivering a continuous, non-pulsed flow, develop an acquired von Willebrand disease. Indeed, in these patients, a significant loss of the fraction of high molecular weight multimers of von Willebrand factor has been observed, thus causing mainly gastrointestinal bleeding, for which the doctors are deprived of treatment.
Fisher et al. (Transfusion, 2015 ; vol . 55( 1), pp 51-54. ) rapporte le cas d'un patient placé sous assistance circulatoire mécanique à l'aide d'une pompe à débit continu (HeartMate II), souffrant de manière répétée des saignements sévères au niveau gastrointestinal, suite à l'implantation de la pompe. Après l'échec des traitements conventionnels, ce patient a reçu 80UI/kg de poids corporel de facteur von Willebrand, au jour 17, 18 et 19 après la mise en place de l'assistance circulatoire mécanique. Le traitement avec le facteur von Willebrand a été maintenu et une nouvelle dose de 80UI/kg de poids corporel a été de nouveau administrée au patient aux jours 21, 23, 27 et 30 après l'opération. Néanmoins, au jour 41, les médecins ont constaté que l'iléon du patient présentait un aspect hyperdense, laissant suggérer une
hémorragie active dans cette région. Une nouvelle administration de facteur von Willebrand a alors été réalisée tous les deux jours à partir du jour 41 jusqu'au jour 53 après l'opération. Au jour 57 après l'opération, les médecins ont découvert trois lésions angiodysplasiques au niveau de duodénum, lésions susceptibles de provoquer des hémorragies graves. Il en résulte donc que malgré une administration massive de facteur von Willebrand aux jours 17 à 19 après l'opération, les médecins n'ont pu enrayer l'apparition d'une nouvelle hémorragie au niveau gastro-intestinal (iléon). Fisher et al. (Transfusion, 2015, vol 55 (1), pp 51-54.) Reports the case of a patient under mechanical circulatory assistance using a continuous flow pump (HeartMate II), suffering repeatedly Severe bleeding at the gastrointestinal level, following implantation of the pump. After the failure of conventional treatments, this patient received 80 IU / kg body weight von Willebrand factor, at day 17, 18 and 19 after the establishment of mechanical circulatory assistance. Treatment with von Willebrand factor was maintained and a new dose of 80 IU / kg of body weight was again administered to the patient on days 21, 23, 27 and 30 postoperatively. Nevertheless, at day 41, the doctors found that the patient's ileum had a hyperdense appearance, suggesting a active hemorrhage in this region. A new von Willebrand factor administration was then performed every two days from day 41 to day 53 postoperatively. At day 57 postoperatively, the doctors discovered three angiodysplastic lesions in the duodenum, lesions likely to cause severe hemorrhage. As a result, despite a massive administration of von Willebrand factor on days 17 to 19 after the operation, doctors could not stop the appearance of a new haemorrhage in the gastrointestinal (ileum).
Cushing et al. (Transfusion, 2012, vol. 52, pp 1535-1541) rapportent le cas d'un patient placé sous assistance circulatoire mécanique à l'aide d'une pompe à débit continu (HeartMate II) dans l'attente d'une transplantation cardiaque. Le patient a développé une hémorragie au niveau du bulbe duodénal 9 jours après la mise en place du dispositif d'assistance circulatoire mécanique. Cette hémorragie a été traitée par transfusion sanguine et administration d'acide aminocaproïque. 47 jours après l'intervention, le patient a présenté un suintement au niveau gastrique et au niveau du bulbe du duodénum ainsi qu'un saignement actif au niveau de l'angle duodéno- jéjunal. Au 49ème jour après la pose du dispositif d'assistance circulatoire mécanique, le patient a reçu une dose de 60UI/kg de poids corporel d'une composition pharmaceutique comprenant du facteur von Willebrand et du facteur VIII toutes les huit heures, à raison de trois doses tout en continuant l'administration d'acide aminocaproïque. Le traitement avec la composition de facteur von Willebrand et de facteur VIII a été continué pendant 33 jours avec des doses décroissantes. Néanmoins, le patient a développé des ecchymoses autour de l'œil gauche et un thrombus au niveau de la pompe quelques jours plus tard, entraînant l'arrêt du traitement. Les auteurs en concluent que le traitement avec la composition de facteur von Willebrand et de facteur VIII a permis de traiter les hémorragies et/ou les saignements gastro-intestinal, mais ce traitement requiert un contrôle très attentif des thromboses dans le circuit de la pompe, du notamment à la présence de facteur VIII dans le concentré thérapeutique. Il en résulte donc que malgré une administration de la composition de facteur von Willebrand et de facteur VIII permettant de traiter les hémorragies chez le patient étudié, l'administration de ce produit peut conduire à l'apparition de thrombose. Par conséquent, il apparaît nécessaire de disposer d'une méthode de prévention et/ou méthode de traitement des hémorragies et/ou des saignements, qui puisse être appliquée aux patients sous assistance circulatoire mécanique, afin de prévenir l'apparition de ces hémorragies et/ou de ces saignements, sans crainte de provoquer une thrombose supplémentaire et sans crainte d'une rechute éventuelle, i.e. sans crainte de développer de nouvelles hémorragies ou de nouveaux saignements. Cushing et al. (Transfusion, 2012, vol 52, pp 1535-1541) report the case of a patient under mechanical circulatory assistance using a continuous flow pump (HeartMate II) while waiting for a heart transplant . The patient developed hemorrhage in the duodenal bulb 9 days after placement of the mechanical circulatory assistance device. This hemorrhage was treated by blood transfusion and administration of aminocaproic acid. At 47 days postoperatively, the patient experienced gastric and duodenal bulb seepage as well as active bleeding at the duodenojejunal angle. At the 49th day after installation of mechanical circulatory assist device, the patient received a dose of 60UI / kg body weight of a pharmaceutical composition comprising von Willebrand factor and factor VIII every eight hours at a rate of three doses while continuing the administration of aminocaproic acid. Treatment with the von Willebrand factor and factor VIII composition was continued for 33 days with decreasing doses. Nevertheless, the patient developed bruising around the left eye and a thrombus at the pump a few days later, resulting in discontinuation of treatment. The authors conclude that treatment with von Willebrand factor and factor VIII treatment has been successful in treating hemorrhage and / or gastrointestinal bleeding, but this treatment requires careful monitoring of thromboses in the pump circuit. in particular to the presence of factor VIII in the therapeutic concentrate. It follows therefore that despite administration of the composition of von Willebrand factor and factor VIII to treat haemorrhage in the patient studied, the administration of this product can lead to the occurrence of thrombosis. Therefore, it appears necessary to have a method of prevention and / or method of treatment of haemorrhage and / or bleeding, which can be applied to patients under mechanical circulatory assistance, to prevent the occurrence of these haemorrhages and / or bleeding, without fear of causing additional thrombosis and without fear of a possible relapse, ie without fear of developing new haemorrhages or bleeding.
Les inventeurs ont montré de manière surprenante que l'administration d'une composition pharmaceutique comprenant du facteur von Willebrand à
une dose déterminée et dans des conditions particulières permettait de prévenir les risques associés à la mise en place d'une assistance circulatoire mécanique. Plus particulièrement, les inventeurs ont montré que cette administration préventive de facteur von Willebrand permettait de manière surprenante de réduire de plus de 60% les risques associés à la mise en place d'une assistance circulatoire mécanique, à savoir de réduire de plus de 60% l'apparition d'hémorragies et/ou de saignements chez ces patients. De préférence, cette administration préventive de facteur von Willebrand permet de réduire de plus de 70%, de préférence 80%, de préférence 90% l'apparition d'hémorragies et/ou de saignements chez ces patients. De manière avantageuse, cette administration de facteur von Willebrand permet d'éliminer définitivement tout risque d'hémorragies et/ou de saignements chez les patients placés sous assistance circulatoire mécanique, y compris les risques de rechute. The inventors have surprisingly shown that the administration of a pharmaceutical composition comprising von Willebrand factor to a specific dose and under specific conditions prevented the risks associated with the establishment of mechanical circulatory assistance. More particularly, the inventors have shown that this preventative administration of von Willebrand factor surprisingly makes it possible to reduce by more than 60% the risks associated with setting up mechanical circulatory assistance, namely to reduce by more than 60% haemorrhage and / or bleeding in these patients. Preferably, this preventive administration of von Willebrand factor makes it possible to reduce by more than 70%, preferably 80%, preferably 90%, the occurrence of haemorrhages and / or bleeding in these patients. Advantageously, this administration of von Willebrand factor makes it possible definitely to eliminate any risk of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, including the risk of relapse.
Dans un autre mode de réalisation avantageux, l'administration d'une composition pharmaceutique comprenant du facteur von Willebrand selon l'invention permet de réduire la fréquence des saignements cliniquement significatifs en comparaison avec les soins habituels. In another advantageous embodiment, the administration of a pharmaceutical composition comprising von Willebrand factor according to the invention makes it possible to reduce the frequency of clinically significant bleeding in comparison with usual care.
Ainsi l'invention porte donc sur une composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans la prévention des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique. Thus the invention relates to a pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
Le terme « saignement » correspond à un écoulement de sang (interne ou externe) en dehors de la circulation sanguine naturelle de petite quantité. Lorsque la perte de sang est importante et susceptible d'engager le pronostic vital, on parle alors « d'hémorragie ». Le saignement ou l'hémorragie peuvent être extériorisés par la peau, ou par un orifice naturel ou peuvent être intériorisés. Le terme « saignement cliniquement significatif » correspond à un saignement interne ou externe menant au décès ou à une hospitalisation prolongée, ou requérant une ré-hospitalisation, une chirurgie ou la transfusion d'au moins 3 unités de globules rouges, ou entraînant une élévation de l'hémoglobine à un taux supérieur à 3 g/dL, ou qui est réfractaire aux approches conventionnelles de traitement. The term "bleeding" refers to a flow of blood (internal or external) outside the small-volume natural bloodstream. When blood loss is significant and potentially life-threatening, it is called "bleeding". Bleeding or bleeding may be externalized through the skin, or through a natural orifice, or may be internalized. The term "clinically significant bleeding" refers to internal or external bleeding leading to death or prolonged hospitalization, or requiring re-hospitalization, surgery or transfusion of at least 3 units of red blood cells, or resulting in elevated blood flow. hemoglobin at a rate greater than 3 g / dL, or which is refractory to conventional approaches to treatment.
Au sens de la présente invention, on entend par «composition pharmaceutique» aussi bien une composition pharmaceutique sous forme liquide, en particulier sous forme de solution ou de suspension qu'une composition pharmaceutique sous forme de poudre. Cette composition pharmaceutique comprend au moins un principe actif, le facteur von Willebrand et des excipients pharmaceutiquement acceptables. For the purposes of the present invention, the term "pharmaceutical composition" is understood to mean both a pharmaceutical composition in liquid form, in particular in the form of a solution or a suspension, and a pharmaceutical composition in the form of a powder. This pharmaceutical composition comprises at least one active ingredient, von Willebrand factor and pharmaceutically acceptable excipients.
Le terme « Facteur von Willebrand » ou « facteur de von Willebrand » ou « FvW » inclut les polypeptides comprenant la séquence du facteur von
Willebrand humain de type sauvage, ou du facteur von Willebrand dérivé d'une autre espèce (par exemple bovin, porcin, canin, murin). Il comprend en outre les variations alléliques naturelles du facteur von Willebrand qui peuvent exister, et toute forme ou degré de glycosylation ou autre modification post-traductionnelle. Le terme « Facteur von Willebrand » inclut aussi les variants du facteur von Willebrand qui présente la même ou une activité biologique supérieure par rapport à l'activité de la forme sauvage, ces variants présentant notamment au moins 70%, de préférence 75%, de préférence 80%, de préférence 85%, de préférence 90%, de préférence 92%, de préférence 94%, de préférence 95%, de préférence 96%, de préférence 97%, de préférence 98%, de préférence 99%, de préférence 100% d'homologie avec la séquence nucléotidique du facteur von Willebrand sauvage. De manière avantageuse, le facteur von Willebrand est un facteur von Willebrand humain. The term "von Willebrand Factor" or "von Willebrand Factor" or "FvW" includes polypeptides comprising the von Wild-type human willebrand, or von Willebrand factor derived from another species (eg bovine, porcine, canine, murine). It further includes natural allelic variations of von Willebrand factor that may exist, and any form or degree of glycosylation or other post-translational modification. The term "von Willebrand factor" also includes von Willebrand factor variants which exhibit the same or a higher biological activity as compared to the activity of the wild form, these variants having in particular at least 70%, preferably 75%, of preferably 80%, preferably 85%, preferably 90%, preferably 92%, preferably 94%, preferably 95%, preferably 96%, preferably 97%, preferably 98%, preferably 99%, preferably preferably 100% homology with the nucleotide sequence of wild von Willebrand factor. Advantageously, the von Willebrand factor is a human von Willebrand factor.
Dans un mode de réalisation avantageux, la composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans la prévention des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique est dépourvue de facteur VIII. Le terme « dépourvue de facteur VIII » signifie que la composition de l'invention ne contient pas de facteur VIII ou qu'il est présent en une quantité négligeable. En effet, les inventeurs ont constaté que l'élimination de ce facteur de la coagulation permettait de réduire les risques d'apparition de thrombose, contrairement aux compositions pharmaceutiques combinées FVIII/FvW déjà commercialisées comme notamment le produit constitué d'une association de 160 UI/mL facteur von Willebrand et de 66,6UI/mL de facteur VIII. In an advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of factor VIII. The term "factor VIII-free" means that the composition of the invention does not contain factor VIII or is present in a negligible amount. In fact, the inventors have found that the elimination of this coagulation factor makes it possible to reduce the risks of occurrence of thrombosis, unlike the combination pharmaceutical compositions FVIII / FvW already marketed, in particular the product consisting of a combination of 160 IU. von Willebrand factor and 66.6 IU / ml factor VIII.
De manière avantageuse, le taux résiduel de facteur VIII dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur ou égal à 10 UI/100 UI VWF: RCo. Ce taux est mesuré par la méthode de dosage du cofacteur de la ristocétine du facteur Willebrand (VWF: RCo) par rapport à l'étalon international de facteur Willebrand concentré défini par l'Organisation Mondiale de la santé (OMS). De préférence, l'activité du facteur von Willebrand dans la composition de l'invention est de 100UI pour 1ml de solution reconstituée. La teneur en facteur VIII résiduelle de la composition selon l'invention est donc divisée au minimum d'un facteur 4 par rapport aux produits sur le marché, permettant ainsi de limiter le risque thrombotique en contrôlant et en réduisant au maximum l'apport exogène de FVIII. De préférence, le taux résiduel de facteur VIII dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur à 10 UI/100 UI VWF: RCo, de préférence inférieur à 8UI/100 UI VWF: RCo, de préférence inférieur à 6UI/100 UI VWF: RCo, de préférence inférieur à 4UI/100 UI VWF: RCo. Dans un mode de réalisation particulier, la composition comprenant du facteur von
Willebrand est totalement exempte de facteur VIII de la coagulation sanguine. Advantageously, the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 10 IU / 100 IU VWF: RCo. This rate is measured by the von Willebrand factor ristocetin cofactor (VWF: RCo) assay method compared to the International Standard for Willebrand Factor Concentrate as defined by the World Health Organization (WHO). Preferably, the von Willebrand factor activity in the composition of the invention is 100 IU per 1 ml of reconstituted solution. The residual factor VIII content of the composition according to the invention is thus divided by a factor of at least a factor of 4 in relation to the products on the market, thus making it possible to limit the thrombotic risk by controlling and minimizing the exogenous contribution of FVIII. Preferably, the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than 10 IU / 100 IU VWF: RCo, preferably less than 8 IU / 100 IU VWF: RCo, preferably less than 6 IU / 100 IU VWF: RCo, preferably less than 4 IU / 100 IU VWF: RCo. In a particular embodiment, the composition comprising von factor Von Willebrand is totally free of factor VIII blood clotting.
Dans un autre mode de réalisation, la composition pharmaceutique comprenant du facteur von Willebrand comprend également du facteur VIII en quantité non négligeable. Le ratio facteur VIII / facteur von Willebrand est alors avantageusement compris entre 1/10 et 5/10 UI/mL. In another embodiment, the pharmaceutical composition comprising von Willebrand factor also comprises factor VIII in a significant amount. The ratio factor VIII / von Willebrand factor is then advantageously between 1/10 and 5/10 IU / mL.
Dans un mode de réalisation avantageux, la composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans la prévention des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique est dépourvue d'ADAMTS13. Le terme « dépourvue d'ADAMTS13 » ou « dépourvue de protéine ADAMTS13 » signifie que la composition de l'invention ne contient pas de protéine ADAMTS13 ou que cette protéine ADAMTS13 est présente en une quantité négligeable ou que l'activité ADAMTS13 est négligeable. En effet, les inventeurs ont constaté que cette protéine avait tendance à fragiliser le facteur von Willebrand, voire à le dégrader, mais également que l'activité de cette protéine est potentialisée par les forces de cisaillement induites par le dispositif d'assistance circulatoire mécanique. Ainsi, l'absence de cette protéine ou sa présence en quantité négligeable permettait de réduire les risques d'apparition d'hémorragies et/ou de saignements chez les patients sous assistance circulatoire mécanique. In one advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of ADAMTS13. The term "ADAMTS13-free" or "ADAMTS13-free protein" means that the composition of the invention does not contain ADAMTS13 protein or that this ADAMTS13 protein is present in a negligible amount or that ADAMTS13 activity is negligible. Indeed, the inventors have found that this protein has a tendency to weaken the von Willebrand factor, or even to degrade it, but also that the activity of this protein is potentiated by the shear forces induced by the mechanical circulatory assistance device. Thus, the absence of this protein or its presence in negligible amount reduced the risk of bleeding and / or bleeding in patients under mechanical circulatory assistance.
De manière avantageuse, la composition pharmaceutique comprenant du facteur von Willebrand est dépourvue d'ADAMTS13. Advantageously, the pharmaceutical composition comprising von Willebrand factor is devoid of ADAMTS13.
Dans un autre mode de réalisation particulier, le taux résiduel d'ADAMTS13 dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur ou égal à 0,15 pg/ml. De préférence, le taux résiduel d'ADAMTS13 est inférieur ou égal à 0,10 pg/ml, de préférence inférieur ou égal à 0,05 pg/ml, de préférence inférieur ou égal à 0,01 pg/ml . De préférence, le taux résiduel d'ADAMTS13 est compris entre 0,01 pg/ml et 0,15pg/ml. In another particular embodiment, the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 0.15 μg / ml. Preferably, the residual level of ADAMTS13 is less than or equal to 0.10 μg / ml, preferably less than or equal to 0.05 μg / ml, preferably less than or equal to 0.01 μg / ml. Preferably, the residual level of ADAMTS13 is between 0.01 μg / ml and 0.15 μg / ml.
De manière avantageuse, la composition pharmaceutique comprenant du facteur von Willebrand ne contient pas d'activité ADAMTS13. Advantageously, the pharmaceutical composition comprising von Willebrand factor does not contain ADAMTS13 activity.
Dans un autre mode de réalisation particulier, le taux résiduel d'activité ADAMTS13 dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur ou égal au seuil de détection, soit inférieur ou égal à 0,03 ADAMTS13 :Act [U/mL] . In another particular embodiment, the residual level of ADAMTS13 activity in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to the detection threshold, that is less than or equal to 0.03 ADAMTS13: Act [U / mL].
Ce taux est mesuré par la méthode décrite dans Kokame et al. (British Journal of Haematology, 2005, vol. 129, pp. 93-100), utilisant la FRET (fluorescence résonance energy transfer) et le substrat fluorogénique FRETS- VWF73 (Peptides International, Louisville, USA). La teneur en ADAMTS13
résiduelle de la composition selon l'invention est au moins 2 à 3 fois inférieure par rapport aux produits sur le marché qui comprennent au moins 0,13 ± 0.07 ADAMTS13 :Act [U/mL], permettant ainsi d'éviter tout risque d'apparition d'hémorragies et/ou de saignements chez les patients sous assistance circulatoire mécanique. Dans un mode de réalisation préféré, le taux résiduel d'ADAMTS13 dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur à 0,10 ADAMTS13 :Act [U/mL], de préférence inférieure à 0,05 ADAMTS13 :Act [U/mL] . Dans un mode de réalisation particulier, la composition comprenant du facteur von Willebrand est totalement exempte d'ADAMTS13. Dans un autre mode de réalisation de l'invention, la quantité d'ADAMTS13 dans la composition comprenant du facteur von Willebrand de l'invention est ajustée pour éviter la présence d'ultralarges multimères (>20 mers). Dans ce cas, l'ADAMTS13 peut avantageusement être d'origine plasmatique et copurifiée avec la composition comprenant du facteur von Willebrand de l'invention, ou bien être d'origine recombinante et être avantageusement ajoutée à la composition comprenant du facteur von Willebrand de l'invention d'origine recombinante. This rate is measured by the method described in Kokame et al. (British Journal of Haematology, 2005, vol 129, pp. 93-100), using FRET (fluorescence resonance energy transfer) and fluorogenic FRETS-VWF73 substrate (Peptides International, Louisville, USA). ADAMTS13 content residual of the composition according to the invention is at least 2 to 3 times lower compared to products on the market which comprise at least 0.13 ± 0.07 ADAMTS13: Act [U / mL], thereby avoiding any risk of haemorrhage and / or bleeding in patients with mechanical circulatory assistance. In a preferred embodiment, the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than 0.10 ADAMTS13: Act [U / mL], preferably less than 0.05 ADAMTS13: Act [U / mL]. In a particular embodiment, the composition comprising von Willebrand factor is totally free of ADAMTS13. In another embodiment of the invention, the amount of ADAMTS13 in the composition comprising von Willebrand factor of the invention is adjusted to avoid the presence of multimeric ultralarges (> 20 mers). In this case, the ADAMTS13 may advantageously be of plasmatic origin and copurified with the composition comprising von Willebrand factor of the invention, or else be of recombinant origin and advantageously be added to the composition comprising von Willebrand factor of the invention. invention of recombinant origin.
La répartition des formes multimériques du facteur von Willebrand est définie après analyse d'un gel électrophorétique permettant la quantification de la taille des mers (sous-unités) en multiples de la sous-unité monomérique de 225 kD. Ainsi on décrit des mers de taille 225x2 à 225x15. Par multimères de haut poids moléculaires de la composition pharmaceutique comprenant du facteur von Willebrand, on entend les multimères à partir de 10 monomères. Dans un mode de réalisation particulier, la teneur en multimères de haut poids moléculaires de la composition pharmaceutique comprenant du facteur von Willebrand est proche de celle du plasma. The distribution of multimeric forms of von Willebrand factor is defined after analysis of an electrophoretic gel allowing the quantification of the size of the seas (subunits) in multiples of the monomeric subunit of 225 kD. Thus we describe seas of size 225x2 to 225x15. By high molecular weight multimers of the pharmaceutical composition comprising von Willebrand factor is meant multimers from 10 monomers. In a particular embodiment, the content of high molecular weight multimers of the pharmaceutical composition comprising von Willebrand factor is close to that of the plasma.
Dans un autre mode de réalisation particulier, la teneur en multimères de haut poids moléculaires de la composition pharmaceutique comprenant du facteur von Willebrand est suffisamment conservée pour permettre une activité suffisante in vivo de la composition pharmaceutique. In another particular embodiment, the high molecular weight multimer content of the pharmaceutical composition comprising von Willebrand factor is sufficiently conserved to allow sufficient in vivo activity of the pharmaceutical composition.
De manière avantageuse, la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention a une teneur en multimères de haut poids moléculaires d'au moins 65 %, de préférence 70%, de manière encore plus préférée 75%, de manière vraiment préférée 80% de la teneur totale en multimères du facteur von Willebrand contenus dans la composition pharmaceutique. La présence d'au moins 65 % de multimères de haut poids moléculaires confère à la composition selon l'invention une meilleure efficacité thérapeutique. Advantageously, the pharmaceutical composition comprising von Willebrand factor according to the invention has a high molecular weight multimer content of at least 65%, preferably 70%, even more preferably 75%, in a very preferred manner. % of the total multimer content of von Willebrand factor contained in the pharmaceutical composition. The presence of at least 65% of multimers of high molecular weight gives the composition according to the invention a better therapeutic efficacy.
La composition pharmaceutique selon l'invention peut comprendre en outre un ou plusieurs excipients, permettant de stabiliser le facteur von Willebrand
et permettant la solubilisation des formes lyophilisées du facteur von Willebrand . The pharmaceutical composition according to the invention may also comprise one or more excipients, making it possible to stabilize the von Willebrand factor. and allowing the solubilization of freeze-dried forms of von Willebrand factor.
Les excipients peuvent notamment être choisis parmi : The excipients may especially be chosen from:
- un acide aminé hydrophile ou portant une chaîne latérale chargée positivement, a hydrophilic amino acid or having a positively charged side chain,
- éventuellement un acide aminé hydrophobe, optionally a hydrophobic amino acid,
- un sel, - a salt,
- un stabilisant protéique, a protein stabilizer,
- ou un mélange de ceux-ci. - or a mixture of these.
Les acides aminés hydrophiles (ou polaires) ou les acides aminés portant une chaîne latérale chargée positivement incluent la Lysine, l'Arginine, l'Histidine, la Glycine, la Serine, la Thréonine, la Tyrosine, l'Asparagine, la Glutamine. Parmi les acides aminés hydrophiles ou portant une chaîne latérale chargée positivement, on peut utiliser préférentiellement l'arginine, ou un de ses sels dérivés comme le chlorhydrate d'arginine ou encore le phosphate d'arginine. Des acides aminés comme la glycine et/ou la lysine, ou un de ses sels dérivés comme le chlorhydrate de lysine peuvent être avantageusement ajoutés. Les acides aminés hydrophobes incluent notamment les acides aminés suivants : Alanine, Valine, Leucine, Isoleucine, Phénylalanine, Tryptophane, Proline. Hydrophilic (or polar) amino acids or amino acids carrying a positively charged side chain include Lysine, Arginine, Histidine, Glycine, Serine, Threonine, Tyrosine, Asparagine, Glutamine. Among the hydrophilic amino acids or carrying a positively charged side chain, it is preferable to use arginine, or a derivative salt thereof, such as arginine hydrochloride or arginine phosphate. Amino acids such as glycine and / or lysine or a derivative salt thereof such as lysine hydrochloride may be advantageously added. Hydrophobic amino acids include the following amino acids: Alanine, Valine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Proline.
Le sel peut être un sel de métal alcalin, un sel de métal alcalino-terreux, ou un sel d'un métal de transition. A titre d'exemple de sel, on peut notamment citer le citrate de sodique, le chlorure de calcium, ou le chlorure de zinc. De manière préférée le sel utilisé est préférentiellement du citrate de sodium ou du chlorure de calcium. The salt may be an alkali metal salt, an alkaline earth metal salt, or a transition metal salt. As an example of salt, there may be mentioned in particular sodium citrate, calcium chloride, or zinc chloride. Preferably, the salt used is preferably sodium citrate or calcium chloride.
Le stabilisant protéique peut être choisi parmi les stabilisants protéiques connus, par exemple l'albumine et le facteur VIII. Avantageusement, le stabilisant protéique préféré est l'albumine, de préférence l'albumine humaine. The protein stabilizer may be selected from known protein stabilizers, for example albumin and factor VIII. Advantageously, the preferred protein stabilizer is albumin, preferably human albumin.
Avantageusement, la composition comprend du facteur von Willebrand en tant que principe actif et les excipients pharmaceutiquement acceptables suivants : l'albumine, le chlorhydrate d'arginine, la glycine, le citrate de sodium et le chlorure de calcium. Plus particulièrement, la composition peut comprendre : Advantageously, the composition comprises von Willebrand factor as active principle and the following pharmaceutically acceptable excipients: albumin, arginine hydrochloride, glycine, sodium citrate and calcium chloride. More particularly, the composition may comprise:
- du facteur von Willebrand humain ; - human von Willebrand factor;
- de l'albumine, de préférence d'albumine humaine ; - albumin, preferably human albumin;
- de l'arginine, éventuellement sous forme de chlorhydrate ; arginine, optionally in the form of hydrochloride;
- de la glycine ; - glycine;
- du citrate de sodium ; - sodium citrate;
- du chlorure de calcium.
La reconstitution à partir de la poudre sous forme de préparation injectable peut être réalisée par ajout d'eau pour préparations injectables (eau ppi).- calcium chloride. Reconstitution from the powder in the form of an injectable preparation can be carried out by adding water for injection (water ppi).
Le terme «prévention » ou « prophylaxie » ou « traitement préventif » ou « traitement prophylactique » comprend aussi bien un traitement aboutissant à la prévention d'une maladie qu'un traitement réduisant et/ou retardant l'incidence d'une maladie ou le risque qu'elle survienne. Selon l'invention, la composition de facteur von Willebrand est particulièrement utile pour prévenir ou réduire les hémorragies et /ou saignements associés à la mise en place du dispositif d'assistance circulatoire mécanique. Aux fins de la présente invention, le traitement préventif ou prophylactique peut intervenir avant la mise en place du dispositif d'assistance circulatoire mécanique chez le patient ou après la mise en place de celui-ci, c'est-à-dire dans les jours qui suivent la mise en place du dispositif, mais dans tous les cas avant l'apparition d'un saignement ou d'une hémorragie. The term "prevention" or "prophylaxis" or "preventive treatment" or "prophylactic treatment" includes both treatment leading to the prevention of a disease and treatment that reduces and / or delays the incidence of a disease or disease. risk of it happening. According to the invention, the von Willebrand factor composition is particularly useful for preventing or reducing haemorrhage and / or bleeding associated with setting up the mechanical circulatory assistance device. For the purposes of the present invention, preventive or prophylactic treatment may take place before the setting up of the mechanical circulatory assistance device in the patient or after the placement of the latter, that is to say in the days following the placement of the device, but in all cases before the occurrence of bleeding or haemorrhage.
Dans un mode de réalisation préféré, la composition pharmaceutique comprenant du facteur von Willebrand, est administrée au patient sous assistance circulatoire mécanique à une dose d'au moins 30UI/kg de poids corporel. In a preferred embodiment, the pharmaceutical composition comprising von Willebrand factor is administered to the patient under mechanical circulatory assistance at a dose of at least 30 IU / kg of body weight.
Par « administration », on entend l'injection au patient de la composition pharmaceutique selon l'invention. Cette administration comprend les injections parentérale, comme notamment les injections par voies intraveineuse, intramusculaire, sous-cutanée, intra-orbitaire, intradermique, intrarachidienne, intrapéritonéale ainsi que la perfusion directe dans un tissu ou un organe. L'administration par voie orale ou aérienne, par exemple par inhalation, sont aussi envisagées dans le cadre de la présente invention. De manière particulièrement avantageuse, la composition pharmaceutique comprenant du facteur von Willebrand est administrée par voie intraveineuse. By "administration" is meant the injection to the patient of the pharmaceutical composition according to the invention. This administration includes parenteral injections such as intravenous, intramuscular, subcutaneous, intraorbital, intradermal, intraspinal, intraperitoneal injections as well as direct perfusion into tissue or organ. Oral or aerial administration, for example by inhalation, are also contemplated within the scope of the present invention. Particularly advantageously, the pharmaceutical composition comprising von Willebrand factor is administered intravenously.
De manière avantageuse, la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est administrée au patient à une dose d'au moins 40UI/kg de poids corporel, de préférence 45UI/kg de poids corporel, de préférence 50UI/kg de poids corporel, de préférence 55UI/kg de poids corporel, de préférence 60UI/kg de poids corporel, de préférence 65UI/kg de poids corporel. De manière particulièrement avantageuse, la dose est de 50UI/kg de poids corporel. L'homme du métier saura adapter la dose en fonction de la voie d'administration choisie. En particulier, lorsque l'administration par voie intraveineuse est choisie, la dose préférée administrée sera de 50UI/kg de poids corporel. Advantageously, the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient at a dose of at least 40 IU / kg of body weight, preferably 45 IU / kg of body weight, preferably 50 IU / kg of weight. body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU / kg body weight. Particularly advantageously, the dose is 50 IU / kg of body weight. Those skilled in the art will be able to adapt the dose according to the chosen route of administration. In particular, when intravenous administration is chosen, the preferred dose administered will be 50 IU / kg body weight.
De manière avantageuse, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation de 20% des multimères supérieurs à 15 mers durant 1 heure après l'injection.
Avantageusement, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 30 min. De préférence, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 45 min. De manière avantageuse, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 1 heure après l'injection. Cette élévation temporaire et cette modification permettent de rétablir une angiogenèse normale dans la microcirculation. Advantageously, the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a 20% increase of multimers greater than 15 mers for 1 hour after injection. Advantageously, the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with an increase of multimers greater than 15 mers for at least 30 min. Preferably, the dosing regimen provides a modification of the von Willebrand Factor multimeric distribution with a multimer rise greater than 15 months for at least 45 min. Advantageously, the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a multimer rise greater than 15 months for at least 1 hour after injection. This temporary elevation and this modification make it possible to restore normal angiogenesis in the microcirculation.
De manière avantageuse, le régime de dosage permet de restaurer une fonctionnalité normale du facteur von Willebrand mesurée par un résultat VWF :Act/VWF :Ag >0,7. De manière avantageuse, la concentration plasmatique moyenne de facteur von Willebrand et la concentration plasmatique maximale moyenne de facteur von Willebrand sont mesurées après l'administration intraveineuse de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention. Advantageously, the dosing regimen makes it possible to restore a normal von Willebrand factor functionality measured by a VWF: Act / VWF: Ag> 0.7 result. Advantageously, the average plasma concentration of von Willebrand factor and the maximum average plasma concentration of von Willebrand factor are measured after the intravenous administration of the pharmaceutical composition comprising von Willebrand factor according to the invention.
Dans un mode de réalisation particulièrement avantageux, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand, est réalisée avant l'apparition de la première hémorragie ou du premier saignement chez le patient sous assistance circulatoire mécanique du patient. In a particularly advantageous embodiment, the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out before the appearance of the first hemorrhage or first bleeding in the patient under mechanical circulatory assistance of the patient.
Avantageusement, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand, est réalisée quatre jours après la mise en place de l'assistance circulatoire mécanique du patient. Advantageously, the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out four days after the establishment of the mechanical circulatory assistance of the patient.
Avantageusement, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand est réalisée cinq jours après la mise en place sous assistance circulatoire mécanique du patient, de préférence six jours, de préférence sept jours après la mise en place de l'assistance circulatoire mécanique du patient. Advantageously, the first administration of the pharmaceutical composition comprising von Willebrand factor is performed five days after placement under mechanical circulatory assistance of the patient, preferably six days, preferably seven days after the establishment of mechanical circulatory assistance. of the patient.
Avantageusement, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand est réalisée entre le 4ème et le 7ème jour après la mise en place sous assistance circulatoire mécanique du patient. Aucune première administration n'est réalisée au-delà du septième jour. En effet, l'administration doit être la plus précoce possible pour observer un effet, confirmant l'efficacité liée à un blocage précoce de l'angiogenèse. Une inclusion plus tardive exposerait à une modulation de l'efficacité.
Avantageusement, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand est réalisée quatre à sept jours après la mise en place de l'assistance circulatoire mécanique du patient. Advantageously, the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out between the 4 th and 7 th day after the establishment of the patient under mechanical circulatory assistance. No first administration is performed beyond the seventh day. Indeed, the administration must be as early as possible to observe an effect, confirming the effectiveness linked to an early blocking of angiogenesis. A later inclusion would expose to a modulation of efficiency. Advantageously, the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out four to seven days after the setting up of the mechanical circulatory assistance of the patient.
De manière particulièrement avantageuse, l'administration de la composition pharmaceutique comprenant du facteur von Willebrand au patient sous assistance circulatoire mécanique est effectuée de manière répétée à raison de deux administrations par semaine. Particularly advantageously, the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly with two administrations per week.
Avantageusement, si la première administration de la composition de facteur von Willebrand a été réalisée le 4ème jour après la mise en place sous assistance circulatoire mécanique du patient, alors la seconde administration de la composition de facteur von Willebrand est réalisée entre le 5ème et le gème j0u r apres |a mjse en place sous assistance circulatoire mécanique du patient. Advantageously, if the first administration of factor composition VWD was completed on Day 4 after the establishment in patient mechanical circulatory support, while the second administration of von factor composition Willebrand is performed between the 5th and the Geme j 0U r ap res | am j is placed under mechanical circulatory assistance of the patient.
Avantageusement, si la première administration de la composition de facteur von Willebrand a été réalisée le 5ème jour après la mise en place sous assistance circulatoire mécanique du patient, alors la seconde administration de la composition de facteur von Willebrand est réalisée entre le 6ème et le gème j0u r après la mise en place sous assistance circulatoire mécanique du patient. Advantageously, if the first administration of factor composition VWD was performed on day 5 after the establishment in patient mechanical circulatory support, while the second administration of factor composition VWD is performed between the 6th and geme j 0u r after placement under mechanical circulatory assistance of the patient.
Avantageusement, si la première administration de la composition de facteur von Willebrand a été réalisée le 6ème jour après la mise en place sous assistance circulatoire mécanique du patient, alors la seconde administration de la composition de facteur von Willebrand est réalisée entre le 7ème et le 8ème jour après la mise en place sous assistance circulatoire mécanique du patient. Advantageously, if the first administration of factor composition VWD was performed on the 6th day after the establishment in patient mechanical circulatory support, while the second administration of factor composition VWD is performed between the 7th and the 8th day after the establishment in patient mechanical circulatory support.
Avantageusement, si la première administration de la composition de facteur von Willebrand a été réalisée le 7ème jour après la mise en place sous assistance circulatoire mécanique du patient, alors la seconde administration de la composition de facteur von Willebrand est réalisée le 8ème jour après la mise en place sous assistance circulatoire mécanique du patient. Advantageously, if the first administration of factor composition VWD was conducted on day 7 after the establishment in patient mechanical circulatory support, while the second administration of von factor composition Willebrand is completed on 8th day after placement under mechanical circulatory assistance of the patient.
De manière particulièrement avantageuse l'intervalle entre deux administrations de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention ne doit pas être inférieur à un jour, de préférence 2 jours. De manière particulièrement avantageuse, l'intervalle entre deux administrations de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention ne doit pas être supérieur à six jours, de préférence cinq jours, de préférence quatre jours, de préférence trois jours.
De manière particulièrement avantageuse, l'administration de la composition pharmaceutique comprenant du facteur von Willebrand au patient sous assistance circulatoire mécanique est effectuée de manière répétée à raison de deux administrations par semaine, pendant au moins 15 jours. Particularly advantageously the interval between two administrations of the pharmaceutical composition comprising von Willebrand factor according to the invention must not be less than one day, preferably 2 days. Particularly advantageously, the interval between two administrations of the pharmaceutical composition comprising von Willebrand factor according to the invention must not be greater than six days, preferably five days, preferably four days, preferably three days. Particularly advantageously, the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at a rate of two administrations per week, for at least 15 days.
Avantageusement, l'administration de la composition pharmaceutique comprenant du facteur von Willebrand au patient sous assistance circulatoire mécanique est effectuée de manière répétée à raison de deux administrations par semaine, pendant au moins 30 jours, de préférence 45 jours, de préférence 60 jours, de préférence 75 jours, de préférence 90 jours. Advantageously, the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 30 days, preferably 45 days, preferably 60 days, of preferably 75 days, preferably 90 days.
Dans un mode de réalisation particulièrement avantageux, la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est administrée au patient sous assistance circulatoire mécanique, à une dose de 50UI/kg de poids corporel, de manière répétée à raison de deux administrations par semaine, pendant 90 jours. In a particularly advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient under mechanical circulatory assistance, at a dose of 50 IU / kg of body weight, repeatedly at the rate of two administrations per week. , for 90 days.
L'administration d'une composition de facteur von Willebrand, de manière préventive, permet de réduire considérablement les risques d'apparition ou de réapparition d'une hémorragie et/ou d'un saignement chez ces patients. De préférence, les risques d'hémorragies associées à la mise en place de l'assistance circulatoire mécanique sont réduits de 60%. De préférence, cette administration préventive de facteur von Willebrand permet de réduire de plus de 70%, de préférence 80%, de préférence 90% l'apparition d'hémorragies et/ou de saignements chez ces patients. De manière avantageuse, cette administration de facteur von Willebrand permet d'éliminer définitivement tout risque d'hémorragies et/ou de saignements chez les patients placés sous assistance circulatoire mécanique, y compris les risques de rechute. The administration of a von Willebrand factor composition, as a preventive measure, considerably reduces the risk of the appearance or recurrence of haemorrhage and / or bleeding in these patients. Preferably, the risk of haemorrhage associated with the establishment of mechanical circulatory assistance is reduced by 60%. Preferably, this preventive administration of von Willebrand factor makes it possible to reduce by more than 70%, preferably 80%, preferably 90%, the occurrence of haemorrhages and / or bleeding in these patients. Advantageously, this administration of von Willebrand factor makes it possible definitely to eliminate any risk of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, including the risk of relapse.
Un autre objet de l'invention concerne une méthode de traitement préventive des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique, comprenant l'administration aux dits patients, d'une composition de facteur von Willebrand . Another object of the invention relates to a method of preventive treatment of haemorrhage and / or bleeding of patients under mechanical circulatory assistance, comprising the administration to said patients of a von Willebrand factor composition.
Dans un mode de réalisation particulièrement avantageux, la présente invention concerne l'utilisation d'une composition pharmaceutique comprenant du facteur von Willebrand dans la fabrication d'un médicament destiné à la prévention des hémorragies et/ou des saignements chez les patients sous assistance circulatoire mécanique. In a particularly advantageous embodiment, the present invention relates to the use of a pharmaceutical composition comprising von Willebrand factor in the manufacture of a medicament for the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance. .
Un autre aspect de l'invention concerne une composition pharmaceutique comprenant du facteur von Willebrand destinée à être
utilisée dans le traitement des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique. Another aspect of the invention relates to a pharmaceutical composition comprising von Willebrand factor intended to be used in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
Les inventeurs ont trouvé de manière surprenant que l'administration d'une dose d'au moins 30UI/kg de poids corporel, à raison de deux administrations par semaine d'une composition pharmaceutique comprenant du facteur von Willebrand à des patients sous assistance circulatoire mécanique permettait de traiter efficacement les hémorragies et/ou les saignements associés à la mise en place de l'assistance circulatoire mécanique chez ces patients. The inventors surprisingly found that the administration of a dose of at least 30 IU / kg of body weight, at a rate of two administrations per week of a pharmaceutical composition comprising von Willebrand factor to patients under mechanical circulatory assistance. used to effectively treat haemorrhage and / or bleeding associated with the establishment of mechanical circulatory assistance in these patients.
Aussi, la présente invention concerne une composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée pour le traitement des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique, qui comprend l'administration aux dits patients à une dose d'au moins 30UI/kg de poids corporel de facteur von Willebrand, à raison de deux administrations par semaine. Also, the present invention relates to a pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, which comprises administering to said patients at a dose of minus 30 IU / kg body weight of von Willebrand factor, at a rate of two administrations per week.
Le terme « traitement » ou « traitement curatif » est défini par un traitement aboutissant à une guérison ou un traitement allégeant, améliorant et/ou éliminant, réduisant et/ou stabilisant les symptômes d'une maladie ou la souffrance qu'elle provoque. The term "treatment" or "curative treatment" is defined as a treatment resulting in a cure or treatment that alleviates, improves and / or eliminates, reduces and / or stabilizes the symptoms of an illness or the suffering it causes.
Avantageusement, la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est administrée au patient à une dose d'au moins 30UI/kg de poids corporel, d'au moins 40UI/kg de poids corporel, de préférence 45UI/kg de poids corporel, de préférence 50UI/kg de poids corporel, de préférence 55UI/kg de poids corporel, de préférence 60UI/kg de poids corporel, de préférence 65UI/kg de poids corporel. De manière préférée, la dose est de 50UI/kg de poids corporel. Advantageously, the pharmaceutical composition comprising von Willebrand factor according to the invention is administered to the patient at a dose of at least 30 IU / kg of body weight, of at least 40 IU / kg of body weight, preferably 45 IU / kg of weight. body weight, preferably 50 IU / kg body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU / kg body weight. Preferably, the dose is 50 IU / kg of body weight.
De manière avantageuse, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation d'au moins 10%, préférentiellement d'au moins 15%, avantageusement d'au moins 20% des multimères supérieurs à 15 mers durant 1 heure après l'injection. Avantageusement, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 30 min. De préférence, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 45 min. De manière avantageuse, le régime de dosage fournit une modification de la répartition multimérique du Facteur von Willebrand avec une élévation des multimères supérieurs à 15 mers durant au moins 1 heure après l'injection. De manière avantageuse, le régime de dosage permet de restaurer une fonctionnalité normale du facteur von Willebrand mesurée par un résultat VWF :Act/VWF :Ag>0,7.
De manière avantageuse, la concentration plasmatique moyenne de facteur von Willebrand et la concentration plasmatique maximale moyenne de facteur von Willebrand sont mesurées après l'administration intraveineuse de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention. Advantageously, the dosing regime provides a modification of the multimeric distribution of von Willebrand Factor with an elevation of at least 10%, preferably at least 15%, advantageously at least 20% of the multimers greater than 15 seas. during 1 hour after the injection. Advantageously, the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with an increase of multimers greater than 15 mers for at least 30 min. Preferably, the dosing regimen provides a modification of the von Willebrand Factor multimeric distribution with a multimer rise greater than 15 months for at least 45 min. Advantageously, the dosing regimen provides a modification of the multimeric distribution of von Willebrand Factor with a multimer rise greater than 15 months for at least 1 hour after injection. Advantageously, the dosing regimen makes it possible to restore a normal von Willebrand factor functionality measured by a VWF: Act / VWF: Ag> 0.7 result. Advantageously, the average plasma concentration of von Willebrand factor and the maximum average plasma concentration of von Willebrand factor are measured after the intravenous administration of the pharmaceutical composition comprising von Willebrand factor according to the invention.
De manière avantageuse, l'administration de la composition pharmaceutique comprenant du facteur von Willebrand au patient sous assistance circulatoire mécanique est effectuée de manière répétée à raison de deux administrations par semaine, pendant au moins 15 jours. Advantageously, the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 15 days.
Avantageusement, l'administration de la composition pharmaceutique comprenant du facteur von Willebrand au patient sous assistance circulatoire mécanique est effectuée de manière répétée à raison de deux administrations par semaine, pendant au moins 30 jours, de préférence 45 jours, de préférence 60 jours, de préférence 75 jours, de préférence 90 jours. Advantageously, the administration of the pharmaceutical composition comprising von Willebrand factor to the patient under mechanical circulatory assistance is carried out repeatedly at the rate of two administrations per week, for at least 30 days, preferably 45 days, preferably 60 days, of preferably 75 days, preferably 90 days.
Dans un mode de réalisation particulièrement avantageux, la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est administrée de manière curative au patient sous assistance circulatoire mécanique, à une dose de 30UI/kg de poids corporel, de manière répétée à raison de deux administrations par semaine, pendant 90 jours. In a particularly advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor according to the invention is administered in a curative manner to the patient under mechanical circulatory assistance, at a dose of 30 IU / kg of body weight, repeatedly at the rate of two administrations per week, for 90 days.
Dans un mode de réalisation avantageux, la composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans le traitement des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique est dépourvue de de facteur VIII. De manière avantageuse, le taux résiduel de facteur VIII dans la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention est inférieur ou égal à 10 UI/100 UI VWF: RCo. In an advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of factor VIII. Advantageously, the residual level of factor VIII in the pharmaceutical composition comprising von Willebrand factor according to the invention is less than or equal to 10 IU / 100 IU VWF: RCo.
Dans un mode de réalisation avantageux, la composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans le traitement des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique est dépourvue d'ADAMTS13. De manière avantageuse, le taux résiduel d'ADAMTS13 dans la composition pharmaceutique comprenant du facteur von Willebrand est inférieur ou égal à 0,10 ADAMTS13 :Act [U/mL] . In an advantageous embodiment, the pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance is devoid of ADAMTS13. Advantageously, the residual level of ADAMTS13 in the pharmaceutical composition comprising von Willebrand factor is less than or equal to 0.10 ADAMTS13: Act [U / mL].
Un autre objet de l'invention concerne une méthode de traitement curative des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique, comprenant l'administration aux dits patients, d'une composition de facteur von Willebrand. Another subject of the invention relates to a method for the curative treatment of haemorrhages and / or bleeds of patients under mechanical circulatory assistance, comprising the administration to said patients of a von Willebrand factor composition.
Avantageusement, la méthode de traitement curative des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique,
comprend l'administration aux dits patients, d'une composition de facteur von Willebrand, dépourvue de facteur VIII de la coagulation sanguine. Advantageously, the method of curative treatment of hemorrhages and / or bleeding of patients under mechanical circulatory assistance, comprises the administration to said patients of a von Willebrand factor composition, free of blood coagulation factor VIII.
Avantageusement, la méthode de traitement curative des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique, comprend l'administration audit patient, d'une composition de facteur von Willebrand, à une dose d'au moins 30 Ul/kg de poids corporel, de préférence 40UI/kg de poids corporel, de préférence 45UI/kg de poids corporel, de préférence 50UI/kg de poids corporel, de préférence 55UI/kg de poids corporel, de préférence 60UI/kg de poids corporel, de préférence 65UI/kg de poids corporel. De manière particulièrement avantageuse, la dose est de 50UI/kg de poids corporel. Advantageously, the method for the curative treatment of hemorrhages and / or bleeds of patients under mechanical circulatory assistance, comprises the administration to said patient of a von Willebrand factor composition at a dose of at least 30 IU / kg of weight. body weight, preferably 40 IU / kg body weight, preferably 45 IU / kg body weight, preferably 50 IU / kg body weight, preferably 55 IU / kg body weight, preferably 60 IU / kg body weight, preferably 65 IU. / kg body weight. Particularly advantageously, the dose is 50 IU / kg of body weight.
Avantageusement, la méthode de traitement curative des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique, comprend l'administration aux dits patients, d'une composition de facteur von Willebrand, de manière répétée à raison de deux administrations par semaine. Advantageously, the method of curative treatment of haemorrhage and / or bleeding of patients under mechanical circulatory assistance, comprises the administration to said patients of a von Willebrand factor composition, repeatedly at the rate of two administrations per week.
Avantageusement, la méthode de traitement curative des hémorragies et/ou des saignements des patients sous assistance circulatoire mécanique, comprend l'administration audit patient, d'une composition de facteur von Willebrand, la première administration de la composition pharmaceutique comprenant du facteur von Willebrand étant réalisée dès l'apparition de la première hémorragie ou du premier saignement chez le patient sous assistance circulatoire mécanique du patient. Advantageously, the method for the curative treatment of haemorrhages and / or bleeds of patients under mechanical circulatory assistance comprises the administration to said patient of a von Willebrand factor composition, the first administration of the pharmaceutical composition comprising von Willebrand factor being performed at the onset of the first hemorrhage or first bleeding in the patient under mechanical circulatory support of the patient.
Dans un mode de réalisation particulièrement avantageux, la méthode de traitement curative comprenant l'administration au patient sous assistance circulatoire mécanique, de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention à une dose de 50UI/kg de poids corporel, de manière répétée à raison de deux administrations par semaine, pendant 90 jours. In a particularly advantageous embodiment, the curative treatment method comprising the administration to the patient under mechanical circulatory assistance, of the pharmaceutical composition comprising von Willebrand factor according to the invention at a dose of 50 IU / kg of body weight, so repeated twice a week for 90 days.
Dans un mode de réalisation particulièrement avantageux, la présente invention concerne l'utilisation d'une composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans la fabrication d'un médicament destiné au traitement des hémorragies et/ou des saignements chez les patients sous assistance circulatoire mécanique. In a particularly advantageous embodiment, the present invention relates to the use of a pharmaceutical composition comprising von Willebrand factor for use in the manufacture of a medicament for the treatment of haemorrhage and / or bleeding in patients undergoing treatment. mechanical circulatory assistance.
Un autre aspect, la présente invention concerne un procédé d'obtention de la composition pharmaceutique comprenant du facteur von Willebrand . La composition de facteur von Willebrand peut être obtenue par des procédés bien connus de l'homme du métier, par exemple par
fractionnement de plasma, par expression par culture cellulaire ou par expression dans le lait d'animaux transgéniques. Another aspect, the present invention relates to a process for obtaining the pharmaceutical composition comprising von Willebrand factor. The von Willebrand factor composition can be obtained by methods well known to those skilled in the art, for example by fractionation of plasma by expression by cell culture or by expression in the milk of transgenic animals.
Selon un mode de réalisation particulier, le facteur von Willebrand de l'invention peut être obtenu à partir du plasma sanguin humain, soit d'une fraction de plasma humain cryoprécipité ou du surnageant de plasma cryoprécipité contenant encore du facteur von Willebrand ou obtenu par des méthodes classiques de fractionnement (Cohn et al. , J. Am . Chem. Soc, 68, 459, 1946 et Kistler et al. , Vox Sang., 7, 1962, 414-424), ayant éventuellement subi un traitement de prépurification notamment par adsorption sur hydroxyde d'aluminium, dans laquelle le FvW est complexé au Facteur VIII On parle alors de facteur von Willebrand dit « plasmatique ». According to a particular embodiment, the von Willebrand factor of the invention can be obtained from human blood plasma, either a fraction of cryoprecipitated human plasma or cryoprecipitated plasma supernatant still containing von Willebrand factor or obtained by conventional methods of fractionation (Cohn et al., J. Am Chem Soc., 68, 459, 1946 and Kistler et al., Vox Sang., 7, 1962, 414-424), having optionally undergone a prepurification treatment including by adsorption on aluminum hydroxide, in which vWF is complexed with Factor VIII This is called "plasma" von Willebrand factor.
Dans un mode de réalisation particulier, le facteur von Willebrand est obtenu à partir d'une fraction du plasma cryoprécipité ayant subi une étape préalable de purification par voie chromatographique utilisant un échangeur d'anions de type DEAE-Fractogel®-TSK 650, tel que décrit dans les brevets EP 0 359 593 et EP 0 503 991. In a particular embodiment, the von Willebrand factor is obtained from a fraction of the cryoprecipitated plasma having undergone a preliminary chromatographic purification step using a DEAE-Fractogel®-TSK 650 type anion exchanger, such as described in patents EP 0 359 593 and EP 0 503 991.
Selon un autre mode de réalisation particulier, le facteur von Willebrand peut être obtenu par génie génétique, notamment produit par des cellules dont l'ADN a été modifié par recombinaison génétique de manière à exprimer une molécule de FVII, et présentant les caractéristiques de glycosylation particulières. On parle alors de facteur von Willebrand recombinant. Ainsi, le facteur von Willebrand de l'invention est issu de la transcription puis de la traduction d'une molécule d'ADN codant pour le facteur von Willebrand dans un hôte cellulaire. Le facteur von Willebrand recombinant de l'invention peut être obtenu au moyen de techniques standards, bien connues de l'homme du métier, permettant l'expression d'une protéine dans un système biologique. Plus particulièrement, on entend par «facteur von Willebrand recombinant » tout facteur von Willebrand obtenu par recombinaison génétique et exprimé par une lignée cellulaire mise en culture. A titre d'exemple, on peut citer les lignées suivantes : BHK (Baby. Hamster Kidney) et notamment BHK tk"tsl3 (CRL 10314, Waechter and Baserga, Proc. Natl . Acad . Sci. USA 79 : 1106- 1110, 1982), CHO (ATCC CCL 61), COS-I (ATCC CRL 1650), HEK293 (ATCC CRL 1573; Graham et al, J. Gen. Virol . 36: 59-72, 1977), Rat Hep I (Rat hepatoma; ATCC CRL 1600) , Rat Hep II (Rat hepatoma; ATCC CRL 1548), TCMK (ATCC CCL 139), Human lung (ATCC HB 8065), NCTC 1469 (ATCC CCL 9.1) and DUKX cells (CHO cell line) (Urlaub and Chasin, Proc. Natl . Acad. Sci . USA 77 :4216-4220, 1980), cellules 3T3, cellules Namalwa, ou des cellules BHK adaptées à la culture sans sérum (Document US 6,903,069). Le facteur von Willebrand recombinant peut ainsi être isolé à partir d'une fraction enrichie en FvW et/ou en complexe Facteur VIII/FvW recombinant isolé à partir de surnageant de cultures cellulaires selon des techniques connues.
Dans un autre mode de réalisation particulier de l'invention, le facteur von Willebrand est un facteur von Willebrand transgénique, c'est-à-dire obtenu par recombinaison génétique et exprimé par un tissu vivant, animal ou végétal. According to another particular embodiment, the von Willebrand factor can be obtained by genetic engineering, in particular produced by cells whose DNA has been modified by genetic recombination so as to express a molecule of FVII, and having the particular glycosylation characteristics. . This is called recombinant von Willebrand factor. Thus, the von Willebrand factor of the invention is derived from the transcription and subsequent translation of a DNA molecule encoding von Willebrand factor into a cellular host. The recombinant von Willebrand factor of the invention can be obtained by standard techniques, well known to those skilled in the art, allowing the expression of a protein in a biological system. More particularly, the term "recombinant von Willebrand factor" means any von Willebrand factor obtained by genetic recombination and expressed by a cell line cultured. By way of example, mention may be made of the following lines: BHK (Baby Hamster Kidney) and in particular BHK tk "tsl3 (CRL 10314, Waechter and Baserga, Proc Natl Acad Sci USA 79: 1106-1110, 1982 ), CHO (ATCC CCL 61), COS-I (ATCC CRL 1650), HEK293 (ATCC CRL 1573, Graham et al., J. Gen. Virol 36: 59-72, 1977), Rat Hep I (Rat hepatoma; ATCC CRL 1600), Rat Hep II (Rat hepatoma, ATCC CRL 1548), TCMK (ATCC CCL 139), Human lung (ATCC HB 8065), NCTC 1469 (ATCC CCL 9.1) and DUKX cells (CHO cell line) (Urlaub and Chasin, Proc Natl Acad Sci USA 77: 4216-4220, 1980), 3T3 cells, Namalwa cells, or BHK cells adapted for serum-free culture (US 6,903,069) .The recombinant von Willebrand factor can thus be isolated from a fraction enriched in FvW and / or recombinant Factor VIII / FvW complex isolated from cell culture supernatant according to known techniques. In another particular embodiment of the invention, the von Willebrand factor is a transgenic von Willebrand factor, that is to say obtained by genetic recombination and expressed by a living tissue, animal or plant.
Avantageusement, le facteur von Willebrand transgénique est obtenu par recombinaison génétique et exprimé dans un animal, dit animal transgénique. On entend par animal transgénique, un animal au génome duquel a été introduit par transgénèse un ou plusieurs gènes. De manière préférée, le facteur von Willebrand est produit notamment dans le lait d'animal transgénique, la formulation de l'invention permettant de conserver au facteur von Willebrand une activité biologique satisfaisante après sa lyophilisation. Selon un mode de réalisation préféré, le facteur von Willebrand humain est produit dans le lait de femelles de mammifères transgéniques non humains, modifiés génétiquement pour produire cette protéine. A titre d'exemple de mammifères transgéniques non humains modifiés génétiquement et capable de produire cette protéine, on peut notamment citer le lapin, la chèvre, la vache, le rongeur, le hamster, le chameau, le lama, le dromadaire, la souris, le rat, le porc, la truie, le cheval, le chien, le chat, la brebis, les ruminants, le cochon..., la liste n'étant pas limitative. De préférence il s'agit du lait d'une lapine ou d'une chèvre transgénique. La sécrétion de facteur von Willebrand par les glandes mammaires, permettant sa sécrétion dans le lait du mammifère transgénique, implique le contrôle de l'expression du facteur von Willebrand de manière tissu-dépendante. De telles méthodes de contrôle sont bien connues de l'homme du métier. Le contrôle de l'expression est effectué grâce à des séquences permettant l'expression de la protéine vers un tissu particulier de l'animal. Il s'agit notamment des séquences promotrices WAP, béta-caséine, béta-lactoglobuline et des séquences peptides signal. Le procédé d'extraction de protéines d'intérêt à partir du lait d'animaux transgénique est décrit dans le brevet EP 0 264 166. Le facteur von Willebrand transgénique peut également être isolé à partir d'une fraction enrichie en FvW et/ou en complexe Facteur VIII/FvW obtenue à partir de lait de mammifères transgéniques comme décrit dans le brevet US 6 518 482.Advantageously, the transgenic von Willebrand factor is obtained by genetic recombination and expressed in an animal, referred to as a transgenic animal. The term "transgenic animal" is understood to mean an animal whose genome has been transgenically introduced into one or more genes. Preferably, the von Willebrand factor is produced in particular in the transgenic animal milk, the formulation of the invention for retaining the von Willebrand factor satisfactory biological activity after lyophilization. According to a preferred embodiment, human von Willebrand factor is produced in the milk of non-human transgenic mammalian animals genetically modified to produce this protein. By way of example of genetically modified non-human transgenic mammals capable of producing this protein, mention may be made especially of the rabbit, the goat, the cow, the rodent, the hamster, the camel, the llama, the dromedary, the mouse, the rat, the pig, the sow, the horse, the dog, the cat, the sheep, the ruminants, the pig ..., the list not being limiting. Preferably it is the milk of a rabbit or a transgenic goat. The secretion of von Willebrand factor by the mammary glands, allowing its secretion into the milk of the transgenic mammal, involves the control of von Willebrand factor expression in a tissue-dependent manner. Such control methods are well known to those skilled in the art. The control of the expression is carried out by means of sequences allowing the expression of the protein towards a particular tissue of the animal. These include the promoter sequences WAP, beta-casein, beta-lactoglobulin and signal peptide sequences. The method of extracting proteins of interest from the milk of transgenic animals is described in EP 0 264 166. The transgenic von Willebrand factor can also be isolated from a fraction enriched in VWF and / or Factor VIII / FvW complex obtained from transgenic mammalian milk as described in US Pat. No. 6,518,482.
Quelle que soit la méthode d'obtention du facteur von Willebrand, à partir du plasma ou par génie génétique (recombinant ou transgénique), la fraction de facteur von Willebrand peut être diafiltrée afin d'incorporer des excipients adéquats destinés à autoriser un chauffage à sec du facteur von Willebrand sans risque de dénaturation, concentrée par ultrafiltration, conditionnée en flacons et lyophilisée, après un ajout préalable d'un stabilisant supplémentaire pharmaceutiquement acceptable, tel que l'albumine. Regardless of the method for obtaining von Willebrand factor, from plasma or by genetic engineering (recombinant or transgenic), the von Willebrand factor fraction may be diafiltered to incorporate suitable excipients to allow dry heating. von Willebrand factor without risk of denaturation, concentrated by ultrafiltration, packaged in flasks and lyophilized, after a prior addition of a pharmaceutically acceptable additional stabilizer, such as albumin.
Enfin, les lyophilisais subissent une ultime étape d'inactivation virale par chauffage à sec du lyophilisât selon des conditions classiques, à 80°C pendant 72 heures, pour l'inactivation des virus non enveloppées qui
n'auraient pas été inactivés et/ou éliminés par au moins l'une des deux étapes d'inactivation et/ou d'élimination virales précédentes. Les lyophilisats chauffés à sec sont ensuite reconstitués dans un milieu aqueux compatible à un usage clinique, de préférence dans 10 ml d'eau purifiée pour injection (PPI) pour obtenir une formulation injectable. Finally, the lyophilisates undergo a final viral inactivation step by dry heating the lyophilizate according to conventional conditions, at 80 ° C. for 72 hours, for the inactivation of non-enveloped viruses which have not been inactivated and / or eliminated by at least one of the two preceding inactivation and / or viral elimination steps. The dry-heated lyophilizates are then reconstituted in an aqueous medium compatible for clinical use, preferably in 10 ml of purified water for injection (PPI) to obtain an injectable formulation.
La formulation injectable peut être administrée par voie parentérale, de préférence par voie intraveineuse, sous-cutanée ou intramusculaire. L'administration de la forme liquide (solution ou suspension, avant dessiccation) ou de la forme poudre, par toute voie et tout moyen appropriés, n'est pas exclue. Dans un mode particulier de l'invention, la formulation injectable est administrée par voie intraveineuse. The injectable formulation may be administered parenterally, preferably intravenously, subcutaneously or intramuscularly. The administration of the liquid form (solution or suspension before drying) or of the powder form by any suitable route and means is not excluded. In a particular embodiment of the invention, the injectable formulation is administered intravenously.
Exemples Examples
Exemple 1 : Préparation d'une composition de facteur von Willebrand Example 1 Preparation of a von Willebrand Factor Composition
1) Obtention d'une fraction contenant du FvW 1) Obtaining a fraction containing VWF
On utilise un cryoprécipité de plasma humain, remis en suspension dans une solution aqueuse d'héparine sodique (à 2 U/ml), à pH de 7-7,1. A cryoprecipitate of human plasma resuspended in an aqueous solution of sodium heparin (at 2 U / ml) at a pH of 7-7.1 was used.
Cette suspension de cryoprécipité est soumise à une prépurification sur hydroxyde d'aluminium pour l'élimination des principaux contaminants, telle que décrite dans le brevet EP 0 359 593. Le surnageant prépurifié est ensuite récupéré et est soumis à un traitement d'inactivation virale classique par solvant-détergent, en présence de Tween®-TNBP. This suspension of cryoprecipitate is subjected to a prepurification on aluminum hydroxide for the removal of the main contaminants, as described in patent EP 0 359 593. The prepurified supernatant is then recovered and is subjected to a conventional viral inactivation treatment. by solvent-detergent, in the presence of Tween®-TNBP.
La solution de cryoprécipité prépurifié est ensuite injectée sur une colonne chromatographique de type Fractogel® TSK-DEAE 650 (M) de 25 cm de longueur et de 1 cm de diamètre, préalablement équilibrée en tampon constitué de citrate trisodique 0,01 M, de chlorure de calcium 0,001 M, de chlorure de sodium 0,11 M, de glycine 0,12 M et de lysine 0,016 M, ajusté à pH 7,01, dont la vitesse linéaire de la phase mobile est fixée à 100 cm/heure. Le Facteur von Willebrand, le Facteur VIII et la fibronectine sont retenus par le support chromatographique. Les protéines faiblement ou pas retenues par le support, principalement le fibrinogène et des immunoglobulines G (IgG), sont éliminées dans le filtrat, ainsi que les Tween® et TNBP, par plusieurs lavages successifs avec le même tampon. The prepurified cryoprecipitate solution is then injected onto a chromatographic column of the Fractogel® TSK-DEAE 650 (M) type 25 cm long and 1 cm in diameter, previously equilibrated in a buffer consisting of 0.01 M trisodium citrate, chloride of 0.001M calcium, 0.11M sodium chloride, 0.12M glycine and 0.016M lysine, adjusted to pH 7.01, the linear velocity of the mobile phase is fixed at 100 cm / hour. The von Willebrand Factor, Factor VIII and fibronectin are retained by the chromatographic medium. Proteins weakly or not retained by the support, mainly fibrinogen and immunoglobulin G (IgG), are removed in the filtrate, as well as Tween® and TNBP, by several successive washings with the same buffer.
La teneur en protéines est suivie par la mesure de l'absorption à 280nm (notée ci-après D.O). The protein content is monitored by measuring the absorption at 280 nm (denoted hereinafter D.O.).
Lorsque la D.O, mesurée à 280 nm, est retombée à la ligne de base, on augmente la concentration en chlorure de sodium du tampon à 0,15 M. Dans ces conditions, le Facteur von Willebrand est élué. L'éluat ainsi obtenu est
très enrichi en Facteur von Willebrand et en fibronectine et contient encore du Tween® et du TN BP, ainsi que du Facteur VIII résiduel . When the OD, measured at 280 nm, has fallen back to the baseline, the sodium chloride concentration of the buffer is increased to 0.15 M. Under these conditions, the von Willebrand factor is eluted. The eluate thus obtained is highly enriched in von Willebrand Factor and fibronectin and still contains Tween® and TN BP, as well as residual Factor VIII.
2) Séparation chromatoqraphique 2) Chromatoqraphic separation
La fraction enrichie en Facteur von Willebrand éluée précédemment, constituant un lot de fraction de départ contenant le Facteur von Willebrand selon l'invention, est chargée sur une colonne chromatographique de type DEAE-Fractogel®-TSK 650 (M) de 25 cm de longueur et de 1 cm de diamètre, préalablement équilibrée en tampon identique à celui de 1), d'osmolarité de 387 mosmolkg- 1, dont la vitesse linéaire est fixée à 100 cm/heure. On injecte 140 ml de cette fraction contenant 12,9 UI FvW/ml et 6,6 UI Facteur VIII/ml, soit un rapport R de 51 ,1% (R= FVIII : C/FvW : RCo) . The fraction enriched in von Willebrand factor eluted previously, constituting a batch of starting fraction containing the von Willebrand factor according to the invention, is loaded onto a DEAE-Fractogel®-TSK 650 (M) type chromatographic column 25 cm in length. and 1 cm in diameter, previously equilibrated in buffer identical to that of 1), osmolarity of 387 mosmolkg-1, whose linear speed is fixed at 100 cm / hour. 140 ml of this fraction containing 12.9 IU FvW / ml and 6.6 IU Factor VIII / ml, an R ratio of 51.1% (R = FVIII: C / FvW: RCo), are injected.
La colonne est ensuite lavée par un tampon acide d'acétate de sodium 20 mM, ajusté à pH 4,35 et 80 mosmolkg- 1, avec une vitesse linéaire de 150 cm/heure. Dans ces conditions, on assure une très bonne élimination non seulement des résidus d'agents d'inactivation virale, mais également de la fibronectine et surtout du Facteur VIII qui était encore complexé au Facteur von Willebrand, sans observer de précipitation de ces protéines dans la colonne. Lorsque la D.O est retombée à la ligne de base, on ramène la vitesse linéaire à 100 cm/heure puis on rince la colonne et on l'équilibre avec le même tampon que précédemment, contenant du NaCI à 0, 11 M . The column is then washed with an acid buffer of 20 mM sodium acetate, adjusted to pH 4.35 and 80 mosmolkg-1, with a linear velocity of 150 cm / h. Under these conditions, very good elimination not only of the residues of viral inactivation agents, but also of fibronectin and especially Factor VIII which was still complexed von Willebrand factor, without observing precipitation of these proteins in the column. When the OD has fallen back to the baseline, the linear rate is brought back to 100 cm / hr and then the column is rinsed and equilibrated with the same buffer as previously, containing 0.11 M NaCl.
L'élution de la fraction contenant le Facteur von Willebrand s'effectue par augmentation de la concentration en NaCI du tampon d'équilibrage à 0, 17 M, ajusté à un pH de 6,95 et 492 mosmolkg- 1. Elution of the fraction containing the von Willebrand factor is effected by increasing the concentration of NaCl in the equilibration buffer at 0.17 M, adjusted to a pH of 6.95 and 492 mosmolkg-1.
La fraction éluée de Facteur von Willebrand subit ensuite les traitements classiques de filtration stérilisante sur filtres de 0,22 pm, de nanofiltration sur des filtres de 35 nm, de diafiltration et d'ultrafiltration selon des techniques connues de façon à ce que le concentré de Facteur von Willebrand présente une activité spécifique (A. S. ) d'au moins 90 UI RCo/mg de protéine. The fraction eluted von Willebrand factor then undergoes the conventional treatments of sterilizing filtration on 0.22 μm filters, nanofiltration on 35 nm filters, diafiltration and ultrafiltration according to known techniques so that the concentrate of Von Willebrand factor has a specific activity (AS) of at least 90 IU RCo / mg protein.
Les concentrés de Facteur von Willebrand ainsi obtenus sont additionnés d'albumine à 10 g/1 puis lyophilisés à -40°C pendant 48 heures. La lyophilisation est suivie d'un traitement thermique d'inactivation virale par chauffage à sec du lyophilisât à 80°C pendant 72 heures. The von Willebrand factor concentrates thus obtained are added with albumin at 10 g / l and then lyophilized at -40 ° C. for 48 hours. Lyophilization is followed by viral inactivation heat treatment by dry heating the lyophilizate at 80 ° C for 72 hours.
Exemple 2 : Effet de l'administration d'une composition de facteur von Willebrand sur la prévention des hémorragies et/ou saignements chez les patients placés sous assistance circulatoire mécanique Example 2 Effect of the Administration of a von Willebrand Factor Composition on the Prevention of Hemorrhage and / or Bleeding in Patients Under Mechanical Circulatory Support
La présente étude a porté sur 136 patients âgés de plus de 18 ans et nécessitant la mise en place d'une assistance circulatoire mécanique due à une insuffisance cardiaque avancée.
Dans ce qui suit par l'abbréviation J, on entend le terme « jour ». L'abbréviation J = 0, correspond au jour de l'intervention, dit jour 0. A titre d'exemple, l'abbréviation J+4, correspond au 4ème jour après l'intervention.The present study involved 136 patients over the age of 18 requiring mechanical circulatory assistance due to advanced heart failure. In what follows by the abbreviation J, we hear the term "day". The abbreviation J = 0, corresponds to the day of the intervention, called day 0. For example, the abbreviation J + 4, corresponds to the 4 th day after the intervention.
A J = 0, les patients ont subi l'implantation du dispositif d'assistance circulatoire mécanique, via l'implantation d'une pompe à débit continu HeartMate II. Entre J+4 et J+7, les patients ont reçu une première administration de la composition pharmaceutique comprenant du facteur von Willebrand selon l'invention à une dose de 50UI/kg de poids corporel. L'administration de cette composition pharmaceutique comprenant du facteur von Willebrand a été poursuivie à raison de deux administrations par semaine et à une dose de 50UI/kg de poids corporel et ce, pendant 90 jours.At J = 0, the patients underwent implantation of the mechanical circulatory assistance device, via the implantation of a HeartMate II continuous flow pump. Between D + 4 and D + 7, the patients received a first administration of the pharmaceutical composition comprising von Willebrand factor according to the invention at a dose of 50 IU / kg of body weight. The administration of this pharmaceutical composition comprising von Willebrand factor was continued at a rate of two administrations per week and at a dose of 50 IU / kg of body weight for 90 days.
L'apparition des hémorragies et/ou des saignements a été contrôlée pour chacun des patients pendant 90 jours. De plus, l'évolution des marqueurs angiogéniques (VEGF, angiopoiétine 2, galectine 1 et 3) ainsi que l'évolution des caractéristiques pharmacologiques du facteur von Willebrand (évolution des rapports vWF :Act, vWF :Ag, vWF :CBA et le taux de multimères de hauts poids moléculaires (HMW) ont été contrôlés à J + 15, J+30, J+45, J+60, J+75 et J+90. The onset of haemorrhage and / or bleeding was monitored for each patient for 90 days. In addition, the evolution of angiogenic markers (VEGF, angiopoietin 2, galectin 1 and 3) as well as the evolution of the pharmacological characteristics of von Willebrand factor (evolution of the vWF: Act, vWF: Ag, vWF: CBA ratios and the rate of High molecular weight multimers (HMW) were monitored at D + 15, D + 30, D + 45, D + 60, D + 75 and D + 90.
Les résultats montrent que l'administration à 50UI/kg de la composition de facteur von Willebrand selon l'invention à raison de deux administrations par semaine, et ce pendant 90 jours, permet de prévenir l'apparition des hémorragies et/ou des saignements chez ces patients.
The results show that the administration at 50 IU / kg of the von Willebrand factor composition according to the invention at the rate of two administrations per week, and this for 90 days, makes it possible to prevent the appearance of haemorrhages and / or bleeding in these patients.
Claims
Revendications claims
Composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans la prévention des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique. A pharmaceutical composition comprising von Willebrand factor for use in the prevention of haemorrhage and / or bleeding in patients under mechanical circulatory assistance.
Composition pharmaceutique comprenant du facteur von Willebrand selon la revendication 1, dans laquelle la composition pharmaceutique est dépourvue de facteur VIII. A pharmaceutical composition comprising von Willebrand factor according to claim 1, wherein the pharmaceutical composition is devoid of factor VIII.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 2, dans laquelle la composition pharmaceutique est dépourvue d'ADAMTS 13. A pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 2, wherein the pharmaceutical composition is devoid of ADAMTS 13.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 3, dans laquelle le taux résiduel de facteur VIII est inférieur ou égal à 10 UI/100 UI VWF: RCo. Pharmaceutical composition comprising von Willebrand factor according to one of Claims 1 to 3, in which the residual level of factor VIII is less than or equal to 10 IU / 100 IU VWF: RCo.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 4, dans laquelle les multimères de haut poids moléculaires représentent au moins 65 %, de préférence 70%, de préférence 75%, de préférence 80% de la teneur totale en multimères du facteur von Willebrand contenus dans la composition pharmaceutique. A pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 4, wherein the high molecular weight multimers represent at least 65%, preferably 70%, preferably 75%, preferably 80% of the total von Willebrand factor multimers contained in the pharmaceutical composition.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 5, dans laquelle la teneur en multimères de haut poids moléculaires est proche de celle du plasma. A pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 5, wherein the content of multimers of high molecular weight is close to that of the plasma.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 6, dans laquelle la teneur en multimères de haut poids moléculaires est suffisamment conservée pour permettre une activité suffisante in vivo. A pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 6, wherein the content of high molecular weight multimers is sufficiently conserved to allow sufficient activity in vivo.
Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 7, caractérisé en ce que la composition de facteur von Willebrand est administrée au patient à une dose d'au moins 30UI/kg de poids corporel, de préférence 40UI/kg de poids corporel, de préférence 50UI/kg de poids corporel, de préférence 60UI/kg de poids corporel. Pharmaceutical composition comprising von Willebrand factor according to one of Claims 1 to 7, characterized in that the von Willebrand factor composition is administered to the patient at a dose of at least 30 IU / kg body weight, preferably 40 IU / kg. body weight, preferably 50 IU / kg body weight, preferably 60 IU / kg body weight.
9. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 8, caractérisé en ce que la composition pharmaceutique comprenant du facteur von Willebrand
est administrée de manière répétée à raison de deux administrations par semaine. 9. Pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 8, characterized in that the pharmaceutical composition comprising von Willebrand factor is administered repeatedly for two administrations per week.
10. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 9, caractérisé en ce que la première administration de la composition pharmaceutique comprenant du facteur von Willebrand est réalisée quatre à sept jours après la mise en place de l'assistance circulatoire mécanique du patient. 10. Pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 9, characterized in that the first administration of the pharmaceutical composition comprising von Willebrand factor is carried out four to seven days after the establishment of the assistance. mechanical circulatory system of the patient.
11. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 1 à 10, dans laquelle la composition est administrée par voie intraveineuse. 11. A pharmaceutical composition comprising von Willebrand factor according to one of claims 1 to 10, wherein the composition is administered intravenously.
12. Composition pharmaceutique comprenant du facteur von Willebrand destinée à être utilisée dans le traitement des hémorragies et/ou des saignements chez des patients sous assistance circulatoire mécanique, caractérisée en ce que la composition de facteur von Willebrand est administrée au patient à une dose d'au moins 30UI/kg de poids corporel, à raison de deux administrations par semaine. A pharmaceutical composition comprising von Willebrand factor for use in the treatment of haemorrhage and / or bleeding in patients under mechanical circulatory assistance, characterized in that the von Willebrand factor composition is administered to the patient at a dose of at least 30 IU / kg body weight, at two administrations per week.
13. Composition pharmaceutique comprenant du facteur von Willebrand selon la revendication 12, caractérisée en ce que la composition de facteur von Willebrand est administrée au patient à une dose d'au moins 40UI/kg de poids corporel, de préférence 50UI/kg de poids corporel, de préférence 60UI/kg de poids corporel. Pharmaceutical composition comprising von Willebrand factor according to claim 12, characterized in that the von Willebrand factor composition is administered to the patient at a dose of at least 40 IU / kg of body weight, preferably 50 IU / kg of body weight. preferably 60 IU / kg body weight.
14. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 12 à 13, dans laquelle la composition pharmaceutique est dépourvue de facteur VIII. A pharmaceutical composition comprising von Willebrand factor according to one of claims 12 to 13, wherein the pharmaceutical composition is devoid of factor VIII.
15. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 12 à 14, dans laquelle la composition pharmaceutique est dépourvue d'ADAMTS 13. 16. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 12 à 15, dans laquelle le taux résiduel de facteur VIII est inférieur ou égal à 10 UI/100 UI VWF: RCo. A pharmaceutical composition comprising von Willebrand factor according to one of claims 12 to 14, wherein the pharmaceutical composition is devoid of ADAMTS 13. A pharmaceutical composition comprising von Willebrand factor according to one of claims 12 to 15, in which the residual level of factor VIII is less than or equal to 10 IU / 100 IU VWF: RCo.
17. Composition pharmaceutique comprenant du facteur von Willebrand selon l'une des revendications 12 à 16, dans laquelle la composition est administrée par voie intraveineuse.
17. A pharmaceutical composition comprising von Willebrand factor according to one of claims 12 to 16, wherein the composition is administered intravenously.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1552982A FR3034669B1 (en) | 2015-04-07 | 2015-04-07 | NEW USE OF THE VON WILLEBRAND FACTOR |
| PCT/EP2016/057494 WO2016162369A1 (en) | 2015-04-07 | 2016-04-06 | Novel use of von willebrand factor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3280436A1 true EP3280436A1 (en) | 2018-02-14 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP16719018.0A Withdrawn EP3280436A1 (en) | 2015-04-07 | 2016-04-06 | Novel use of von willebrand factor |
Country Status (11)
| Country | Link |
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| US (2) | US10478475B2 (en) |
| EP (1) | EP3280436A1 (en) |
| JP (2) | JP6636041B2 (en) |
| KR (1) | KR20180016983A (en) |
| CN (1) | CN107743395A (en) |
| AR (1) | AR104194A1 (en) |
| AU (1) | AU2016245156A1 (en) |
| CA (1) | CA2980232A1 (en) |
| FR (2) | FR3034669B1 (en) |
| TW (1) | TW201642900A (en) |
| WO (1) | WO2016162369A1 (en) |
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| AU2018298232A1 (en) * | 2017-07-07 | 2020-01-30 | Takeda Pharmaceutical Company Limited | Treatment of patients with severe von willebrand disease undergoing elective surgery by administration of recombinant VWF |
| EP3488858A1 (en) * | 2017-11-27 | 2019-05-29 | Laboratoire Français du Fractionnement et des Biotechnologies | A von willebrand factor composition for use in treating a pathology mediated by angiogenesis |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE122007000007I2 (en) | 1986-04-09 | 2010-12-30 | Genzyme Corp | Genetically transformed animals secreting a desired protein in milk |
| FR2632309B1 (en) | 1988-06-07 | 1990-08-24 | Lille Transfusion Sanguine | PROCESS FOR THE CHROMATOGRAPHIC PURIFICATION OF PROTEINS, PARTICULARLY FACTOR VIII, AND THE PRODUCTS OBTAINED |
| FR2673632A1 (en) | 1991-03-08 | 1992-09-11 | Lille Transfusion Sanguine | PROCESS FOR THE PREPARATION OF HUMAN VON WILLEBRAND FACTOR CONCENTRATE OF HIGH PURITY, SUITABLE FOR THERAPEUTIC USE |
| US6518482B2 (en) | 1994-09-13 | 2003-02-11 | American National Red Cross | Transgenic non-human mammals expressing human coagulation factor VIII and von Willebrand factor |
| US6903069B2 (en) | 2000-10-02 | 2005-06-07 | Novo Nordisk Health Care A/S | Factor VII glycoforms |
| EP3858375B1 (en) * | 2011-06-10 | 2024-03-20 | Takeda Pharmaceutical Company Limited | Treatment of coagulation disease by administration of recombinant vwf |
| US20150086524A1 (en) * | 2012-04-16 | 2015-03-26 | Cantab Biopharmaceuticals Patents Limited | Optimised subcutaneous therapeutic agents |
| EP2662083A1 (en) * | 2012-05-08 | 2013-11-13 | CSL Behring GmbH | Sugar compositions for treating hemophilia a and/or von willebrand disease |
-
2015
- 2015-04-07 FR FR1552982A patent/FR3034669B1/en not_active Expired - Fee Related
- 2015-08-25 FR FR1557912A patent/FR3034670B1/en not_active Expired - Fee Related
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2016
- 2016-04-06 US US15/564,783 patent/US10478475B2/en not_active Expired - Fee Related
- 2016-04-06 EP EP16719018.0A patent/EP3280436A1/en not_active Withdrawn
- 2016-04-06 CN CN201680020708.0A patent/CN107743395A/en active Pending
- 2016-04-06 AU AU2016245156A patent/AU2016245156A1/en not_active Abandoned
- 2016-04-06 WO PCT/EP2016/057494 patent/WO2016162369A1/en active Application Filing
- 2016-04-06 CA CA2980232A patent/CA2980232A1/en not_active Abandoned
- 2016-04-06 KR KR1020177032275A patent/KR20180016983A/en unknown
- 2016-04-06 JP JP2017553017A patent/JP6636041B2/en not_active Expired - Fee Related
- 2016-04-06 AR ARP160100927A patent/AR104194A1/en unknown
- 2016-04-07 TW TW105110886A patent/TW201642900A/en unknown
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2019
- 2019-10-10 US US16/598,373 patent/US20200038489A1/en not_active Abandoned
- 2019-11-06 JP JP2019201247A patent/JP2020097571A/en active Pending
Also Published As
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| FR3034669A1 (en) | 2016-10-14 |
| KR20180016983A (en) | 2018-02-20 |
| WO2016162369A1 (en) | 2016-10-13 |
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| JP6636041B2 (en) | 2020-01-29 |
| AU2016245156A1 (en) | 2017-10-12 |
| FR3034670A1 (en) | 2016-10-14 |
| FR3034670B1 (en) | 2020-02-14 |
| CA2980232A1 (en) | 2016-10-13 |
| JP2020097571A (en) | 2020-06-25 |
| AR104194A1 (en) | 2017-07-05 |
| US10478475B2 (en) | 2019-11-19 |
| TW201642900A (en) | 2016-12-16 |
| CN107743395A (en) | 2018-02-27 |
| US20200038489A1 (en) | 2020-02-06 |
| FR3034669B1 (en) | 2020-02-14 |
| JP2018513858A (en) | 2018-05-31 |
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| 18D | Application deemed to be withdrawn |
Effective date: 20200911 |