WO2014142780A1 - Procédés de traitement, diminution de l'incidence, et/ou prévention d'événements ischémiques - Google Patents

Procédés de traitement, diminution de l'incidence, et/ou prévention d'événements ischémiques Download PDF

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Publication number
WO2014142780A1
WO2014142780A1 PCT/US2013/030081 US2013030081W WO2014142780A1 WO 2014142780 A1 WO2014142780 A1 WO 2014142780A1 US 2013030081 W US2013030081 W US 2013030081W WO 2014142780 A1 WO2014142780 A1 WO 2014142780A1
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Prior art keywords
pci
cangrelor
pharmaceutical composition
patients
incidence
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PCT/US2013/030081
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English (en)
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Clive Arthur ARCULUS-MEANWELL
Simona Skerjanec
Jayne Prats
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The Medicines Company
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Priority to PCT/US2013/030081 priority Critical patent/WO2014142780A1/fr
Publication of WO2014142780A1 publication Critical patent/WO2014142780A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to methods of treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing percutaneous coronary intervention (PCI), comprising administering to the patient a pharmaceutical composition comprising cangrelor.
  • the methods may further comprise administering an additional therapeutic agent to the patient, the additional therapeutic agent comprising a P2Yi 2 inhibitor.
  • the present invention also relates to pharmaceutical compositions useful for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI.
  • the pharmaceutical compositions comprise cangrelor.
  • the present invention further relates to methods of preparing a pharmaceutical composition for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising admixing cangrelor with one or more pharmaceutically acceptable excipients.
  • An ischemic event may include stent thrombosis, myocardial infarction, ischemia-driven revascularization (IDR), and mortality.
  • PCI is a procedure that opens narrowed arteries that supply heart muscle with blood.
  • PCI with stent implantation is widely used to reduce the risk of mortality or myocardial infarction in patients with acute coronary syndromes and to reduce the burden of angina and improve the quality of life in patients with stable angina. 1
  • thrombotic complications during PCI are a major concern, particularly if the procedure involves implantation of a stent,
  • the present invention demonstrates how cangrelor may be utilized in treating, reducing the incidence of, and/or preventing an ischemic event.
  • An ischemic event may include stent thrombosis, myocardial infarction, IDR, and mortality.
  • An ischemic event can occur before, during, or after PCI.
  • An aspect of the present invention is directed to a method of treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI.
  • the method comprises administering to the patient a pharmaceutical composition comprising cangrelor.
  • the pharmaceutical composition may be administered before, during, and/or after PCI, and through various routes of administration.
  • the pharmaceutical composition may be administered intravenously, including as a bolus and/or infusion.
  • the pharmaceutical composition may be administered to a patient undergoing PCI involving stent implantation.
  • the method of the present invention may treat, reduce the incidence of, and/or prevent an ischemic event during or after PCI. In some instances, the method is not accompanied by a significant increase in severe bleeding or the need for transfusions.
  • the method may further comprise
  • the additional therapeutic agent may be administered separately from the pharmaceutical composition comprising cangrelor, either sequentially or concurrently. Alternatively, the additional therapeutic agent may be administered in the same pharmaceutical composition as cangrelor.
  • the additional therapeutic agent comprises a P2Yi 2 inhibitor, such as clopidogrel, prasugrel, or ticagrelor. In alternative embodiments, the additional therapeutic agent comprises bivalirudin.
  • Another aspect of the present invention is directed to a pharmaceutical composition useful for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI.
  • the pharmaceutical composition comprises cangrelor and may further
  • the pharmaceutical composition may be a solid, liquid, or suspension.
  • the pharmaceutical composition of the present invention may be useful for treating, reducing the incidence of, and/or preventing an ischemic event that occurs during or after PCI. In some instances, the pharmaceutical composition does not lead to a significant increase in severe bleeding or the need for transfusions when administered to a patient undergoing PCI.
  • a further aspect of the present invention is directed to a method of preparing a pharmaceutical composition for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising admixing cangrelor with a
  • the pharmaceutically acceptable excipient may comprise NaCl, dextrose, mannitol, or a combination thereof.
  • FIG. 1 Figure 1 - diagram showing trial design for the study described in Example 1.
  • FIG. 1 Figure 2 - diagram showing the primary modified intent-to-treat analysis population in the study described in Example 1.
  • Figures 3 A, 3B and 3C landmark analysis of Kaplan-Meier curves for the primary efficacy endpoint (Figure 3A), stent thrombosis (Figure 3B), and mortality at 48 hours and 30 days (Figure 3C) in the study described in Example 1.
  • FIG. 4 diagram showing transfusion rates for all patients (including coronary artery bypass graft) in subgroups at high risk of bleeding in the study described in Example 1.
  • Figures 6 A and 6B - display the primary endpoint odds ratio (OR) data for key subgroups in the study described in Example 2.
  • FIG. 8 diagram showing the modified intention-to-treat population in the study described in Example 3.
  • Figure 9 A and 9B landmark analysis of Kaplan Meier curves for the primary endpoint (Figure 9A) and the key secondary end point of stent thrombosis (Figure 9B) in the study described in Example 3.
  • Figure 10 diagram showing the subgroup analysis of the primary efficacy end point in the study described in Example 3.
  • FIG. 11 diagram showing the subgroup analysis of Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe or moderate bleeding in the study described in Example 3.
  • GUSTO Global Use of Strategies to Open Occluded Coronary Arteries
  • the present invention is based on the discovery that cangrelor, a reversible, fast acting, adenosine triphosphate analogue inhibitor of the P2Yi 2 ADP receptor, is effective in treating, reducing the incidence of, and/or preventing an ischemic event.
  • the present invention is directed to a method of treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising administering to the patient a pharmaceutical composition comprising cangrelor.
  • the present invention is also directed to a pharmaceutical composition useful for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, wherein the pharmaceutical composition comprises cangrelor and may further comprise one or more pharmaceutically acceptable excipients. Further, the present invention is directed to a method of preparing a pharmaceutical composition for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising admixing cangrelor with one or more pharmaceutically acceptable excipients.
  • Cangrelor is a non-thienopyridine adenosine triphosphate analogue which reversibly binds to and inhibits the P2Yi 2 ADP receptor.
  • Cangrelor is direct-acting, reversible, and selective, and it has a short half-life. It is metabolized through dephosphorylation pathways and has a plasma half-life of 3-5 minutes; platelet function returns to normal within 30-60 minutes of drug termination. 13 When given as a bolus plus infusion, it quickly and consistently inhibits platelets to a high degree with normalization of platelet function shortly after discontinuation.
  • a phase 2 trial in patients undergoing PCI demonstrated dose-dependent platelet inhibition similar to that achieved with abciximab, less bleeding time prolongation, and more rapid return to platelet function. 14
  • the chemical structure of cangrelor is shown in Formula I.
  • the term “cangrelor” encompasses the compound of Formula I, as well as tautomeric, enantiomeric and diastereomeric forms thereof, and racemic mixtures thereof, and pharmaceutically acceptable salts of these
  • the present invention demonstrates how cangrelor may be utilized in treating, reducing the incidence of, and/or preventing an ischemic event.
  • An ischemic event may include stent thrombosis, myocardial infarction, IDR, and mortality.
  • An ischemic event can occur before, during, or after PCI.
  • the present invention relates to treating, reducing the incidence of, and/or preventing stent thrombosis in a patient undergoing PCI.
  • Stent thrombosis may result from any means related to the implantation, presence, or maintenance of the stent in the vasculature of the patient.
  • stent thrombosis may be induced by implantation of a stent into the patient or may develop over time due to the presence of a stent, such as a bare- metal stent, a drug-eluting stent, or other type of stent.
  • stent thrombosis is defined in accordance with or derived from the Academic Research Consortium definition of stent thrombosis.
  • stent thrombosis may be intraprocedural stent thrombosis, acute stent thrombosis ( ⁇ 24 hours post implantation), sub-acute stent thrombosis (>24 hours and ⁇ 30 days post implantation), late stent thrombosis (>30 days and ⁇ 12 months post implantation) or very late stent thrombosis (>12 months post implantation).
  • the present invention relates to treating, reducing the incidence of, and/or preventing myocardial infarction in a patient undergoing PCI.
  • Myocardial infarction may be any form of myocardial infarction, including acute myocardial infarction (first few hours to 7 days), healing myocardial infarction (7 to 28 days), healed myocardial infarction (29 days and beyond), acute non-ST-elevated myocardial infarction (NSTEMI), and acute ST-elevated myocardial infarction (STEMI).
  • myocardial infarction is defined in accordance with or derived from the universal definition of myocardial infarction. 16
  • Myocardial infarction may arise during PCI, or may be induced by any mechanism, including implantation of a stent into the patient. Myocardial infarction may also be caused by stent thrombosis or occlusion of a coronary artery.
  • IDR Ischemia-Driven Revascularization
  • the present invention relates to treating, reducing the incidence of, and/or preventing IDR in a patient undergoing PCI.
  • IDR refers to any type of intervention following PCI in which blood flow through a vessel must be increased or re-established.
  • IDR examples include, but are not limited to, an additional PCI or surgery.
  • the present invention relates to reducing the incidence of and/or preventing mortality in a patient undergoing PCI.
  • mortality may be associated with other ischemic events.
  • mortality may be caused by stent thrombosis, occlusion of a coronary artery, and/or myocardial infarction.
  • An aspect of the present invention is methods of treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI, comprising administering to the patient a pharmaceutical composition comprising cangrelor.
  • PCI may comprise balloon angioplasty without implantation of a stent, or may also comprise the implantation of a stent.
  • the stent may be a bare-metal stent, or a drug-eluting stent, as known in the art.
  • a method of the present invention comprises administering the pharmaceutical composition before, during, and/or after PCI.
  • the administration may continue for a short period of time, such as less than about an hour, or may be one or more hours. In some embodiments, the administration may continue for at least the duration of the PCI. In other embodiments, the administration may continue after the PCI has concluded. In certain embodiments, the administration may continue for at least about 2 hours or the duration of the PCI procedure, whichever is longer. In an additional embodiment, the administration may continue for about 4 hours or longer.
  • a method may comprise administering the pharmaceutical composition multiple times before, during, and/or after PCI.
  • administration of the pharmaceutical composition may be for a short period of time before the PCI, and then again once PCI has begun.
  • the method may comprise administering the pharmaceutical composition periodically after the PCI has concluded.
  • the pharmaceutical composition may be administered once, twice, thrice or more times a day, once every two days, once every three days, etc., and for weeks, months, or even years, after the PCI, particularly if the PCI involved stent implantation.
  • the method may comprise administering the pharmaceutical composition once the ischemic event is recognized or diagnosed, or at the onset of symptoms of the ischemic event.
  • the pharmaceutical composition may be administered if symptoms of a myocardial infarction are observed.
  • the pharmaceutical composition may be administered within a short period of time from the onset of symptoms of the ischemic event. The short period of time may range from about one or two minutes to about one or two hours.
  • the method may comprise administering the pharmaceutical composition as a prophylaxis against an ischemic event, such as myocardial infarction.
  • Patients appropriate for such prevention include any patient suspected of having early symptoms of the ischemic event or other disease, or a condition that could lead to the ischemic event against which the pharmaceutical compositions of the invention would be effective.
  • the pharmaceutical composition may be administered to the patient within a short period of time of when early or initial symptoms of the ischemic event are detected.
  • Methods of the present invention may comprise administering the pharmaceutical composition concurrently or sequentially with at least one additional therapeutic agent.
  • the additional therapeutic agent may be a P2Yi 2 receptor inhibitor, such as clopidogrel, ticagrelor, or prasugrel, or the additional therapeutic agent may be a glycoprotein Ilb/IIIa inhibitor.
  • the additional therapeutic agent may be aspirin.
  • the additional therapeutic agent may be administered after the administration of cangrelor, either immediately after or following a short period of time.
  • the additional therapeutic agent such as clopidogrel, may be administered after the infusion of cangrelor is complete.
  • the routes of administration of the methods of the present invention include, for example, oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or parenteral administration.
  • Parenteral modes of administration include without limitation, intradermal, subcutaneous (s.c, s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra-articular (joint),
  • intrasynovial joint fluid area
  • intracranial intracranial
  • intraspinal intrathecal
  • Any known device useful for parenteral injection or infusion of drug formulations can be used in the methods of the present invention.
  • administration is via parenteral administration, preferably intravenous administration, or oral administration.
  • the pharmaceutical composition comprising cangrelor may be administered as a bolus, as a continuous infusion, or as a bolus followed by a continuous infusion.
  • the pharmaceutical composition may be administered prior to PCI as a bolus, and may be administered during PCI as a continuous infusion.
  • Doses of cangrelor in the pharmaceutical compositions administered in the methods of the present invention may vary depending upon the stated goals of the methods (treating, reducing the incidence of, and/or preventing), the physical characteristics of the patient, the significance of the ischemic event, existence of related or unrelated medical conditions, the composition of the formulation and the means used to administer the drug to the patient.
  • the dose for a given patient will generally be set by the judgment of the attending physician.
  • cangrelor When administered as a continuous infusion, cangrelor may be administered at about 0.1 to about 30 ⁇ g/kg/min, for example, between about 1 and about 10 ⁇ g/kg/min, or about 4 ⁇ g/kg/min.
  • the dose may differ in the periods before PCI, during PCI and after PCI.
  • the method of the present invention comprises administering a bolus of about 30 ⁇ g/kg cangrelor, followed by administering an infusion of about 4 ⁇ g/kg/min cangrelor.
  • a dose of between about 0.5 to about 100 mg/kg cangrelor or about 5 to about 30 mg/kg cangrelor is administered per day.
  • Oral administration may occur once a day or multiple times per day.
  • an additional therapeutic agent is administered in addition to the pharmaceutical composition comprising cangrelor.
  • the additional therapeutic agent comprises clopidogrel
  • it may be administered orally with a dose of clopidogrel from about 75 mg to about 600 mg.
  • a "patient" upon which the methods of the present invention may be practiced refers to an animal, such as a mammalian or an avian species, including a human, a non-human primate, a horse, a cow, a sheep, a goat, a dog, and a cat.
  • Such patients may have an ischemic event, such as stent thrombosis, myocardial infarction, IDR, or mortality.
  • the patient may have a condition selected from the group consisting of STEMI, NSTEMI, stable angina, unstable angina, and acute coronary syndrome.
  • the patient may be of any age, gender, or weight.
  • the patient may have received different therapeutic agents, such as a periprocedural glycoprotein Ilb/IIIa inhibitor, periprocedural unfractionated heparin (UFH), periprocedural low-molecular-weight heparin (LMWH), periprocedural bivalirudin, or periprocedural clopidogrel.
  • the patient may have suffered a stroke, or may have diabetes mellitus, hypertension, hyperlipidemia, a myocardial infarction, or may have a family history of coronary artery disease (CAD).
  • the patient may have undergone percutaneous transluminal coronary angioplasty (PTCA), PCI, or coronary artery bypass graft (CABG).
  • PTCA percutaneous transluminal coronary angioplasty
  • PCI PCI
  • CABG coronary artery bypass graft
  • the patient may have congestive heart failure, peripheral arterial disease (PAD), or stent thrombosis in more than one artery or vein.
  • the patient may be on periprocedural medications such as clopidogrel, bivalirudin, unfractionated heparain, low-molecular-weight heparin, fondaparinux, or aspirin.
  • Each of the methods recited in the present invention may include the additional step of measuring the effectiveness of the administration of the pharmaceutical composition comprising cangrelor, including the timing, duration, and route of administration of the pharmaceutical composition.
  • the measurement may include the effectiveness of the administration of any additional therapeutic agent.
  • this additional step may be performed about 0.5 to about 24 hours after administration is complete.
  • Characteristics that are representative of effectiveness include, for example, an increase in luminal diameter within a stent, a decrease in the size of the stent thrombus, and a decreased incidence of myocardial infarction.
  • compositions Useful for Treating, Reducing the Incidence of, and/or Preventing Ischemic Events
  • An aspect of the present invention is directed to a pharmaceutical composition useful for treating, reducing the incidence of, and/or preventing an ischemic event in a patient undergoing PCI.
  • the pharmaceutical composition comprises cangrelor, and may further comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be administered according to any of the methods of the present invention described above.
  • compositions may comprise one or more pharmaceutically acceptable excipients including, but not limited to, carriers, diluents, stabilizing agents, solubilizing agents, surfactants, buffers, antioxidants, preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending or viscosity agents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibacterials, chelating agents, sweeteners, perfuming agents, flavouring agents, coloring agents, administration aids, and combinations thereof.
  • pharmaceutically acceptable excipients including, but not limited to, carriers, diluents, stabilizing agents, solubilizing agents, surfactants, buffers, antioxidants, preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending or viscosity agents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibacterials, chelating agents, sweeteners,
  • excipients include, but are not limited to, cornstarch or gelatin, lactose, sucrose, dextrose, microcrystalline cellulose, kaolin, mannitol, sorbitol, dicalcium phosphate, sodium chloride, alginic acid, croscarmellose sodium, sodium starch glycolate, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g.
  • Cremophor EL poloxamer 407 and 188
  • cyclodextrin or cyclodextrin derivatives including HPCD ((2-hydroxypropyl)-cyclodextrin) and (2-hydroxyethyl)-cyclodextrin
  • hydrophilic and hydrophobic carriers include, for example, fat emulsions, lipids, PEGylated phospholipids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes.
  • the pharmaceutical compositions may comprise polyols, such as sorbitol, lactose, sucrose, inositol or trehalose.
  • compositions of the present invention may be formulated for the route by which they are administered to the patients, which include solids, liquids, and suspensions.
  • routes by which they are administered to the patients which include solids, liquids, and suspensions.
  • the pharmaceutical composition is formulated for IV
  • the pharmaceutical composition may comprise an intravenous fluid, which includes, but is not limited to, water- for-injection (WFI), physiological saline, 0.9% NaCl, phosphate buffered saline, 5% dextrose in water, and 0.002% polysorbate 80 in water or
  • WFI water- for-injection
  • physiological saline 0.9% NaCl
  • phosphate buffered saline 0.9% dextrose in water
  • polysorbate 80 in water or
  • the pharmaceutical composition may comprise an intravenous fluid, which includes, but is not limited to, WFI, physiological saline, 0.9%> NaCl, phosphate buffered saline, and 5% dextrose in water.
  • the pharmaceutical composition is formulated for oral administration, the
  • compositions may comprise excipients that include, but are not limited to diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Povidone), sorbitol, tragacanth, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and ethylcellulose), fillers (e.g., calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose), wetting agents, lubricating agents (e.g., metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloidal silica, silicon fluid or talc), disintegrating agents (e.g., potato starch, corn starch and alginic acid), flavouring agents (e.g. peppermint,
  • the pharmaceutical composition may be made in the form of a tablet, capsule, suspension or liquid syrup or elixir, wafers and the like.
  • compositions of the present invention may be prepared by admixing cangrelor with the one or more pharmaceutically acceptable excipients.
  • Methods of admixing and devices useful for admixing are known in the art.
  • cangrelor and the one or more pharmaceutically acceptable excipients are dissolved and then admixed.
  • the resulting mixture may be dried, such as through lyophilization, to form a solid pharmaceutical composition, or the resulting mixture may remain in solution form as a liquid pharmaceutical composition.
  • the solid pharmaceutical composition may be solubilized in an intravenous fluid before administration, for example, as a bolus or infusion.
  • the pharmaceutical composition is prepared by dissolving and admixing cangrelor, mannitol, sorbitol, and optionally sodium hydroxide, and then lyophilizing the mixture. Prior to administration, the lyophilized mixture is dissolved in an intravenous fluid such as WFI or physiological saline.
  • Example 1 Intravenous Platelet Blockade with Cangrelor Versus Placebo During
  • Patients were enrolled at 218 sites in 18 countries from October 2006 to May 2009. Patients were randomized in a double-blind, placebo-controlled, double-dummy design to receive either (i) placebo bolus and infusion or (ii) cangrelor 30 ⁇ g/kg bolus and 4 ⁇ g/kg/min infusion for the duration of PCI, with a minimum infusion duration of 2 hours and a maximum of 4 hours. Patients in the placebo arm of the trial received 600 mg of clopidogrel at the end of the procedure, while patients in the cangrelor arm received 600 mg of clopidogrel after the end of the cangrelor infusion (Fig. 1).
  • non-ST-segment elevation myocardial infarction was initially allowed at the beginning of the trial prior to a protocol amendment.
  • the diagnosis of non-ST-segment elevation myocardial infarction required troponin I or T greater than the upper limit of normal within 24 hours of randomization (or if troponin results were unavailable at that time, creatine kinase-myocardial band isoenzyme [CK- MB] greater than the upper limit of normal).
  • the diagnosis of unstable angina required ischemic chest discomfort occurring at rest and lasting >10 minutes within the 24 hours prior to
  • the exclusion criteria included the following: prior thienopyridine use in the past 7 days, planned staged PCI procedure where the second stage would occur ⁇ 30 days after the first PCI, admission planned for ⁇ 12 hours following PCI, ST-segment elevation myocardial infarction within 48 hours of randomization, known or suspected pregnancy, lactating females, increased bleeding risk (ischemic stroke within the last year or any previous hemorrhagic stroke), intracranial tumor, cerebral arteriovenous malformation, intracranial aneurysm, recent ( ⁇ 1 month) trauma or major surgery (including coronary artery bypass grafting), current warfarin use, active bleeding, known International Normalized Ratio >1.5, past or present bleeding disorder, platelet count ⁇ 100,000/ ⁇ , severe hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg), fibrinolytic therapy or glycoprotein Ilb/IIIa inhibitor use in the 12 hours preceding randomization.
  • the primary efficacy endpoint was the composite of mortality, myocardial infarction, or ischemia-driven revascularization at 48 hours.
  • the primary analysis was performed on a modified intent-to-treat population. Confirmatory analyses were performed on an intent-to-treat population. Secondary endpoints included the individual rates of mortality, myocardial infarction, new Q-wave myocardial infarction, ischemia-driven revascularization, abrupt vessel closure, or stroke at 48 hours. Mortality at 30 days and 1 year was also recorded.
  • stent thromboses The clinical events committee adjudicated myocardial infarction, Q-wave myocardial infarction, ischemia- driven revascularization, stent thromboses, and stroke (ischemic or hemorrhagic).
  • the definition of stent thrombosis was similar to the Academic Research Consortium definition of definite stent thrombosis. After review of the prespecified analyses, two exploratory endpoints less reliant on periprocedural biomarker ascertainment were examined.
  • the exploratory endpoints which were composed of prespecified and adjudicated endpoints, were the composite of mortality, Q-wave myocardial infarction, or ischemia-driven revascularization and the composite of mortality, Q- wave myocardial infarction, or stent thrombosis. Bleeding and adverse events through 48 hours were compared.
  • CABG denotes coronary artery bypass grafting
  • CAD coronary artery disease
  • GP glycoprotein
  • HF heart failure
  • ITT intent to treat
  • IV intravenous
  • LMWH low molecular weight heparin
  • MI myocardial infarction
  • MITT modified intent to treat
  • NSTEMI non-ST-segment elevation myocardial infarction
  • PAD peripheral artery disease
  • PCI percutaneous coronary intervention
  • PTCA percutaneous transluminal coronary angioplasty
  • TIA transient ischemic attack
  • UFH unfractionated heparin.
  • CI denotes confidence interval
  • IDR ischemia-driven revascularization
  • ITT intent to treat
  • MI myocardial infarction
  • MITT modified intent to treat
  • OR odds ratio
  • CI denotes confidence interval
  • IDR ischemia-driven revascularization
  • ITT intent to treat
  • MI myocardial infarction
  • MITT modified intent to treat
  • OR odds ratio
  • Variables are presented as no. (%) unless otherwise indicated.
  • the bleeding options under each criterion are not mutually exclusive. For example, a patient may have a clinically significant bleed and a minor bleed based on the ACUITY criteria, if more than 1 bleed is present. Each patient was counted only once for each criteria level, regardless of the number of bleeds identified under each criterion. Bleeding listed here included CABG-related bleeding.
  • Example 2 Platelet Inhibition with Cangrelor in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention
  • the primary efficacy endpoint was the 48-hour composite of all-cause mortality, MI, or ischemia-driven revascularization.
  • Prespecified secondary efficacy endpoints included the composite of mortality or MI at 48 hours and 30 days; the composite of mortality, MI, or ischemia-driven revascularization at 30 days; the components of the composite endpoints at 48 hours and 30 days; stroke at 48 hours; abrupt closure, threatened abrupt closure, need for urgent coronary artery bypass grafting, or unsuccessful procedure during the index PCI; acute (24 hours) and subacute (48 hours) stent thrombosis; and all-cause mortality at 6 months and 1 year.
  • Ischemia-driven revascularization was defined as symptoms of myocardial ischemia leading to urgent (within 24 hours of the last episode of ischemia) revascularization, which must have occurred after the index procedure concluded (ie, guidewire removal). New electrocardiographic changes, acute pulmonary edema, ventricular arrhythmias, or hemodynamic instability could also constitute evidence of ischemia.
  • MI was defined by a new Q wave (duration >0.03 seconds) in two contiguous electrocardiographic leads or elevations in creatine kinase (CK) and CK-MB, including a rise of CK-MB >3 times the local upper limit or normal and, when biomarkers were elevated prior to PCI, an additional 50% above baseline (Thygesen K. et al, Circulation 116:2634-53 (2007)).
  • One baseline troponin measurement was required for patients undergoing urgent PCI.
  • periprocedural MI can be challenging when most patients have elevated biomarkers and a single baseline sample. After the initial analyses were completed and reviewed, additional post-hoc composites were performed to better understand the potential effect of the drug on periprocedural outcomes less reliant on biomarkers (e.g., mortality, stent thrombosis, and Q-wave MI).
  • biomarkers e.g., mortality, stent thrombosis, and Q-wave MI
  • the sample size was based on the estimated composite incidence of all-cause mortality, MI, and ischemia-driven revascularization at 48 hours. Since there was no prior information about the use of cangrelor in the setting of STEMI and primary PCI and given the challenge of measuring re-infarction in the early hours of STEMI, the primary efficacy endpoint excluded these patients from the analysis, though they were included in analyses of safety.
  • the composite event rate was estimated at 7% in the control clopidogrel arm.
  • the trial was designed as a superiority trial to demonstrate a benefit of cangrelor over 600 mg clopidogrel. Assuming a 22% risk reduction, a sample size of 8000 patients would provide approximately 82% power with an alpha level of 0.05.
  • the plan was to include up to 1000 patients with STEMI, raising the sample size to 9000 patients.
  • the primary efficacy analysis was to be determined in the modified intent-to-treat (mITT) population, defined as all randomized patients (excluding STEMI cohort) who received at least one dose of study drug and underwent the index PCI.
  • the safety population consisted of all randomized patients who received any study drug. Patients in the safety analyses were assigned to a treatment arm based on treatment received, not as randomized. The ITT analysis with and without the STEMI cohort is reported.
  • Baseline demographics on the ITT population are shown in Table 5.
  • Baseline demographics for the MITT and safety populations are shown in Tables 6 and 7.
  • CABG coronary artery bypass grafting
  • CAD coronary artery disease
  • GP glycoprotein
  • HF heart failure
  • ITT intent to treat
  • IV intravenous
  • LMWH low molecular weight heparin
  • MI myocardial infarction
  • NSTEMI non-ST-segment elevation myocardial infarction
  • PAD peripheral artery disease
  • PCI percutaneous coronary intervention
  • PTCA percutaneous transluminal coronary angioplasty
  • STEMI ST-segment elevation myocardial infarction
  • TLA transient ischemic attack
  • UFH unfractionated heparin.
  • CABG denotes coronary artery bypass grafting
  • CAD coronary artery disease
  • GP glycoprotein
  • HF heart failure
  • IV intravenous
  • LMWH low molecular weight heparin
  • MI myocardial infarction
  • MITT modified intent to treat
  • NSTEMI non-ST-segment elevation myocardial infarction
  • PAD peripheral artery disease
  • PCI percutaneous coronary intervention
  • PTCA percutaneous transluminal coronary angioplasty
  • STEMI ST-segment elevation myocardial infarction
  • TLA transient ischemic attack
  • UFH unfractionated heparin.
  • CABG denotes coronary artery bypass grafting
  • CAD coronary artery disease
  • GP glycoprotein
  • HF heart failure
  • IV intravenous
  • LMWH low molecular weight heparin
  • MI myocardial infarction
  • NSTEMI non-ST-segment elevation myocardial infarction
  • PAD peripheral artery disease
  • PCI percutaneous coronary intervention
  • PTCA percutaneous transluminal coronary angioplasty
  • STEMI ST-segment elevation myocardial infarction
  • TIA transient ischemic attack
  • UFH unfractionated heparin.
  • PCI was attempted in all but 161 patients (1.8%), 65 in the cangrelor group (1.5%) and 96 in the clopidogrel group (2.2%).
  • the median duration of PCI was 0.4 hours (0.2, 0.6) and the median time from hospital admission to PCI was 6.3 hours (2.6, 23.7).
  • Most procedures involved single-vessel or two-vessel PCI (87.7% and 11.4%, respectively).
  • Drug-eluting stents were used in the majority of interventions (59.1%), bare-metal stents were used in 37.6%.
  • CI denotes confidence interval
  • IDR ischemia-driven revascularization
  • ITT intent to treat
  • MI myocardial infarction
  • MITT modified intent to treat
  • OR odds ratio
  • STEMI ST- segment elevation myocardial infarction.
  • Variables are presented as no. (%) unless otherwise indicated.
  • the bleeding options under each criterion are not mutually exclusive. For example, a patient may have a clinically significant bleed and a minor bleed based on the ACUITY criteria, if more than 1 bleed is present. Each patient will be counted once for each criteria level, regardless of the number of bleeds identified under each criterion.
  • Key secondary and composite exploratory (post-hoc) endpoints are displayed in Table
  • 600 mg has any effect on platelet inhibition by clopidogrel.
  • Patients in the substudy were required to be clopidogrel naive and could not have received glycoprotein Ilb/IIIa inhibition during the procedure.
  • Platelet function parameters were measured using the VerifyNow P2Yi 2 Assay (Accumetrics, San Diego, CA). Samples were taken before study drug administration, at approximately 2 hours (during cangre lor/placebo infusion), and 10 hours or next day following randomization.
  • Randomization was performed before PCI with the use of an interactive voice-response or Web-response system, with stratification according to site, baseline status (normal or abnormal, as defined by a combination of biomarker levels, electrocardiographic changes, and symptoms), and intended loading dose of clopidogrel (600 mg or 300 mg). Randomization divided the patients into two groups: the cangrelor group and the clopidogrel group.
  • Patients assigned to the cangrelor group were administered: (i) placebo capsules (before or immediately after PCI to match clopidogrel capsules administered in the clopidogrel group); (ii) a cangrelor bolus (30 ⁇ g/kg)/infusion (4 ⁇ g/kg/min); and (iii) capsules containing 600 mg of clopidogrel administered at the end of infusion.
  • clopidogrel capsules 300 mg or 600 mg before or immediately after PCI, with the dose and timing of administration determined at the discretion of the site investigator
  • a placebo bolus/infusion to match the cangrelor bolus/infusion administered in the cangrelor group
  • placebo capsules administered at the end of the infusion to match the capsules containing 600 mg of clopidogrel administered at the end of the infusion in the cangrelor group.
  • the cangrelor or placebo infusion was administered for at least 2 hours or the duration of the PCI procedure, whichever was longer.
  • a periprocedural anticoagulant bivalirudin, unfractionated heparin, low-molecular-weight heparin, or fondaparinux was also at the discretion of the investigator.
  • Glycoprotein Ilb/IIIa inhibitors were allowed only as rescue therapy during PCI to treat new or persistent thrombus formation, slow or no reflow, side-branch compromise, dissection, or distal embolization.
  • the investigator at the site determined the protocol for management of the arterial sheath.
  • the inclusion criteria for the trial were men or nonpregnant women, 18 years of age or older with coronary atherosclerosis who required PCI for stable angina, a non-ST-segment elevation acute coronary syndrome, or ST-segment elevation myocardial infarction (STEMI). Patients were required to provide written informed consent.
  • the primary efficacy end point was the composite rate of death from any cause, myocardial infarction, IDR, or stent thrombosis in the 48 hours after randomization in the modified intention-to-treat population (which comprised patients who actually underwent PCI and received the study drug).
  • the protocol specified that if more than 15% of the patients received a 300-mg loading dose of clopidogrel (as compared with a 600-mg dose) at the time of randomization, the primary analysis was to be adjusted for loading dose in addition to baseline status.
  • the key secondary end point was the incidence of stent thrombosis at 48 hours.
  • Intraprocedural stent thrombosis was defined as any new or worsened thrombus related to the stent procedure that was confirmed angiographically.
  • Events of death, myocardial infarction, IDR, and stent thrombosis that occurred during the first 30 days after randomization were adjudicated by the clinical events committee at the Duke Clinical Research Institute.
  • the criteria that the clinical events committee used to define myocardial infarction are provided in Tables 12A and 12B. The study adhered to the universal definition of myocardial infarction for myocardial infarction unrelated to PCI but expanded on the definition of PCI-related myocardial infarction.
  • CKMB creatine kinase-myocardial band isoenzyme
  • ECG denotes electrocardiography
  • MI denotes myocardial infarction
  • NSTE-ACS denotes non-ST-segment elevation acute coronary syndrome
  • STEMI denotes ST-segment elevation myocardial infarction.
  • ECG changes ST segment elevation/ depression > 0. lmV (>lmm) in at least 2 contiguous leads; new LBBB; new Q wave (greater than 0.03 seconds).
  • ECG collection post PCI within 1 hour after PCI; pre-discharge.
  • Ischemic symptoms angina or equivalent symptoms that need to be treated medically or lasting > 20 min. Ischemic symptoms as determined by the treating physician include but are not limited to weakness, shortness of breath, wheezing, tiredness, fainting, sweating, nausea/vomiting, abdominal pain, back pain, jaw pain, palpitations, fast heartbeat, drug use for chest pain
  • MI myocardial infarction
  • CKMB creatine kinase-myocardial band isoenzyme
  • NSTE-ACS denotes non-ST- segment elevation acute coronary syndrome
  • ULN denotes upper limit of normal
  • PCI percutaneous coronary intervention.
  • CKMB collection post PCI 6 hourly collection through 24 hours (minimum of 3 samples required). Core lab values take priority; hospital labs may be used if core lab not available (CKMB priority but troponin may be used).
  • TIMI 2 flow after baseline TIMI 3 flow also termed slow reflow
  • IPTE Intra-Procedural Thrombotic Event
  • IPST may present as either acute thrombotic stent closure after a stent was implanted in a patient with a patent vessel beforehand, or new thrombus formation within or adjacent to a stent in a vessel in which thrombus either was not present or had diminished or resolved before the stent was implanted.
  • Ischemic symptoms angina or equivalent symptoms that need to be treated medically or lasting > 20 min.
  • Ischemic symptoms as determined by the treating physician include but are not limited to weakness, shortness of breath, wheezing, tiredness, fainting, sweating, nausea/vomiting, abdominal pain, back pain, jaw pain, palpitations, fast heartbeat, drag use for chest pain (nitroglycerin, morphine, beta blocker, etc.).
  • ECG changes ST segment elevation/ depression > 0. lmV (>lmm) in at least 2 contiguous leads; new LBBB; new Q wave (greater than 0.03 seconds).
  • ECG collection post PCI within 1 hour after PCI; pre-discharge.
  • the primary safety end point was severe bleeding not related to coronary-artery bypass grafting, according to the Global Use of Strategies to Open Occluded Coronary Arteries
  • CABG coronary-artery bypass grafting
  • NSTE-ACS denotes non-ST-segment elevation acute coronary syndrome, PCI percutaneous coronary intervention, PTCA percutaneous transluminal coronary angioplasty, STEMI ST-segment elevation myocardial infarction, and TIA transient ischemic attack.
  • J Cardiac biomarker status was considered to be abnormal if at least one of the baseline troponin I or T levels, obtained within 72 hours before randomization or after randomization but before imtiation of the study drug, was greater than the upper limit of the normal range, as determined by the local laboratory. If the baseline troponin level was not available, the baseline MB fraction of creatine kinase was used. Table 14 - Additional baseline and procedural characteristics for the modified intention-to-treat population, according to the treatment group.*
  • CAD coronary artery disease
  • IDDM insulin- dependent diabetes mellitus
  • MITT modified intent to treat
  • Type 3 22/5529 ( 0.4) 13/5527 (0.2) 1.69 (0.85, 3.37) 0.13
  • Type 3 a 11/5529 (0.2) 4/5527 (0.1) 2.75 (0.88, 8.65) 0.07
  • Type 3 b 9/5529 (0.2) 8/5527 (0.1) 1.12 (0.43, 2.92) 0.81
  • MI myocardial infarction
  • ST denotes stent thrombosis
  • IDR denotes ischemia-driven revascularization
  • CV denotes cardiovascular
  • GUSTO denotes Global Use of Strategies to Open Occluded Coronary Arteries
  • ACUITY denotes Acute Catheterization and Urgent Intervention Triage Strategy trial
  • BARC denotes Bleeding Academic Research Consortium.
  • the use of rescue therapy with a glycoprotein Ilb/IIIa inhibitor was 2.3% with cangrelor as compared with 3.5% with clopidogrel (odds ratio, 0.65; 95% CI, 0.52 to 0.82; PO.001).
  • a subgroup analysis showed a similar effect of cangrelor among patients who received the infusion for 129 minutes or less (odds ratio, 0.85; 95% CI, 0.68 to 1.07) and those who received the infusion for more than 129 minutes (odds ratio, 0.72; 95% CI, 0.56 to 0.92) (P 0.31 for interaction) (Fig. 10).
  • Example 1 and Example 2 suggested a clinical benefit of cangrelor, including a significant reduction in the secondary end point of stent thrombosis.
  • the rate of the primary end point was not reduced in the previous examples, probably because the definition of periprocedural myocardial infarction in those studies did not allow discrimination of reinfarction in patients presenting for PCI soon after admission with a biomarker-positive acute coronary syndrome.
  • the definition of periprocedural myocardial infarction required careful assessment of patients' baseline biomarker status.
  • the use of an angiographic core laboratory allowed objective determination of intraprocedural complications. Table 20 lists the differences between the trials described in Example 1/Example 2 and the trial described in Example 3.
  • PCI percutaneous coronary intervention
  • STEMI denotes ST-segment elevation myocardial infarction
  • NSTEMI denotes non-ST-elevated myocardial infarction
  • ECG denotes electrocardiography
  • NSTE-ACS denotes non-ST-segment elevation acute coronary syndrome
  • MI denotes myocardial infarction
  • IDR denotes ischemia-driven revascularization
  • ST denotes stent thrombosis
  • UDMI denotes universal definition of myocardial infarction
  • CKMB denotes creatine kinase- myocardial band isoenzyme
  • ULN denotes upper limit of normal.

Abstract

La présente invention concerne des procédés de traitement, diminution de l'incidence, et/ou prévention d'un événement ischémique chez un patient subissant une intervention coronarienne percutanée (PCI) comprenant l'administration au patient d'une composition pharmaceutique comprenant du cangrélor. Le procédé peut comprendre en outre l'administration d'un agent thérapeutique additionnel au patient, l'agent thérapeutique additionnel comprenant un inhibiteur de P2Yi2. La présente invention concerne en outre des compositions pharmaceutiques utiles pour traiter, diminuer l'incidence, et/ou prévenir un événement ischémique chez un patient subissant une PCI. Les compositions pharmaceutiques comprennent du cangrélor. La présente invention concerne en outre des procédés de préparation d'une composition pharmaceutique pour traiter, diminuer l'incidence, et/ou prévenir un événement ischémique chez un patient subissant une PCI, comprenant le mélange de cangrélor avec un ou plusieurs excipients pharmaceutiquement acceptables. Un événement ischémique peut comprendre une thrombose d'endoprothèse, un infarctus du myocarde, une revascularisation induite par ischémie, et la mortalité.
PCT/US2013/030081 2013-03-09 2013-03-09 Procédés de traitement, diminution de l'incidence, et/ou prévention d'événements ischémiques WO2014142780A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110112030A1 (en) * 2009-11-11 2011-05-12 The Medicines Company Methods of treating or preventing stent thrombosis
US20120141468A1 (en) * 2008-05-13 2012-06-07 Lisa Ruderman Chen Maintenance of platelet inhibition during antiplatelet therapy
US20130040898A1 (en) * 2010-04-29 2013-02-14 Pär Johansson Methods of treatment of patients at increased risk of development of ischemic events and compounds hereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120141468A1 (en) * 2008-05-13 2012-06-07 Lisa Ruderman Chen Maintenance of platelet inhibition during antiplatelet therapy
US20110112030A1 (en) * 2009-11-11 2011-05-12 The Medicines Company Methods of treating or preventing stent thrombosis
US20130040898A1 (en) * 2010-04-29 2013-02-14 Pär Johansson Methods of treatment of patients at increased risk of development of ischemic events and compounds hereof
WO2013025476A1 (fr) * 2011-08-12 2013-02-21 The Medicines Company Entretien d'inhibition de plaquettes pendant thérapie antiplaquettaire

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