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US20220073888A1 - Combination treatment - Google Patents

Combination treatment Download PDF

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US20220073888A1
US20220073888A1 US17/405,670 US202117405670A US2022073888A1 US 20220073888 A1 US20220073888 A1 US 20220073888A1 US 202117405670 A US202117405670 A US 202117405670A US 2022073888 A1 US2022073888 A1 US 2022073888A1
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inhibitor
protein
administered
hours
recombinant
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Leif Carlsson
Sven Nylander
Ola Fjellstrom
Lina Badimon Maestro
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AstraZeneca AB
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Assigned to FUNDACIÓ INSTITUT DE RECERCA DE I'HOSPITAL DE LA SANTA CREU I SANT PAU reassignment FUNDACIÓ INSTITUT DE RECERCA DE I'HOSPITAL DE LA SANTA CREU I SANT PAU ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BADIMON MAESTRO, LINA
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NYLANDER, Sven, FJELLSTROM, OLA, CARLSSON, LEIF
Publication of US20220073888A1 publication Critical patent/US20220073888A1/en
Priority to US18/352,414 priority patent/US20240026318A1/en
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    • 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
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • 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
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    • 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
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
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    • C12Y—ENZYMES
    • C12Y306/00—Hydrolases acting on acid anhydrides (3.6)
    • C12Y306/01—Hydrolases acting on acid anhydrides (3.6) in phosphorus-containing anhydrides (3.6.1)
    • C12Y306/01005—Apyrase (3.6.1.5), i.e. ATP diphosphohydrolase
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Definitions

  • the present invention relates to methods for treating ischemic events in a patient, especially ST-segment elevation myocardial infarction and acute ischemic stroke, by administering a recombinant apyrase protein in conjunction with a P2Y 12 inhibitor.
  • MI Myocardial infarction
  • ischaemia blood flow
  • a primary goal of therapy with MI is therefore to expedite restoration of normal coronary blood flow with the aim of decreasing heart muscle damage through reperfusion therapy.
  • Reperfusion therapy typically involves the use of therapeutics to increase blood flow and reduce thrombosis combined with surgical techniques such as percutaneous coronary intervention (PCI).
  • PCI percutaneous coronary intervention
  • small molecule therapeutics include the P2Y 12 receptor inhibitors such as clopidogrel, ticagrelor, prasugrel and cangrelor, which are known for their ability to inhibit platelets and prevent blood clots.
  • P2Y 12 receptor inhibitors such as clopidogrel, ticagrelor, prasugrel and cangrelor
  • the effectiveness of both clopidogrel and ticagrelor in reducing cardiovascular morbidity and mortality in secondary prevention has been demonstrated in clinical trials and both drugs have been approved for use in the prevention of thrombotic events.
  • NICE National Institute for Health and Care Excellence
  • ticagrelor in combination with low-dose aspirin for up to 12 months as a therapy for adults with acute coronary syndromes (ACS).
  • ACS acute coronary syndromes
  • apyrases as a protein-based therapeutic.
  • Apyrases ecto-ATP diphosphohydrolases
  • ATP a group of enzymes catalysing metabolism of ATP to ADP and ADP to AMP.
  • the AMP produced by apyrase-induced hydrolysis of ATP and ADP is converted into adenosine by the ubiquitously expressed extracellular CD73/ecto-5′-nucleotidase.
  • apyrase reduces ATP and ADP interaction with all three platelet P2 receptors (P2X 1 , P2Y 1 and P2Y 12 ), therefore acting to inhibit platelet activation and recruitment.
  • P2X 1 , P2Y 1 and P2Y 12 the use of apyrase to deplete ADP and ATP levels does not result in the increased levels of bleeding in preclinical models.
  • apyrase also has cardioprotective effects, which is understood to be mediated through i) the depletion of the pro-inflammatory ATP and ADP molecules; and ii) through the increased levels of the anti-inflammatory adenosine produced through apyrase action. More information of the mechanisms of action of endogenous apyrase is provided in FIG. 1 of Moeckel et al. (2014).
  • Moeckel et al. (2014) reports on the design and production of a recombinant optimised form of soluble CD39L3, a member of the human CD39 family.
  • the resulting recombinant protein is termed ‘APT102’ or ‘AZD3366’.
  • the authors report that this recombinant protein exhibited four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than native apyrase and that treatment with APT102 in animal models decreased infarction size without an increase in bleeding time.
  • the corresponding treatment with clopidogrel alone was not cardioprotective in this model whilst combining APT102 and clopidogrel treatment did not change the protective efficacy seen with APT102 alone (FIG. 6 of Moeckel et al. (2014)).
  • the present inventors have determined that administration of a recombinant apyrase protein in conjunction with a P2Y 12 inhibitor provides improved cardioprotective benefits compared to the individual use of P2Y 12 inhibitor alone.
  • the combined treatment can be used as an effective treatment of ischemic events in the heart such as myocardial infarction (e.g. ST-Elevation Myocardial Infarction) and ischemic events in the brain such as acute ischemic stroke and, for example, can be used to prevent or ameliorate injury resulting from the ischemic event (e.g. cardiac damage formed as a result of the myocardial infarction, or brain damage formed as a result of acute ischemic stroke).
  • myocardial infarction e.g. ST-Elevation Myocardial Infarction
  • ischemic events in the brain such as acute ischemic stroke
  • acute ischemic stroke e.g. cardiac damage formed as a result of the myocardial infarction, or brain damage formed as a result of
  • a recombinant apyrase protein e.g. AZD3366
  • a P2Y 12 inhibitor e.g. ticagrelor
  • the improved cardioprotective effect provided by the combination treatment is at least in part caused by the P2Y 12 inhibitor resulting in increased levels of extracellular adenosine. Since the cardioprotective effect of AZD3366 is reported to also involve increasing levels of extracellular adenosine, it was unexpected that the combined use of two agents (P2Y 12 inhibitor and recombinant apyrase protein) acting on the same pathway and modulating levels of the same end product would induce a greater cardioprotective effect than observed through the use of a single agent alone.
  • the proposed combination is unexpectedly a first example where net clinical benefit can be improved by targeting and enhancing effects attributable to the same biological pathway in settings such as MI.
  • one aspect of the present disclosure provides a method of treating an ischemic event in a patient, the method comprising administering a recombinant apyrase protein in conjunction with a P2Y 12 inhibitor.
  • the present disclosure provides a recombinant apyrase protein for use in a method of treating an ischemic event in a patient, the method comprising administering the recombinant apyrase protein to the patient, wherein the recombinant apyrase protein is administered in conjunction with a P2Y 12 inhibitor.
  • the present disclosure provides a recombinant apyrase protein and a P2Y 12 inhibitor for use in a method of treating an ischemic event in a patient, the method comprising administering the recombinant apyrase protein in conjunction with the P2Y 12 inhibitor to the patient.
  • the present disclosure provides a P2Y 12 inhibitor for use in a method of treating an ischemic event in a patient, the method comprising administering the P2Y 12 inhibitor to the patient, wherein the P2Y 12 inhibitor is administered in conjunction with a recombinant apyrase protein.
  • the present disclosure provides the use of a recombinant apyrase protein and/or a P2Y 12 inhibitor in the manufacture of a medicament for the treatment of an ischemic event in a patient, the treatment comprising administering the recombinant apyrase protein to the patient in conjunction with the P2Y 12 inhibitor.
  • the P2Y 12 inhibitor may be selected from the group consisting of ticagrelor, clopidogrel, ticlopidine, prasugrel, and cangrelor. In some embodiments, P2Y 12 inhibitor is selected from the group consisting of ticagrelor, clopidogrel and prasugrel. Preferably, the P2Y 12 inhibitor is ticagrelor or clopidogrel. Even more preferably, the P2Y 12 inhibitor is ticagrelor.
  • the recombinant apyrase protein may be a recombinant human CD39L3 apyrase, optionally a soluble recombinant human CD39L3 apyrase.
  • the apyrase may be a soluble CD39L3 or an ADPase enhanced apyrase as described in any one of U.S. Pat. No. 7,247,300B1, EP2133430B1 and EP2523971 B1.
  • An exemplary recombinant human CD39L3 apyrase is provided here as SEQ ID NO: 2.
  • the recombinant apyrase protein is a soluble CD39L3 protein comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to positions 49-485 of SEQ ID NO: 1, wherein the recombinant apyrase protein retains ADPase and ATPase activity.
  • the recombinant apyrase protein comprises one or more modifications (e.g. amino acid substitutions) compared with a reference apyrase, where said reference apyrase may be a wild-type apyrase (e.g.
  • an apyrase having the amino acid sequence set forth in SEQ ID NO: 1) or a soluble apyrase e.g. a soluble apyrase having the amino acid sequence set forth as position 49-485 of SEQ ID NO: 1).
  • the one or more modifications may comprise or consist of substitutions at positions 67 and 69, wherein the positions are numbered according to SEQ ID NO: 1.
  • the substitution at position 67 may be to a glycine and the substitution at position 69 may be to an arginine, or the substitution at position 67 may be to an alanine and the substitution at position 69 may be to an arginine.
  • the substitution at position 67 is to a glycine and the substitution at position 69 is to an arginine.
  • the recombinant apyrase protein comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 98%, at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 2 (AZD3366).
  • the recombinant apyrase protein comprises the amino acid sequence set forth as SEQ ID NO: 2.
  • the patient may already be undergoing treatment with the P2Y 12 inhibitor when the ischemic event occurs.
  • the prescribing information for ticagrelor in treating acute coronary syndromes describes initiating treatment with a 180 mg “loading” dose and then administering a “maintenance” dose of 90 mg twice daily during the first year after an ACS event and after one year administering 60 mg twice daily.
  • the patient may have previously experienced a prior ischemic event in the past 2 years and is currently undergoing chronic treatment with the P2Y 12 inhibitor, e.g. by taking ticagrelor twice daily, when the ischemic event being treated here occurs.
  • optimal anti-platelet and anti-thrombotic treatment there still remains a risk of a new ischemic event occurring.
  • patient may have received (been administered with) the P2Y 12 inhibitor in the preceding 72 hours, or preceding 36 hours, or preceding 48 hours, or preceding 24 hours, or preceding 20 hours, or preceding 16 hours, or preceding 12 hours, or preceding 8 hours, or preceding 6 hours prior to the present method being performed.
  • the P2Y 12 inhibitor is ticagrelor
  • the patient has received the P2Y 12 inhibitor in the preceding 8-16 hours, e.g. 12 hours (i.e. as part of the maintenance dose administered twice daily).
  • the patient may not be currently undergoing treatment with the P2Y 12 inhibitor.
  • Such patients are described as “na ⁇ ve” patients. This includes situations where the patient has never been administered the P2Y 12 inhibitor as well as situations where the patient has previously been administered the P2Y 12 inhibitor but no administrations have taken place for at least 24 hours, 48 hours, 72 hours or a week prior to the present method being performed.
  • the method comprises administering the P2Y 12 inhibitor to the patient (e.g. a patient undergoing treatment with the, or another, P2Y 12 inhibitor, or a na ⁇ ve patient) in addition to the recombinant apyrase protein.
  • the method comprises administering the P2Y 12 inhibitor and recombinant apyrase protein as separate formulations that are administered separately, e.g. simultaneously or sequentially.
  • a skilled physician or other skilled medical personnel can determine the most suitable manner of administering each therapeutic agent to the patient.
  • the recombinant apyrase protein and P2Y 12 inhibitor are preferably administered within 24 hours, 12 hours, 1 hour or more preferably within 30 minutes of each other.
  • the recombinant apyrase protein is administered first, followed by the sequential administration of the P2Y 12 inhibitor.
  • the P2Y 12 inhibitor is administered first, followed by the sequential administration of the recombinant apyrase protein.
  • the ischemic event being treated is an acute coronary syndrome.
  • Acute coronary syndromes include ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina.
  • the ischemic events being treated is a ST segment elevation myocardial infarction (STEMI) in a patient.
  • apyrase protein e.g. AZD3366
  • P2Y 12 inhibitor e.g. ticagrelor
  • apyrase protein in conjunction with the P2Y 12 inhibitor in patients suffering from an acute coronary syndrome should preferably be done as soon as possible following onset of the acute coronary syndrome and preferably as close as possible to the time when the patient undergoes percutaneous coronary intervention (PCI)).
  • PCI percutaneous coronary intervention
  • the ischemic event being treated is acute ischemic stroke. Every year, 100 new patients have an ischaemic stroke in a population of 70 000. Without treatment, 55 patients die or become dependent within a year. Most of the 100 patients have mild or transient stroke and receive only antiplatelet drugs to reduce recurrence. About 25-35 patients receive reperfusion therapy, which saves 5-6 patients from death or dependency and increases numbers with no disability. Therefore, it is an unmet clinical need to reduce morbidity and mortality associated with acute ischaemic stroke (AIS).
  • AIS acute ischaemic stroke
  • Preclinical and clinical trials have evaluated the use of P2Y 12 inhibitors and aspirin to treat and/or prevent stroke after an ischemic stroke event. Furthermore, preclinical data has demonstrated that the recombinant apyrase protein AZD3366 can be used to enhance reperfusion, reduce re-occlusion and reduce intracerebral bleeding in animal models of ischemic stroke (Sun et al., 2011; Tan et al., 2014). It was therefore realised that the beneficial results in the preclinical myocardial infarction animal model described herein associated with the combined administration of AZD3366 and P2Y 12 inhibitor could also be beneficial in the treatment of ischaemic stroke. For example, the combination treatment may reduce infarct size and/or reduce brain damage in patients suffering from ischaemic stroke and achieve this effect without a significantly increased risk of bleeding compared to P2Y 12 inhibitors alone.
  • the time taken for onset of action for oral P2Y 12 inhibitors is typically several hours, meaning that even if the P2Y 12 inhibitor is administered very early after onset of the ischemic event (e.g. acute coronary syndrome), there is a period of several hours when the patient is not protected from associated damage (e.g. cardiac damage formed as a result of the myocardial infarction).
  • the ischemic event e.g. acute coronary syndrome
  • associated damage e.g. cardiac damage formed as a result of the myocardial infarction
  • the recombinant apyrase protein AZD3366 has been shown in preclinical models to have high levels of activity within minutes of administration and to maintain this activity for more than 24 hours (Moekel et al. 2015)
  • administering the recombinant apyrase protein early this would provide cardioprotective effects during the initial phase of the myocardial infarction before sufficient levels of the P2Y 12 inhibitor are bioavailable in the blood stream of the patient in order to exert a cardioprotective effect.
  • the recombinant apyrase protein is administered to the patient in conjunction with the P2Y 12 24 hours or less, or 18 hours or less, or 12 hours or less, or 6 hours or less, or 4 hours or less, or 2 hours or less, or 1 hour or less, or even 30 minutes or less after onset of the ischemic event (e.g. an acute coronary syndrome such as STEMI).
  • the method further comprises carrying out surgical reperfusion therapy (e.g. PCI) on the patient less than 48 hours, less than 24 hours, less than 12 hours, less than 6 hours, less than 3 hours, less than 2 hours, or less than 1 hour following administering the recombinant apyrase protein in conjunction with the P2Y 12 inhibitor.
  • the recombinant apyrase protein and P2Y 12 inhibitor remain bioavailable in the patient's blood stream during surgical reperfusion therapy (e.g. PCI).
  • the recombinant apyrase protein is administered at a dose of 10 to 1000 mg.
  • the P2Y 12 inhibitor is ticagrelor and is administered at a dose of between 60 to 200 mg, e.g. at 60 mg, 90 mg, 120 mg or 180 mg. In some embodiments, ticagrelor is administered at its recommended loading dose of 180 mg.
  • the P2Y 12 inhibitor is clopidogrel and is administered at a dose of between 75 to 600 mg, e.g. at 75 mg, 150 mg, 225 mg, 300 mg, 375 mg, 450 mg, 525 mg or 600 mg. In some embodiments, clopidogrel is administered at its recommended loading dose of 300 mg or 600 mg.
  • the P2Y 12 inhibitor is ticlopidine and is administered at a dose of 250 to 500 mg, e.g. at 250 mg or 500 mg. In some embodiments, ticlopidine is administered at its recommended loading dose of 500 mg.
  • the P2Y 12 inhibitor is prasugrel and is administered at a dose of 5 to 60 mg, e.g. at 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg.
  • ticlopidine is administered at its recommended loading dose of 60 mg.
  • the P2Y 12 inhibitor is cangrelor and is administered at a dose of 30 ⁇ g/kg intravenous bolus followed by 4 ⁇ g/kg per minute intravenous infusion.
  • the method further comprises administering aspirin to the patient, e.g. such that the recombinant apyrase protein is administered in conjunction with the P2Y 12 inhibitor and aspirin.
  • the method typically comprises administering the recombinant apyrase protein, P2Y 12 inhibitor and aspirin as separate formulations that are administered separately, e.g. simultaneously or sequentially.
  • the aspirin may be administered at a dose of 50 to 325 mg.
  • kits comprising the recombinant apyrase protein and the P2Y 12 inhibitor described herein, optionally wherein the kit further comprises aspirin.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • FIG. 1 illustrates the experimental protocol used to examine whether administration of recombinant apyrase protein AZD3366 confers additional benefits to that of ticagrelor alone in terms of reduced infarct size and improved heart function in a pig animal model of myocardial infarction.
  • FIG. 2 shows results obtained from a mouse tail bleeding experiment showing the amount of blood loss measured following administration with ticagrelor (T), 1 mg/kg AZD3366 (AZD1), 3 mg/kg AZD3366 (AZD3) and the combined administration of AZD3366 and ticagrelor (T+AZD1).
  • T ticagrelor
  • AZD3366 1 mg/kg AZD3366
  • AZD3 3 mg/kg AZD3366
  • T+AZD1 the combined administration of AZD3366 and ticagrelor
  • An apyrase (EC 3.6.1.5) catalyses the hydrolysis of phosphoanhydride bonds of adenosine triphosphate (ATP) to adenosine monophosphate (AMP) and adenosine diphosphate (ADP) to AMP.
  • CD39 family members (also termed ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) family members) represent some of the best characterised apyrases.
  • Human CD39 family members include the native proteins set out in the following table:
  • NCBI Name of accession native protein Additional names number CD39 ATPDase, ecto-apyrase, U87967.1 NTPDase1 CD39L1 NTPDase2, ecto-ATPase AF144748.1 CD39L2 NTPDase6 AY327581.1 CD39L3 NTPDase3, CD39L3, HB6 AF034840.2 CD39L4 NTPDase5, ER-UDPase, AF039918.1 PCPH LALP70 UDPase, NTPDase4 AF016032.1 LALP1 NTPDase7 AF269255.1 liver canalicular NTPDase8, hATPDase AY430414.1 ecto-ATPase
  • the recombinant apyrase protein is a recombinant human apyrase protein or an engineered version thereof. In some embodiments, the recombinant apyrase protein is a member of the CD39 family, e.g. any of the native proteins set forth in the above table, or an engineered version thereof.
  • the recombinant apyrase protein may be a soluble recombinant human apyrase protein, e.g. an apyrase protein that lacks some or all of the amino acid residues that make up a transmembrane domain of the apyrase protein, which may be a member of the CD39 family.
  • human CD39L3 is a 529 amino acid residue protein shown in SEQ ID NO: 1.
  • a particular exemplary soluble CD39L3 apyrase protein has the amino acid sequence set forth as position 49-485 of SEQ ID NO: 1.
  • engineered or “engineered version thereof” in the context of recombinant apyrase proteins means that the engineered protein has a similar, but not identical, amino acid sequence to a reference apyrase protein.
  • a reference apyrase protein may be a wild-type apyrase protein (e.g. the full-length CD39L3 apyrase protein) or a soluble apyrase protein (e.g. the a protein that has the amino acid sequence set forth as position 49-485 of SEQ ID NO: 1).
  • the engineered recombinant apyrase protein may comprise one or more amino acid substitutions, e.g. a substitution that alters the enzymatic activity (e.g.
  • An engineered recombinant apyrase protein may have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the reference apyrase protein.
  • the recombinant apyrase protein set forth in SEQ ID NO: 2 is an engineered version of the soluble CD39L3 apyrase protein having the amino acid sequence set forth as position 49-485 of SEQ ID NO: 1.
  • the recombinant apyrase protein is a CD39L3 protein or an engineered version thereof.
  • the recombinant apyrase protein may have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 1.
  • the recombinant apyrase protein is a soluble CD39L3 protein or an engineered version thereof.
  • the recombinant apyrase protein may have an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth as position 49-485 of SEQ ID NO: 1.
  • soluble recombinant apyrase proteins including engineered versions of CD39L3 (e.g. enhanced apyrases) are described in U.S. Pat. No. 7,247,300B1, EP2133430B1 and EP2523971B1, all of which are incorporated herein by reference in their entireties.
  • the recombinant apyrase protein described herein may be any of the apyrases described in those publications.
  • EP2133430B1 describes ADPase enhanced apyrases. These ADPase enhanced apyrases comprise modified forms of reference apyrases, wherein the modification results in increased ADPase activity compared with the reference apyrase or the same ADPase activity as the reference apyrase combined with decreased ATPase activity as compared with the reference apyrase.
  • Exemplary ADPase enhanced apyrases include those comprising substitutions at positions 67 and 69 of CD39L3, wherein the position numbering is in accordance with SEQ ID NO: 1.
  • ADPase enhanced apyrases include protein 8742, comprising R67G and T69R substitutions; and protein 8906, comprising R67A and T69R substitutions, as described in EP2133430B1.
  • ATPase and ADPase enzyme activities of purified soluble ADPase enhanced apyrases can be determined at 37° C. in a 1 ml solution containing 8 mM CaCl 2 , 200 ⁇ M substrate (ATP for ATPase or ADP for ADPase), 50 mM imidazole, and 50 mM Tris, pH 7.5 (Picher, et al., Biochem. Pharmacol. (1938) 51 :1453).
  • the reaction can be stopped and inorganic phosphate released can be measured by addition of 0.25 ml of malachite green reagent (Baykov, et al., Anal. Biochem. (1988) 171:266).
  • one unit of ATPase corresponds to release of 1 ⁇ mole of inorganic phosphate/min at 37° C.
  • Key kinetic constants for the enzyme such as Km and kcat may be obtained by fitting data into, for example, a Michaelis-Menten equation.
  • Other assays useful for monitoring biochemical function include, but are not limited to, a radiometric assay, a HPLC assay both described by Gayle III, et al. (J. Clin Invest. (1998) 101:1851-1859) or a radio-TLC assay described by Marcus, A. J., et al. (J. Clin Invest. (1991) 88:1690-1696).
  • the recombinant apyrase protein described herein may comprise one or more modifications (e.g. amino acid substitutions) compared with a reference apyrase having the amino acid sequence set forth as positions 49-485 of SEQ ID NO: 1 (i.e. a soluble version of CD39L3).
  • modifications e.g. amino acid substitutions
  • a reference apyrase having the amino acid sequence set forth as positions 49-485 of SEQ ID NO: 1 i.e. a soluble version of CD39L3
  • modifications may result in increased ADPase activity compared with the reference apyrase or the same ADPase activity as the reference apyrase combined with decreased ATPase activity as compared with the reference apyrase.
  • the one or more modifications may comprise or consist of substitutions at positions 67 and 69, wherein the positions are numbered according to SEQ ID NO: 1.
  • the substitution at position 67 may be to a glycine and the substitution at position 69 may be to an arginine, or the substitution at position 67 may be to an alanine and the substitution at position 69 may be to an arginine.
  • the substitution at position 67 is to a glycine and the substitution at position 69 is to an arginine.
  • EP2523971 B1 describes apyrases and methods of producing apyrases that comprise a homogeneous N-terminus, e.g. such that more than 80% of the apyrase molecules have the same N-terminus which comprises EVLP. These proteins with a homogenous N-terminus are described as having an average isoelectric point in the range of 3.0 to 4.5 and/or having enhanced half lives in rabbits and pigs.
  • the recombinant apyrase protein described herein may comprise a homogenous N-terminus such that more than 80% of the apyrase molecules have the same N-terminus, which N-terminus is EVLP, as described in EP2523971B1.
  • the recombinant apyrase protein may further comprise one or more functionally conservative substitutions (e.g. in addition to the substitutions in the ADPase enhanced apyrases described above).
  • Functionally conservative substitutions are substitutions that do not affect (or do not substantially affect) one or more functional properties (e.g. enzymatic activity) as compared to the equivalent unsubstituted protein.
  • the recombinant apyrase protein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 functionally conservative substitutions.
  • the recombinant apyrase protein comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO: 2, optionally wherein the amino acid residue at position 67 is a glycine and the amino acid residue at position 69 is an arginine, wherein the positions are numbered according to SEQ ID NO: 1.
  • the recombinant apyrase protein may comprise the amino acid sequence of SEQ ID NO: 2 with 1 or more (e.g.
  • amino acid residue at position 67 is a glycine and the amino acid residue at position 69 is an arginine, wherein the positions are numbered according to SEQ ID NO: 1.
  • amino acid residue positions 67 and 69 according to SEQ ID NO: 1 correspond to amino acid residue positions 19 and 21 respectively according to SEQ ID NO: 2.
  • the recombinant apyrase protein comprises the amino acid sequence of SEQ ID NO: 2.
  • the P2Y 12 inhibitor may be selected from a list consisting of: ticagrelor, clopidogrel, ticlopidine, prasugrel, and cangrelor. Reference herein to P2Y 12 inhibitor includes any of these compounds as well as any metabolites, e.g. active metabolites.
  • the P2Y 12 inhibitor may be selected from a list consisting of: ticagrelor, clopidogrel, ticlopidine and prasugrel, e.g. selected from the list consisting of ticagrelor, clopidogrel and prasugrel.
  • the P2Y 12 inhibitor may be ticagrelor or clopidogrel. In particularly preferred embodiments, the P2Y 12 inhibitor is ticagrelor.
  • Ticagrelor [(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol] is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. It has the following chemical structure:
  • Ticagrelor is the active ingredient in the drug product known as BRILINTA® (or BRILIQUE in Europe) which has been approved for use in multiple jurisdictions including the USA and Europe. Ticagrelor is currently marketed in the form of 60 mg and 90 mg immediate release tablets.
  • WO 2008/024045 discloses certain pharmaceutical formulations containing ticagrelor for oral administration.
  • WO 2017/182589 discloses rapidly disintegrating oral dosage forms of ticagrelor.
  • Ticagrelor is typically rapidly absorbed after oral administration. Unlike clopidogrel and prasugrel, ticagrelor is not a prodrug and does not require metabolic activation for activity. Still, ticagrelor is extensively metabolised, with ticagrelor and its active and approximately equipotent metabolite (AR-C124910XX), comprising the major circulating components in the plasma. Plasma concentrations of ticagrelor and its active metabolite increase in a dose-dependent manner; peak concentrations achieved within approximately 1.5 and 2.5 hours, respectively. Maximum inhibition of platelet aggregation is observed approximately 2 hours after a dose and this is maintained for more than 8 hours after a dose. The mean elimination half-lives for ticagrelor and its active metabolite are described in the drug label as 7 hours and 9 hours, respectively. Following discontinuance, platelet activity returns to baseline after 5 days.
  • ticagrelor is administered orally as a 180 mg loading dose in conjunction with the recombinant apyrase protein.
  • Ticagrelor may be administered in an orodispersible tablet (ODT) form, e.g. as described in WO 2017/182589.
  • ODT orodispersible tablet
  • One or more subsequent maintenance doses may be administered after the loading dose, e.g. without the recombinant apyrase protein.
  • the prescribing information for ticagrelor describes administering a maintenance dose of 90 mg twice daily during the first year after an ACS event and after one year administering 60 mg twice daily.
  • the one or more subsequent maintenance doses may comprise twice daily doses of 90 mg of ticagrelor, or twice daily doses of 60 mg of ticagrelor.
  • the prescribing information further describes administering ticagrelor with daily maintenance doses of aspirin of 75-100 mg. Accordingly, the one or more subsequent maintenance doses may further comprise administering daily doses of aspirin of 75-100 mg.
  • the P2Y 12 -receptor inhibitor may be clopidogrel.
  • Clopidogrel is typically administered via oral route.
  • clopidogrel is administered as a 300 mg or 600 mg loading dose in conjunction with the recombinant apyrase protein.
  • One or more subsequent maintenance doses may comprise about 75 mg of clopidogrel and may be administered after the loading dose, e.g. without the recombinant apyrase protein.
  • the maintenance doses of clopidogrel may be administered daily doses of aspirin of 75-100 mg.
  • Clopidogrel is a prodrug and requires metabolic activation for its activity. Peak plasma concentrations of the active metabolite occur approximately 30-60 minutes following an oral dose, with dose-dependent platelet aggregation inhibition observed in around 2 hours following administration. Following oral administration of a single dose, dose-dependent platelet aggregation inhibition can be observed in 2 hours. Clopidogrel has an elimination half-life of approximately 6 hours following a single dose of 75 mg, whilst its active metabolite has an elimination half-life of approximately 30 minutes. After discontinuance, platelet aggregation and bleeding times gradually return to baseline in about 5 days.
  • the P2Y 12 -receptor inhibitor may be prasugrel.
  • Prasugrel is typically administered via oral route.
  • prasugrel is administered as a 60 mg loading dose in conjunction with the recombinant apyrase protein.
  • One or more subsequent maintenance doses may comprise about 5 mg or 10 mg of prasugrel and may be administered after the loading dose, e.g. without the recombinant apyrase protein.
  • the maintenance doses of prasugrel may be administered with daily doses of aspirin of 75-100 mg.
  • Prasugrel is a prodrug and rapidly metabolised to a pharmacologically active metabolite. Peak plasma concentrations of the active metabolite occur approximately 30 minutes after dosing. It has an elimination half-life of about 7.4 hours.
  • the P2Y 12 -receptor inhibitor may be ticlopidine.
  • Ticlopidine is typically administered via oral route.
  • ticlopidine is typically administered via oral route.
  • ticlopidine is administered as a 500 mg loading dose in conjunction with the recombinant apyrase protein.
  • One or more subsequent maintenance doses may comprise about 250 mg of ticlopidine and may be administered after the loading dose, e.g. without the recombinant apyrase protein.
  • the maintenance doses of ticlopidine may be administered daily doses of aspirin of 75-100 mg.
  • Peak plasma levels of ticlopidine are typically observed around 2 hours after oral administration. Half-life following a single dose ranges from 7 to 13 hours. Half-life following repeated dosing is about 4 to 5 days.
  • the P2Y 12 -receptor inhibitor may be cangrelor.
  • Cangrelor may be administered intravenously as a bolus, as a continuous infusion, or as a bolus followed by a continuous infusion. In some embodiments, cangrelor is administered as a 30 ⁇ g/kg intravenous bolus followed immediately by 4 ⁇ g/kg per minute intravenous infusion.
  • Cangrelor rapidly reaches steady state plasma levels and platelet aggregation inhibition within 30 min of onset of infusion and the plasma half-life is short, being approximately less than 9 min. Maximal platelet inhibition is achieved within 15 min.
  • the elimination half-life of cangrelor is about 3-6 minutes and platelet responses typically return to baseline within 15 minutes of discontinuation.
  • the methods and products for use described herein are for treating an ischemic event in a patient (e.g. a human patient), which includes diseases and disorders where the blood supply is restricted to a particular part of the patient's body, e.g. the patient's heart or brain, where the restriction may be caused by a blood clot (thrombus).
  • Ischemic events in the heart include an acute coronary syndrome.
  • Ischemic events in the brain include acute ischemic stroke (AIS).
  • Acute coronary syndromes include myocardial infarctions classified as ST segment elevation myocardial infarction (STEMI) or non-ST segment elevation myocardial infarction (NSTEMI), and unstable angina.
  • the treatment is a treatment of a ST segment elevation myocardial infarction (STEMI) in a patient.
  • Myocardial infarctions are generally clinically classified into STEMI and NSTEMI. These are based on changes to an electrocardiogram (ECG) and can be diagnosed by a physician or other skilled medical personnel.
  • ECG electrocardiogram
  • the type of myocardial infarction may be as defined in accordance with or derived from the universal definition of myocardial infarction set out in Thygesen et al. 2018.
  • the recombinant apyrase protein is administered in conjunction with the P2Y 12 inhibitor.
  • Use of the term “in conjunction” is this context is intended to mean that following administration (e.g. within 30 minutes, or within an hour, or within 2 hours, or within 3 hours), both the P2Y 12 inhibitor (and/or a metabolite thereof) and recombinant apyrase protein are bioavailable (i.e. have an active effect) in the blood stream of the patient.
  • administration of the recombinant P2Y 12 inhibitor AZD3366 becomes active within 5 minutes and does not return to baseline for 3 to 4 weeks, whereas it typically takes longer for P2Y 12 inhibitors to become active following administration. For example, maximum activity of ticagrelor is not normally observed until around 2 hours after a dose and this is maintained for more than 8 hours.
  • both the recombinant apyrase protein and the P2Y 12 inhibitor may be physically administered at the same time in order for the recombinant apyrase protein to administered in conjunction with the P2Y 12 inhibitor.
  • the one of the recombinant apyrase protein and P2Y 12 inhibitor may be administered first, followed by the other agent being administered later (e.g. an hour or more later) provided that following administration both the recombinant apyrase protein and P2Y 12 inhibitor are bioavailable in the blood stream of the patient.
  • some patients exhibiting an ischemic event may already be regularly administering a P2Y 12 inhibitor, e.g. as part of a maintenance doses following a previous ischemic event. Such patients are referred to herein as “currently undergoing treatment with a P2Y 12 inhibitor”. For example, 90 mg doses of ticagrelor are typically administered twice daily as part of maintenance doses. In such patients that are administered with the recombinant apyrase protein according to the method herein, it may not always be necessary to administer another dose of the P2Y 12 inhibitor because the inhibitor (and/or a metabolite thereof) is still considered bioactive in the blood stream of the patient.
  • a reduced dose than the normal loading dose of the P2Y 12 inhibitor may be administered in order to top up the levels of bioactive P2Y 12 inhibitor in the blood stream.
  • a dose of 60 mg or 90 mg or 150 mg may be administered if ticagrelor is still bioactive in the patient's blood stream, as opposed to a typical loading dose of 180 mg.
  • Effective dosages may be determined by a skilled physician or other skilled medical personnel.
  • the method still comprises administering the P2Y 12 inhibitor (e.g. a loading dose) to the patient.
  • a P2Y 12 inhibitor may still be considered bioactive in the blood stream in the patient if the last dose of the inhibitor was administered within a time period corresponding to the mean elimination half-life of the P2Y 12 inhibitor, more than twice the mean elimination half-life of the P2Y 12 inhibitor, or more than three times the mean elimination half-life of the P2Y 12 inhibitor, or more than five times the mean elimination half-life of the P2Y 12 inhibitor.
  • the mean elimination half-life is 7 hours for ticagrelor and 9 hours for its active metabolite.
  • ticagrelor may be considered bioactive in the blood stream in the patient if the last dose was within the last 9 hours, within the last 18 hours, within the last 27 hours, within the last 36 hours, or within the last 45 hours.
  • the P2Y 12 inhibitor may be considered bioactive in the blood stream until activity returns to baseline following discontinuance of dosing, which in the case of ticagrelor is after 5 days.
  • na ⁇ ve patients Other patients exhibiting an ischemic event may not have previously been administered a P2Y 12 inhibitor, or may have discontinued previous P2Y 12 inhibitor administration, e.g. such that the P2Y 12 inhibitor is no longer considered bioactive in the patient's blood stream. These patients may be referred to as “na ⁇ ve” patients. In na ⁇ ve patients, in order to administer the recombinant apyrase protein in conjunction with the P2Y 12 inhibitor, it is necessary for the method to comprise a step of administering the P2Y 12 inhibitor to the patient.
  • the recombinant apyrase protein and P2Y 12 inhibitor may be administered as a combined formulation, e.g. via intravenous injection.
  • administration of the recombinant apyrase protein and P2Y 12 inhibitor to the patient may be simultaneous or sequential.
  • Simultaneous administration as used herein refers to the administration of both the recombinant apyrase protein and P2Y 12 inhibitor to the patient at essentially the same time (e.g. within 10 minutes, within 5 minutes, or within 1 minute of each other), optionally via different administration routes.
  • intravenous injection of the recombinant apyrase protein within 1 minute of the P2Y 12 inhibitor being provided by oral administration would be considered simultaneous administration.
  • the recombinant apyrase protein and P2Y 12 inhibitor are preferably administered within 24 hours, 18 hours, 12 hours, 6 hours, 2 hours, 1 hour or more preferably within 30 minutes of each other.
  • the recombinant apyrase protein is administered first, followed by the sequential administration of the P2Y 12 inhibitor.
  • the P2Y 12 inhibitor is administered first, followed by the sequential administration of the recombinant apyrase protein.
  • the recombinant apyrase protein is administered to the patient in conjunction with the P2Y 12 inhibitor 24 hours or less, or 18 hours or less, or 12 hours or less, or 6 hours or less, or 4 hours or less, or 2 hours or less, or 1 hour or less, or even 30 minutes or less after onset of the ischemic event (e.g. acute coronary syndrome such as STEMI).
  • onset of the ischemic event e.g. acute coronary syndrome such as STEMI
  • Onset of the ischemic event as referred to herein may be at the onset of one or more symptoms of the ischemic event (e.g. chest pain in the case of STEMI) or at the time of diagnosis, (e.g. via electrocardiogram in the case of acute coronary syndrome), which may be carried out prior to or shortly after the patient arrives at a hospital (or equivalent thereof) for treatment.
  • the patient is administered with the recombinant apyrase protein in conjunction with the P2Y 12 inhibitor prior to surgical reperfusion therapy (e.g. percutaneous coronary intervention (PCI)) being performed on the patient suffering from the acute coronary syndrome.
  • surgical reperfusion therapy e.g. percutaneous coronary intervention (PCI)
  • PCI percutaneous coronary intervention
  • PCI may comprise, without limitation, balloon angioplasty, stent implantation, rotational or laser atherectomy, and/or brachytherapy.
  • the stent may be, without limitation, a bare-metal stent, a drug-eluting stent, an absorbable stent, etc., as known in the art.
  • the cardioprotective effect provided by the combination of recombinant apyrase protein and P2Y 12 inhibitor may be useful to prevent and/or alleviate any injury to cardiac tissue or function attributed to the restoration of circulation following reperfusion therapy.
  • the method further comprises carrying out surgical reperfusion therapy (e.g. PCI) on the patient less than 48 hours, less than 24 hours, less than 12 hours, less than 6 hours following administering the recombinant apyrase protein.
  • surgical reperfusion therapy e.g. PCI
  • the recombinant apyrase protein and the P2Y 12 inhibitor are both administered to the patient before carrying out surgical reperfusion therapy (e.g. PCI).
  • the recombinant apyrase protein is administered to the patient before carrying out surficial reperfusion therapy (e.g. PCI) and the P2Y 12 inhibitor is administered shortly after, e.g. within 6 hours, within 4 hours, within 2 hours, or within 1 hour of the surgical reperfusion therapy being performed.
  • the recombinant apyrase protein and P2Y 12 inhibitor remain bioavailable in the patient's blood stream during surgical reperfusion therapy (e.g. PCI).
  • the disclosure includes embodiments where any of the timings described above regarding i) simultaneous or sequential administration of the recombinant apyrase protein and the P2Y 12 inhibitor; ii) timing of administration in relation to the onset of the ischemic event; and iii) timing of administration in relation to the surgical reperfusion therapy (e.g. PCI) are combined.
  • the method may comprise administering the recombinant apyrase protein within 6 hours of the onset of the ischemic event, wherein the method further comprises carrying out surgical reperfusion therapy (e.g.
  • PCI surgical reperfusion therapy
  • any of the methods described herein may further comprise administering aspirin to the patient.
  • Aspirin is typically administered as a separate formulation to the P2Y 12 inhibitor and recombinant apyrase protein and is administered simultaneously or sequentially to either one or both of the P2Y 12 inhibitor and recombinant apyrase protein.
  • aspirin is administered within 24 hours, 18 hours, 12 hours, 6 hours, 2 hours, 1 hour or more preferably within 30 minutes of administering the P2Y 12 inhibitor.
  • aspirin is administered within 24 hours, 18 hours, 12 hours, 6 hours, 2 hours, 1 hour or more preferably within 30 minutes of administering the recombinant apyrase protein.
  • aspirin is administered simultaneously with the P2Y 12 inhibitor or recombinant apyrase protein. In some embodiments, the aspirin is administered to the patient in conjunction with the P2Y 12 inhibitor 24 hours or less, or 18 hours or less, or 12 hours or less, or 6 hours or less, or 4 hours or less, or 2 hours or less, or 1 hour or less, or even 30 minutes or less after onset of the ischemic event (e.g. acute coronary syndrome such as STEMI).
  • ischemic event e.g. acute coronary syndrome such as STEMI
  • Aspirin may be administered to the patient at a dose between 50 mg to 325 mg, or 50 mg to 350 mg, e.g. 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 162 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg or 350 mg.
  • aspirin is administered to the patient at a dose between 50 mg and 200 mg, or between 100 mg and 200 mg, e.g. 162 mg.
  • aspirin is administered to the patient between 200 mg and 350 mg, or between 250 and 325 mg, e.g. 300 mg or 325 mg.
  • aspirin is administered to the patient at a dose between 75 mg and 150 mg, or between 75 mg and 100 mg.
  • treatment pertains generally to treatment and therapy of a human, in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis, prevention is also included.
  • recombinant apyrase protein described herein may be given by, for example, bolus injection, intravenously, intramuscularly, subcutaneously, inhalation, continuous infusion, sustained release, or other pharmaceutically acceptable techniques.
  • the recombinant apyrase protein will be administered to patients in a pharmaceutically acceptable form containing physiologically acceptable carriers, excipients or diluents.
  • Such diluents and excipients may be comprised of neutral buffered saline solution, antioxidants (for example ascorbic acid), low molecular weight polypeptides (for example polypeptides ⁇ 10 amino acids) amino acids, carbohydrates (for example, glucose, dextrose, sucrose, or dextrans), chelating agents such as EDTA, stabilizers (such as glutathione).
  • antioxidants for example ascorbic acid
  • low molecular weight polypeptides for example polypeptides ⁇ 10 amino acids
  • carbohydrates for example, glucose, dextrose, sucrose, or dextrans
  • chelating agents such as EDTA
  • stabilizers such as glutathione
  • co-substrates for the recombinant apyrase proteins for example, calcium (Ca 2+ ) may be administered at time of dosage for maximal activity of the enzyme.
  • Such carriers and diluents are selected to be nontoxic to the patient at recommended dosages and concentrations.
  • ticagrelor clopidogrel, ticlopidine and prasugrel are typically administered to patients in a pharmaceutically acceptable oral dosage form, while cangrelor is typically administered to patients via intravenous injection.
  • Dosage requirements of recombinant apyrase proteins may vary significantly depending on age, race, weight, height, gender, duration of treatment, methods of administration, biological activity of recombinant apyrase protein, and severity of condition or other clinical variables. Effective dosages may be determined by a skilled physician or other skilled medical personnel.
  • the method may comprise administering the recombinant apyrase proteins as a single effective dose in conjunction with a suitable dose (e.g. loading dose) of the P2Y 12 inhibitor, and optionally aspirin if present. Whilst only a single effective dose of the recombinant apyrase protein is typically used, the method may further comprise administering one or more oral doses of the P2Y 12 inhibitor periodically and subsequent to the loading dose, as part of a chronic or maintenance treatment. For example, the P2Y 12 inhibitor may be administered once or twice a day, for weeks, months or even years following the initial loading dose, e.g. at the maintenance doses described above. The maintenance doses of P2Y 12 inhibitor may be administered with aspirin, as is known in the art. Chronic or maintenance treatment of P2Y 12 inhibitors following an ischemic event is known in the art and appropriate doses and timing can be determined by a skilled physician or other skilled medical personnel.
  • a suitable dose e.g. loading dose
  • the method may further comprise
  • the recombinant apyrase protein may be administered as a pharmaceutical composition comprising the recombinant apyrase protein and a pharmaceutically acceptable carrier or diluent.
  • the P2Y 12 inhibitor may be administered as a pharmaceutical composition comprising the P2Y 12 inhibitor and a pharmaceutically acceptable carrier or diluent.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • pigs underwent temporary (90 minutes) balloon occlusion of the mid-left anterior descending coronary artery (experimental MI) and then reperfused, essentially as described in Vilahur et al. 2016. Throughout the following 42 days, the pigs received daily oral maintenance dosing of placebo (group I) or ticagrelor (90 mg/bid, groups II to IV) and serial Cardiac Magnetic Resonance (CMR) assessments were performed at day 3 (early remodeling phase) and day 42 (late remodeling phase) post-MI.
  • placebo group I
  • ticagrelor 90 mg/bid, groups II to IV
  • CMR serial Cardiac Magnetic Resonance
  • FIG. 1 This experimental design is schematically illustrated in FIG. 1 .
  • MI Magnetic ink senor
  • amiodarone 300 mg
  • lidocaine 150 mg
  • saline 250 mL/h
  • a bolus of heparin 100 U/kg
  • MI was experimentally induced by a minimally invasive closed chest myocardial balloon occlusion of the mid-portion of the left anterior descending coronary artery as previously described in Vilahur et al. 2016. Complete coronary ischemia (verified by angiography) was maintained for 90 minutes.
  • Electrocardiographic (ECG) and hemodynamic parameters were continuously recorded throughout the entire procedure and the echocardiographic system (Phillips iE33) equipped with a S5-1 sector array transducer was used prior- and post-MI induction to document the initial worsening of left ventricular ejection fraction (LVEF, M-mode analysis using the parasternal long-axis view; Vilahur et al. 2016).
  • ECG Electrocardiographic
  • RVEF left ventricular ejection fraction
  • CMR studies were conducted serially in all animals at Day 3 (early remodeling phase) and Day 42 (late remodeling phase) post-MI. The studies were performed on a 3.OT-CMR system (AchievaVR, Philips, Amsterdam, The Netherlands) and CMR image acquisition was carried out by a CMR specialized technician blinded in terms of treatment.
  • animals were anaesthetized with an intramuscular injection of a cocktail composed of ketamine, xylazine, and atropine and maintained by a continuous intravenous infusion of propofol to ensure mechanical ventilation. Once the animals were positioned in a head-first supine position with a flexible phased-array surface coil placed over the chest, ECG gating was used to acquire still images of the heart.
  • the following dedicated CMR sequences were acquired in all cases: ‘cine’ Balanced Steady-State Free Precession (bSSFP) imaging sequence to assess wall motion (WM) and cardiac function; T2-weighted short-tau inversion recovery (T2w-STIR) sequence to assess myocardial edema; early gadolinium enhancement to study microvascular obstruction (no reflow phenomenon); and late gadolinium enhancement (LGE) to assess the amount and extent of myocardial necrosis. All the CMR studies followed the same scheme. First, scout images [T1-turbo field echo (TFE) sequence] were obtained to localize the true axes of the heart and define a field of view involving the whole heart.
  • TFE T1-turbo field echo
  • the bSSFP cine imaging was performed in both horizontal and vertical long axes (four-chamber and two-chamber views) and in multiple contiguous short-axis images covering the whole left ventricle (LV).
  • the short-axis cine sequence we acquired 24 cardiac phases of every slice to guarantee a correct evaluation of the WM and heart function.
  • a T2w-STIR sequence was obtained to assess myocardial edema.
  • a gadolinium-based contrast agent was injected intravenously (Gd-GTPA, MagnevistVR, Berlex Laboratories Inc., Wayne, N.J., USA) at a dose of 0.1 mmol/kg.
  • the early gadolinium enhancement sequence was acquired 1 min after the administration of the contrast.
  • the LGE sequences were obtained 10 min after the administration of contrast.
  • the details of the technical parameters for CMR sequences and the protocol of analysis for global and regional functional/anatomical parameters has been previously published (Vilahur et al. 2016).
  • necrotic area in the ticagrelor+3 mg/kg AZD 3366 compared to ticagrelor alone and the numerical lower necrotic area in the ticagrelor+1 mg/kg AZD3366 demonstrates a dose-dependent enhanced cardioprotective effect of the combination.
  • this model is the best pre-clinical model for human disease, this is the strongest evidence possible to suggest a therapeutic effect in humans.
  • the aim of this study was to evaluate the bleeding risk and platelet aggregation inhibition of AZD3366 alone or in combination with ticagrelor in mice in vivo.
  • mice were administered an intravenous bolus of AZD3366 or vehicle.
  • mice were administered AZD3366 and ticagrelor or ticagrelor only as a bolus and continuous infusion of ticagrelor.
  • the groups, doses and volumes of administration were as described in the following table:
  • Dose Volume Bolus Infusion Bolus Infusion Group Treatment (mg/kg) ( ⁇ g/kg*min) (mL/kg) ( ⁇ L/kg*min) Vehicle (V) 5% mannitol + NA NA 1.0 + 1.0 200 + NA buffer Ticagrelor (T) ticagrelor + 1.2 + NA 30 + NA 1.0 + 1.0 200 + NA buffer AZD3366 (AZD1) 5% mannitol + NA + 1.0 NA + NA 1.0 + 1.0 200 + NA AZD3366 AZD3366 (AZD3) 5% mannitol + NA + 3.0 NA + NA 1.0 + 1.0 200 + NA AZD3366 Ticagrelor + ticagrelor + 1.2 + 1.0 30 + NA 1.0 + 1.0 200 + NA AZD3366 AZD3366 (T + AZD1)
  • Buffer 20 mmol/L Tris, 150 mmol/L NaCl, pH 7.4. NA; Not Applicable. Twelve animals were included in each study group.
  • BT blood loss and bleeding time
  • the blood sample from the abdominal aorta was collected in an Omnifix®-F 1 mL syringe (Braun Medical AG, Emmenbrucke, Germany) together with a Terumo® Neolus 27G, 0.4 ⁇ 20 mm needle (Terumo Europe N.V., Leuven Belgium).
  • Lepirudin Refludan® Bayer HealthCare Pharmaceuticals Inc
  • 10 ⁇ L, 5 mg/mL to a maximum of 1 mL blood which gives a final blood concentration of 7 ⁇ mol/L, was used as anticoagulant.
  • Whole blood was used for platelet aggregation using the Multiplate® impedance aggregometer.
  • Plasma was prepared from the remaining blood by centrifugation at 10000*g for 5 min (Ole Dich, Hvidovre, Denmark). Plasma was transferred to new tubes and stored at ⁇ 20° C. for later analysis of total plasma concentration of ticagrelor and AZD3366.
  • the plasma concentration of ticagrelor was determined by means of a Liquid Chromatographic-Mass Spectrometric (LC-MS/MS) method.
  • the plasma concentration of AZD3366 was determined by ELISA involving capture of AZD3366 with monoclonal mouse anti-AZD3366 antibody (mAb2567, Covance, Princeton, N.J., USA) coated on 96-well plates and detection of bound AZD3366 with horseradish peroxidase-conjugated polyclonal rabbit anti-AZD3366 antibody (pAb3939-HRP, Covance) using TMB as the substrate.
  • monoclonal mouse anti-AZD3366 antibody mAb2567, Covance, Princeton, N.J., USA
  • horseradish peroxidase-conjugated polyclonal rabbit anti-AZD3366 antibody pAb3939-HRP, Covance
  • Results for blood loss and BT are presented in the table below and illustrated in FIG. 2 .
  • BT Blood loss and bleeding time
  • BT Blood loss and bleeding time
  • BT Blood loss and bleeding time
  • BT Blood loss
  • BT Range Range Group Median
  • min-max Median
  • Vehicle 160 28-778 655 66-2734 Ticagrelor 1157a, b, c 139-1542 3433a, d 420-3587 AZD3366 157 34-1415 589 107-3582 1.0 mg/kg AZD3366 342e 52-1072 1438 268-2931 3.0 mg/kg Ticagrelor + 961 176-1464 2657 930-3585 AZD3366 1.0 mg/kg
  • Blood loss and BT in ticagrelor-treated animals increased 7.2-fold (p ⁇ 0.001) and 5.2-fold (p ⁇ 0.001) as compared to animals administered vehicle, respectively.
  • treatment with AZD3366 at 1 or 3 mg/kg was not associated with a statistically significant increase in blood loss or BT vs vehicle.
  • blood loss and BT in the combined ticagrelor and AZD3366 group did not differ as compared to that seen in the group of animals administered ticagrelor only.
  • AZD3366 AZD
  • T ticagrelor
  • PA AU* min
  • T ⁇ mol/L
  • AZD ticagrelor

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WO2025104274A1 (fr) * 2023-11-16 2025-05-22 Hyloris Developments Sa Ticagrélor iv destiné à être utilisé dans la prévention d'événements thromboemboliques

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WO2025104274A1 (fr) * 2023-11-16 2025-05-22 Hyloris Developments Sa Ticagrélor iv destiné à être utilisé dans la prévention d'événements thromboemboliques

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