Combination treatment

Abstract

The present invention relates to methods for treating ischemic events in a patient, especially ST-segment elevation myocardial infarction and acute ischemic stroke, by administrating a recombinant apyrase protein in conjunction with a P2Y 12 inhibitor.

1 . 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. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A method according to  claim 1 , wherein the method comprises administering the recombinant apyrase protein and the P2Y 12  inhibitor to the patient simultaneously, or administering the recombinant apyrase protein and the P2Y 12  inhibitor to the patient sequentially, optionally on the same day. 
     
     
         6 . A method according to  claim 5 , wherein the method comprises
 a. administering the recombinant apyrase protein to the patient, followed by the sequential administration of the P2Y 12  inhibitor; or   b. administering the P2Y 12  inhibitor to the patient, followed by the sequential administration of the recombinant apyrase protein.   
     
     
         7 . A method according to  claim 1  wherein the recombinant apyrase protein is administered to the patient within 24 hours or within 12 hours of the P2Y 12  inhibitor being administered to the patient. 
     
     
         8 . A method according to  claim 1 , wherein the method further comprises at least daily administrations of the P2Y 12  inhibitor to the patient starting at least 24 hours after the recombinant apyrase protein is administered in conjunction with the P2Y 12  inhibitor, optionally wherein these daily administrations are continued for at least 1 month, at least 2 months, or at least 6 months. 
     
     
         9 . A method according to  claim 1 , wherein the P2Y 12  inhibitor is selected from a list consisting of: ticagrelor, clopidogrel, ticlopidine, prasugrel, and cangrelor. 
     
     
         10 . A method according to  claim 9 , wherein the P2Y 12  inhibitor is ticagrelor. 
     
     
         11 . A method according to  claim 1 , wherein the recombinant apyrase protein is a soluble CD39L3 protein comprising an amino acid sequence that is at least 80% identical to positions 49-485 of SEQ ID NO: 1. 
     
     
         12 . A method according to  claim 11 , wherein the recombinant apyrase protein comprises one or more modifications compared to a reference CD39L3 protein that has the amino acid sequence set forth in positions 49-485 of SEQ ID NO: 1, wherein the modification results in increased ADPase activity compared with the reference apyrase or wherein said modification results in the same ADPase activity as the reference apyrase combined with decreased ATPase activity as compared with the reference apyrase. 
     
     
         13 . A method according to  claim 12 , wherein the recombinant apyrase protein comprises substitutions at position 67 and 69 compared to the reference CD39L3 protein, wherein the positions are numbered according to SEQ ID NO: 1. 
     
     
         14 . A method according to  claim 13 , wherein the substitution at position 67 is to a glycine and the substitution at position 69 to an arginine. 
     
     
         15 . A method according to  claim 1 , wherein the recombinant apyrase protein comprises the amino acid sequence set forth as SEQ ID NO: 2. 
     
     
         16 . A method according to  claim 1 , wherein the recombinant apyrase protein is administered at a dose of 10 mg to 1000 mg. 
     
     
         17 . A method according to  claim 1 , wherein:
 a. the P2Y 12  inhibitor is ticagrelor and is administered at a dose of between 60 to 200 mg, optionally 180 mg;   b. the P2Y 12  inhibitor is clopidogrel and is administered at a dose of between 75 to 600 mg, optionally 300 mg or 600 mg;   c. the P2Y 1 2inhibitor is ticlopidine and is administered at a dose of 250 to 500 mg, optionally 500 mg;   d. the P2Y 12  inhibitor is prasugrel and is administered at a dose of 5 to 60 mg, optionally 60 mg; or   e. the P2Y 12  inhibitor is cangrelor and is administered at a dose of 30 μg/kg intravenous bolus followed by 4 μg/kg per minute intravenous infusion.   
     
     
         18 . A method according to  claim 1 , wherein the method further comprises administering aspirin to the patient, optionally wherein the aspirin is administered at between 50 to 325 mg. 
     
     
         19 . A method according to  claim 1 , wherein the ischemic event is an acute ischemic stroke. 
     
     
         20 . A method according to  claim 1 , wherein the ischemic event is an acute coronary syndrome. 
     
     
         21 . A method according to  claim 20 , wherein the ischemic event is ST-segment elevation myocardial infarction (STEMI). 
     
     
         22 . A method according to  claim 20 , wherein the recombinant apyrase protein is administered to the patient in conjunction with the P2Y 12  inhibitor 24 hours or less, or 12 hours or less, or 6 hours or less after onset of the ischemic event. 
     
     
         23 . A method according to  claim 20 , wherein the method further comprises carrying out surgical reperfusion therapy 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 in conjunction with the P2Y 12  inhibitor, optionally wherein the surgical reperfusion therapy is percutaneous coronary intervention (PCI).