US2015080309A1PendingUtilityA1

Compounds Suitable for Treatment of Haemophilia

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Assignee: NOVA NORDISK ASPriority: Apr 24, 2012Filed: Mar 13, 2013Published: Mar 19, 2015
Est. expiryApr 24, 2032(~5.8 yrs left)· nominal 20-yr term from priority
Inventors:Gert BoltDitte Maria KarpfFrederik RodeJesper HaaningKirstine RoepstorffLars ThimMaj PetersenMarianne KjalkeOle Hvilsted OlsenJens Jacob Hansen
A61K 9/0019C07K 14/755A61K 38/37A61P 7/04
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Claims

Abstract

The present invention relates to VWF compounds as well as compositions suitable for treatment of blood clotting diseases.

Claims

exact text as granted — not AI-modified
1 . A VWF fragment comprising up to 1200 amino acids, wherein said VWF fragment comprises the TIL′ domain. 
     
     
         2 . A VWF fragment according to  claim 1 , wherein said fragment comprises the TIL′ and the E′ domains. 
     
     
         3 . A VWF fragment according to  claim 1 , wherein said VWF fragment comprises one or two amino acid substitution(-s) of the 1099 and/or 1142 cysteine(s-). 
     
     
         4 . A VWF fragment according to  claim 1 , wherein less than 5% of said VWF fragment are in the form of oligomers and/or multimers. 
     
     
         5 . A VWF fragment according to  claim 1 , wherein said VWF fragment is part of a dimer. 
     
     
         6 . A VWF fragment according to  claim 1 , wherein said VWF fragment is a monomer. 
     
     
         7 . A VWF fragment according to  claim 1 , wherein said fragment comprises an amino acid sequence selected from the list consisting of: SEQ ID NO 4, SEQ ID NO 5, SEQ ID NO 6, SEQ ID NO 7, SEQ ID NO 8, SEQ ID NO 9, SEQ ID NO 10, SEQ ID NO 11, SEQ ID NO 12, SEQ ID NO 13, SEQ ID NO 14, SEQ ID NO 15, SEQ ID NO 16, SEQ ID NO 17, SEQ ID NO 18, SEQ ID NO 19, SEQ ID NO 20 and SEQ ID NO 21. 
     
     
         8 . A VWF fragment according to  claim 1 , wherein said fragment comprises SEQ ID NO 9, wherein the 1099 cysteine residue is substituted with another amino acid. 
     
     
         9 . A VWF fragment according to  claim 8 , wherein the 1099 cysteine residue is substituted with serine. 
     
     
         10 . A VWF fragment according to  claim 1 , wherein said fragment comprises an amino acid sequence selected from the list consisting of: SEQ ID NO 10, SEQ ID NO 11, SEQ ID NO 12, SEQ ID NO 13, SEQ ID NO 14, SEQ ID NO 15, SEQ ID NO 16, SEQ ID NO 17, SEQ ID NO 18, SEQ ID NO 19, SEQ ID NO 20 and SEQ ID NO 21, wherein the 1099 and the 1142 cysteine residues are substituted with another amino acid. 
     
     
         11 . A VWF fragment according to  claim 10 , wherein the 1099 and the 1142 cysteine residues are substituted with serine. 
     
     
         12 . A pharmaceutical composition comprising: (i) a VWF fragment according to  claim 1 ; and (ii) a FVIII molecule. 
     
     
         13 . A pharmaceutical composition according to  claim 12 , wherein said FVIII molecule comprises a truncated B domain at a size of 5-700 amino acids. 
     
     
         14 . A pharmaceutical composition according to  claim 12 , wherein FVIII is a B domain truncated variant, wherein the amino acid sequence of said truncated B domain is derived from the wt FVIII B domain amino acid sequence as set forth in SEQ ID NO 1. 
     
     
         15 . A pharmaceutical composition according to  claim 14 , wherein said B domain comprises an O-glycan linked to the Ser 750 amino acid residue as set forth in SEQ ID NO 1. 
     
     
         16 . A pharmaceutical composition according to  claim 12 , wherein said FVIII molecule is conjugated with at least one half-life extending moiety. 
     
     
         17 . A pharmaceutical composition according to  claim 12 , wherein at least one half life extending moiety is covalently attached to an O-glycan present in the FVIII B domain. 
     
     
         18 . A pharmaceutical composition according to  claim 12 , wherein the bioavailability of said FVIII molecule is at least 5% following subcutaneous administration. 
     
     
         19 . A pharmaceutical composition according to  claim 12 , wherein the molar ratio between FVIII and VWF is 1:1. 
     
     
         20 . A pharmaceutical formulation according to  claim 12 , wherein the concentration of FVIII is at least 500 IU/ml. 
     
     
         21 . A pharmaceutical formulation according to  claim 12 , wherein the amount of FVIII bound to VWF fragment is at least 70% of the total amount of FVIII in said formulation. 
     
     
         22 . A pharmaceutical composition according to  claim 12  for use in treating haemophilia, wherein said pharmaceutical composition is for subcutaneous administration. 
     
     
         23 . A pharmaceutical composition wherein said composition comprises a VWF fragment, wherein the amino acid sequence of said VWF fragment is selected from the list consisting of: SEQ ID NO 4, SEQ ID NO 5, SEQ ID NO 6, SEQ ID NO 7, SEQ ID NO 8, SEQ ID NO 9, SEQ ID NO 10, SEQ ID NO 11, SEQ ID NO 12, SEQ ID NO 13, SEQ ID NO 14, SEQ ID NO 15, SEQ ID NO 16, SEQ ID NO 17, SEQ ID NO 18, SEQ ID NO 19, SEQ ID NO 20 and SEQ ID NO 21. 
     
     
         24 . A pharmaceutical composition according to  claim 23  for use in treatment of von willebrand disease by intravenous or subcutaneous administration.

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