US2016318991A1PendingUtilityA1

Compounds Suitable for Treatment of Haemophilia

Assignee: NOVO NORDISK ASPriority: Apr 24, 2012Filed: May 4, 2016Published: Nov 3, 2016

Est. expiryApr 24, 2032(~5.7 yrs left)· nominal 20-yr term from priority

Inventors:Gert Bolt Ditte Maria Karpf Frederik Rode Jesper Haaning Kirstine Roepstorff Lars Thim Maj Petersen Marianne Kjalke Ole Hvilsted Olsen Jens Jacob Hansen

C07K 14/755A61K 9/0019A61K 38/37A61P 7/04

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References

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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