Fgf21 compound / glp-1r agonist combinations with optimized activity ratio

Abstract

The present invention relates to combinations, pharmaceutical compositions and fusion molecules comprising an FGF21 (fibroblast growth factor 21) compound and a GLP-1R (glucagon-like peptide-1 receptor) agonist with optimized GLP-1R agonist/FGF21 compound activity ratio. It further relates to their use as medicaments, in particular for the treatment of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and/or atherosclerosis.

1 . A combination comprising an FGF21 (fibroblast growth factor 21) compound and a GLP-1R (glucagon-like peptide-1 receptor) agonist, wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21, and wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36). 
     
     
         2 . The combination according to  claim 1 , wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 482-fold or 9- to 319-fold or 9- to 121-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36). 
     
     
         3 . The combination according to  claim 1 , wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 18- to 501-fold or 18- to 469-fold or 18- to 313-fold or 18-to 123-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36). 
     
     
         4 . The combination according to  claim 1 , wherein the FGF21 compound is native FGF21 or an FGF21 variant having at least 80% or at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of native FGF21. 
     
     
         5 . The combination according to  claim 1 , wherein the GLP-1R agonist comprises or consists of the amino acid sequence 
       
         
           
                 
               
                   (SEQ ID NO: 37) 
                 
                   H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X14-X 15 -E-E-X 18 -V-X 20 - 
                 
                   X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30 ,  
                 
             
                
                
                
               
            
           
         
       
       wherein
 X 10  is L or K; 
 X 12  is K or I; 
 X 14  is L or M; 
 X 15  is E or D; 
 X 18  is A or R; 
 X 20  is R or Q; 
 X 21  is L or E; 
 X 27  is L, E, K or V; 
 X 28  is A, N or K; 
 X 29  is T or G; 
 X 30  is G or R; 
 wherein, optionally, the amino acid sequence comprises at least one additional amino acid residue at its N-terminus; and 
 wherein, optionally, the amino acid sequence comprises a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus. 
 
     
     
         6 . The combination according to  claim 1 , wherein the GLP-1R agonist comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 10, 12, 14, 15, 16, 17, 19 and 20. 
     
     
         7 . A pharmaceutical composition comprising an FGF21 (fibroblast growth factor 21) compound and a GLP-1R (glucagon-like peptide-1 receptor) agonist together with a pharmaceutically acceptable carrier and/or excipient, wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21, and wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36) or
 a fusion molecule comprising an FGF21 (fibroblast growth factor 21) compound and a GLP-1R (glucagon-like peptide-1 receptor) agonist,   wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21, and   wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36).   
     
     
         8 . (canceled) 
     
     
         9 . The pharmaceutical composition according to  claim 7 , wherein the wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 482-fold or 9- to 319-fold or 9- to 121-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36), and/or the FGF21 compound is native FGF21 or an FGF21 variant having at least 80% or at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of native FGF21. 
     
     
         10 . A nucleic acid molecule encoding a fusion molecule according to  claim 8 . 
     
     
         11 . A host cell containing a nucleic acid molecule according to  claim 10 . 
     
     
         12 . A kit comprising a combination according to  claim 1 . 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A method of treating a disease or disorder selected from the group consisting of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopathy, hyperglycemia, dyslipidemia, Non-Alcoholic SteatoHepatitis (NASH) and atherosclerosis, the method comprising administering a combination according to  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the diabetes mellitus is type 1 diabetes mellitus or type 2 diabetes mellitus. 
     
     
         18 . A GLP-1R agonist having a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36). 
     
     
         19 . The GLP-1R agonist according to  claim 18  comprising or consisting of the amino acid sequence 
       
         
           
                 
               
                   (SEQ ID NO: 37) 
                 
                   H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X14-X 15 -E-E-X 18 -V-X 20 - 
                 
                   X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30 ,  
                 
             
                
                
                
               
            
           
         
       
       wherein
 X 10  is L or K; 
 X 12  is K or I; 
 X 14  is L or M; 
 X 15  is E or D; 
 X 18  is A or R; 
 X 20  is R or Q; 
 X 21  is L or E; 
 X 27  is L, E, K or V; 
 X 28  is A, N or K; 
 X 29  is T or G; 
 X 30  is G or R; 
 wherein, optionally, the amino acid sequence comprises at least one additional amino acid residue at its N-terminus; and 
 wherein, optionally, the amino acid sequence comprises a peptide extension consisting of up to 12, 11 or 10 amino acid residues at its C-terminus. 
 
     
     
         20 . The GLP-1R agonist according to  claim 18  comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 10, 12, 14, 15, 16, 17, 19 and 20. 
     
     
         21 . A kit comprising a nucleic acid molecule according to  claim 10 . 
     
     
         22 . A kit comprising a host cell according to  claim 11 . 
     
     
         23 . The fusion molecule according to  claim 7 , wherein the wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 482-fold or 9- to 319-fold or 9- to 121-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36). 
     
     
         24 . The fusion molecule according to  claim 7 , wherein the wherein the FGF21 compound is native FGF21 or an FGF21 variant having at least 80% or at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of native FGF21.