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 - 7 . (canceled) 
     
     
         8 . 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).   
     
     
         9 . (canceled) 
     
     
         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 container comprising a fusion molecule according to  claim 8 , and a data carrier. 
     
     
         13 - 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 an effective amount of a fusion molecule according to  claim 8  to a subject in need thereof. 
     
     
         17 . The method of  claim 16 , wherein the diabetes mellitus is type 1 diabetes mellitus. 
     
     
         18 - 20 . (canceled) 
     
     
         21 . The method of  claim 16 , wherein the diabetes mellitus is type 2 diabetes mellitus. 
     
     
         22 . The fusion molecule according to  claim 8 , 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). 
     
     
         23 . The fusion molecule according to  claim 8 , 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). 
     
     
         24 . The fusion molecule according to  claim 8 , 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. 
     
     
         25 . The fusion molecule according to  claim 8 , wherein the GLP-1R agonist comprises the amino acid sequence H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X 14 -X 15 -E-E-X 15 -V-X 20 -X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30  (SEQ ID NO: 37),
 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 2 i 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; and   X 30  is G or R.   
     
     
         26 . The fusion molecule according to  claim 25 , wherein the GLP-1R agonist consists of the amino acid sequence H-G-E-G-T-F-T-S-D-X 10 -S-X 12 -Q-X 14 -X 15 -E-E-X 18 -V-X 20 -X 21 -F-I-E-W-L-X 27 -X 28 -X 29 -X 30  (SEQ ID NO: 37),
 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 2 i 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; and   X 30  is G or R.   
     
     
         27 . The fusion molecule according to  claim 25 , wherein the amino acid sequence comprises at least one additional amino acid residue at its N-terminus. 
     
     
         28 . The fusion molecule according to  claim 25 , wherein the amino acid sequence comprises a peptide extension consisting of up to 10, 11 or 12 amino acid residues at its C-terminus. 
     
     
         29 . The fusion molecule according to  claim 8 , wherein the GLP-1R agonist comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 10, 12, 14, 15, 16, 17, 19 and 20. 
     
     
         30 . The fusion molecule according to  claim 8 , wherein the GLP-1R agonist 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.