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

A pharmaceutical composition or a fusion molecule comprising a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist,

• wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as an FGF21 activity of a native FGF21 and is an FGF21 variant comprising at least one mutation selected from the group consisting of:
• a substitution of amino acid residues at positions 98 to 101 from a N-terminus of the native FGF21 having a sequence of SEQ ID NO:
• 2 with an amino acid sequence EIRP (SEQ ID NO:
• 44);
• a substitution of amino acid residues at positions 170 to 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAV (SEQ ID NO:
• 45);
• a substitution of amino acid residues at positions 170 to 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAN (SEQ ID NO:
• 46);
• a substitution of an amino acid residue at position 170 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid N;
• a substitution of an amino acid residue at position 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with the amino acid N;
• a substitution of an amino acid residue at position 180 from the N-terminus of the native FGF21 having a sequence of SEQ ID NO:
• 2 with an amino acid E, along with one or more mutations as defined above;
• and
• a mutation of 1 to 10 amino acid residues for reducing immunogenicity of the FGF21 variant as compared to the native FGF21 having the sequence of SEQ ID NO:
• 2,
• wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to a GLP-1R agonistic activity of a native GLP-1(7-36), and
• wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.

A kit comprising a combination , a pharmaceutical composition, a fusion molecule, a nucleic acid molecule encoding the fusion molecule, or a host cell containing the nucleic acid molecule,

• wherein the combination, the pharmaceutical composition, and the fusion molecule comprise a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist,
• wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as an FGF21 activity of a native FGF21 and is an FGF21 variant comprising at least one mutation selected from the group consisting of:
• a substitution of amino acid residues at positions 98 to 101 from a N-terminus of the native FGF21 having a sequence of SEQ ID NO:
• 2 with an amino acid sequence EIRP (SEQ ID NO:
• 44);
• a substitution of amino acid residues at positions 170 to 174 from a N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAV (SEQ ID NO:
• 45);
• a substitution of amino acid residues at positions 170 to 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAN (SEQ ID NO:
• 46);
• a substitution of an amino acid residue at position 170 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid N;
• a substitution of an amino acid residue at position 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with the amino acid N;
• a substitution of an amino acid residue at position 180 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid E, along with one or more mutations as defined above;
• and
• a mutation of 1 to 10 amino acid residues for reducing immunogenicity of the FGF21 variant as compared to the native FGF21 having the sequence of SEQ ID NO:
• 2,
• wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to a GLP-1R agonistic activity of a native GLP-1(7-36), and
• wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.

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, nonalcoholic steatohepatitis (NASH), and atherosclerosis, the method comprising administering a combination, a pharmaceutical composition, a fusion molecule, a nucleic acid molecule encoding the fusion molecule, or a host cell containing the nucleic acid molecule to a subject in need thereof,

• wherein the combination, the pharmaceutical composition, and the fusion molecule comprise a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist,
• wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as an FGF21 activity of a native FGF21 and is an FGF21 variant comprising at least one mutation selected from the group consisting of:
• a substitution of amino acid residues at positions 98 to 101 from a N-terminus of the native FGF21 having a sequence of SEQ ID NO:
• 2 with an amino acid sequence EIRP (SEQ ID NO:
• 44);
• a substitution of amino acid residues at positions 170 to 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAV (SEQ ID NO:
• 45);
• a substitution of amino acid residues at positions 170 to 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid sequence TGLEAN (SEQ ID NO:
• 46);
• a substitution of an amino acid residue at position 170 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid N;
• a substitution of an amino acid residue at position 174 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with the amino acid N;
• a substitution of an amino acid residue at position 180 from the N-terminus of the native FGF21 having the sequence of SEQ ID NO:
• 2 with an amino acid E, along with one or more mutations as defined above;
• and
• a mutation of 1 to 10 amino acid residues for reducing immunogenicity of the FGF21 variant as compared to the native FGF21 having the sequence of SEQ ID NO:
• 2,
• wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to a GLP-1R agonistic activity of a native GLP-1(7-36), and
• wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.