Methods of treating metabolic disorders with FGF21 variants

Abstract

To provide a human FGF21 protein variant for use in improved FGF21 therapies with clinically acceptable dosing regimen, useful for the treatment of metabolic diseases and for reduction of cardiovascular risk in patients.SOLUTION: The present invention provides a human FGF21 protein variant for use in a method of treating, preventing, or managing a metabolic disorder or a cardiovascular disorder in a human subject, wherein the human FGF21 protein variant is provided for administration at a dose in the range of 100 mg to 600 mg.SELECTED DRAWING: None

Description

[Technical field]

[0001] I. Field of the Invention The present disclosure provides FGF21 protein mutants, including Fc-FGF21 mutant fusion proteins. Methods for treating, preventing, and managing metabolic or cardiovascular disorders using the body, and methods for reducing cardiovascular risk This invention relates to a method for reducing [Background technology]

[0002] II. Background technology Insulin resistance is common and plays a central role in the pathogenesis of multiple diseases Central fat storage has been shown to have detrimental effects on insulin sensitivity. , an important source of proinflammatory cytokines and nonesterified fatty acids. Insulin resistance and metabolic disorders related to fat accumulation include diabetes, obesity, dyslipidemia, coronary heart disease, and N It manifests in various forms such as AFLD / NASH. Fibroblast growth factor 21 (FGF2 1) Improves insulin sensitivity, lowers triglycerides, and reduces fat storage Therefore, it is considered that the drug acts on the liver and adipose tissues by increasing the amount of FGF21 analogs with dosing regimens that can be used to treat these metabolic disorders are a frontline treatment option. It is hoped that it will be therapeutic.

[0003] FGF21 is a member of the fibroblast growth factor family and has multiple metabolic functions. FGF21 is secreted primarily from hepatocytes and, to a lesser extent, from adipose and pancreatic β cells. In mice, FGF21 expression is induced under both starvation and obesity conditions. FGF21 has been shown to be a critical metabolic regulator in various Beneficial metabolic effects, e.g., in both preclinical models and in patients with type 2 diabetes mellitus (T2DM) Weight loss, improved insulin sensitivity, and high-density lipoprotein cholesterol in Increase in HDL-C and low-density lipoprotein-cholesterol (LDL-C), FGF21 induces a decrease in triglyceride (TG) and hepatic TG content. Effectively reduces glucose without inducing hypoglycemia in a non-clinical animal model of diabetes In T2DM patients with increased body mass index, FGF21 protein analogs were used. Four weeks of treatment with DMARDs resulted in significant improvements in lipid profiles, with results in animal models comparable to those in humans. The translatability of the metabolic effects observed in 3,Cell Metab.18(3):333-40;Dong et al.,20 15,Br J Clin Pharmacol.doi:10.1111 / bcp.1 2676). Gaich et al. LY240531, a mutant form of FGF21, in a randomized, placebo-controlled, double-blind, proof-of-concept study 9, in which patients received either placebo or 3, 10, or 20 mg of L The subjects were administered Y2405319 daily for 28 days. Dong et al. Single-dose administration of PF-05231023, a potent fibroblast growth factor 21 (FGF21) analogue To evaluate the pharmacokinetics / pharmacodynamics (PK / PD), safety, and tolerability of the intravenous (IV) dose We describe the first-in-human trial for PF-05231023 and The mean terminal half-life of the intact C- and N-termini was 1.0-fold higher than that of the intact C- and N-termini. The mean time to death was 6.5 to 7.7 hours and 66.5 to 96.6 hours, respectively. . Summary of the Invention [Problem to be solved by the invention]

[0004] Clinically acceptable and useful for treating metabolic disease and reducing cardiovascular risk in patients There remains a need for improved FGF21 therapies with dosing regimens that [Means for solving the problem]

[0005] III. Summary of the Invention Novel modifications to FGF21 have reduced half-life and / or efficacy relative to wild-type FGF21. The present invention provides a method for treating or managing metabolic or cardiovascular disorders with improved efficacy and clinically favorable dosing regimens. to treat (e.g., reduce one or more symptoms of) a disorder or to reduce cardiovascular risk We can present an FGF21 treatment for this purpose.

[0006] In particular embodiments, hypertriglyceridemia and cardiac risk, genetic mutations in the insulin receptor Insulin resistance and lipodystrophy, diabetes, obesity, and Nonalcoholic fatty liver disease (NAFLD) / nonalcoholic steatohepatitis (NASH) FGF21 Protein Mutations for Use in Methods of Treatment, Prevention, and / or Management - Patent application FGF21 protein variants (e.g., Fc fusion proteins, etc.) described in Table 1 ), and pharmaceutical compositions comprising such FGF21 protein variants are provided herein.

[0007] V103 is stabilized through the introduction of a novel disulfide bond and contains a histone residue at its N-terminus. It is a genetically engineered variant of human FGF21 fused to human IgG1 Fc (PCT publication No. WO 2013 / 049247, the entire contents of which are incorporated herein by reference. (See also the literature for more details.) Stability of human FGF21 mutants and their fusion to IgG1 Fc The combination of wild-type (WT) human FGF2 This results in approximately a 50- to 100-fold improvement in half-life compared to 1 (approximately 2 hours).

[0008] V103 is a published study of FGF21 in animal models of insulin-resistant T2DM. Effects such as reductions in body weight, glucose, insulin, serum TG and liver TG content V103 also inhibits the expression of β-lactamase in a mouse model of nonalcoholic steatohepatitis (NASH). The study showed a significant reduction in liver lipids, fibrosis and inflammation in patients with high triglycerides. and cardiovascular risk, and insulin resistance, including in patients with genetic mutations in the insulin receptor. Respiratory and lipodystrophy, diabetes, obesity, and nonalcoholic fatty liver disease (NAF Treatment, prevention, and / or treatment of metabolic disorders, including nonalcoholic steatohepatitis (LD) and nonalcoholic steatohepatitis (NASH) Pharmaceutical composition comprising FGF21 protein variant V103 (SEQ ID NO: 11) for administration is provided herein.

[0009] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder in a human subject is provided. Provided herein are human FGF21 protein variants for use in the methods, The human FGF21 protein variant is intended for administration at a dose ranging from 100 mg to 600 mg. In one aspect, the present invention provides a method for treating, preventing, or treating a metabolic or cardiovascular disorder in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering wherein the human FGF21 protein variant is administered in an amount ranging from 100 mg to 600 mg. The present invention is provided for administration at .

[0010] In some embodiments of this aspect, the metabolic or cardiovascular disorder is hypercholesterolemia. diabetes, dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), The disease is selected from alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

[0011] In some embodiments of this aspect, the method comprises treating, preventing, or managing a metabolic or cardiovascular disorder. The purpose of the present invention is to measure the body weight, liver fat content, increased LDL-C, total cholesterol, Reduce one or more of the following: triglycerides, apolipoprotein B levels In certain embodiments thereof, the method comprises administering to a subject a metabolic or cardiovascular disorder. Treating, preventing, or managing can include increasing HDL-C levels in a subject. In some embodiments thereof, the method comprises administering to the subject a therapeutically effective amount of a therapeutically effective amount of a metabolic or cardiovascular disorder. Treating, preventing, or managing a vascular disorder includes reducing triglyceride levels in a subject. and / or characterized by a reduction of at least about 40% or at least about 50%. In some embodiments thereof, the method comprises the steps of treating, preventing, or managing a metabolic or cardiovascular disorder. The method includes or is characterized by reducing cardiovascular risk in a subject. It can be attached.

[0012] In some embodiments of this aspect, the human FGF21 mutant is based on the numbering of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. The specific fusion protein is a fusion protein comprising a human Fc region fused to a protein or a fragment thereof. In embodiments, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11. .

[0013] In some embodiments of this aspect, the human FGF21 protein variant comprises at least 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, or 40 In some embodiments thereof, human FGF21 TATA is provided for administration at a dose of 0 mg. Protein variants are approximately 100mg, 110mg, 120mg, 130mg, 140mg, For administration in doses of 150 mg, 160 mg, 170 mg, 180 mg, or 190 mg and optionally, the human FGF21 protein variant is about 100 mg or 15 mg. In some embodiments thereof, the human FGF21 protein variant is provided in a dose of 0 mg. Variants: Approx. 200mg, 210mg, 220mg, 230mg, 240mg, 250mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320 20 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg doses, optionally Typically, the human FGF21 protein variant is administered at a dose of about 200 mg, 250 mg, or 300 mg. It is provided in a dose of 1 g.

[0014] In some embodiments of this aspect, the human FGF21 protein variant is administered subcutaneously. In some embodiments, the human FGF21 protein variant is provided in a form that is once every 4 weeks, once every 3 weeks, once every 2 weeks, or once every week In some embodiments thereof, the human FGF21 protein variant is Once a month, once every 4 weeks, once every 3 weeks, once every 2 weeks, or once a week In some embodiments thereof, the human FGF21 protein variant is provided in the form of a dosage form. The variant is provided in a form to be administered subcutaneously.

[0015] In one aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, or managing a metabolic or cardiovascular disorder. Provided herein are human FGF21 protein variants, wherein the human FGF21 variants The unit dose of the protein variant is in the range of 100 mg to 600 mg. Human FGF in the manufacture of a medicament for treating, preventing, or managing a metabolic or cardiovascular disorder Provided herein is a human FGF21 protein variant, the amount of the human FGF21 protein variant being: It is in the range of 100mg to 600mg.

[0016] In some embodiments of this aspect, the metabolic or cardiovascular disorder is hypercholesterolemia. diabetes, dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), The disease is selected from alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

[0017] In some embodiments of this aspect, the method comprises treating, preventing, or managing a metabolic or cardiovascular disorder. What you should do is measure your body weight, liver fat content, increased LDL-C, total cholesterol, triglycerides, and apolipoprotein B levels. In some embodiments thereof, the present invention is characterized in that the Preventing or controlling may include or involve increasing HDL-C levels. In some embodiments thereof, the triglyceride level is at least about In some embodiments thereof, the metabolic or cardiac disorder is reduced by at least about 40% or at least about 50%. Treating, preventing, or managing vascular disorders may include or include reducing cardiovascular risk. is characterized by it.

[0018] In some embodiments of this aspect, the human FGF21 mutant is based on the numbering of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. A fusion protein is a protein that contains a human Fc region fused to a protein or a fragment thereof. In some embodiments, the human FGF21 protein variant has the amino acid sequence of SEQ ID NO:11. include.

[0019] In some embodiments of this aspect, the human FGF21 protein variant comprises at least 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, or 40 In some embodiments, the human FGF21 protein is provided for administration at a dose of 0 mg. The protein variants are approximately 100mg, 150mg, 200mg, 250mg, 300mg, and 35mg. In some embodiments, the method is provided for administration to humans at a dose of 0 mg, 100 mg, 200 mg, or 400 mg. The FGF21 protein variants were administered in doses of approximately 100 mg, 110 mg, 120 mg, 130 mg, Doses of 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or 190 mg and optionally the human FGF21 protein variant is provided for administration at about 100 In some embodiments, human FG is provided for administration at a dose of 100 mg or 150 mg. The F21 protein variants were approximately 200mg, 210mg, 220mg, 230mg, and 24mg. 0mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, For administration in doses of 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg Optionally, the human FGF21 protein variant is about 200 mg, 250 mg, It is provided for administration in doses of 100 mg, 200 mg, or 300 mg.

[0020] In some embodiments, the human FGF21 protein variant is administered once a month or every four weeks. are provided for administration once every week, once every 3 weeks, once every 2 weeks, or once every week. In some embodiments, the human FGF21 protein variant is administered once a month or every four weeks. once every 3 weeks, once every 2 weeks, or once every week. In some embodiments, the human FGF21 protein variant is formulated for subcutaneous administration. In some embodiments, the human FGF21 protein variant is administered subcutaneously. It is provided in a form that should be

[0021] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder in a human subject is provided. The method comprises administering a human FGF21 protein variant at a dose in the range of 100 mg to 600 mg. In one aspect, a method is provided herein for administering to a subject in a human subject. The present invention relates to a method for treating, preventing, or managing a metabolic or cardiovascular disorder caused by human FGF21. and administering to the subject an amount of the protein variant in the range of 100 mg to 600 mg. is provided herein.

[0022] In some embodiments, the metabolic or cardiovascular disorder is hypercholesterolemia, dyslipidemia, Normal, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic The disease is selected from non-alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

[0023] In some embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder includes administering to a subject a therapeutically effective amount of ... medicament for which the therapeutically effective amount is at least 50 mg / kg. , body weight, liver fat content, increased LDL-C, total cholesterol, triglycerides in subjects and / or apolipoprotein B levels. In certain embodiments, the method is characterized by treating, preventing, or treating a metabolic or cardiovascular disorder. Managing may include or involve increasing HDL-C levels in the subject. In some embodiments, the method is for treating or preventing a metabolic or cardiovascular disorder. Managing or decreasing triglyceride levels in a subject by at least about 40% or less Some include or are characterized by a reduction of at least about 50%. In embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder comprises administering to a subject The present invention includes or is characterized by reducing cardiovascular risk associated with

[0024] In some embodiments, the human FGF21 mutant is Q55 based on the numbering of SEQ ID NO:1. C, R105K, G148C, K150R, P158S, S195A, P199G, and or a mature human FGF21 protein comprising one or more mutations selected from In a particular embodiment, the fusion protein comprises a human Fc region fused to the fragment. The human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0025] In some embodiments, the method comprises administering to a subject at least one human FGF21 protein variant. 00mg, 150mg, 200mg, 250mg, 300mg, 350mg, or 400 In some embodiments, the method comprises administering to the subject a dose of human FG F21 protein variants were administered at approximately 100mg, 110mg, 120mg, 130mg, and 140mg. mg, 150mg, 160mg, 170mg, 180mg, or 190mg doses In some embodiments, the method comprises administering to a subject a human FGF21 protein. In some embodiments, the method comprises administering the variant to a subject at a dose of about 100 mg or 150 mg. In an embodiment, the method comprises administering about 200 mg, 210 mg, or 300 mg of a human FGF21 protein variant. 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280m g, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or In some embodiments, the method comprises administering to the subject a dose of 350 mg. The FGF21 protein variant was administered at a dose of about 200 mg, 250 mg, or 300 mg. This includes administering it to elephants.

[0026] In some embodiments, the human FGF21 protein variant is administered once a month or every four weeks. It is administered once every week, once every three weeks, once every two weeks, or once every week. In one embodiment, the human FGF21 protein variant is administered once a month or once every four weeks. It is administered once every three weeks, once every two weeks, or once every week. The method comprises administering a human FGF21 protein variant in a form suitable for subcutaneous administration. In some embodiments, the method comprises administering a human FGF21 protein variant subcutaneously. In some embodiments, the human FGF21 protein variant is administered to It is administered subcutaneously.

[0027] Each of the foregoing aspects and embodiments, as well as other elements described herein, may be used in any They may be combined in a fashion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] IV. DETAILED DESCRIPTION OF THE PRESENT EMBODIMENT Treating, preventing, or managing a metabolic or cardiovascular disorder (e.g., one or more symptoms of the disorder) The present invention relates to a method and pharmaceutical composition for use in reducing the symptoms of rheumatoid arthritis in a subject in need thereof, comprising administering to said subject Human FGF21 protein variants (e.g., Fc-FGF21 mutant fusion proteins) , for example V103 (SEQ ID NO: 11)) in a dose or amount ranging from 100 mg to 600 mg In a specific embodiment, methods and pharmaceutical compositions are provided herein that include administering Human FGF21 protein variants, such as V103 (SEQ ID NO: 11), are available in amounts of 200 mg to 4 In a specific embodiment, the human FGF21 protein mutant is administered at a dose in the range of 0.00 mg. The body, for example V103 (SEQ ID NO: 11), is at least 200 mg, at least 300 mg In a specific embodiment, the human FGF21 protein is administered in a dose of 100 mg or more. Protein variants, such as Fc-FGF21 mutant fusion proteins, such as V103 (sequence Column number 11) indicates the range of use from 100 mg to 600 mg, for example, 250 mg to 350 mg. By quantity, once every 4 weeks (or once every month), or once every 3 weeks, or once every 2 weeks , is administered.

[0029] In one aspect, the metabolic disorder to be treated, prevented, or managed by the methods provided herein is Non-limiting examples of adverse events or cardiovascular disorders include hypertriglyceridemia, diabetes, e.g., type 2 diabetes. Disease, obesity, type 1 diabetes, pancreatitis, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, gluco glucose intolerance, hyperglycemia, metabolic syndrome, hypertension, cardiovascular disease, acute myocardial infarction , atherosclerosis, peripheral artery disease, stroke, heart failure, coronary heart disease, kidney disease, diabetes Diabetic complications, neuropathy, and severe inactivating mutations in the insulin receptor Disorders and / or gastroparesis.

[0030] Terminology The term "native" or "wild-type" in reference to FGF21 refers to a biologically active, naturally occurring It refers to FGF21, e.g., biologically active, naturally occurring FGF21 mutants. The human FGF21 wild type sequence has the NCBI reference sequence NP_061986.1, e.g. For example, the present invention can be found in issued patents such as U.S. Pat. No. 6,716,626 B1. (SEQ ID NO: 1). [ka] The corresponding mRNA sequence encoding the full-length FGF21 polypeptide (NCBI Reference Sequence No. No. NM_019113.2) is shown below (SEQ ID NO:2): [ka] The mature FGF21 sequence lacks a leader sequence and may contain other modifications of the polypeptide, such as Amino-terminal (with or without leader sequence) and / or carboxyl-terminal protein Proteolytic processing, cleavage of smaller polypeptides from larger precursors, N-linkages and / or O-linked glycosylation, as well as other post-translational modifications understood by those of skill in the art. A representative example of a mature FGF21 sequence has the following sequence (full length: Amino acid sequence of FGF21 protein (NCBI reference sequence number NP_061986.1) SEQ ID NO:3 representing positions 29 to 209): [ka] The corresponding cDNA sequence encoding the mature FGF21 polypeptide (SEQ ID NO:3) is shown below. As shown (SEQ ID NO:4): [ka]

[0031] The terms "FGF21 protein mutant," "human FGF21 mutant," and "FGF21 polypeptide" are used interchangeably. "peptide or protein variant," "FGF21 mutant," or any similar term, is intended to mean The naturally occurring (i.e., wild-type) FGF21 amino acid sequence is modified, e.g., At least one amino acid in the protein has been replaced with another amino acid and / or deleted. In addition, the mutant is defined as including human FGF21, which is known to be a mutant of wild-type FGF21. N- and / or C-terminal truncations to the 21 protein, or wild-type human FGF2 In general, the mutants are similar to the wild-type protein. The mutant has some modified structural or functional properties of the protein. The enhanced or improved physical stability in concentrated solutions (e.g., less hydrophobic media) mediated agglutination), enhanced or improved plasma aggregation when incubated with plasma Enhanced or improved biological activity while maintaining stability or favorable biological activity properties. It may have.

[0032] Mutants and mutants of FGF21 polypeptides and proteins of the methods provided herein. Permissible amino acid substitutions and modifications that constitute the differences between the mutant and wild-type FGF21 including, but not limited to, one or more amino acid substitutions, such as non-naturally occurring amino acids. Thus, FGF21 protein mutations include substitutions with homologues and truncations. Examples of such mutants include, but are not limited to, site-specific FGF21 mutants as described herein. , truncated FGF21 polypeptides, proteolysis-resistant FGF21 mutants, aggregation-reducing Reduced FGF21 mutants, FGF21 combination mutants, FGF21 conjugates (e.g., fatty acid-FGF21 conjugates, PEG-FGF21 conjugates), and FGF21 fusion proteins (e.g., Fc domain fusion proteins, human serum albumin fusion proteins, min fusion protein).

[0033] The variants may be modified with pharmaceutical preservatives (e.g., m-cresol, phenol, benzyl alcohol, etc. and thus improving the physicochemical properties and This allows the preparation of preserved pharmaceutical formulations that maintain their biological activity. Mutants with enhanced pharmaceutical stability compared to wild-type FGF21 are physiological and therapeutic candidates. Improved physical stability while maintaining biological potency in concentrated solutions under conservative pharmaceutical formulation conditions. As a non-limiting example, the variants provided herein have the following properties: It may be more resistant to degradation and enzymatic degradation; it may have improved stability; They may also be less likely to aggregate than their wild-type counterparts. When used in combination, these terms are not mutually exclusive or limiting and, taken together, refer to the nature of the variants that may be present in a given genome. It may have one or more modified properties of the native protein.

[0034] In a specific embodiment, the FGF21 protein variant is a mutant of one or more biosimilar sequences of wild-type FGF21. It is a biologically active variant of the wild-type FGF21 protein that exhibits activity as previously reported. The biological activities of wild-type FGF21 include, but are not limited to, the following: (i) FGF21 F21 has been shown to induce insulin-independent glucose uptake; i) FGF21 has also been shown to ameliorate hyperglycemia in various rodent models of diabetes. (iii) transgenic mice overexpressing FGF21 have been shown to increase the rate of food-induced It has been found that the drug is resistant to metabolic disorders and reduces body weight and fat mass, as well as showed an increase in insulin sensitivity (Badman, MK et al. (200 7) Cell Metab 5,426-37); (iv) FGF21 in non-human diabetes mellitus Administration to primates increased fasting plasma glucose, triglycerides, insulin and glucagon causing a reduction in lipoprotein levels and a significant improvement in lipoprotein profile, e.g. This resulted in an approximately 80% increase in HDL cholesterol (Kharitonenkov ,A.et al.,2007,Endocrinology 148,774-81) (v) FGF21 is an important endocrine hormone that helps regulate the fasting state (Badman et al., 2009, Endocrinology 150,4 931;Inagaki et al.,2007,Cell Metabolism 5,415); and (vi) FGF21 is, but is not limited to, glucose or 2- Deoxyglucose uptake, pERK and other phosphorylated or acetylated kinases The downstream markers may be regulated, including protein or NAD levels.

[0035] The term "native Fc" refers to the Fc fragment obtained from digestion of a whole antibody, either in monomeric or multimeric form. refers to a molecule or sequence that contains the sequence of a non-antigen-binding fragment produced by any of the methods described above, or by other means; The original immunoglobulin source of the native Fc is preferably of human origin, The native Fc fragment may be any immunoglobulin, but IgG1 and IgG2 are preferred. The molecules are linked by covalent (i.e., disulfide) and non-covalent bonds to form dimers or multimers. It is composed of monomeric polypeptides that can form monomeric subunits of the native Fc molecule. The number of intermolecular disulfide bonds between the peptides determines the class (e.g., IgG, IgA, and IgE). ) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, and IgGA2 An example of a native Fc is obtained from papain digestion of IgG. It is a disulfide-linked dimer (Ellison et al., 1982, Nucl eic Acids Res. 10:4071-9). The term "native Fc" is used herein When used, it is general to monomeric, dimeric, and multimeric forms.

[0036] The term "Fc variant" refers to a variant that is modified from a native Fc but still contains a salvage receptor. It refers to a molecule or sequence that contains a binding site for FcRn (neonatal Fc receptor). No. 97 / 34631, and WO 96 / 32478 FRET describes the interaction with the salvage receptor along with exemplary Fc variants and is hereby incorporated by reference for this purpose. Thus, the term "Fc variant" refers to a non- The native Fc may comprise a molecule or sequence humanized from a human native Fc. A fusion protein that provides structural features or biological activity not required for the fusion molecule. Thus, the term "Fc variant" includes regions that can be removed from one or more natural lacking a natural Fc site or residue, or having one or more Fc sites or residues modified These findings suggest that: (1) disulfide bond formation; (2) incompatibility with the selected host cell; (3) N-terminal heterogeneity upon expression in the selected host cell; (4) glycosylation; (5 ) interaction with complement, (6) binding to Fc receptors other than the salvage receptor, and / or ( 7) Molecules or sequences that affect or are involved in antibody-dependent cellular cytotoxicity (ADCC) Fc variants are described in further detail below.

[0037] The term "Fc domain" includes native Fc and Fc variants and sequences as defined above. As with Fc variants and native Fc molecules, the term "Fc domain" refers to a fragment that is digested from a whole antibody. Molecules in monomeric or polymeric form, whether synthesized by polymerization or produced by other means. In some embodiments of the invention, the Fc domain comprises FGF21 or FGF21 The mutants (including truncated forms of FGF21 or FGF21 mutants) may be, for example, The fusion protein may be formed by a covalent bond between the domain and the FGF21 sequence. These fusion proteins can form multimers through the association of the Fc domains. Both and multimers thereof are an aspect of the present invention.

[0038] The term "modified Fc fragment" as used herein refers to an Fc fragment of an antibody that contains a modified sequence. Fc fragment means the portion of an antibody that contains CH2, CH3, and a portion of the hinge region. The modified Fc fragment is, for example, an IgG1, IgG2, IgG3, or IgG4 fragment. FcLALA induces ADCC with reduced efficiency and is specific to human complement. Modified F with LALA mutations (L234A, L235A) that binds weakly and activates c fragment. Hessell et al.2007 Nature 449:101 Further modifications to the Fc fragment are described, for example, in U.S. Pat. No. 7,217,798. , which is incorporated by reference for this purpose.

[0039] The term "acute myocardial infarction" refers to a myocardial infarction caused by an acute blockage of the blood supply to part of the heart, for example due to an acute occlusion of a coronary artery. This refers to myocardial necrosis resulting from interruption of myocardial supply. The resulting ischemia and oxygen deprivation, if sustained for a sufficient period of time, If left untreated, it can cause damage or death (infarction) of heart muscle tissue (myocardium). do.

[0040] The term "atherosclerosis" refers to the narrowing of the arterial lumen that eventually leads to fibrosis and Irregularly distributed lipid deposits in the intima of large and medium-sized arteries, progressing to vascular endothelial cell carcinoma and calcification. The disease is usually localized and is slow and intermittent. The blood flow restriction is most often a clinical manifestation that varies with the distribution and severity of the lesions. Explain the situation.

[0041] The term "cardiovascular disease" refers to diseases involving the heart or blood vessels.

[0042] The term "cardiovascular risk" refers to the likelihood of experiencing a cardiovascular event (e.g., a stroke or heart attack). This refers to a combination of factors that are associated with an increased rate of cardiovascular disease. Such factors include, but are not limited to, body weight, BMI, cholesterol levels, blood pressure, triglyceride levels, diet, exercise routine, age Age, sex, family history, obesity, diabetes, and / or other metabolic factors. Guidelines for assessing and managing the disease have been published. American College of Cardiology (ACC ) and the American Heart Association ( The American Heart Association (AHA) provides cardiovascular risk assessment, lifestyle changes to reduce cardiovascular risk, and For the management of blood cholesterol in humans and for the management of overweight and obesity in adults To develop clinical practice guidelines for National Heart, Lung, and Blood Institute (NHLBI) and Collaborating with stakeholders and professional organizations (Stone et al., 2014, Jour nal of the American College of Cardiology y,63(25 Part B)2889-2934;DOI:10.1016 / jj acc.2013.11.002 (herein incorporated by reference for this purpose). The World Health Organization also recommends that countries with cardiovascular For example, persistent hypertension ≥ 160 / 100 mmHg, blood cholesterol ≥ 8 mmol / L / l, for evaluating individuals with established ischemic heart disease, or diabetes with renal disease Guidelines are provided.

[0043] The term "coronary heart disease," also known as coronary artery disease, refers to the small blood vessels that supply blood and oxygen to the heart. It is a narrowing of the canal.

[0044] The terms "diabetes" and "diabetic" refer to a condition characterized by hyperglycemia and glycosuria. It often refers to a progressive disorder of carbohydrate metabolism involving inadequate production or utilization of insulin. "Prediabetes" and "prediabetic" refer to a condition in which a subject is experiencing symptoms that are typically seen in diabetes. A condition that has no signs, symptoms, etc., but which, if left untreated, can progress to diabetes The presence of these conditions refers to conditions having, for example, fasting plasma glucose (FPG) test, oral glucose tolerance test (OGTT), or hemoglobin A1c (Hb A1c) test may be used to determine the level of urinary incontinence. Typically, subjects are required to fast for at least 8 hours prior to the start of the study. In the present study, the subject's blood glucose is measured following a fast: typically, the subject fasts overnight and blood glucose is measured. is measured in the morning before a meal. In healthy subjects, it is generally about 90 to 100 mg / dl, and if the subject has "prediabetes," Generally, people with diabetes have an FPG concentration between about 100 and about 125 mg / dl. " generally have an FPG level greater than about 126 mg / dl. In the OGTT, subjects' blood glucose was measured after fasting and after drinking a glucose-rich drink. Glucose lipoprotein (Glucose-rich beverage) is consumed and then measured again 2 hours later. Two hours after consuming the beverage, healthy subjects generally have blood glucose concentrations below about 140 mg / dl. A prediabetic subject generally has a blood glucose concentration of about 140 to about 199 mg / dl and Diabetic subjects generally have blood glucose concentrations of about 200 mg / dl or greater. While the subjects were euglycemic, moderately hyperglycemic and overt hyperglycemic, the subjects were In healthy mice after fasting for 4 hours, the concentration is generally about 100 to about 15 0 mg / dl. will generally have an FPG concentration between about 175 and about 250 mg / dl, In addition, mice with diabetes generally have an FPG level above about 250 mg / dl. In the HbA1c test, an HbA1c level <5.7% is Generally considered to be within the normal range, HbA1c levels in the range of 5.7-6.4% are generally considered to be within the normal range. HbA1c levels of 6.5% or higher are generally considered to be at the pre-diabetic level. (e.g., American Diabetes Association on(ADA), Practice Guideline, Diabetes Care , 2018 Supplement 1, which is incorporated herein by reference for this purpose. (see).

[0045] The term "dyslipidemia" refers to any disorder of lipoprotein metabolism, including lipoprotein overproduction or deficiency. Dyslipidemia is a disorder characterized by a high level of total cholesterol, low-density lipoprotein (LDLP), and cholesterol in the blood. Increased cholesterol and triglyceride levels, as well as high density lipoprotein (HDL) levels L) may be manifested by a decrease in cholesterol levels.

[0046] The term "glucose intolerance" or "impaired fasting glucose" (IFG) or "impaired glucose tolerance" Intracranial hyperglycemia (IGT) is a hyperglycemic prediabetic state associated with an increased risk of cardiovascular pathology. A diabetic state is when a subject is unable to efficiently transport glucose into cells and use it as an efficient fuel source. This prevents the body from using insulin, resulting in elevated glucose levels in the blood and some degree of insulin resistance. results.

[0047] The term "heart failure," also known as congestive heart failure, refers to the inability of the heart to pump enough blood to the rest of the body. This is a condition in which blood can no longer be expelled.

[0048] The term "hyperglycemia," also known as high blood sugar, refers to a higher than normal amount of glucose (a type of sugar) in the blood. Hyperglycemia refers to a condition characterized by a higher amount of glucose in the blood than is measured during fasting. The present invention can be diagnosed using methods known in the art, including the use of immunological tests.

[0049] The term "hypertension" or high blood pressure refers to an increase in systemic arterial pressure leading to cardiovascular damage or other deleterious consequences. Hypertension refers to a condition that corresponds to a transient or persistent increase in blood pressure to a level that is likely to cause heart failure. The condition is characterized by a systolic blood pressure (SBP) of more than 140mmHg or a diastolic blood pressure (SBP) of more than 90mmHg. Although arbitrarily defined as DBP, it is based on published clinical guidance. For example, the following guidance is given for blood pressure: :Normal SBP<120mmHg or DBP<80mmHg; 120~129mmHg Elevated SBP within range or DBP < 80mmHg; SB for hypertension (HTN) stage 1 P in the range of 130-139 mmHg or DBP in the range of 80-89 mmHg; and S BP≧140 or DBP≧90.

[0050] The term "hypertriglyceridemia" refers to high (excessive) blood levels of triglycerides (hyperglyceridemia). Elevated triglyceride levels can occur even if you have hypercholesterolemia (high cholesterol). is associated with atherosclerosis even in the absence of α-cholesterol levels and predisposes to cardiovascular disease (e.g., contributing to increased cardiovascular risk). In general, 150-199 mg / dL Serum triglyceride levels in the range of 1.70 to 2.25 mmol / L are considered borderline In- It is considered to be high serum triglyceride level; 200-499 mg / dL [2.26 A serum triglyceride level in the range of [~5.64 mmol / L] is considered to be high serum triglyceride. Lipo level is considered; serum in the range of 500 mg / dL [5.65 mmol / L] or higher. The triglyceride level is considered to be an extremely high triglyceride level. These general guidelines are based on updated clinical guidelines for clinicians. The amount of the ion exchange reaction may be adjusted accordingly.

[0051] The term "hypoglycemia," also known as low blood sugar, refers to a condition in which blood sugar levels fall too low and physical activity is reduced. This occurs when there is not enough energy available for

[0052] The term "hyperinsulinemia" is defined as higher than normal levels of insulin in the blood. will be done.

[0053] The term "insulin resistance" refers to the condition in which normal amounts of insulin result in a subnormal biological response. It is defined as the state in which the

[0054] The term "kidney disease" or nephropathy is any disease of the kidneys. Diabetic nephropathy is the progressive loss of blood flow caused by diabetes. In severe cases, it refers to kidney damage caused by diabetes mellitus; This can lead to renal failure, a leading cause of morbidity and mortality in people with diabetes.

[0055] The term "metabolic syndrome" refers to elevated blood pressure, high blood sugar, excess body fat around the abdomen, and It refers to a group of conditions, including diabetes, cardiovascular disease, and abnormal cholesterol or triglyceride levels. Together, these conditions increase the risk of heart disease, stroke, and diabetes. For example, most men Excess body fat around the abdomen in men is associated with a waist size of 40 inches or more. Hyperglycemia is defined as a blood glucose level of at least 110 milligrams per deciliter (mg / dl) after fasting. / Glucose levels; high triglycerides at least 150 mg / dL in the bloodstream low HDL is associated with levels below 40 mg / dl; elevated blood pressure is associated with levels below 1 with levels of 30 / 85mmHg or higher.

[0056] The term "myocardial infarction" (MI), also known as a heart attack, is a condition caused by a persistent lack of oxygen supply (ischemia). It is defined as the irreversible death (necrosis) of myocardium resulting from myocardial infarction.

[0057] The term "NAFLD" or "nonalcoholic fatty liver disease" refers to the accumulation of excess fat in the liver. This accumulation of fat is not due to heavy alcohol use. When heavy alcohol use causes fat to accumulate in the liver, this condition is called alcoholism. NAFLD is typically classified as simple fatty liver disease (SFL) or nonalcoholic fatty liver disease (NAFLD). There are two types of NASH.

[0058] The term "NASH" or "nonalcoholic steatohepatitis" refers to a condition in which patients develop fatty liver disease. Nonalcoholic fatty liver disease (NAFL), which also has hepatitis (inflammation of the liver) and liver cell damage. D) Inflammation and hepatocellular injury can lead to fibrosis, or scarring, of the liver. In some cases, NASH can lead to cirrhosis or liver cancer.

[0059] The term "simple fatty liver," also known as nonalcoholic fatty liver (NAFL), refers to the condition in which the patient has liver problems. It is a form of NAFLD that has fat but little inflammation or liver cell damage. Simple fatty liver typically does not progress far enough to cause liver damage or complications.

[0060] The term "pancreatitis" is inflammation of the pancreas.

[0061] "Obesity" is defined as abnormal or excessive fat accumulation that represents a risk to health. A common aggregate measure is the body mass index (BMI = weight (kg) / [height (m)] 2 )(Someone weight (in kilograms) divided by the square of the person's height (in meters) A person with a BMI of 30 or above is generally considered obese. A person with a BMI of 25 or above is generally considered obese. Although people with can be adjusted for ethnic differences. For example, Using the ment), BMI ≥ 27.5 can be considered obese in Asians. (WHO Expert Consultation, 2004, Lancet, 36 3(9403):157-63). Asians, for example, are people of Asian descent or Asian ancestry. It could be an elephant.

[0062] The term "peripheral arterial disease" or "PAD" refers to the disease of the peripheral arteries (most commonly the arteries of the legs, stomach, arms, and head). PAD and CAD are both conditions characterized by narrowing of the arteries of the legs. Atherosclerosis, which narrows and blocks arteries in various critical areas of the body PAD is similar to coronary artery disease (CAD) in that it is caused by a narrowing of the arteries, typically Over time, it hardens and narrows the arteries, making it harder for oxygen-rich blood to reach organs and other parts of the body. This is due to plaque which can restrict flow.

[0063] The term "stroke" refers to any acute clinical event associated with a disturbance in the cerebral circulation lasting more than 24 hours. A stroke is considered a transient ischemic attack (TIA), whereas a shorter duration is considered a transient ischemic attack (TIA). irreversible brain damage, the type and severity of which depend on the location and extent of brain tissue to which circulation is impaired. Includes symptoms of severity.

[0064] The term "type 1 diabetes mellitus" or "T1DM" refers to high blood sugar levels caused by a lack of insulin. It is a condition characterized by the body's immune system blocking insulin production in the pancreas. This can happen when the body attacks beta cells and destroys them. The pancreas then produces very little insulin. Not produced.

[0065] The term "type 2 diabetes" or "type 2 diabetes" 2 Diabetes mellitus (T2D) or T2DM is a condition that affects diabetes This causes insulin to accumulate in the bloodstream, resulting in insulin deficiency or the body being unable to use insulin efficiently. It refers to a metabolic disorder characterized by high blood sugar levels due to either the inability to consume enough sugar or the inability to consume enough alcohol. Blood glucose levels are measured in milligrams per deciliter (mg / dL) or millimoles per liter. can be.

[0066] The terms "management" or "manage" or "managing" do not result in a cure, but rather in the treatment of a disease. , alleviating one or more symptoms of a disease condition or disorder and / or reducing length of hospital stay; It is understood as the management and care of a patient with the aim of combating a disease, condition or disorder.

[0067] The terms "prevention" or "prevent" or "preventing" refer to one or more of the In healthy subjects or those at risk of developing a disease, condition or disorder, to prevent the occurrence of the above conditions In addition, the present invention refers to prophylactic administration to subjects who are prediabetic (e.g., subjects who are believed to be prediabetic). The term "prevention" may also include prophylactic administration to patients in a pre-stage of the condition to be treated. do.

[0068] The terms "treatment" or "treat" or "treating" refer to combating a disease, condition, or disorder. and, for example, reducing or ameliorating the progression, severity, and / or duration of a disease, disorder, or condition. The term "treatment" refers to the management and treatment of a patient with a particular condition. When used, it includes, but is not limited to, FGF21 or FGF21 variants provided herein. In the context of a disease, disorder, or condition that can be treated by administering a heterologous protein, ) Lowering triglyceride levels (blood / serum triglyceride levels), e.g. or within a manageable or normal range as determined by clinical guidelines. (ii) weight loss, e.g., as determined by a clinician or clinical guidelines; within a manageable or normal range as determined by, or at least about 5%; 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, A decrease of 25%, 30%, 35%, 40%, 50%, 55%, 60% or more; (iii) an increase in insulin-independent glucose uptake; (iv) an increase in blood / serum glucose Decreased radioactivity levels (e.g., as determined by a clinician or clinical guidelines) Within such manageable or normal ranges, or at least about 5%, 10%, 20%, %, 30%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or (v) improvement in lipoprotein profile; ) Increase in HDL cholesterol (HDL-C) levels (e.g., at least about 5%, 10% %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more (vii) an increase in LDL cholesterol (LDL-C) and / or total cholesterol A decrease in total C, e.g., as determined by a clinician or clinical guidelines Within a manageable or normal range as determined by , 10%, 20%, 30%, 40%, or 50% or more decrease; i) reduction in liver fat content, e.g., as determined by a clinician or clinical guidelines; within a manageable or normal range, or at least about 5%, 10%, 20% (ix) a reduction in the incidence of morbidity or mortality; The term may include one or more of the following:

[0069] The term "therapeutically effective amount" or "effective amount" refers to the amount of a compound that is determined by a researcher or clinician. Eliciting a desired biological and / or medical response in a tissue, system or animal (including humans). The term "FGF21" refers to the amount of a drug or therapeutic agent that is effective in treating FGF21 and FGF21 variants provided herein. In the context of a variant protein, the desired biological and / or medical response may be: (i) a triglyceride-binding protein; For example, at least about 5% %, 10%, 20%, 30%, 40%, 45%, 50%, 55%, 60%, 70%, 80 %, 90%, or 95% or more reduction in body weight, e.g., At least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% , 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, young (iii) an increase in insulin-independent glucose uptake; iv) a decrease in blood / serum glucose levels (e.g., at least about 5%, 10%, 20%, 3 0%, 40%, 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 9 (v) improvement in lipoprotein profile; (vi) HD Increase in HDL cholesterol (HDL-C) levels (e.g., at least about 5%, 10%, 2 0%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more (vii) Increased LDL cholesterol (LDL-C) and / or total cholesterol ( For example, at least about 5%, 10%, 20%, 30%, 40% of total-C or a 50% or greater reduction; and (viii) a reduction in liver fat content, e.g. For example, at least about 5%, 10%, 20%, 30%, 40%, or 50% or more In certain embodiments, the triglyceride level may be reduced by one or more of the following: In certain embodiments, the concentration of the tocopherol may be reduced by at least about 40% or at least about 50%. Triglyceride levels may be reduced by at least about 40%. Glyceride levels may be reduced by at least about 50%. The fat content is at least about 5%, 10%, 20%, 30%, 40%, or 50%. In some embodiments, the liver fat content may be reduced by at least about 5 In some embodiments, the liver fat content is reduced by at least about 10%. In some embodiments, liver fat content may be reduced by at least about 20%. In some embodiments, liver fat content may be reduced by at least about 30%. In some embodiments, liver fat content may be reduced by at least about 40%. In some embodiments, liver fat content may be reduced by at least about 50%. Liver fat content is easy to manage as determined by a clinician or clinical guidelines. may be decreased to within the low or normal range.

[0070] As used herein, the singular forms "a," "an," and "the" are used where context requires. Plural references are included unless expressly indicated otherwise. Thus, for example, "an antibody" is used in A reference to a "specific antibody" includes a mixture of two or more such antibodies.

[0071] As used herein, the terms "about" or "approximately" mean + / - 20% of a value, more preferably Preferably it refers to + / - 10%, or even more preferably + / - 5%.

[0072] The terms "polypeptide" and "protein" are used interchangeably and refer to amino acids of any length. It refers to the polymeric form of amino acids, including coded and non-coded amino acids, naturally occurring amino acids, and amino acids and non-naturally occurring amino acids, chemically or biochemically modified or derivatized amino acids; as well as polypeptides having modified peptide backbones. The term also includes fusion proteins comprising fusion proteins having heterologous amino acid sequences, heterologous and homologous leaders, -sequence fusions (with or without an N-terminal methionine residue); immunological tags Produced proteins; and the like.

[0073] The term "fragment" as used herein refers to a physically contiguous portion of the primary structure of a biomolecule. In the case of a protein, a portion refers to a contiguous portion of the amino acid sequence of the protein. At least 3-5 amino acids, at least 8-10 amino acids, At least 11-15 amino acids, at least 17-24 amino acids, at least 25-30 amino acids It refers to a sequence of at least 30 to 45 amino acids. The portion is defined by a contiguous portion of the nucleic acid sequence of the oligonucleotide and is at least 9 ~15 nucleotides, at least 18-30 nucleotides, at least 33-45 nucleotides Nucleotides, at least 48-72 nucleotides, at least 75-90 nucleotides In some embodiments, the nucleic acid sequence refers to a nucleic acid sequence of at least 90 to 130 nucleotides. The portions of the molecule that have biological activity. In the context of the FGF21 polypeptide, FGF2 A polypeptide fragment does not contain the entire FGF21 polypeptide sequence shown in SEQ ID NO:3. .

[0074] The terms "individual," "subject," "host," and "patient" are used interchangeably and include, but are not limited to, diagnosis, treatment, and / or The term "subject" refers to any subject for which treatment is desired, particularly humans. Other subjects include cattle, dogs, cats, etc. , guinea pigs, rabbits, rats, mice, horses, etc. In an embodiment, the subject is a human.

[0075] As used herein, the term "sample" refers to a biological material from a patient. The sample that is assayed according to the invention is not limited to any particular type. Non-limiting examples include single cells, multi-cells, tissues, tumors, bodily fluids, biomolecules, or any of the foregoing. Examples include tissue removed for biopsy, tissue removed during resection, and Examples include tissue, blood, urine, lymphatic tissue, lymphatic fluid, cerebrospinal fluid, mucous membranes, and stool samples. The sample used will depend on the assay format, the detection method, and the tumor, tissue, or cell to be assayed. The method for preparing the sample will vary based on the nature of the extract. are well known in the art and can be readily adapted to obtain samples compatible with the method being used. be.

[0076] The term "pharmaceutical acceptable carrier" refers to a carrier that is capable of carrying a therapeutic agent, e.g., an antibody or polypeptide, a gene, The term refers to a carrier for administration of the composition, such as a medicament for administering a therapeutic agent, such as a medicament for administering a therapeutic agent to a subject. Any pharmaceutical carrier that does not induce the production of unwanted antibodies and can be administered without undue toxicity may be used. Suitable carriers are large, slowly metabolized macromolecules such as proteins, polysaccharides, polysaccharides, and the like. Polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and / or or inactive virus particles. Such carriers are well known to those skilled in the art. The pharma- ceutically acceptable carriers may be liquids, such as water, saline, glycerol, and / or Auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may also be present. It may also be present in such a medium.

[0077] Treatment method Treating, preventing, or managing (e.g., alleviating one or more symptoms of) a metabolic or cardiovascular disorder The present invention relates to a method and pharmaceutical composition for use in administering to a subject in need thereof a therapeutically effective amount of FGF21 protein variants (e.g., Fc-FGF21 mutant fusion proteins, For example, V103 (SEQ ID NO: 11)) at a dose in the range of 100 mg to 600 mg, e.g. For example, once a day, once every 2, 3, 4, 5, or 6 days, once a week, or once every two weeks. This includes administering the drug once every three weeks, once every four weeks (or once a month). Provided herein are methods and pharmaceutical compositions, including those comprising administering to the patient a therapeutically effective amount of human FGF21 protein. Protein variants (e.g., Fc-FGF21 mutant fusion proteins, e.g., V103( SEQ ID NO: 11) is administered at a dose ranging from 200 mg to 400 mg. In this study, human FGF21 protein mutants (e.g., Fc-FGF21 mutant fusion proteins) were used. Proteins such as V103 (SEQ ID NO: 11) are administered at approximately 200 mg, 250 mg, 300 mg , 350 mg, or 400 mg, for example, once weekly, once every two weeks, 3 It is administered once per week or once every four weeks (or once per month). FGF21 protein variants (e.g., Fc-FGF21 mutant fusion proteins, For example, V103 (SEQ ID NO: 11) is administered once every 4 weeks (or once a month). In certain embodiments, human FGF21 protein variants, such as V103 (SEQ ID NO: 11) is administered once every 3 weeks, once every 2 weeks, or once every week.

[0078] In a specific embodiment, the present invention relates to a method for treating a metabolic or cardiovascular disorder (e.g., obesity or hypertriglyceridemia). A method for treating, preventing, or managing (e.g., reducing one or more symptoms of) a chronic disease (such as a pulmonary disease) and administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc-FGF 21 mutant fusion protein, such as V103 (SEQ ID NO: 11), 00 mg once weekly or once every two weeks. In a specific aspect, a method is provided herein for treating a metabolic or cardiovascular disorder (e.g., obesity To treat, prevent, or manage (e.g., treat one or more symptoms of) hypertriglyceridemia or hypertriglyceridemia The present invention relates to a method for alleviating symptoms of a human FGF21 protein mutation in a subject in need thereof. Fc-FGF21 mutant fusion proteins, such as V103 (SEQ ID NO:1) 1)) at a dose ranging from 100 mg to 600 mg once every 3 weeks or once every 4 weeks Provided herein are methods comprising administering the compound once a month (or once a month).

[0079] In a specific embodiment, the present invention relates to a method for treating a metabolic or cardiovascular disorder (e.g., obesity or hypertriglyceridemia). A method for treating, preventing, or managing (e.g., reducing one or more symptoms of) a chronic disease (such as a pulmonary disease) and administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc-FGF 21 mutant fusion protein, such as V103 (SEQ ID NO: 11), 200 mg to 4 00 mg once weekly or once every two weeks. In a specific aspect, a method is provided herein for treating a metabolic or cardiovascular disorder (e.g., obesity To treat, prevent, or manage (e.g., treat one or more symptoms of) hypertriglyceridemia or hypertriglyceridemia The present invention relates to a method for alleviating symptoms of a human FGF21 protein mutation in a subject in need thereof. Fc-FGF21 mutant fusion proteins, such as V103 (SEQ ID NO:1) 1)) at a dose ranging from 200 mg to 400 mg once every 3 weeks or once every 4 weeks Provided herein are methods comprising administering the compound once a month (or once a month).

[0080] In a specific embodiment, the present invention relates to a method for treating a metabolic or cardiovascular disorder (e.g., obesity or hypertriglyceridemia). A method for treating, preventing, or managing (e.g., reducing one or more symptoms of) a chronic disease (such as a pulmonary disease) and administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc-FGF 21 mutant fusion protein, such as V103 (SEQ ID NO: 11), 00 mg once weekly or once every two weeks. In a specific aspect, a method is provided herein for treating a metabolic or cardiovascular disorder (e.g., obesity To treat, prevent, or manage (e.g., treat one or more symptoms of) hypertriglyceridemia or hypertriglyceridemia The present invention relates to a method for alleviating symptoms of a human FGF21 protein mutation in a subject in need thereof. Fc-FGF21 mutant fusion proteins, such as V103 (SEQ ID NO:1) 1)) at a dose ranging from 100 mg to 300 mg once every 3 weeks or once every 4 weeks Provided herein are methods comprising administering the compound once a month (or once a month).

[0081] In a specific embodiment, the present invention relates to a method for treating a metabolic or cardiovascular disorder (e.g., obesity or hypertriglyceridemia). A method for treating, preventing, or managing (e.g., reducing one or more symptoms of) a chronic disease (such as a pulmonary disease) and administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc-FGF 21 mutant fusion protein, e.g., V103 (SEQ ID NO: 11), at least about For use in doses of 00mg, 150mg, 200mg, 250mg, 300mg, or 350mg Provided herein are methods for administering the compound to a subject in an amount of 0.1 mg / kg once per week or once every two weeks. In a specific embodiment, the present invention relates to a method for treating a metabolic or cardiovascular disorder (e.g., obesity or hypertriglyceridemia). For treating, preventing, or managing (e.g., reducing one or more symptoms of) hypercalcaemia (hypercalcaemia) and administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc-F GF21 mutant fusion protein, such as V103 (SEQ ID NO: 11), Approximately 100mg, 150mg, 200mg, 250mg, 300mg, or 350mg once every 3 weeks or once every 4 weeks (or once a month) at a dose of Methods are provided herein.

[0082] In one aspect, a metabolic disorder to be treated, prevented, or managed by the methods provided herein. Non-limiting examples of cardiovascular disorders include obesity, hypertriglyceridemia, dyslipidemia, non-alcoholic fatty liver disease, and the like. Nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), diabetes, e.g. For example, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), Disorders associated with severe inactivating mutations, pancreatitis, insulin resistance, hyperinsulinemia, Glucose intolerance, hyperglycemia, metabolic syndrome, hypertension, cardiovascular disease, acute cardiac Muscle infarction, atherosclerosis, peripheral artery disease, stroke, heart failure, coronary heart disease, kidney disease These include diabetes, diabetic complications, neuropathy, and gastroparesis.

[0083] In one aspect, a metabolic disorder to be treated, prevented, or managed by the methods provided herein. or cardiovascular disorders, non-limiting examples of which include obesity, hypertriglyceridemia and cardiac risk, insulin resistance, and Insulin resistance and lipodystrophy, including in patients with genetic mutations in the insulin receptor , diabetes (e.g., T1DM or T2DM), and nonalcoholic fatty liver disease (NAF LD) / nonalcoholic steatohepatitis (NASH).

[0084] In one aspect, a method for treating, preventing, or managing a metabolic disorder (e.g., obesity) or a cardiovascular disorder. administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion protein variant) A synthetic protein, for example, V103 (SEQ ID NO: 11), is added in the range of 100 mg to 600 mg. or more specifically at a dose of 100 mg to 300 mg or 200 mg to 400 mg For example, once daily, once every 2, 3, 4, 5, or 6 days, once a week, Once every week, once every two weeks, once every three weeks, or once every four weeks (or once every month) Provided herein are methods comprising administering the compound to a subject, for example, subcutaneously, once a day. A method for treating, preventing, or managing a disorder (e.g., obesity) or a cardiovascular disorder, comprising administering to said patient a The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., For example, V103 (SEQ ID NO: 11) at about 100 mg, 110 mg, 120 mg, 130 mg , 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200 mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 2 70mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg For example, once daily for 2, 3, 4, 5, or 6 weeks. or once every 6 days, once every week, once every 2 weeks, once every 3 weeks, or once every 4 weeks The methods provided herein include administering the compound to a subject once a year (or once a month), e.g., subcutaneously. In certain embodiments, the compounds are used to treat, prevent, or manage metabolic disorders (e.g., obesity) or cardiovascular disorders. The present invention relates to a method for treating a subject in need thereof, the method comprising administering to the subject a human FGF21 protein variant (e.g., For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), at a dose of about 300 mg Provided herein are methods that include administering, for example subcutaneously, every 4 weeks (or monthly). In certain embodiments, the present invention is directed to treating, preventing, or managing a metabolic disorder (e.g., obesity) or a cardiovascular disorder. The method includes administering to a subject in need thereof a human FGF21 protein variant (e.g., FGF21 c fusion protein, e.g., V103 (SEQ ID NO: 11), at a dose of about 300 mg for 3 weeks Provided herein are methods for administering, for example subcutaneously, A method for treating, preventing, or managing a metabolic disorder (e.g., obesity) or a cardiovascular disorder, comprising: A human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject in need thereof. , e.g., V103 (SEQ ID NO: 11)) at a dose of about 300 mg every two weeks, e.g., by skin injection. In a specific embodiment, a method for treating a metabolic disorder (e.g., A method for treating, preventing, or managing a disease, such as obesity, or a cardiovascular disorder, comprising administering to a patient in need thereof, The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., V1 03 (SEQ ID NO: 11)) at a dose ranging from about 200 mg to 250 mg every 3 weeks, Provided herein are methods comprising administering subcutaneously to the subject. The methods provided herein include treating hypercholesterolemia (e.g., primary hypercholesterolemia) or lipid The invention is for treating a human subject having a dyslipidemia (e.g., mixed dyslipidemia). In one embodiment, the methods provided herein are directed to treating hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the present invention provides a method for treating a human subject having lysidemia. The methods provided herein are for treating a human subject with type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein involve the use of human FGF21 protein. (i) 30–45 kg / m 2 BMI (ethnicity adjusted and and 27.5 kg / m for Asian subjects. 2 or higher), and (ii) 150–5 Triglyceride levels within the range of 1.00 mg / dL (1.69 to 5.65 mmol / L) The subject invention is for treating human subjects aged 18 to 55 years with

[0085] In certain embodiments, hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), or The drug is intended to treat, prevent, or manage (e.g., alleviate one or more symptoms of) hypertriglyceridemia. The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. For example, 100 mg to 600 mg of an Fc fusion protein, such as V103 (SEQ ID NO: 11) mg, or more specifically, 100 mg to 300 mg or 200 mg Doses in the range of ~400 mg, e.g., once daily, every 2, 3, 4, 5, or 6 days once a week, once every two weeks, once every three weeks, or once every four weeks (or Provided herein are methods comprising administering to the subject a therapeutically effective amount of the compound (once per month). is associated with hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), or hypertriglyceridemia. Methods for treating, preventing, or managing (e.g., reducing one or more symptoms of) hypercalcaemia and administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion Protein, e.g., V103 (SEQ ID NO: 11), at about 100 mg, 110 mg, 120 mg, mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 1 90mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320 For example, once daily at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 Once every 3, 4, 5, or 6 days, once every week, once every 2 weeks, once every 3 weeks or once every four weeks (or once every month). In certain embodiments, the present invention provides a method for treating hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), and / or or hypertriglyceridemia (e.g., one or more of The method of claim 1, further comprising administering to a subject in need thereof a human FGF21 protein. The variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was incubated at 37° C. for 1 h at 4° C. for 2 h at 4° C. for 1 h at 4° C. mg subcutaneously once every four weeks (or once every month). In certain embodiments, the present invention provides a method for treating hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), or hypertriglyceridemia (e.g., The method of claim 1, further comprising administering to a subject in need thereof human FGF21 Protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11)) The method includes administering subcutaneously once every three weeks at a dose of about 300 mg. In certain embodiments, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), and / or or to treat, prevent, or manage hypertriglyceridemia (e.g., one or more of The present invention relates to a method for alleviating symptoms of a disease caused by a human FGF21 protein variant administered to a subject in need thereof. A variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was injected into a 300 μl tube. Provided herein are methods comprising administering subcutaneously once every two weeks at a dose of 100 mg / kg. In certain embodiments, the patient is diagnosed with hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), or hyperlipidemia. Treating, preventing, or managing triglyceridemia (e.g., reducing one or more symptoms thereof) The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. , an Fc fusion protein, such as V103 (SEQ ID NO: 11), at a dose of about 300 mg, Provided herein are methods comprising administering subcutaneously once weekly. , hypercholesterolemia, dyslipidemia (e.g., mixed dyslipidemia), or hypertriglyceridemia A method for treating, preventing, or managing (e.g., reducing one or more symptoms of) hypertension. Thus, a human FGF21 protein variant (e.g., an Fc fusion protein) can be administered to a subject in need thereof. Protein, for example V103 (SEQ ID NO: 11), in the range of about 200 mg to 250 mg The method described herein includes subcutaneously administering to the subject a dose of 0.1 mg / kg or more once every three weeks or once every two weeks. In a specific embodiment, the methods provided herein include treating hypercholesterolemia (e.g., have primary hypercholesterolemia) or dyslipidemia (e.g. mixed dyslipidemia) For treating a human subject. In certain aspects, the methods provided herein include: For treating human subjects with hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the methods provided herein are for the treatment of people with type 2 diabetes. In a specific embodiment, the method described herein is for treating a neonatal subject or a human subject who is obese. The method provided herein further comprises the steps of: (i) administering to the patient a 30-45kM FGF21 protein variant; g / m 2 BMI (ethnicity adjusted for Asian subjects: 27.5 kg / m 2 or higher), and (ii) 150–500 mg / dL (1.69–5.65 mg / dL). To treat human subjects aged 18 to 55 years with triglyceride levels in the range of 100 mg / L. This is for the purpose.

[0086] In specific embodiments, the subject is provided with a method for reducing body weight (e.g., reducing body weight by at least 5%, 6%, 7%, 8%, %, 9%, 10%, 15%, or 20% or more reduction in A human FGF21 protein variant (e.g., an Fc fusion protein, For example, V103 (SEQ ID NO: 11) at a dose in the range of 100 mg to 600 mg, or More specifically, a dose in the range of 200 mg to 400 mg or 100 mg to 300 mg. For example, once a day, once every 2, 3, 4, 5, or 6 days, once a week, Administer once per week, once per 3 weeks, or once per 4 weeks (or once per month) In certain embodiments, methods are provided herein for measuring body weight as provided herein. Lose weight (e.g., at least 5%, 6%, 7%, 8%, 9%, 10%, 15% or 20% or more reduction in the expression of human F GF21 protein variants (e.g., Fc fusion proteins, such as V103 (SEQ ID NO:1) 1)) at approximately 100mg, 110mg, 120mg, 130mg, 140mg, and 150mg g, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 22 0mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, or At a dose of 350 mg, for example, once daily, once every 2, 3, 4, 5, or 6 days, Once per week, once per two weeks, once per three weeks, or once per four weeks (or once per month) Provided herein are methods for administering the compound to a subject, the compound comprising administering the compound once or twice a day to the subject. In certain embodiments, the compound is used to reduce body weight. (e.g., by reducing body weight by at least 5%, 6%, 7%, 8%, 9%, 10%, 15%, or or 20% or more reduction in the level of fibroblast growth factor receptor β (FGF-γ) in a subject in need thereof. 21 protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11) ) should be administered subcutaneously at a dose of approximately 300 mg once every four weeks (or once a month). Provided herein are methods that include reducing body weight (e.g., reducing body weight). At least 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% or more reduction The present invention relates to a method for reducing the incidence of FGF21 in a subject in need thereof, the method comprising administering to the subject a human FGF21 protein mutant ( For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), is used for approximately 300 mg. Provided herein are methods for administering to a subject a therapeutically effective amount of 5-aminopropyl tert-butyl ether subcutaneously once every three weeks. In such cases, lose weight (e.g., lose at least 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% or more reduction in The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., V10 3 (SEQ ID NO: 11)) at a dose of about 300 mg, administered subcutaneously once every two weeks. Provided herein are methods that include reducing body weight (e.g., reducing body weight). At least 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% or more reduction The present invention relates to a method for reducing the incidence of FGF21 in a subject in need thereof, the method comprising administering to the subject a human FGF21 protein mutant ( For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), is used for approximately 300 mg. Provided herein are methods of administering to the patient subcutaneously once weekly in an amount of In such cases, lose weight (e.g., lose at least 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% or more reduction in The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., V10 3 (SEQ ID NO: 11)) at a dose ranging from about 200 mg to 250 mg once every three weeks or once every two weeks. In accordance with the present invention, the methods provided herein are directed to treating hypercholesterolemia (e.g., primary hypercholesterolemia). For treating a human subject having hyperlipidemia (e.g., hyperlipidemia) or dyslipidemia (e.g., mixed dyslipidemia) In certain aspects, the methods provided herein include treating hypertriglyceridemia, In particular, for treating human subjects with severe hypertriglyceridemia. In an aspect, the methods provided herein include administering to a human subject having type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein are for treating a human subject. At the time of screening before administration of the FGF21 protein variant, (i) subjects were 30 to 45 kg / kg m 2 BMI (ethnicity adjusted for Asian subjects: 27.5 kg / m 2 or higher), and (ii) 150 to 500 mg / dL (1.69 to 5.65 mmol / L) / L) It is of the following.

[0087] In certain embodiments, the method comprises treating, preventing, or managing obesity (e.g., alleviating one or more symptoms thereof). The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g., For example, 100 mg to 600 mg of an Fc fusion protein, such as V103 (SEQ ID NO: 11) mg, or more specifically, 200 mg to 400 mg or 100 mg Doses in the range of ~300 mg, e.g., once daily, every 2, 3, 4, 5, or 6 days once a week, once every two weeks, once every three weeks, or once every four weeks (or Provided herein are methods comprising administering to the subject a therapeutically effective amount of the compound (once per month). is a method for treating, preventing, or managing (e.g., reducing one or more symptoms of) obesity. and administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion Protein, e.g., V103 (SEQ ID NO: 11), at about 100 mg, 110 mg, 120 mg, mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 1 90mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320 For example, once daily at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 Once every 3, 4, 5, or 6 days, once every week, once every 2 weeks, once every 3 weeks or once every four weeks (or once every month). In certain embodiments, the present invention provides a method for treating, preventing, or managing obesity (e.g., one or more of The method of claim 1, further comprising administering to a subject in need thereof a human FGF21 protein. The variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was incubated at 37° C. for 1 h at 4° C. for 2 h at 4° C. for 1 h at 4° C. The method described herein includes administering subcutaneously at a dose of 100 mg once every 4 weeks (once a month). In certain embodiments, the present invention provides a method for treating, preventing, or managing obesity (e.g., one or more of The method comprises administering to a subject in need thereof a human FGF21 protein. A mutant variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was added to the fusion protein for about 30 minutes. Provided herein are methods comprising administering subcutaneously at a dose of 0.0 mg once every three weeks. In certain embodiments, the present invention relates to a method for treating, preventing, or managing obesity (e.g., alleviating one or more symptoms thereof). The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g., For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), is administered at a dose of about 300 mg. Provided herein are methods comprising administering subcutaneously once every two weeks at 100 mg / kg / day of Methods for treating, preventing, or managing obesity (e.g., reducing one or more symptoms thereof) are provided herein. administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion protein variant) A combination protein, such as V103 (SEQ ID NO: 11), at a dose of about 300 mg once a week In certain embodiments, methods are provided herein for treating obesity, comprising subcutaneously administering the A method for treating, preventing, or managing (e.g., alleviating one or more symptoms of) a A human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject in need thereof. , for example V103 (SEQ ID NO: 11)) at a dose in the range of about 200 mg to 250 mg, Provided herein are methods comprising administering the compound subcutaneously once every three weeks or once every two weeks. In specific embodiments, the methods provided herein are directed to treating hypercholesterolemia (e.g., primary hypercholesterolemia). A human subject having dyslipidemia (e.g., mixed dyslipidemia) or In certain aspects, the methods provided herein are for treating high triglyceride levels. For treating human subjects with hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain aspects, the methods provided herein involve administering to a human subject having type 2 diabetes or The present invention relates to a method for treating a human subject suffering from obesity. The method to be used includes, during screening prior to administration of a human FGF21 protein mutant, (i) 0~45kg / m 2 BMI in the range of 27 for Asian subjects (adjusted for ethnicity) .5kg / m 2 or higher), and (ii) 150–500 mg / dL (1.69–5 Human subjects aged 18-55 years with triglyceride levels in the range of 0.65 mmol / L It is intended to treat

[0088] In certain embodiments, the method comprises treating, preventing, or managing NASH (e.g., one or more symptoms thereof). The present invention relates to a method for reducing the symptoms of rheumatoid arthritis, comprising administering to a subject in need thereof a human FGF21 protein variant. (For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11)) 00mg, or more specifically, 200mg to 400mg or 100 Doses ranging from 1 mg to 300 mg are administered once a day for 2, 3, 4, 5, or 6 days. Once every week, once every two weeks, once every three weeks, or once every four weeks ( or once every month). In such cases, therapies are intended to treat, prevent, or manage (e.g., reduce one or more symptoms of) NASH. ) a method comprising administering to a subject in need thereof a human FGF21 protein variant (e.g., Fc fusion protein, e.g., V103 (SEQ ID NO: 11), at about 100 mg, 110 mg , 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180 mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 2 50mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg , 320 mg, 330 mg, 340 mg, or 350 mg, for example, once a day once every 2, 3, 4, 5, or 6 days; once every week; once every 2 weeks; once every 3 weeks The method includes administering the drug once every week or once every four weeks (or once every month). In certain embodiments, the method comprises treating, preventing, or managing NASH (e.g., The method comprises administering to a subject in need thereof a human FGF2 1 protein variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) The dose is approximately 300 mg, administered subcutaneously once every four weeks (or once a month). Provided herein are methods for treating, preventing, or managing NASH. (e.g., alleviating one or more symptoms thereof), comprising administering to a subject in need thereof FGF21 protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: No. 11)) at a dose of about 300 mg subcutaneously once every three weeks. Provided herein are methods for treating, preventing, or managing NASH (e.g., and alleviating one or more symptoms thereof, comprising administering to a subject in need thereof human FGF-1 21 protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11) ), at a dose of about 300 mg, subcutaneously once every two weeks. In certain embodiments, the present invention provides a method for treating, preventing, or managing NASH (e.g., The present invention relates to a method for alleviating one or more symptoms of a cancer, the method comprising administering to a subject in need thereof a human FGF21 protein. Protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11)) were fused to approximately Provided herein are methods comprising administering subcutaneously once weekly at a dose of 300 mg. In certain embodiments, the method comprises treating, preventing, or managing NASH (e.g., one or more of The present invention relates to a method for alleviating symptoms of a disease caused by a human FGF21 protein variant administered to a subject in need thereof. A variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was injected into a 200-μl tube. The drug should be administered subcutaneously at a dose ranging from 100 mg to 250 mg once every 3 weeks or once every 2 weeks. Provided herein are methods comprising: Hypercholesterolemia (e.g. primary hypercholesterolemia) or dyslipidemia (e.g. mixed In certain embodiments, the present invention is for treating a human subject having a pulmonary edema (combined dyslipidemia). The methods provided herein are directed to treating patients with hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain aspects, the methods provided herein are for treating a human subject suffering from is for treating a human subject who has type 2 diabetes or who is obese. In a specific embodiment, the methods provided herein involve administration of a human FGF21 protein variant. Before, (i) 30-45 kg / m 2 BMI (ethnicity adjusted for Asians) in the range For 27.5kg / m 2 or higher), and (ii) 150–500 mg / dL 18-5 with triglyceride levels in the range of (1.69-5.65 mmol / L) Intended to treat human subjects aged 5 years.

[0089] In certain embodiments, the method comprises treating, preventing, or managing NAFLD (e.g., one or more symptoms thereof). The present invention relates to a method for alleviating symptoms of a human FGF21 protein mutation in a subject in need thereof. 100 mg to 100 mg of a fusion protein (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) At a dose in the range of 600 mg, or more specifically 200 mg to 400 mg or 10 A dose in the range of 0 mg to 300 mg, for example, once a day, 2, 3, 4, 5, or 6 Once per day, once per week, once per 2 weeks, once per 3 weeks, or once per 4 weeks (or once per month). In embodiments, the method includes treating, preventing, or managing (e.g., alleviating one or more symptoms of) NAFLD. The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. For example, about 100 mg, 110 mg, or 200 mg of an Fc fusion protein, such as V103 (SEQ ID NO: 11) mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 1 80mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg , 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310 For example, at a dose of 1 mg, 320 mg, 330 mg, 340 mg, or 350 mg. Once a day; once every 2, 3, 4, 5, or 6 days; once a week; once every 2 weeks; once every 3 weeks or once every 4 weeks (or once every month). In certain embodiments, a method for treating, preventing, or managing NAFLD (e.g., The present invention relates to a method for administering a human F GF21 protein variants (e.g., Fc fusion proteins, such as V103 (SEQ ID NO:1) 1)) will be administered subcutaneously at a dose of approximately 300 mg once every four weeks (or once a month). In certain embodiments, a method for treating, preventing, or treating NAFLD is provided herein. A method for managing (e.g., alleviating one or more symptoms of) a disease in a patient in need thereof. Equine mice were administered human FGF21 protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11)) at a dose of about 300 mg, administered subcutaneously once every three weeks. Provided herein are methods for treating, preventing, or managing NAFLD. The method comprises administering to a subject in need thereof (e.g., reducing one or more symptoms thereof), Human FGF21 protein variants (e.g., Fc fusion proteins, such as V103 (sequence No. 11)) at a dose of about 300 mg, administered subcutaneously once every two weeks. In certain embodiments, a method for treating, preventing, or managing NAFLD (e.g., The present invention relates to a method for administering a human F GF21 protein variants (e.g., Fc fusion proteins, such as V103 (SEQ ID NO:1) 1)) at a dose of about 300 mg, subcutaneously administered once weekly. In certain embodiments, the method is for treating, preventing, or managing NAFLD (e.g., The method comprises administering to a subject in need thereof a human FGF2 1 protein variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) at a dose in the range of about 200 mg to 250 mg, once every 3 weeks or once every 2 weeks, Provided herein are methods comprising administering subcutaneously to the subject. In a specific embodiment, the method provides The method includes treating hypercholesterolemia (e.g., primary hypercholesterolemia) or dyslipidemia. The present invention is intended to treat a human subject having a chronic condition (e.g., mixed dyslipidemia). In an aspect, the methods provided herein are directed to treating hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the present invention provides a method for treating a human subject having ceramide-deficiency syndrome (CESD). The methods provided are for treating a human subject with type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein involve the use of human FGF21 protein. (i) 30–45 kg / m 2 BMI (adjusted for ethnicity) in the range and 27.5 kg / m for Asian subjects. 2 or higher), and (ii) 150–5 Triglyceride levels within the range of 1.00 mg / dL (1.69 to 5.65 mmol / L) The subject invention is for treating human subjects aged 18 to 55 years with

[0090] In certain embodiments, a method for reducing fat or lipids in the liver is provided, comprising administering to a subject in need thereof a The method comprises administering human FGF21 protein to a subject (e.g., a subject having NASH or NAFLD) A mutant variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was added to the At a dose in the range of 200 mg to 600 mg, or more specifically, 200 mg to 400 mg or The dose is within the range of 100 mg to 300 mg, for example, once a day, 2, 3, 4, 5, or 6 times a day. or once every 6 days, once every week, once every 2 weeks, once every 3 weeks, or once every 4 weeks Provided herein are methods that include administering the compound once a year (or once a month). In one embodiment, a method for reducing fat or lipids in the liver is provided, comprising administering to a subject in need thereof a therapeutically effective amount of

[0023] The present invention relates to a method for treating NASH or NAFLD, comprising administering to a subject having NASH or NAFLD a human FGF21 protein. A variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was added at approximately mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 1 70mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg , 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300 mg, 310mg, 320mg, 330mg, 340mg, or 350mg For example, once a day, once every 2, 3, 4, 5, or 6 days, once a week, once every two weeks should be administered once every week, once every 3 weeks, or once every 4 weeks (or once a month). In certain embodiments, methods are provided herein that include reducing fat or lipids in the liver. The method includes administering to a subject in need thereof (e.g., a subject with NASH or NAFLD). A human FGF21 protein variant (e.g., an Fc fusion protein, e.g., a V 103 (SEQ ID NO: 11)) at a dose of approximately 300 mg once every 4 weeks (or once a month) In certain embodiments, methods are provided herein that include subcutaneously administering to the liver a The method of claim 1, further comprising administering to a subject in need thereof (e.g., a patient suffering from NASH or In one embodiment, a human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject with NAFLD. Proteins such as V103 (SEQ ID NO: 11) at a dose of about 300 mg, once every 3 weeks Provided herein are methods for treating liver disease comprising administering the compound subcutaneously once. The method of claim 1, further comprising administering to a subject in need thereof (e.g., a patient suffering from NASH or In one embodiment, a human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject with NAFLD. Proteins such as V103 (SEQ ID NO: 11) at a dose of about 300 mg, administered once every two weeks Provided herein are methods for treating liver disease comprising administering the compound subcutaneously once. The method of claim 1, further comprising administering to a subject in need thereof (e.g., a patient suffering from NASH or In one embodiment, a human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject with NAFLD. and a protein such as V103 (SEQ ID NO: 11) at a dose of about 300 mg once a week. Provided herein are methods for treating liver disease comprising administering the compound subcutaneously once. The method of claim 1, further comprising administering to a subject in need thereof (e.g., a patient suffering from NASH or In one embodiment, a human FGF21 protein variant (e.g., an Fc fusion protein) is administered to a subject with NAFLD. Protein, for example V103 (SEQ ID NO: 11), in the range of about 200 mg to 250 mg The method described herein includes subcutaneously administering to the subject a dose of 0.1 mg / kg or more once every three weeks or once every two weeks. In a specific embodiment, the methods provided herein include methods for treating NASH or NAFLD. In a specific embodiment, the methods provided herein are for treating a human subject having The method is for treating hypercholesterolemia (e.g., primary hypercholesterolemia) or dyslipidemia (e.g., For example, for treating a human subject with mixed dyslipidemia. The methods provided herein are directed to treating hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the compositions provided herein are intended to treat a human subject having a pulmonary artery disease. The method is for treating a human subject having type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein involve the use of a human FGF21 protein mutant. At screening before administration of 2 BMI (civilian) in the range For Asian subjects, the ethnic adjustment was 27.5 kg / m 2 or greater), and (ii) Triglycerides in the range of 150-500 mg / dL (1.69-5.65 mmol / L) The drug is intended to treat human subjects aged 18 to 55 years with high blood pressure and other metabolic disorders.

[0091] In a specific embodiment, increased LDL cholesterol (LDL-C), total cholesterol ( Methods for reducing total cholesterol, triglycerides, and / or apolipoprotein B administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion protein variant) A synthetic protein, for example, V103 (SEQ ID NO: 11), is added in the range of 100 mg to 600 mg. For example, once daily, once every 2, 3, 4, 5, or 6 days, once weekly, once every 2 weeks, once every 3 weeks, or once every 4 weeks (or once a month) In certain embodiments, methods are provided herein for treating elevated LDL-C, total Methods for reducing cholesterol, triglycerides, and / or apolipoprotein B - Patent application and administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion Protein, for example V103 (SEQ ID NO: 11), in the range of 100 mg to 600 mg in doses, or more specifically in the range of 200 mg to 400 mg or 100 mg to 300 mg In one specific embodiment, an increased LDL-C, total cholesterol, triglycerides, and / or apolipoprotein B The present invention relates to a method for reducing FGF21 protein in a subject in need thereof, the method comprising administering to the subject a human FGF21 protein mutant ( For example, about 100 mg of an Fc fusion protein, such as V103 (SEQ ID NO: 11), 10mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg , 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240 mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 3 At doses of 10 mg, 320 mg, 330 mg, 340 mg, or 350 mg, e.g. , once a day, once every 2, 3, 4, 5, or 6 days, once a week, once every 2 weeks once every 3 weeks, or once every 4 weeks (or once a month) Methods are provided herein for treating elevated LDL-C, total cholesterol, A method for reducing triglycerides and / or apolipoprotein B, comprising: The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., For example, V103 (SEQ ID NO: 11)) at a dose of about 300 mg once every 4 weeks (or once a month) Provided herein are methods comprising administering subcutaneously once each to a subject. In certain embodiments, the increased LDL-C, total cholesterol, triglycerides, and / or apolipoprotein B The present invention relates to a method for reducing FGF21 protein in a subject in need thereof, the method comprising administering to the subject a human FGF21 protein mutant ( For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), is used for approximately 300 mg. Provided herein are methods for administering to a subject a therapeutically effective amount of 5-aminopropyl tert-butyl ether subcutaneously once every three weeks. In such cases, increased LDL-C, total cholesterol, triglycerides, and / or apolipoproteins A method for reducing human FGF21 protein B, comprising administering to a subject in need thereof human FGF21 protein B. Protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: 11)) were fused to approximately Provided herein are methods comprising administering subcutaneously once every two weeks at a dose of 300 mg. In certain embodiments, increased LDL-C, total cholesterol, triglycerides, and and / or a method for reducing apolipoprotein B, comprising administering to a subject in need thereof a human FGF21 protein variants (e.g., Fc fusion proteins, such as V103 (SEQ ID NO: 11)) at a dose of about 300 mg subcutaneously once weekly. In certain embodiments, elevated LDL-C, total cholesterol, triglycerides, and A method for reducing lipids, cholesterol, and / or apolipoprotein B in a subject in need thereof, comprising: The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., V1 03 (SEQ ID NO: 11)) at a dose ranging from about 200 mg to 250 mg every 3 weeks Provided herein are methods comprising administering the compound subcutaneously once every two weeks or once every two weeks. In one aspect, the methods provided herein include treating elevated LDL-C, total cholesterol, triglycerides, and / or cholesterol. and / or apolipoprotein B at least about 5%, 6%, 7%, 8%, %, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30% , 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80% , 85%, or 90% or more. The methods provided herein include treating hypercholesterolemia (e.g., primary hypercholesterolemia) or lipid The invention is for treating a human subject having a dyslipidemia (e.g., mixed dyslipidemia). In one embodiment, the methods provided herein are directed to treating hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the present invention provides a method for treating a human subject having lysidemia. The methods provided herein are for treating a human subject with type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein involve the use of human FGF21 protein. During screening before administration of the mutant, (i) 30–45 kg / m 2 Inclusive BMI (ethnicity adjusted for Asian subjects: 27.5 kg / m 2 BMI above 18.5, and and (ii) a concentration in the range of 150 to 500 mg / dL (1.69 to 5.65 mmol / L). It is intended to treat human subjects aged 18 to 55 years with hypoglyceride levels.

[0092] In a specific embodiment, the method increases HDL-C (e.g., increases HDL-C by at least 5%, Increase by 0%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% The method comprises administering to a subject in need thereof a therapeutically effective amount of a human FGF21 protein variant. A fusion protein containing a variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO:1) 1)) at a dose within the range of 100 mg to 600 mg, for example, once a day, 2, 3, 4, Once every 5 or 6 days, once every week, once every 2 weeks, once every 3 weeks, or Provided herein are methods comprising administering the compound once every four weeks (or once every month). In certain embodiments, HDL-C is increased (e.g., HDL-C is increased by at least 5%, Increase by 0%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. , Fc fusion protein, for example V103 (SEQ ID NO: 11), about 200 mg to 400 ml In one specific embodiment, a method is provided herein comprising administering to the subject a dose in the range of 1 g. Increase HDL-C (e.g., increase HDL-C by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase and administering a human FGF21 protein variant (e.g., an Fc fusion protein) to a subject in need thereof. Protein, e.g., V103 (SEQ ID NO: 11), at about 100 mg, 110 mg, 120 mg , 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190 mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 2 60mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg , 330 mg, 340 mg, or 350 mg once a day, for example, 2, 3, Once every 4, 5, or 6 days, once every week, once every 2 weeks, once every 3 weeks, or once every four weeks (or once every month). In certain embodiments, HDL-C is increased (e.g., HDL-C is increased by at least 5%). , 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. For example, an Fc fusion protein, such as V103 (SEQ ID NO: 11), is administered at a dose of about 300 mg. Subcutaneous injection once every 4 weeks (or once a month), once every 3 weeks, or once every 2 weeks. Provided herein are methods for increasing HDL-C, comprising administering to the subject a therapeutically effective amount of a medicament for treating or preventing HDL-C. (e.g., increase HDL-C by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase in the number of patients who need it In addition, human FGF21 protein variants (e.g., Fc fusion proteins, e.g., V103( SEQ ID NO: 11)) at a dose ranging from about 200 mg to 250 mg once every 3 weeks or Provided herein are methods comprising administering subcutaneously once every two weeks. The methods provided herein include treating hypercholesterolemia (e.g., primary hypercholesterolemia). and for treating a human subject having dyslipidemia (e.g., mixed dyslipidemia) or dyslipidemia (e.g., mixed dyslipidemia). In certain aspects, the methods provided herein are directed to treating hypertriglyceridemia, particularly For treating a human subject with severe hypertriglyceridemia. Thus, the methods provided herein include administering to a human subject having type 2 diabetes or to a human subject who is obese. In a specific embodiment, the methods provided herein are for treating elephants. At the time of screening before administration of the GF21 protein variant, (i) a baseline body weight of 30 to 45 kg / m 2 BMI (ethnicity adjusted for Asian subjects: 27.5 kg / m 2 End and (ii) BMI between 150 and 500 mg / dL (1.69 and 5.65 mmol / L). (i) for treating a human subject aged 18 to 55 years having a triglyceride level within the range of That is why.

[0093] In certain embodiments, the compound is intended to reduce triglyceride levels, e.g., fasting triglyceride levels. (e.g., increase blood / serum triglyceride levels by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more reduction in and administering a human FGF21 protein variant (e.g., an Fc fusion protein) to a subject in need thereof. Proteins, such as V103 (SEQ ID NO: 11), in doses ranging from 100 mg to 600 mg For example, once a day, once every 2, 3, 4, 5, or 6 days, once a week, Administer once per week, once per 3 weeks, or once per 4 weeks (or once per month) Provided herein are methods for reducing triglyceride levels, comprising: (e.g., increase blood / serum triglyceride levels by at least 20%, 30%, 40% , 50%, 60%, 70%, 80%, or 90% or more) Thus, a human FGF21 protein variant (e.g., an Fc fusion protein) can be administered to a subject in need thereof. Protein, for example V103 (SEQ ID NO: 11), in the range of about 200 mg to 400 mg Provided herein are methods comprising administering to the subject a dose of triglyceride. lowering fasting triglyceride levels (e.g. blood / serum triglyceride levels) Increase your triglyceride levels by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 160%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300%, 310%, 0%, or 90% or more reduction in the level of , human FGF21 protein variants (e.g., Fc fusion proteins, e.g., V103 (sequence Column number 11)) at approximately 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210m g, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 28 0mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, or 350 mg, e.g., once daily, every 2, 3, 4, 5, or 6 days Once, once every week, once every two weeks, once every three weeks, or once every four weeks (or once Provided herein are methods comprising administering to the subject a dose of 100 mg / kg / month (once per month). Lowering triglyceride levels, e.g. fasting triglyceride levels (e.g. blood / Increase serum triglyceride levels by at least 20%, 30%, 40%, 50%, 60%, 70% %, 80%, or 90% or more reduction in The subject is administered a human FGF21 protein variant (e.g., an Fc fusion protein, e.g., V10 3 (SEQ ID NO:11)) at a dose of about 300 mg once every 4 weeks (or once a month); or once every 3 weeks or once every 2 weeks. In certain embodiments, triglyceride levels, e.g., fasting triglyceride levels, are measured. Lower (e.g., reduce blood / serum triglyceride levels by at least 20%, 30%, 4 0%, 50%, 60%, 70%, 80%, or 90% or more reduction administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion protein variant) A synthetic protein, for example, V103 (SEQ ID NO: 11), is added in the range of about 200 mg to 250 mg. The drug should be administered subcutaneously once every 3 weeks, once every 2 weeks, or once every week at a dose within the range of Provided herein is a method comprising: , for at least 1 to 4 weeks, triglyceride levels, e.g., fasting triglyceride levels The level can be reduced by at least about 40% or at least about 50%. So, for at least 1-4 weeks, you should monitor your triglyceride levels, e.g. fasting triglycerides. A method for reducing the level of chlorine in a blood vessel by at least about 40% to 60% (e.g., at least about 50%). administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion protein variant) A combination protein, such as V103 (SEQ ID NO: 11), at a dose of about 300 mg every 4 weeks Subcutaneous administration should be once a year (or once a month), once every 3 weeks, or once every 2 weeks. In certain embodiments, methods are provided herein that include culturing birds for at least 1-4 weeks. Glyceride levels, e.g., fasting triglyceride levels, at least about 40% to 60% ( For example, a method for reducing the level of IL-1 in a subject in need thereof by at least about 50%. FGF21 protein variants (e.g., Fc fusion proteins, such as V103 (SEQ ID NO: 11)) in the range of 200 mg to 300 mg (e.g., at least 220 mg, 230 mg, mg, 240 mg, 250 mg, 260 mg, 270 mg, or 280 mg Administer subcutaneously once every 4 weeks (or once a month), once every 3 weeks, or once every 2 weeks. Provided herein are methods comprising: Hypercholesterolemia (e.g. primary hypercholesterolemia) or dyslipidemia (e.g. In certain embodiments, the method is for treating a human subject having a chronic inflammatory disease, such as dyslipidemia. The methods provided herein are directed to treating hypertriglyceridemia, particularly severe hypertriglyceridemia. In certain embodiments, the present invention provides a method for treating a human subject having The method is for treating a human subject having type 2 diabetes or a human subject who is obese. In a specific embodiment, the methods provided herein involve the preparation of human FGF21 protein mutants. At pre-treatment screening, (i) 30–45 kg / m 2 BMI (including ethnicity) in the range Adjusted for Asian subjects: 27.5 kg / m 2 (ii) BMI of 1 Triglycerides in the range of 50 to 500 mg / dL (1.69 to 5.65 mmol / L) The subject invention is intended to treat human subjects aged 18 to 55 years with pulmonary arterial disease (PAD) levels.

[0094] In a specific embodiment, the methods provided herein include, for example, administering a therapeutic agent to a subject over a period of at least 1-4 weeks. and increasing triglyceride levels, e.g., fasting triglyceride levels, by at least about 40% or The method can reduce the level of HIV infection by at least about 50%, and can include administering HIV to a subject in need thereof. FGF21 protein variants (e.g., Fc fusion proteins, e.g., V103 (SEQ ID NO: No. 11)) at a dose within the range of about 250 mg to 300 mg (e.g., 300 mg), This includes administering the drug subcutaneously once weekly (or once a month) or once every three weeks. In embodiments, triglyceride levels, e.g., fasting triglyceride levels, are measured, e.g., for at least 1-4 weeks. Reduce triglyceride levels by at least about 40% to 60% (e.g., at least about 50%) The method comprises administering to a subject in need thereof a human FGF21 protein variant (e.g. For example, about 250 mg to 300 mg of an Fc fusion protein, such as V103 (SEQ ID NO: 11) once every 4 weeks (or once a month) at a dose in the mg range (e.g., 300 mg) or Provided herein are methods comprising administering the compound subcutaneously once every three weeks or once every two weeks. do.

[0095] In certain embodiments, the cardiovascular risk is reduced (e.g., by at least about 5%, 10%, 15%, 20%, %, 25%, 30%, 35%, 40%, 45%, or 50% or more) decrease The method comprises administering to a subject in need thereof a therapeutically effective amount of human FGF21 protein. A mutant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was added to 100 ml of Doses ranging from 100 mg to 600 mg can be taken, for example, once a day, every 2, 3, 4, 5, or 6 days. once every week, once every two weeks, once every three weeks, or once every four weeks (or Provided herein are methods comprising administering, to a subject, a subject, a subject, a method for treating a subject, ... , to reduce cardiovascular risk (e.g., by at least about 5%, 10%, 15%, 20%, 25%, 30%, %, 35%, 40%, 45%, or 50% or more. and administering a human FGF21 protein variant (e.g., an Fc fusion protein) to a subject in need thereof. About 200 mg to 400 mg or 100 mg of a protein, such as V103 (SEQ ID NO: 11), Doses ranging from 100 mg to 300 mg may be administered, for example, once a week, once every 2 weeks, or once every 3 weeks. or once every four weeks. So, what is the best way to reduce cardiovascular risk (e.g., by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more) and administering to a subject in need thereof a human FGF21 protein variant (e.g., an Fc fusion Protein, e.g., V103 (SEQ ID NO: 11), at about 100 mg, 110 mg, 120 mg, mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 1 90mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320 For example, once daily at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 Once every 3, 4, 5, or 6 days, once every week, once every 2 weeks, once every 3 weeks or once every four weeks (or once every month). In certain embodiments, the cardiovascular risk is reduced (e.g., by at least about 5%, 10%, 5%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more The present invention relates to a method for reducing the amount of human FGF21 protein mutations in a subject in need thereof. A variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was injected into a 300 μl tube. The method includes administering the drug subcutaneously once every four weeks (or once every month) at a dose of 1 g per day. In certain embodiments, the cardiovascular risk is reduced (e.g., by at least about 5%, %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or less The present invention relates to a method for reducing (or further reducing) the level of human FGF21 protein in a subject in need thereof. A protein variant (e.g., an Fc fusion protein, e.g., V103 (SEQ ID NO: 11)) was administered at about 3 Provided herein are methods comprising administering subcutaneously once every three weeks at a dose of 0.00 mg. In certain embodiments, the cardiovascular risk is reduced (e.g., by at least about 5%, 10%, 15%, 20%, %, 25%, 30%, 35%, 40%, 45%, or 50%), comprising: Administering a human FGF21 protein variant (e.g., an Fc fusion protein) to a subject in need thereof V103 (SEQ ID NO: 11)) at a dose in the range of about 200 mg to 250 mg. Provided herein are methods comprising administering the compound to the patient subcutaneously every three weeks. Reduce vascular risk (e.g., by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% or more), comprising: Administering a human FGF21 protein variant (e.g., an Fc fusion protein) to a subject in need thereof V103 (SEQ ID NO: 11)) at a dose of about 300 mg once every two weeks or Provided herein are methods comprising administering subcutaneously once weekly. The methods provided herein include treating hypercholesterolemia (e.g., primary hypercholesterolemia). for treating a human subject having dyslipidemia (e.g., mixed dyslipidemia) In certain aspects, the methods provided herein are directed to treating hypertriglyceridemia, particularly severe The present invention is intended to treat a human subject having severe hypertriglyceridemia. The methods provided herein include administering to a human subject having type 2 diabetes or a human subject who is obese. In a specific embodiment, the method provided herein is for treating human FG Prior to administration of the F21 protein variant, (i) 30–45 kg / m 2 BMI in the range (Adjusted for ethnicity: 27.5 kg / m for Asian subjects)2 BMI above 18.5 years, and (i i) Triglycerides in the range of 150 to 500 mg / dL (1.69 to 5.65 mmol / L) The subject is intended to treat a human subject aged 18 to 55 years with seride levels.

[0096] In a specific embodiment, the methods provided herein include administering a human FGF21 protein variant. During screening before administration, (i) 30 to 45 kg / m 2 BMI (ethnic survey) For Asian subjects, the adjustment is 27.5 kg / m 2 (ii) BMI of 15 or more; Triglyceride levels in the range of 0 to 500 mg / dL (1.69 to 5.65 mmol / L) The drug is intended to treat human subjects aged 18 to 55 years with glaucoma.

[0097] In various embodiments, the methods provided herein involve treating a human subject who is at least 18 years of age. In another aspect, the methods provided herein are for administering to a subject who is at least 55 years of age. In another aspect, the methods provided herein are for treating a human subject. In another embodiment, the method provides for the treatment of a human subject at least 60 years of age. The methods described are for treating a human subject who is at least 65 years of age.

[0098] In a specific embodiment, the methods provided herein are for a process for producing a 30-45 kg / m 2 BM within the range In certain embodiments, the methods provided herein are intended to treat a human subject having I. The method is 25kg / m 2 The present invention is intended to treat a human subject having a BMI of 100 mg or greater. In certain embodiments, the methods provided herein are 2 People with a BMI of 100 or more In certain embodiments, the methods provided herein are for treating a patient having a pulmonary circulation disorder. 5kg / m 2 In some embodiments, the present invention is for treating a human subject having a BMI of 100 or greater. In such cases, the methods provided herein may be used to treat Asians with a BMI (with ethnicity adjustment) of >= 27.5 for treating a human subject having

[0099] In certain aspects, the methods provided herein include administering a human FGF21 protein variant. Prior to administration, triglyceride levels were within the range of 150–500 mg / dL (1.69–5.65 mmol / L). In certain embodiments, the present invention is for treating a human subject having an elevated glyceride level. The methods provided herein include administering to the subject human FGF21 protein variant a therapeutically effective amount of at least 15 mg of the human FGF21 protein variant. Have a triglyceride level of at least 1.69 mmol / L (0.0 mg / dL) For treating a human subject. In certain aspects, the methods provided herein include: At least 200 mg of human FGF21 protein variants at the time of screening prior to administration / dL. In some embodiments, the methods provided herein include administering a human FGF21 protein variant prior to administration of the variant. , triglycerides at least 500 mg / dL (at least 5.65 mmol / L) The present invention is intended to treat a human subject having high blood levels of

[0100] In certain embodiments, a human subject having one or more of the following can be treated according to the methods provided herein: is not treated. - History of hepatic encephalopathy, esophageal varices, or portacaval shunts, or ultrasound screening History of hepatobiliary disease, cholelithiasis, or biliary sludge at the time of leaning; Abnormal liver function tests (ALT, When indicated by AST, GGT, alkaline phosphatase, or serum bilirubin liver disease or damage; - Human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) chronic infection; HBV surface antigen (HBsAg) test positive or HBV colonization if standard local testing is performed Antigen test positive · Positive (detectable) HCV RNA; · History of pancreatic injury or pancreatitis, or other pancreatic disease; Amylase or lipase above the ULN at screening or baseline; FGF21 protein analogs or Fc fusion proteins of similar biological classes History of hypersensitivity to medications; Bone disorders including but not limited to osteoporosis, osteopenia, osteomalacia, severe vitamin D deficiency History of the disorder; and Plasma 25-hydroxyvitamin D levels below the lower limit of normal at screening do.

[0101] In one embodiment, a therapeutically effective amount of an FGF21 protein variant described herein (e.g., V 103) and one or more additional therapeutically active agents (e.g., The present invention relates to the treatment and prevention of metabolic or cardiovascular disorders, including administering a therapeutic agent for metabolic or cardiovascular disorders. Provided herein are combination therapies for preventing or managing FGF-. Non-limiting examples of other therapeutically active agents for use in combination with the .21 protein variant include fertilizers. Antidepressants (e.g., phentermine / topiramate, orlistat, lorcaserin, raglutide, bupropion / naltrexone), hypertension medications (e.g., diuretics, beta-blockers Drugs, alpha blockers, ACE inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors, calcium channel blockers, central agonists, peripheral adrenergic blockers, vascular dilating agents, and combinations), diabetes medications (e.g., insulin, α-glucosidase inhibitors Anti-inflammatory drugs, biguanides, dopamine agonists, DPP-4 inhibitors, glucagon-like peptides, Glitinides, sodium glucose transporter (SGLT) inhibitors, sulfonyluria Substances, thiazolidinediones, amylinomimetics ), NAFLD / NASH and cardiovascular medications (e.g., statins, fibrates, aspirins, Phosphorus, anticoagulants).

[0102] In one embodiment, a therapeutically effective amount of an FGF21 protein variant described herein (e.g., V 103), as well as amiloride (midamor), bumetanide ( Bumex), chlorthalidone (Hygroton), chlorothiazide (Diuril) , furosemide (Lasix), hydrochlorothiazide or HCTZ (Esidrix , Hydrodiuril, Microzide), Indapamide (Lozol), Meth Lazone (Mykrox, Zaroxolyn), Spironolactone (Aldactone ), Triamterene (Dyrenium), Acebutolol (Sectral), Ateno lol (Tenormin), betaxolol (Kerlone), bisoprolol (Z ebeta), carteolol (Cartrol), metoprolol (Lopresso r, ToprolXL), nadolol (Corgard), nebivolol (Bystol ic), penbutolol (Levatol), pindolol (Visken), Nolol (Inderal), sotalol (Betapace), timolol (Bloc adren), doxazosin (Cardura), prazosin (Minipress), Terazosin (Hytrin), Benazepril (Lotensin), Captopril (Ca poten), enalapril (Vasotec), fosinopril (Monopril), Lisinopril (Prinivil, Zestril), Moexipril (Univasc ), Perindopril (Aceon), Quinapril (Accupril), Ramipril (A ltace), trandolapril (Mavik), Norvasc (amlodipine), Ple ndil (felodipine), DynaCirc (isradipine), Cardene (nicotine) Ludipine), Procardia XL, Adalat (nifedipine), Cardizem, Dilacor, Tiazac, Diltia XL (diltiazem), Sular (nitric oxide) Soldipin, Isoptin, Calan, Verelan, Covera-HS (Verelan) Rapamil), Capoten (captopril), Vasotec (enalapril), Pr inivil, Zestril (lisinopril), Lotensin (benazepril), Monopril (fosinopril), Altace (ramipril), Accupril ( Quinapril), Aceon (Perindopril), Mavik (Trandolapril), Un ivasc (moexipril), Atacand (candesartan), Avapro (indole) Rubesartan), Benicar (olmesartan), Cozart (losartan), Dio van (valsartan), Micardis (telmisartan), Teveten (epidermal Losartan), Chlorthalidone (Hygroton), Chlorothiazide (Diuril) , hydrochlorothiazide or HCTZ (Esidrix, Hydrodiuril, Mi crozide), indapamide (Lozol), metolazone (Mykrox, Zaro) xolyn), amiloride (Midamor), bumetanide (Bumex), furosemide (Lasix), Spironolactone (Aldactone), Triamterene (Dileny) Dyrenium), Acebutolol (Sectral), Atenolol (Te normin), betaxolol (Kerlone), bisoprolol (Zebeta, Ziac), carteolol (Cartrol), carvedilol (Coreg), labe Tallol (Normodyne, Trandate), Metoprolol (Lopress or, Toprol-XL), nadolol (Corgard), nebivolol (Byst olic), penbutolol (Levatol), pindolol (Visken), pro Pranolol (Inderal), sotalol (Betapace), timolol (Bl ocadren), fibric acid derivatives, niacin, and omega-3 fatty acids, fenofib RATO, Gemfibrozil, Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin Statins, pravastatin, rosuvastatin, simvastatin, pramlintide, acal Precose, Miglitol (Glyset), Metformin, Bromocriptine putin, alogliptin, linagliptin, saxagliptin, sitagliptin, albiliptin Glutide (Tanzeum), dulaglutide (Trulicity), exenatide (Bye tta), exenatide extended release (Bydureon), liraglutide (Victoza) , nateglinide (Starlix), repaglinide (Prandin), repaglinide- Metformin (Prandimet), dapagliflozin (Farxiga), Flozin-metformin (Xigduo XR), canagliflozin (Invokana ), Canagliflozin-Metformin (Invokamet), Empagliflozin (Di Gradiance), Empagliflozin-linagliptin (Glyxambi), Empagliflozin Liflozin-metformin (Synjardy), sotagliflozin, tofogliflozin , remogliflozin, luseogliflozin, ipragliflozin, atigliflozin (a tigliflozin, bexagliflozin, henagliflozin lozin), licorizin, glimepiride (Amaryl), glimepiride-pion Glitazones (Duetact), glimepiride-rosiglitazone (Avandaryl) , Gliclazide, Glipizide-Metformin (Metaglip), Glyburide (Dia Beta, Glynase, Micronase), Glyburide-Metformin (Glu covance), chlorpropamide (Diabinese), tolazamide (Tolin ase), tolbutamide (Orinase, Tol-Tab), rosiglitazone (Ava ndia), rosiglitazone-glimepiride (Avandaryl), rosiglitazone- Metformin (AmarylM), pioglitazone (Actos), pioglitazone-A Logliptin (Oseni), pioglitazone-glimepiride (Duetact), and pioglitazone-glimepiride (Duetact) Glitazone-metformin (Actoplus Met, Actoplus Met X) R) for the treatment of metabolic or cardiovascular disorders. Provided herein are combination therapies for treating, preventing, or managing the harms.

[0103] In some embodiments, a sodium glucose transporter (SGLT) inhibitor Dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, Sotagliflozin, Tofogliflozin, Remogliflozin, Luseogliflozin, Ipra Gliflozin, Atigliflozin, Bexagliflozin, Henagliflozin, Lycogliflozin and rosin, and any pharma- ceutically acceptable salt thereof. In terms of form, sodium glucose transporter (SGLT) inhibitors include dapagliflozin. In some embodiments, the sodium glucose transporter (SGL In some embodiments, the T) inhibitor is empagliflozin. The SGLT inhibitor is canagliflozin. In terms of form, sodium glucose transporter (SGLT) inhibitors are In some embodiments, the sodium glucose transporter (SG The LT) inhibitor is licogliflozin.

[0104] In some embodiments, a sodium glucose transporter (SGLT) inhibitor is dapagliflozin or a pharma- ceutically acceptable salt thereof. In some embodiments, Sodium glucose transporter (SGLT) inhibitors are empagliflozin or and pharma- ceutically acceptable salts thereof. In some embodiments, sodium glucose tetrahydrofuran is The SGLT inhibitor is canagliflozin or a pharma- ceutical acceptable salt thereof. In some embodiments, sodium glucose transporter (SGLT) inhibitors The inhibitor is ertugliflozin or a pharma- ceutically acceptable salt thereof. So, the sodium glucose transporter (SGLT) inhibitor is licogliflozin. or a pharma- ceutically acceptable salt thereof.

[0105] In a specific embodiment, an FGF21 protein variant (e.g., an Fc fusion protein such as V103) is The methods provided herein include administering a diet (e.g., a health diet, a calorie diet, a protein) to the subject. For use as an adjunct to a controlled diet, exercise, and / or other lifestyle modifications It is something.

[0106] FGF21 mutants Modifications to FGF21 improve half-life and / or potency over wild-type FGF21 This allows for the treatment or prevention of metabolic or cardiovascular disorders, along with clinically favorable dosing regimens. manage (e.g., reduce one or more symptoms of a disorder) or reduce cardiovascular risk It may be possible to obtain an FGF21 therapeutic agent for this purpose.

[0107] In a specific embodiment, a metabolic or cardiovascular disorder is treated or managed (e.g., one of the disorders). For use in a method for reducing one or more symptoms of The FGF21 protein mutants, for example, the FGF21 protein mutants listed in Table 1, are used herein. Provided in the specification.

[0108] Mutants and mutants of FGF21 polypeptides and proteins of the methods provided herein. Permissible amino acid substitutions and modifications that constitute the differences between the mutant and wild-type FGF21 including, but not limited to, one or more amino acid substitutions, such as non-naturally occurring amino acids. Thus, the FGF21 protein may be Mutants include, but are not limited to, site-specific FGF21 mutants, truncated FGF21 polypeptides, and the like. peptides, proteolysis-resistant FGF21 mutants, aggregation-reducing FGF21 mutants variants, FGF21 combination mutants, FGF21 conjugates (e.g., fatty acid- FGF21 conjugates, PEG-FGF21 conjugates) and FGF21 fusion proteins Proteins (e.g., Fc domain fusion proteins, human serum albumin fusion proteins) Examples include:

[0109] In one embodiment, the FGF21 protein variant is a wild-type variant according to the numbering scheme of SEQ ID NO:1. Residues reserved for FGF21 type: Q55, R105, G148, K150, P15 8, S195, P199, and G202.

[0110] In one embodiment, the FGF21 protein variant is a wild-type variant according to the numbering scheme of SEQ ID NO:1. Substitutions made to FGF21: Q55C, R105K, G148C, K150R , P158S, S195A, P199G, and G202A.

[0111] Exemplary fusion protein sequences provided herein are listed in Table 1. The description includes the FGF21 mutant and, where applicable, the linker. The modifications or substitutions used by the present invention are numbered and described relative to wild-type FGF21. .

[0112] As an example, "Mutant 101 (V101)" (SEQ ID NO: 10) is a mutant that has two amino acid linkers. and substitutions made relative to wild-type FGF21 according to the numbering scheme of SEQ ID NO:1: Q 55C, A109T, G148C, K150R, P158S, P174L, S195A, It is an Fc-FGF21 fusion construct having P199G and G202A.

[0113] As another example, "Mutant 103 (V103)" (SEQ ID NO: 11) contains two amino acids The sequence is set relative to wild-type FGF21 according to the numbering scheme of SEQ ID NO:1, with a GS linker. Replaced: Q55C, R105K, G148C, K150R, P158S, S195 A, P199G, and G202A.

[0114] [Table 1]

[0115] [Table 2]

[0116] All mutations in the FGF21 portion and the corresponding amino acid numbering for said mutations are , (SEQ ID NO: 1), and the complete sequence of this table, which may also include the Fc and linker regions. Do not reference long arrays.

[0117] In a specific embodiment, a metabolic or cardiovascular disorder (e.g., obesity, NALFD, NASH, or 1, comprising the steps of: Q55C, Q65C, Q75C, Q85C, Q95C, Q10C, Q11C, Q20C, Q30C, Q40C, Q55C, Q65C, Q75C, Q85C, Q95C, Q12C, Q13C, Q14C, Q15C, Q16C, Q20C, Q30C, Q17C, Q18C R105K, G148C, K150R, P158S, S195A, P199G, and G2 A mature human FGF21 protein comprising one or more mutations selected from the group consisting of 02A and 02B, or A fusion protein that includes a human Fc region (e.g., a modified human Fc region) fused to the fragment. Methods are provided herein that include administering a human FGF21 protein variant.

[0118] In a specific embodiment, a metabolic or cardiovascular disorder (e.g., obesity, NALFD, NASH, or A method for treating, preventing or managing diabetes, comprising administering to a subject a mature human FGF21 protein or A fusion protein comprising a human Fc region (e.g., a modified human Fc region) fused to the fragment. For example, a human FGF21 protein variant, such as V103, which comprises the amino acid sequence of SEQ ID NO:11. Methods are provided herein that include administering the variant.

[0119] A functional assay for determining or measuring the biological activity of FGF21 or a mutant or fragment thereof. For example, PCT Publication No. 2013 / 04 See, for example, US Pat. No. 9247, incorporated herein by reference in its entirety. In a specific embodiment, the functional assay is an in vitro assay. In certain embodiments, the functional assay is an in vivo assay. It is a request.

[0120] In a specific embodiment, downstream biomarkers of FGF21 are assessed to detect FGF21 or its The biological activity of the mutant or fragment thereof can be determined. As used herein, refers to a gene or gene product, or a gene or gene product. In some embodiments, a gene that is a downstream marker of FGF21 is The gene or activity exhibits altered levels of expression, i.e., in vascular tissue. In some embodiments, the activity of the downstream marker is altered in the presence of an FGF21 modulator. In this study, downstream markers were identified when FGF21 was perturbed with FGF21 modifiers, and the altered receptor The following figures show the expression of FGF21 downstream markers, including, but not limited to, glucose or 2-deoxy-glucose uptake, pERK and other phosphorylated or acetylated kinases Including protein or NAD levels.

[0121] Pharmaceutical Compositions and Formulations In particular embodiments, metabolic or cardiovascular disorders, e.g., hypertriglyceridemia and cardiac risk, insulin resistance, e.g., insulin receptor gene mutations and lipodystrophy, Diabetes, Obesity, and Nonalcoholic Fatty Liver Disease (NAFLD) / Nonalcoholic Fatty Liver For use in methods of treating, preventing, and / or managing patients with nonalcoholic steatohepatitis (NASH) of FGF21 protein variants, such as those listed in Table 1, e.g. For example, pharmaceutical compositions comprising V103 (SEQ ID NO:11) are provided herein.

[0122] The pharmaceutical compositions described herein comprise a therapeutically effective amount of an FGF21 protein variant and a pharmaceutical Alternatively, the carrier may include a physiologically acceptable carrier. The carrier will generally be suitable for the intended mode of administration. For example, the pH, osmolality, viscosity, clarity, color, tonicity, etc. of the composition may be selected to improve the composition's modifying the properties, odor, sterility, stability, rate of dissolution or release, adsorption, and / or permeability Typically, these carriers are aqueous or The liquid may be an alcoholic / aqueous solution, an emulsion or a suspension, e.g., saline and / or buffer. Contains buffered medium.

[0123] Drugs suitable for inclusion in pharmaceutical compositions include, but are not limited to, amino acids (glycine, Glutamine, asparagine, arginine, histidine, or lysine), antibacterial, antioxidant buffers (such as ascorbic acid, sodium sulfite, or sodium hydrogen sulfite); borate, bicarbonate, tris-HCl, citrate, phosphate, or other organic acids) , bulking agent (such as mannitol or glycine), chelating agent (ethylenediaminetetraacetic acid (EDTA), complexing agents (caffeine, polyvinylpyrrolidone, β-cyclodextrin phosphorus, or hydroxypropyl-β-cyclodextrin, etc.), bulking agents, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrin), proteins ( serum albumin, gelatin, or immunoglobulin), coloring agents, flavoring agents and diluents, milk Hydrophilic polymers (e.g., polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming agents ions (sodium, etc.), preservatives (benzalkonium chloride, benzoic acid, salicylic acid, Merosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexyl , sorbic acid, or hydrogen peroxide), solvents (glycerin, propylene glycol, or polyethylene glycol, etc.), sugar alcohols (mannitol or sorbitol, etc. ), suspending agents, surfactants or wetting agents (e.g., Pluronic®; PEG; Rubitan esters; polysorbates such as polysorbate 20 or polysorbate 80; Triton; tromethamine; lecithin; cholesterol or tyloxap al)), stability enhancers (such as sucrose or sorbitol), osmolality enhancers (e.g., Alkali metal halides, such as sodium or potassium chloride, or mannitol sorbitol), delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants. .

[0124] Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose chloride, and Suitable physiologically acceptable thickening agents include sodium chloride and lactated Ringer's. Examples include carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates. Intravenous vehicles may include fluid and nutrient replenishers and electrolyte replenishers, such as Ringer's In some cases, the composition, e.g., the pharmaceutical composition, may include those based on maltose. , sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride It will be preferable to include an agent to regulate the osmolarity of the It is desirable for the composition to be substantially isotonic. Preservatives and other additives, e.g., antimicrobial agents, Antioxidants, chelating agents and inert gases may also be present. The exact formulation will depend on the route of administration. Further suitable principles, methods and ingredients in pharmaceutical formulations are well known in the art. (See, for example, Allen, Loyd V. Ed. (2012) Remington 's Pharmaceutical Sciences,22th Edition( For this purpose, see ).

[0125] When parenteral administration is contemplated, the pharmaceutical composition is usually sterile, pyrogen-free, and In the form of a parenterally acceptable composition. A particularly suitable vehicle for parenteral injection is a properly preserved The pharmaceutical composition is in the form of a lyophilisate, e.g. a lyophilised cake. Possible.

[0126] In certain aspects, the pharmaceutical compositions provided herein (e.g., FGF21 protein variants) are The composition comprising variant V103 is for subcutaneous administration. Suitable formulations and methods for subcutaneous administration of antibodies (such as fusion proteins) are known in the art. For example, U.S. Patent Application Publication No. 2011 / 0044977 and U.S. Patent No. 8,333,663. Nos. 8,476,239 and 8,465,739, each of which is incorporated herein by reference in its entirety. (which is incorporated by reference for this purpose). Typically, pharmaceutical compositions for subcutaneous administration are The composition may contain suitable stabilizers (e.g., amino acids such as methionine, and / or sucrose, etc. sugars), buffers, and / or tonicifying agents do.

[0127] In a specific embodiment, the FGF21 protein variant (e.g., those shown in Table 1) is administered as a lyophilizate. Provided herein are pharmaceutical compositions comprising FGF21 protein variants, such as V103. In certain embodiments, the FGF21 protein variant (e.g., The present invention provides FGF21 protein variants, including those shown in Table 1, such as V103. The pharmaceutical composition is reconstituted as a solution prior to administration (e.g., subcutaneous administration) to a subject.

[0128] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. The pharmaceutical compositions provided herein, which contain a 100 mM MHC class I protein variant, e.g., V103, 100 mg / mL of FGF21 protein variants, e.g., V103 (e.g., reconstitution of lyophilized In some embodiments, the FGF21 protein variant (e.g., For example, the FGF21 protein variants provided herein include those shown in Table 1, e.g., V103. The provided pharmaceutical compositions have a concentration of at least about 50 mg / mL, 60 mg / mL, 70 mg / mL , 80mg / mL, 90mg / mL, 100mg / mL, 110mg / mL, 120mg / mL, 130mg / mL, 140mg / mL, or 150mg / mL of FGF21 The form of a solution (e.g., after reconstitution of a lyophilisate) comprising a protein variant, e.g., V103 In some embodiments, the FGF21 protein variant (e.g., the FGF21 variant shown in Table 1) is The pharmaceutical compositions provided herein include GF21 protein variants, such as V103. , about 50 mg / mL to 150 mg / mL or 100 mg / mL to 150 mg / mL of FG A solution (e.g., after reconstitution of a lyophilisate) comprising an F21 protein variant, e.g., V103 In one embodiment, the FGF21 protein variant (e.g., the FGF21 variant shown in Table 1) is in the form of The pharmaceutical compositions provided herein comprising an F21 protein variant, e.g., V103), About 75 mg / mL to 150 mg / mL of V103, for example 100 mg / mL of V103 ( The compound is in the form of a solution (e.g. after reconstitution of a lyophilisate) comprising SEQ ID NO:11).

[0129] In some embodiments, an FGF21 protein variant (e.g., an FGF2 The pharmaceutical compositions provided herein, which include a thrombopoietin variant, such as V103, Metamol buffer is added at, for example, 10 mM, 20 mM, 30 mM, 40 mM, or 50 mM in the form of a solution (e.g. after reconstitution of a lyophilisate) containing trometamol in a buffer solution at a concentration of In some embodiments, an FGF21 protein variant (e.g., an FGF21 variant shown in Table 1) is used. The pharmaceutical compositions provided herein, which include a thrombopoietin variant, such as V103, A trometamol buffer solution may be used, for example, a 10 mM to 50 mM trometamol buffer solution, for example, 30 In the form of a solution (e.g. after reconstitution of a lyophilisate) containing trometamol in a buffer solution at a concentration of 10 mM be.

[0130] In some embodiments, an FGF21 protein variant (e.g., an FGF2 The pharmaceutical compositions provided herein, which include a variant of the scrub protein, e.g., V103, are For example, at least about 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, 0 mM, 250 mM, 260 mM, 270 mM, 280 mM, 290 mM, or 30 It is in the form of a solution (e.g. after reconstitution of a lyophilisate) containing 0 mM sucrose. In this embodiment, the FGF21 protein variant (e.g., the FGF21 protein variant shown in Table 1) is The pharmaceutical compositions provided herein, comprising sucrose, For example, it contains at least about 250 mM to 300 mM sucrose, for example 270 mM (e.g. The formulation may be in the form of a solution (e.g. after reconstitution of a lyophilized product).

[0131] In some embodiments, an FGF21 protein variant (e.g., an FGF2 The pharmaceutical compositions provided herein that include a polypeptide variant (e.g., V103) are of solutions (e.g., after reconstitution of a lyophilisate) containing sorbates, e.g., polysorbate 20 In a specific embodiment, the FGF21 protein variant (e.g., the FGF21 variant shown in Table 1) is The pharmaceutical compositions provided herein include GF21 protein variants, such as V103. , at least about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.0 6%, 0.07%, 0.08%, 0.09%, or 0.10% polysorbate 20 In a specific embodiment, the FGF2 1 protein variant (e.g., an FGF21 protein variant shown in Table 1, such as V1 The pharmaceutical compositions provided herein, including 0.02% to 0.10% polysorbate 03), Polysorbate 20, e.g., 0.06% polysorbate 20 (e.g., after reconstitution of the lyophilized product) ) in the form of a solution.

[0132] In some embodiments, an FGF21 protein variant (e.g., an FGF2 The pharmaceutical compositions provided herein comprising the 101 protein variant, e.g., V103), are 6. of a solution (e.g. after reconstitution of a lyophilisate) with a pH in the range of 5-9, e.g. a pH of 8.0 In some embodiments, the FGF21 protein variants (e.g., those shown in Table 1) are The pharmaceutical compositions provided herein include FGF21 protein variants, such as V103. The article has a viscosity of at least about 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 or It is in the form of a solution (eg after reconstitution of a lyophilisate) at a pH of 9.5.

[0133] In some embodiments, an FGF21 protein variant (e.g., an FGF2 The pharmaceutical compositions provided herein, which include a thrombopoietin variant, such as V103, Contains metamol buffer, sucrose, and polysorbate 20 (e.g., for reconstitution of lyophilized material) It is in the form of a solution (after constitution).

[0134] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. The pharmaceutical compositions provided herein, which include a protein variant, e.g., V103, are capable of binding to a pH of 7. 5 to 8.5, for example, pH 8.0, and about 80 mg / mL to 100 mg / mL of FGF21. Protein variants, such as V103 (SEQ ID NO: 11), in about 30 mM trometamol buffer , 270 mM sucrose, and 0.06% polysorbate 20 (e.g., lyophilized The solution is in the form of a solution (after reconstitution of the material).

[0135] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. The pharmaceutical compositions provided herein, which contain a protein variant, e.g., V103, are capable of binding to a pH of 8. 0 and about 100 mg / mL of an FGF21 protein variant, such as V103 (SEQ ID NO:1 1), approximately 30 mM trometamol buffer, 270 mM sucrose, and 0.06% poly It is in the form of a solution (e.g., after reconstitution of a lyophilizate) containing resorbate 20.

[0136] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. A method for preparing a pharmaceutical composition comprising an FGF2 protein variant, e.g., V103, comprising: 1. A method comprising formulating the protein variant as a lyophilizate suitable for reconstitution in solution. Methods are provided herein.

[0137] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. A method for preparing a pharmaceutical composition comprising a lyophilized protein variant, e.g., V103, comprising the steps of: The substance is added to a solution described herein, for example, at up to about 100 mg / mL (e.g., For example, about 50 mg / mL to about 100 mg / mL) of an FGF21 protein variant, for example V103 (SEQ ID NO: 11), approximately 30 mM trometamol buffer, 270 mM sucrose The method includes reconstituting the compound in a solution containing 0.06% polysorbate 20. Provided in the fine print.

[0138] In certain embodiments, FGF21 protein variants (e.g., FGF21 variants shown in Table 1) are used. A method for preparing a pharmaceutical composition comprising a protein variant, e.g., V103, at a pH of 8. 0 and about 100 mg / mL of an FGF21 protein variant, such as V103 (SEQ ID NO:1 1), approximately 30 mM trometamol buffer, 270 mM sucrose, and 0.06% poly Provided herein are methods that include preparing a solution that includes Resorbate 20.

[0139] In certain embodiments, the methods for preparing the pharmaceutical compositions described herein include administering to a subject an FGF21 protein. and FGF21 protein variants (e.g., FGF21 protein variants shown in Table 1, e.g., V103). The method includes a step of diluting the solution having the above-mentioned amine to a concentration in the range of 10 mg / mL to 90 mg / mL. In one specific embodiment, the solution is diluted with saline, for example 0.9% saline. do. EXAMPLES

[0140] V. Working Examples The following examples are intended to illustrate the invention and are not to be construed as limitations thereon. The term "abbreviations" should not be construed as limiting the present invention, and should not be construed as limiting the present invention. Abbreviations are used as is common in the art.

[0141] Example 1 For Fc-FGF21 mutant fusion proteins, e.g., V103 comprising SEQ ID NO: 11 For example, in the PCT Publication No. International Publication No. 2013 / 049247, For example, V103 was synthesized in ob / ob mice (a mouse model for type 2 diabetes). In mice lacking functional leptin as a control, 2- Induce deoxyglucose uptake and ERK phosphorylation in a cell-based assay Induce RK signaling and reduce total plasma glucose, plasma insulin, and body weight V103 has also been reported to have a longer half-life and a lower melting temperature, e.g. It has been reported that it is more thermodynamically stable as assessed by degree of oxidation.

[0142] The PK characteristics of V103 in cynomolgus monkeys were evaluated using two doses IV and SP with a 4-week recovery period. C injection toxicity study and 13-week IV and SC injection toxicity studies with a 13-week recovery period. Each is judged.

[0143] The pharmacokinetics of V103 was similar in both studies, with no apparent gender differences. Moderate accumulation of 03 was observed in a 13-week GLP toxicity study (after the first and final doses). As measured by Cmax and AUC0-7 days, the accumulation index across the four dose groups was 1.1 5~2.36).

[0144] Exposure to V103 (Cmax and AUC) was observed in the dose range of 0.3 to 100 mg / kg. The pharmacokinetics of the intravenous dose was linear with a terminal elimination phase. After subcutaneous administration (100 mg / kg), V103 slowly increased Maximum exposure was observed 1-4 days after subcutaneous administration. The terminal elimination phase was absorption-limited. The estimated subcutaneous bioavailability was 60-90%. Calculated for the penultimate dose (day 85) and the final dose (day 92) of the toxicology study The mean toxicokinetic parameters obtained are summarized.

[0145] [Table 3]

[0146] Consistent with the rat pharmacokinetics, HPLC-MS / MS evaluation demonstrated that the in vivo cytotoxicity In monkeys, the central part of the FGF21 subdomain of V103 is involved in the FGF21 receptor The C-terminal subdomain (T 1 / 2 (About 5~8 days) It is stable (T 1 / 2 The results showed that the duration of the study was approximately 9 to 12 days. Biological activity and pharmacokinetic properties of truncated / inactive forms of V103 as determined in clinical toxicology studies. Summarize gender.

[0147] [Table 4]

[0148] Anti-V103 antibodies (ADA) were observed in some animals. The placement-associated ADA response was associated with accelerated clearance of V103, but these studies Overall effects of total and sustained exposure to V103 in the 1 During a 3-week GLP toxicity study, selectivity of the ADA response was evaluated, and among ADA-positive samples, endogenous None of the antibodies showed cross-reactivity with wild-type FGF21.

[0149] Example 2 The objective of the clinical trial was to evaluate the efficacy and safety of multiple doses of V1 administered subcutaneously over a 3-month period in obese subjects. The objective of the study was to evaluate the safety and tolerability of 03. and / or early efficacy signals in various obesity-related metabolic diseases, and V103 metabolic disorders such as hypertriglyceridemia, obesity, and / or nonalcoholic fatty liver disease The study also aims to determine whether the drug demonstrates clinical safety and efficacy characteristics as a suitable therapeutic agent for the development of the disease. It becomes.

[0150] Objectives and Endpoints The primary objective was to evaluate the efficacy and safety of V103 in treating obesity after repeated subcutaneous (SC) injections over a 12-week period. The objective of this study was to evaluate the safety and tolerability of the drug in rats. , Adverse Events (AEs) Vital signs Aspartate transaminase (AST), alanine transaminase (AL T), total bilirubin (Total Bili) and alkaline phosphatase (ALP) Liver function tests 24-hour urinary cortisol ·Electrolytes Includes.

[0151] The secondary objective is To evaluate the effect of V103 on triglycerides and lipid profiles after 12 weeks of treatment. and At 12 weeks of treatment, bone biopsy was performed in terms of the balance of resorption versus bone formation and deposition. To evaluate the potential effects of V103 on ophthalmological markers At 12 weeks, the weight, body mass index (BMI) and waist circumference were measured. To evaluate the effectiveness of V103 Includes.

[0152] The endpoints for these purposes are: Total cholesterol, LDL-C, HDL-C and triglycerides at 12 weeks (fasting ) Biomarkers of bone resorption at 12 weeks (serum CTX-1, urinary NTX-1) -Bone formation biomarkers at 12 weeks (serum BSAP, PlNP, and osteocalcin ) Weight, body mass index (BMI), waist circumference, and percent liver fat fraction at 12 weeks (MRI (when measured by Includes.

[0153] Other test objectives are: To evaluate the pharmacokinetics (PK) of V103 in obese subjects after repeated dosing over 12 weeks To To evaluate the immunogenicity of V103 after repeated subcutaneous administration of V103 To evaluate the potential blood glucose metabolic effects of V103 Includes.

[0154] Non-limiting examples of endpoints for these other study objectives include: Determination of PK parameters including AUClast, Cmax, and Tmax; Fasting glucose, insulin, glucagon, and C-peptide for up to 12 weeks; Estimates obtained for insulin sensitivity and secretion (HOMA); ·HbAlc, glycated albumin; Adiponectin; and - Anti-drug antibodies (ADA) pre- and post-treatment over 26 weeks Examples include:

[0155] Test Design: The study will involve obese subjects receiving multiple subcutaneous doses of V103 or placebo over a 3-month period. A non-validated, multicenter, randomized, investigator- and subject-blinded, placebo-controlled safety trial in Design it as an experiment.

[0156] Approximately 60 subjects will receive three doses of V103 at 300 mg subcutaneously (SC) once every four weeks. or will be randomized (1:1, active:placebo) to receive a matching placebo.

[0157] The study will have three main periods: (1) screening, which will last between 1 and 4 weeks; 2) A subject- and investigator-blinded, randomized treatment period planned to last 12 weeks, and ( 3) The end-of-study evaluation will consist of approximately 120 days (approximately 6 half-lives) after the last dose of study drug.

[0158] Cohort expansion: After interim analysis (e.g., approximately 15 subjects in each group completed treatment (day 84) After reaching 100 mg / kg / day, there is evidence of efficacy and additional doses are recommended to inform future trials before population expansion. If necessary, lower dose cohorts may be evaluated.

[0159] Population: The study population consisted of approximately 60 adult male and female obese subjects aged 18 to 55 years (inclusive). It will be done.

[0160] Key inclusion criteria: · Targeted at men and women aged 18-55 years; 30~45kg / m 2 Body mass index (BMI) in the range of Asian For humans, the mean is ≥27.5 (WHO Expert Consultation, 200 4,Lancet,363(9403):157-63);BMI=weight(kg) / [body Length (m)] 2 Contains; and At screening, 150-500 mg / dL (1.69-5.65 mmol / L) Triglycerides including

[0161] Key exclusion criteria: - History of hepatic encephalopathy, esophageal varices, or portacaval shunts or ultrasound screening History of hepatobiliary disease, cholelithiasis, or biliary sludge at the time of screening; Abnormal liver function tests (ALT, When indicated by AST, GGT, alkaline phosphatase, or serum bilirubin liver disease or damage; - Human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) Chronic infection with HBV surface antigen (HBsAg) test positive or standard local Subjects with a positive HBV core antigen test were excluded. Subjects with a positive HCV antibody test were excluded. HCV RNA levels should be measured. subjects must be excluded; Fasting triglycerides above 500 mg / dL [5.65 mmol / L] or high triglycerides Combination medications for hyperglyceridemia (fibrates, omega-3 fatty acids, nicotinic acid) ; History of pancreatic injury or pancreatitis, or other pancreatic disease. At screening or baseline, UL amylase or lipase exceeding N; FGF21 protein analogs or Fc fusion proteins of similar biological classes History of hypersensitivity to medications; Bone disorders including but not limited to osteoporosis, osteopenia, osteomalacia, severe vitamin D deficiency History of disorders; Plasma 25-hydroxyvitamin D levels below the lower limit of normal at screening r; Contraindications to MRI; · weight change (self-reported change of more than 5% or self-reported change of 5 kg in the past 3 months); Weight loss drugs: Orlistat (Xenical, Alli), Lorcaserin (Bel viq), phentermine-topiramate (Qsymia), naltrexone-bupropion on (Contrave), or liraglutide (Victoza or Saxenda), or were compared with other glucagon-like peptide 1 (GLP1) receptor agonists (exenatide (Byetta) / Bydureon, lixisenatide (Luxumia), albiglutide (Tanz eum) or dulaglutide (Trulicity or other); and - Diet, weight loss, or exercise program with the specific intent to lose weight within 3 months prior to randomization Enrollment in a pediatric diet or clinical diagnosis of any eating disorder are also exclusionary.

[0162] Pharmacokinetic assessment: When feasible, Cmax, Tmax, and C last, Tlast, AUClast, AUCtau, AUCinf, T1 / 2, Vz / F and CL / F

[0163] Efficacy / PD assessment: Fasting triglycerides ·body weight Major safety evaluations Monitoring for adverse events and serious adverse events Bone biomarkers Liver function Ultrasound Pancreatic function Pituitary-adrenal function · Safety monitoring of other pituitary-endocrine Physical examination and vital signs -Monitoring routine laboratory markers in blood and urine ·electro-cardiogram Columbia-Suicide Severity Rating Scale (C-SSRS) Mechanistic and biomarkers of inflammation

[0164] Additional Embodiments In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder, comprising: Human FGF21 protein variants are administered in the range of 100mg to 600mg to subjects in need of treatment. and administering at a dose of

[0165] In another aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia. The present invention relates to a method for treating, preventing, or managing a disorder comprising administering to a subject in need thereof a human FGF21 protein. The method includes administering the protein variant at a dose in the range of 100 mg to 600 mg. Provided in the fine print.

[0166] In another embodiment, a method for reducing weight comprises administering to a subject in need thereof human FGF2 A method comprising administering a protein variant at a dose in the range of 100 mg to 600 mg. is provided herein.

[0167] In another embodiment, increased LDL-C, total cholesterol, triglycerides, and / or A method for reducing apolipoprotein B, comprising administering human FGF2 to a subject in need thereof. A method comprising administering a protein variant at a dose in the range of 100 mg to 600 mg. is provided herein.

[0168] In another embodiment, a method for increasing HDL-C is provided by administering human F The method includes administering the GF21 protein variant at a dose ranging from 100 mg to 600 mg. Methods are provided herein for

[0169] In another aspect, a method for lowering triglyceride levels is provided, comprising administering to a subject in need thereof The human FGF21 protein mutant was administered to the rats at a dose ranging from 100 mg to 600 mg. Provided herein is a method comprising:

[0170] In another aspect, a method for reducing cardiovascular risk comprises administering to a subject in need thereof a human The FGF21 protein variant should be administered at a dose ranging from 100 mg to 600 mg. Methods including the steps of:

[0171] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder, comprising: Human FGF21 protein variants are administered in the range of 100mg to 600mg to subjects in need of treatment. HUMAN FGF21 PROTEIN MUTANT FOR USE IN A METHOD COMPRISING ADMINISTRATION OF THE HUMAN FGF21 PROTEIN MUTANT AT A DOSE OF is provided herein.

[0172] In one aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia is A method of treating, preventing, or managing a subject in need thereof, comprising administering to a subject a human FGF21 protein. The method includes administering a protein variant at a dose in the range of 100 mg to 600 mg. Provided herein are human FGF21 protein variants for use.

[0173] In one aspect, a method for reducing weight is provided comprising administering to a subject in need thereof human FGF21 administering the protein variant at a dose in the range of 100 mg to 600 mg. Provided herein are human FGF21 protein variants for use in

[0174] In one embodiment, the elevated LDL-C, total cholesterol, triglycerides, and / or adipose tissue A method for reducing polypoprotein B by administering human FGF21 to a subject in need thereof. administering the protein variant at a dose in the range of 100 mg to 600 mg. Provided herein are human FGF21 protein variants for use in

[0175] In one embodiment, a method for increasing HDL-C is provided by administering human FG to a subject in need thereof. and administering the F21 protein variant at a dose in the range of 100 mg to 600 mg. Provided herein are human FGF21 protein variants for use in the methods.

[0176] In one aspect, a method for lowering triglyceride levels in a subject in need thereof. Administer human FGF21 protein variants at doses ranging from 100mg to 600mg to Provided herein is a human FGF21 protein variant for use in a method comprising: will be done.

[0177] In one aspect, a method for reducing cardiovascular risk is provided comprising administering to a subject in need thereof a human F The method includes administering the GF21 protein variant at a dose ranging from 100 mg to 600 mg. Provided herein are human FGF21 protein variants for use in methods including administering to a patient a therapeutically effective amount of FGF21.

[0178] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder, comprising: Human FGF21 protein variants are administered in the range of 100mg to 600mg to subjects in need of treatment. in the preparation of a medicament for use in a method comprising administering to a subject a human FGF2 Uses of the 1 protein variants are provided herein.

[0179] In one aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia is A method of treating, preventing, or managing a subject in need thereof, comprising administering to a subject a human FGF21 protein. The method includes administering a protein variant at a dose in the range of 100 mg to 600 mg. Provided herein is the use of a human FGF21 protein variant in the preparation of a medicament for use. It will be offered.

[0180] In one aspect, a method for reducing weight is provided comprising administering to a subject in need thereof human FGF21 administering the protein variant at a dose in the range of 100 mg to 600 mg. The present disclosure relates to the use of human FGF21 protein variants in the preparation of a medicament for use in provided in the book.

[0181] In one embodiment, the elevated LDL-C, total cholesterol, triglycerides, and / or adipose tissue A method for reducing polypoprotein B by administering human FGF21 to a subject in need thereof. administering the protein variant at a dose in the range of 100 mg to 600 mg. The present disclosure relates to the use of human FGF21 protein variants in the preparation of a medicament for use in provided in the book.

[0182] In one embodiment, a method for increasing HDL-C is provided by administering human FG to a subject in need thereof. and administering the F21 protein variant at a dose in the range of 100 mg to 600 mg. Use of a human FGF21 protein variant in the preparation of a medicament for use in a method Provided herein.

[0183] In one aspect, a method for lowering triglyceride levels in a subject in need thereof. Administer human FGF21 protein variants at doses ranging from 100mg to 600mg to 4. A method for the preparation of a medicament for use in a method comprising: Uses of the body are provided herein.

[0184] In one aspect, a method for reducing cardiovascular risk is provided comprising administering to a subject in need thereof a human F The method includes administering the GF21 protein variant at a dose ranging from 100 mg to 600 mg. US20130233633A1 - Use of human FGF21 protein variants in the preparation of a medicament for use in a method for treating ... - Google Patents is provided herein.

[0185] In one aspect, a method for reducing cardiovascular risk is provided comprising administering to a subject in need thereof a human F The method includes administering the GF21 protein variant at a dose ranging from 100 mg to 600 mg. US20130233633A1 - Use of human FGF21 protein variants in the preparation of a medicament for use in a method for treating ... - Google Patents is provided herein.

[0186] In one aspect, the present invention relates to a method for treating, preventing, or managing a metabolic or cardiovascular disorder. In the preparation of the drug for Uses of protein variants are provided herein.

[0187] In one aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia is 100 mg to 6 in the preparation of a medicament for use in a method of treatment, prevention, or management Provided herein is the use of a human FGF21 protein variant in an amount ranging from 0.1 to 100 mg. do.

[0188] In one embodiment, the composition comprises 100 ml of a medicament for use in a method for reducing weight. The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is provided herein. It will be offered.

[0189] In one embodiment, the elevated LDL-C, total cholesterol, triglycerides, and / or adipose tissue 100 ml in the preparation of a medicament for use in a method for reducing polypoprotein B The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is provided herein. It will be offered.

[0190] In one embodiment, the present invention relates to a method for increasing HDL-C. The present invention relates to the use of human FGF21 protein variants in amounts ranging from 0.00 mg to 600 mg. provided in the book.

[0191] In one aspect, preparation of a medicament for use in a method for lowering triglyceride levels The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg in Uses are provided herein.

[0192] In one embodiment, the method reduces triglyceride levels by at least about 40% or less. It also reduces the temperature by about 50%.

[0193] In one aspect, in the preparation of a medicament for use in a method for reducing cardiovascular risk, The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is disclosed herein. Provided in the fine print.

[0194] In one aspect, the present invention relates to a method for treating, preventing, or managing a metabolic or cardiovascular disorder. Human FGF21 protein in amounts ranging from 100 mg to 600 mg in the manufacture of a drug for Uses of protein variants are provided herein.

[0195] In one aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia is 100 mg to 6 mg in the manufacture of a drug for use in the treatment, prevention, or management of Provided herein is the use of a human FGF21 protein variant in an amount ranging from 0.1 to 100 mg. do.

[0196] In one embodiment, the compound is a 100 ml The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is provided herein. It will be offered.

[0197] In one embodiment, the elevated LDL-C, total cholesterol, triglycerides, and / or adipose tissue 100m in the manufacture of a medicament for use in reducing polypoprotein B The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is provided herein. It will be offered.

[0198] In one embodiment, the present invention relates to a method for the preparation of a medicament for use in increasing HDL-C. The present invention relates to the use of human FGF21 protein variants in amounts ranging from 0.00 mg to 600 mg. provided in the book.

[0199] In one embodiment, the manufacture of a medicament for use in lowering triglyceride levels. The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg in Uses are provided herein.

[0200] In one embodiment, the method reduces triglyceride levels by at least about 40% or less. It also reduces the temperature by about 50%.

[0201] In one aspect, the method comprises the steps of: The use of human FGF21 protein variants in amounts ranging from 100 mg to 600 mg is disclosed herein. Provided in the fine print.

[0202] In one aspect, the use of human FGF-α in the manufacture of a medicament for treating a metabolic or cardiovascular disorder. Use of human FGF21 protein variants is provided herein, wherein the human FGF21 protein variants are The unit dose of the variant is in the range of 100 mg to 600 mg.

[0203] In one aspect, hypercholesterolemia, mixed dyslipidemia, or hypertriglyceridemia is The use of a human FGF21 protein variant in the manufacture of a medicament for treating wherein the unit dose of the human FGF21 protein variant is 100 mg to 600 mg. g range.

[0204] In one aspect, the present invention relates to a method for the treatment of a chronic rheumatoid arthritis, comprising administering to a patient a therapeutically effective amount of human FGF2 or human FGF2+ in the manufacture of a medicament for use in reducing body weight. The use of human FGF21 protein variants is provided herein, wherein the human FGF21 protein variants The unit dose for the body is in the range of 100 mg to 600 mg.

[0205] In one embodiment, LDL-C, total cholesterol, triglycerides, and / or apolipoproteins are measured. Human FGF21 in the manufacture of a medicament for use in reducing protein B levels. Uses of protein variants are provided herein, wherein the human FGF21 protein variant The unit dose is in the range of 100 mg to 600 mg.

[0206] In one aspect, the present invention relates to a method for increasing HDL-C. Use of human FGF21 protein variants is provided herein, wherein the human FGF21 protein variants are The unit dose of the protein variant is in the range of 100 mg to 600 mg.

[0207] In one aspect, in the manufacture of a medicament for use in lowering triglyceride levels. Provided herein is the use of a human FGF21 protein variant in The unit dose of one protein variant is in the range of 100 mg to 600 mg.

[0208] In one aspect, the present invention relates to a method for reducing cardiovascular risk, comprising administering to a subject a subject in need thereof a Use of human FGF21 protein variants is provided herein, wherein the human FGF21 variant is The unit dose of the protein variant is in the range of 100 mg to 600 mg.

[0209] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder in a human subject is provided. Provided herein are human FGF21 protein variants for use in the methods, The human FGF21 protein variant is intended for administration at a dose ranging from 100 mg to 600 mg. In one aspect, the present invention provides a method for treating, preventing, or treating a metabolic or cardiovascular disorder in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering wherein the human FGF21 protein variant is administered in an amount ranging from 100 mg to 600 mg. The present invention is provided for administration at .

[0210] In some embodiments of these aspects, the metabolic or cardiovascular disorder is hypercholesterolemia. hyperlipidemia, dyslipidemia, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

[0211] In some embodiments of these aspects, a metabolic or cardiovascular disorder is treated, prevented, or The control reduces the body weight, liver fat content, increased LDL-C, total cholesterol, and and reducing one or more of the following: cholesterol, triglycerides, and apolipoprotein B levels. In certain embodiments, the method comprises administering to the patient a therapeutically effective amount of a metabolic or cardiovascular disorder. Treating, preventing, or managing can include increasing HDL-C levels in a subject. Characterized by or comprising:

[0212] In some embodiments of these aspects, a metabolic or cardiovascular disorder is treated, prevented, or Managing means reducing triglyceride levels in a subject by at least about 40% or less. In some embodiments, the method includes or is characterized by reducing the amount of oxidative stress by about 50%. In certain embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder includes administering to a subject a comprising or characterized by reducing glyceride levels by at least about 40%. In some embodiments, the present invention is directed to treating, preventing, or managing a metabolic or cardiovascular disorder. The method includes reducing triglyceride levels in a subject by at least about 50%. Characterized by or comprising:

[0213] In some embodiments of these aspects, a metabolic or cardiovascular disorder is treated, prevented, or Managing may include or result in reducing cardiovascular risk in a subject. To be characterized.

[0214] In some embodiments of these aspects, the metabolic or cardiovascular disorder is dyslipidemia, Optionally, mixed dyslipidemia, hypertriglyceridemia, optionally severe hypertriglyceridemia Triglyceridemia, or hypercholesterolemia, optionally primary hypercholesterolemia In some embodiments, the metabolic or cardiovascular disorder is non-alcoholic fatty liver disease. Disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the subject is between 18 and 55 years old. In some embodiments, the subject is between 30 and 45 kg. / m 2 and Asian or Asian ancestry as ethnicity adjustment. In some embodiments, the subject is of 30 to 40 ancestry. 5kg / m 2 and optionally, the BMI is within the range of For subjects of Zia or Asian ancestry, the IL-1 gene is > 27.5. The subject is to have a mean age of 150-500 years as measured before administration of the human FGF21 protein variant. Have triglyceride levels in the range of g / dL (1.69 to 5.65 mmol / L) .

[0215] In some embodiments of these aspects, the human FGF21 mutant has the sequence number of SEQ ID NO:1. Based on Q55C, R105K, G148C, K150R, P158S, S195A, P Mature human FGF21 containing one or more mutations selected from 199G and G202A. A fusion protein is a protein or a fragment thereof that contains a human Fc region fused to the protein. In embodiments, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11. .

[0216] In some embodiments of these aspects, the human FGF21 protein variant comprises at least 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, or In some embodiments, the human FGF21 marker is provided for administration at a dose of 400 mg. Protein variants are approximately 100mg, 110mg, 120mg, 130mg, 140mg, For administration in doses of 150 mg, 160 mg, 170 mg, 180 mg, or 190 mg and optionally, the human FGF21 protein variant is about 100 mg or 15 mg. In some embodiments, the human FGF21 protein variant is provided in a dose of 0 mg. is about 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 2 60mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg , 330 mg, 340 mg, or 350 mg, and optionally The human FGF21 protein variant is administered at a dose of about 200, 250 mg, or 300 mg. In some embodiments, the human FGF21 protein variant comprises at least Also provided for administration at a dose of 100 mg. In some embodiments, human FGF21 The protein variant is provided for administration in a dosage of about 100 mg. In this study, the human FGF21 protein variant is proposed for administration in a dose of at least 150 mg. In some embodiments, the human FGF21 protein variant is provided at about 150 mg. In some embodiments, the human FGF21 protein variant is provided for administration at a dose of The variant is provided for administration in a dose of at least 200 mg. The human FGF21 protein variant is provided for administration in a dosage of about 200 mg. In some embodiments, the human FGF21 protein variant is administered in an amount of at least 250 mg. In some embodiments, the human FGF21 protein variant is provided for administration in an amount of In some embodiments, human FGF is provided for administration at a dose of about 250 mg. The 21 protein variant is provided for administration in a dose of 250 mg. In one embodiment, the human FGF21 protein variant is formulated for administration at a dose of at least 300 mg. In some embodiments, the human FGF21 protein variant is about 300 mV. In some embodiments, the human FGF21 protein is provided for administration at a dose of 1 g. The variant is provided for administration in a dosage of 300 mg.

[0217] In some embodiments of these aspects, the human FGF21 protein variant comprises at least 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, or In some embodiments, the human FGF21 protein is provided for administration in an amount of 400 mg. The protein variants are approximately 100mg, 110mg, 120mg, 130mg, 140mg, and 1 Available for administration in amounts of 50 mg, 160 mg, 170 mg, 180 mg, or 190 mg and optionally, the human FGF21 protein variant is about 100 mg or 150 mg. g. In some embodiments, the human FGF21 protein variant is provided in an amount of about 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260m g, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 33 and optionally, for administration to humans in amounts of 0 mg, 340 mg, or 350 mg. The FGF21 protein variant is provided in an amount of about 200 mg, 250 mg, or 300 mg. In some embodiments, the human FGF21 protein variant is at least 10 In some embodiments, the human FGF21 protein is provided for administration in an amount of 0 mg. The mutant variant is provided for administration in an amount of about 100 mg. The FGF21 protein variant is provided for administration in an amount of at least 150 mg. In some embodiments, the human FGF21 protein variant is administered in an amount of about 150 mg. In some embodiments, the human FGF21 protein variant comprises at least In some embodiments, human FGF21 is provided for administration in an amount of 200 mg. The protein variant is provided for administration in an amount of about 200 mg. The human FGF21 protein variant is provided for administration in an amount of at least 250 mg. In some embodiments, the human FGF21 protein variant is administered in an amount of about 250 mg. In some embodiments, the human FGF21 protein variant is provided for administration in In some embodiments, the human FGF21 marker is provided for administration in an amount of 250 mg. The protein variant is provided for administration in an amount of at least 300 mg. In the form, the human FGF21 protein variant is provided for administration in an amount of about 300 mg. In some embodiments, the human FGF21 protein variant is administered in an amount of 300 mg. Provided for administration.

[0218] In some embodiments, the human FGF21 protein variant is provided in a subcutaneous form. In some embodiments, the human FGF21 protein variant is administered once a month or Available for administration once every 4 weeks, once every 3 weeks, once every 2 weeks, or once every week In some embodiments, the human FGF21 protein variant is administered once a month or Once every 4 weeks, once every 3 weeks, once every 2 weeks, or once every week In some embodiments, the human FGF21 protein variant is administered subcutaneously. provided in a form that should be

[0219] In one aspect, a method for treating, preventing, or managing a metabolic or cardiovascular disorder in a human subject is provided. The method comprises administering a human FGF21 protein variant at a dose in the range of 100 mg to 600 mg. In one aspect, a method is provided herein for administering to a subject in a human subject. The present invention relates to a method for treating, preventing, or managing a metabolic or cardiovascular disorder caused by human FGF21. and administering to the subject an amount of the protein variant in the range of 100 mg to 600 mg. is provided herein.

[0220] In some embodiments, the metabolic or cardiovascular disorder is hypercholesterolemia, dyslipidemia, Normal, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic The disease is selected from non-alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

[0221] In some embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder includes administering to a subject a therapeutically effective amount of ... medicament for which the therapeutically effective amount is at least 50 mg / kg. , body weight, liver fat content, increased LDL-C, total cholesterol, triglycerides in subjects and / or apolipoprotein B levels. In certain embodiments, the method is characterized by treating, preventing, or treating a metabolic or cardiovascular disorder. Managing may include or involve increasing HDL-C levels in the subject. Thus, it is characterized.

[0222] In some embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder includes administering to a subject a therapeutically effective amount of ... medicament for which the therapeutically effective amount is at least 50 mg / kg. reducing triglyceride levels in a subject by at least about 40% or at least about 50% In some embodiments, the method comprises or is characterized by: Treating, preventing, or managing a cardiovascular injury or cardiovascular disorder includes increasing triglyceride levels in a subject. The method includes or is characterized by reducing the amount of acetylcholine by at least about 40%. In some embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder comprises administering to a subject or by reducing triglyceride levels in the Thus, it is characterized.

[0223] In some embodiments, treating, preventing, or managing a metabolic or cardiovascular disorder includes administering to a subject a therapeutically effective amount of ... medicament for which the therapeutically effective amount is at least 50 mg / kg. or characterized by reducing cardiovascular risk in a subject. .

[0224] In some embodiments, the metabolic or cardiovascular disorder is dyslipidemia, hypertriglyceridemia, In some embodiments, the metabolic or cardiovascular disorder is hypercholesterolemia. In some embodiments, the metabolic or cardiovascular disorder is hyperlipidemia. In some embodiments, the metabolic or cardiovascular disorder is hypercholesterolemia. In some embodiments, the metabolic or cardiovascular disorder is mixed lipoproteinemia. In some embodiments, the metabolic or cardiovascular disorder is a severe hypertriglyceridemia. In some embodiments, the metabolic or cardiovascular disorder is primary hypercholesterolemia. In some embodiments, the metabolic or cardiovascular disorder is non-alcoholic fatty liver disease. cholangiocarcinoma of the liver (NAFLD) or nonalcoholic steatohepatitis (NASH). In some embodiments, the metabolic or cardiovascular disorder is nonalcoholic fatty liver disease (NAFLD). In some embodiments, the metabolic or cardiovascular disorder is a non-alcoholic fatty liver disease (FLD). In a particular embodiment, the subject is 18 to 55 years old. In some embodiments, the subject is 2 Body Mass Index (BM) in the range I) and, for subjects of Asian descent or Asian ancestry, ≥ 27.5 as an ethnic adjustment. In some embodiments, the subject has a body mass index (BMI).

[0225] In one aspect, a method for treating, preventing, or managing hypercholesterolemia in a human subject. Provided herein are human FGF21 protein variants for use in The FGF21 protein variant is available in 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200m g, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 27 0mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340 mg, 350 mg, or 360 mg, and optionally The human FGF21 protein variants are available in doses of approximately 100 mg, 150 mg, 200 mg, and 25 mg. and the human FGF21 variant is provided in a dose of 0 mg, 100 mg, 200 mg, 300 mg, or 300 mg. Based on the numbering: Q55C, R105K, G148C, K150R, P158S, S195A A mature human FGF having one or more mutations selected from the group consisting of P199G, P202A, and G202A. 21 protein or a fragment thereof, Optionally, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11. In one embodiment thereof, the human FGF21 variant is administered in a dose of about 100 ml for administration once per week. It is available in doses of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In an embodiment, the human FGF21 variant is administered in a dose of about 100 mg, 15 mg, or 20 mg once every two weeks. In one embodiment, the compound is provided in a dose of 0 mg, 200 mg, 250 mg, or 300 mg. In this study, human FGF21 mutants were administered at approximately 100 mg, 150 mg, or 200 mg once every 3 weeks. In one embodiment, the human ovarian supplement is provided in a dose of 200 mg, 250 mg, or 300 mg. The FGF21 variant is administered in a dose of approximately 100 mg or 100 ng / month for administration once every 4 weeks or once a month. It comes in doses of 50 mg, 200 mg, 250 mg, or 300 mg.

[0226] In one aspect, the present invention relates to a method for treating, preventing, or managing dyslipidemia in a human subject. Provided herein is a human FGF21 protein variant for use in 1 Protein variants available in 100mg, 110mg, 120mg, 130mg, 140mg , 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210 mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 2 80mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg or 350 mg, and optionally comprising human F The GF21 protein variant is about 100 mg, 150 mg, 200 mg, 250 mg, or is provided in a dose of 300 mg, and the human FGF21 variant is provided in a dose of 300 mg based on the numbering of SEQ ID NO:1. <Q55C, R105K, G148C, K150R, P158S, S195A, P199 A mature human FGF21 protein comprising one or more mutations selected from G and G202A. a fusion protein comprising a human Fc region fused to a protein or fragment thereof, and optionally In one embodiment, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11. In an embodiment, the human FGF21 variant is administered in a dose of about 100 mg, 150 mg, or 200 mg once a week. In one embodiment, the compound is provided in a dose of 100 mg, 200 mg, 250 mg, or 300 mg. The human FGF21 variant is available in doses of approximately 100 mg, 150 mg, and 2 In one embodiment, the method is provided in a dose of 00 mg, 250 mg, or 300 mg. The FGF21 variants are available in doses of approximately 100 mg, 150 mg, and 200 mg for administration once every 3 weeks. In one embodiment, human FGF2 is provided in a dose of 100 mg, 250 mg, or 300 mg. One variant is available in a dose of approximately 100 mg, 150 mg, or 200 mg for administration once every four weeks or once a month. It comes in doses of 200mg, 250mg, or 300mg.

[0227] In one aspect, a method for treating, preventing, or managing hypertriglyceridemia in a human subject. Provided herein are human FGF21 protein variants for use in The FGF21 protein variant is available in 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200m g, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 27 0mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340 mg, 350 mg, or 360 mg, and optionally The human FGF21 protein variants are available in doses of approximately 100 mg, 150 mg, 200 mg, and 25 mg. and the human FGF21 variant is provided in a dose of 0 mg, 100 mg, 200 mg, 300 mg, or 300 mg. Based on the numbering: Q55C, R105K, G148C, K150R, P158S, S195A A mature human FGF having one or more mutations selected from the group consisting of P199G, P202A, and G202A. 21 protein or a fragment thereof, Optionally, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11. In one embodiment thereof, the human FGF21 variant is administered in a dose of about 100 ml for administration once per week. It is available in doses of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In an embodiment, the human FGF21 variant is administered in a dose of about 100 mg, 15 mg, or 20 mg once every two weeks. In one embodiment, the compound is provided in a dose of 0 mg, 200 mg, 250 mg, or 300 mg. In this study, human FGF21 mutants were administered at approximately 100 mg, 150 mg, or 200 mg once every 3 weeks. In one embodiment, the human ovarian supplement is provided in a dose of 200 mg, 250 mg, or 300 mg. The FGF21 variant is administered in a dose of approximately 100 mg or 100 ng / month for administration once every 4 weeks or once a month. It comes in doses of 50 mg, 200 mg, 250 mg, or 300 mg.

[0228] In one embodiment, the method comprises treating or preventing non-alcoholic fatty liver disease (NAFLD) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering wherein the human FGF21 protein variant is provided in an amount of 100 mg, 110 mg, 120 mg, mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 1 90mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg , 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320 provided for administration in doses or amounts within the range of 300 mg, 330 mg, 340 mg, or 350 mg and optionally, the human FGF21 protein variant is about 100 mg, 150 mg, , 200 mg, 250 mg, or 300 mg doses, and The antibody has the sequence Q55C, R105K, G148C, K150R, P1 one or more mutations selected from 58S, S195A, P199G, and G202A A fusion tag comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is a human FGF21 protein variant of SEQ ID NO: 11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. For administration in doses of approximately 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg In one embodiment, the human FGF21 mutant is administered once every two weeks. Available in doses of about 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg In one embodiment, the human FGF21 variant is administered in an amount of about 100 mg / kg for administration once every three weeks. It is available in doses of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In one embodiment, the human FGF21 variant is administered once every four weeks or once a month. provided in doses of about 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. can be.

[0229] In one aspect, the present invention relates to a method for treating, preventing, or treating non-alcoholic steatohepatitis (NASH) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering wherein the human FGF21 protein variant is provided in an amount of 100 mg, 110 mg, 120 mg, g, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 19 0mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320m 2. The composition is provided for administration in doses or amounts within the range of 200 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg. and optionally, the human FGF21 protein variant is about 100 mg, 150 mg, It is provided in doses of 200 mg, 250 mg, or 300 mg, and is also a human FGF21 variant. is Q55C, R105K, G148C, K150R, P15 based on the numbering of SEQ ID NO:1 8S, S195A, P199G, and G202A. A fusion protein comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is an amino acid sequence of SEQ ID NO:11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. It is provided in doses of approximately 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In one embodiment thereof, the human FGF21 variant is provided in an amount of about 100 mg / kg / day for administration once every two weeks. Available in doses of 100mg, 150mg, 200mg, 250mg, or 300mg In one embodiment, the human FGF21 variant is administered in a dose of about 100 ml for administration once every three weeks. It is available in doses of 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. In embodiments, the human FGF21 variant is administered once every four weeks or once a month. Available in doses of about 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg do.

[0230] In one aspect, the present invention relates to a method for treating, preventing, or managing type 2 diabetes in a human subject. Provided herein is a human FGF21 protein variant for use in 1 Protein variants available in 100mg, 110mg, 120mg, 130mg, 140mg , 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210 mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 2 80mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg or 350 mg, and optionally comprising human F The GF21 protein variant is about 100 mg, 150 mg, 200 mg, 250 mg, or is provided in a dose of 300 mg, and the human FGF21 variant is provided in a dose of 300 mg based on the numbering of SEQ ID NO:1. <Q55C, R105K, G148C, K150R, P158S, S195A, P199 A mature human FGF21 protein comprising one or more mutations selected from G and G202A. a fusion protein comprising a human Fc region fused to a protein or fragment thereof, and optionally In one embodiment, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11. In an embodiment, the human FGF21 variant is administered in a dose of about 100 mg, 150 mg, or 200 mg once a week. In one embodiment, the compound is provided in a dose of 100 mg, 200 mg, 250 mg, or 300 mg. The human FGF21 variant is available in doses of approximately 100 mg, 150 mg, and 2 In one embodiment, the method is provided in a dose of 00 mg, 250 mg, or 300 mg. The FGF21 variants are available in doses of approximately 100 mg, 150 mg, and 200 mg for administration once every 3 weeks. In one embodiment, human FGF2 is provided in a dose of 100 mg, 250 mg, or 300 mg. One variant is available in a dose of approximately 100 mg, 150 mg, or 200 mg for administration once every four weeks or once a month. It comes in doses of 200mg, 250mg, or 300mg.

[0231] In one aspect, the present invention provides a method for treating, preventing, or managing obesity in a human subject. Provided herein are human FGF21 protein variants for use in Protein variants are 100mg, 110mg, 120mg, 130mg, 140mg, and 15 0mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280m g, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg, optionally containing human FGF2 One protein variant may contain approximately 100 mg, 150 mg, 200 mg, 250 mg, or 30 mg of 0 mg dose, and the human FGF21 variant is provided in the Q5 5C, R105K, G148C, K150R, P158S, S195A, P199G, and and G202A, and / or G202B, or is a fusion protein comprising a human Fc region fused to a fragment thereof, optionally The FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11. In this study, the human FGF21 mutant was administered at approximately 100 mg, 150 mg, or 200 mg once a week. In one embodiment, the human ovarian supplement is provided in a dose of 200 mg, 250 mg, or 300 mg. The FGF21 variant is available in doses of approximately 100 mg, 150 mg, and 200 mg for administration once every two weeks. In one embodiment, the human FGF The 21 variants are available in doses of approximately 100 mg, 150 mg, 200 mg, and 25 mg for administration once every 3 weeks. In one embodiment, the human FGF21 mutant is provided in a dose of 0 mg or 300 mg. The body is administered approximately 100 mg, 150 mg, 200 mg, or 300 mg for administration once every four weeks or once a month. It is available in doses of 100 mg, 250 mg, or 300 mg.

[0232] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The subject matter is provided for administration in doses or amounts in the range of 100 mg, and the subject matter is a human FGF21 mutant. The antibody has the sequence Q55C, R105K, G148C, K150R, P1 one or more mutations selected from 58S, S195A, P199G, and G202A A fusion tag comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is a human FGF21 protein variant of SEQ ID NO: 11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. In one embodiment thereof, the human FGF21 mutant is provided for administration once every two weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every three weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every four weeks or is provided for one dose per month.

[0233] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The subject matter is provided for administration in doses or amounts in the range of 150 mg and is a human FGF21 mutant. The antibody has the sequence Q55C, R105K, G148C, K150R, P1 one or more mutations selected from 58S, S195A, P199G, and G202A A fusion tag comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is a human FGF21 protein variant of SEQ ID NO: 11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. In one embodiment thereof, the human FGF21 mutant is provided for administration once every two weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every three weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every four weeks or is provided for one dose per month.

[0234] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The subject matter is provided for administration in doses or amounts in the range of 200 mg and is also The antibody has the sequence Q55C, R105K, G148C, K150R, P1 one or more mutations selected from 58S, S195A, P199G, and G202A A fusion tag comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is a human FGF21 protein variant of SEQ ID NO: 11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. In one embodiment thereof, the human FGF21 mutant is provided for administration once every two weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every three weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every four weeks or is provided for one dose per month.

[0235] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The subject matter is provided for administration in doses or amounts within the range of 250 mg and is also The antibody has the sequence Q55C, R105K, G148C, K150R, P1 one or more mutations selected from 58S, S195A, P199G, and G202A A fusion tag comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant is a human FGF21 protein variant of SEQ ID NO: 11. In one embodiment, the human FGF21 mutant comprises an amino acid sequence. In one embodiment thereof, the human FGF21 mutant is provided for administration once every two weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every three weeks. In one embodiment thereof, the human FGF21 mutant is provided for administration once every four weeks or is provided for one dose per month.

[0236] In one aspect, the present invention relates to a method for treating, preventing, or treating non-alcoholic steatohepatitis (NASH) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering wherein the human FGF21 protein variant is provided in a dose or amount within the range of 300 mg. and the human FGF21 mutant is provided for administration of Q55C, Q65C, Q75C, Q85C, Q95C, Q105C, Q115C, Q125C, Q135C, Q145C, Q155C, Q165C, Q175C, Q185C, Q2165C, Q195C, Q225C, Q185C, Q195C, Q235 , R105K, G148C, K150R, P158S, S195A, P199G, and G A mature human FGF21 protein or its derivatives, comprising one or more mutations selected from the group consisting of 202A, 202B, 203A, 204A, 205A, 206A, 207A, 208A, 209A, 210A, 211A, 212A, 213A, 214A, 215A, 216A, 217A, and optionally a fusion protein comprising a human Fc region fused to a fragment of human F. The GF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11. In one embodiment In one embodiment, the human FGF21 variant is provided for administration once per week. In one embodiment, the human FGF21 variant is provided for administration once every two weeks. In one embodiment, the human FGF21 variant is provided for administration once every three weeks. The human FGF21 variant is provided for administration once every four weeks or once a month.

[0237] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The composition is provided for administration in doses or amounts within the range of 100 mg or 150 mg once per week. The human FGF21 mutant is provided as follows: Q55C, R105K, based on the numbering of SEQ ID NO:1. , G148C, K150R, P158S, S195A, P199G, and G202A fused to a mature human FGF21 protein or a fragment thereof containing one or more selected mutations fusion protein comprising a human Fc region, optionally including a human FGF21 protein. The protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0238] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The composition is provided for administration in doses or amounts within the range of 150 mg or 200 mg once every two weeks. The human FGF21 mutant is provided as follows: Q55C, R105K, based on the numbering of SEQ ID NO:1. , G148C, K150R, P158S, S195A, P199G, and G202A fused to a mature human FGF21 protein or a fragment thereof containing one or more selected mutations fusion protein comprising a human Fc region, optionally including a human FGF21 protein. The protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0239] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The composition is provided for administration in doses or amounts within the range of 200 mg or 250 mg once every three weeks. The human FGF21 mutant is provided as follows: Q55C, R105K, based on the numbering of SEQ ID NO:1. , G148C, K150R, P158S, S195A, P199G, and G202A fused to a mature human FGF21 protein or a fragment thereof containing one or more selected mutations fusion protein comprising a human Fc region, optionally including a human FGF21 protein. The protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0240] In one aspect, the present invention relates to a method for treating hypercholesterolemia, dyslipidemia, hypertriglyceridemia in a human subject. Hyperlipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) ), type 2 diabetes, or obesity. Provided herein are human FGF21 protein variants, including human FGF21 protein variants The body is administered once every four weeks or once a month at doses ranging from 250 mg to 300 mg. and the human FGF21 mutant is provided for administration in an amount of Q based on the numbering of SEQ ID NO:1. 55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A. or a fragment thereof, optionally comprising a human Fc region fused to The human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0241] In one aspect, a method for treating, preventing, or managing hypercholesterolemia in a human subject. Provided herein are human FGF21 protein variants for use in The FGF21 protein variants are intended for administration in combination with one or more additional therapeutically active agents. wherein the one or more additional therapeutically active agents are dapagliflozin, empagliflozin, Rosin, Canagliflozin, Ertugliflozin, Sotagliflozin, Tofogliflozin , Remogliflozin, Luseogliflozin, Ipragliflozin, Atigliflozin, Vegliflozin Xagliflozin, henagliflozin, licorigliflozin, and pharmaceuticals of any of these and a SGLT inhibitor selected from the group consisting of a therapeutically acceptable salt thereof and a human FGF21 The mutants are Q55C, R105K, G148C, K150R, One or more mutations selected from P158S, S195A, P199G, and G202A A fusion protein comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof containing the mutation. and optionally, the human FGF21 protein variant is a human FGF21 protein variant having the sequence represented by SEQ ID NO:1. 1. In one embodiment thereof, the SGLT inhibitor is licogliflozin. be.

[0242] In one aspect, the present invention relates to a method for treating, preventing, or managing dyslipidemia in a human subject. Provided herein is a human FGF21 protein variant for use in One protein variant is provided for administration in combination with one or more additional therapeutically active agents. wherein the one or more additional therapeutically active agents are dapagliflozin, empagliflozin, Nagliflozin, Ertugliflozin, Sotagliflozin, Tofogliflozin, Remogliflozin Flozin, Luseogliflozin, Ipragliflozin, Atigliflozin, Bexaglyf Rosin, henagliflozin, licogliflozin, and any pharma- ceutical acceptable salt thereof and the human FGF21 mutant is an SGLT inhibitor selected from the group consisting of salts which can be Q55C, R105K, G148C, K150R, P158S based on the numbering of SEQ ID NO:1 , S195A, P199G, and G202A. Fusion proteins comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof and optionally the human FGF21 protein variant has the amino acid sequence of SEQ ID NO:11. In one embodiment thereof, the SGLT inhibitor is licogliflozin.

[0243] In one aspect, a method for treating, preventing, or managing hypertriglyceridemia in a human subject. Provided herein are human FGF21 protein variants for use in The FGF21 protein variants are intended for administration in combination with one or more additional therapeutically active agents. wherein the one or more additional therapeutically active agents are dapagliflozin, empagliflozin, Rosin, Canagliflozin, Ertugliflozin, Sotagliflozin, Tofogliflozin , Remogliflozin, Luseogliflozin, Ipragliflozin, Atigliflozin, Vegliflozin Xagliflozin, henagliflozin, licorigliflozin, and pharmaceuticals of any of these and a SGLT inhibitor selected from the group consisting of a therapeutically acceptable salt thereof and a human FGF21 The mutants are Q55C, R105K, G148C, K150R, One or more mutations selected from P158S, S195A, P199G, and G202A A fusion protein comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof containing the mutation. and optionally, the human FGF21 protein variant is a human FGF21 protein variant having the sequence represented by SEQ ID NO:1. 1. In one embodiment thereof, the SGLT inhibitor is licogliflozin. be.

[0244] In one embodiment, the method comprises treating or preventing non-alcoholic fatty liver disease (NAFLD) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering In one embodiment, the human FGF21 protein variant is administered in combination with one or more additional therapeutically active agents. wherein the one or more additional therapeutically active agents are dapagliflozin. Gin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin , tofogliflozin, remogliflozin, luseogliflozin, ipragliflozin, a Tigliflozin, bexagliflozin, henagliflozin, licogliflozin, and the like and a pharma- ceutically acceptable salt thereof, The human FGF21 mutant also includes Q55C, R105K, G14 8C, K150R, P158S, S195A, P199G, and G202A. A human FGF21 protein or fragment thereof fused to a mature human FGF21 protein or fragment thereof containing one or more mutations and optionally a fusion protein comprising a human FGF21 protein variant. The variant comprises the amino acid sequence of SEQ ID NO: 11. In one embodiment thereof, the SGLT inhibitor is Licogliflozin.

[0245] In one aspect, the present invention relates to a method for treating, preventing, or treating non-alcoholic steatohepatitis (NASH) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering In one embodiment, the human FGF21 protein variant is combined with one or more additional therapeutically active agents. Provided for combined administration, wherein the one or more additional therapeutically active agents are dapagliflozin and empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, Tofogliflozin, Remogliflozin, Luseogliflozin, Ipragliflozin, Achi Gliflozin, bexagliflozin, henagliflozin, licogliflozin, and and a SGLT inhibitor selected from the group consisting of any one of the pharma- ceutically acceptable salts of The human FGF21 mutants are Q55C, R105K, G148, and G216 based on the numbering of SEQ ID NO:1. C, K150R, P158S, S195A, P199G, and G202A. Human fused to mature human FGF21 protein or a fragment thereof containing one or more mutations A fusion protein comprising an Fc region, and optionally a human FGF21 protein variant. In one embodiment, the SGLT inhibitor comprises the amino acid sequence of SEQ ID NO: 11. Cogliflozin.

[0246] In one aspect, the present invention relates to a method for treating, preventing, or managing type 2 diabetes in a human subject. Provided herein is a human FGF21 protein variant for use in One protein variant is provided for administration in combination with one or more additional therapeutically active agents. wherein the one or more additional therapeutically active agents are dapagliflozin, empagliflozin, Nagliflozin, Ertugliflozin, Sotagliflozin, Tofogliflozin, Remogliflozin Flozin, Luseogliflozin, Ipragliflozin, Atigliflozin, Bexaglyf Rosin, henagliflozin, licogliflozin, and any pharma- ceutical acceptable salt thereof and the human FGF21 mutant is an SGLT inhibitor selected from the group consisting of salts which can be Q55C, R105K, G148C, K150R, P158S based on the numbering of SEQ ID NO:1 , S195A, P199G, and G202A. Fusion proteins comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof and optionally the human FGF21 protein variant has the amino acid sequence of SEQ ID NO:11. In one embodiment thereof, the SGLT inhibitor is licogliflozin.

[0247] In one aspect, the present invention provides a method for treating, preventing, or managing obesity in a human subject. Provided herein are human FGF21 protein variants for use in The protein variants are provided for administration in combination with one or more additional therapeutically active agents, and one or more additional therapeutically active agents are dapagliflozin, empagliflozin, canagliflozin, Flozin, Ertugliflozin, Sotagliflozin, Tofogliflozin, Remogliflozin , luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin , henagliflozin, licogliflozin, and any pharma- ceutically acceptable salt thereof and the human FGF21 mutant is selected from the group consisting of SEQ ID NO: Q55C, R105K, G148C, K150R, P158S, S1 based on No. 1 A mature human having one or more mutations selected from 95A, P199G, and G202A. A fusion protein comprising a human Fc region fused to an FGF21 protein or a fragment thereof. and optionally, the human FGF21 protein variant has the amino acid sequence of SEQ ID NO:11. In one embodiment thereof, the SGLT inhibitor is licogliflozin.

[0248] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) A protein variant is provided herein, wherein the human FGF21 protein variant is and for administration in a dose or amount ranging from 100 mg per dose or amount to 100 mg per dose, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0249] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every two weeks. and for administration in a dose or amount ranging from 100 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0250] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 3 weeks. and for administration in a dose or amount ranging from 100 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0251] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 4 weeks. and for administration in a dose or amount ranging from 100 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0252] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) A protein variant is provided herein, wherein the human FGF21 protein variant is and for administration in a dose or amount ranging from 150 mg per dose or amount to 150 mg per dose, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0253] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every two weeks. and for administration in a dose or amount ranging from 150 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0254] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 3 weeks. and for administration in a dose or amount ranging from 150 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0255] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 4 weeks. and for administration in a dose or amount ranging from 150 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0256] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) A protein variant is provided herein, wherein the human FGF21 protein variant is and for administration in a dose or amount ranging from 200 mg per dose or amount to 200 mg per dose, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0257] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every two weeks. and for administration in a dose or amount ranging from 200 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0258] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 3 weeks. and for administration in a dose or amount ranging from 200 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0259] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 4 weeks. and for administration in a dose or amount ranging from 200 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0260] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) A protein variant is provided herein, wherein the human FGF21 protein variant is and for administration in a dose or amount ranging from 250 mg per dose or amount to 250 mg per dose, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0261] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every two weeks. and for administration in a dose or amount ranging from 250 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0262] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 3 weeks. and for administration in a dose or amount ranging from 250 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0263] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 4 weeks. and for administration in a dose or amount ranging from 250 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0264] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) A protein variant is provided herein, wherein the human FGF21 protein variant is and for administration in a dose or amount within the range of 300 mg per dose or amount, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0265] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every two weeks. and for administration in a dose or amount ranging from 300 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0266] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 3 weeks. and for administration in a dose or amount ranging from 300 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0267] In one embodiment, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis Human FGF21 protein for use in a method for treating, preventing, or managing nonalcoholic steatohepatitis (NASH) Provided herein are protein variants, wherein the human FGF21 protein variants are administered every 4 weeks. and for administration in a dose or amount ranging from 300 mg once per day, and for use in determining the liver fat content of a subject. The amount should be within a manageable range as determined by the clinician or clinical guidelines. or within the normal range or at least about 5%, 10%, 20%, 30%, 40%, or The human FGF21 mutant is represented by the numbering scheme of SEQ ID NO:1. Q55C, R105K, G148C, K150R, P158S, S195A, P19 and one or more mutations selected from the group consisting of G202A, G209G, and G202A. fusion protein comprising a human Fc region fused to a protein or fragment thereof, optionally In the present invention, the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0268] In one embodiment, the method comprises treating or preventing non-alcoholic fatty liver disease (NAFLD) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering wherein the human FGF21 protein variant is licogliflozin or a pharmaceutical formulation thereof. and the liver fat content of the subject may be determined by a clinician or Within a manageable or normal range as determined by clinical guidelines up to or at least about 5%, 10%, 20%, 30%, 40%, or 50% or The human FGF21 mutant is further reduced, and the Q55C, R 105K, G148C, K150R, P158S, S195A, P199G, and G20 A mature human FGF21 protein or a fragment thereof comprising one or more mutations selected from the group consisting of: fusion protein comprising a human Fc region fused to a fragment thereof, optionally comprising a human FGF 21 protein variants include the amino acid sequence of SEQ ID NO:11.

[0269] In one aspect, the present invention relates to a method for treating, preventing, or treating non-alcoholic steatohepatitis (NASH) in a human subject. Provided herein are human FGF21 protein variants for use in methods of administering or administering wherein the human FGF21 protein variant is licogliflozin or a pharmaceutical equivalent thereof. The liver fat content of the subject may be determined by a clinician or Within manageable or normal ranges as determined by clinical guidelines or at least about 5%, 10%, 20%, 30%, 40%, or 50% or more The human FGF21 mutant has a Q55C, R1 05K, G148C, K150R, P158S, S195A, P199G, and G202 A mature human FGF21 protein or a fragment thereof comprising one or more mutations selected from A and optionally a fusion protein comprising a human Fc region fused to human FGF2. One protein variant comprises the amino acid sequence of SEQ ID NO:11.

[0270] In one aspect, the present invention provides a method for treating, preventing, or managing hypertriglyceridemia. Provided herein are human FGF21 protein variants for use in Protein variants are administered once per week, once every two weeks, once every three weeks, once every four weeks, or once a month in a dose or amount ranging from 100 mg to 100 mg per month, and Triglyceride levels are reduced by at least about 40% or at least about 50%, and The FGF21 mutants are Q55C, R105K, G148C, K based on the numbering of SEQ ID NO:1. One or more selected from 150R, P158S, S195A, P199G, and G202A A human Fc domain fused to a mature human FGF21 protein or a fragment thereof containing the above mutation. and optionally, the human FGF21 protein variant is a fusion protein comprising a region It comprises the amino acid sequence of SEQ ID NO:11.

[0271] In one aspect, the present invention provides a method for treating, preventing, or managing hypertriglyceridemia. Provided herein are human FGF21 protein variants for use in Protein variants are administered once per week, once every two weeks, once every three weeks, once every four weeks, or once a month in a dose or amount ranging from 150 mg to 150 mg per month, and Triglyceride levels are reduced by at least about 40% or at least about 50%, and The FGF21 mutants are Q55C, R105K, G148C, K based on the numbering of SEQ ID NO:1. One or more selected from 150R, P158S, S195A, P199G, and G202A A human Fc domain fused to a mature human FGF21 protein or a fragment thereof containing the above mutation. and optionally, the human FGF21 protein variant is a fusion protein comprising a region It comprises the amino acid sequence of SEQ ID NO:11.

[0272] In one aspect, the present invention provides a method for treating, preventing, or managing hypertriglyceridemia. Provided herein are human FGF21 protein variants for use in Protein variants are administered once per week, once every two weeks, once every three weeks, once every four weeks, or once a month in a dose or amount ranging from 200 mg to 200 mg per month, and Triglyceride levels are reduced by at least about 40% or at least about 50%, and The FGF21 mutants are Q55C, R105K, G148C, K based on the numbering of SEQ ID NO:1. One or more selected from 150R, P158S, S195A, P199G, and G202A A human Fc domain fused to a mature human FGF21 protein or a fragment thereof containing the above mutation. and optionally, the human FGF21 protein variant is a fusion protein comprising a region It comprises the amino acid sequence of SEQ ID NO:11.

[0273] In one aspect, the present invention provides a method for treating, preventing, or managing hypertriglyceridemia. Provided herein are human FGF21 protein variants for use in Protein variants are administered once per week, once every two weeks, once every three weeks, once every four weeks, or once a month in a dose or amount ranging from 250 mg to 250 mg per month, and Triglyceride levels are reduced by at least about 40% or at least about 50%, and The FGF21 mutants are Q55C, R105K, G148C, K based on the numbering of SEQ ID NO:1. One or more selected from 150R, P158S, S195A, P199G, and G202A A human Fc domain fused to a mature human FGF21 protein or a fragment thereof containing the above mutation. and optionally, the human FGF21 protein variant is a fusion protein comprising a region It comprises the amino acid sequence of SEQ ID NO:11.

[0274] In one aspect, the present invention provides a method for treating, preventing, or managing hypertriglyceridemia. Provided herein are human FGF21 protein variants for use in Protein variants are administered once per week, once every two weeks, once every three weeks, once every four weeks, or once a month in a dose or amount ranging from 300 mg to 300 mg per month, and Triglyceride levels are reduced by at least about 40% or at least about 50%, and The FGF21 mutants are Q55C, R105K, G148C, K based on the numbering of SEQ ID NO:1. One or more selected from 150R, P158S, S195A, P199G, and G202A A human Fc domain fused to a mature human FGF21 protein or a fragment thereof containing the above mutation. and optionally, the human FGF21 protein variant is a fusion protein comprising a region It comprises the amino acid sequence of SEQ ID NO:11.

[0275] Each of the foregoing aspects and embodiments, as well as other elements described herein, may be used in any They may be combined in a fashion.

Claims

1. A pharmaceutical composition comprising a human FGF21 protein variant in solution, The human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11; The solution comprises 50 mg / mL to 150 mg / mL of the human FGF21 protein variant, trometamol buffer, sucrose, and polysorbate 20.

2. The pharmaceutical composition described in claim 1, which is a solution reconstituted from a lyophilized material containing the human FGF21 protein mutant.

3. The pharmaceutical composition described in claim 1 or 2, wherein the human FGF21 protein mutant is Fc-FGF21 mutant fusion protein V103 (sequence number 11).

4. A pharmaceutical composition described in any one of claims 1 to 3, wherein the solution contains 100 mg / mL to 150 mg / mL of the human FGF21 protein variant.

5. A pharmaceutical composition described in any one of claims 1 to 4, wherein the solution contains 150 mg / mL of the human FGF21 protein variant.

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein the solution contains trometamol buffer at a concentration of 10 mM to 50 mM.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein the solution contains 250 mM to 300 mM sucrose.

8. A pharmaceutical composition described in any one of claims 1 to 7, wherein the solution contains 0.02% to 0.10% polysorbate 20.

9. A pharmaceutical composition described in any one of claims 1 to 8, wherein the solution has a pH in the range of 6.5 to 9.

10. A pharmaceutical composition described in any one of claims 1 to 9, wherein the solution has a pH of 7.5 to 8.5 and comprises 30 mM trometamol buffer, 270 mM sucrose and 0.06% polysorbate 20.

11. A pharmaceutical composition described in any one of claims 1 to 10, wherein the solution contains 30 mM trometamol buffer, 270 mM sucrose and 0.06% polysorbate 20 at pH 8.

0.

12. A pharmaceutical composition comprising a human FGF21 protein variant as a lyophilizate for reconstitution as a solution prior to administration, comprising: The human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11; The solution comprises 50 mg / mL to 150 mg / mL of the human FGF21 protein variant, trometamol buffer, sucrose, and polysorbate 20.

13. A pharmaceutical composition for use in a method for treating or managing a metabolic or cardiovascular disorder in a human subject, comprising: the composition is for subcutaneous administration at a dose ranging from 100 mg to 600 mg; 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the metabolic or cardiovascular disorder is selected from hypercholesterolemia, dyslipidemia, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), type 2 diabetes, and obesity.

14. The pharmaceutical composition of claim 13, wherein the human FGF21 mutant is for administration at a dose of 300 mg.

15. The pharmaceutical composition described in claim 13 or 14, wherein the human FGF21 mutant is for administration every four weeks.

16. The pharmaceutical composition described in any one of claims 13 to 15, wherein the metabolic disorder or cardiovascular disorder is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

17. A pharmaceutical composition according to any one of claims 13 to 16, wherein the human FGF21 protein variant is provided in combination with one or more additional therapeutically active agents.

18. The pharmaceutical composition of any one of claims 13 to 17, wherein the human FGF21 protein variant is provided in combination with one or more additional therapeutically active agents selected from the group consisting of compounds useful for the treatment of obesity, diuretics, beta-blockers, alpha-blockers, ACE inhibitors, angiotensin II receptor blockers (ARBs), direct renin inhibitors, calcium channel blockers, central agonists, peripheral adrenergic blockers, vasodilators, insulin, alpha-glucosidase inhibitors, biguanides, dopaminergic agents, DPP-4 inhibitors, glucagon-like peptides, meglitinides, sodium glucose transporter (SGLT) inhibitors, sulfonylureas, thiazolidinediones, amylinomimetics, statins, fibrates, aspirin, and anticoagulants.

19. A method for preparing a pharmaceutical composition, comprising reconstituting the pharmaceutical composition from a lyophilized material containing the FGF21 protein variant having the amino acid sequence of SEQ ID NO: 11, and obtaining a solution containing 50 mg / mL to 150 mg / mL of the human FGF21 protein variant, trometamol buffer, sucrose and polysorbate 20.