Methods of treating metabolic disorders with fgf21 variants

Abstract

Provided herein are methods of treating, preventing, and managing metabolic or cardiovascular disorders and methods of reducing cardiovascular risk with FGF21 protein variants, including Fc-FGF21 variant fusion proteins.

1 . 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. 
     
     
         2 . The human FGF21 protein variant for use according to  claim 1 , wherein the metabolic disorder or cardiovascular disorder is selected from hypercholesterolemia, dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), type 2 diabetes, and obesity. 
     
     
         3 . The human FGF21 protein variant for use according to  claim 1  or  2 , wherein treating, preventing, or managing the metabolic disorder or cardiovascular disorder comprises or is characterized by reducing one or more of the following: body weight, liver fat content, elevated LDL-C, total-C, triglyceride, and Apo B levels in the subject. 
     
     
         4 . The human FGF21 protein variant for use according to any one of  claims 1  to  3 , wherein treating, preventing, or managing the metabolic disorder or cardiovascular disorder comprises or is characterized by increasing HDL-C levels in the subject. 
     
     
         5 . The human FGF21 protein variant for use according to  claim 3 , wherein treating, preventing, or managing the metabolic disorder or cardiovascular disorder comprises or is characterized by reducing triglyceride levels in the subject by at least about 40% or at least about 50%. 
     
     
         6 . The human FGF21 protein variant for use according to  claim 1  or  2 , wherein treating, preventing, or managing the metabolic disorder or cardiovascular disorder comprises or is characterized by reducing cardiovascular risk in the subject. 
     
     
         7 . The FGF21 protein variant for use according to any one of  claims 2  to  6 , wherein the metabolic disorder or cardiovascular disorder is dyslipidemia, optionally mixed dyslipidemia, hypertriglyceridemia, optionally severe hypertriglyceridemia, or hypercholesterolemia, optionally primary hypercholesterolemia. 
     
     
         8 . The FGF21 protein variant for use according to any one of  claims 2  to  6 , wherein the metabolic disorder or cardiovascular disorder is nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). 
     
     
         9 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the subject is 18 to 55 years of age. 
     
     
         10 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the subject has a body mass index (BMI) within the range of 30 to 45 kg/m 2 , inclusive, with ethnic adjustment ≥27.5 for a subject of Asian descent or Asian ancestry. 
     
     
         11 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the subject has triglyceride levels in the range of 150-500 mg/dL (1.69-5.65 mmol/L) when measured prior to administration of the human FGF21 protein variant. 
     
     
         12 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 variant is a fusion protein comprising a human Fc region fused to a mature human FGF21 protein or a fragment thereof comprising one or more mutations selected from: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A according to the numbering of SEQ ID NO: 1. 
     
     
         13 . The human FGF21 protein variant for use according to  claim 12 , wherein the human FGF21 protein variant comprises the amino acid sequence of SEQ ID NO: 11. 
     
     
         14 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 protein variant is provided for administration at a dose of at least 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg. 
     
     
         15 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 protein variant is provided for administration at a dose of approximately 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, or 350 mg, optionally wherein the human FGF21 protein variant is provided at a dose of approximately 250 mg or 300 mg. 
     
     
         16 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 protein variant is provided in combination with one or more additional therapeutically active agents. 
     
     
         17 . The human FGF21 protein variant for use according to  claim 16 , wherein the one or more additional therapeutically active agents is selected from the group consisting of compounds useful in obesity therapies, diuretics, beta-blockers, alpha-blockers, ACE inhibitors, Angiotensin II Receptor Blockers (ARBs), direct renin inhibitors, calcium channel blockers, central agonists, peripheral adrenergic blockers, vasodialators, insulin, alpha-glucosidase inhibitors, biguanides, dopamine agonist, DPP-4 inhibitors, glucagon-like peptides, meglitinides, sodium glucose transporter (SGLT) inhibitors, sulfonylureas, thiazolidinediones, amylinomimetics, statins, fibrates, aspirin, and anticoagulants. 
     
     
         18 . The human FGF21 protein variant for use according to  claim 17 , wherein the sodium glucose transporter (SGLT) inhibitor is selected from dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, sotagliflozin, tofogliflozin, remogliflozin, luseogliflozin, ipragliflozin, atigliflozin, bexagliflozin, henagliflozin, licogliflozin, and a pharmaceutically acceptable salt of any of these. 
     
     
         19 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 protein variant is provided in a form for subcutaneous administration. 
     
     
         20 . The human FGF21 protein variant for use according to any one of the preceding claims, wherein the human FGF21 protein variant is provided for administration once a month or once every 4 weeks, once every 3 weeks, once every 2 weeks, or once every week.