Modified fibroblast growth factor 21 (fgf-21) for use in methods for treating nonalcoholic steatohepatitis (nash)

Abstract

Provided herein are methods for treating a patient having NASH who has been determined to have a particular threshold level of serum Pro-C3 (e.g., greater than 10 ng/ML) by administering to the patient a modified Fibroblast growth factor 21 (FGF-21) in an amount and with a frequency sufficient to treat NASH. Also provided are methods for monitoring responsiveness of a patient having NASH to treatment with a modified FGF-21, the method comprising: determining the serum Pro-C3 level in a blood sample from the patient obtained during or after treatment, wherein: a decreased serum Pro-C3 level in the blood sample from the patient obtained during or after treatment, as compared to the serum Pro-C3 level in a blood sample from the patient obtained prior to treatment with the modified FGF-21, indicates that the patient is responsive to treatment with the modified FGF-21.

1 . A method for treating a patient having Nonalcoholic Steatohepatitis (NASH) comprising: (a) determining the serum Pro-C3 level in a blood sample from the patient and (b) administering to the patient a modified Fibroblast growth factor 21 (FGF-21) in an amount and with a frequency sufficient to treat NASH, if the serum Pro-C3 level is greater than 10 ng/ML. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . A method for monitoring responsiveness of a patient having NASH to treatment with a modified FGF-21, the method comprising: determining the serum Pro-C3 level in a blood sample from the patient obtained during or after treatment, wherein: a decreased serum Pro-C3 level in the blood sample from the patient obtained during or after treatment, as compared to the serum Pro-C3 level in a blood sample from the patient obtained prior to treatment with the modified FGF-21, indicates that the patient is responsive to treatment with the modified FGF-21. 
     
     
         6 . The method of  claim 1 , wherein the serum Pro-C3 level prior to administration to the patient of a modified Fibroblast growth factor 21 (FGF-21) is greater than about 11 ng/ML, 12 ng/ML, 13 ng/ML, 14 ng/ML, 15 ng/ML, 16 ng/ML, 17 ng/ML, 18 ng/ML, 19 ng/ML, 20 ng/ML, 21 ng/ML, 22 ng/ML, 23 ng/ML, 24 ng/ML, or 25 ng/ML. 
     
     
         7 . The method of  claim 6 , wherein the serum Pro-C3 level is greater than about 15 ng/ML. 
     
     
         8 . The method of  claim 1 , wherein the Pro-C3 level or levels are measured by an FDA-approved test. 
     
     
         9 . The method of  claim 1 , wherein the Pro-C3 level or levels are measured by using an immunoassay, immunochemistry, immunohistochemistry assay, nucleoprobe assay, in situ hybridization, fluorescent RNA probes, RT-PCR, microarray transcription assay, or RNA transcription assay. 
     
     
         10 . The method of  claim 9 , wherein the immunoassay is an enzyme-linked immunosorbent assay (ELISA) or a radioimmunoassay (RIA). 
     
     
         11 . The method of  claim 1 , wherein the modified FGF-21 comprises the polypeptide of SEQ ID NO:1, except that an amino acid in the polypeptide is substituted by a non-naturally encoded amino acid, wherein: (a) said non-naturally encoded amino acid is at a position corresponding to residue 108 of SEQ ID NO:1; and (b) said non-naturally encoded amino acid comprises para-acetyl phenylalanine linked to a polymer comprising a poly(ethylene glycol). 
     
     
         12 . The method of  claim 1 , wherein the modified FGF-21 comprises the polypeptide of SEQ ID NO:1 except that the amino acid at position 108 of SEQ ID NO:1 is substituted by a non-naturally encoded amino acid, wherein: (a) said non-naturally encoded amino acid comprises para-acetyl phenylalanine, and (b) said non-naturally encoded amino acid is linked to a polymer comprising a poly(ethylene glycol) having an average molecular weight of about 30 kDa. 
     
     
         13 . The method of  claim 11 , wherein said poly(ethylene glycol) has an average molecular weight of about 30 kDa. 
     
     
         14 . The method of  claim 11 , wherein said non-naturally encoded amino acid is linked to said polymer through an oxime linkage. 
     
     
         15 . The method of  claim 1 , wherein the modified FGF-21 comprises SEQ ID NO:2. 
     
     
         16 . The method of  claim 15 , wherein the modified FGF-21 comprises a poly(ethylene glycol) having an average molecular weight of about 30 kDa. 
     
     
         17 . The method of  claim 16 , wherein the poly(ethylene glycol) is linked to para-acetyl phenylalanine. 
     
     
         18 . The method of  claim 1 , wherein the modified FGF-21 is administered at a once weekly dose of 20 mg or a once daily dose of 10 mg. 
     
     
         19 . The method of  claim 1 , comprising administration of a second therapeutic agent. 
     
     
         20 . The method of  claim 1 , wherein the treatment:
 (a) results in a decrease in serum Pro-C3 levels in the patient;   (b) produces a shift toward normal serum levels of Pro-C3 in the patient;   (c) results in a reduction in liver stiffness in the patient compared to the patient's liver stiffness prior to treatment, wherein liver stiffness is assessed by magnetic resonance elastography (MRE); and/or   (d) results in a reduction in hepatic fat fraction in the patient compared to the patient's hepatic fat fraction prior to treatment, wherein hepatic fat fraction is as assessed by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF).   
     
     
         21 .- 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the treatment produces at least one therapeutic effect in the patient selected from the group consisting of a reduction or cessation in fatigue, malaise, weight loss, and/or right upper quadrant abdominal discomfort. 
     
     
         28 .- 30 . (canceled)