Pegbelfermin (BMS-986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study

Edgar D Charles, Brent A Neuschwander-Tetri, Juan Pablo Frias, Sudeep Kundu, Yi Luo, Giridhar S Tirucherai, Rose Christian, Edgar D Charles, Brent A Neuschwander-Tetri, Juan Pablo Frias, Sudeep Kundu, Yi Luo, Giridhar S Tirucherai, Rose Christian

Abstract

Objective: Obesity and type 2 diabetes mellitus (T2DM) are risk factors for nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. This study assessed pegbelfermin (BMS-986036), recombinant PEGylated human fibroblast growth factor 21 (FGF21), in patients with obesity and T2DM predisposed to fatty liver.

Methods: In this randomized, double-blind, placebo-controlled study, patients with T2DM and BMI of 30 to 50 kg/m2 received subcutaneous pegbelfermin (1, 5, or 20 mg daily or 20 mg weekly; n = 96) or placebo (n = 24) for 12 weeks. Primary end points were safety, tolerability, and change in HbA1c. Additional end points included insulin sensitivity, lipids, adiponectin, and disease progression biomarkers.

Results: There were no significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol (P = 0.015) and triglycerides (P = 0.037). All pegbelfermin regimens significantly increased adiponectin levels; 20-mg daily and weekly regimens decreased serum PRO-C3. Most adverse events were mild; the most frequent adverse events were injection-site bruising and diarrhea.

Conclusions: Twelve-week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity-related metabolic diseases (e.g., nonalcoholic steatohepatitis).

Trial registration: ClinicalTrials.gov NCT02097277.

© 2018 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

Figures

Figure 1
Figure 1
CONSORT flow diagram. aFour individuals completed screening but did not receive at least one dose of placebo and were not considered to have entered the lead‐in period. AE, adverse event; LTFU, lost to follow‐up; QD, daily dosing; QW, weekly dosing.
Figure 2
Figure 2
Change from baseline to week 12 in (a) LDL, (b), HDL, and (c) triglycerides. *P values not adjusted for multiple testing. CI, confidence interval; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; QD, daily dosing; QW, weekly dosing.
Figure 3
Figure 3
Change from baseline to week 12 in (a) adiponectin, (b) PRO‐C3, (c) PAI‐1, and (d) YKL‐40. CI, confidence interval; PAI‐1, plasminogen activator inhibitor‐1; PRO‐C3, N‐terminal type III collagen propeptide; QD, daily dosing; QW, weekly dosing; SE, standard error of the mean; YKL‐40, chitinase‐3‐like protein.
Figure 4
Figure 4
ALT and AST levels during treatment in patients with elevated ALT or AST. aALT >44 U/L (men), >32 U/L (women); AST >40 U/L; bn = 24, cn = 10, and dn = 1 in the 1 mg/d and 5 mg/d groups. ALT, alanine aminotransferase; AST, aspartate aminotransferase; SE, standard error of the mean; QD, daily dosing; QW, weekly dosing.

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