The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial

Abstract

Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment of severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report the results of a phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses (n = 67; 52 male) versus placebo (n = 18; 12 male) for 8 weeks in patients with SHTG (triglycerides (TGs), ≥500 mg dl−1 and ≤2,000 mg dl−1). Treated patients showed a significant reduction in median TGs for the pooled pegozafermin group versus placebo (57.3% versus 11.9%, difference versus placebo −43.7%, 95% confidence interval (CI): −57.1%, −30.3%; P < 0.001), meeting the primary endpoint of the trial. Reductions in median TGs ranged from 36.4% to 63.4% across all treatment arms and were consistent regardless of background lipid-lowering therapy. Results for secondary endpoints included significant decreases in mean apolipoprotein B and non-high-density lipoprotein cholesterol concentrations (−10.5% and −18.3% for pooled doses compared to 1.1% and −0.6% for placebo (95% CI: −21.5%, −2.0%; P = 0.019 and 95% CI: −30.7%, −5.1%; P = 0.007, respectively), as well as a significant decrease in liver fat fraction for pooled treatment (n = 17) versus placebo (n = 6; −42.2% pooled pegozafermin, −8.3% placebo; 95% CI: −60.9%, −8.7%; P = 0.012), as assessed in a magnetic resonance imaging sub-study. No serious adverse events were observed to be related to the study drug. If these results are confirmed in a phase 3 trial, pegozafermin could be a promising treatment for SHTG (ClinicalTrials.gov registration: NCT0441186).

The plasma proteome of plant-based diets: analyses of 1463 proteins in 50,000 people

“…FGF21 has been hypothesised to be high in vegans as a downstream effect of low intake of methionine [15], an essential amino acid that is known to be limiting in vegan diets [3]. Studies of FGF21 administration in rodents have found favourable effects on adiposity, lipid profiles, and non-alcohol fatty liver disease, but possible adverse effects on bone homeostasis [22]; randomised trials of FGF21 analogues also support the reduction in triglycerides [23] and improvement of fibrosis in patients with non-alcoholic steatohepatitis [24]. Consistent with these observations, we have previously reported lower BMI and body fat [25], more favourable lipid profiles [26] and lower heart disease risk [27], but also lower bone mineral density [25] and higher fracture risk [28] in vegetarians and vegans when compared with meat eaters; another study has reported lower odds of non-alcohol fatty liver disease in vegetarians than non-vegetarians [29].…”

Hyperlipidaemia in diabetes: are there particular considerations for next-generation therapies?

“…The results of these studies vary according to drug, dose and duration of treatment. However, generally, reductions of up to 69% in TG, 30% in LDL-C, 34% in non-HDL-C and 25% in apoB and an increase of up to 61% in HDL-C are observed [ 60 , 61 ]. In the study of non-alcohol-related steatohepatitis (NASH) [ 60 ], the liver fat fraction was reduced after treatment with the FGF21 analogue.…”

Pemafibrate and other triglyceride-lowering therapies to reduce risk of cardiovascular and metabolic disease

“…In patients with severe HTG (i.e. ∼500–1000 mg/dl) at increased risk of nonalcoholic fatty liver disease (NAFLD) may also benefit from treatment with the fibroblast growth factor 21 (FGF21) analog, pegozafermin, based upon the appreciable reduction in liver fat observed over a 2-month interval [ 45 ▪▪ ]. Pemafibrate may also be a consideration in view of the 22% reduction in Investigator-reported NAFLD in PROMINENT [ 7 ] and improved biomarkers of liver fibrosis in patients with NAFLD and less severe HTG [ 46 ▪▪ ].…”