Pegozafermin lowers high triglycerides, non-HDL and ApoB vs. placebo in small trial
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Key takeaways:
- Compared with placebo, pegozafermin reduced atherogenic particles in patients with severely high triglycerides.
- Findings of the ENTRIGUE trial were consistent regardless of baseline therapy.
Pegozafermin, a fibroblast growth factor 21 analog, reduced atherogenic particles in patients with severe hypertriglyceridemia and improved liver fat and insulin resistance compared with placebo, a speaker reported.
Michael Miller, MD, FACC, FAHA, chief of medicine at the Corporal Michael J. Crescenz VA Medical Center in Philadelphia and vice chair of medicine at the University of Pennsylvania School of Medicine, presented the results of the phase 2, randomized, double-blind ENTRIGUE trial at the National Lipid Association Scientific Sessions.
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“Fibroblast growth factor 21 (FGF21) is an endogenous stress and metabolic hormone that plays a major role in regulating lipid and glucose homeostasis as well as energy expenditure. There have been a number of proposed mechanisms of the action of FGF21 in severe hypertriglyceridemia,” Miller said during the presentation. “They include adipose tissue; for example, decreased lipogenesis and release of free fatty acids owing in part to thermogenic activation of brown adipose tissue or fat. FGF21 also increases adiponectin, improves insulin resistance as well as triglyceride uptake.
“With respect to the liver, there’s increased beta-oxidation, in part reflecting upregulation of several lipases, including hormone-sensitive lipase as well as adipose triglyceride lipase,” Miller said. “There’s a decrease in de novo lipogenesis, and this, again, partially reflects suppression or downregulation in the genetic expression of sterol regulatory element-binding protein 1 (SREBP-1). There’s decrease in free fatty acids and triglycerides and in muscles there’s increased fatty acid oxidation and enhanced energy expenditure.”
Miller said pegozafermin (89bio) is an FGF21 analog with a long dosing interval. Native FGF21 lasts in circulation for less than 2 hours, whereas a single dose of pegozafermin lasts 100 hours or more, according to the presentation.
For the ENTRIGUE trial, the researchers enrolled 85 patients with mean triglyceride levels of 733 mg/dL (mean age, 54 years; 75% men) and assigned them to once-weekly pegozafermin doses of 9 mg, 18 mg or 27 mg; a once every other week dose of pegozafermin 36 mg; or placebo.
The primary endpoint was percent change in triglyceride level from baseline at 8 weeks. Secondary endpoints included change in non-HDL, HDL, apolipoprotein B, liver fat and insulin sensitivity.
In the pooled analysis, participants assigned to pegozafermin experienced a placebo-corrected 44-percentage-point greater average reduction in triglyceride level compared with placebo (pegozafermin, –57%; placebo, –12%; P < .001). This finding was consistent regardless of whether the patient was on background therapy at baseline or not.
Miller and colleagues also observed significant reductions in non-HDL (–1% vs. –18%; P < .001) and ApoB (–1% vs. –11%; P < .05) among those assigned to pegozafermin compared with placebo, regardless of background therapy. In addition, the median percent change in apolipoprotein C3 was –42% in the pooled pegozafermin group and –9% in the placebo group (P < .001).
At 8 weeks, 29% of patients assigned to placebo met their triglyceride goal compared with 80% of patients assigned to pegozafermin (P < .001). This finding also remained significant regardless of background therapy.
Pegozafermin was associated with increased HDL compared with placebo, with no significant effect on LDL, according to the presentation.
Moreover, treatment with pegozafermin was associated with a significant reduction in liver fat (8% vs. 42%; P < .05) and improved insulin sensitivity compared with placebo.
Miller reported that pegozafermin was well tolerated, and was not associated with any serious treatment-related adverse events.
“Pegozafermin significantly reduced atherogenic particles across the board. That’s non-HDL cholesterol, ApoB, triglycerides, ApoC3 and liver fat in subjects with severe hypertriglyceridemia,” Miller said. “Additional cardiometabolic improvements may make this therapy attractive in our patients with severe hypertriglyceridemia, especially as many of them do suffer from other comorbidities, including cardiac, endocrinologic and hepatic manifestations. These data appear promising for a planned phase 3 trial utilizing dosages on a weekly basis.”
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Miller M, et al. Phase 2 Trial of Pegozafermin in Severe Hypertriglyceridemia. Presented at: National Lipid Association Scientific Sessions; June 1-4, 2023; Atlanta (hybrid meeting).
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