Phase 2 Trial of Pegozafermin in Severe Hypertriglyceridemia - ENTRIGUE
Contribution To Literature:
Among patients with severe hypertriglyceridemia in the ENTRIGUE trial, treatment with subcutaneous pegozafermin, an FGF21 analog, significantly reduced triglycerides across all dose groups versus placebo without serious treatment adverse effects.
The goal of the trial was to compare efficacy and safety of subcutaneous pegozafermin, an FGF21 analog, versus placebo among patients with severe hypertriglyceridemia.
The ENTRIGUE trial was a randomized, double-blind, phase 2 trial of patients with severe hypertriglyceridemia. Patients were randomized in 1:1:1:1:1 fashion to subcutaneous weekly pegozafermin (9 mg, n = 16; 18 mg, n = 17; 27 mg, n = 18), subcutaneous twice weekly pegozafermin (36 mg, n = 16), or placebo (n = 18).
- Total randomized participants: 85
- Median duration of follow-up: 8 weeks
- Mean patient age: 54 years
- Percentage female: 25%
- Patients with diabetes: 50.6%
- Triglycerides ≥500 mg/dL and ≤2000 mg/dL
- Background therapy: statins and/or prescription omega-3 fatty acids, and/or fibrates OR none
Other salient features/characteristics:
- Mean body mass index: 33 kg/m2
- Mean triglycerides: 733 mg/dL
- Mean low-density lipoprotein cholesterol (LDL-C): 89 mg/dL
- 45% on baseline statin therapy
The primary outcome, reduction in triglycerides across all dose groups, for pooled pegozafermin versus placebo, was: -57% vs. -12% (p < 0.001). Across doses of weekly pegozafermin: 9 mg, -57%; 18 mg, -56%; 27 mg, -63%; twice weekly 36 mg, -36%.
Results were consistent among patients on background therapy of statins or statin combinations, prescription omega-3s, and fibrates.
Secondary outcomes for 27 mg weekly subcutaneous pegozafermin versus placebo:
- Triglyceride reduction ≥50% from baseline: 75% vs. 6% (p < 0.05)
- Mean percent change in high-density lipoprotein cholesterol (HDL-C): +42% vs. +10%
- Mean percent change in LDL-C: +4% vs. +7%
- Mean percent change in non-HDL-C: -29% vs. -3%
- Mean percent change in apolipoprotein B (ApoB): -11% vs. -1%
- Percent change in insulin: -32% vs. +18%
- Mean relative reduction in liver fat for pooled subcutaneous pegozafermin vs. placebo: -43% vs. -5% (p = 0.012)
The results of this trial show that, among patients with severe hypertriglyceridemia, treatment with pegozafermin led to significant reductions in triglyceride levels as compared to placebo. The level of triglyceride reduction in just 8 weeks of therapy was marked, with 75% of participants who received 27 mg weekly of pegozafermin achieving a >50% reduction. Importantly, there were also significant reductions in non-HDL-C and ApoB in addition to signal for improved insulin sensitivity. Finally, there was substantial reduction in liver fat over the short study period.
FGF21 is an endogenous stress hormone and plays an important role in regulating lipid and glucose metabolism and energy expedition. Pegozafermin is an FGF21 analog, which extends half-life of native FGF21 from <2 hours 25-50 fold. The current study is limited in that, as a phase 2 study, it was not powered for clinical events. However, the study results are very encouraging, and phase 3 trial results will be extremely informative.
Presented by Dr. Deepak Bhatt at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 26, 2022.
Keywords: ESC Congress, ESC22, Apolipoproteins B, Body Mass Index, Cholesterol, HDL, Cholesterol, LDL, Dyslipidemias, Fatty Acids, Omega-3, Fatty Liver, Glucose, Hypertriglyceridemia, Insulin Resistance, Metabolic Syndrome, Primary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Triglycerides
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