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ENTRIGUE: Subcutaneous pegozafermin in severe hypertriglyceridaemia

Presented by
Prof. Deepak Bhatt, Harvard Medical School, MA, USA
ESC 2022
In a phase 2 study, treating patients with severe hypertriglyceridaemia with subcutaneous FGF21 analogue pegozafermin significantly reduced triglycerides across all dose groups compared with placebo. Triglyceride reductions after 8 weeks of therapy showed that 75% of participants who received 27 mg of pegozafermin weekly achieved a >50% triglycerides reduction, without serious side effects.

FGF21 regulates lipid and glucose metabolism, and its analogue pegozafermin extends FGF21 half-life by 25–50-fold. The dose-finding ENTRIGUE trial (NCT04541186) hypothesised that pegozafermin would give some signal of reduced triglycerides in patients with severe hypertriglyceridaemia. The initial findings were presented by Prof. Deepak Bhatt (Harvard Medical School, MA, USA) [1]. ENTRIGUE was a randomised, double-blind, phase 2 trial of patients (n=85, average age 54 years, 25% women, 50.6% with diabetes, 45% on baseline statin therapy) with severe hypertriglyceridemia (≥500 mg/dL to ≤2,000 mg/dL, mean was 733 mg/dL). Participants were randomised to different doses of 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). The median duration of follow-up was 8 weeks.

The pooled data across doses of pegozafermin versus placebo for the primary endpoint, reduction in triglycerides across all dose groups, showed a 12% reduction in the placebo group versus a 57% reduction in the pegozafermin groups (P<0.001). When the data was broken down by dose of weekly pegozafermin, the percentage reduction was steady; -57% for those taking 9 mg; -56% for those taking 18 mg; -63% for those taking 27 mg, and -36% for those taking 36 mg twice weekly.

Secondary outcomes analysed for the 27 mg weekly subcutaneous pegozafermin versus placebo indicated that 75% in the intervention group showed a ≥50% reduction of triglycerides from baseline, as compared with only 6% showing reduction in the placebo group (P<0.05).

In conclusion, treatment with pegozafermin led to significant reductions in triglyceride levels as compared with placebo. The level of triglycerides over 8 weeks of therapy in 75% of participants who received 27 mg weekly of pegozafermin dropped by >50%. Furthermore, there was a substantial reduction in liver fat over the 8 weeks for pooled subcutaneous pegozafermin versus placebo (-43% vs -5%; P=0.012). No serious safety signals were reported. In short, these data warrant a phase 3 investigation of pegozafermin in a larger cohort of patients.

  1. Bhatt D, et al. ENTRIGUE: Pegozafermin for the treatment of severe hypertriglyceridemia. Late-Breaking Science - Innovations in drug treatment, ESC Congress 2022, Barcelona, Spain, 26–29 August.


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