Pegozafermin significantly reduces triglyceride levels in severe hypertriglyceridemia: ESC 2022
USA: Phase II data from the ENTRIGUE trial showed that in patients with severe hypertriglyceridemia, the investogational FGF21 analog pegozafermin was well-tolerated and greatly redued triglyceride levels.
The findings were presented at the 53rd Annual European Society of Cardiology Congress held online from August 26 to 29 by the lead author Deepak L. Bhatt, MD, MPH, of Harvard Medical School and Brigham and Women's Hospital in Boston.
Dr. Bhatt in his presentation said, "FGF21 is an endogenous stress hormone. It plays an important part in the regulation of lipid and glucose metabolism and energy expenditure. Pegozafermin is an analog of FGF21 that has been engneered optimally for efficacy with a long dosing interval."
In the trial, the researchers included 85 patients with severe hypertriglyceridemia. They were randomized in the ratio of 1:1:1:1:1 to placebo or to pegozafermin delivered subcutaneously once weekly at a dose of 9, 18, or 27 mg, or to 36 mg given enery 2 weeks. The duration of the treatment was 8 weeks. All patients had triglyceride levels ≥ 500 and ≤ 2000 mg/dL on a background therapy that could include prescription omega-3 fatty acids, statins, and/or fibrates.
A precent change in triglyceride levels from baseline was the trial's primary endpoint. Key secondary endpoints were liver fat (measured using MRI proton density fat fraction), additional lipid endpoints, and glyemic control.
Key findings include:
· Baseline characteristics were well-balanced among the study arms. Patients' average age was 54 years, about half had diabetes, and the average baseline triglyceride level was 733 mg/dL.
· Average liver fat content was 20.1% among the 24 patients who were evaluated using MRI proton density fat fraction, despite an average alanine aminotransferase (ALT) of only 32.8 U/L.
· Just over half of patients (55%) were on lipid modifying therapy, including 45% taking a statin.
· Pegozafermin was well-tolerated across all doses.
· The incidence of treatment-related adverse events was low, and the most common of these events were grade 1/2 nausea, diarrhea, or injection site reactions.
· There were only 2 serious adverse events in the active treatment groups, and these were not deemed to be related to the study drug. No elevations in ALT were reported.
· When pooling across all active therapy groups, triglyceride levels decreased by 57%, compared with 12% in the placebo group, for a placebo-corrected reduction of 45%.
· Looking at each treatment arm individually, the 9 mg dose was associated with a 57% reduction in triglycerides, the 18 mg dose a 56% reduction, the 27 mg dose a 63% reduction, and the 36 g every 2 weeks dose a 36% reduction.
· These were all statistically significant changes. Significant reductions were evident among patients who were and who were not on background lipid-lowering therapy.
· In the pooled analysis, 80% of patients were responders to pegozafermin, defined as achieving a triglyceride level < 500 mg/dL. In the placebo group, this proportion was 29%. Triglyceride levels were normalized (< 150 mg/dL) among 18% in the pooled active therapy arms, 31% in the 27 mg arm, and in none of the patients on placebo. Findings were consistent among all prespecified subgroups.
· Pegozafermin had minimal impact on LDL cholesterol levels and increased HDL cholesterol levels by 25% in the pooled analysis and by 42% in the 27 mg group, compared with 10% among those on placebo. It also reduced non-HDL cholesterol, by 19% in the pooled analysis versus 3% with placebo.
· Other effects of pegozafermin were significant reductions in apolipoprotein B-100, apolipoprotein B-48, and apolipoprotein C3. It also appeared to improve insulin sensitivity, based on its effects on insulin levels, fasting plasma glucose, and hemoglobin A1c. Patients taking the 27 mg dose lost an average of 1.3 kg, compared with 0.2 kg in the placebo group.
· Reductions in liver fat with pegozafermin were significant, with a mean reduction of 43% in the pooled analysis, compared with 5% in the placebo group. A ≥ 30% reduction in liver fat was achieved by 88% of patients on active therapy, and 24% had a normalization of their liver fat. These endpoints were not attained by any of the patients in the placebo group.
The researchers conclude, ""These findings appear very promising for the planned phase III trial utilizing the higher weekly doses of pegozafermin given for a longer duration."
Reference:
Presented by Dr. Deepak Bhatt at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 26, 2022.
