Phase II data reveal treatment potential of pegozafermin for severe hypertriglyceridaemia

The phase II ENTRIGUE trial presented at ESC 2022 showed the potential of pegozafermin to improve triglyceride levels and other lipid-related metrics in individuals with severe hypertriglyceridaemia.

“[In our study,] pegozafermin significantly reduced triglycerides by up to about 60 percent, non-HDL-C* by up to 30 percent, ApoB by ~10 to 20 percent, and liver fat fraction by ~40 percent,” said Professor Deepak Bhatt from Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, US.

ENTRIGUE randomized 85 participants (mean age 53.7 years, 75 percent male) 1:1:1:1:1 to either placebo or pegozafermin 9 mg QW, 18 mg QW, 27 mg QW, or 36 mg Q2W. Fifty-five percent of participants were on background lipid-modifying therapy (45 percent on statins). All patients had hepatic steatosis (ie, liver fat fraction >5 percent). [ESC 2022, Late-Breaking Science session]

At week 8, median percent change in triglycerides from baseline was greater with pegozafermin vs placebo (–57 percent [pooled] vs –12 percent; p<0.001). The reductions remained regardless whether they had background therapy (median percent change, –59 percent vs –18 percent; p<0.001) or not (median percent change, –51 percent vs 5 percent; p<0.01).

More pegozafermin recipients achieved the initial treatment goal of <500 mg/dL as opposed to those on placebo (80 percent [pooled] vs 29 percent; p<0.001). A similar trend favouring pegozafermin over placebo was seen in terms of fractions of participants achieving ≥50 percent triglyceride reduction from baseline (61 percent vs 6 percent) and triglyceride normalization (<150 mg/dL; 18 percent vs 0 percent).

 

Non-HDL-C, apolipoprotein

There was also a significant drop in non-HDL-C with pegozafermin vs placebo (mean absolute change, –44 [pooled] vs –14 mg/dL). “Absolute non-HDL-C reduction has been associated with MACE** improvement,” Bhatt explained. “[Although ENTRIGUE] was not designed or powered to look at cardiovascular (CV) events, [this finding is] certainly a signal of potential benefit on CV events.”

There were also clinically meaningful improvements in ApoB – a key marker of CV risk – with pegozafermin vs placebo (mean absolute change, –15 [pooled] vs –3 mg/dL). This effect was similarly seen when evaluating ApoB subtypes (mean percent change, –8 percent vs –0.6 percent [ApoB-100] and –34 percent vs 25 percent [ApoB-48]), as well as apolipoprotein C3 levels (–42 percent vs –9 percent; p<0.001).

 

Markers of insulin sensitivity, liver fat

Compared with placebo, pegozafermin 27 mg appeared to improve insulin sensitivity, as evidenced by the increased adiponectin (53 percent vs 6 percent; p=0.017) and reductions in insulin (–32 percent vs 18 percent), fasting plasma glucose (–9 percent vs 1 percent), HbA_1c (–0.4 vs –0.2), and weight (–1.3 vs –0.2 kg).

Mean relative reduction in liver fat at week 8 vs baseline was also significantly greater with pegozafermin vs placebo (–43 percent [pooled] vs –5 percent; p=0.012). About 90 percent of participants in the pooled pegozafermin arms achieved ≥30 percent liver fat reduction, 41 percent achieved ≥50 percent reduction, while about a quarter achieved liver fat normalization. None of the placebo recipients achieved these metrics.

 

Good tolerability profile

Overall, pegozafermin was well tolerated. The incidence of treatment-related adverse events (AEs; nausea, diarrhoea, injection-site reaction) was quite low, ranging between 9 and 10 percent with pegozafermin; these events were not reported with placebo. Only one unrelated serious AE was reported with pegozafermin.

“All AEs were grade 1/2. There were no grade ≥3 treatment-emergent AEs and, importantly, there were no transaminase elevation AEs reported,” said Bhatt.

 

Encouraging data

“[Although the trial was] not powered for clinical events such as pancreatitis, liver failure, CV endpoints … these initial data do seem encouraging,” Bhatt stressed. “Additional cardiometabolic improvement potentially make pegozafermin an attractive therapy in severe hypertriglyceridaemia to address multiple comorbidities simultaneously, including cardiac, glycaemic, and hepatic risks.”

The current findings seem very promising for a planned phase III trial using the higher weekly doses (18 and 27 mg) given for a longer duration, Bhatt continued. A longer period of drug exposure at the target dose in a larger number of patients may further shed light on long-term efficacy, safety, and tolerability of the drug.