Rohit Loomba, MD

New research suggest pegozafermin is well-tolerated and safe, while improving liver function for patients with non-alcoholic steatohepatitis (NASH).

A team, led by Rohit Loomba, MD, NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, evaluated the safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with NASH.

Current Treatment

Currently, the best strategies to manage NASH are based on lifestyle modifications, as there are no treatments approved by the US Food and Drug Administration (FDA).

Pegozafermin, a glycoPEGylated FGF21 analogue, is 1 potential option.

In the randomized, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study, the investigators examined patients aged 21-75 years who had NASH with stage F1-F3 fibrosis or non-alcoholic fatty liver disease and a high risk of NASH because of central obesity with type 2 diabetes or central obesity with increased alanine aminotransferase or a Fibroscan score of 7 kPa or greater. The patients were seen at 12 specialist centers and clinics in the US.

Treatment

The patients were randomized to receive subcutaneously administered pegozafermin 3 (n = 6), 9 (n = 12), 18 (n = 11), or 27 mg (n = 10) once weekly, 18 (n = 14) or 36 mg (n = 9) once every 2 weeks, or placebo (n = 19( for 12 weeks. In addition, 19% (n = 15) of participants had biopsy confirmed NASH.

The investigators sought primary endpoints of the safety, tolerability, and pharmacokinetics of pegozafermin.

Between July 29, 2019 and August 3, 2020, the investigators screened 275 patients.

For safety, adverse events were found in 44% (n = 8) in the pooled placebo group, 86% (n = 6) in the 3 mg once weekly pegozafermin group, 33% (n = 4) in the 9 mg once weekly group, 64% (n = 7) in the 18 mg once weekly group, 70% (n = 7) in the 27 mg once weekly group, 57% (n = 8) in the 18 mg once every 2 weeks group, and 89% (n = 8) in the 36 mg once every 2 weeks group.

The most common treatment-related adverse event was mild increased appetite (16%; n = 10 the pooled pegozafermin group vs none of 18 in the pooled placebo group). However, this was not associated with increased bodyweight gains.

There were 2 patients in the study that discontinued treatment because of an adverse event and there were no treatment-related serious adverse events or deaths.

The investigators also observed dose-proportional pharmacokinetics and detected anti-drug antibodies in 65% (n = 41) of patients treated with pegozafermin.

By week 13, pegozafermin reduced the least squares mean absolute differences in hepatic fat fraction compared to pooled placebo (−8·9%; 95% CI, −14.8 to −3.1; P = 0.0032 for 3 mg once weekly; −11·5%; 95% CI, −16.1 to −6.9; P <0.0001 for 9 mg once weekly; −8.9%; 95% CI, −13.7 to −4.2; P = 0.0004 for 18 mg once weekly; −14·9%; 95% CI, −20.1 to −9.7; P <0.0001 for 27 mg once weekly, −10.4%; 95% CI, −14.7 to −6.1; P <0.0001 for 18 mg once every 2 weeks, and −11.1%; 95% CI, −16.2 to −6.0; P <0.0001 for 36 mg once every 2 weeks).

Reductions

The results also show significant LSM relative reductions compared to pooled placebo in aspartate aminotransferase for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks.

The treatment also resulted in significantly improvements in triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). C

However, there were not significant improvements found in insulin resistance or HbA_1c.

“Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted,” the authors wrote.

The study, “Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study,” was published online in The Lancet Gastroenterology & Hepatology.