VIENNA — A fibroblast growth factor 21 (FGF21) analogue, pegozafermin, significantly improved fibrosis without worsening of nonalcoholic steatohepatitis (NASH) and led to resolution of NASH without worsening of fibrosis for patients with noncirrhotic disease, according to late-breaker results of the phase 2b ENLIVEN trial. The results were presented at the European Association for the Study of the Liver (EASL) 2023 and were simultaneously published online in The New England Journal of Medicine.
Two dosages of the drug — 44 mg every 2 weeks, and 30 mg weekly — led to statistically significant changes on both primary endpoints with improvement in fibrosis of at least one stage without worsening of NASH (27% and 26%, respectively, for the two dosages). This was 3.5 times the placebo rate (7%). In addition, NASH resolved without worsening of fibrosis (26% and 23%, respectively), which was 12 to 14 times the placebo rate (2%).
The investigational drug, which was designed to balance efficacy and long dosing interval, also significantly improved results on key noninvasive tests for NASH, including measures of fat content, fibrosis, and liver inflammation, and showed a favorable safety and tolerability profile.
"These data appear very promising for the planned phase 3 program," said Rohit Loomba, MD, chief, Division of Gastroenterology and Hepatology, University of California, San Diego, who presented the results. "It's both incredibly encouraging and exciting to see the positive, consistent results from this research across all aspects — efficacy, safety, tolerability, and dosing convenience."
The randomized, double-blind, placebo-controlled trial evaluated 219 adult patients, of whom 192 had biopsy-confirmed fibrosis of stages F2-F3 NASH and a nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) of at least 4 for 24 weeks. Participants were randomly assigned to receive pegozafermin 44 mg every 2 weeks (Q2W, n = 51), 30 mg weekly (QW, n = 66), 15 mg weekly (n = 14), or placebo (n = 61).
Mean body mass index was 37 kg/m2; type 2 diabetes was present in around 66% of participants; 60% had stage 3 fibrosis (F3), mean liver fat content was 16.4%, and mean liver stiffness was 13 kPa.
Following the initial 24-week treatment period, participants were shifted to a blinded extension phase for a further 24 weeks. Some patients who had received placebo were randomly assigned to receive pegozafermin in the extension phase.
Primary endpoints were either the proportion of participants who experienced resolution of NASH without worsening of fibrosis, or the proportion of participants who experienced a decrease in fibrosis of at least one stage with no worsening of NASH at 24 weeks. Secondary measures included changes from baseline in liver fat, liver enzymes, noninvasive markers of liver fibrosis, glycemic control, lipoproteins, and body weight, as well as safety and tolerability measures.
Biopsy specimens were independently scored by three pathologists — who were blinded to participant, treatment, and study time point — on the NAS components and fibrosis (NASH-CRN criteria). Readers' scores were compared, and a final consensus score was reached.
At 24 weeks, the proportions of participants who had experienced a decrease in fibrosis of least one stage without worsening of NASH were 26% (P = .009), 27% (P = .008), 22% (P = .1) and 7% for 44-mg Q2W, 30-mg QW, 15-mg QW, and placebo, respectively. The proportions of participants who achieved resolution of NASH without worsening of fibrosis were 26%, 23%, 37%, and 2% (P < .001 for all), respectively.
"For patients on 44-mg Q2W, the relative risk for at least one stage decrease in fibrosis with no worsening of NASH for pegozafermin compared with placebo is four times [1.3, 12.9]," reported Loomba, "while the relative risk for 44-mg Q2W compared with placebo was 12.7 [1.9, 84.7]."
Loomba and his colleagues also evaluated the proportion who achieved both improvement in fibrosis and NAS resolution and found that 20% of the 44-mg Q2W and 14% of the 30-mg QW satisfied this, while none of the participants who received placebo did. They also analyzed the proportion of participants who achieved at least a 2-point improvement in NAS, MRI proton density fat fraction (MRI-PDFF) response, and ALT response and found that 52% and 60% did, respectively.
For 14 patients with stage 4 fibrosis at baseline who received pegozafermin, 45% showed an improvement in fibrosis of at least one stage without worsening of NASH, while MRI-PDFF dropped 33%, alanine transferase levels dropped by 53%, and aspartate transferase levels dropped by 31%.
"In patients on pegozafermin, robust reduction in liver fat was seen with high responder rates according to MRI-PDFF at week 24," said Loomba. Reductions of 55%, 50%, and 15% were seen with 44-mg Q2W, 30-mg QW, and placebo. "Super-responders with over 50% reduction in liver fat were also identified in 67% and 66% and in 44-mg Q2W and 30-mg QW respectively."
The 44-mg Q2W and 30-mg QW pegozafermin doses also yielded significant improvements for noninvasive markers for fibrosis and significant reductions in noninvasive markers of hepatic inflammation and fibrosis. Greater reductions were also seen in key markers in patients who received background GLP-1 therapy.
Adverse effects with pegozafermin were diarrhea (up to 24%), nausea (up to 21%), injection site reactions (up to14%), and increased appetite for patients who received pegozafermin compared to those who received placebo (up to 13%). Drug-related discontinuations were more common with pegozafirmin than with placebo (up to 6%).
These are "very exciting data" and represent "by far the most comprehensive and broadly positive set of results in a NASH clinical trial. In NASH, these are the best data we have," said Michael Charlton, MD, director, Center for Liver Diseases, University of Chicago Medicine, Chicago, Illinois.
"It was a substantial trial in terms of patient numbers, and that's encouraging, but it is phase 2b, so it'll be interesting to see the phase 3 results and the longer-term results," he noted. "This [FGF21] mechanism of action has a track record for tachyphylaxis, but this hasn't been observed here at all. In other FGF21 studies, it has. Also, NASH always has its underlying problem — it is not treated and gone — so I'd like to see it go for longer and maybe use a smaller dose so there are fewer gastrointestinal side effects for patients."
International Liver Congress (ILC) 2023: Presented June 24, 2023.
N Engl J Med. Published online June 24, 2023. Abstract
Loomba has consulted for and received research grants from numerous pharmaceutical companies. He holds stock options in 89Bio and Sagimet Biosciences and is co-founder of LipoNexus Inc. Charlton has been a consultant for 89Bio and has stock options in Aardvark Therapeutics, Allergan, Altimune, and Anylam.
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Cite this: Pegozafermin Improves Fibrosis in NASH in Phase 2b Study - Medscape - Jun 28, 2023.
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