Novel Agent Leads to Fibrosis Improvement in NASH

VIENNA – Treatment with an investigational FGF21 analogue improved fibrosis in patients with nonalcoholic steatohepatitis (NASH), according to a phase IIb trial.

In the ENLIVEN study, patients with biopsy-confirmed NASH and moderate or severe fibrosis were randomized to subcutaneous pegozafermin or placebo. Among 219 patients, 7% met the criteria for fibrosis improvement in two pooled placebo group (weekly or once every 2 weeks dosing), while those on pegozafermin had better results at different doses, reported Rohit Loomba, MD, of the University of California San Diego, at the European Association for the Study of the Liver (EASL) annual meeting. Specifically:

• 15-mg weekly dose: 22% met the criteria for fibrosis improvement for a 14% difference vs placebo (95% CI -9 to 38)
• 30-mg weekly dose: 26% for a 19% difference (95% CI 5-32, P=0.009)
• 44-mg once every 2 weeks: 27% for a 20% difference (95% CI 5-35, P=0.008)

ENLIVEN had two primary endpoints: An improvement in fibrosis, which was defined as reduction by ≥1 stage (0-4 scale; higher stages indicating greater severity), with no worsening of NASH at 24 weeks, and NASH resolution without worsening of fibrosis at 24 weeks.

Loomba said at EASL that "treatment effects were consistent across various subgroups, including in [patients] on background GLP-1 therapy, and that efficacy was similar with weekly and every-2-week dosing intervals." ENVLIVEN results were also published in the New England Journal of Medicine.

He pointed out that pegozafermin demonstrated a favorable safety and tolerability profile, with nausea and diarrhea as the most common adverse events (AE) tied to pegozafermin therapy. There was one patient in the 44-mg group who had a serious AE of pancreatitis after a single dose. This patient "had gallbladder sludge on imaging. The clinical course was typical for uncomplicated acute pancreatitis," Loomba and colleagues stated.

"These data appear very promising for the planned phase III program," Loomba said.

Pegozafermin is a long-acting glycopegylated fibroblast growth factor 21 analogue in development for the treatment of NASH and severe hypertriglyceridemia.

ENLIVEN investigators also reported that only 2% of placebo patients met the criteria for NASH resolution versus patients on pegozafermin at the various doses:

• 15-mg: 37% for a 35% difference vs placebo (95% CI 10-59)
• 30-mg: 23% for a 21% difference (95% CI 9-33)
• 44-mg: 26% for a 24% difference (95% CI 10-37)

EASL session co-moderator Debbie Shawcross, MD, PhD, of King's College London, told MedPage Today that the results were "impressive, but also they're not complete."

"One of the things that is quite apparent in the data is that there's a lot of diabetic patients in this study," she noted. "They were all overweight. We want to see more data on the impact pegozafermin is having on weight and diabetes." Loomba's group reported that BMI for the total study population was 36.6, and they weighed in at around 200 lbs, while 66% had type 2 diabetes (T2D).

Shawcross stressed that "all of these medications need to be given alongside lifestyle interventions, dietary interventions, and exercise. We can't just all take pills the rest of our lives."

The trial was done at 61 U.S. sites for 24 weeks. Patient age for the total population was around 56 and 39% were men. Inclusion criteria were NASH fibrosis stage F2 or F3 and a nonalcoholic fatty liver disease activity score of at least 4, with at least one point for steatosis, ballooning, and lobular inflammation. All had to be biopsy-confirmed at screening or no more than 6 months before screening. Key exclusion criteria were liver disease other than NASH, cirrhosis, uncontrolled or newly diagnosed T2D, or "or any illness that, in the opinion of the investigator, might affect the results of the trial or pose an additional risk to the participant," the researchers stated.

Loomba's group pointed out that their findings suggest "pegozafermin may have positive effects on adiponectin, serum triglyceride, and HDL cholesterol levels." The agent fared well for cutting severe hypertriglyceridemia and liver fat, as well as for boosting glucose control, in the ENTRIGUE trial.

ENLIVEN limitations included its short duration so a "single-blind extension study for 24 additional weeks may provide data on longer-term safety and noninvasive biomarker assessments," they said. Also, 94% of the study population was white so the results may not be generalizable.

A related presentation at EASL of the MAESTRO-NASH trial showed that investigational resmetirom was effective at reducing fibrosis.

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