Pegbelfermin improves non-alcoholic fatty livers in mid-stage trial

Last Updated: 2019-01-02

By Will Boggs MD

NEW YORK (Reuters Health) - Pegbelfermin reduced the hepatic-fat fraction in patients with non-alcoholic steatohepatitis (NASH) in a phase 2a trial.

"Our findings provide proof of principle that administration of the fibroblast growth factor (FGF) 21 analogue pegbelfermin in NASH patients leads to improvements in hepatic fat, liver injury, liver stiffness, markers of fibrogenesis, and metabolic health within a relatively short timeframe of 16 weeks," said Dr. Edgar D. Charles from Bristol-Myers Squibb, in Princeton, New Jersey, which funded the study and employed several of the authors.

"Thus, this study supports further clinical study of pegbelfermin in NASH patients with advanced fibrosis," he told Reuters Health by email.

FGF21 is a key regulator of energy metabolism, and its recombinant analog pegbelfermin improved non-alcoholic fatty liver disease activity score and fibrosis in preclinical mouse models.

Dr. Charles's team evaluated the safety and efficacy of daily and weekly administration of pegbelfermin for 16 weeks in a randomized trial of 75 patients with NASH: 25 assigned to pegbelfermin 10 mg once a day, 24 assigned to pegbelfermin 20 mg once a week and 26 assigned to placebo.

Study enrollment was ended prior to enrolling the planned sample size of 30 patients per group because of a significant effect of pegbelfermin on hepatic fat fraction during the interim analysis at treatment week 8.

After 16 weeks of treatment, mean hepatic fat fraction dropped by 6.8% with pegbelfermin once daily, by 5.2% with pegbelfermin once weekly and by 1.3% compared with placebo (both P<0.01).

Most patients treated with pegbelfermin developed anti-pegbelfermin and anti-FGF21 antibodies, but titers were generally low and not associated with immune-related adverse events, the researchers report in The Lancet, December 13.

Pegbelfermin treatment was also associated with significant improvements in adiponectin concentration and with significant decreases in PRO-C3, a biomarker of fibrosis.

Mean concentrations of alanine aminotransferase and aspartate aminotransferase decreased with pegbelfermin treatment, as did mean liver stiffness as measured by magnetic resonance elastography (MRE).

"We are continuing this work in two concurrent Phase 2b studies of pegbelfermin given for 48 weeks in patients with NASH and stage 3 fibrosis (FALCON 1) or compensated cirrhosis (FALCON 2)," Dr. Charles said. "In both of these studies, we are assessing the effects of pegbelfermin on liver fibrosis and NASH disease activity, as measured by liver biopsy as well as by noninvasive assessments."

"These studies will also assess the safety and tolerability of pegbelfermin," he said. "Our hope is that the data from these trials will provide a basis for moving into phase 3 trials with pegbelfermin."

Dr. Vincent W. S. Wong from Chinese University of Hong Kong, Prince of Wales Hospital, in Shatin, Hong Kong, who co-authored an accompanying editorial, told Reuters Health by email, "It is important to note that the current study, though encouraging, is an early-phase study. We still do not know the impact of pegbelfermin on liver histology and clinical outcomes. However, if the efficacy is proven, I think this would be an interesting agent for NASH."

"The study also highlights the difficulty in drug development for NASH at the moment," he said. "We are currently relying on relatively small studies with surrogate outcomes for initial evaluation. Hopefully, we will learn much from the first few phase 3 NASH trials and become smarter in evaluating new agents."

The editorial notes that patient acceptance for injection therapies like pegbelfermin for a relatively asymptomatic disease will need further evaluation.

Dr. Ali Canbay from Otto-von-Guericke University Magdeburg, in Germany, who recently reviewed the development of pharmacological treatments for NASH and non-alcoholic fatty liver disease (NAFLD), told Reuters Health by email, "Pegbelfermin is among the more promising agents to counter progression of liver disease in the setting of overweight, obesity, and non-alcoholic fatty liver disease. Though, it has to be kept in mind that all currently tested substances are still experimental, and long-term effects are not known."

"The first and foremost therapy should be a strict and consistent change of lifestyle to reduce weight as an underlying condition," said Dr. Canbay, who was not involved in the study. "Improved food choices, but in particular more activity and regular exercise with sufficient intensity, must be strongly emphasized in prevention and therapy of this disease."

"This drug has good potential to be successful in the treatment of NAFLD/NASH, which affects more the 25% of world population!" he concluded.

SOURCE: https://bit.ly/2AqnxDr and https://bit.ly/2TmDdhM

Lancet 2018.