Fibroblast growth factor analog shows promise in non-alcoholic steatohepatitis

Last Updated: 2018-03-16

By David Douglas

NEW YORK (Reuters Health) - An engineered analog of FGF-19, a hormone that regulates bile-acid synthesis and glucose homoeostasis, rapidly curbs liver fat in patients with non-alcoholic steatohepatitis, but has frequent side effects, according to an industry-funded trial.

So far, there is no Food and Drug Administration (FDA)-approved treatment for non-alcoholic steatohepatitis, Dr. Stephen A. Harrison of Pinnacle Clinical Research Group, in Live Oak, Texas, and colleagues note in The Lancet, online March 5.

The team conducted a double-blind, placebo-controlled phase 2 trial of NGM282, as the experimental compound is known. Participants were randomized to receive 3 mg or 6 mg of subcutaneous NGM282 or placebo.

At 12 weeks, 20 patients (74%) in the low-dose group and 22 (79%) in the high-dose group showed a reduction of at least 5% in liver fat content from baseline. This was true of only two placebo patients (7%, P<0.0001 for both comparisons).

Liver fat content became completely normal in 26% and 39% in the low- and high-dose groups, respectively. No placebo patients achieved normalization.

The agent also significantly decreased alanine aminotransferase (ALT), aspartate aminotransferase, and non-invasive serum fibrosis biomarkers. The greatest treatment effect was in patients with more severe disease (high baseline liver fat content and ALT).

Adverse events were much more common in the treatment arm. Most (67%) were grade 1 and only five patients (6%) experienced grade 3 or higher adverse events. A total of six patients in the treatment arm required early discontinuation compared to none in the placebo group.

The researchers say the results "support the further exploration of NGM282 for the safe and effective treatment of non-alcoholic steatohepatitis."

Dr. Michael Charlton of the Center for Liver Diseases at the University of Chicago, who wrote an accompanying editorial, told Reuters Health that the study "dramatically demonstrates the capacity for FGF-19 agonists to rapidly delipidate the liver with associated signals for improved inflammation and fibrosis."

Dr. Charlton added, "The results are, however, preliminary, with frequent side effects limiting tolerability at the doses used and some rebounding of inflammatory markers at the conclusion of this short study."

Dr. Vlad Ratziu of Hospital Piti Salp tri re and Sorbonne University, in Paris, told Reuters Health by email that this proof-of-principle trial demonstrates "vigorous target engagement that results in a strong and robust antisteatogenic effect and in an improvement of liver cell injury markers."

Dr. Ratziu, who has conducted research in the field but was not involved in the new work, added that it "remains to be seen how this translates into an improvement of liver overall histological damage."

Also of note is that "metabolic benefit was limited with no effect on glucose parameters and an anticipated increase in LDL albeit not in the most atherogenic LDL subparticles," he said.

"Like with all drugs involving the farnesoid X receptor FGF-19 axis," he concluded, "we need to understand from longer-term studies whether this LDL increase truly increases the cardiovascular risk. An issue will be tolerance, mainly the digestive side effects and the rather high discontinuation rate (11%) for side effects in the active arms over 12 weeks only."

NGM Biopharmaceuticals, which is developing the drug, funded the study. Three of the authors are employees of the company.

Dr. Harrison did not respond to requests for comments.

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Lancet 2018.