PARIS — An investigational agent that targets the human fibroblast growth factor 19 (FGF19) pathway is in development to reduce fibrosis and other hepatic injuries in patients with nonalcoholic steatohepatitis (NASH).
In a phase 2 trial of patients with biopsy-confirmed NASH, the new drug, developed by NGM Bio, was associated with “unprecedented” improvements in liver histology, said Stephen Harrison, MD, from the Brooke Army Medical Center in San Antonio, who is currently a visiting professor at the University of Oxford in the United Kingdom.
“It’s just encouraging to see that we can actually modulate the characteristics of NASH on biopsies relatively quickly, and quicker than we ever thought possible,” he said here at the International Liver Congress 2018.
NGM282 is an engineered, nontumorogenic analog of FGF19. In preclinical models of NASH, it has been shown to improve nonalcoholic fatty liver disease scores, fibrosis, and markers of hepatic injury.
The agent has been evaluated in more than 400 patients with type 2 diabetes, NASH, primary sclerosing cholangitis, and primary biliary sclerosis.
NASH Trial
Harrison and his colleagues conducted a single-center exploratory 12-week study of NGM282 3 mg to assess the potential for early histologic changes on liver biopsy in 22 patients.
All had biopsy-confirmed NASH, nonalcoholic fatty liver disease scores of at least 4 and at least one point from each component in the scale, stage 1 to 3 fibrosis, and liver fat content of at least 8%, as measured by MRI-derived proton density fat fraction. Nineteen patients completed the 12 weeks of therapy and underwent baseline and 12-week liver biopsies.
As in other studies, decreases from baseline to week 12 in C4 levels (relative decline, 93%) and in bile acids (relative decline, 64%) were significant.
The absolute reduction in liver fat content was at least 5% in all 19 patients, and the relative decline from baseline was at least 30%.
Declines in liver transaminases that were evident by week 2 were sustained on treatment, as were the significant reductions in markers of fibrosis — such as the collagen marker PRO-C3 and Enhanced Liver Fibrosis score — that were evident by week 6.
In addition, independent review of 12-week biopsy results showed decreases in all NASH histologic parameters.
Table. Histologic Response at 12 Weeks in Patients With NASH (n = 19)
| Parameter | Improved, % | Unchanged, % | Worse, % | Mean Score Change From Baseline |
|---|---|---|---|---|
| Nonalcoholic fatty liver disease score | 84 | 11 | 5 | –2.3 |
| Steatosis | 74 | 26 | 0 | –1.1 |
| Inflammation | 42 | 53 | 5 | –0.5 |
| Hepatocyte ballooning | 53 | 42 | 5 | –0.7 |
Three patients experience reductions in fibrosis stage from F3 to F1.
Increases in low-density-lipoprotein cholesterol, an adverse effect of the medication, were successfully managed with rosuvastatin 100 mg/dL. The most common treatment-emergent adverse events were mild gastrointestinal symptoms, and most resolved during treatment. There were no withdrawals due to drug-related adverse events.
These data support the phase 2b study of NGM282 for patients with NASH, Harrison said.
In a recent phase 2 study Harrison was involved in, a subcutaneous injection of NGM282, at 3 mg or 6 mg, was associated with rapid and significant decreases in liver fat content and an acceptable safety profile (Lancet. 2018;391:1174-1185).
Primary Sclerosing Cholangitis Study
In a randomized double-blind study of primary sclerosing cholangitis, Gideon Hirschfield, MD, PhD, from the University of Birmingham in the United Kingdom, and his team assessed 62 patients with ALP levels more than 1.5 times the upper limit of normal.
The patients, from 27 sites in Europe and the United States, were treated with NGM282 1 mg, NGM282 3 mg, or placebo for 12 weeks.
The reduction in ALP was not sustained at week 12.
However, reductions in serum alanine aminotransferase and aspartate aminotransferase in the 3 mg treatment group were significant (P < .01 for both). Serum C4 and total bile acid levels were also significantly lower at 12 weeks.
In addition, reductions in markers of fibrogenesis were significant in the two NGM282 groups, with the greatest reductions seen in patients at high risk.
Patients tolerated the drug well, Hirschfield reported. As in the NASH study, the most frequently reported adverse drug-related events were diarrhea, frequent stools and injection site reactions, the majority of which were mild and resolved on treatment.
The drug was well tolerated, Hirschfield said. As in the study of patients with NASH, the most frequently reported drug-related adverse events were diarrhea, frequent stools, and injection-site reactions, the majority of which were mild and resolved during treatment.
Going forward, investigators should focus on markers of fibrosis as primary end points, Hirschfield explained.
There’s a theory that if you get rid of fat, everything else in the liver — all the other consequences that cause the fibrosis and cirrhosis in NASH — may also be reduced.
“It is very important that we do these studies and that industry is interested in doing studies in these patients,” said Markus Cornberg, MD, PhD, from Hannover Medical School in Germany.
“We don’t know if ursodeoxycholic acid really works, but we give it because we have nothing else,” he told with Medscape Medical News. “If ALP decreases, than we feel happy.”
“We need biomarkers; that’s why this study is so important. If we see biomarkers decrease, we hope that it might prolong the survival of these patients, but we don’t know yet. I think this is a great start for more studies,” he said.
For NASH in particular, effective and safe therapies are needed, said Ronald Sokol, MD, from the University of Colorado School of Medicine in Aurora.
“There’s a theory that if you get rid of fat, everything else in the liver — all the other consequences that cause the fibrosis and cirrhosis in NASH — may also be reduced,” he told Medscape Medical News.
Both studies were supported by NGM Bio. Harrison reports being on the advisory board for NGM and other companies. Hirschfield reports relationships with companies other than NGM. Cornberg and Sokol have disclosed no financial relationships relevant to these studies.
International Liver Congress (ILC) 2018: Abstracts GS-014 and LBO-002. Presented April 14, 2018.
Follow Medscape Gastro on Twitter @MedscapeGastro and Neil Osterweil @NeilOsterweil
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