NGM282, an experimental fibroblast growth factor analogue, reduced liver fat build-up and the development of scar tissue in people with non-alcoholic steatohepatitis, according to studies presented at the recent AASLD Liver Meeting in San Francisco.
Researchers reported that a lower dose of NGM282 worked nearly as well as a previously tested higher dose, and its effects were still apparent six weeks after stopping treatment. These findings set the stage for longer and larger clinical trials.
Non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH), are associated with obesity and the metabolic syndrome. The build-up of fat in the liver triggers inflammation and production of scar tissue (fibrosis), which over time can lead to cirrhosis, liver cancer and the need for a liver transplant. There are currently no good treatments for fatty liver disease, and its management instead relies on lifestyle changes such as weight loss.
Stephen Harrison of the University of Oxford and Pinnacle Clinical Research Center in San Antonio, Texas, presented the latest findings from a phase 2 study of NGM282, a genetically engineered analogue of human fibroblast growth factor 19 (FGF19), a hormone that regulates bile acid synthesis and fat metabolism. NGM282 targets multiple processes involved in the development of NASH, including decreasing the toxic effects of fatty acids and bile acids and reducing fat liver build-up.
A previous phase II trial showed that people who received 3mg or 6mg daily injections of NGM282 experienced rapid liver fat reduction according to MRI-PDFF (magnetic resonance imaging estimation of proton density fat fraction), an imaging method for assessing liver fat accumulation.
This was followed by a paired biopsy study to see if treatment led to improvements in liver histology, or appearance of liver tissue. At last year’s EASL International Liver Congress in Paris, Harrison presented results from 19 people with NASH treated with 3mg NGM282 for 12 weeks. All participants had at least a 30% relative reduction and at least a 5% absolute reduction in liver fat content and nearly two-thirds saw their liver fat content normalise (falling to 5% or less).
Bile acid, ALT liver enzyme and fibrosis biomarker levels also decreased by 6 weeks. These non-invasive assessments correlated with improvements in NAFLD activity score, inflammation, steatosis, liver cell ‘ballooning’ and fibrosis on the second biopsy. A late-breaking poster presented at The Liver Meeting showed that liver fat content, ALT and the Pro-C3 fibrosis marker remained below baseline levels at week 18, or six weeks after stopping treatment.
NGM282 was safe and generally well tolerated, with the most common side-effect being mild diarrhoea. However, NGM282 led to an increase in LDL cholesterol levels, which can raise cardiovascular disease risk.
At The Liver Meeting, Harrison presented results from a new cohort of 24 people treated with a lower dose of 1mg daily NGM282 for 12 weeks. About 80% were women, the median age was about 50 years, average liver fat content at baseline was nearly 20% and about 40% had advanced (stage F3) fibrosis. They could start rosuvastatin at week 2, if needed, to manage LDL cholesterol.
The result showed that the 1mg dose worked nearly as well as the 3mg dose, with “significant, meaningful reductions” across a variety of non-invasive markers of fatty liver disease, Harrison said.
The relative liver fat reduction at week 12 was -57% in the 1mg group compared with -67% in the 3mg group; the absolute fat reduction was about 11% in both groups. Just over 90% had at least a 30% relative reduction and at least a 5% absolute reduction in fat content in the 1mg group, versus 100% in the 3mg group. However, those in the lower-dose group were about half as likely to achieve liver fat normalisation (33% vs 63%).
ALT and AST liver enzyme levels decreased rapidly, and by similar amounts, in both dose groups. Pro-C3 levels fell significantly in both groups by week 6, but the relative and absolute reductions were smaller in the 1mg group. Both groups had reduced ELF scores, an index associated with NASH severity.
Again, paired biopsies done at week 12 showed improvements; however, a smaller proportion of people in the 1mg group had improvements in NAFLD activity score (75% vs 84%), steatosis (67% vs 74%), inflammation (33% vs 42%), ‘ballooning’ (42% vs 53%) and fibrosis (25% vs 42%). In both groups, those with worse fibrosis at baseline saw the most improvement.
Here too, treatment was safe and well tolerated. LDL levels rose after starting NGM282, but fell at week 2 after adding the statin, and from week 4 onward were below baseline level. Gastrointestinal symptoms were the most common side-effects, mostly mild and transient, though two people stopped treatment due to diarrhoea. Separating injections from meal times and eating smaller meals appears to reduced GI symptoms.
Asked about the apparent lesser improvement in liver histology in the 1mg group versus the 3mg group, Harrison suggested that people may need to be treated longer with the lower dose to see similar improvement.
Based on these findings, NGM Bio will conduct a larger phase 2b study of NGM282 treatment for 24 weeks in people with NASH and moderate to advanced fibrosis. In addition to NASH, NGM282 is also being tested as a treatment for type 2 diabetes, primary biliary cholangitis and primary sclerosing cholangitis (two conditions involving inflammation and blockage of bile ducts in the liver).
NGM Bio is also developing a FGF21 drug called NGM313 for NASH and type 2 diabetes. Another late-breaking poster at The Liver Meeting showed that a single dose led to “robust reductions” in liver fat content and improved insulin sensitivity in obese people with NAFLD.
“The significant histological improvements observed after just 12 weeks of treatment with NGM282 point to an agent that, if ultimately approved, could provide an important and much needed medicine for physicians to reverse fibrosis in NASH patients with well-established disease,” Harrison said in a NGM Bio press release.
By Liz Highleyman
Harrison S et al. NGM282 rapidly improves NAFLD activity score (NAS) and fibrosis in 12 weeks in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH): results of a phase 2 multi-center dose finding study.The Liver Meeting, abstract 0104, 2018.
Paredes et al. NGM282 maintains a durable off-treatment response on hepatic steatosis, inflammation and fibrogenesis in patients with biopsy-confirmed nonalcoholic steatohepatitis: results of a multi-center phase 2 dose-finding study. The Liver Meeting, abstract LB-22, 2018.
DePaoli A et al. NGM313, a novel once-monthly activator of β-klotho/FGFR1c, significantly reduces hepatic steatosis and key biomarkers of nonalcoholic steatohepatitis: results of a randomized, active-controlled clamp study in obese insulin resistant patients with NAFLD. The Liver Meeting, abstract LB-21 2018.