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Nearly 80% Respond to Novel Growth Factor for NASH
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AMSTERDAM — With 12 weeks of treatment, more than one-third of biopsy-diagnosed non-alcoholic steatohepatitis patients who received novel growth factor NGM282 achieved normal liver fat content, according to data at the International Liver Congress.
“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis, although more work needs to be done to define this histopathologically,” Stephen A. Harrison, MD, medical director at Pinnacle Clinical Research and visiting professor of hepatology at the Radcliffe Department of Medicine at University of Oxford, U.K., said during his late breaker presentation. “The data strongly support continued development in non-alcoholic steatohepatitis.”
Harrison explained that NGM282 (NGM Bio) is an engineered variant of human fibroblast growth factor 19 (FGF19). The researchers in the randomized, double-blinded, placebo controlled trial looked to test its safety and efficacy in treating NASH.
The study group included 82 individuals across 18 sites in Australia and the United States. Subjects had biopsy-confirmed NASH and a NASH activity score greater than 4, stage 1, 2 or 3 fibrosis, a minimum of 8% absolute liver fat content by MRI-PDFF and abnormal ALT.
Harrison and colleagues randomized patients to placebo, NGM282 3 mg or NGM282 6 mg for 12 weeks. All three groups were similarly matched at baseline. Response was defined as greater than a 5% decrease in fat content at 12 weeks and normalization was defined as absolute liver fat content less than 5% at 12 weeks.
Primary endpoints
No placebo-treated participants normalized at 12 weeks, but 25.9% in the 3-mg group and 42.3% in the 6-mg group normalized by that time frame. In the 3-mg group, 74% of participants responded, while 85% of those in the 6-mg group responded for an overall response of 79%.
“Importantly, 34% of the treated cohort achieved normal liver fat content. This wasn’t limited to minimal fat content in the liver. ... Significant fat reductions were seen with patients with high levels of fat content,” Harrison said.
He showed that the placebo group had a 0.9% decrease in absolute liver fat while the 3-mg group had a 9.7% decrease (P < .001) and the 6-mg group had an 11.9% decrease (P < .001). Patients in the placebo group experienced a 1% relative decrease in liver fat, as compared to a 47% relative decrease in the 3 mg group (P <.001) and a 61% relative decrease in the 6 mg group (P < .001), according to Harrison.
“Importantly, 89% of subjects achieved a clinically meaningful, greater than 30% relative change in fat,” Harrison said. “Also, the decreases in liver fat strongly correlated with reductions in ALT, AST and serum C4 levels.”
In those with baseline MRI-PDFF greater than 20%, the participants who received 3 mg of NGM282 dropped from 26.1% liver fat content to 13.2% liver fat content (P = .002), while those who received 6 mg dropped from 26.8% liver fat content to 7.9% liver fat content (P < .001) at 12 weeks.
Other metrics
Harrison said the decreases in ALT also support the overall reductions in inflammation.
“Overall, 36% of subjects normalized the ALT, the majority of those by week 2,” he said. It was “a rapid and profound reduction of ALT by week 2. This was sustained throughout the course of therapy.”
He showed that triglycerides decreased slightly, while LDL increased, though data also presented at the meeting showed addition of a statin normalized these outcomes. Further studies will be conducted, according to Harrison.
“Ultimately, there was significant absolute and percentage change in total ELF score for 3 mg NGM282 cohort with numeric decreases observed with 6 mg cohort and no significant changes observed in hyaluronic acid,” he said.
In the safety report, Harrison said there were mostly “mild and general” adverse events and only one severe adverse event — pancreatitis — was possibly related.
Lastly, Harrison reported significant weight reduction with 6-mg NGM282 vs. placebo (–2.6 kg vs –0.7, P = 0.023), but not at the 3-mg dose.
“The decrease in liver fat content appears independent of weight loss,” he said. – by Katrina Altersitz
Reference:
Harrison SA. LBO-08. Presented at: International Liver Congress; April 19-24, 2017; Amsterdam.
Disclosures: Harrison reports being on the speakers’ bureaus of Alexion and Gilead Sciences; acting as a consultant or advisory board member for Allergan, Chronic Liver Disease Foundation, Cirius, Echosens, Fibrogen, Galmed, Genfit, Gilead, Intercept, Madrigal, NGM Bio, Novartis, Perspectum and Pfizer; and receiving grant or research support from Allergan, Conatus, Galectin, Galmed, Genfit, Gilead, Immuron, Intercept, Madrigal, NGM Bio and Taiwan J.