NGM Bio’s NGM282 succeeds in nonalcoholic steatohepatitis phase 2 trial

NGM282, which is a non-tumorigenic, engineered variant of the human hormone FGF19, demonstrated a significant reduction in liver fat content and improvement of biomarkers associated with the resolution of NASH in this 12-week, randomized, double blind, placebo-controlled trial. The data were featured today at a late-breaker oral presentation at The International Liver Congress 2017.

Stephen A. Harrison, M.D., Medical Director at Pinnacle Clinical Research and Visiting Professor of Hepatology at the Radcliffe Department of Medicine at University of Oxford, UK said:  “There is an urgent need to develop pharmacologic treatments that can help NASH patients restore their liver health. NGM282 is the first agent I’ve tested that holds the potential to completely reverse steatosis in as short as 12 weeks of therapy.

“I look forward to participating in additional trials to further elucidate the robust activity of this agent in treating NASH patients.”

Exploratory Phase 2 Trial Results

This Phase 2 trial evaluated the activity, safety and tolerability of 3 and 6 mg daily subcutaneous injections of NGM282 over 12 weeks of treatment compared to placebo. Eighty-two patients with biopsy-confirmed NASH were enrolled, all of whom had a minimum NAFLD activity score (NAS) ≥ 4 (with at least one point in each component), Stage 1-3 fibrosis and ≥8% absolute liver fat content by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF).

The primary endpoint was an absolute decrease in liver fat content by a minimum of 5% as measured by MRI-PDFF. Secondary endpoints included relative decreases in liver fat content as well as biomarkers of liver function and lipid metabolism. Biomarkers of fibrosis were examined as exploratory endpoints.

Patients treated with NGM282 for 12 weeks showed statistically significant and clinically meaningful reductions in both absolute and relative MRI-PDFF measures of liver fat content, with the 3 mg and 6 mg dose groups demonstrating a reduction in absolute liver fat content of 9.7% and 11.9%, respectively (both p<0.001 versus placebo). Of the patients treated with NGM282, 34% reached a normal liver fat content.

The greatest magnitude of effect was observed in patients with the highest baseline liver fat content (i.e., >20% by MRI-PDFF) and most active disease (i.e., alanine transaminase (ALT) levels greater than 60 U/l). Significant improvements in other serum biomarkers of liver function, lipid metabolism and fibrosis were observed.

Notable treatment effects included a decrease in triglycerides of 39 and 44 mg/dl for the 3 and 6 mg doses, respectively, consistent with FGFR1c activity. Patients on NGM282 also experienced LDL cholesterol (LDL-C) increases of 52 and 38 mg/dl for the 3 and 6 mg doses, respectively, at 12 weeks, reflecting potent FGFR4-mediated CYP7A1 inhibition.

The most common adverse events reported in this study were lower gastrointestinal symptoms, nausea and injection site erythema, the majority of which were mild and dose-dependent. There was a single serious adverse event (acute pancreatitis) in the 3 mg dose group.

The safety and tolerability of NGM282 has been consistent across more than 275 healthy volunteers and patients treated to date in multiple clinical studies.

NGM Bio presented a poster with data from a non-human primate study showing that NGM282-induced increases in total cholesterol and LDL-C were reversed after two weeks of statin treatment without impacting the efficacy of NGM282.

Additionally, preliminary data from an ongoing, open-label study of patients with biopsy-confirmed NASH treated with NGM282 demonstrated similarly rapid LDL-C decreases following introduction of statin therapy.

The majority of patients with NGM282-related LDL-C elevations achieved LDL-C levels that were at or below their baseline after only two weeks of treatment with rosuvastatin. After six weeks of rosuvastatin treatment, patients (n=15 as of this date) experienced an average reduction of 93 mg/dl from peak LDL-C levels (37 mg/dl average reduction from baseline).

These data provide evidence that treatment with a statin can effectively mitigate the LDL-C increases associated with NGM282’s potent FGFR4-mediated CYP7A1 inhibition.

NGM Bio also presented a poster outlining the previously unreported downstream signaling pathways that mediate FGF19-dependent tumorigenicity in rodents. The data reveal a key role for the IL-6/STAT3 axis in potentiating FGF19-driven hepatocellular carcinoma.

The poster provided in vitro and in vivo evidence demonstrating that this signaling mechanism was engineered out of NGM282, further adding to the robust preclinical dataset confirming NGM282’s non-tumorigenic properties.

Alex DePaoli, M.D., Chief Medical Officer of NGM Bio said: “NGM282 achieved an unprecedented reduction of liver fat as measured by MRI-PDFF in only 12 weeks, which supports its potential to rapidly resolve NASH,” said Alex DePaoli, M.D., Chief Medical Officer of NGM Bio.

“The clinical data we presented at The International Liver Congress confirms our original conviction that FGF19 plays a critical role in regulating liver and metabolic functions in patients who have had gastric bypass surgery, which is currently the only curative treatment for patients with NASH.

“These data suggest that treatment with NGM282 mimics the beneficial effects of increased FGF19 levels observed in NASH patients after gastric bypass surgery without the potential tumorigenic properties of FGF19 identified in animal models.”