NGM Bio, a research-driven biotechnology company, announced data from a phase 2 study of its lead product candidate, NGM282, demonstrating clinically meaningful improvements in histological measures of disease in nonalcoholic steatohepatitis (NASH) patients at twelve weeks.
NGM282, an analogue of the human hormone FGF19, showed a rapid and robust impact on both fibrosis stage and disease activity as measured by non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in this open-label study of NGM282. Comprehensive data from this phase 2 study presented in a plenary session at The International Liver Congress 2018 in Paris.
“It is unprecedented to see such profound histological improvement in well-established NASH after only twelve weeks of treatment, confirming that NGM282 is potently impacting many clinical dimensions of the disease,” said Stephen A. Harrison, M.D., Medical Director at Pinnacle Clinical Research, Visiting Professor of Hepatology at University of Oxford, UK and principal investigator on the Phase 2 study. “These data reinforce the potential of NGM282 to resolve disease and reverse fibrosis across a broad range of NASH patients, strongly supporting the continued development of NGM282 in NASH.”
The phase 2 trial evaluated the efficacy, safety and tolerability of daily subcutaneous injections of 3 mg NGM282 over 12 weeks of treatment in patients with biopsy-confirmed NASH. Twenty-two patients were enrolled, nineteen completed the study with paired biopsies, and three withdrew early for reasons unrelated to the drug.
A blinded, pooled reading of patient biopsies at baseline and after 12 weeks of therapy demonstrated that eight of nineteen NGM282-treated patients had liver fibrosis improve by at least one stage from baseline, with three patients demonstrating a two-stage improvement in fibrosis (all F3 to F1). After 12 weeks, 84% of patients saw improvement in their NAS, with 58% of patients achieving an improvement in NAS of =2 points with at least one point of improvement in either inflammation or ballooning. These changes in histology were consistent with the degree and rapidity of improvements seen in non-invasive measures of NASH, including MRI-PDFF measures of LFC and serum biomarkers of liver inflammation, lipid metabolism and fibrosis.
NGM282 demonstrated a favorable safety and tolerability profile consistent with prior clinical studies. As seen in previous NGM282 studies in NASH patients, LDL-C increased above baseline across the study group but was reduced below baseline levels within two to four weeks by administration of a statin. The most common adverse events were mild loose/frequent stools, which were transient and resolved on therapy. There were three serious adverse events, none of which was deemed to be related to treatment by the investigator.
“NGM282 treatment once again led to a dramatic improvement in non-invasive measures of NASH that have been associated with the resolution of disease. These new histology data support the translation of those mechanisms into reversals of liver fibrosis in many patients, a clinically meaningful measure of disease outcomes,” noted Alex DePaoli, M.D., chief medical officer of NGM Bio. “We look forward to exploring the anti-steatotic, anti-inflammatory and anti-fibrotic activity of NGM282, which we anticipate will lead to further consolidation of benefit for NASH patients with continued treatment.”
The phase 2 NGM282 programme includes two studies: (1) a 12-week, randomized, double-blind, placebo-controlled multi-center study that assessed the efficacy and safety of NGM282 3 mg and 6 mg once daily vs. placebo in adults with biopsy-confirmed NASH; and (2) a subsequent 12-week, single-blind expansion study that assessed the efficacy and safety of NGM282 0.3 mg, 1 mg and 3 mg once daily in a similar patient population, with the 3 mg cohort including the histology endpoints discussed above. Key eligibility criteria were similar in both studies and included NAS =4 (with at least one point in each component of steatosis, lobular inflammation and hepatocellular ballooning), stage 1-3 fibrosis and =8% LFC via MRI-PDFF. Complete results from the initial phase 2 study with NGM282 were presented at last year’s International Liver Congress and recently published in The Lancet. The phase 2 expansion study with NGM282 is ongoing.
The primary endpoint in both studies was the change from baseline to week 12 in absolute LFC as measured by MRI-PDFF. Secondary outcomes included absolute and relative change in LFC at week 6, relative change in LFC at week 12, normalization of LFC (defined as patients with a value of =5%) at week 12, changes from baseline and normalization in ALT levels, changes in lipids and lipoprotein particles and safety and tolerability of NGM282. Exploratory outcomes included assessment of serum fibrosis biomarkers, including released N-terminal pro-peptide of type III collagen (PRO-C3), total enhanced liver fibrosis (ELF) score and multi-parametric imaging with LiverMultiScan.
NGM282 is a non-tumorigenic engineered variant of the human hormone FGF19 that reduces liver fat content, improves liver function and reverses fibrosis by targeting multiple pathogenic pathways of liver disease. NGM Bio has generated robust preclinical and clinical evidence supporting the ability of NGM282 to resolve disease and reverse fibrosis in NASH patients. This wholly-owned therapeutic has been evaluated in four phase 2 studies in primary biliary cholangitis, primary sclerosing cholangitis, type 2 diabetes and NASH. NGM282’s safety database includes clinical data from more than 400 individuals.
Approximately 20% of NAFLD patients develop NASH, a chronic disease characterized by a buildup of fat in the liver, inflammation and cell damage that can cause fibrosis and scarring of the liver. Frequently correlated with a poor diet, obesity and type 2 diabetes, NASH can lead to cirrhosis, liver cancer, organ failure and, absent a liver transplant, death. Experts estimate that approximately 3% to 12% of adults in the United States, and as many as 400 million people worldwide, have NASH. There are currently no approved therapies for the disease.
NGM Bio is a research-driven biotechnology company committed to discovering and developing novel biologics for the treatment of life-threatening diseases.