NGM Bio Announces NGM282 Dramatically Reduced Liver Fat and Other Biomarkers Associated With Nonalcoholic Steatohepatitis (NASH) in Phase 2 Trial

NGM282 demonstrated a rapid and statistically significant reduction in liver fat

79% of NGM282-treated patients met the primary endpoint and 34% of treated patients reached normal liver fat content at 12 weeks

Significant improvements also seen in serum biomarkers of liver function, lipid metabolism and fibrosis

Comprehensive research presented at The International Liver Congress™ 2017 demonstrate NGM282's potential to fully resolve NASH

AMSTERDAM, April 22, 2017 /PRNewswire/ -- NGM Bio announced that its lead product candidate, NGM282, met the primary endpoint and key secondary endpoints in a Phase 2 trial of patients with nonalcoholic steatohepatitis (NASH). 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. 

"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," said 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. "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.

Placebo

NGM282 3 mg

NGM282 6 mg

Mean Baseline MRI-PDFF

16.8%

18.1%

19.5%

Change in MRI-PDFF (Absolute)

-0.9%

-9.7%*

-11.9%*

Patients w/ MRI-PDFF >20% at Baseline

-0.3%

-12.9%*

-18.9%*

Change in MRI-PDFF (Relative)

-1%

-47%*

-61%*

# (%) of patients w/ >30% relative change

2 (7%)

23 (85%)*

24 (92%)*

Primary Endpoint Response Rate

7%

74%*

85%*

ALT (Absolute, U/L)

-2

-35*

-33*

Patients w/ ALT >60 U/L at Baseline (U/L)

-10

-63*

-55*

ALT (Relative)

-1%

-43%*

-45%*

*p<0.001

The International Liver Congress™ 2017 Posters Further Characterize NGM282 - Lipid Mitigation and Lack of Tumorigenicity  
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.

"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."

Members of the European Association for the Study of the Liver can access a video of Dr. Harrison's oral presentation as well as the NGM Bio abstracts and ePosters viaThe International Liver Congress website. A slide show of Dr. Harrison's presentation and multiple NGM282 publications, posters and abstracts are also available at http://www.ngmbio.com/pipeline/ngm282/#phase2data.

About NASH  
Approximately 20% of nonalcoholic fatty liver disease (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.

About NGM282  
NGM282 is a non-tumorigenic, engineered variant of the human hormone FGF19 that dramatically reduces liver fat content and improves liver function by targeting multiple pathogenic pathways of NASH. NGM Bio has generated robust preclinical and early clinical evidence supporting NGM282's ability to significantly improve steatosis, inflammation and fibrosis. This wholly-owned, single-agent therapeutic has been evaluated in three Phase 2 studies in primary biliary cholangitis, type 2 diabetes and NASH. Data are expected from a Phase 2 trial of NGM282 in primary sclerosing cholangitis in the second half of this year. NGM's safety database includes clinical data from more than 275 individuals treated with NGM282.

About NGM Biopharmaceuticals, Inc.  
NGM Bio is a research-driven biotechnology company committed to discovering and developing novel biologics for the treatment of life-threatening diseases. NGM Bio's portfolio consists of multiple programs in clinical testing and more than a dozen additional programs in various stages of preclinical development. The company's most advanced compound, NGM282, is a wholly-owned asset that recently completed a Phase 2 trial in NASH. NGM Bio has established a broad strategic collaboration with Merck. NGM Bio is backed by The Column Group, Merck, Prospect Ventures, Topspin Partners, Rho Ventures, Tichenor Ventures and other leading investors around the world. For more information, please visit www.ngmbio.com.

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SOURCE NGM Bio

http://www.ngmbio.com

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