NGM282

NGM282 Phase 2 Data | Publications | Scientific Presentations

Our lead product, NGM282, is a first-in-class, 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 nonalcoholic steatohepatitis (NASH). NGM has generated robust preclinical and early clinical evidence supporting NGM282’s ability to significantly improve liver steatosis, inflammation and fibrosis as a single agent. This wholly-owned therapeutic has the potential to resolve NASH rapidly, completely and across a broad spectrum of patients. 

The human hormone FGF19 is a primary regulator of bile acid synthesis in the liver and a key signaling molecule in metabolic processes involved in body weight maintenance, including glucose homeostasis and triglyceride regulation. However, overexpression of FGF19 has been shown to promote liver tumor development in rodents. Our research on this hormone has revealed the mechanism by which endogenous FGF19 induces hepatocellular carcinoma in those animal models. The biologic insights gained from years of in-house research led us to design NGM282 to eliminate the elements of FGF19 signaling associated with the tumorigenic properties while retaining the biologic activity of the human hormone that direct the regulation of metabolism and bile acid synthesis. 

NGM282 represents a unique opportunity to leverage the dual targets of FGF19 without the potential tumorigenicity risk, and NGM282 demonstrates this pharmacological profile in numerous in vitro and in vivo experiments. NGM is now pursuing a multi-pronged development program for NGM282 to efficiently evaluate its drug profile and maximize its clinical and commercial potential:

Clinical Development Programs

NGM282 is a once-daily subcutaneous injectable with the following completed and ongoing clinical development programs:

  • Phase 1 trial to assess safety and pharmacokinetics in normal volunteers (Completed).
  • Phase 2a proof-of-concept trial for 28 days in patients with primary biliary cholangitis (PBC) (Completed).
  • Phase 2b trial for 52-weeks in patients with PBC to assess extended safety and durability of response (Completed).
  • Phase 2a proof-of-concept trial for 28 days in patients with type 2 diabetes (Completed).
  • Phase 2 dose finding trial for 12 weeks in patients with histologically confirmed nonalcoholic steatohepatitis (NASH) (Ongoing).
  • Phase 2 proof-of-concept trial in patients with primary sclerosing cholangitis trial (Ongoing).

Over 400 patients have been enrolled into the clinical development program, with more than 275 patients treated with clinically relevant doses of NGM282.

These studies have demonstrated proof of biological activity consistent with FGF19-like activity related to FGFR1c and FGFR4 signaling as demonstrated by the following activities:

  • Regulation of bile acid synthesis, as evidenced by significant reductions in C4, which is relevant to both NASH and cholestatic liver diseases.
  • Improvements in hepatic injury, with statistically significant reductions in liver transaminases and markers of cholestasis.
  • Significant reductions in hepatic fat and serum triglycerides.  
  • A consistent and generally favorable safety and tolerability profile across all study populations.
  • Regulation of bile acid synthesis, as evidenced by significant reductions in CYP7a1 activity, a key enzyme of bile acid production in the liver.
  • Improvement in liver health, with statistically significant reductions in ALP, ALT and AST.
  • Improvement in metabolic profile, including increased insulin sensitivity, body weight loss and triglyceride lowering.
  • Generally acceptable tolerability profile, with no statistically significant worsening of pruritus.

About NASH

Fatty liver, or steatosis, has been shown to be associated with metabolic abnormalities, including type 2 diabetes, obesity, hypertension and dyslipidemia. Some patients with non-alcoholic fatty liver disease (NAFLD) will progress to NASH and eventually liver fibrosis and cirrhosis, requiring liver transplantation. The progression of NASH is driven by multiple pathways involving lipid metabolism and steatosis, bile acid synthesis and dysregulation of insulin sensitization. NGM282 has demonstrated biologic activity on several of these pathways resulting in the potential resolution of NASH and slowing or improvement in fibrogenesis.  

About Bile Acid Related Diseases

We are developing NGM282 as a treatment for certain bile acid-related diseases (BARDs), including primary sclerosing cholangitis (PSC). PSC is a chronic cholestatic liver disease, characterized by progressive inflammation, fibrosis and obstruction of the bile ducts for which there are no approved therapeutics. The results of our Phase 2a trial in PBC study demonstrated a significant reduction in ALP, a biochemical marker of liver health, along with no significant worsening of pruritus with 28 days of NGM282 treatment. The potent regulation of bile acid synthesis with NGM282 administration observed in PBC patients may also be important in slowing the progression of PSC. We are currently conducting a Phase 2 study in PSC patients to evaluate the efficacy and safety profile of NGM282 after 12 weeks of treatment.

The worldwide rights to NGM282 and the FGF19 program are wholly owned by NGM.

NGM282 Phase 2 Data

Expert Commentary

Stephen Harrison, M.D., Medical Director of Pinnacle Clinical Research, San Antonio, TX, explains what he considers to be the most promising aspects of NGM282.

Alex DePaoli M.D., Vice President and Chief Medical Officer of NGM Bio, explains how the company came to focus on the human hormone FGF19 as a modulator of multiple pathways key to the development and progression of NASH.

Additional videos available here.

NGM282 Phase 2 Data Presentation

Stephen Harrison, M.D., Medical Director of Pinnacle Clinical Research, San Antonio, TX, presents NGM282 Phase 2 data, which was originally reported at The International Liver Congress™ 2017.

Download presentation here.

Publications

Engineered FGF19 Eliminates Bile Acid Toxicity and Lipotoxicity Leading to Resolution of Steatohepatitis and Fibrosis in Mice 
Hepatology Communications, 2017

Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis
Nature Communications, 2017

Mice Species-specific Control of Hepatocarcinogenesis and Metabolism by FGF19/FGF15
Journal of Hepatology, 2017

Engineered Fibroblast Growth Factor 19 Reduces Liver Injury and Resolves Sclerosing Cholangitis in Mdr2-Deficient Mice
Hepatology, 2016

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19
Cancer Research, 2014

A nontumorigenic Variant of FGF19 Treats Cholestatic Liver Diseases
Science Translational Medicine, 2014

Scientific Presentations

NGM282 Significantly Reduces Hepatic Steatosis Independent of Baseline Patient Characteristics and Highly Correlates with Markers of FGFR4 Target Engagement:  Results from a Phase 2 Trial in Biopsy-Confirmed NASH Patients (R. Loomba, et al, AASLD October 23, 2017)

NGM282 Induces Low Density Lipoprotein Cholesterol (LDLc) Changes, Consistent with Potent FGFR4 Signaling, which are Rapidly Mitigated with Statin Therapy in Patients with Biopsy-Confirmed Nonalcoholic Steatohepatitis (NASH) (M. E. Rinella, et al, AASLD October 23, 2017)

NGM282 Ameliorates Hepatic Lipotoxicity as Measured by Lipidomics and Gene Expression in a Diet-Induced Mouse Model of Nonalcoholic Steatohepatitis (NASH) (L. Ling, et al, AASLD October 23, 2017)

NGM282, a novel variant of FGF19, significantly reduces hepatic steatosis and key biomarkers of NASH: results of a Phase 2, multicenter, randomized, double-blinded, placebo controlled trial in biopsy-confirmed NASH patients (S.A. Harrison, et al, EASL April 22, 2017)

Activation of IL-6/STAT3 Signaling Mediates FGF19-Driven Hepatocarcinogenesis (L. Ling, et al EASL April 21, 2017)

Serum Cholesterol Changes Associated with NGM282 Treatment in Obese Insulin Resistant Cynomolgus Monkeys and NASH Patients are Reversed with Lipid Lowering Agents (Jian Luo, et al, EASL April 21, 2017)

NGM282, A Novel Variant of FGF19, Demonstrates Biologic Activity in Primary Biliary Cirrhosis Patients with an Incomplete Response to Ursodeoxycholic Acid: Results of a Phase 2 Multicenter, Randomized, Double Blinded, Placebo Controlled Trial (M.J. Mayo, et al, AASLD November 16, 2015)

Anti-inflammatory and Antifibrotic Activity of NGM282, A Novel Variant of FGF19, in an Mdr2-Deficient Mouse Model of Primary Sclerosing Cholangitis (L. Ling, et al, AASLD November 16, 2015)

Impact of NGM282 on the Incidence and Severity of Pruritus in Primary Biliary Cirrhosis Patients and Correlations with Liver Chemistries and Serum Bile Acids (M.J. Mayo, et al, AASLD November 14, 2015; Poster)

FGF15 and FGF19 Induce Disparate FGFR4-Mediated Hepatocarcinogenicity In Vitro and In Two Murine Models: Implications for Drug-Associated Carcinogenicity Risk Assessments (L. Ling, et al, AASLD November 17, 2015; Poster)