Our lead product candidate, NGM282, is an engineered version of the human FGF19 hormone, a primary regulator of bile acid synthesis in the liver. It is also 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 transgenic mice. NGM282, accordingly, has been engineered to eliminate the elements of FGF19’s signaling that are associated with those tumorigenic properties while retaining both the FGFR1c- and FGFR4-mediated signaling activities of the native hormone that direct the regulation of metabolism and bile acid synthesis. Thus, we believe that NGM282 presents a unique opportunity to leverage the dual mechanism of FGF19 without the potential tumorigenicity risk, and are pursuing a multi-pronged development program to efficiently evaluate its drug profile and maximize the clinical and commercial potential of NGM282.
NGM282 is a once-daily injectable for which we have completed Phase 1 clinical testing and two Phase 2a trials in type 2 diabetes and primary biliary cirrhosis (PBC) patients. A 52-week Phase 2b trial in PBC is ongoing for long-term safety assessment of NGM282. These studies have demonstrated proof of biological activity consistent with FGF19-like activity related to FGFR1c and FGFR4 signaling, and a favorable safety and tolerability profile with NGM282 treatment:
- Regulation of bile acid synthesis, as evidenced by significant reductions in CYP7a1, a marker 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.
- No safety signals identified.
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. Phase 2a results from our PBC study demonstrated a significant reduction in ALP from baseline, a biochemical marker of liver health, along with no significant worsening of pruritus with 28 days of NGM282 treatment. We believe that the potent regulation of bile acid synthesis with NGM282 administration, as observed in PBC patients, may help slow the progression of PSC. We will initiate a Phase 2 study in PSC patients to evaluate the efficacy and safety profile of NGM282 after 12 weeks of treatment.
Fatty liver, or steatosis, has been shown to be associated with metabolic abnormalities, including type 2 diabetes, obesity, hypertension and dyslipidemia. Patients with non-alcoholic fatty liver disease (NAFLD) progress to non-alcoholic steatohepatitis (NASH) and eventually liver fibrosis and cirrhosis, requiring liver transplantation. Bile acid synthesis and serum bile acid levels are correlated with NAFLD and progression of disease to NASH, and we believe that NGM282 has the potential to disrupt the cascade by reducing triglycerides, improving insulin sensitivity, blocking bile acid synthesis and reducing body weight. We are initiating an exploratory Phase 2 clinical trial of NGM282 in patients with biopsy-confirmed NASH.
The worldwide rights to NGM282 and the FGF19 program are wholly owned by NGM.
Mice Species-specific Control of Hepatocarcinogenesis and Metabolism by FGF19/FGF15
Journal of Hepatology, 2017
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
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)