Gideon M Hirschfield1, Olivier Chazouillères2, Joost P Drenth3, Douglas Thorburn4, Stephen A Harrison5, Charles S Landis6, Marlyn J Mayo7, Andrew J Muir8, James F Trotter9, Diana J Leeming10, Morten A Karsdal10, Mark J Jaros11, Lei Ling12, Kathline H Kim12, Stephen J Rossi12, Ransi M Somaratne12, Alex M DePaoli12, Ulrich Beuers13. 1. National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada. Electronic address: gideon.hirschfield@uhn.ca. 2. Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department, Saint-Antoine University Hospital, Assistance Publique-Hopitaux de Paris, and INSERM UMR S938, Sorbonne University, Paris, France. 3. Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, the Netherlands. 4. Sheila Sherlock Liver Centre and UCL Institute of Liver and Digestive Health, Royal Free Hospital, London, United Kingdom. 5. University of Oxford, Oxford, United Kingdom. 6. Division of Gastroenterology and Hepatology, University of Washington, Seattle, United States. 7. University Texas Southwestern Medical Center, Dallas, United States. 8. Division of Gastroenterology, Department of Medicine, Duke University, Durham, United States. 9. Texas Digestive Disease Consultants, Clinical Research, Southlake, United States. 10. Nordic Bioscience, Herlev, Denmark. 11. Summit Analytical, Denver, United States. 12. NGM Biopharmaceuticals, South San Francisco, United States. 13. Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Abstract
BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.
RCT Entities:
BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS: In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS: At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS: In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY: We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.
Authors: Nicholas Willumsen; Christina Jensen; George Green; Neel I Nissen; Jaclyn Neely; David M Nelson; Rasmus S Pedersen; Peder Frederiksen; Inna M Chen; Mogens K Boisen; Astrid Z Johansen; Daniel H Madsen; Inge Marie Svane; Allan Lipton; Kim Leitzel; Suhail M Ali; Janine T Erler; Daan P Hurkmans; Ron H J Mathijssen; Joachim Aerts; Mohammed Eslam; Jacob George; Claus Christiansen; Mina J Bissel; Morten A Karsdal Journal: Cell Mol Life Sci Date: 2022-03-25 Impact factor: 9.207