3 years ago

Effect of NGM282, a FGF19 analogue, in Primary Sclerosing Cholangitis: a Multicentre, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

Gideon M. Hirschfield, Olivier Chazouillères, Joost P. Drenth, Douglas Thorburn, Stephen A. Harrison, Charles S. Landis, Marlyn J. Mayo, Andrew J. Muir, James F. Trotter, Diana J. Leeming, Morten A. Karsdal, Mark J. Jaros, Lei Ling, Kathline H. Kim, Stephen J. Rossi, Ransi M. Somaratne, Alex M. Depaoli, Ulrich Beuers

Publication date: Available online 9 November 2018

Source: Journal of Hepatology

Author(s): Gideon M. Hirschfield, Olivier Chazouillères, Joost P. Drenth, Douglas Thorburn, Stephen A. Harrison, Charles S. Landis, Marlyn J. Mayo, Andrew J. Muir, James F. Trotter, Diana J. Leeming, Morten A. Karsdal, Mark J. Jaros, Lei Ling, Kathline H. Kim, Stephen J. Rossi, Ransi M. Somaratne, Alex M. DePaoli, Ulrich Beuers

Abstract
Background and 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 2 trial, patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5xULN 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

62 patients were randomized to receive NGM282 1 mg (n=21), NGM282 3 mg (n=21) or placebo (n=20). 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 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.

Graphical abstract

Graphical abstract for this article

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