In the Journals

NGM282 safely reduces bile acid, fibrosis markers in PSC

NGM282 inhibited bile acid synthesis and decreased fibrosis markers without significantly affecting alkaline phosphatase levels among patients with primary sclerosing cholangitis, according to data published in Journal of Hepatology.

“Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by strictures of the biliary tree for which there is presently a dearth of effective medical treatment,” Gideon M. Hirschfield, MD, PhD, from the Birmingham Biomedical Research Center in the United Kingdom, and colleagues wrote. “The current trial confirms the clinical relevance of the FGF19 pathway in patients with PSC and the concept that it could be harnessed therapeutically to change the course of the disease.”

The phase 2 randomized control trial comprised 21 patients with PSC who received NGM282 1 mg, 21 patients who received NGM282 3 mg, and 20 patients who received placebo. Four patients discontinued before the end of study.

At 12 weeks, the researchers observed no significant difference in ALP between either the NGM282 1 mg group or 3 mg group compared with placebo.

Patients who received NGM282 had significant reductions in 7alpha-hydroxy-4-cholesten-3-one, or the C4 serum marker of hepatic CYP7A1 activity, compared with placebo. Mean C4 changed from baseline by 6.2 ng/mL in the NMG282 1 mg group (P = .008) and by 9.4 ng/mL in the 3 mg group (P < .001).

Treatment with NGM282 also resulted in significantly decreased circulating bile acids and secondary bile acids compared with placebo.

Both alanine aminotransferase (–45.1 U/L; P < .001) and aspartate aminotransferase (–30.9 U/L; P < .001) decreased significantly in the NGM282 3 mg group compared with placebo.

Additionally, Enhanced Liver Fibrosis (ELF) scores decreased significantly in the NGM282 1 mg group (–0.29; P = .028) and 3 mg group (–0.37; P = .009) compared with placebo.

NGM282 was generally well-tolerated with no serious adverse events at grade 4 or higher and no deaths. Injection site reactions were more common in the NGM282 3 mg group, but appeared to be tolerated over time.

“NGM282 demonstrated significant and robust activities on bile acid metabolism and anti-fibrotic effects, without reducing ALP,” Hirschfield and colleagues wrote. “Further trials with NGM282 in patients with PSC should focus on longer term administration and an array of biochemical and imaging endpoints that reflect closer the underlying pro-fibrotic nature of PSC.” – by Talitha Bennett

Disclosure: Hirschfield reports being on advisory committees or review panels for GlaxoSmithKline and Intercept; consulting for Cymbay and Novartis; and grant or research support from BioTie, Falk and Takeda. Please see the full study for the other authors’ relevant financial disclosures.

NGM282 inhibited bile acid synthesis and decreased fibrosis markers without significantly affecting alkaline phosphatase levels among patients with primary sclerosing cholangitis, according to data published in Journal of Hepatology.

“Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by strictures of the biliary tree for which there is presently a dearth of effective medical treatment,” Gideon M. Hirschfield, MD, PhD, from the Birmingham Biomedical Research Center in the United Kingdom, and colleagues wrote. “The current trial confirms the clinical relevance of the FGF19 pathway in patients with PSC and the concept that it could be harnessed therapeutically to change the course of the disease.”

The phase 2 randomized control trial comprised 21 patients with PSC who received NGM282 1 mg, 21 patients who received NGM282 3 mg, and 20 patients who received placebo. Four patients discontinued before the end of study.

At 12 weeks, the researchers observed no significant difference in ALP between either the NGM282 1 mg group or 3 mg group compared with placebo.

Patients who received NGM282 had significant reductions in 7alpha-hydroxy-4-cholesten-3-one, or the C4 serum marker of hepatic CYP7A1 activity, compared with placebo. Mean C4 changed from baseline by 6.2 ng/mL in the NMG282 1 mg group (P = .008) and by 9.4 ng/mL in the 3 mg group (P < .001).

Treatment with NGM282 also resulted in significantly decreased circulating bile acids and secondary bile acids compared with placebo.

Both alanine aminotransferase (–45.1 U/L; P < .001) and aspartate aminotransferase (–30.9 U/L; P < .001) decreased significantly in the NGM282 3 mg group compared with placebo.

Additionally, Enhanced Liver Fibrosis (ELF) scores decreased significantly in the NGM282 1 mg group (–0.29; P = .028) and 3 mg group (–0.37; P = .009) compared with placebo.

NGM282 was generally well-tolerated with no serious adverse events at grade 4 or higher and no deaths. Injection site reactions were more common in the NGM282 3 mg group, but appeared to be tolerated over time.

“NGM282 demonstrated significant and robust activities on bile acid metabolism and anti-fibrotic effects, without reducing ALP,” Hirschfield and colleagues wrote. “Further trials with NGM282 in patients with PSC should focus on longer term administration and an array of biochemical and imaging endpoints that reflect closer the underlying pro-fibrotic nature of PSC.” – by Talitha Bennett

Disclosure: Hirschfield reports being on advisory committees or review panels for GlaxoSmithKline and Intercept; consulting for Cymbay and Novartis; and grant or research support from BioTie, Falk and Takeda. Please see the full study for the other authors’ relevant financial disclosures.