1 Radcliffe Department of Medicine, University of Oxford, United Kingdom.
2 Pinnacle Clinical Research, San Antonio, TX, United States.
3 NGM Biopharmaceuticals, South San Francisco, CA, United States.
4 San Antonio Military Medical Center, San Antonio, TX, United States.
5 Clinical Research and Education, Texas Digestive Disease Consultants, Dallas, TX, United States.
6 Radiology and Medicine (Gastroenterology), Duke University, Durham, NC, United States.
7 Pathology, Duke University, Durham, NC, United States.
8 Perspectum Diagnostics, Oxford, United Kingdom.
9 Summit Analytical, Denver, CO, United States.
NGM282, an engineered FGF19 analogue, rapidly and significantly reduced liver fat content in a multi-center, randomized, double-blind, placebo-controlled study in patients with biopsy-confirmed nonalcoholic steatohepatitis. However, it is unclear whether these changes would be accompanied by histological improvement. In this open-label study, we assessed the histological efficacy of NGM282 in patients with biopsy-confirmed NASH. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1mg, n=24; 3mg, n=19) once daily for 12 weeks were evaluated blinded to time point, subject and clinical informaion. At week 12, NGM282 significantly reduced NAS (-1.9, 95% confidence interval [CI], -2.6 to -1.2, P<0.001 in the 1mg group; -2.2, -3.1 to -1.3, P<0.001 in the 3mg group) and fibrosis (-0.5, -0.9 to 0, P=0.035 in the 3mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1mg or 3mg, respectively, improved NAS by two or more points without fibrosis worsening. 25% and 42% of the patients receiving NGM282 1mg or 3mg, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (-58% and -67% in the 1mg and 3mg groups, respectively), cT1 (-8% and -9%), ALT (-67% and -60%), AST (-57% and -52%) and fibrogenesis biomarkers Pro-C3 (-22% and -33%) and ELF (-3% and -6%) at week 12. Greater reductions in Pro-C3, ELF and cT1, but not in liver fat content, C4 or ALT, were observed in histological responders than in non-responders. CONCLUSIONS: In this open-label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in non-invasive imaging and serum markers.