NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis

Abstract

NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double‐blind, placebo‐controlled study in patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). 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 nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; −1.9; 95% confidence interval, −2.6 to −1.2; P < 0.001 in the 1 mg group; −2.2, −3.1 to −1.3; P < 0.001 in the 3 mg group) and fibrosis (−0.5; −0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, 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 1 mg and 3 mg groups, respectively), corrected T1 (cT1; −8% and −9%), alanine aminotransferase (ALT) (−67% and −60%), aspartate aminotransferase (−57% and −52%), and fibrogenesis biomarkers neoepitope‐specific N‐terminal propeptide of type III collagen (Pro‐C3; −22% and −33%) and enhanced liver fibrosis score (ELF; −3% and −6%) at week 12. Greater reductions in Pro‐C3, ELF, and cT1, but not in liver fat content, 7alpha‐hydroxy‐4‐cholesten‐3‐one, or ALT, were observed in histological responders than in nonresponders. Conclusion: 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 noninvasive imaging and serum markers.

Collagen biology and non‐invasive biomarkers of liver fibrosis

“…Vastatin is a non‐collagenous C‐terminal fragment of type VIII collagen and is known as an endogenous anti‐angiogenic polypeptide in normal liver tissue, but is deficient in most cases of human hepatocellular carcinoma (HCC) . Restin is also a non‐collagenous C‐terminal fragment of type XV collagen, which is predominantly in the liver portal ECM . Endostatin derives from the non‐collagenous C‐terminus of type XVIII collagen, which is a protein of the liver sinusoidal basement membrane.…”

“…32,33 Restin is also a non-collagenous C-terminal fragment of type XV collagen, which is predominantly in the liver portal ECM. [34][35][36][37] Endostatin derives from the non-collagenous C-terminus of type XVIII collagen, which is a protein of the liver sinusoidal basement membrane. This fragment is known to interact with yet incompletely defined cell membrane receptors, and can induce endothelial cell apoptosis.…”

Bile Acid Biology, Pathophysiology, and Therapeutics

“…Recently, obeticholic acid, a synthetic bile acid and potent FXR agonist, has been used for PBC treatment and is in phase III clinical trials for NASH fibrosis. NGM282, a nontumorigenic FGF19 analogue, has been used in clinical trials to treat PSC and PBC, and improves NASH fibrosis . However, bile acid–based drugs may have undesirable side effects such as pruritus, diarrhea, and hypercholesterolemia.…”

“…NGM282, a nontumorigenic FGF19 analogue, has been used in clinical trials to treat PSC and PBC, and improves NASH fibrosis. 10 However, bile acid-based drugs may have undesirable side effects such as pruritus, diarrhea, and hypercholesterolemia. It is anticipated that bile acid-based drug therapies will be approved for NASH treatment in the near future.…”

The FGF metabolic axis

“…In this sense, the metabolic FGF acts as a key to ignite the FGF-FGFR-KLB/KLB triad complex, which functions similarly as an engine with an axis to drive effects in a tissue-specific manner, thereby leading to beneficial effects that offset the initial adverse metabolic changes and prevent metaflammation and tissue damage not only in the FGF-producing tissues but also systemically [2,7] (Table 2). Consequently, both the analogs of endocrine FGFs and the agonists of FGF-KL/ KLB have been actively pursued clinically for the prevention and treatment of a wide range of metabolic diseases and comorbidities [2,[70][71][72][73][74][75].…”