Beyond efficacy: Insights from the norursodeoxycholic acid phase III trial in metabolic dysfunction-associated steatotic liver disease

Table 1 Comparative overview of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis pharmacotherapies

Drug class/agent (example)	Sample size (total randomized)	Trial duration	Baseline fibrosis stage1	Primary regulatory endpoint(s) achieved	Placebo-subtracted effect size2	Key safety trade-offs
TRβ agonist resmetirom	966 (MAESTRO-NASH, phase III)	52 weeks	F1B-F3	√ MASH resolution with no worsening of fibrosis; √ fibrosis improvement with no worsening of MASH (≥ 1 stage)	MASH resolution with no worsening of fibrosis: 16.4%-20.7%; fibrosis improvement with no worsening of MASH: 10.2%-11.8%; liver fat: -26.7% to 37.9% (MRI-PDFF)	GI intolerance (diarrhea and nausea); generally well tolerated
GLP-1 RA semaglutide	1197 (ESSENCE, phase III)	72 weeks	F2-F3	√ MASH resolution with no worsening of liver fibrosis; √ fibrosis improvement with no worsening of MASH	MASH resolution with no worsening of liver fibrosis: 28.7%; fibrosis improvement with no worsening of MASH: 14.4%; Weight loss: -8.5%	GI intolerance (nausea/vomiting); contraindicated in medullary thyroid cancer risk; low hypoglycemia risk
FXR agonist obeticholic acid	1968 (REGENERATE, phase III)	18 months	F1-F3	× MASH resolution with no worsening of liver fibrosis; √ fibrosis improvement with no worsening of MASH	MASH resolution with no worsening of fibrosis: 3%-4% (NS); fibrosis improvement with no worsening of MASH: 6%-11%	Pruritus (28%-51%, often grade 1- grade 2); LDL-C ↑ (1.4-2.7 mg/dL); HDL ↓
Pan-PPAR agonist lanifibranor	247 (NATIVE, phase IIb)	24 weeks	F1-F3	√ A decrease of SAF-A score and no worsening of fibrosis	A decrease of SAF-A score and no worsening of fibrosis: 15%-22%; resolution of MASH without worsening of fibrosis: 17%-27%; fibrosis improvement with no worsening of MASH: 5%-17%	Weight gain (2.4-2.7 kg); mild edema; GI intolerance (diarrhea and nausea)

¹Baseline fibrosis stage: Based on central histology (nonalcoholic steato hepatitis clinical research network system) unless otherwise noted.

²Effect sizes: Approximate placebo-adjusted differences.

NS: Not significant; MAESTRO-NASH: Metabolic associated steatotic liver disease and metabolic associated steatohepatitis research network; MASH: Metabolic dysfunction-associated steatohepatitis; GI: Gastrointestinal; MRI-PDFF: Magnetic resonance imaging - proton density fat fraction; LDL-C: Low-density lipoprotein cholesterol; HDL: High-density lipoprotein; REGENERATE: Randomized global phase 3 study to evaluate the impact on NASH with fibrosis of obeticholic acid treatment; NATIVE: Name of a phase 2b/3 clinical trial evaluating the efficacy and safety of lanifibranor in adult patients with nonalcoholic steatohepatitis and liver fibrosis; SAF-A: Steatosis, activity, fibrosis - activity score; TRβ: Thyroid hormone receptor β; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor.