Recent randomized controlled clinical trials with new drugs in the MASH arena.
| Drug | Method | Findings | Conclusion | Reference |
|---|---|---|---|---|
| Tirzepatide | A Phase 2 dose-finding, multicenter, double-blind RCT with 157 participants who had biopsy-proven MASH and stage F2 or F3 fibrosis. They were randomly assigned to receive either ow sc tirzepatide (5, 10, or 15 mg) or a placebo for 52 weeks. | The proportion of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5 mg tirzepatide group (∆ vs. placebo, 34% points; 95% CI, 17 to 50), 56% in the 10 mg tirzepatide group (∆ 46% points; 95% CI, 29 to 62), and 62% in the 15 mg tirzepatide group (∆ 53% points; 95% CI, 37 to 69) (p < 0.001 for all three comparisons).The proportion of participants who exhibited improvement of ≥ 1 fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5 mg tirzepatide group (∆ vs. placebo, 25% points; 95% CI, 5 to 46), 51% in the 10 mg tirzepatide group (∆, 22% points; 95% CI, 1 to 42), and 51% in the 15 mg tirzepatide group (∆, 21% points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were mostly mild or moderate GI events. | Tirzepatide administration for 52 weeks to participants with MASH and moderate or severe fibrosis was more effective than placebo in inducing MASH resolution without worsening fibrosis. | Loomba et al., 2024 [16] |
| Denifanstat | A Phase 2b multi-center, double-blind RCT including 168 participants who were randomized to receive either 50 mg denifanstat od (n = 112) or placebo (n = 56). | 38% of participants in the denifanstat group had a ≥ 2-point improvement in NAS without worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (p = 0.0035). 26% of participants in the denifanstat group showed MASH resolution with a ≥ 2-point improved NAS without fibrosis worsening vs. 11% of participants in the placebo group (p = 0.0173). The most common treatment-emergent adverse events were COVID-19 (17% of those receiving denifanstat vs. 11% in the placebo group), ocular dryness, and hair loss. | Denifanstat induced a significant improvement in NAS, MASH resolution, and fibrosis. | Loomba et al., 2024 [17] |
| Semaglutide | Ongoing Phase 3 multicenter, double-blind RCT involving 1,197 subjects with biopsy-proven MASH and stage 2–3 fibrosis. They were assigned to receive either ow sc 2.4 mg semaglutide or a placebo for 240 weeks. | MASH resolution without worsening of fibrosis was observed in 62.9% of those receiving semaglutide vs. 34.3% of those in the placebo group (p < 0.001). Reduced liver fibrosis without MASH worsening was found in 36.8% of those assigned to semaglutide vs. 22.4% of those receiving placebo (p < 0.001). | Ow 2.4 mg semaglutide improved liver histology findings at week 72 among individuals with MASH and moderate or advanced liver fibrosis. | Sanyal et al., 2025 [15] |
| Dapagliflozin | 54 adults with biopsy-proven MASH, with or without T2D, were randomly assigned to receive 10 mg of dapagliflozin orally or a matching placebo od for 48 weeks. | MASH improvement without worsening of fibrosis was reported in 53% of those assigned to dapagliflozin vs. 30% receiving placebo (p = 0.006). The mean difference in NAS was also significant (p < 0.001). MASH resolution without worsening of fibrosis occurred in 23% of participants receiving dapagliflozin vs. 8% in the placebo group (p = 0.01). Fibrosis improvement without worsening of MASH was reported in 45% of participants treated with dapagliflozin vs. 20% of those receiving placebo (p = 0.001). The proportion of those who had adverse events leading to discontinued treatment was 1% with dapagliflozin vs. 3% with placebo. | Compared to placebo, dapagliflozin administration for 48 weeks led to a higher percentage of individuals with MASH improvement without worsening fibrosis, as well as MASH resolution without worsening fibrosis and fibrosis improvement without worsening of MASH. | Lin et al., 2025 [18] |
| Efruxifermin | Phase 2b multicenter, double-blind, RCT including 126 participants who were assigned to receive sc efruxifermin (28 or 50 mg) once per week or a placebo. | Of 88 participants with week-96 biopsies, ≥ 1-stage fibrosis improvement without MASH worsening was observed in 24% of 34 participants randomized to the placebo group, 46% of those receiving 28 mg (p = 0.070), and 75% of those in the 50 mg group (p < 0.0001). Mild-to-moderate GI adverse events were more common with efruxifermin than with placebo. | After 96 weeks, treatment with efruxifermin resulted in greater improvements in fibrosis than placebo. | Noureddin et al., 2025 [19] |
CI: confidence interval; ∆: difference; GI: gastrointestinal; MASH: metabolic dysfunction-associated steatohepatitis; NAS: nonalcoholic fatty liver disease activity score; od: once daily; ow: once-weekly; RCT: randomized, placebo-controlled trial; sc: subcutaneous; T2D: type 2 diabetes.