Table 2: Thyroid hormone receptor-β agonists in development for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.
| Completed studies with THR-β agonists | ||||
|---|---|---|---|---|
| Study | Study design | LDL | Liver fat | LFT |
| MGL-3196 (phase IIb)47 | 125 patients with biopsy-proven NASH; 36 weeks; 60 or 80 mg daily | LDL-C -11% (placebo +6%) | Liver fat -50% (80 mg) (placebo -14%) | AST, ALT↓ |
| VK-2809 (MB07811) (phase IIa)48 | 42 patients with NAFLD and increased LDL-C; 12 weeks; 5 mg/10 mg every other day or 10 mg daily | LDL-C -18% (placebo +2%) | Liver fat -60% (10 mg) (placebo -9%) | AST, ALT↓ |
| TERN-501 (phase I)49 | 18 patients with elevated LDL-C (not NAFLD); 14 days increasing dose 1 mg to 10 mg | LDL-C -20% (placebo -4%) | N/A | N/A |
| ASC41 (phase I)50 | 36 patients with LDL-C >110mg/dL (not NAFLD); 14 day once daily oral dosing (1 mg, 2 mg, 5 mg) | 5 mg dose placebo-adjusted LDL-C -20% | N/A | N/A |
| ASC41 (phase I)51 | 20 patients overweight/obese with LDL-C >110 mg/dL (not NAFLD); 10 mg daily for 14 and 28 days | n=13; 14 day placebo-adjusted LDL-C -39%; 28 day placebo-adjusted LDL-C -37% | N/A | N/A |
| On-going phase II studies with non-resmetirom THR-β agonists | ||||
| Study (ClinicalTrials.gov identifier) | Phase of development | Study population | Primary endpoints | Key secondary endpoints |
| VK-2809; VOYAGE (NCT04173065) | IIb | NASH with F2/F3 fibrosis | Relative change in liver fat content (assessed by MRI-PDFF) from baseline to Week 12 compared with placebo | 52 weeks: Proportion of subjects with resolution of steatohepatitis on overall histopathological reading and no worsening of liver fibrosis on NASH CRN fibrosis score |
| TERN-501; DUET (NCT05415722) | IIa | Presumed NASH based on biopsy or imaging. Monotherapy: TERN 501; Dual therapy: TERN 501+ 101 (FXR agonist) |
Relative change from baseline to Week 12 in MRI-PDFF for TERN-501 monotherapy (arms 1, 2 and 3) compared with placebo | 1. Change from baseline to 12 weeks in cT1 relaxation time for TERN-501 monotherapy (arms 1, 2 and 3) compared with placebo; 2. Relative change from baseline to 12 weeks in MRI-PDFF for TERN-501+TERN-101 combination (arms 4 and 5) compared with placebo; 3. Change from baseline to 12 weeks in cT1 relaxation time for TERN-501+TERN-101 combination (arms 4 and 5) compared with placebo; 4. Patient incidence of treatment emergent adverse events for all treatment groups (16 weeks) |
| ASC-1 (NCT05118360) | II | NASH on liver biopsy; NASH F1 (up to 15%), F2, or F3, NAS ≥4 | 52 weeks: Resolution of NASH with at least 2-point reduction in NAS (improvement in inflammation or ballooning) with no worsening of fibrosis; OR reduction in fibrosis stage by 1 point with no worsening of NAS | LDL-C lowering at Weeks 12, 24 and 52 |
Only studies with MGL-3196 (resmetirom) and VK-2809 included patients with NAFLD. All compounds show promising results in their lipid-lowering effects.
↓ = decrease; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein-cholesterol ; LFT = liver function tests; MRI-PDFF = magnetic resonance imaging proton density fat fraction; N/A = not available; NAFLD = non-alcoholic fatty liver disease; NAS = non-alcoholic fatty liver disease score; NASH = non-alcoholic steatohepatitis.