TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial.

Thyroid hormone receptor-β (THRβ) agonism is a validated mechanism for treating metabolic dysfunction-associated steatohepatitis (MASH). DUET was a 12-week, randomized, double-blind, placebo-controlled, multicenter phase 2a study investigating the efficacy, safety and pharmacodynamics and pharmacokinetics of once-daily TERN-501 (THRβ agonist) as monotherapy or combined with TERN-101 (farnesoid X receptor agonist), in patients with presumed MASH. Overall, 162 patients were randomized to: TERN-501 monotherapy (1 mg (n = 23), 3 mg (n = 23) or 6 mg (n = 22)), TERN-101 10-mg monotherapy (n = 24), TERN-501 (3 mg (n = 23) or 6 mg (n = 23)) plus TERN-101 10-mg combination therapy or placebo (n = 24). The primary endpoint was relative change from baseline at week 12 in liver fat content with TERN-501 monotherapy versus placebo, using magnetic resonance imaging proton density fat fraction (MRI-PDFF). Least squares mean (s.e.) changes from baseline at week 12 in MRI-PDFF with TERN-501 were: -15.4% (5.2%) with 1 mg, -27.5% (5.7%) with 3 mg (P = 0.0036) and -44.8% (5.9%) with 6 mg (P < 0.0001), versus -4.0% (5.4%) with placebo. The incidence of adverse events was similar with TERN-501 monotherapy or placebo. In conclusion, TERN-501 treatment resulted in dose-dependent, significant reductions from baseline in MRI-PDFF compared to placebo in patients with MASH. ClinicalTrials.gov registration: NCT05415722 .