TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial
Mazen Noureddin, Naim Alkhouri, Eric Lawitz, Kris V. Kowdley, Rohit S. Loomba, Lois K. Lee, Christopher T. Jones, Amnon Schlegel, Tonya Marmon, Kacey Anderson, Yizhao Li, Erin Quirk, Stephen A. Harrison
Abstract
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 .