お知らせ • Jun 15
Terns Pharmaceuticals, Inc. Reports Positive Top-Line Results from Phase 2a Lift Study of FXR Agonist TERN-101 in Patients with NASH
Terns Pharmaceuticals, Inc. reported positive top-line results from the Phase 2a LIFT clinical trial of TERN-101, a liver-distributed farnesoid X receptor (FXR) agonist for the treatment of patients with NASH. The LIFT study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase 2a clinical trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of orally-administered TERN-101 tablets at doses of 5 mg, 10 mg and 15 mg in 100 adult patients with presumed non-cirrhotic non-alcoholic steatohepatitis (NASH). The primary objective of the clinical trial was to evaluate the safety and tolerability of TERN-101 over 12 weeks of treatment plus a four-week post-treatment follow-up period. Secondary endpoints included percentage change from baseline in ALT levels and plasma pharmacokinetics of TERN-101. Exploratory efficacy endpoints included changes in liver fibro-inflammation measured by MRI corrected T1 (cT1), liver fat content by MRI proton density fat fraction (MRI-PDFF), pharmacodynamic parameters, and serum NASH biomarkers. In the LIFT trial, TERN-101 was generally well tolerated with a similar incidence of adverse events (AEs) across treatment groups. All treatment-related adverse events were mild/moderate with no apparent dose relationship. There were no treatment-related serious adverse events, and no patient discontinued TERN-101 due to any adverse event including pruritus. The most frequent treatment-emergent adverse events included pruritus, headache, constipation, diarrhea, decreased appetite and dizziness. Pruritus was reported in four patients (16%) in the 5 mg TERN-101 arm, three patients (11.5%) in the 10 mg TERN-101 arm, four patients (17.4%) in the 15 mg TERN-101 arm and no patients in the placebo group. Three pruritus cases were Grade 2 (widespread and intermittent); the rest were Grade 1 (mild or localized). Notably, there were no Grade 3 (widespread and constant) pruritus events and no discontinuations due to pruritus. Most pruritus cases resolved during continued TERN-101 treatment. No change in LDL cholesterol was observed in patients in the 5 mg and 10 mg TERN-101 arms as compared to placebo (Week 12 mean change: 4.8% for placebo, 6.7% for 5 mg TERN-101, 3.2% for 10 mg TERN-101, not significant). Statistically significant LDL changes were observed only in the 15 mg arm (Week 12 mean change: 15.9%, p<0.05). Significant decreases in HDL cholesterol were observed in all TERN-101 dose groups at Week 4 and Week 8 but returned toward baseline in the 5 mg and 10 mg dose groups without differences from placebo at Week 12. Decreases in HDL were significantly different from placebo for the 15 mg group at all observed timepoints through Week 12. Multiple efficacy biomarkers of NASH, including corrected T1 (cT1), MRI-PDFF and ALT, were evaluated in the LIFT Study: Mean changes in cT1 at Week 12 were -0.8 msec for placebo, -38.0 msec (p=0.033) for the 5 mg arm, -57.7 msec (p=0.002) for the 10 mg arm, and -74.0 msec (p<0.001) for the 15 mg arm. Improvements of at least 80 msec in cT1 were observed in a significant proportion of patients in the 5 mg and 10 mg groups at Week 12 (as compared to placebo). Significant decreases in cT1 were also observed at Week 6 for all dose groups. cT1 is a magnetic resonance-based imaging test measuring free-water content in liver tissue, which has shown a strong correlation with inflammation and fibrosis histology and clinical outcomes in patients with liver disease. Mean relative changes in MRI-PDFF were -8.4% (placebo), -15.1% (5 mg), -19.7% (10 mg), and -12.9% (15 mg) at Week 12. Mean relative changes in MRI-PDFF were significant at Week 6 for the 10 mg and 15 mg dose groups compared to placebo, although these changes were not statistically significant at Week 12. MRI-PDFF is an imaging marker that measures liver fat content. Mean percentage changes in ALT at Week 12 were -5.3% (placebo), -2.6% (5 mg), -18% (10 mg), and -13.2% (15 mg). No discernable trends were observed in initial analyses of the enhanced liver fibrosis (ELF) score, CK-18 and Pro-C3. Terns plans to submit data from the LIFT Study to an upcoming scientific conference. Based on these positive results, Terns continues to plan a combination trial of TERN-101 together with TERN-501, the Company’s thyroid hormone receptor beta agonist (THR-ß) also in development for the treatment of NASH. The multiple ascending dose portion of the TERN-501 Phase 1 trial started in June 2021, and top-line data from the trial is expected in the second half of 2021. The combination trial of TERN-101 and TERN-501 is expected to start in the first half of 2022.