EVIDENCE OF DURABLE RESPONSE TO BEPIROVIRSEN IN B-CLEAR ON-NA RESPONDERS: B-SURE SECOND REPORT

초록

Background: TERN-501, a highly selective THRβ agonist with enhanced metabolic stability suitable for combination therapy, showed robust target engagement and favorable safety/PK profile in a Ph1 study. In this first MASH trial assessing efficacy and safety of a THR-β and FXR agonist combination, we evaluated TERN-501 when used alone or in combination with TERN-101, a liver directed nonsteroidal FXR agonist. Methods: Patients(pts) with phenotypic or prior histologic MASH were randomized to 1 of 7 treatments: once daily TERN-501(1,3,6 mg), TERN-101(10 mg), TERN-501(3 or 6 mg) with TERN-101(10 mg), or placebo. The primary endpoint was relative change in MRI-PDFF at Wk12 for TERN-501 monotherapy vs placebo. Liver fibroinflammation by cT1, sex hormone binding globulin(SHBG), lipids, MASH/fibrosis biomarkers, safety/tolerability were assessed. Results: Among 162 pts randomized, 55% female; 42% type2 diabetes; mean age 53yrs; BMI 38kg/m2; LDL 94 mg/dL. Mean baseline liver fat content(LFC) 18%, cT1 936ms indicated high-risk MASH population. Significant reductions in LFC were seen as early as Wk6; mean relative reduction of 27% (3 mg[p=0.0036]) and 45% (6 mg[p<0.0001]) TERN-501 vs 4% in placebo were seen at Wk12, meeting the primary endpoint(Table). Significantly higher %pts achieved ≥30%MRI-PDFF reduction in TERN-501 arms and ≥50% reduction at TERN-501 6 mg. Significant, rapid cT1 decrease was seen at TERN-501 6 mg with significantly higher %pts achieving ≥80 ms reduction, recovering from at-risk MASH category. When TERN-501 was combined with TERN-101, efficacy was generally maintained or improved. TERN-501 significantly increased SHBG(marker of target engagement and predictor of histologic response in the THRβ class) and improved lipids with significant apolipoproteinB reductions in TERN-501 monotherapy arms and numeric LDL decreases in combination with TERN-101. TERN-501 was well tolerated. Treatment-related adverse event(AE) rates were similar to placebo with low overall rates(7.4%) of gastrointestinal(GI)AEs reported similarly across arms. No treatment-related cardiovascular(CV)AEs or serious AEs were reported. Conclusion: 12wks TERN-501 treatment significantly improved LFC and fibroinflammation in MASH pts and was well tolerated with no GI or CV AE concerns. This first placebo-controlled MASH combination trial of a THRβ and an FXR agonist met all key endpoints without additional safety findings. The compelling overall efficacy/tolerability/combinability profile of TERN-501 warrants further investigation for MASH.