Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH

Abstract

Resmetirom (MGL-3196), a selective thyroid hormone receptor-β agonist, was evaluated in a 36-week paired liver biopsy study (NCT02912260) in adults with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI-proton density fat fraction (MRI-PDFF), and secondary endpoints included histopathology. Subsequently, a 36-week active treatment open-label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI-PDFF reduction at OLE week 36 was -11.1% (1.5%) mean reduction (standard error [SE]; P < 0.0001) and -52.3% (4.4%) mean relative reduction, P < 0.0001. Low-density lipoprotein (LDL) cholesterol (-26.1% [4.5%], P < 0.0001), apolipoprotein B (-23.8% [3.0%], P < 0.0001), and triglycerides (-19.6% [5.4%], P = 0.0012; -46.1 [14.5] mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (-2.1 [0.8] mean kilopascals [SE], P = 0.015) and N-terminal type III collagen pro-peptide (PRO-C3) (-9.8 [2.3] ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO-C3/C3M (matrix metalloproteinase-degraded C3), a marker of net fibrosis formation, was reduced in resmetirom-treated patients (-0.76 [-1.27, -0.24], P = 0.0044 and -0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36-week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO-NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.

Fig. 1

Disposition (A) of and treatment schematic (B) of patients in the MGL‐3196‐05 main and OLE studies. Abbreviations: BL, baseline; DC, discontinued.

Fig. 2

MRI‐PDFF results in the OLE study relative median (−54.6 [−35.6, −65.8]) (A) and absolute mean fat reduction (B) (Table 2) as determined by MRI‐PDFF at week 36 in the primary population (Pbo/Res and Res/Res patients with a dose increase during the OLE study) and by final dose. Time course of PDFF in the Pbo/Res (blue line) and primary Res/Res (red line) population compared with change in PRO‐C3.

Fig. 3

Time course in OLE study patients of liver enzymes ALT, AST, and GGT (A) and SHBG (B). The baseline (week 0) is the OLE baseline for both Res/Res and Pbo/Res patients.

Fig. 4

Time course of PRO‐C3/C3M in the main (A) and OLE (B) studies. Both the main and OLE times are shown in (B). Res/Res patients were on resmetirom for both the main and OLE 36‐week studies, and Pbo/Res were on placebo during the main study and started on resmetirom on OLE day 1 for 36 weeks.

Fig. 5

Time course of CT1 and PDFF and dose in individual Pbo/Res and Res/Res patients. (A) CT1 images at indicated assessment times of a Pbo/Res patient. (B,C) The Res/Res and Pbo/Res patient, respectively, time course of CT1, PDFF, and dose administered over time from the start of the main study to the end of the OLE.

Fig. 6

Effects of resmetirom on RT3 and FT3/RT3 in patients with NASH. (A) Baseline FT3/RT3 in normal (non‐NASH) and NASH according to liver biopsy fibrosis stage. Shown as a box and whisker plot with box defined by quartile 1, 3, and median, with quartile line shown; “x” indicates the mean, SD, and error bars. (B) Effect of resmetirom on thyroid pathway hormones at week 36 in the main study or OLE. Compared with placebo in the main study, within‐group comparison over time in the OLE. Abbreviation: F2/F3, patients with baseline NASH fibrosis stage of F2 or F3.