Abstract

Background: MAESTRO-NAFLD-1 is a 52-week >1200 patient Phase 3 randomized double blind placebo controlled NASH clinical trial to study safety and biomarker effects of resmetirom, a selective thyroid hormone receptor beta agonist, in NASH patients identified using non-invasive biomarkers and imaging (NCT04197479). A goal of this “real life” NASH study is to identify non-invasive markers that correlate with individual patient response to resmetirom treatment. The study includes a separate open label active resmetirom treatment arm in 180 well-compensated Child-Pugh A NASH cirrhotic patients in 2 cohorts, cohort 1 (n=105) has completed 52 weeks; cohort 2 (n=75) is ongoing.

Methods: Eligibility required at least 3 metabolic risk factors (metabolic syndrome), and NASH cirrhosis diagnosed on liver biopsy or according to accepted criteria. The primary and key secondary endpoints of the cirrhotic arm include safety, relative percent reduction of MRI-PDFF (week 16), LDL cholesterol (LDL-C) (week 24), Apolipoprotein B and triglycerides, and imaging and biomarkers of fibrosis. Patients received 80 or 100 mg daily dose of resmetirom for 52 weeks.

Results:

Cohort 1, 105 well-compensated NASH cirrhotic patients, most confirmed by NASH cirrhosis on liver biopsy, completed 52 weeks of treatment (completion rate 91%). Demographics include mean age 62.7 (9.0 (SD)), female 64%, BMI 35.4 (7.4), diabetes 70%, hypertension 77%, dyslipidemia >70%, mean ASCVD score 16.1%, hypothyroid 32.4%, 51% on statins, platelets 158K(61K), MELD 8.2(1.7), MRE kPa, 5.7 (2.1); fibroscan kPa, 24.6 (14.9), CAP, 318 (59) and mean MRI-PDFF, 8.1% (5). Stage of cirrhosis was inversely correlated with baseline PDFF; 3 groups (Gp) were defined: PDFF <=5%, Gp 1; >5 to <8%, Gp 2; and, >=8%, Gp 3. In patients with baseline PDFF >5% (5%=UL normal), week 52 PDFF decreased by 38% (p<0.0001), and fibroscan CAP decreased by 38 units (p<0.0001). Fibroscan VCTE was reduced -5.2 kPa overall, and -10.2 kPa in Gp1 (p=0.03); 40% overall had a VCTE decrease of at least 25% kPa. MRE decreased by 0.73 kPa in Gp1 and -0.35 kPa n Gp 2-3; 23% overall had an MRE reduction of ≥19% (Table). ALT, AST and GGT were reduced from baseline. Liver volume (LV), which was elevated in NASH cirrhosis patients at baseline, was reduced -15.9% (8%) at week 16 and -20% (9%) at week 52 (p<0.0001), independent of baseline PDFF. LV reduction was correlated with reduction in MRE, MRI-PDFF, TIMP, P3NP, and the SHBG responses to resmetirom. Resmetirom reduced LDL-C (20%), triglycerides (21%), ApoB (20%), Lp(a) (30%), independent of cirrhosis stage. BP was reduced by 4-5 mm. Resmetirom was safe and well-tolerated, and no decompensation events occurred during 52 weeks of treatment. Cohort 1 and 2 data will be updated for the presentation.

Conclusion: Resmetirom treatment of patients with NASH cirrhosis for up to 52 weeks was safe and effective at lowering markers of CV risk and NASH fibrosis.