Abstract Background MGL-3196 is a liver-directed, orally active, highly selective thyroid hormone receptor-β agonist being developed for the treatment of non-alcoholic steatohepatitis (NASH). In a 36-week Phase 2 NASH study, MGL-3196 treatment compared with placebo (PbO) resulted in significant reductions in hepatic fat, liver enzymes, NASH on liver biopsy, and atherogenic lipids including low-density lipoprotein cholesterol (LDL-C) and triglycerides. Most NASH patients die of cardiovascular disease (CVD), and, in NASH patients, CV risk correlates better with LDL particle than LDL-C levels. Purpose To determine the effects of MGL-3196 on lipoprotein particle concentrations in patients with NASH. Methods MGL-3196–05 (NCT02912260) is a 36-week multicenter, randomized, double-blind, placebo controlled study of NASH patients assessed with serial liver imaging and liver biopsies. Patients received 2:1 MGL-3196 80 mg (blinded ± 20 mg dose adjustment possible at Week 4 based on Week 2 pharmacokinetic data) or placebo once daily, for 36 weeks. Lipoprotein particle concentrations were assessed in fasting blood samples at baseline and Week (Wk) 36. Results As shown (Table), MGL-3196 significantly reduced the level of lipoprotein particles, with greater reductions in patients with baseline (BL) LDL-C ≥100 mg/dL and the patient group with higher MGL-3196 exposures (High exp). Lipoprotein particles Particles (by NMR) (nmol/L) Time Point Placebo, n=34 MGL-3196 (all), n=73 MGL-3196 BL LDL-C ≥100 mg/dL, n=44; High Exp, n=25 (PbO BL ≥100 mg/dL, n=23 mean data not shown) Total LDL, mean (SD) BL 1234 (276) 1275 (328) 1443 (290) 1407 (267) Wk 36 1251 (323) 1045 (264) 1155 (248) 1090 (216) % change from BL vs PbO (SE), p value −19.6 (4.2), <0.0001 −19.8 (5.6), 0.0008 −22.8 (6.3), 0.0006 Small LDL, mean (SD) BL 746 (295) 835 (294) 887 (329) 916 (314) Wk 36 749 (343) 641 (207) 641 (234) 618 (149) % change from BL vs PbO (SE), p value −27.7 (8.9), 0.002 −34.3 (13.1), 0.01 −39.4 (14.7), 0.009 Total VLDL and Chylomicron, mean (SD) BL 56.8 (23.9) 55.9 (22.9) 61.4 (24.5) 66.0 (24.8) Wk 36 58.8 (24.4) 46.0 (21.1) 47.6 (22.9) 47.4 (23.1) % change from BL vs PbO (SE), p value −22.7 (6.9), 0.001 −27.2 (7.5), 0.0006 −34.7 (8.3), <0.0001 Large VLDL and Chylomicron, mean (SD) BL 6.3 (4.3) 8.7 (5.8) 8.9 (6.1) 10.2 (6.8) Wk 36 7.2 (4.5) 6.6 (3.9) 6.7 (4.1) 7.2 (4.7) % change from BL vs PBO (SE), p value −52.5 (11.8), <0.0001 −65.6 (15.5), <0.0001 −71.3 (17.4), 0.0001 BL, baseline; High exp, high MGL-3196 exposure based on % increase from baseline in sex hormone binding globulin, BL LDL-C ≥100, a prespecified group. Conclusions MGL-3196 significantly reduced atherogenic lipoprotein particles, particularly in NASH patients with greater BL hypercholesterolemia. These findings are consistent with a potentially beneficial effect of MGL-3196 on the CV risk profile in NASH patients.