In a Placebo Controlled 36 Week Phase 2 Trial, Treatment with - PowerPoint PPT Presentation

In a Placebo Controlled 36 Week Phase 2 Trial, Treatment with MGL-3196 Compared to Placebo Results in Significant Reductions in Hepatic Fat (MRI-PDFF), Liver Enzymes, Fibrosis Biomarkers, Atherogenic Lipids, and Improvement in NASH on Serial Liver Biopsy Dr. Stephen A. Harrison, Dr. Cynthia D. Guy, Dr. Mustafa Bashir, Dr. Juan Pablo Frias, Dr. Naim Alkhouri, Dr. Seth Baum, Dr. Rebecca Taub, Dr. Cynthia A. Moylan, Dr. Meena B. Bansal, Dr. Brent A. Neuschwander-Tetri, Dr. Sam Moussa 1

Mechanism of Action: The Importance of Liver THR-β in NASH In humans, thyroid hormone receptor-β (THR-β) agonism: Thyroid Nuclear THR- α , THR- β Gland ê Lowers LDL-cholesterol ê Lowers triglycerides T 4 T 4 T 3 ê Lowers liver fat, potentially reducing Liver lipotoxicity, NASH T4, prohormone T 4 è T 3 T3, active hormone No thyrotoxicosis (THR-α effect) Thyroid Hormone Pathway MGL-3196 n THR-β selective molecule with proven safety and efficacy in more than 300 subjects and patients treated — No exposure outside the liver or activity at the systemic THR-α receptor n Pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly) — Reduction of liver fat through breakdown of fatty acids, normalization of liver function Sinha and Yen Cell Biosci (2016) 6:46 DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 2 1341-1357, DOI: 10.1080/15548627.2015.1061849

Study Design: Randomized, Double-Blind, PBO Controlled Trial MRI-PDFF MRI-PDFF Liver Biopsy PK Liver Biopsy MRI-PDFF MRI-PDFF Screening ExD1 D1 W2 W4 W12 W36 W12 W36 Extension Study 36 Week Main Study Comparator/Arms n 2:1 MGL-3196 to placebo n 125 patients enrolled in USA, 18 sites n MGL-3196 or placebo, oral, once daily; dose 80 mg (+/-20 mg dose adjustment possible at Week 4 ) Inclusion/Exclusion n NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3 n ≥10% liver fat on MRI-PDFF n Includes diabetics, statin therapy, representative NASH population 3

Study Endpoints n Primary endpoint — Relative reduction of liver fat (MRI-PDFF) at 12 weeks (at 36 weeks, secondary) n Key secondary endpoints at 12, 36 weeks — Reduction (2-point on NAS) or resolution of NASH without worsening of fibrosis with at least a 2-pt reduction in NAS in MGL-3196-treated compared to placebo patients — One point reduction in fibrosis on liver biopsy — Numbers achieving ≥ 30% liver fat reduction at 12, 36 weeks; absolute liver fat reduction — Liver enzymes, fibrosis biomarkers and lipids at 12, 36 weeks n Ongoing exploratory endpoint extension study in a subset of patients who completed the main 36 week study 4

Baseline Characteristics Placebo (41) MGL-3196 (84) Mean age, years (SD) 47.3 (11.7) 51.8 (10.4) Male, n (%) 24 (58.5) 38 (45.2) White 37 (90.2) 79 (94.0) Hispanic/Latino 22 (53.7) 37 (44.0) Diabetic, n (%) 13 (31.7) 35 (41.7) Mean BMI (SD) 33.6 (5.8) 35.8 (6.2) Mean ALT 60.1 (32.8) 50.0 (29.2) PRO-C3 16.2 (8.3) 17.8 (10.3) ELF 9.2 (1.0) 9.2 (0.88) Mean LDL-C 116.9 (30.0) 111.3 (30.4) Mean Triglycerides (TG) 161.1 (75.2) 178.5 (82.4) Mean MRI-PDFF* 19.8 (6.7) 20.7 (7.0) Mean NAS 4.8 (1.1) 4.9 (1.0) Fibrosis stage 1, n (%) 19 (46.3) 47 (55.9) 2-3, n (%) 20 (48.8) 36 (42.8) * Patients with both baseline and week 12 assessments 5

Week 36: Sustained Reduction in Liver Fat on MRI-PDFF Relative Fat Reduction (%) Absolute Fat Reduction (%) Relative Change MRI-PDFF (% ) 12 36 Week 12 36 12 36 Week 12 36 12 36 12 36 0 -1.6 -8 -1 -10 -2.3 -10 Placebo -3 -7.6 -36 MGL-3196 -37 -8.5 -20 -8.8 -42 -9.4 -5 ( all ) -49 MGL-3196 -30 -7 ( high exp ) -40 -9 -50 -11 p<0.0001 p<0.0001 p<0.0001 p<0.0001 ≥30% Fat Reduction (%) Main, 36 Week Study 80 F2/F3 n Sustained statistically 60 significant reduction in hepatic fat Week 40 77 75 12 to Week 36 68 68 60 61 20 n Placebo response 30 22 18 11 generally related to 0 weight loss ≥5% Week 12 36 12 36 12 36 12 36 12 36 p<0.0001 p<0.0001 ND p=0.009 P value, placebo compared to MGL-3196; MGL-3196, n=78; placebo, n=38; 6 prespecified high exposure (High Exp) n=44; F2/F3, placebo, n=19; MGL-3196, n=33

Extension Study: Reduction in Liver Fat on MRI-PDFF Relative Fat ≥30% Fat Absolute Fat Reduction (%) Reduction (%) Reduction (%) Extension Study 2 0 100 0.6 - 0 Former 36 Week placebo 1.9 -10 80 patients treated with 80 or -2 100 mg MGL-3196 for 36 -20 -4 60 -50 Weeks in an open label -10 -30 -6 extension study ( bar graphs 87 show all extension patients; 40 -8 -40 study still ongoing ) -10 20 -50 -12 Noninvasive endpoints, 7 -60 0 -14 only Main Extension 7

Week 36: Sustained Robust Lipid Lowering Lipids (% Change from Baseline) 0 -10 -21.9 -22.3 -36 -36.8 -36.5 -20 -30 -40 -50 LDL-C ApoB TGs Lp(a) ApoCIII (BL>100) (BL>=10) p<0.0001 p<0.0001 p<0.0001 p<0.001 p<0.0001 Significant sustained lowering effect in multiple atherogenic lipids Placebo corrected; p value, placebo compared to MGL-3196; MGL-3196, n=79; placebo, n=39 8

Week 36: Liver Enzymes n Week 36, 40% reduction in ALT in 80 patients with elevated baseline 70 60 (p=0.01), and all MGL-3196 relative 50 to placebo patients (p=0.002) U/L 40 ALT 30 n At Week 36, 60% of MGL-3196 20 10 patients with ALT <30 vs 37% of 0 placebo (p=0.03) 0 12 36 38 Week 60 50 Week 36, statistically significant n 40 U/L 30 AST reduction in MGL-3196 vs AST 20 placebo (% change and absolute 10 change) p=0.002 0 0 12 36 38 Week 20 % Change 10 n Week 36, statistically significant 0 GGT GGT reduction MGL-3196 vs -10 placebo (% change and absolute -20 change) p=0.002 0 12 36 38 Week Placebo MGL-3196 Statistically significant reductions in ALT, AST and GGT versus placebo; no change in bilirubin or alkaline phosphatase Baseline elevated ALT =45 male, 30 female. GGT shown as % change from baseline, females and 9 males have different normal GGT ranges

Week 36: NASH Liver Biopsy Endpoints 70 2-Point NAS Reduction 60 <5% Weight loss 50 with at least a 1-pt % of biopsies 2-pt reduction in NAS in reduction in 40 65 ballooning or placebo patients was 30 61 51 inflammation 47 correlated with body 20 32 (% of liver biopsies) weight loss 10 18 0 p=0.09 p=0.006 p=0.02 p=0.02 Placebo MGL-3196 (all) 45 no fibrosis worsening MGL-3196 (high exp) 40 MGL-3196, MRI responder 35 NASH Resolution % of biopsies 30 ballooning=0, 25 inflammation =0, 1 In MGL-3196 treated 20 39 with at least 2-point 37 patients with NASH 15 reduction in NAS 27 resolution, 50% had 25 10 (% of liver biopsies) fibrosis resolution (F=0) 5 6 0 p=0.02 p=0.001 p=0.03 p=0.003 MRI Responder; ≥ 30% fat reduction on Week 12 MRI-PDFF High Exp,, n=44; 2-pt NAS reduction; MGL-3196, n=73, placebo n=34; NASH Resolution, prespecified endpoint: at least 2-pt reduction in NAS; ballooning=0, inflammation=0, 1, <9.5% weight loss; 10

Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy MRI-PDFF Week 12, % Relative Change: NASH Resolution (%) Correlation with Change in MGL-3196-treated Ballooning Plus Inflammation Scores 40 MGL-3196 35 % Change in MRI-PDFF (Week 12) 60 30 40 25 20 20 37 15 0 10 -20 5 4 -40 0 -60 p=0.001 -80 MRI-PDFF MRI-PDFF Responder Non- -100 -3 -2 -1 0 1 2 Responder Change in Ballooning Plus Inflammation MGL-3196-treated n Patients who were not MRI-PDFF Responders (≥30% fat reduction) had a low rate of NASH resolution ( left panel ) n In both MGL-3196 (correlation coefficient 0.42) ( right panel ) and placebo (correlation coefficient 0.58) % relative change in MRI-PDFF was correlated with reduction in ballooning plus inflammation scores on liver biopsy (steatosis score removed) 11

Week 36: Reduction of Fibrosis, Biomarkers ELF BL≥9 CK-18 (M30) U/L Pro-C3 (ng/ml) 0.0 0 0.00 -59 -7.7 -8.6 -2.7 -171 -100 -230 -10.0 -0.40 -0.20 -21.4 -0.48 -363 -0.62 -0.63 -32.1 -200 -20.0 -0.40 -300 -30.0 -0.60 -400 -40.0 -0.80 -500 Baseline >= 17.5 ng/ml -50.0 -1.00 -600 12 36 12 36 36 week 12 36 36 36 12 36 36 36 p=0.08 p=0.007 p=0.02 p=0.003 p=0.01 p=0.009 p=0.02 p=0.007 p=0.05 NS p=0.003 p=0.0004 p=0.02 -18% -38% -41% -88% -119% % change NA -25% -33% -38% MGL-3196 (high exp) F2/F3 MGL-3196 (all) ELF, CK-18 and Pro-C3 scores, biomarkers correlated with liver fibrosis stage, were statistically significantly reduced in MGL-3196 treated, especially in patients with advanced fibrosis at baseline BL, baseline; compared with placebo; all, placebo n=38; MGL-3196 n=78; *Liver Int. 2015 Feb;35(2):429-37; Journal of ELF≥9 placebo n=21; MGL-3196 n=40; Pro-C3 BL≥17.5, placebo n=12; Hepatology 2013 vol. 59 j 236–242; 12 MGL-3196 n=29