MGL-3196, a selective thyroid hormone receptor …

1 1 MGL-3196, a selective thyroid hormone receptor -beta agonist, significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy studyStephen Harrison1, Sam Moussa2, Mustafa Bashir3, NaimAlkhouri4, Juan Frias5, Seth Baum6, Brent Tetri7, MeenaBansal8, Rebecca Taub9; 1 Oxford University ; 2 University of Arizona for Medical Sciences ; 3 Duke University Medical Center ; 4 Texa s L i v e r I n s t i t u t e , S a n A n t o n i o , T X ; 5 University of California San Diego, Endocrinology, San Diego, United States ; 6 Florida Atlantic University ; 7St Louis University School of Medicine ; 8 Icahn School of Medicine at Mount Sinai ; 9 Madrigal PharmaceuticalsMechanism of Action: The Importance of Liver THR- in NASH2 thyroid Gland Liver T4 T3 T4 T3 Nuc thyroid hormone receptor or TSH thyroid hormone Pathway T4 T4, prohormone T3, ac/ve hormone TSH, thyroid s/mula/ng hormone Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially reducing lipotoxicity, NASHNo thyrotoxicosis (THR- effect)In humans THR- agonism:Sinhaand Yen Cell Biosci(2016) 6:46 DOI.

2 Autophagy, 11:8, 1341-1357, DOI: has pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly)nTHR- agonists reduce liver fat through breakdown of fatty acids, and stimulate mitochondrial biogenesis in the NASH liver, thereby reducing lipotoxicityand improving liver functionnIn human NASH, the liver has relatively low THR- activity, exacerbating mitochondrial dysfunction and lipotoxicitynTHR- may have direct hepatic anti-fibrotic effects in that THR agonismhas been shown to dampen inflammation in vivo and to inhibit TGF- signaling in cell culture and in vivoMGL-3196.

3 A First-in-Class Liver-Directed THR- AgonistFirst bona fide THR- selective molecule with key advantagesnDiscovery of MGL-3196 utilized a novel in vitro functional assay Additional selectivity conferred by highly specific uptake into liver, avoiding any systemic thyroid receptor effectsnin vivo preclinical and clinical data confirm MGL-3196 s high liver uptake and safety Avoids activity atthe systemic THR- receptor (no increased heart rate, osteoporosis) Long-term animal studies completed: no cartilage/bone findings in chronic toxicology Tested in more than 160subjects in Phase 1 studies and 150patients in Phase 2 studies MGL-3196 well-tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increasesnLipid lowering Robust, pleiotrophicanti-atherogeniclipid lowering properties In In Phase 1 healthy volunteer and Phase 2 heterozygous familial cholesterolemia(HeFH) studies lowered LDL-cholesterol (LDL-C) up to 30%,apolipoprotein B (ApoB) 28%, lipoprotein(a) Lp(a) up to 40% and triglycerides (TGs) up to 40%J Med Chem.

4 2014;57(10):3912-3923 3 Study Design: Randomized, Double-Blind, PBO Controlled Trial4D1W2W4W8W12W24W36 ExtensionScreeningMRI-PDFFL iver BiopsyMRI-PDFFL iver BiopsyMRI-PDFFMRI-PDFFW12PK assessmentComparator/Armsn2:1 MGL-3196 to placebon125 patients enrolled in USA, 18 sitesnMGL-3196 or placebo, once daily; starting dose 80 mg per day, +-20 mg dose adjustment possible at Week 4 Inclusion/ExclusionnNASH on liver biopsy: NAS 4 with fibrosis stage 1-3n 10% liver fat on MRI-PDFFnIncludes diabetics, statin therapy, representative NASH populationStudy Endpoints5nPrimary endpoint Relative reduction of liver fat (MRI-PDFF) at 12 weeksnSecondary, exploratory biomarker and imaging endpoints Numbers achieving 30% liver fat reduction at 12 weeks; absolute liver fat reduction NASH, fibrosis biomarkers and lipids at 12, 36 weeks.

5 Multi-parametric imaging substudy Repeat MRI-PDFF at 36 weeksnSecondary, exploratory liver biopsy endpoints at 36 weeks Reduction (2-point on NAS) or resolution of NASH without worsening of fibrosis in MGL-3196-treated compared to placebo One point reduction in fibrosis Reduction in components of NASHnOngoing exploratory endpoint extension study in a subset of patients who completed the main 36 week studyBaseline CharacteristicsPlacebo (41)MGL-3196 (84)Mean age, years (SD) ( ) ( )Male, n (%)24 ( )38 ( )White37 ( )79 ( )Hispanic/Latino22 ( )37 ( )Diabetic, n (%)13 ( )35 ( )Mean BMI (SD) ( ) ( )Mean ( ) ( )Mean ( ) ( )Mean ( ) ( )Mean ( ) ( )Mean MRI-PDFF* ( ) ( )Mean ( ) ( )Fibrosis stage n, % 0-121 ( )48 ( )n, % 2-320 ( )36 ( )6* Patients with both baseline and week 12 assessments < < < MGL-3196 Low MGL-3196 Relative Change in MRI-PDFF (%) MGL-3196 Low MGL-3196 30% Fat Reduction (%) < < < MGL-3196 Absolute Change MRI-PDFFP rimary Endpoint Achieved7p< < *p< *compared with placebo **within group p-valuep< < *p< endpoint was met.

6 Relative change in MRI-PDFF (% change from baseline (median)) and absolute fat reduction were both highly significantnPrespecifiedhigh exposure MGL-3196 patients achieved a 75% response for 30% liver fat reductionnNo effect of MGL-3196 on body weight; 5 out of the 7 placebo patients who achieved 30% fat reduction lost 5% body weightp< *p< < **Fat Reduction Relative to NAS/Fibrosis Stage8nMGL-3196 reduces liver fat effectively in both early and advanced NASH 1 Fibrosis 2-3 NAS 4 NAS > 4 30% Fat Reduction (%)-45-40-35-30-25-20-15-10-50p= < < < < 1 Fibrosis 2-3 NAS 4 NAS > 4 Relative Change in MRI-PDFF (%)**within group p-value**p= in Multiple AtherogenicLipids 9Lp(a), % change from baseline, other lipids absolute reductions (ng/ml); LDL-C>100 mg/dL, BL; Lp(a) >10 nmolBL; TGs Week 4, MGL-3196 patients on 80 mg dose; SE shown.

7 ND, not determinednExtension study: Open label study of eligible week 36 completers, all patients on MGL-3196 Dose adjustment based on biomarkers Significant lipid lowering, correlating with sex hormone binding globulin (SHBG) increase ApoBlowering equal to LDL-C, reflects lowering of LDL and VLDL particles; ApoBcorrelates with CV risk more than LDL-C level-30-25-20-15-10-505 ApoBTGsLDL-CNASH ExtensionStudy0102030405060708090100 SHBG% Change from BaselineBiomarker Monitoring in Patients:Extension Study nSignificant (p< ) reductions relative to placebo in multiple atherogeniclipids including LDL-cholesterol, Lp(a), Apo B and TGsnAverage reductions in LDL-C, ApoBand triglyceride reductions not maximal, many patients had drug exposures consistent with half-maximal lipid lowering effect-50-40-30-20-100102030(n=39)(n=79) (n=44)PlaceboMGL-3196 High MGL-3196 Lipids LDL-CLp(a)

8 Non-HDL-CApoBTGsChange from baseline ng/dLND NDMultiparametricMRI Substudy10nMultiparametricMRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation*nMeasures inflammation and liver fat across the whole livernMGL-3196 NASH substudy: evaluation of 17 patients with paired baseline and week 12 multiparametricscansnMGL-3196 treated patients showed statistically significant improvements in MRI-PDFF and CT1 Improvement 44%; deterioration 0%BL CT1 926 msWeek 12 CT1 840 msMGL-3196 treated patient (nlCT1 826 ms)Change in *Liver International. 2017;37:1065 < MGL-3196 ALT MGL-3196 AST Reduction at Week 12 of Liver Enzymes and Reverse T3, Markers of Inflammation11nDecrease in liver enzymes is correlated with improvement in NASH on serial liver biopsynSignificant decrease in ALT, AST (within group MGL-3196); significant decrease in ALT (patients with ALT*elevations at baseline) and AST (p= , , respectively) compared with placebo in high MGL-3196 patientsnSignificant decrease in reverse T3 (p< ), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH (doi: ) Clinical Gastroenterology and Hepatology 2018.

9 16:123 131*Baseline ALT, >=45 males; >=30 femalesT4, T3 Reverse T3 (inactivated thyroid hormone )NASH Inflammation-6-5-4-3-2-10p= < ace boMGL-3196U/LReverse T3 **within group p-value**-10-8-6-4-2024p= BL Pro-C3 < BL ELFELF Reduction of Fibrosis Biomarkers by MGL-319612nPro-C3 and ELF scores have been correlated with the liver fibrosis score on liver biopsy in NASH patients*nMGL-3196 significantly decreases ELF and Pro-C3 (up to 40% relative to placebo) fibrosis biomarkers particularly in patients with > normal level at baseline reflective of more advanced baseline liver fibrosisp= , baseline; elevated BL Pro-C3>= ngl/ml; elevated BL ELF >= 9**within group p-value**Liver Feb;35(2):429-37; Journal of Hepatology 2013 vol.

10 59 j 236 242-8-6-4-20246 NSp=< Pressure Safety Results13nStudy remains blinded, completion of dosing and follow up in 36 week study by end of April 2018nVery good all subject tolerability: mostly mild and a few moderate AEs, the numbers of which are balanced between placebo and drug-treated groups; 3 reported SAEs all unrelated to drug nOnly 2/9 discontinuations secondary to AEsnNo change in heart rate or other vital signs, significant decrease in blood pressure in MGL-3196-treatednNo change in thyroid axisAdverse EventsPlaceboMGL-3196 Mild n (%)19 ( )55 ( )Moderate n (%)7 ( )18 ( )Severe*00* Study is blinded; 3 SAEs, all unrelatedp= Hg**within group p-valueConclusionsnOnce daily MGL-3196 for 12 weeks compared with placebo significantly decreased hepatic fat in patients relative to placebonResults from liver enzyme, inflammatory and fibrosis biomarker data, including a multiparametricMRI substudyare suggestive of an impact of MGL-3196 to reduce NASH and fibrosisnMGL-3196 significantly reduced blood pressure and