Mechanism of Action: The Importance of Liver THR-β in NASH

Transcription

1 MGL-3196, a selective thyroid hormoe receptor-beta agoist, sigificatly decreases hepatic fat i NASH patiets at 12 weeks, the primary edpoit i a 36 week serial liver biopsy study Stephe Harriso 1, Sam Moussa 2, Mustafa Bashir 3, Naim Alkhouri 4, Jua Frias 5, Seth Baum 6, Bret Tetri 7, Meea Basal 8, Rebecca Taub 9; 1 Oxford Uiversity ; 2 Uiversity of Arizoa for Medical Scieces ; 3 Duke Uiversity Medical Ceter ; 4 Texas Liver Istitute, Sa Atoio, TX; 5 Uiversity of Califoria Sa Diego, Edocriology, Sa Diego, Uited States ; 6 Florida Atlatic Uiversity ; 7 St Louis Uiversity School of Medicie ; 8 Icah School of Medicie at Mout Siai ; 9 Madrigal Pharmaceuticals 1

2 Mechaism of Actio: The Importace of Liver THR-β i NASH TSH T4, prohormoe T3, ac/ve hormoe TSH, thyroid s/mula/g hormoe I humas THR-β agoism: T 4 Thyroid Glad T 4 T 3 Liver T 4 è T 3 Thyroid Hormoe Pathway Nuc Thyroid Hormoe Receptor α or β ê Lowers LDL-cholesterol ê Lowers triglycerides ê Lowers liver fat, potetially reducig lipotoxicity, NASH No thyrotoxicosis (THR-α effect) MGL-3196 has pleiotropic effects with potetial for addressig the uderlyig metabolic sydrome ad hallmark features of NASH: steatosis/lipotoxicity, iflammatio, ballooig, fibrosis (both directly ad idirectly) THR-β agoists reduce liver fat through breakdow of fatty acids, ad stimulate mitochodrial biogeesis i the NASH liver, thereby reducig lipotoxicity ad improvig liver fuctio I huma NASH, the liver has relatively low THR-β activity, exacerbatig mitochodrial dysfuctio ad lipotoxicity THR-β may have direct hepatic ati-fibrotic effects i that THR agoism has bee show to dampe iflammatio i vivo ad to ihibit TGF-β sigalig i cell culture ad i vivo Siha ad Ye Cell Biosci (216) 6:46 DOI /s ; Autophagy, 11:8, , DOI: 1.18/

3 MGL-3196, a First-i-Class Liver-Directed THR- β Agoist First boa fide THR-β selective molecule with key advatages Discovery of MGL-3196 utilized a ovel i vitro fuctioal assay Additioal selectivity coferred by highly specific uptake ito liver, avoidig ay systemic thyroid receptor effects i vivo precliical ad cliical data cofirm MGL-3196 s high liver uptake ad safety Avoids activity at the systemic THR-α receptor (o icreased heart rate, osteoporosis) Log-term aimal studies completed: o cartilage/boe fidigs i chroic toxicology Tested i more tha 16 subjects i Phase 1 studies ad 15 patiets i Phase 2 studies MGL-3196 well-tolerated i cliical dosig, ormal thyroid axis ad vital sigs, o liver ezyme icreases Lipid lowerig Robust, pleiotrophicati-atherogeic lipid lowerig properties I I Phase 1 healthy voluteer ad Phase 2 heterozygous familial cholesterolemia (HeFH) studies lowered LDL-cholesterol (LDL-C) up to 3%,apolipoprotei B (ApoB) 28%, lipoprotei(a) Lp(a) up to 4% ad triglycerides (TGs) up to 4% J Med Chem. 214;57(1):

4 Study Desig: Radomized, Double-Blid, PBO Cotrolled Trial MRI-PDFF Liver Biopsy Screeig PK assessmet MRI-PDFF MRI-PDFF Liver Biopsy D1 W2 W4 W8 W12 W24 W36 Extesio MRI-PDFF W12 Comparator/Arms 2:1 MGL-3196 to placebo 125 patiets erolled i USA, 18 sites MGL-3196 or placebo, oce daily; startig dose 8 mg per day, +-2 mg dose adjustmet possible at Week 4 Iclusio/Exclusio NASH o liver biopsy: NAS 4 with fibrosis stage 1-3 1% liver fat o MRI-PDFF Icludes diabetics, stati therapy, represetative NASH populatio 4

5 Study Edpoits Primary edpoit Relative reductio of liver fat (MRI-PDFF) at 12 weeks Secodary, exploratory biomarker ad imagig edpoits Numbers achievig 3% liver fat reductio at 12 weeks; absolute liver fat reductio NASH, fibrosis biomarkers ad lipids at 12, 36 weeks; multi-parametric imagig substudy Repeat MRI-PDFF at 36 weeks Secodary, exploratory liver biopsy edpoits at 36 weeks Reductio (2-poit o NAS) or resolutio of NASH without worseig of fibrosis i MGL treated compared to placebo Oe poit reductio i fibrosis Reductio i compoets of NASH Ogoig exploratory edpoit extesio study i a subset of patiets who completed the mai 36 week study 5

6 Baselie Characteristics Placebo (41) MGL-3196 (84) Mea age, years (SD) 47.3 (11.7) 51.8 (1.4) Male, (%) 24 (58.5) 38 (45.2) White 37 (9.2) 79 (94.) Hispaic/Latio 22 (53.7) 37 (44.) Diabetic, (%) 13 (31.7) 35 (41.7) Mea BMI (SD) 33.6 (5.8) 35.8 (6.2) Mea ALT 6.1 (32.8) 5. (29.2) Mea AST 38.2 (21.2) 35.7 (17.8) Mea LDL-C (3.) (3.4) Mea TGs (75.2) (82.4) Mea MRI-PDFF* 19.8 (6.7) 2.7 (7.) Mea NAS 4.8 (1.1) 4.9 (1.) Fibrosis stage, % (51.2) 48 (57.1), % (48.8) 36 (42.8) * Patiets with both baselie ad week 12 assessmets 6

7 Primary Edpoit Achieved Relative Chage i MRI-PDFF (%) Absolute Chage MRI-PDFF 3% Fat Reductio (%) Placebo MGL-3196 High MGL Low MGL =38 =78 =44 =34 ** p=.2 p<.1 p<.1 p<.1 High Placebo MGL-3196 MGL-3196 p=.2 Low MGL =38 =78 =44 =34 p<.1 p<.1 p< Placebo MGL-3196 p<.1 High MGL Low MGL p<.1 p< *p< p<.1 p< *p< p< *p< Primary edpoit was met: Relative chage i MRI-PDFF (% chage from baselie (media)) ad absolute fat reductio were both highly sigificat Prespecified high exposure MGL-3196 patiets achieved a 75% respose for 3% liver fat reductio No effect of MGL-3196 o body weight; 5 out of the 7 placebo patiets who achieved 3% fat reductio lost 5% body weight *compared with placebo **withi group p-value 7

8 Fat Reductio Relative to NAS/Fibrosis Stage Fibrosis 1 Fibrosis 2-3 NAS 4 NAS > 4 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 ** Relative Chage i MRI-PDFF (%) =19 =45 =19 =33 =2 =34 =18 =44 p=.9 p<.1 NS p<.1 NS p<.1 p=.1 p< p= % Fat Reductio (%) p= p= p= p=.1 p=.7 p=.2 p=.5 =19 =45 =19 =33 =2 =34 =18 =44 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Fibrosis 1 Fibrosis 2-3 NAS 4 NAS > 4 MGL-3196 reduces liver fat effectively i both early ad advaced NASH fibrosis **withi group p-value 8

9 Reductios i Multiple Atherogeic Lipids Chage from baselie g/dl Lipids Placebo MGL-3196 High MGL-3196 (=39) (=79) (=44) ND ND % Chage from Baselie Biomarker Moitorig i Patiets: Extesio Study ApoB TGs LDL-C SHBG -5 LDL-C Lp(a) o-hdl-c ApoB TGs Extesio study: Ope label study of eligible week 36 completers, all patiets o MGL-3196 Dose adjustmet based o biomarkers Sigificat (p<.1) reductios relative to placebo i multiple atherogeic lipids icludig LDL-cholesterol, Lp(a), Apo B ad TGs Sigificat lipid lowerig, correlatig with sex hormoe bidig globuli (SHBG) icrease Average reductios i LDL-C, ApoB ad triglyceride reductios ot maximal, may patiets had drug exposures cosistet with half-maximal lipid lowerig effect ApoB lowerig equal to LDL-C, reflects lowerig of LDL ad VLDL particles; ApoB correlates with CV risk more tha LDL-C level Lp(a), % chage from baselie, other lipids absolute reductios (g/ml); LDL-C>1 mg/dl, BL; Lp(a) >1 mol BL; TGs Week 4, MGL-3196 patiets o 8 mg dose; SE show; ND, ot determied 9

10 Multiparametric MRI Substudy BL CT1 926 ms Week 12 CT1 84 ms Improvemet 44%; deterioratio % MGL-3196 treated patiet (l CT1 826 ms) MGL-3196 Placebo Multiparametric MRI has bee validated as a predictive test for NASH, ad the CT1 predicts NAS o liver biopsy, particularly correlatig with iflammatio* MGL-3196 NASH substudy: evaluatio of 17 patiets with paired baselie ad week 12 multiparametric scas Chage i CT1 Measures iflammatio ad liver fat across the whole liver MGL-3196 treated patiets showed statistically sigificat improvemets i MRI-PDFF ad CT1 *Liver Iteratioal. 217;37: p=.3

11 Reductio at Week 12 of Liver Ezymes ad Reverse T3, Markers of Iflammatio -5 Placebo =29 =47 =29 ** NS p=.2 p< ALT MGL-3196 High MGL Placebo =38 =78 =44 NS p=.1 p= AST MGL-3196 High MGL Reverse T3 (iactivated T4, T3 thyroid hormoe) NASH Iflammatio Reverse T3 Placebo ** p=.8 MGL-3196 =37 =76 p< U/L Decrease i liver ezymes is correlated with improvemet i NASH o serial liver biopsy Sigificat decrease i ALT, AST (withi group MGL-3196); sigificat decrease i ALT (patiets with ALT * elevatios at baselie) ad AST (p=.4,.2, respectively) compared with placebo i high MGL-3196 patiets Sigificat decrease i reverse T3 (p<.1), a iflammatory biomarker that is relatively icreased i patiets with NASH, particularly advaced NASH (doi: 1.121/e ) Cliical Gastroeterology ad Hepatology 218;16: *Baselie ALT, >=45 males; >=3 females **withi group p-value 11

12 Reductio of Fibrosis Biomarkers by MGL Pro-C3 ELF All Elevated BL Pro-C3 All Elevated BL ELF Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 =38 =78 =12 =29 =32 =64 =22 =4 ** p=ns.57 p=ns.19 ** p=ns p=.12 p=ns p< g/ml -2-4 p= p= p= p=.9 Pro-C3 ad ELF scores have bee correlated with the liver fibrosis score o liver biopsy i NASH patiets* MGL-3196 sigificatly decreases ELF ad Pro-C3 (up to 4% relative to placebo) fibrosis biomarkers particularly i patiets with > ormal level at baselie reflective of more advaced baselie liver fibrosis BL, baselie; elevated BL Pro-C3>=17.5 gl/ml; elevated BL ELF >= 9 *Liver It. 215 Feb;35(2):429-37; Joural of Hepatology 213 vol. 59 j **withi group p-value 12

13 Safety Results Blood Pressure 6 4 Diastolic Systolic Placebo MGL-3196 Placebo MGL-3196 =39 =79 =39 =79 ** NS p=<.1 NS p=.4 Study remais blided, completio of dosig ad follow up i 36 week study by ed of April 218 Very good all subject tolerability: mostly mild ad a few moderate AEs, the umbers of which are balaced betwee placebo ad drug-treated groups; 3 reported SAEs all urelated to drug mm Hg 2-2 Oly 2/9 discotiuatios secodary to AEs No chage i heart rate or other vital sigs, sigificat decrease i blood pressure i MGL-3196-treated p=.2 p=.5 No chage i thyroid axis Adverse Evets Placebo MGL-3196 Mild (%) 19 (46.3) 55 (65.5) Moderate (%) 7 (17.1) 18 (21.4) Severe* * Study is blided; 3 SAEs, all urelated **withi group p-value 13

14 Coclusios Oce daily MGL-3196 for 12 weeks compared with placebo sigificatly decreased hepatic fat i patiets relative to placebo Results from liver ezyme, iflammatory ad fibrosis biomarker data, icludig a multiparametric MRI substudy are suggestive of a impact of MGL-3196 to reduce NASH ad fibrosis MGL-3196 sigificatly reduced blood pressure ad multiple atherogeic lipids which provides support for potetial cardiobeeficial effects i NASH patiets who most frequetly die of cardiovascular disease MGL-3196 appeared safe ad was well-tolerated Histopathologic assessmet by 36 week liver biopsy will allow for correlatios with the baselie biopsy i additio to multiple 12 week ad 36 week o-ivasive imagig ad biomarker assessmets J Med Chem. 214;57(1):