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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 study

Stephen Harrison1 , Sam Moussa2 , Mustafa Bashir3 , Naim Alkhouri4 , Juan Frias5 , Seth Baum6 , Brent Tetri7 , Meena Bansal8 , Rebecca Taub9; 1Oxford University ; 2University of Arizona for Medical Sciences ; 3Duke University Medical Center ; 4 Texas Liver Institute, San Antonio, TX; 5University of California San Diego, Endocrinology, San Diego, United States ; 6Florida Atlantic University ; 7St Louis University School of Medicine ; 8Icahn School of Medicine at Mount Sinai ; 9Madrigal Pharmaceuticals

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

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Thyroid Gland

Liver T4è T3

T4 T3

Nuc

Thyr

oid

Horm

one

Rece

ptor

α o

r β

TSH

Thyroid Hormone Pathway

T4

T4,prohormoneT3,ac/vehormoneTSH,thyroids/mula/nghormone

ê Lowers LDL-cholesterol

ê Lowers triglycerides

ê Lowers liver fat, potentially reducing

lipotoxicity, NASH

No thyrotoxicosis (THR-α effect)

In humans THR-β agonism:

Sinha and Yen Cell Biosci (2016) 6:46

DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8,

1341-1357, DOI: 10.1080/15548627.2015.1061849

n MGL-3196 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)

n THR-β agonists reduce liver fat through breakdown of fatty acids, and stimulate mitochondrial biogenesis in the NASH liver,

thereby reducing lipotoxicity and improving liver function

n In human NASH, the liver has relatively low THR-β activity, exacerbating mitochondrial dysfunction and lipotoxicity

n THR-β may have direct hepatic anti-fibrotic effects in that THR agonism has been shown to dampen inflammation in vivo

and to inhibit TGF-β signaling in cell culture and in vivo

MGL-3196, a First-in-Class Liver-Directed THR- β Agonist

First bona fide THR-β selective molecule with key advantages

n Discovery of MGL-3196 utilized a novel in vitro functional assay

• Additional selectivity conferred by highly specific uptake into liver, avoiding any systemic thyroid

receptor effects

n in vivo preclinical and clinical data confirm MGL-3196’s high liver uptake and safety

• Avoids activity at the systemic THR-α receptor (no increased heart rate, osteoporosis)

• Long-term animal studies completed: no cartilage/bone findings in chronic toxicology

• Tested in more than 160 subjects in Phase 1 studies and 150 patients in Phase 2 studies

• MGL-3196 well-tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increases

n Lipid lowering

• Robust, pleiotrophic anti-atherogenic lipid 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. 2014;57(10):3912-3923 3

Study Design: Randomized, Double-Blind, PBO Controlled Trial

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D1 W2 W4 W8 W12 W24 W36 ExtensionScreening

MRI-PDFFLiver Biopsy

MRI-PDFFLiver BiopsyMRI-PDFF MRI-PDFF

W12

PK assessment

Comparator/Armsn 2:1 MGL-3196 to placebon 125 patients enrolled in USA, 18 sitesn MGL-3196 or placebo, once daily; starting dose 80 mg per day, +-20 mg dose

adjustment possible at Week 4

Inclusion/Exclusionn NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3n ≥10% liver fat on MRI-PDFFn Includes diabetics, statin therapy, representative NASH population

Study Endpoints

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n Primary endpoint

• Relative reduction of liver fat (MRI-PDFF) at 12 weeks

n Secondary, 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; multi-parametric imaging substudy• Repeat MRI-PDFF at 36 weeks

n Secondary, 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 NASH

n Ongoing exploratory endpoint extension study in a subset of patients who completed the main 36 week study

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)

Mean AST 38.2 (21.2) 35.7 (17.8)

Mean LDL-C 116.9 (30.0) 111.3 (30.4)

Mean TGs 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 n, % 0-1 21 (51.2) 48 (57.1)

n, % 2-3 20 (48.8) 36 (42.8)

6* Patients with both baseline and week 12 assessments

-9.6

-36.3

-42.0

-22.5

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0p=0.02 p<0.0001 p<0.0001 p<0.0001

n=38 n=78 n=44 n=34

Placebo MGL-3196High MGL-

3196Low MGL-

3196

Relative Change in MRI-PDFF (%)

18.4

60.3

75.0

41.2

0

10

20

30

40

50

60

70

80Placebo MGL-3196

High MGL-3196

Low MGL-3196

≥30% Fat Reduction (%)

-2.4

-7.6-8.8

-5.0

-12

-10

-8

-6

-4

-2

0p=0.02 p<0.0001 p<0.0001 p<0.0001

n=38 n=78 n=44 n=34

Placebo MGL-3196High

MGL-3196Low MGL-

3196

Absolute Change MRI-PDFF

Primary Endpoint Achieved

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p<0.0001

p<0.0001

*p<0.02

*compared with placebo **within group p-value

p<0.0001

p<0.0001

*p<0.04

n Primary endpoint was met: Relative change in MRI-PDFF (% change from baseline (median)) and absolute fat reduction were both highly significant

n Prespecified high exposure MGL-3196 patients achieved a 75% response for ≥30% liver fat reduction

n No effect of MGL-3196 on body weight; 5 out of the 7 placebo patients who achieved ≥ 30% fat reduction lost ≥5% body weight

p<0.0001

*p<0.02

p<0.0001

**

Fat Reduction Relative to NAS/Fibrosis Stage

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n MGL-3196 reduces liver fat effectively in both early and advanced NASH fibrosis

26.3

60.0

10.5

60.6

20.0

52.9

16.7

65.9

0

10

20

30

40

50

60

70

n=19 n=45 n=19 n=33 n=20 n=34 n=18 n=44

Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196

Fibrosis ≤ 1 Fibrosis 2-3 NAS ≤ 4 NAS > 4

≥30% Fat Reduction (%)

-45

-40

-35

-30

-25

-20

-15

-10

-5

0p=0.0009 p<0.0001 NS p<0.0001 NS p<0.0001 p=0.01 p<0.0001

n=19 n=45 n=19 n=33 n=20 n=34 n=18 n=44

Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196

Fibrosis ≤ 1 Fibrosis 2-3 NAS ≤ 4 NAS > 4

Relative Change in MRI-PDFF (%)

**within group p-value

**

p=0.0007 p=0.002 p=0.005p=0.01

p=0.002 p=0.001p=0.02

p=0.02

Reductions in Multiple Atherogenic Lipids

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Lp(a), % change from baseline, other lipids absolute reductions (ng/ml); LDL-C>100 mg/dL, BL; Lp(a) >10 nmol BL; TGs Week 4, MGL-3196 patients on 80 mg dose; SE shown; ND, not determined

n Extension 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

• ApoB lowering 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

-5

0

5ApoB TGs LDL-CNASH ExtensionStudy

0

10

20

30

40

50

60

70

80

90

100

SHBG

% C

hang

e fr

om B

asel

ine

Biomarker Monitoring in Patients:Extension Study

n Significant (p<0.0001) reductions relative to placebo in multiple atherogenic lipids including LDL-cholesterol, Lp(a), Apo B and TGs

n Average reductions in LDL-C, ApoB and triglyceride reductions not maximal, many patients had drug exposures consistent with half-maximal lipid lowering effect

-50

-40

-30

-20

-10

0

10

20

30(n=39) (n=79) (n=44)

Placebo MGL-3196 High MGL-3196

Lipids

LDL-C Lp(a) non-HDL-C ApoB TGs

Cha

nge

from

bas

elin

e ng

/dL

ND ND

Multiparametric MRI Substudy

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n Multiparametric MRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation*

n Measures inflammation and liver fat across the whole liver

n MGL-3196 NASH substudy: evaluation of 17 patients with paired baseline and week 12 multiparametric scans

n MGL-3196 treated patients showed statistically significant improvements in MRI-PDFF and CT1

Improvement 44%; deterioration 0%BL CT1 926 ms Week 12 CT1 840 ms

MGL-3196 treated patient (nl CT1 826 ms)

Chan

ge in

CT1

-95.3

-18.8

-120

-100

-80

-60

-40

-20

0MGL-3196 Placebo

p=0.03

*Liver International. 2017;37:1065–1073

-7.7

-13.5

-21

-30

-25

-20

-15

-10

-5

0NS p=0.002 p<0.0001

n=29 n=47 n=29

Placebo MGL-3196High MGL-

3196

ALT

-1.6

-7.4

-9.2

-14

-12

-10

-8

-6

-4

-2

0NS p=0.001 p=0.0002

n=38 n=78 n=44

Placebo MGL-3196High MGL-

3196

AST

Reduction at Week 12 of Liver Enzymes and Reverse T3, Markers of Inflammation

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n Decrease in liver enzymes is correlated with improvement in NASH on serial liver biopsy

n Significant decrease in ALT, AST (within group MGL-3196); significant decrease in ALT (patients with ALT*

elevations at baseline) and AST (p=0.04, 0.02, respectively) compared with placebo in high MGL-3196 patients

n Significant decrease in reverse T3 (p<0.0001), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH (doi: 10.1210/en.2014-1302) Clinical Gastroenterology and Hepatology 2018;16:123–131

*Baseline ALT, >=45 males; >=30 females

T4, T3Reverse T3 (inactivated thyroid hormone)

NASH Inflammation

-6

-5

-4

-3

-2

-1

0p=0.08 p<0.0001

n=37 n=76

Placebo MGL-3196

U/L

Reverse T3

**within group p-value

**

**

-10

-8

-6

-4

-2

0

2

4p=NS 0.057 p=NS 0.0019

n=38 n=78 n=12 n=29

Placebo MGL-3196 Placebo MGL-3196

All Elevated BL Pro-C3ng/m

l

Pro-C3

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2p=NS p=.12 p=NS p<0.0001

n=32 n=64 n=22 n=40

Placebo MGL-3196 Placebo MGL-3196

All Elevated BL ELF

ELF

Reduction of Fibrosis Biomarkers by MGL-3196

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n Pro-C3 and ELF scores have been correlated with the liver fibrosis score on liver biopsy in NASH patients*

n MGL-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 fibrosis

p=0.002

p=0.08

p=0.009

p=0.05

BL, baseline; elevated BL Pro-C3>=17.5 ngl/ml; elevated BL ELF >= 9 **within group p-value

** **

*Liver Int. 2015 Feb;35(2):429-37; Journal of Hepatology 2013 vol. 59 j 236–242

-8

-6

-4

-2

0

2

4

6NS p=<0.0001 NS p=0.0004

n=39 n=79 n=39 n=79

Placebo MGL-3196 Placebo MGL-3196

Diastolic Systolic

Blood Pressure

Safety Results

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n Study remains blinded, completion of dosing and follow up in 36 week study by end of April 2018

n Very 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

n Only 2/9 discontinuations secondary to AEs

n No change in heart rate or other vital signs, significant decrease in blood pressure in MGL-3196-treated

n No change in thyroid axis

Adverse Events

Placebo MGL-3196

Mild n (%) 19 (46.3) 55 (65.5)

Moderate n (%) 7 (17.1) 18 (21.4)

Severe* 0 0

* Study is blinded; 3 SAEs, all unrelated

p=0.005p=0.002

mm

Hg

**

**within group p-value

Conclusions

n Once daily MGL-3196 for 12 weeks compared with placebo significantly decreased hepatic fat in patients relative to placebo

n Results from liver enzyme, inflammatory and fibrosis biomarker data, including a multiparametric MRI substudy are suggestive of an impact of MGL-3196 to reduce NASH and fibrosis

n MGL-3196 significantly reduced blood pressure and multiple atherogenic lipids which provides support for potential cardiobeneficial effects in NASH patients who most frequently die of cardiovascular disease

n MGL-3196 appeared safe and was well-tolerated

n Histopathologic assessment by 36 week liver biopsy will allow for correlations with the baseline biopsy in addition to multiple 12 week and 36 week non-invasive imaging and biomarker assessments

J Med Chem. 2014;57(10):3912-3923 14