Nonconfidential

June 2019

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2

Any statements, other than statements of historical facts, made in this presentation regarding our future financial or business performance, conditions, plans, prospects, trends, or strategies and other financial and business matters; our ability to obtainadditional financing; the estimated size of the market for our product candidates, the timing and success of our development and commercialization of our anticipated product candidates; and the availability of alternative therapies for our target market, are, or may be deemed, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “could,” “should,” “would,” “anticipate,” “believe,” “estimate,” “continue,” “design,” “expect,” “intend,” “plan,” “potential,” “predict,” “seek” or the negative of these words and similar expressions and their variants may identify forward-looking statements.

These forward-looking statements reflect management’s current expectations, are based on certain assumptions and involve certain risks and uncertainties, which change over time. Our actual results may differ materially from the results discussed in these forward-looking statements due to various factors. Important factors that may cause actual results to differ materially from theresults discussed in these forward-looking statements include, but are not limited to, risks related to securing and maintainingrelationships with collaborators; risks relating to our clinical trials; risks relating to the commercialization, if any, of our proposed product candidates (such as marketing, regulatory, product liability, supply, competition, and other risks); dependence on the efforts of third parties; dependence on intellectual property; and risks related to our cash resources and ability to obtain working capital to fund our proposed operations. Further information regarding on the factors that could affect our business, financial conditions and results of operations are contained our filings with the U.S. Securities and Exchange Commission, which are available at www.sec.gov. These forward-looking statements represent management’s expectations as of the date hereof only, and we specifically disclaim any duty or obligation to update forward-looking statements as a result of subsequent events or developments, except as required by law.

Forward Looking Statements

Pipeline: Madrigal has Initiated the Phase 3 in NASH Fibrosis

Compound Indication Pre-Clinical Phase 1 Phase 2 Phase 3 Upcoming Catalysts

MGL-3196Thyroid Hormone Receptor-β (THR-β) Agonist

Nonalcoholic Steatohepatitis (NASH)With Fibrosis Stage 2-3

Phase 3 Initiated

Dyslipidemia Dyslipidemia Phase 3

study in NAFLD/NASH in planning stage

MGL-3745THR-β Agonist

NASH andDyslipidemia

3

Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Dyslipidemia

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

4

Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially reducing

lipotoxicity, NASH

No thyrotoxicosis (THR-α effect)

In humans, thyroid hormone receptor-β (THR-β) agonism:

Sinha and Yen Cell Biosci (2016) 6:46DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 1341-1357, DOI: 10.1080/15548627.2015.1061849

MGL-3196 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

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

Thyroid Gland

Liver T4 T3

T3

Nucle

ar T

HR-α

, THR

-βThyroid Hormone Pathway

T4T4

T4, prohormoneT3, active hormone

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

First bona fide THR-β selective molecule with key advantages

Discovery of MGL-3196 utilized a novel in vitro functional assay, 28 fold THR-β selective with virtually no THR-α activity

— Other thyromimetic compounds lacked beta selectivity in this assay

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

— Avoids activity at the systemic THR-αreceptor (no increased heart rate, osteoporosis)

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

— Multiple Phase 1 studies completed, well-tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increases (right panel)

J Med Chem. 2014;57(10):3912-3923; Atherosclerosis 230 (2013) 373e3805

Radiographic Tissue Distribution Demonstrates Liver Uptake

6

MGL-3196 is highly protein bound (>99%) and is taken up into the liver by hepatic transporters— Uptake is low to undetectable in heart, bone and brain at the Cmax and throughout the timecourse

The primary route of elimination after oral dose of [14C]MGL-3196 in rats, dogs and humans is feces via biliary excretion

Focused uptake in liver, with low to undetectable levels in heart, bone and brain, further support the safety of MGL-3196

0 5 10 15 20 25

Liver

Kidney (medulla)

Kidney (cortex)

Skeletal Muscle

Heart

Pituitary Gland

Brain (medula)

Brain (cerebrum)

Brain (cerebellum)

Bone Marrow

Bone (femur)

Ratio to BloodC14 MGL-3196 2h post dose

MGL-3196 Development Path Across the Spectrum of NAFLD/NASH

7

F3

F4Phase 3 NASH study: NASH Resolution (primary), LDL-C, fibrosis (key secondary); Phase 4 (post-approval): cirrhosis and MACE

F2

F1B

F1

F0

NAFLD with dyslipidemia, diabetics, metabolic syndrome

CV Benefits

Fatty liverLDL-CApoBTriglyceridesLp(a) Phase 3 Lipid study:

LDL-C (primary)(no liver biopsy requirement)Phase 4 (post-approval): MACE

2.0 million

3.5 million

15 million

6.3 million

3.4 million

1.3 million

NASH/NAFLD Spectrum1

PatientNumbers (US)

1 Estes et al; Hepatology, Vol. 67, No. 1, 2018

Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled

8

Extension Study

Screening

MRI-PDFFLiver Biopsy

MRI-PDFFLiver BiopsyMRI-PDFF MRI-PDFFPK

Comparator/Arms 2:1 MGL-3196 to placebo 125 patients enrolled in USA, 18 sites MGL-3196 or placebo, oral, once daily; dose 80 mg (+/-20 mg dose adjustment

possible at Week 4 )

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

D1 W2 W4 W12 W36 W12 W36ExD136 Week Main Study

Study Endpoints

Primary endpoint — Relative reduction of liver fat (MRI-PDFF) at 12 weeks (at 36 weeks,

secondary)

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

Completed 36 week extension study in 30 patients who completed the main 36 week study

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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)

10

* Patients with both baseline and week 12 assessments; **F0 placebo=2 (4.9); MGL-3196=1 (1.2) were included in all analyses

Dose-related Sustained Reduction in Liver Fat on MRI-PDFF

11

Relative Fat Reduction (%)

Main, 36 Week Study Sustained statistically significant reduction in

hepatic fat Week 12 to Week 36 Placebo response generally related to weight

loss ≥5%

P value, placebo compared to MGL-3196; MGL-3196, n=78; placebo, n=38; extension study shown for former pbo patients, 3 took 100 mg, 11/14, 80 mg.

36 Week Extension Study Thirty patients, 14 former placebo patients

were treated with MGL-3196, 80 mg for an additional 36 weeks

Well tolerated, excellent safety, lipid and liver enzyme responses

Absolute Fat Reduction (%)

Week 36: Sustained Robust Lipid Lowering

Significant sustained lowering effect in multiple atherogenic lipids

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Lipids (% Change from Baseline)

MGL-3196 compared with placebo; all analyses and cutoffs were prespecified; based on prespecified mITT; placebo n=39; MGL-3196 n=79 (LOCF)

◼MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory approval for dyslipidemia; an also reduces fatty liver, an independent CV risk factor

◼ApoB, not LDL-C is the major risk factor in CV disease

◼NASH patients die of CV disease more frequently than liver disease

Week 36: Liver Enzymes

ALT

AST

GGT

Statistically significant reductions in ALT, AST and GGT versus placebo; no change in bilirubin or alkaline phosphatase

Placebo MGL-3196

13All analyses were prespecified. Baseline elevated ALT =45 male, 30 female. GGT shown

as % change from baseline, females and males have different normal GGT ranges, placebo n=39; MGL-3196, n=79, LOCF

Week 36, 40% reduction in ALT in MGL-3196 with elevated baseline (p=0.01), and all MGL-3196 relative to placebo patients (p=0.002)

At Week 36, 60% of MGL-3196 patients with ALT <30 vs 37% of placebo (p=0.03)

Week 36, statistically significant AST reduction in MGL-3196 vs placebo (% change and absolute change) p=0.002

Week 36, statistically significant GGT reduction MGL-3196 vs placebo (% change and absolute change) p=0.002

Week 36: NASH Liver Biopsy Endpoints

14

2-pt reduction in NAS in placebo patients was correlated with body weight loss

PlaceboMGL-3196 (all)MGL-3196 (high exp)MGL-3196, MRI responder

In MGL-3196 treated patients with NASH resolution, 50% had fibrosis resolution (F=0) and 61% had ≥ 1 point fibrosis reduction; 39% had baseline NAS≥5 compared with 0 in placebo

2-Point NAS Reduction

with at least a 1-pt reduction in

ballooning or inflammation

(% of liver biopsies)

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; Prespecified: Excluded patients with >9.5% weight loss from NR

NASH Resolutionballooning=0,

inflammation =0, 1 with at least 2-point

reduction in NAS(% of liver biopsies)

NASH Resolution: Ballooning = 0; Inflammation = 0,1; No worsening of fibrosis stage

36 @72 5252

*included NAS=3; @ NASH resolution required at least a 2-pt NAS reduction in addition to ballooning 0; inf 0,1, no fibrosis worsening ; FXR, farnesoid X receptor; NASH, non-alcoholic steatohepatitis; NAS, NAFLD activity score; OCA, obeticholic acid; Pbo, placebo; PDFF, proton density fat fraction; PPAR, peroxisome proliferator-activated receptor; THR, thyroid hormone receptor. Younossi ZM. EASL 2019 (F1-F3 population); Ratziu Gastroenterology 2016;150:1147-1159; Ratziu AASLD 2018; Harrison AASLD 2018. For elafibrinor only enrolled patients with NAS>3 at baseline were evaluated for NASH resolution

Treatmentdose (n)

Weeks

OCA25 mg

(n=407)

Pbo0 mg

(n=34)

MGL-319660–80 mg

(n=73)

3196 PDFF+60–80 mg

(n=46)

Pbo0 mg

(n=40)

Aramchol600 mg(n=78)

Pbo0 mg

(n=76)

Elafibranor120 mg(n=75)

Pbo0 mg

(n=404)

0Biop

sies

with

reso

lutio

n (%

)

7.914.9 9

19

5

16.7

6

25

0

5

10

15

20

25

30

35

40

37

5

F1–3F1–3 F0–3

4.9* 4.8 4.9Baseline NAS

Baseline Fibrosis

Reduces NAS ≥2

Target THR-𝛽𝛽FXR Fatty/bile acid SCD inhPPAR𝛂𝛂δ

15

NASH Resolution: ”Non-NASH” or Ballooning=0; no worsening of fibrosis

GLP-1, glucagon-like peptide-1; Lira, liraglutide; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; Pbo, placebo; PPAR, peroxisome proliferator-activated receptor. sc, subcutaneous. Sanyal AJ et al. N Engl J Med. 2010;362:1675–85; Vilar-Gomez et al. Gastroenterology. 2015;149:367–78; Armstrong MJ et al. Lancet. 2016;387:679–90.

Biop

sies

with

reso

lutio

n (%

)

213 6

4 7

1 0

9 0

9

3 9

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

Target GLP-1Weight loss

Baseline NAS

Baseline Fibrosis

Reduces NAS ≥2

Pioglitazone30 mg(n=80)

Pbo0 mg

(n=23)

Lira1.8 mg sc

(n=22)

≥5% wt loss(n=205)

≥10% wt loss(n=29)

Treatment dose (n)

Vitamin E800 mg(n=84)

Pbo0 mg

(n=83)

5 4.8 4.94.85.14.8

F0–4F0 (61%)F0–4

Non-NASH at Baseline 28 1817

48 weeks96 weeks (PIVENS trial) 52 weeksWeeks

PPARγ Antioxidant

In older studies Inflammation score not considered

MRI-PDFF Absolute Fat Reduction (%)

Pbo0

(n=26)

GS-0976

20(n=46

)

Lira1.2 sc(n=68)

VK2809

10, 10 qod

(n=24)

Pbo0

(n=12)

OCA/pb25

(n=40/38)

Pbo0

(n=33)

Pbo0

(n=27)

NGM282

3 sc(n=27)

MGL-319660/80(n=74)

MGL-3196

80 ext(n=14

)

Pbo0

(n=26)

Peg10 sc

(n=25)

TargetDisease

FGF19 THR-𝛽𝛽 FXR FGF21 THR-𝛽𝛽GLP-1ACC

Weeks

Treatment dose (mg)

n

12 36 72 16 12 24 12

NASH NAFLD Early NAFLDNASH NASH NAFLD Early NAFLD

Abso

lute

fat

redu

ctio

n (%

)

ACC, acetyl-CoA carboxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; Lira, liraglutide; MRI-PDFF, magnetic resonance imaging – proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; Pbo, placebo; Peg, pegbelfermin; sc, subcutaneous; THR, thyroid hormone receptor. Harrison SA. Lancet. 2018;391:1174–85; Harrison AASLD 2018; Loomba AASLD 2017; Sanyal AJ. Lancet. 2018;392:2705-717; Loomba R. Gastroenterology. 2018;155:1463–1473; Petit JM. J Clin Endocrinol Metab. 2017;102:407–15; Loomba AASLD 2018.

13.7 15.9 17.3 18.113.218–2019.816.8 18.1 20.6 18 21 18

Baseline fat fraction

17

Pbo0

(n=26)

GS-0976

20(n=46

)

Lira1.2 sc(n=68)

VK2809

10, 10 qod

(n=24)

Pbo0

(n=12)

OCA/pb25

(n=40/38)

Pbo0

(n=33)

Pbo0

(n=27)

NGM282

3 sc(n=27)

MGL-319660/80(n=74)

MGL-3196

80 ext(n=14

)

Pbo0

(n=26)

Peg10 sc

(n=25)

MRI-PDFF Relative Fat Reduction (%)

TargetDisease

Rela

tive

fat r

educ

tion

(%)

FGF19 THR-𝛽𝛽 FXR FGF21 THR-𝛽𝛽GLP-1ACC

Weeks

ACC, acetyl-CoA carboxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; Lira, liraglutide; MRI-PDFF, magnetic resonance imaging – proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; Pbo, placebo; Peg, pegbelfermin; sc, subcutaneous; THR, thyroid hormone receptor. Harrison SA. Lancet. 2018;391:1174–85; Harrison AASLD 2018; Loomba AASLD 2017; Sanyal AJ. Lancet. 2018;392:2705-717; Loomba R. Gastroenterology. 2018;155:1463–1473; Petit JM. J Clin Endocrinol Metab. 2017;102:407–15; Loomba AASLD 2018.

Treatment dose (mg)

12 36 72 16 12 24 12

NASH NAFLD Early NAFLDNASH NASH NAFLD Early NAFLD

13.7 15.9 17.3 18.113.218–2019.816.8 18.1 20.6 18 21 18

Baseline fat fraction

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Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy

19

Patients who were not MRI-PDFF Responders (≥30% fat reduction) had a low rate of NASH resolution (left panel)

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)

NASH Resolution (%); Biopsies with Both Ballooning and Inflammation

Improvement

MRI-PDFF Week 12, % Relative Change: Correlation with Change in

Ballooning and Inflammation Scores

MGL-3196-treated

Week 36: Reduction of Fibrosis, Biomarkers

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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; ELF≥9 placebo n=21; MGL-3196 n=40; Pro-C3 BL≥17.5, placebo n=12; MGL-3196 n=29; cutoffs (ELF, PRO-C3) were prespecified based on lab normal values; Pro-C3>10 baseline, was also stat sig

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

MGL-3196 (all) MGL-3196 (high exp) F2/F3

ELF BL≥9 CK-18 (M30) U/L Pro-C3 (ng/ml)

week

% change

Week 36: Change in Fibrosis Score on Liver Biopsy

21

Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen

SHG score was generated and aligned with the pathologist baseline score (baseline, r=0.76), (left panel), blinded to treatment code

Using SHG, MGL-3196 treated compared with placebo showed a statistically significant ≥1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo

≥1 pt reduction in fibrosis on liver biopsy (SHG)

Pathologist Score

SHG

(qfib

rosi

s)

https://doi.org/10.1371/journal.pone.0199166Week 36 pathology scores and treatment code were not provided to SHG

3

21

0

SHG Score

qSteatosis Scoring Correlation with Pathologist Scoring and Baseline and Week 36 MRI-PDFF

22

qSteatosis, an automated slide analysis technology (Histoindex), demonstrates, that like qFibrosis, there is a strong relationship to pathologist steatosis score; however, unlike the pathology steatosis socre, qSteatosisprovides a continuous variable score that correlates well with MRI-PDFF

In this study, qSteatosis and qfibrosis are reduced in the same regions of the liver lobule suggesting that lipotoxicitydrives fibrosis

Brunt et al (2018) demonstrated that fibrosis improvement is predicted by NASH resolution, NAS reduction, ballooning or steatosis decrease

Hepatology. 2018 Dec 14. doi: 10.1002/hep.30418.

Phase 3/4: MGL-3196 NASH Trial Design

Inclusion/Exclusion

NASH on liver biopsy: NAS≥4, high risk F1, F2/3

Comparator/Arms

MGL-3196 80 or 100 mg or Placebo, once daily

Primary Endpoint

Phase 3: Liver biopsy at 52 weeks - resolution of NASH associated with a ≥2 pt reduction in NAS and no worsening of fibrosis

Phase 4: reduction in liver related events or progression to cirrhosis

Key Secondary Endpoints

LDL-C lowering

≥1 pt reduction in fibrosis with no worsening of NAS

Other Secondary and Exploratory Endpoints

Additional NASH biopsy endpoints

Imaging MRI-PDFF

Fibrosis biomarkers

Design

Stage

Drug MGL-3196 (resmetirom)

Blinded 1:1:1

Phase 3/4

Number of Patients

Centers

Treatment Duration

Phase 3: 900 Phase 4: up to 2000

~100, USA; EU

52 Weeks; 4.5 years

Study Overview Study Details

23

Phase 3 Largely Replicates the Phase 2 Design at Higher Doses

Phase 2 NASH Phase 3 NASHLiver biopsy confirmed NASH; NAS≥4 F1-3 NAS≥4, F2-F3, primary assessment; F1B

MRI-PDFF≥10% fat fraction MRI-PDFF ≥8% fat fraction

Enrollment 125 1:2 placebo: resmetirom Enrollment 900 1:1:1 placebo: 2 doses

Dose: 60, 80 mg once daily Dose: 80, 100 mg once daily

36 Weeks 52 Weeks

Centers: USA, 30 Centers: Global, 150, primary USA

Primary endpoint: Relative reduction in liver fat on MRI-PDFF

Primary endpoint: NASH resolution with at least a 2-point reduction in NAS, no worsening of fibrosis powered >>90% to achieve endpoint

Secondary endpoints: 2-pt reduction in NAS Key secondary endpoints:

LDL-C, other lipids LDL-C powered>>90% to achieve endpoint

NASH resolution with at least a 2-point reduction in NAS and no worsening of fibrosis; 1 stage fibrosis reduction with no NAS worsening

At least a 1 stage reduction in fibrosis with no worsening of NASpowered>90% to achieve endpoint

Multiple exploratory biomarkers for fibrosis, inflammation, imaging assessed in Phase 2 and 3

Phase 4: Clinical benefit, reduction in cirrhosis, liver related outcomes up to 4.5 years

24

Catalysts: Our Expectations for Development Timing

Initiation of 12-week Phase 2 trial of MGL-3196 for HeFH

Positive topline 12-week data from Phase 2 trial of MGL-3196 for NASH

Positive topline data from Phase 2 trial of MGL-3196 for HeFH

Positive 36-week topline liver biopsy data from Phase 2 trial of MGL-3196 for NASH

Completed Milestones:

201920182017

Ongoing NASH Phase 3 milestones Potential initiation of Phase 3

dyslipidemia study in 2H 2019

25

Completion of 36 Week NASH Extension Study

Initiation of Phase 3 Study in NASH

Acknowledgements

We are grateful to the patients and staff who made the Phase 2 NASH study possible and are participating in the Phase 3 NASH study

Phase 2 InvestigatorsDr. Stephen A. Harrison, Dr. Cynthia D. Guy, Dr. Mustafa Bashir, Dr. Juan Pablo Frias, Dr. Naim Alkhouri, Dr. Seth Baum, Dr. Cynthia A. Moylan, Dr. Meena B. Bansal, Dr. Brent A. Neuschwander-Tetri, Dr. Sam Moussa and the rest of the team

26

Safety and Additional Biomarkers

27

AEs, mostly mild, a few moderate, balance between groups. Increase in MGL-3196 treated relative to placebo in loose stools, typically a single episode, only at the beginning of therapy

No lab abnormalities or other AEs were increased in MGL-3196 compared with placebo patients

7 SAEs, distributed between placebo and drug-treated, all single occurrences, none related

AEs

Inflammation Biomarker

Safety Biomarkers

No effects on TSH, bone mineral density, heart rate, QTc, other CV biomarkers or diabetes biomarkers

Small (<3%, not statistically significant) reduction in diastolic BP at Week 36 in MGL-3196 patients, consistent with reduced liver fat

Sustained statistically significant reduction in reverse T3 — Reverse T3 is a marker of inflammation. Elevations in reverse T3 may be

indicative of high hepatic thyroid hormone degradation, in NASH, potentially caused by activated stellate cells

Conclusions

In a Phase 2 36 week serial liver biopsy study in patients with NASH fibrosis stage 1-3, patients treated with MGL-3196 as compared with placebo showed

◼ Sustained statistically significant reduction in liver fat on MRI-PDFF in MGL-3196 treated as compared with placebo patients

◼ Sustained statistically significant lowering of multiple atherogenic lipids including LDL-C, ApoB, triglycerides, ApoCIII and Lp(a)

◼ Statistically significant lowering and normalization of liver enzymes; overall safety

◼ Statistically significant resolution of NASH that is correlated with reduction in liver fat on MRI-PDFF and provides evidence for efficacy at a registrational endpoint for Phase 3 development in NASH

28

CV Risk in NASH and NAFLD

◼ Strong association between NAFLD and increased risk of CVD events and mortality

◼ Patients with NAFLD have a pro-atherogenic lipid profile: — Increased triglycerides— Increased apolipoprotein B— Higher concentration of small dense LDL

◼ Patients with NAFLD are at high risk for cardiovascular morbidity and mortality. Thus, aggressive modification of CVD risk factors is mandatory in all patients with NAFLD.

◼ Chalasani N et al. NAFLD Treatment Guidance, Hepatology 2018;67:328-357

Fatty Liver Associates with Overall CVD Mortality

30Pisto P et al. BMJ Open 2014;4:e004973. doi:10.1136/bmjopen-2014-004973

MGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLD

◼MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory approval for dyslipidemia; an also reduces fatty liver, an independent CV risk factor

◼Significant dyslipidemia opportunity exists in early NASH / NAFLD (>30M people in the US) and diabetes populations (~70% have dyslipidemia)

—Potential target population includes early NASH / NAFLD patients not eligible for most NASH clinical trials or NASH drugs in development

—50% to 67% of diabetics on statins do not reach their LDL-c target and also have elevated triglycerides; CV outcome studies consistently show that lower LDL-c/ApoB leads to better CV disease risk reduction: “lower is better”

◼Possibility of regulatory approval based on LDL-c (and ApoB) reduction, with a post-approval Phase 4 clinical trial demonstrating CV disease benefit

—Reduction of ApoB, Lp(a), ApoCIII/triglycerides, and liver fat in addition to CV benefit conferred by LDL-c lowering

31

Phase 3: MGL-3196 Dyslipidemia Trial

32

Inclusion/Exclusion

NASH/NAFLD, metabolic syndrome, diabetics, primary dyslipidemia patients not at target on current lipid therapy

Fatty liver disease patients

Comparator/Arms

MGL-3196 80 mg or Placebo, once daily

Primary Endpoint

LDL cholesterol/Apo B lowering

Key Secondary Endpoints

TGs, Lp(a), ApoCIII, hsCRP lowering

MRI-PDFF (subset)

Safety

Design

Stage

Drug MGL-3196

2:1

Phase 3

Number of Patients

Centers

Treatment Duration

2000

USA, Europe, ROW

12 months

Study Overview Study Details

MGL-3196 is Inactive in in vivo Heart Studies

MGL-3196 is the only negative analogue, even given at very high doses (no increase vs untreated control)

Confirms selectivity and lack of heart penetration

No adverse heart findings reported in efficacy or toxicology studies (histopathology)

In vivo assessment of marker of THR-α activity in the heart

THR-α signal from T3 (control) and putative THR-β analogues demonstrates heart penetration and confirms lack of functional THR-β selectivity

Hypothyroid rats treated with compound for 6 hrs

mRNA isolated and α-MHC quantified by RT-PCR

Results relative to T3 Exposure MGL-3196:

— 5 mg/kg at 6 hr: 15.4 uM— 20 mg/kg at 6 hr: 57 uM— 37.5 mg/kg at 6 hr: 94 uM

Rela

tive

alph

a-M

HC m

RNA

0

30

5

10

15

20

25

Untreated Euthyroid T31ug

GC-13ug

Eprotirome1mg

MGL-31965mg/kg

MGL-319620mg/kg

MGL-319640mg/kg

NASH Extension Study

34

◼ Former placebo patient, diabetic on multiple medications whose ALT was ~200 IU/L during the Main study

◼ Following initiation of MGL-3196 at Week 36, rapid decrease in liver fat, improvement in liver imaging (Perspectum) normalized corrected T1 (measure of liver inflammation), 85% decrease in liver enzymes

MGL-3196

BaselinecT1 894 ms

Week 12cT1 883 ms

Week 36cT1 884 ms

Week 12 ExtcT1 836 ms

Week 36 ExtcT1 811 ms

% Fat MRI-PDFF

0 12 36 12 Ext 36 Ext

Importance of Steatosis Response in Improving Fibrosis and NAS

◼ Hepatic fat is most accurately measure by MRI-PDFF, not the steatosis score on liver biopsy, which is a crude measure, that only generally correlates with MRI-PDFF

— Steatosis =1 includes 5-33% of hepatocytes with fat and does not effectively distinguish between a liver fat content that is normal ~5% and abnormal ~20%

— Both placebo (weight loss) and MGL-3196 treated patients show an association between MRI-PDFF response and reduction in other NAS components, ballooning and inflammation

◼ Recent publication Brunt et al (NASH CRN, Hepatology 2019) demonstrated that fibrosis response on liver biopsy was associated most strongly with

— Resolution of NASH (PIVENS OR=3.9, 95% CI 2.0-7.6, p<0.001; FLINT OR=8.0, 95% CI 3.1-20.9, P<0.001), and improved NAS by ≥ 2 (PIVENS OR=2.4, 95% CI 1.3-4.3, p=0.003; FLINT OR=4.2, 95% CI 2.1-8.3, P<0.001).

— Improvement in histologic features associated with improved fibrosis for both studies included steatosis and ballooning, but not lobular, inflammation.

35Hepatology. 2018 Dec 14. doi: 10.1002/hep.30418.