Company Overview

March 2019

NASDAQ: MDGL

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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

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Madrigal Investment Highlights

Multiple Possible Value-Creating Catalysts over Next 18 Months

MGL-3196: First-in-Class Thyroid Hormone Receptor (THR)-β Agonist

Large & Underserved Markets in NASH & Dyslipidemia

Seasoned Management Team

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Well-Financed with ~$484M of Cash & Securities at December 31, 20185

Pipeline: Madrigal has Two Phase 2 Programs and Is Nearing Potential Phase 3 Initiation

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

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

Nonalcoholic Steatohepatitis (NASH) Phase 3 initiation

Dyslipidemia Dyslipidemia Phase 3

study in NAFLD/NASH in planning stage

MGL-3745THR-β Agonist

NASH andDyslipidemia

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

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

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F3

F4 Small study to show metabolic benefits in cirrhotics, larger study, combination with anti-fibrotic agent

Phase 3 NASH study: NASH Resolution (primary), LDL-C (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

1.6 million

2 million

15 million

5 million

2.5 million

0.5 million

NASH/NAFLD Spectrum

PatientNumbers (US)

Unmet Need: Madrigal Aims to Treat Patients with NASH, a Large and Underserved Population

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~3-5% of the US population has NASH

NAFLD is the most common liver disease world-wide~25% of US population

Rapid progression,

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

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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— Restoration of mitochondrial function in fatty liver disease

Thyroid Gland

Liver T4 T3

T3

Nucle

ar T

HR-α

, THR

-βThyroid Hormone Pathway

T4T4

T4, prohormoneT3, active hormone

Phase 2: MGL-3196 36 Week NASH Trial Read Out in 2018

Inclusion/Exclusion

NASH on liver biopsy: NAS≥4 with fibrosis

≥10% liver fat on MRI-PDFF

Include diabetics, statin therapy

Comparator/Arms

MGL-3196 or Placebo, once daily

Primary Endpoint

Reduction of liver fat (MRI-PDFF) at 12 weeks

Secondary Endpoints

NASH biomarkers and lipids at 12, 36 weeks

Repeat MRI-PDFF at 36 weeks

Liver biopsy at 36 weeks - reduction/resolution of NASH in patients on drug; reduction of fibrosis

Extension study completed in a subset of patients who had completed the Main 36 week study

Design

Stage

Drug MGL-3196

Blinded 2:1

Phase 2

Number of Patients

Centers

Treatment Duration

125

~30, USA

36 Weeks

Study Overview Study Details

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Week 36: Sustained Reduction in Liver Fat on MRI-PDFF

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Relative Fat Reduction (%)

≥30% 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; prespecified high exposure (High Exp) n=44; F2/F3, placebo, n=19; MGL-3196, n=33

PlaceboMGL-3196 (all)MGL-3196 (high exp)

Absolute Fat Reduction (%)

Extension Study of 36 Week Phase 2 Trial

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Extension Study

The Extension study included 14 former placebo patients with persistently mildly to markedly elevated liver enzymes from the Main 36 Week study, ~ two thirds F2/F3

Noninvasive end points, only To optimize exposure, all patients in the

Extension study received 80 or 100 mg per day of MGL-3196, a higher average dose than in the 36 Week study to move all patients into the “high exposure” category

Highly significant reduction in lipids including LDL-C, ApoB and triglycerides

Well tolerated, few AEs, improvement in liver enzymes from baseline

Extension Study: Reduction in Liver Fat on MRI-PDFF

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≥30% Fat Reduction (%)

Relative Fat Reduction (%)

Absolute Fat Reduction (%)

Main Extension

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 patients 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

Week 36: NASH Liver Biopsy Endpoints

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

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, no worsening of fibrosis. Patients with >9.5% weight loss excluded (prespecified)

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)

2-Point NAS Reduction

with at least a 1-pt reduction in

ballooning or inflammation

(% of liver biopsies)

NASH Resolutionballooning=0,

inflammation =0, 1 with at least 2-point

reduction in NAS(% of liver biopsies)

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

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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 (%) MGL-3196-treated

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

Ballooning Plus Inflammation Scores

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

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

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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 readers.

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21

0

SHG Score

https://doi.org/10.1371/journal.pone.0199166

Safety and Additional Biomarkers

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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 (

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

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Phase 3: MGL-3196 Dyslipidemia Trial

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Inclusion/Exclusion

NASH/NAFLD, metabolic syndrome, diabetics, primary dyslipidemia patients not at target on current lipid therapy; documented fatty liver (MRI-PDFF >=8%)

Comparator/Arms

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

Primary Endpoint

LDL cholesterol/Apo B lowering

Key Secondary Endpoints

MRI-PDFF

TGs, Lp(a), ApoCIII, hsCRP lowering

Safety

Design

Stage

Drug MGL-3196

1:1:1

Phase 3, 52 week

Number of Patients

Centers

Treatment Duration

Up to 2000

USA, Europe, ROW

12 months

Study Overview Study Details

Catalysts: Our Expectations for Development Timing

Completion of long-term toxicology studies for MGL-3196

Completion of Phase 1 trial of MGL-3196 dosed with statins for NASH

Initiation of Phase 2 trial of MGL-3196 for NASH

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

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

Positive End-of-Phase 2 FDA meeting (NASH)

Completed Milestones:

2018+20172016

Upcoming Catalysts: Phase 3 initiation in NASH 1Q19 - CRO

selected, API and tablet formulation ready Potential initiation of Phase 3 dyslipidemia

study in 2H 2019

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Madrigal Investment Highlights

Multiple Possible Value-Creating Catalysts over Next 18 Months

MGL-3196: First-in-Class Thyroid Hormone Receptor (THR)-β Agonist

Large & Underserved Markets in NASH & Dyslipidemia

Seasoned Management Team

1

2

3

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Well-Financed with ~$484M of Cash & Securities at December 31, 20185

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Appendix:

Additional Material

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

confidential

Radiographic Tissue Distribution

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 Blood

confidential

C14 MGL-3196 2h post dose

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;67:328-35727

Fatty Liver Predicts Risk of CV Events

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

**p

Genetic versus Therapeutic LDL-c Reduction

Key takeaways

Lower LDL-C is better, use combination therapies to lower LDL-C as low as possible

Start treatment of LDL early, patients with genetic predisposition to high LDL-C have life-time risk

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◼ MGL-3196 statistically significantly lowers LDL-c and other atherogenic lipids in patients with HeFH, a difficult to treat genetic dyslipidemia, including Lp(a)

◼ Lp(a) reduction appears greater than other known mechanisms

◼ MGL-3196 is most effective in patients intolerant to high intensity statins, lowering LDL-c 28.5%

◼ Unlike other mechanisms, ApoB and LDL-c reduction are similar, suggesting that MGL-3196 may directly lower ApoB, a better marker of atherogenicity than LDL

confidential

MGL-3196: Lipid Effects in FH

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◼ MGL-3196 reduces triglycerides, VLDL and LDL-particles, particularly small LDL particles which are highly atherogenic

◼ ApoCIII reduction is likely an important mechanism by which MGL-3196 lowers TGs

◼ MGL-3196 reduces hsCRP, an important inflammatory marker predictive of CV risk

TGs, ApoCIII Small LDL Particles

hsCRP

confidential

MGL-3196: Lipid Effects in FH

HeFH Phase 2 Study: MGL-3196 Effects on Lipids

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LDL Cholesterol

Apolipoprotein B

Lp(a)

◼ MGL-3196 statistically significantly lowers LDL-C and other atherogenic lipids in patients with HeFH, a difficult to treat genetic dyslipidemia, including Lp(a)

◼ Lp(a) reduction appears greater than other known mechanisms

◼ MGL-3196 is most effective in patients intolerant to high intensity statins, lowering LDL-C 28.5%

◼ Unlike other mechanisms, ApoB and LDL-C reduction are similar, suggesting that MGL-3196 may directly lower ApoB, a better marker of atherogenicity than LDL

HeFH Phase 2 Study: Effects on Lipids, Lipid Particles, hsCRP

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◼ MGL-3196 reduces triglycerides, VLDL and LDL-particles, particularly small LDL particles which are highly atherogenic

◼ ApoCIII reduction is likely an important mechanism by which MGL-3196 lowers TGs

◼ MGL-3196 reduces hsCRP, an important inflammatory marker predictive of CV risk

◼ The effect to reduce multiple atherogenic lipids makes MGL-3196 an excellent candidate to lower CHD risk in NAFLD/NASH, diabetics and mild to severely statin intolerant patients

TGs, ApoCIII Small LDL Particles

VLDL Particles

hsCRP

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

◼MGL-3196 lowers lipids, including LDL-C, to a level consistent with regulatory approval for dyslipidemia; also reduces fatty liver, an independent CV risk factor

—Key differentiator from other NASH therapeutics◼Significant dyslipidemia opportunity exists in early NASH / NAFLD ( up to 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

34confidential

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

A lipid indication, if approved, would allow treatment of early NASH / NAFLD patients based on reduction of LDL-cholesterol/ApoB lowering (no liver biopsy requirement)

35confidential

Remnant cholesterol

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In non-fasting state, there is also remnant cholesterol in chylomicrons, a small fraction of total remnant cholesterol

Phase 1: Robust LDL and Triglyceride Lowering Established in 14 Day Multiple Ascending Dose Study

Once daily oral treatment led to highly statistically significant and dose-dependent up to ~30% reduction of apolipoprotein B (ApoB), total, LDL, non-HDL cholesterol; Strong trends in triglyceride reduction up to 60%;

Near maximal effect at 80 mg dose

Change from Baseline (CFB) by mean % CFB calculated for each individual subject 24h after 14th dose; baseline value obtained just prior to first dose; ApoB, apolipoprotein B; Chol, total cholesterol; LDL-C, LDL cholesterol directly measured; Non-HDL-C, non-HDL cholesterol; TG, triglycerides (median %CFB)

*** p

THR-β Agonism: Potential Anti-Fibrotic Actions

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Treating NASH, rather than fibrosis, is key to addressing the disease

— Resolution of NASH, without reducing fibrosis, is an approvable endpoint— Recognition that liver fibrosis will decrease with time after NASH resolves (similar to reduction of

fibrosis as the liver regenerates after cure of HCV)

THR-β, the operative receptor in hepatocytes, may ameliorate lipotoxicity and resultant local inflammation which lead to hepatocyte dysregulation and apoptosis. These perturbations lead to a profibrotic environment through:

— Ongoing inflammation— Production by the dysregulated / damaged / dying hepatocytes of profibrotic factors, with TGF-β

among the most important

THR-β may have direct anti-fibrotic effects

— Thyroid hormone receptor agonism has been shown to dampen inflammation in vivo and to inhibit TGF-β signaling in cell culture and in vivo

— In animal models of liver fibrosis, the extent of fibrosis is decreased by thyroid hormone administration and increased if thyroid hormone receptors are knocked out

PNAS 113: 3451, 2016

Lipotoxicity: THR-β Agonists May Reduce Lipotoxicity

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Most hepatic fat derives from external sources, particularly free fatty acids from adipocytes; in NASH, β-oxidation of liver lipids is reduced contributing to lipotoxicity

THR-β agonists reduce liver fat through breakdown of fatty acids, and stimulate mitochondrial biogenesis in the NASH liver, thus, we believe, reducing lipotoxicity and improving liver function

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

We believe MGL-3196 has pleiotropic effects characteristic of an “ideal” NASH drug, with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly)

Treating NASH, rather than fibrosis, is key to addressing the disease

— Resolution of NASH, without reducing fibrosis, is an approvable endpoint

— Recognition that liver fibrosis will decrease with time after NASH resolves (similar to reduction of fibrosis as the liver regenerates after cure of HCV)

β-oxidation of fat in mitochondria

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

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

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Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially

reducing lipotoxicity, NASH

No thyrotoxicosis (THR-α effect)

In humans, THR-β agonism:

Unlike other pathways which raise LDL-cholesterol (FXR, FGF-19) or triglycerides (ACC1 antagonist), THR-β agonism reduces both plasma triglycerides and LDL-cholesterol and may provide CV benefit to NASH patients

We believe that MGL-3196, a selective THR-β agonist, will treat the underlying disease in NASH patients

T4, prohormoneT3, active hormoneTSH, thyroid stimulating hormone

Nuc

Thy

roid

Hor

mon

e R

ecep

tor α

or β

MGL-3196: Agonism of Hepatic THR-β

In livers of euthyroid individuals T3 induces about half the maximal transcriptional activity of THR-beta

MGL-3196 can further beneficially increase this transcriptional activity as we have shown in euthyroid animal models and humans.

Interestingly, systemic hypothyroidism, at the level of the thyroid gland itself, leads to increases in plasma lipids (LDL-C and triglycerides) and increases the risk of nonalcoholic fatty liver disease.

In fact, actual NASH is at least twice as common in hypothyroid individuals as in the general population.

Further, liver-specific hypothyroidism is present in human NASH, caused by degradation of thyroid hormone (increased deiodinase 3 produced by stellate and inflammatory cells) in the NASH liver

— In a vicious cycle this liver-specific hypothyroidism increases as NASH progresses— Thus, MGL-3196, which is not affected by deiodinases, can increase transcriptional activity over

an even broader range than in the non-NASH euthyroid state

— With MGL-3196-induced resolution of NASH, with the concomitant decrease in numbers and level of activation of stellate cells, normalization of hepatic thyroid function should occur.

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Diabetic Dyslipidemia

◼ There is a strong relationship between triglycerides and coronary heart disease in type 2 diabetes.

◼ Triglyceride-rich lipoproteins (chylomicrons and VLDL) are not known to participate directly in atherogenesis, but they are central to the mechanism by which small dense LDL and remnant cholesterol is generated

◼ Levels of small dense LDL and remnants are increased, and the relatively “normal” cholesterol and ApoB levels observed in many patients with diabetes hides a major atherogenic burden.

MGL-3196: A First-in-Class Liver-Directed THR- β Agonist

We believe MGL-3196 is the first bona fide THR-β selective molecule with key advantages over other companies’ previous analogues

Discovery of MGL-3196 and backups at Roche utilized a novel functional assay that went beyond what previous companies had done (simple receptor binding assay)— Earlier compounds from other companies, purported to be THR-β selective, show no functional selectivity in this assay and, like

thyroid hormone, activate the THR-α receptor equally well as the β receptor

in vivo data confirm MGL-3196’s high liver uptake and preclinical safety— Avoids activity at the systemic THR-α receptor (increased heart rate, osteoporosis) — Unlike other company’s earlier thyroid receptor agonists, no cartilage findings in chronic toxicology or liver enzyme increases in

human studies— Tested in more than 180 subjects in Phase 1 studies and 150 patients in Phase 2 studies— Phase 2 dosing in humans includes 9 months of treatment in humans with NASH— MGL-3196 treated healthy volunteers and patients show normal central thyroid axis and vital signs

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

less α potent

m

ore ß selectiveα-potency (nM)

β/α relative to T3

-5

0

5

10

15

20

25

30

35

-500 500 1500 2500 3500 4500

Thyroid Hormone (T3) MB07811 (GC1)MGL-3196 EprotiromeKB

GC-1

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Phase 2 Data

In summary we believe Phase 2 results:

◼ Established minimum effective dose, once a day oral, for statistically significant NASH resolution endpoint, recognized by FDA

◼ Presented strong fibrosis biomarker and exploratory data, especially in advanced F3 patients, suggesting 3196 has potential to hit the 1 -pt fibrosis reduction endpoint in a larger patient data set in Phase 3

◼ Established MRI-PDFF as a non invasive method to predict NASH Resolution◼ Demonstrated safety including benefits in liver enzymes◼ Demonstrated robust lipid lowering, a unique profile, that allows potential benefit in

MACE as well as liver endpoints in Phase 3 (Kastelein emphasized how critical these lipid benefits are in this population including reduction of liver fat which is independently associated with MACE

— LDL, ApoB (the atherogenic particle)—with add on of TG, ApoCIII and Lp(a).

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Non-invasive correlates with NAS response

◼ Non-invasive tests correlated with NASH improvement provide additional support of the NR with 2-pt reduction as reasonably likely to predict clinical benefit

— ALT improves with improvement in histology ( Factors Associated with Histologic Response in Adult Patients with Nonalcoholic Steatohepatitis Rohit Loomba et al, Gastronterology, September 2018)

— Decreased CK18 has been shown to correlate with histological improvement in trials of subjects with stage 0-3 disease

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Company Overview

March 2019

NASDAQ: MDGL

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Company Overview ��March 2019���NASDAQ: MDGL���Forward Looking StatementsSlide Number 3Pipeline: Madrigal has Two Phase 2 Programs and Is Nearing Potential Phase 3 InitiationMGL-3196 Development Path Across the Spectrum of NAFLD/NASHUnmet Need: Madrigal Aims to Treat Patients with NASH, a Large and Underserved PopulationMechanism of Action: The Importance of Liver THR-β in NASHPhase 2: MGL-3196 36 Week NASH Trial Read Out in 2018Week 36: Sustained Reduction in Liver Fat on MRI-PDFFExtension Study of 36 Week Phase 2 TrialExtension Study: Reduction in Liver Fat on MRI-PDFFWeek 36: Sustained Robust Lipid LoweringWeek 36: Liver EnzymesWeek 36: NASH Liver Biopsy EndpointsCorrelation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver BiopsyImportance of Steatosis Response in Improving Fibrosis and NASWeek 36: Reduction of Fibrosis, BiomarkersWeek 36: Change in Fibrosis Score on Liver BiopsySafety and Additional BiomarkersPhase 3/4: MGL-3196 NASH Trial DesignPhase 3: MGL-3196 Dyslipidemia TrialCatalysts: Our Expectations for Development TimingSlide Number 23Slide Number 24MGL-3196 is Inactive in in vivo Heart StudiesRadiographic Tissue DistributionCV Risk in NASH and NAFLDFatty Liver Predicts Risk of CV EventsGenetic versus Therapeutic LDL-c Reduction Slide Number 30Slide Number 31HeFH Phase 2 Study: MGL-3196 Effects on LipidsHeFH Phase 2 Study: Effects on Lipids, Lipid Particles, hsCRPMGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLDMGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLDRemnant cholesterolPhase 1: Robust LDL and Triglyceride Lowering Established in 14 Day Multiple Ascending Dose StudyTHR-β Agonism: Potential Anti-Fibrotic ActionsLipotoxicity: THR-β Agonists May Reduce LipotoxicityMechanism of Action: The Importance of Liver THR-β in NASHMGL-3196: Agonism of Hepatic THR-βDiabetic DyslipidemiaMGL-3196: A First-in-Class Liver-Directed THR- β AgonistPhase 2 DataNon-invasive correlates with NAS responseCompany Overview ��March 2019���NASDAQ: MDGL���