Company Overview

June 2018

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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Madrigal’s Team: Led by an Experienced Management Team with Multiple Successful NDA/MAAs and Marketed Products

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Paul Friedman, M.D.

Chairman and CEO

Former CEO of Incyte

Former President of R&D at Dupont Pharmaceuticals

Marc Schneebaum

CFO, SVP

Former CFO, SVP at Synta

Former CEO at Predictive Biosciences

Rebecca Taub, M.D.

CMO, EVP R&D

Founder of Madrigal

Aided in discover of Eliquisand MGL-3196 at Roche

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

FH / Dyslipidemia Potential Phase 3 in FH

and/or mixed dyslipidemias

MGL-3745THR-β Agonist

NASH and FH / Dyslipidemia

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Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Familial Hypercholesterolemia (FH) / Dyslipidemia

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, <2 years 25% of NASH Stage 3 fibrosis progress to cirrhosis

NASH is the most severe form of nonalcoholic fatty liver disease (NAFLD)

Characterized by inflammation and damage caused by a buildup of fat in the liver that leads to cirrhosis, fibrosis, and cell death

Develops most often in patients with obesity/metabolic syndrome, diabetes and dyslipidemia

NASH represents an indication with significant unmet need

Estimated to affect 3-5% of the US adult population

Expected to be the leading cause of liver transplant

There are currently no approved therapies for the treatment of NASH

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

Thyr

oid

Hor

mon

e R

ecep

tor α

or β

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

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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MGL-3196: Improved Safety Profile Relative to T3

******

******

Significantly reduced bone mineral density with T3

p<.05*p<.01**P<.001***

******

****** *****

T3

MGL-3196

Thyroid hormone (T3, thyroxine) treatment may cause osteoporosis

24d study in 40 week old diet-induced obese (DIO) mice on High Fat Diet (HFD) for 38 weeks

BMJ 2011;342:d2238 10

Preclinical: MGL-3196 Proof-of-Concept Well Established in Animal Models

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Reduced Hepatic TGs Improved Insulin Sensitivity

Reduced Liver Enzymes Improved Liver Histology All NASH Components

Liver Triglycerides

***

** *

***

* p<0.05

*

Insulin Tolerance Test (0.5 U/kg insulin)

ALT

************

Liver Fat (Histology)

MGL-3196Control

MGL-3196: Reduction of Key NASH, Fibrosis Pathway Genes at Human Comparable Drug Levels

TIMP1 tissue inhibitor metalloproteinaseCTGF connective tissue growth factorSMA smooth muscle actinSAA serum amyloid ACRP C-reactive protein

“HFD”, lane 1 mean HFD gene expression normalized to mean Lean; Lanes (2-7) mean gene expression normalized to mean of DIO; “Rosi” (rosiglitazone, 3 mg/kg, 24 wks) Red, higher expression; blue decreased expression

Inflammation HFD Lean 0.1 0.3 1 3 RosiMCP-1/CCL2MIP-2α/CXCL2MIP-2ß/CXLCL3A20/TNFaip3CRPAnnexin 2SAA1FibrosisCollagen 1Galectin-3TIMP1Collagen 4a2SMACollagen 4a1CTGFKeratin 18Collagen 3Galectin-1

25 week study in lean control mice and HFD mice treated with Vehicle, 0.1 to 3 mg/kg MGL-3196 or Rosiglitazone (3mg/kg)

Bad Good

1 2 3 4 5 6 7

MGL-3196 (mg/kg)

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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<0.001 ** p<0.01 * p≤0.05 “p≤0.1

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*

*

“

“

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Six dose cohorts, 36 total healthy volunteers dosed daily with MGL-3196 (5, 20, 50, 80, 100, or 200 mg) and 12 with placebo for 14 days

Healthy volunteers with slightly elevated LDL cholesterol (> 110 mg/dL)

Well-tolerated, appeared safe at all doses tested

No effect on vital signs, heart rate, central thyroid axis, or liver enzymes

MGL-3196: Phase 1 and Long-term Dosing in Humans

Single Ascending Dose (SAD) study Multiple Ascending Dose (MAD) study Phase 1 studies dosing MGL-3196 with statins and mass balance study Phase 1 tablet formulation study of MGL-3196

Number of patients treated— Tested in more than 180 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, without liver

enzyme increases

Lipid lowering— Robust, pleiotrophic anti-atherogenic lipid lowering properties— 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%, triglycerides (TGs) up to 40%, and ApoCIII

Series of GLP toxicology and CMC studies support all indications— Manufacturing and product formulation— Chronic toxicology package— Phase 3-enabling

Atherosclerosis 230 (2013) 373-380

Completed:

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Phase 2: MGL-3196 Trial Design is Targeted at Highly Relevant Primary and Secondary Endpoints

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

Ongoing extension study in a subset of patients who completed the Main 36 week study

Design

Stage

Drug MGL-3196

Blinded 2:1

Phase 2

Number of Patients

Centers

Treatment Duration

125, Fully Enrolled

~30, USA

36 Weeks

Study Overview Study Details

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Phase 2: Primary Endpoint Achieved at 12 Weeks

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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

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

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

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

**

Phase 2: Reduction at Week 12 of Liver Enzymes and Markers of Inflammation, Fibrosis

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

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

Multiparametric MRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation. Significant decrease in MGL-3196 treated patients.

Significant decrease in reverse T3 (p<0.0001), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH

*Baseline ALT, >=45 males; >=30 femalesdoi: 10.1210/en.2014-1302) Clinical Gastroenterology and Hepatology 2018;16:123–131

**within group p-value

**

Chan

ge in

ALT

(U/L

)

Chan

ge in

AST

(U/L

)

Phase 2: MGL-3196 Achieved Primary and Key Secondary Liver Biopsy Endpoints in NASH at 36 Weeks

MGL-3196

MGL-3196 MRI-PDFF Responders¹ Placebo

36 Week Biopsy Results (Secondary Endpoints)

Number of patients2 73 46 34

≥ 2 Point Decrease in NAS

56%p=0.02

70%p=0.001 32%

NASH Resolution 27%p=0.02

39%p=0.001 6%

Sustained, highly statistically significant (p<0.0001) reduction in liver fat compared with placebo on Week 36 MRI-PDFF; mean fat reduction MGL-3196 37%; placebo, 8.9%

Sustained, statistically significant reductions in low-density lipoprotein cholesterol (LDL-C), ApoB, triglycerides, and lipoprotein(a)

Well-tolerated: mostly mild and a few moderate AEs, generally balanced between drug treated and placebo

— An increase in incidence of transient mild diarrhea in MGL-3196-treated compared with placebo, often a single episode, occurring only early in the course of treatment

— 7 reported SAEs all unrelated to drug; 5 in MGL-3196-treated, 2 placebo (2-1 randomization)

¹ MGL-3196 MRI-PDFF Responders = MGL-3196 treated patients with >=30% relative fat reduction on Week 12 MRI-PDFF.

2 Includes only patients with base line and end-of-study liver biopsies. Does not include one patient whose end-of-study liver biopsy was deemed inadequate.

Phase 2 liver biopsy results demonstrate the potential for MGL-3196 to show a clear benefit in patients with NASH, including both reduction and resolution of NASH and improvement in multiple atherogenic lipids

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Phase 2: MGL-3196 Achieved Primary and Key Secondary Liver Biopsy Endpoints in NASH at 36 Weeks

Positive Signals on Fibrosis Statistically significant reductions in fibrosis biomarkers in MGL-3196 treated vs placebo On liver biopsy, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients

vs. 23% in placebo Of the MGL-3196 treated patients that achieved NASH resolution, 50% also achieved

fibrosis resolution All MGL-3196 treated patients that achieved NASH resolution also achieved a statistically

significantly fibrosis decrease relative to placebo patients

Reductions in Liver Enzyme Levels Statistically significant reductions in liver enzymes relative to placebo, with reductions of

greater magnitude with longer duration of MGL-3196 treatment Statistically significantly more MGL-3196 treated than placebo patients had

normalization of ALT

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FH: In addition to NASH, Madrigal also Targeted Familial Hypercholesterolemia in Phase 2 Trial

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HeFH and HoFH caused primarily by inactivating mutations in LDL receptor

Early onset cardiovascular disease, HoFH < age 20

Associated with several of potentially severe cardiovascular diseases including coronary heart disease, carotid artery disease, and chronic kidney disease

Severe Debilitating

Dyslipidemia

Novel Therapeutic Approaches

Needed

1/200-1/500 HeFH; 1/250,000-1/1,000,000 HoFH

Higher frequency in certain genetically homogeneous populations

High prevalence for a genetic disease

High Genetic Prevalence

Despite current and newer therapies, HoFH and most HeFH not achieving treatment goals on standard care

Significant commercial opportunity for MGL-3196 in HoFH, refractory HeFH

FH: Phase 2 HeFH Clinical Trial Which Read Out in 2018

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Inclusion/Exclusion

HeFH on maximally tolerated statins (typically high dose), ezetimibe

Comparator/Arms

MGL-3196 or Placebo, once daily

Primary Endpoint

LDL cholesterol lowering

Secondary Endpoints

TGs, Lp(a), ApoB lowering

Safety

Design

Stage

Drug MGL-3196

2:1

Phase 2

Number of Patients

Centers

Treatment Duration

116, fully enrolled

13, Europe

12 weeks

Study Overview Study Details

Phase 2: MGL-3196 Achieved Primary and Secondary Endpoints in Patients with HeFH

ALL MGL-3196

Optimal MGL-31962

Total patients/MGL-3196 113/76 76/39

Primary Endpoint:Pbo-adjusted reduction of

LDL-cholesterol 1 -18.8%p<0.0001

-21.0%p<0.0001

Secondary Endpoints: p<0.0001 for all endpointsPbo-adjusted reduction of

Triglycerides

ApoB

Lp(a)

-25 to -31%

~-20%

-25 to -40%

Baseline characteristics balanced between placebo (pbo) and MGL-3196-treated; 75% taking high intensity statins (20/40 mg rosuvastatin or 80 mg atorvastatin), and about 2/3 of patients also taking ezetimibe

Statistically significant improvements in multiple lipid biomarkers (LDL-C, ApoB, Lp(a), triglycerides, ApoCIII) represents a novel and differentiated lipid-management profile with respect to other statin-sparing oral treatments

Efficacy in moderate to low/no statin subgroup -28.5% LDL-C lowering (p<0.0001) supports the use of MGL-3196 for HeFH and other high CV risk patients whose LDL-C is not at target despite maximally tolerated lipid-lowering therapies

Well-tolerated with mostly mild and a few moderate AEs balanced between placebo and drug-treated groups; 2 SAEs (1 each in pbo and drug-treated group (unrelated to treatment)

¹ Data are presented using standard convention for lipid endpoints, as placebo-adjusted or compared to the placebo group, which exhibited ~8% upward LDL drift from baseline during the 12 week study that would occur equally in the drug-treated patients. 2Prespecified ”Optimal” MGL-3196 group showed drug levels consistent with near maximal lipid lowering effects

Efficacy and tolerability profile provide further support for MGL-3196’s overall safety profile and potential for CV benefits in

NASH patients, HeFH and other dyslipidemic patients, particularly those on moderate statin doses or intolerant to statins

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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

Completed Milestones:

2018+20172016

Upcoming Catalysts:

End-of-Phase 2 FDA meeting and Phase 3 initiation in NASH

Potential Phase 3 in FH and/or mixed dyslipidemias

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Competitive Position: MGL-3196 is Differentiated in the NASH Landscape

Potential pleiotropic and cardio-beneficial actions position MGL-3196 as stand alone NASH therapeutic

Opportunities for differentiation from other NASH agents

Efficacy on NASH and cardiovascular endpoints provide opportunity for MGL-3196 to be used in combination with anti-fibrotic and/or anti-inflammatory agents

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Targetcompound

NAS Score

FibrosisScore Liver Lipids

NASH Prevention

Insulin Sensitivity LDL TGs

CV Risk Side Effects

FXR, FGF-19 ✔ ✔ ✔ ✔ ✔ — LDL-C Pruritus (BA analogues)

Anti-fibrotic ? ✔ — ✖ — — — ? Unknown

PPARαδ ✔ ✖ — ? ✔ ? Well-tolerated

Anti-inflam ✔ ? — — — — — ? Well-tolerated

Pioglitazone ✔ ✔ ✔ ✔ ✔ PPAR CHF,bone,weight

MGL-3196 ✔ ✔ ✔ ✔ ✔ Potential

CV Benefit Well-tolerated

Lancet 385:956-65; 2015; Gastroenterology Feb 11 2016; pii:S0016-5085(10)00140-2Tobira press release July 25, 2016; Ann Intern Med. doi:10.7326/M15-1774 2016

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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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Appendix:

Additional Material

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

THR-β Agonism: Decreased Liver Fibrosis and Apoptosis

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• THR-β knockout and hypothyroid mice have delayed liver regeneration, increased apoptosis (PLoS ONE 5(1): e8710, 2010)

• THR-β -/- mice have increased liver fibrosis with age

• Treatment with thyroid hormone reduces fibrosis in animal models of liver fibrosis (PNAS 113: 3451, 2016)

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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MGL-3196: Radiographic Tissue Distribution

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MGL-3196 is highly protein bound (>99%) and is taken up into the liver by hepatic transporters

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

Uptake is low to undetectable in heart, bone and brain, further supporting the safety of MGL-3196

LiverKidney (medulla)

Kidney (cortex)Skeletal Muscle

HeartPituitary GlandBrain (medulla)

Brain (cerebrum)Brain (cerebellum)

Bone MarrowBone (femur)

Ratio to Blood

MGL-3196: Lipid Lowering in Additional Phase 1 Studies

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Baseline (BL); triglycerides (TG) (all) or >150 mg/dL at BL; Lp(a) shown only for subjects with measurable BL Lp(a)

p<.003p <.0001

• In Phase 1 studies, 38 healthy volunteers were dosed with one-two days of a statin and multiple daily doses (9-11) of MGL-3196 (100 or 200 mg)

• Robust lipid lowering was observed (up to 60% LDL-C), subjects reaching an average LDL-C of 70 mg/dL, ApoB of 59 mg/dL

• Consistent with MAD data, subjects with higher MGL-3196 exposures did not demonstrate more lipid lowering.

p=.001

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

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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/Arms 2:1 MGL-3196 to placebo 125 patients enrolled in USA, ~30 sites MGL-3196 or placebo, once daily; starting dose 80 mg per day, +-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

Phase 2: Study Endpoints

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

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

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

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

Phase 2: 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)

34* Patients with both baseline and week 12 assessments

Phase 2: MGL-3196 Study Achieved Primary Endpoint in Interim Readout

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ALL MGL-3196

HIGH MGL-3196¹

Placebo

Number of patients 78 44 38

Primary Endpoint:Relative change in MRI-PDFF (% change from baseline, median)Significance relative to placebo

-36.3%

p<0.0001

-42.0%

p<0.0001

-9.6%

Percentage of patients attaining ≥30% liver fat reductionSignificance relative to placebo

60.3%

p<0.0001

75.0%

p<0.0001

18.4%

Statistically significant improvements in low-density lipoprotein cholesterol (LDL-C), triglycerides and lipoprotein (a) Lp(a)²

Statistically significant improvements in liver enzymes in drug-treatment group²

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 considered unrelated to drug

Two regularly scheduled DSMB meetings held May 2017 and September 2017 to review data from the Madrigal NASH Phase 2 trial. DSMB recommended to continue the trial with no changes to the protocol

¹ Prespecified group of patients (44/78) with relatively higher MGL-3196 drug levels² These beneficial effects are more pronounced in the group of pre-specified patients with

higher levels of MGL-3196Ther. Adv. Gastroenterol. 2016; 9:692-701

Growing clinical data set demonstrating correlation between decline in fat content on MRI-PDFF, fibrosis biomarkers and NAS score on biopsy

Presentation of 12 week endpoints at EASL 2018

Phase 2: Fat Reduction Relative to NAS/Fibrosis Stage

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

**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

Phase 2: Reductions in Multiple Atherogenic Lipidsat 12 Weeks

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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; NA, not assessed

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

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Biomarker Monitoring in Patients:Extension Study

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

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

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Phase 2: Multiparametric MRI Substudy

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

Measures inflammation and liver fat across the whole liver

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

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)

*Liver International. 2017;37:1065–1073 ** within group p-value

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CT1

p=0.03

**

Phase 2: Reduction at Week 12 of Liver Enzymes and Reverse T3, Markers of Inflammation

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

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

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

**within group p-value

**

**

Phase 2: Reduction of Fibrosis Biomarkers by MGL-3196 at 12 Weeks

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

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

Phase 2: 12-Week Safety Results

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

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

Only 2/9 of the discontinuations were secondary to AEs No THR-𝛼𝛼 activity, no change in heart rate or other vital signs;

mild, significant decrease in blood pressure in MGL-3196-treated consistent with improvement in metabolic syndrome

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

FH: Current Treatment Challenges

HoFH

Most patients still not reaching LDL-C goal

Newer agents, Lomitapide (Juxtapid, MTPi) and Mipomersen (Kynamro, anti-ApoB) may have safety issues

— Both carry FDA label warning*, hepatotoxicity

— Increased ALT and hepatic fat

Elevated Lp(a) remains an issue

HeFH

In HeFH, standard care (statins, ezetimibe) most HeFH still not achieving goal

— Even with PCSK9 inhibitor, 40% not at target

Further treatment opportunities include relative statin intolerance in some and elevated Lp(a)

HoFHLipid Lowering Therapy

LDL decrease

Conventional

Statins Up to 28%

Ezetimibe <10%

LDL apheresis 20-40%

New Treatment Options

Lomitapide Up to 50%

Mipomersen 25%

PCSK9 inh 23%

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MGL-3196: Unique and Complementary Lipid Lowering Profile

Thyroid pathway clinically validated and differentiated in FH

Both LDL receptor-dependent and –independent cholesterol lowering:— Stimulates cholesterol breakdown and elimination— Lowers ApoB and Lp(a)

– Decreases levels of PCSK9 (human data) and angiopoietin-like protein 3 ANGPTL3 (gene expression)

— MGL-3196 lowers LDL in concert with statins in clinical & preclinical studies— Thyroid agonists lower cholesterol in LDL receptor knockout mice*— In Phase 3 trials in HeFH, an earlier THR agonist lowered LDL cholesterol and Lp(a)**— MGL-3196 acts through a mechanism that potentially lowers Lp(a), a severely atherogenic

particle that is elevated in FH

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In FH, we believe MGL-3196 will deliver additional LDL-C and Lp(a) lowering on top of conventional treatment