MGL-3196, a Thyroid Hormone Receptor-βagonist, for the Treatment of NASH

London NASH 2018

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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 obtain additional 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 the results discussed in these forward-looking statements include, but are not limited to, risks related to securing and maintaining relationships 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 MGL-3196 Phase 2 Studies in NASH and FH

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

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

Nonalcoholic Steatohepatitis (NASH)

n Phase 2 liver biopsy data

n Potential Phase 3 initiation

Familial Hypercholesterolemia

(FH)

n Topline Phase 2 data

n Potential Phase 3 initiation

MGL-3745THR-β Agonist NASH and FH

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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)

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

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Thyroid Gland

Liver T4è T3

T4 T3

Nuc

Thyr

oid

Horm

one

Rece

ptor

α o

r β

TSH

Thyroid Hormone Pathway

T4

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

ê Lowers LDL-cholesterolê Lowers triglyceridesê Lowers liver fat, potentially

reducing lipotoxicity, NASH

No thyrotoxicosis (THR-α effect)

In humans THR-β agonism:

nUnlike 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

Lipotoxicity May be Reduced by THR-β Agonists

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n Most hepatic fat derives from external sources, particularly free fatty acids from adipocytes

n In NASH, β-oxidation of liver lipids is reduced contributing to lipotoxicity

n 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

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

n 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)

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

THR-β Agonism: Potential Anti-Fibrotic Actions

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n 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)

n 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

n 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

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

n 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

n 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 135 subjects in Phase 1 studies and 150 patients in Phase 2 studies• Ongoing Phase 2 dosing in humans includes 9 months of treatment in humans with NASH

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

less α potent è

çm

ore ß selectiveα-potency (nM)

β/α relative to T3

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-500 500 1500 2500 3500 4500

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

GC-1

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MGL-3196: Radiographic Tissue Distribution

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

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

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

0 5 10 15 20 25

Bone(femur)BoneMarrow

Brain(cerebellum)Brain(cerebrum)Brain(medulla)PituitaryGland

HeartSkeletalMuscleKidney(cortex)

Kidney(medulla)Liver

RatiotoBlood

MGL-3196: Inactive in in vivo Heart Studies

• 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

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n In vivo assessment of marker of THR-α

activity in the heart

n THR-α signal from T3 (control) and

putative THR-β analogues demonstrates

heart penetration and confirms lack of

functional THR-β selectivity

n MGL-3196 is the only negative analogue,

even given at very high doses (no

increase compared to untreated control)

• Confirms selectivity and lack of heart

penetration

• No adverse heart findings reported in

efficacy or toxicology studies

(histopathology)

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MGL-3196: Improved Safety Profile Relative to T3

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Control T3 : 10 ug/kg

T3 : 30 ug/kg T3 : 100 ug/kg

Significantly reduced bone mineral density with T3

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

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Bone Mineral Density

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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 2/24/1810

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MGL-3196 3 mg/kg Rosiglitazone: 10 mg/kg

MGL-3196: Data Supports Improvement in Liver Health

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Upper panels: 24d study in 17 wk old DIO mice (po, qd) on high fat diet (HFD) 13 wks; lower panels: 24d study in 40 wk old DIO mice on HFD 35 wks

Liver Size

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MGL-3196

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Liver Triglycerides

*** p<0.001 ** p<0.01* p<0.05

Liver Fat (Histology)

Insulin Tolerance Test (0.5 U/kg insulin)

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* p<0.05

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IU/L

Control MGL-3196 .3mg/kg

MGL-3196 1mg/kg MGL-3196 3mg/kg

MGL-3196 10mg/kg

ALT

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MGL-3196§ Reduced hepatic

triglycerides (>50%), normalized liver size

§ Insulin sensitivity improved at all doses

§ Reduced liver enzymes (ALT, AST)

§ Improved liver histology, reduced NASH score

Control

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Normalization of Hepatic Gene Expression in Long-term HFD Mice

§ 25 week treatment with HFD changes the hepatic expression of a large number of gene transcripts, including both increased (red) and decreased (blue) expression

§ Treatment with MGL-3196 at doses comparable to human doses normalizes hepatic gene expression as well as hepatic architecture and size without affecting body weight

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HFD 0.1 0.3 1 3 Rosi MGL-3196 (mg/kg)

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

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MGL-3196 (mg/kg)

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MGL-3196: Long-term Dosing in Humans is Enabled

§ Single Ascending Dose (SAD) study

§ Multiple Ascending Dose (MAD) study

§ Phase 1 studies dosing MGL-3196 with statins and mass balance study

§ Series of GLP toxicology and CMC studies support all indications• Manufacturing and product formulation• Chronic toxicology package• Phase 2-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

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Inclusion/Exclusion

n NASH on liver biopsy: NAS≥4 with fibrosis

n ≥10% liver fat on MRI-PDFF

n Include diabetics, statin therapy

Comparator/Arms

n MGL-3196 or Placebo, once daily

Primary Endpoint

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

Secondary Endpoints

n NASH biomarkers and lipids at 12, 36 weeks

n Repeat MRI-PDFF at 36 weeks

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

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

Design

Stage

Drug n MGL-3196

n Blinded 2:1

n Phase 2

Number of Patients

Centers

Treatment Duration

n 125, Fully Enrolled

n ~30, USA

n 36 Weeks

Study Overview Study Details

NASH Phase 2 Demographics

Baseline Demographics

n 125

Mean age 50.4

Gender - n (%)

Female 63 ( 50.4)

Male 62 ( 49.6)

Ethnicity - n (%)

Not Hispanic or Latino 66 ( 52.8)

Hispanic or Latino 59 ( 47.2)

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NASH Phase 2 Baseline Characteristics

BaselineBMI (kg/m²) 35.07 (mean)

Type 2 diabetes n (%) 44 ( 35.2)

Hypertension n (%) 37 ( 29.6)

Triglycerides 172.0 (mean)

MRI-PDFF 20.17% FF (mean)

NAS at Screening 4.9 (mean)

Fibrosis score - (%)

1A, B 56%

2/3 43%

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§ NAS score of at least 4, range 4-8 and fibrosis 1-3

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%

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

n Statistically significant improvements in liver enzymes in drug-treatment group²

n Very good all subject tolerability: mostly mild and a few moderate AEs, the numbers of which are balanced between placebo and drug-treated groups; 3 reported SAEs all considered unrelated to drug

n 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

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

n Presentation of 12 week endpoints at EASL 2018

FH: Phase 2 HeFH Clinical Trial

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Inclusion/Exclusionn HeFH on maximally tolerated statins (typically high dose),

ezetimibe

Comparator/Armsn MGL-3196 or Placebo, once daily

Primary Endpoint n LDL cholesterol lowering

Secondary Endpointsn TGs, Lp(a), ApoB lowering

n Safety

Design

Stage

Drug n MGL-3196

n 2:1

n Phase 2

Number of Patients

Centers

Treatment Duration

n 116, fully enrolled

n 13, Europe

n 12 weeks

Study Overview Study Details

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

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ALL MGL-3196

Optimal MGL-31962

Total patients/MGL-3196 113/76 73/39

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%

n 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

n 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

n 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

n 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

Competitive Position: MGL-3196 is Differentiated in the NASH

Landscape

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

n Opportunities for differentiation from other NASH agents

n 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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Target

compound

NAS

Score

Fibrosis

Score Liver LipidsNASH

Prevention

Insulin Sensitivity LDL TGs

CV

Risk Side Effects

FXR, FGF-19 ✔ ✔ ✔ ✔ ✔ é — éLDL-CPruritus (BA

analogues)

Anti-fibrotic ? ✔ — ✖ — — — ? Unknown

PPARαδ ✔ ✖ — ? ✔ ê ê ? Well-tolerated

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

Pioglitazone ✔ ✔ ✔ ✔ ✔ ê ê PPARCHF,ê

bone,éweight

MGL-3196 ✔ ✔ ✔ ✔ ✔ ê êPotential

CV BenefitWell-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

Expectations for Development Timing

ü Completion of long-term toxicology studies for MGL-3196

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

ü Initiation of Phase 2 trial of MGL-3196 for NASH

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

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

Upcoming:

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

n Topline data from Phase 2 trial of MGL-3196 for HeFH

n Potential for Phase 3 NASH

n Potential for Phase 3 Lipids

Completed Milestones:

2018+20172016