H.C. Wainwright March 2018 NASDAQ: MDGL 1 Forward Looking - - PowerPoint PPT Presentation

H.C. Wainwright

March 2018 NASDAQ: MDGL

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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 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

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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 & Genetic Lipid Disorders Seasoned Management Team 1 2 3 4

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 Eliquis and MGL-3196 at Roche

Pipeline: Madrigal has Two Phase 2 Programs with Multiple Near-Term Catalysts

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

MGL-3196

Thyroid Hormone Receptor-β (THR-β) Agonist Nonalcoholic Steatohepatitis (NASH)  Phase 2 liver biopsy data  Phase 3 initiation Familial Hypercholesterolemia (FH)  Phase 3 initiation

MGL-3745

THR-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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 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

Lipotoxicity May be Reduced by THR-β Agonists

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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)

β-oxidation of fat in mitochondria

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

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

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 160 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
• 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 

more ß selective

α-potency (nM) β/α relative to T3

• 5

5 10 15 20 25 30 35

• 500

500 1500 2500 3500 4500

Thyroid Hormone (T3) MB07811 (GC1) MGL-3196 Eprotirome KB GC-1

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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

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-3196 Control

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

TIMP1 tissue inhibitor metalloproteinase CTGF connective tissue growth factor SMA smooth muscle actin SAA serum amyloid A CRP 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 Rosi

MCP-1/CCL2 MIP-2α/CXCL2 MIP-2ß/CXLCL3 A20/TNFaip3 CRP Annexin 2 SAA1

Fibrosis

Collagen 1 Galectin-3 TIMP1 Collagen 4a2 SMA Collagen 4a1 CTGF Keratin 18 Collagen 3 Galectin-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) 12

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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 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: 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, mass balance study and tablet

formulation

• 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:

3/27/2018 14

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

15 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

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

Baseline BMI (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 reduction

Significance 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 levels ² These beneficial effects are more pronounced in the group of pre-specified patients with higher levels of MGL-3196

• Ther. 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 MGL-3196 12 week data in main plenary at EASL 2018 will include additional biomarker and imaging (multi- parametric substudy) with inflammation and fibrosis endpoints potentially predictive for 36 week liver biopsy

Phase 2 Liver Biopsy, Extension Study and Phase 3 NASH Plans

• Read out of 36 week liver biopsy by end May
• Preparation for end of Phase 2 FDA meeting

and conduct of manufacturing, preclinical studies that support Phase 3

• Extension of NASH study beyond 36 weeks to

collect additional long-term data in a subset

• f patients who meet criteria for mild to

moderate elevations in liver enzymes

• Blinded as to treatment assignment in

main study (includes former placebo patients)

• All patients in the extension study

receive MGL-3196

• Unblinded, monitor safety and efficacy

biomarkers on an ongoing basis

• Only non-invasive readouts in the

extension study, including MRI-PDFF, circulating biomarkers

3/27/2018 19

*doi:10.1016/j.jacc.2008.04.052

Biomarker Monitoring in Patients Enrolled in the NASH Extension Study

% Change from Baseline

• Highly significant lipid lowering, correlating with SHBG

increase

• ApoB is thought to be a better marker of atherosclerotic

risk than LDL-C*

• MGL-3196 reduces ApoB at similar magnitude as LDL-C
• Statins reduce ApoB up to 30% less than LDL-C in high

TG patients; elevated TGs, common in NASH

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

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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 endpoints

Pbo-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

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 22

Target compound NAS Score Fibrosis Score 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)00140-2 Tobira press release July 25, 2016; Ann Intern Med. doi:10.7326/M15-1774 2016

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

• f MGL-3196 for NASH

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 Initiation of 12-week Phase 2 trial

• f MGL-3196 for HeFH

 Positive topline 12-week data from Phase 2 trial of MGL-3196 for NASH ✔ Topline data from Phase 2 trial of MGL- 3196 for HeFH Completed Milestones:

2018+ 2017 2016

Upcoming Catalysts:  36-week topline liver biopsy data from Phase 2 trial of MGL-3196 for NASH  Potential Phase 3 NASH  Potential Phase 3 HeFH/dyslipidemia

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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 & Genetic Lipid Disorders Seasoned Management Team 1 2 3 4

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Appendix: Additional Material