Welcome to the Madrigal Analyst/Investor AASLD KOL Event November - - PowerPoint PPT Presentation

Welcome to the Madrigal Analyst/Investor AASLD KOL Event

November 12, 2018

Forward-Looking Statements

Any statements, other than statements of historical facts, made in this presentation regarding our clinical studies and our research and development programs; our ability to advance product candidates into clinical studies; our anticipated clinical development milestones; the timing or likelihood of regulatory filings and approvals for our product candidates; the timing and success of our development and commercialization of our product candidates; and the potential of our product candidates to safely treat cardiovascular, metabolic, and liver diseases, including non-alcoholic steatohepatitis and dyslipidemia, 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 our actual results to differ materially from the results discussed in these forward-looking statements include, but are not limited to, uncertainties associated with the outcomes, cost and timing of our product candidate development activities and clinical trials; uncertainties inherent in clinical testing; the timing, cost, and uncertainty of obtaining regulatory approvals for our product candidates; our ability to successfully progress or complete further development of our product candidates; our ability to commercialize our product candidates; our ability to protect our intellectual property; our cash resources and ability to obtain working capital to fund our proposed operations; changes in the regulatory landscape or the imposition of regulations that affect our product candidates; our reliance on third- parties to meet our obligations; and other factors that are described in our most recent periodic reports filed with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2017, and subsequent Quarterly Reports on Form 10-Q, including the risk factors set forth in those filings. 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.

Agenda

• Welcome & Introductions
• Paul A Friedman, MD, Chairman & Chief Executive Officer
• Becky Taub, MD, Director, Founder, Chief Medical Officer and Executive

Vice President, Research & Development

• Clinical Discussions
• Phase 2 Clinical Trial Results NASH: Stephen Harrison, M.D., Principal

Investigator of the study, Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University Q&A

• Dyslipidemia Opportunity: John J. P. Kastelein, MD, Ph.D., FESC,

Professor of Medicine in the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam and the principal investigator Q&A

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In a Placebo Controlled 36 Week Phase 2 Trial, Treatment with MGL-3196 Compared to Placebo Results in Significant Reductions in Hepatic Fat (MRI-PDFF), Liver Enzymes, Fibrosis Biomarkers, Atherogenic Lipids, and Improvement in NASH on Serial Liver Biopsy

• Dr. Stephen A. Harrison, Dr. Cynthia D. Guy, Dr. Mustafa Bashir, Dr.

Juan Pablo Frias, Dr. Naim Alkhouri, Dr. Seth Baum, Dr. Rebecca Taub, Dr. Cynthia A. Moylan, Dr. Meena B. Bansal, Dr. Brent A. Neuschwander-Tetri, Dr. Sam Moussa

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) 6:46 DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 1341-1357, DOI: 10.1080/15548627.2015.1061849

MGL-3196  THR-β selective molecule with proven safety and efficacy in more than 300 subjects and patients treated — No exposure outside the liver or activity at the systemic THR-α receptor  Pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly) — Reduction of liver fat through breakdown of fatty acids, normalization of liver function Thyroid Gland Liver T4 T3 T3

Nuclear THR-α, THR-β

Thyroid Hormone Pathway T4 T4

T4, prohormone T3, active hormone

Study Design: Randomized, Double-Blind, PBO Controlled Trial

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Extension Study Screening MRI-PDFF Liver Biopsy MRI-PDFF Liver Biopsy MRI-PDFF MRI-PDFF PK Comparator/Arms

 2:1 MGL-3196 to placebo  125 patients enrolled in USA, 18 sites  MGL-3196 or placebo, oral, once daily; dose 80 mg (+/-20 mg dose adjustment possible at Week 4 )

Inclusion/Exclusion

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

D1 W2 W4 W12 W36 W12 W36 ExD1 36 Week Main Study

Study Endpoints

 Primary endpoint — Relative reduction of liver fat (MRI-PDFF) at 12 weeks (at 36 weeks, secondary)  Key secondary endpoints at 12, 36 weeks — Reduction (2-point on NAS) or resolution of NASH without worsening of fibrosis with at least a 2-pt reduction in NAS in MGL-3196-treated compared to placebo patients — One point reduction in fibrosis on liver biopsy — Numbers achieving ≥ 30% liver fat reduction at 12, 36 weeks; absolute liver fat reduction — Liver enzymes, fibrosis biomarkers and lipids at 12, 36 weeks  Ongoing exploratory endpoint extension study in a subset of patients who completed the main 36 week study

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Baseline Characteristics

Placebo (41) MGL-3196 (84) Mean age, years (SD) 47.3 (11.7) 51.8 (10.4) Male, n (%) 24 (58.5) 38 (45.2) White 37 (90.2) 79 (94.0) Hispanic/Latino 22 (53.7) 37 (44.0) Diabetic, n (%) 13 (31.7) 35 (41.7) Mean BMI (SD) 33.6 (5.8) 35.8 (6.2) Mean ALT 60.1 (32.8) 50.0 (29.2) PRO-C3 16.2 (8.3) 17.8 (10.3) ELF 9.2 (1.0) 9.2 (0.88) Mean LDL-C 116.9 (30.0) 111.3 (30.4) Mean Triglycerides (TG) 161.1 (75.2) 178.5 (82.4) Mean MRI-PDFF* 19.8 (6.7) 20.7 (7.0) Mean NAS 4.8 (1.1) 4.9 (1.0) Fibrosis stage 1, n (%) 19 (46.3) 47 (55.9) 2-3, n (%) 20 (48.8) 36 (42.8)

10 * Patients with both baseline and week 12 assessments

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

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

Absolute Fat Reduction (%)

Extension Study of 36 Week Phase 2 Trial

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confidential

Extension Study

 The Extension study includes 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

NASH Extension Study

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◼ Former placebo patient, diabetic on multiple medications whose ALT was ~200 IU/L during the Main study ◼ Following initiation of MGL-3196 at Week 36, rapid decrease in liver fat, improvement in liver imaging (Perspectum) normalized CT1 (measure of liver inflammation), 85% decrease in liver enzymes (ALT shown on right)

MGL-3196

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Week 36: Sustained Robust Lipid Lowering

Significant sustained lowering effect in multiple atherogenic lipids

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Lipids (% Change from Baseline)

Placebo corrected; p value, placebo compared to MGL-3196; MGL-3196, n=79; placebo, n=39

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

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Baseline elevated ALT =45 male, 30 female. GGT shown as % change from baseline, females and males have different normal GGT ranges

 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 <30 vs 37% of placebo (p=0.03)  Week 36, statistically significant AST reduction in MGL-3196 vs placebo (% change and absolute change) p=0.002  Week 36, statistically significant GGT reduction MGL-3196 vs placebo (% change and absolute change) p=0.002

Week 36: NASH Liver Biopsy Endpoints

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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, <9.5% weight loss;

Placebo MGL-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 Resolution

ballooning=0, inflammation =0, 1 with at least 2-point reduction in NAS (% of liver biopsies)

NAS Endpoint-Defining Dose

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Statistically significant dose and exposure dependent improvement in NAS with low/no effect dose demonstrated Change in NAS, baseline to Week 36

MRI Responder; ≥ 30% fat reduction on Week 12 High exposure, n=44; low exposure n=29; based on prespecified exposure groups

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

• f 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

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 *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

• n liver biopsy (SHG)

Pathologist Score SHG (qfibrosis)

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

3 2 1 SHG Score

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 (<3%, not statistically significant) reduction in diastolic BP at Week 36 in MGL-3196 patients, consistent with reduced liver fat  Sustained statistically significant reduction in reverse T3 — Reverse T3 is a marker of inflammation. Elevations in reverse T3 may be indicative of high hepatic thyroid hormone degradation, in NASH, potentially caused by activated stellate cells

AE Table

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Placebo n = 41 MGL-3196 n = 84 Patients with Adverse Events 28 (68.3) 73 (86.9) Severe 2 (4.9) 6 (7.1) Moderate 13 (31.7) 27 (32.1) Mild 13 (31.7) 40 (47.6) Patients with SAEs 2 (4.9) 5 (6.0) Patients with Drug-related SAEs Diarrhea (loose stools Week 12 3 (7.3) 28 (33.3) Week 12 to Week 36 1 (2.4) 3 (3.7) Headache 6 (14.6) 11 (13.1) Dizziness 4 (9.8) 6 (7.1) Fatigue 4 (9.8) 4 (4.8) UTI 4 (9.8) 9 (10.7) Grade 3 CTC ALT 3-5X ULN (Grade 2-3) 5 (12.2) 2 (2.4)** AST 3-5XULN (Grade 2-3) 2 (4.9) 2 (2.4)** GGT > 5X ULN 5 (12.2) 1 (1.2) CK > 5XULN 2 (4.9) 2 (2.4) Glucose > 250 mg/dL 3 (7.3) 4 (4.8) Lipase > 2XULN 1 (2.4) 3 (3.6) TGs > 500 mg/dL 2 (4.9) 1 (1.2)

In healthy volunteers 3% (128 subjects) reported transient diarrhea on 100 mg dose, two weeks of dosing

**one MGL-3196 patient took an overdose for two weeks, continued on 80 mg with normalization from baseline of liver enzymes; severe AEs, SAEs plus 1 patients with knee pain for one day, called “severe”

Conclusions

In a Phase 2 36 week serial liver biopsy study in patients with NASH fibrosis stage 1-3, patients treated with MGL-3196 as compared with placebo showed ◼ Sustained statistically significant reduction in liver fat on MRI-PDFF in MGL-3196 treated as compared with placebo patients ◼ Sustained statistically significant lowering of multiple atherogenic lipids including LDL-C, ApoB, triglycerides, ApoCIII and Lp(a) ◼ Statistically significant lowering and normalization of liver enzymes; overall safety ◼ Statistically significant resolution of NASH that is correlated with reduction in liver fat on MRI-PDFF and provides evidence for efficacy at a registrational endpoint for Phase 3 development in NASH

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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 or Placebo, once daily Primary Endpoint  Phase 3: Liver biopsy at 52 weeks - resolution of NASH  Phase 4: reduction in liver related events or progression to cirrhosis Secondary Endpoints  Reduction in atherogenic lipids  Reduction of fibrosis  2-pt reduction in NAS Exploratory  Imaging MRI-PDFF  NASH biomarkers Design Stage Drug  MGL-3196  Blinded 2:1  Phase 3/4 Number of Patients Centers Treatment Duration  Phase 3: 900 Phase 4: up to 2000  ~80, USA; EU  52 Weeks; 4.5 years

Study Overview Study Details

confidential

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.

Q & A

The future of cardiovascular disease prevention

John JP Kastelein Professor of Internal Medicine Academic Medical Center Amsterdam, the Netherlands

Outline

• Approach in the Past
• Fire and Forget
• Statins only
• Current Focus
• From LDL-c targets to LDL-c elimination
• From statins to combination therapy
• Opportunities Moving Forward
• Statin intolerance
• Other lipid targets to pursue

Causative factors versus bystanders

Boren J, Curr Opin Lipidol 2016;27:473-483

LDL-C Lowering Therapies Reduce CV Risk

• 2013 ACC/AHA guidelines state that lowering LDL-c lowers ASCVD risk, but

since no randomized clinical trials have been done to specifically treat to goals, an optimal goal was not supported

• 2013 ACC/AHA guidelines did not routinely allow for non-statin therapy to

treat high-risk patients who:

• Have a less-than-anticipated response to statins
• Are unable to tolerate a less-than-recommended intensity of a statin
• Are completely statin intolerant

Stone et al. J Am Coll Cardiol 2014;63:2889-2934; Keaney JF et al. N Engl J Med 2014;370:275-278

Outline

• Approach in the Past
• Fire and Forget
• Statins only
• Current Approach
• From LDL-c targets to LDL-c elimination
• From statins to combination therapy
• Opportunities Moving Forward
• Statin intolerance
• Other lipid targets to pursue

Genetic versus Therapeutic LDL-c Reduction

Concept Change I: Start Treatment Early

Less ‘LDL-exposure’ leads to prevention of lesion formation

Wiegman et al. European Heart Journal, 2015

FH

Cumulative exposure is important

Treat the earlier, the better!

Concept Change II: Use Combination Therapy

Ezetimibe induced LDL-c lowering reduces CV-risk

• CTTC. Lancet 2005;366:1267–1278. CTTC. Lancet 2010;376:1670–1681.

Cannon et al. N Engl J Med 2015;372:2387–2397.

50% 40% 30% 20% 10% 0% 0.5 1.0 1.5 2.0

Reduction in LDL-C (mmol/L) Proportional Reduction in Event Rate (SE)

IMPROVE-IT CTT-meta-analysis

PCSK9-antibody on top of statins: FOURIER

3 5

Evolocumab SC

140 mg Q2W or 420 mg QM

Placebo SC

Q2W or QM LDL-c ≥70 mg/dL or non-HDL-c ≥100 mg/dL

Follow-up Q 12 weeks

Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED DOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101

LDL-c reduction and CV benefit

• ↓ LDL-C by 59% (from 2.4 -> 0.8 [0.5, 1.2] mM)
• ↓ CV outcomes in patients already on statin therapy
• Evolocumab was safe and well-tolerated

0.0 0.5 1.0 1.5 2.0 2.5 4 12 24 48 72 96 120 144 168 LDL-C (mM) Weeks after randomization

Evolocumab Median 0.78 mM IQR [0.49-1.27] Placebo 59% mean decline P<0.00001

Absolute↓1.45 mM (1.42-1.47)

HR 0.85 (0.79-0.92) P<0.0001 Sabatine MS et al. New Engl J Med 2017;376:1713-22

Concept change III: Treat (much more) aggressively

From desirable target to ‘elimination’ of LDL-c

Achieved on-trial LDL-C concentration, mg/dL (mmol/L) < 50 (< 1.29) (n = 4375) 50–< 75 (1.29–< 1.94) (n = 10,395) 75–< 100 (1.94–< 2.58) (n = 10,091) 100–< 125 (2.58–< 3.23) (n = 8953) 125–< 150 3.23– <3.88 (n = 3128) 150–< 175 (3.88–< 4.52) (n = 836) ≥ 175 (≥ 4.52) (n = 375) Major CV events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 194 (4.4) 0.20 (0.16–0.25)

0.44

(0.35–0.55) 1185 (11.4) 0.40 (0.33–0.48)

0.51

(0.42–0.62) 1664 (16.5) 0.50 (0.42–0.60)

0.56

(0.46–0.67) 1480 (16.5) 0.48 (0.40–0.58)

0.58

(0.48–0.69) 557 (17.8) 0.51 (0.42–0.62)

0.64

(0.53–0.79) 184 (22.0) 0.64 (0.51–0.81)

0.71

(0.56–0.89) 123 (32.8) 1.00 (ref)

1.00

(ref) Major coronary events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 129 (2.9) 0.15 (0.12–0.20) 0.47 (0.36–0.61) 918 (8.8) 0.36 (0.29–0.43) 0.53 (0.43–0.65) 1431 (14.2) 0.50 (0.41–0.61) 0.58 (0.48–0.71) 1336 (14.9) 0.51 (0.42–0.62) 0.62 (0.51–0.75) 492 (15.7) 0.53 (0.43–0.65) 0.67 (0.55–0.83) 170 (20.3) 0.69 (0.54–0.88) 0.78 (0.61–0.99) 107 (28.5) 1.00 (ref) 1.00 (ref) Major cerebrovascular events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 72 (1.6) 0.47 (0.29–0.74) 0.36 (0.22–0.59) 315 (3.0) 0.62 (0.41–0.95) 0.46 (0.30–0.71) 302 (3.0) 0.52 (0.34–0.79) 0.49 (0.32–0.75) 205 (2.3) 0.38 (0.25–0.58) 0.45 (0.29–0.69) 91 (2.9) 0.47 (0.30–0.75) 0.58 (0.36–0.91) 21 (2.5) 0.41 (0.23–0.74) 0.43 (0.24–0.78) 23 (6.1) 1.00 (ref) 1.00 (ref)

Data taken from 8 randomized statin trials. Values are n (%) unless otherwise indicated. The highest LDL-C category was used as the reference category. *Adjusted for sex, age, smoking status, presence of diabetes mellitus, systolic blood pressure, HDL-C concentration and trial. HDL-C, high-density lipoprotein cholesterol;

Boekholdt SM, et al. J Am Coll Cardiol 2014;64:485–94.

FOURIER: The lower the better

CV Death, MI, or Stroke

Giugliano RP, Lancet 2017;390:1962-1971

LDL-C (mM) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent

P = 0.0001

LDL-c (mM) at 4 weeks

Exploratory analysis of patients with LDL-C <0.26 mM (10 mg/dL)

11.9 7.8 7.3 4.4

5 10 15

CVD, MI, Stroke, UA, Coronary Revasc CVD, MI, Stroke

≥2.6 mM <0.26 mM

Efficacy

HR 0.69 (0.49-0.97) P=0.035 HR 0.59 (0.37-0.92) P=0.020

23.3 3.4 22.8 3.6

5 10 15 20 25 30

Serious adverse event AE -> drug discontinued

≥2.6 mM <0.26 mM

HR 0.94 (0.74-1.20) P=0.61 HR 1.08 (0.63-1.85) P=0.78

Safety

Giugliano RP, Lancet 2017;390:1962-1971

Outline

• Approach in the Past
• Fire and Forget
• Statins only
• Current Focus
• From LDL-c targets to LDL-c elimination
• From statins to combination therapy
• Opportunities Moving Forward
• Statin intolerance
• Other lipid targets to pursue

Opportunities Moving Forward

• Statin intolerance
• Other lipid targets to pursue
• Apolipoprotein B
• Lp(a)
• Apolipoprotein C-III and triglycerides

Other lipid targets to pursue

• All ApoB containing lipoproteins are atherogenic
• Statins are less effective in lowering ApoB than in lowering LDL-c
• Lp(a) is atherogenic and promotes atherothrombosis
• It is an independent risk factor for atherothrombotic events
• Statins have little effect on elevated levels of Lp(a)
• ApoCIII and triglycerides levels
• ApoCIII levels are associated with hypertriglyceridemia and CVD
• Triglyceride rich remnant lipoproteins promote atherothrombosis
• ApoCIII inhibits remnant uptake by the liver

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.

CV Risk in NASH and NAFLD

• Strong association between NAFLD and increased risk of CVD events and

mortality

• Patients with NAFLD have a pro-atherogenic lipid profile:
• Increased triglycerides
• Increased apolipoprotein B
• Higher concentration of small dense LDL
• Patients with NAFLD are at high risk for cardiovascular morbidity and mortality.

Thus, aggressive modification of CVD risk factors is mandatory in all patients with NAFLD.

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

Fatty Liver Predicts Risk of CV Events

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

**p<0.01 *p<0.05

MGL-3196: Lipid Effects in NASH

 ApoB is lowered by MGL-3196 about as much as LDL-c is lowered, a unique feature of this mechanism  ApoCIII was robustly lowered  Magnitude of triglyceride reduction equivalent or better than other therapeutics  These effects have the potential to provide clinical benefit to both early and late NASH patients, who all are at increased CV risk and who die most frequently of CV disease

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Lipids (% Change from Baseline)

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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

• f atherogenicity than LDL

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MG MGL-3196 3196: L Lipi pid Effec ects i in F n 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

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MG MGL-3196 3196: L Lipi pid Effec ects i in F n FH

MG MGL-3196 3196: Pot

• ten

ential of

• f a Dyslipi

pidem emia I Ind ndication i

• n in

n NA NASH/NA NAFLD

• MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory

approval for dyslipidemia

• Significant dyslipidemia opportunity exists in early NASH / NAFLD (>30M people in the US)

and diabetes populations (~70% have dyslipidemia)

• Potential target population includes early NASH / NAFLD patients not eligible for most NASH clinical

trials or NASH drugs in development

• 50% to 67% of diabetics on statins do not reach their LDL-c target and also have elevated

triglycerides; CV outcome studies consistently show that lower LDL-c/ApoB leads to better CV disease risk reduction: “lower is better”

• Possibility of regulatory approval based on LDL-c (and ApoB) reduction, with a post-approval

Phase 4 clinical trial demonstrating CV disease benefit

• Reduction of ApoB, Lp(a), ApoCIII/triglycerides, and liver fat in addition to CV benefit conferred by

LDL-c lowering

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confidential

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)

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Inclusion/Exclusion  NASH/NAFLD, metabolic syndrome, diabetics, primary dyslipidemia patients not at target on current lipid therapy  Fatty liver disease patients Comparator/Arms  MGL-3196 80 mg or Placebo, once daily Primary Endpoint  LDL cholesterol/Apo B lowering Key Secondary Endpoints  ApoB, Lp(a), ApoCIII and triglycerides, hsCRP lowering  MRI-PDFF (subset)  Safety Design Stage Drug  MGL-3196  2:1  Phase 3 Number of Patients Centers Treatment Duration  2500  USA, Europe, ROW  12 months

Study Overview Study Details

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MG MGL-3196 3196: : Pivotal P l Phase III III Programme

Conclusions

• LDL-c, unlike all other biomarkers in CV disease, has no biological lower

threshold for major adverse CV event reduction in CV disease

• Once LDL-c is controlled, the next horizon in the CVD field is reduction of

ApoB, Lp (a), ApoCIII and triglycerides

• Statin intolerance is a major clinical problem and new therapies the most

promising avenue to correct it

• The next major clinical problem in our field is the NAFLD-metabolic

syndrome-insulin resistance-dyslipidemia-axis: Madrigal is excellently suited to develop a comprehensive pharmacological strategy for this

• mnipresent risk factor constellation

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Q & A

Welcome to the Madrigal Analyst/Investor AASLD KOL Event

November 12, 2018