Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL

Madrigal Pharmaceuticals — Investor Presentation (December 2017)

32 slides from Madrigal Pharmaceuticals's investor presentation, December 2017

  1. Slide 1: Company Overview

    Company Overview December 2017 NASDAQ: MDGL 1

  2. Slide 2: Forward Looking Statements

    Forward Looking Statements 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 finan

  3. Slide 3: Madrigal Investment Highlights

    Madrigal Investment Highlights MGL-3196: First-in-Class 1 Thyroid Hormone Receptor (THR)-β Agonist Large & Underserved Markets in 2 NASH & Genetic Lipid Disorders Multiple Possible Value-Creating 3 Catalysts over Next 18 Months 4 Seasoned Management Team 3

  4. Slide 4: Madrigal's Team: Led by an Experienced Management Team

    Madrigal’s Team: Led by an Experienced Management Team with Multiple Successful NDA/MAAs and Marketed Products Paul Friedman, M.D. Rebecca Taub, M.D. Marc Schneebaum Chairman and CEO CMO, EVP R&D CFO, SVP  Former CEO of Incyte  Founder of Madrigal  Former CFO, SVP at Synta  Former President of R

  5. Slide 5: Pipeline: Madrigal has Two Phase 2 Programs with Multiple Near-Term Catalysts

    Pipeline: Madrigal has Two Phase 2 Programs with Multiple Near-Term Catalysts Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Familial Hypercholesterolemia (FH) Pre- Compound Indication Phase 1 Phase 2 Phase 3 Upcoming Catalysts Clinical  Phase

  6. Slide 6: Unmet Need: Madrigal Aims to Treat Patients with NASH

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

  7. Slide 7: Mechanism of Action: The Importance of Liver THR-β in NASH

    Mechanism of Action: The Importance of Liver THR-β in NASH We believe that MGL-3196, a selective THR-β agonist, will treat the underlying disease in NASH patients  The THR-β receptor mediates the beneficial effects of thyroid hormone in the liver, on LDL- cholesterol and triglycerides, fatty liver

  8. Slide 8: Safety: Highly Selective THR-β Agonist Avoids Off-target Effects

    Safety: Addressing Safety is Critical; Highly Selective THR-β Agonist Avoids Off-target Effects Selective Mechanism of Action Strong Preclinical and Clinical Safety Data  High selectivety for THR- β may reduce toxicity, which is  Unlike thyroid hormone (T3), MGL-3196 decreases mediated through the

  9. Slide 9: Preclinical: MGL-3196 Proof-of-Concept Well Established in Animal Models

    Preclinical: MGL-3196 Proof-of-Concept Well Established in Animal Models  Reduced Hepatic TGs  Improved Insulin Sensitivity Liver Triglycerides Insulin Tolerance Test (0.5 U/kg insulin) ** * * * ** ** * * p<0.05  Reduced Liver Enzymes  Improved Liver Histology ALT  All NASH Components Liver Fat

  10. Slide 10: Phase 1: Robust LDL and Triglyceride Lowering in 14 Day MAD Study

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

  11. Slide 11: Phase 2: MGL-3196 Trial Design

    Phase 2: MGL-3196 Trial Design is Targeted at Highly Relevant Primary and Secondary Endpoints Study Overview Study Details Inclusion/Exclusion Drug  MGL-3196  NASH on liver biopsy: NAS≥4 with fibrosis  ≥10% liver fat on MRI-PDFF  Include diabetics, statin therapy Design  Blinded 2:1 Comparator/

  12. Slide 12: Phase 2: MGL-3196 Study Achieved Primary Endpoint in Interim Readout

    Phase 2: MGL-3196 Study Achieved Primary Endpoint in Interim Readout ALL MGL- HIGH MGL- Placebo  Statistically significant improvements 3196 3196¹ in low-density lipoprotein cholesterol (LDL-C), triglycerides and lipoprotein (a) Lp(a)²  Statistically significant improvements Number of patients 78

  13. Slide 13: Competitive Position: MGL-3196 Well-Positioned in the NASH Landscape

    Competitive Position: MGL-3196 Well-Positioned in the NASH Landscape Target NAS Fibrosis NASH Insulin CV compound Score Score Liver Lipids Prevention Sensitivity LDL TGs Risk Side Effects FXR ✔ ✔ ✔ ✔ ✔  — LDL-C Pruritus Anti-fibrotic ? ✔ — ✖ — — — ? Unknown PPARαδ ✔ ✖ — ? ✔   PPARα/δ Well-tolera

  14. Slide 14: FH: Madrigal also Targeting Familial Hypercholesterolemia in Phase 2 Trials

    FH: In addition to NASH, Madrigal also Targeting Familial Hypercholesterolemia in Phase 2 Trials  HeFH and HoFH caused primarily by inactivating mutations in LDL receptor Severe  Early onset cardiovascular disease, HoFH < age 20 Debilitating Dyslipidemia  Associated with several of potentially se

  15. Slide 15: FH: Phase 2 HeFH Clinical Trial with Anticipated Readout in 1Q 2018

    FH: Phase 2 HeFH Clinical Trial with Anticipated Readout in 1Q 2018 Study Overview Study Details Inclusion/Exclusion Drug  MGL-3196  HeFH on maximally tolerated statins (typically high dose), ezetimibe Design  2:1 Comparator/Arms  MGL-3196 or Placebo, once daily Stage  Phase 2 Primary Endpoint

  16. Slide 16: Catalysts: Our Expectations for Development Timing

    Catalysts: Our Expectations for Development Timing 2016 2017 2018+ Completed Milestones: Upcoming Catalysts:  Completion of long-term  Initiation of 12-week Phase 2 trial  36-week topline liver biopsy data from toxicology studies for of MGL-3196 for HeFH Phase 2 trial of MGL-3196 for NASH MGL-319

  17. Slide 17: Madrigal Investment Highlights

    Madrigal Investment Highlights MGL-3196: First-in-Class 1 Thyroid Hormone Receptor (THR)-β Agonist Large & Underserved Markets in 2 NASH & Genetic Lipid Disorders Multiple Possible Value-Creating 3 Catalysts over Next 18 Months 4 Seasoned Management Team 17

  18. Slide 18: Appendix: Additional Material

    Appendix: Additional Material 18

  19. Slide 19: THR-β Agonism: Expected Direct Anti-Fibrotic Actions

    THR-β Agonism: Expected Direct Anti-Fibrotic Actions • Fat deposition, lipotoxicity and resultant local inflammation are seen in NASH • Hepatocyte dysregulation and damage ensue up to and including apoptosis. These perturbations lead to a profibrotic environment through: • Ongoing inflammation; • Pr

  20. Slide 20: THR-β: Decreased Liver Fibrosis and Apoptosis

    THR-β: Decreased Liver Fibrosis and Apoptosis • 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) • THR-β knockout and hypothyroid mice have delayed liver regeneration, increased apoptosis

  21. Slide 21: MGL-3196, a First-in-Class Liver-Directed THR-β Agonist

    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 previous companies’ analogues • Discovery of MGL-3196 and backups at Roche utilized a novel functional assay that went beyond what previous companie

  22. Slide 22: MGL-3196 Agonism of Hepatic THR-β

    MGL-3196 Agonism of Hepatic THR-β • In livers of euthyroid individuals T3 induces about half the maximal transcriptional activity of THR- beta • MGL-3196 can further beneficially increase this transcriptional activity as we have shown in euthyroid animal models and humans. • Interestingly, systemic

  23. Slide 23: MGL-3196: Reduction of Key NASH, Fibrosis Pathway Genes

    MGL-3196: Reduction of Key NASH, Fibrosis Pathway Genes at Human Comparable Drug Levels 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) MGL-3196 (mg/kg) Inflammation HFD Lean 0.1 0.3 1 3 Rosi MCP-1/CCL2 MIP-2α/CXCL2 MIP-2ß/CXLCL

  24. Slide 24: MGL-3196: Radiographic Tissue Distribution

    MGL-3196: Radiographic Tissue Distribution22 • 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 was the feces via biliary excretion • Uptake was low to undetectable h

  25. Slide 25: MGL-3196: Long-term Dosing in Humans is Enabled

    MGL-3196: Long-term Dosing in Humans is Enabled Completed: • Single Ascending Dose (SAD) study • Multiple Ascending Dose (MAD) study • Six dose cohorts, 36 total HV 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 L

  26. Slide 26: Lipid Lowering in Additional Phase 1 Studies

    Lipid Lowering in Additional Phase 1 Studies • 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 o

  27. Slide 27: MGL-3196 Phase 2 NASH Study: Likelihood of Success

    MGL-3196 Phase 2 NASH Study: Likelihood of Success • Excellent correlation between decline in fat content on MRI-PDFF and NAS score, steatosis and ballooning on biopsy (Ther. Adv. Gastroenterol. 2016; 9:692-701) • Rapid liver fat changes detectable with MRI-PDFF after caloric restriction and weight

  28. Slide 28: NASH Phase 2 Demographics

    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) 28

  29. Slide 29: NASH Baseline Characteristics

    NASH 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% NAS score of at least 4, range 4-8 and fibrosis 1-3 2

  30. Slide 30: Current Challenges in Treatment of FH

    Current Challenges in Treatment of FH HoFH HoFH LDL • Most patients still not reaching LDL-C goal Lipid Lowering Therapy decrease • Newer agents, Lomitapide (Juxtapid, MTPi) and Conventional Mipomersen (Kynamro, anti-ApoB) may have safety issues Statins Up to 28% • Both carry FDA label warning*, hep

  31. Slide 31: MGL-3196: Unique and Complementary Lipid Lowering Profile

    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

  32. Slide 32: Proposed Phase 2a HoFH Clinical Trial Protocol

    Proposed Phase 2a HoFH Clinical Trial Protocol Study Study Details Drug MGL-3196 Inclusion/Exclusion • HoFH on standard care, may include PCSK9ab, statins, ezetimibe Design Open label Comparator/Arms Stage Ph2 • Patient is his own control • MGL-3196 may be titrated # Patients 6-8 Primary Endpoint Ce

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