Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL

Madrigal Pharmaceuticals — H.C. Wainwright conference March 2018

25 slides from Madrigal Pharmaceuticals's conference presentation, March 2018

  1. Slide 1: H.C. Wainwright March 2018

    H.C. Wainwright March 2018 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: 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 In humans THR-β agonism:  Lowers LDL-cholesterol  Lowers triglycerides  Lowers liver fat, potentially reducing lipotoxicity, NASH No t

  7. Slide 7: Lipotoxicity May be Reduced by THR-β Agonists

    Lipotoxicity May be Reduced by THR-β Agonists  Most hepatic fat derives from external sources, particularly free fatty acids from adipocytes  In NASH, β-oxidation of liver lipids is reduced contributing to β-oxidation of fat in lipotoxicity mitochondria  THR-β agonists reduce liver fat through br

  8. Slide 8: THR-β Agonism: Potential Anti-Fibrotic Actions

    THR-β Agonism: Potential Anti-Fibrotic Actions  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 fib

  9. Slide 9: 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 other companies’ previous analogues  Discovery of MGL-3196 and backups at Roche utilized a novel functional assay that went beyond what previous comp

  10. Slide 10: MGL-3196: Radiographic Tissue Distribution

    MGL-3196: Radiographic Tissue Distribution  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 he

  11. Slide 11: 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

  12. Slide 12: 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

  13. Slide 13: 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

  14. Slide 14: 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  Phase 1 studies dosing MGL-3196 with statins, mass balance study and tablet formulation  Series of GLP toxicology and CMC studies support all indications • Manufact

  15. Slide 15: Phase 2: MGL-3196 Trial Design and Endpoints

    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/

  16. Slide 16: 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) 16

  17. Slide 17: NASH Phase 2 Baseline Characteristics

    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%  NAS score of at least 4, range 4-8 and fibr

  18. Slide 18: 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

  19. Slide 19: Phase 2 Liver Biopsy, Extension Study and Phase 3 NASH Plans

    Phase 2 Liver Biopsy, Extension Study and Phase 3 NASH Plans  Read out of 36 week liver biopsy by end May Biomarker Monitoring in Patients Enrolled in the NASH Extension Study  Preparation for end of Phase 2 FDA meeting and conduct of manufacturing, preclinical studies that support Phase 3 % Chang

  20. Slide 20: FH: Phase 2 HeFH Clinical Trial Which Read Out in 2018

    FH: Phase 2 HeFH Clinical Trial Which Read Out in 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 Number of  1

  21. Slide 21: Phase 2: MGL-3196 Achieved Primary and Secondary Endpoints in HeFH

    Phase 2: MGL-3196 Achieved Primary and Secondary Endpoints in Patients with HeFH ALL MGL- Optimal  Baseline characteristics balanced between 3196 MGL-31962 placebo (pbo) and MGL-3196-treated; 75% taking high intensity statins (20/40 mg Total patients/MGL-3196 113/76 76/39 rosuvastatin or 80 mg ator

  22. Slide 22: Competitive Position: MGL-3196 is Differentiated in the NASH Landscape

    Competitive Position: MGL-3196 is Differentiated in the NASH Landscape Target NAS Fibrosis NASH Insulin CV compound Score Score Liver Lipids Prevention Sensitivity LDL TGs Risk Side Effects Pruritus (BA FXR, FGF-19 ✔ ✔ ✔ ✔ ✔  — LDL-C analogues) Anti-fibrotic ? ✔ — ✖ — — — ? Unknown PPARαδ ✔ ✖ — ?

  23. Slide 23: Catalysts: Our Expectations for Development Timing

    Catalysts: Our Expectations for Development Timing 2016 2017 2018+ Completed Milestones:  Completion of long-term  Initiation of 12-week Phase 2 trial ✔ Topline data from Phase 2 trial of MGL- toxicology studies for of MGL-3196 for HeFH 3196 for HeFH MGL-3196  Positive topline 12-week data Upcomi

  24. Slide 24: 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 24

  25. Slide 25: Appendix: Additional Material

    Appendix: Additional Material 25

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