Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL
Madrigal Pharmaceuticals — Investor Presentation (June 2017)
28 slides from Madrigal Pharmaceuticals's investor presentation, Jun 5, 2017
Slide 1: Madrigal Pharmaceuticals, Inc.
Madrigal Pharmaceuticals, Inc. NASDAQ: MDGL 1 6/5/2017
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
Slide 3: Madrigal Investment Highlights
Madrigal Investment Highlights MGL-3196: First-in-Class • Phase 2 once-daily oral, liver-directed thyroid hormone receptor-β agonist (THR-β); efficacy THR-ß Agonist and safety profile validated by preclinical and clinical data Large & Underserved Markets in NASH & • Initial indications are NASH and
Slide 4: Madrigal Leadership
Madrigal Leadership • Combined company is led by an experienced management team with multiple successful NDA/EMAs and marketed products • Paul Friedman, M.D. - Chairman and CEO • Former CEO of Incyte Pharmaceuticals; former President of DuPont Pharmaceuticals Research R & D • Rebecca Taub, M.D. - Ch
Slide 5: The Importance of Liver THR-β in NASH
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 and insulin sensitivit
Slide 6: 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
Slide 7: MGL-3196: Improved Safety Profile Relative to T3
MGL-3196: Improved Safety Profile Relative to T3 24d study in 40 week old diet-induced obese (DIO) mice on High Fat Diet (HFD) for 38 weeks Cholesterol T3 Bone Mineral Density 300.0 0.06 Cholesterol (mg/dl±s.d.) Bone Density (g/cm*cm) 250.0 0.05 ** 200.0 *** *** Thyroid hormone *** 0.04 150.0 *** 0.
Slide 8: MGL-3196: Data Supports Improvement in Liver Health
MGL-3196: Data Supports Improvement in Liver Health 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 Liver Triglycerides 5 70 Insulin Tolerance Test Liver % Body Weight 120 Triglycerides mg/g
Slide 9: 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
Slide 10: 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
Slide 11: 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
Slide 12: MGL-3196: Robust LDL and Triglyceride Lowering in Multiple Dose Phase 1 Study
MGL-3196: Robust LDL and Triglyceride Lowering in 14 Day Multiple Dose Phase 1 Study Change in Lipids After 14 Days 20 10 %Change From Baseline MGL-3196, 0 Placebo Subtracted Chol LDL-C ApoB Non-HDL-C TG -10 * * * -20 ** ** *** ** *** ** ** ** *** *** -30 *** *** *** -40 -50 “ *** p<0.001 ** p<0.01
Slide 13: Lipid Lowering in Additional Phase 1 Studies
Lipid Lowering in Additional Phase 1 Studies 0) L 15 D ll) C -H (> (a oB ) L- (a on TG TG Ap LD Lp N 0 • In Phase 1 studies, 38 healthy volunteers were %change from baseline (CFB) -10 dosed with one-two days of a statin and -20 multiple daily doses (9-11) of MGL-3196 (100 or 200 mg) -30 • Robust lip
Slide 14: Phase 2 Proof-of-Concept NASH Protocol
Phase 2 Proof-of-Concept NASH Protocol Study Study Details Drug MGL-3196 Inclusion/Exclusion • NASH on liver biopsy • 10% liver fat on MRI-PDFF Design Blinded • Include diabetics, statin therapy 2:1 Comparator/Arms Stage Ph2 • MGL-3196 or Placebo, once daily Primary Endpoint # Patients 117 • Reducti
Slide 15: 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
Slide 16: Strong Positioning in NASH Landscape
Strong Positioning in NASH Landscape NAS Fibrosis Liver NASH Insulin CV Target compound LDL TGs Side Effects Score Score Lipids Prevention Sensitivity Risk FXR ✔ ✓ ✓ ✓ ✔ — LDL-C Pruritus Anti-fibrotic ? ✔ — ✖ — — — ? Unknown PPARαδ ✓ ✔Benefit ✖ — ✓Small benefit ? Decrease ✔ Green = Good PPAR
Slide 17: Unmet Needs in FH, a Severe Genetic Dyslipidemia
Unmet Needs in FH, a Severe Genetic Dyslipidemia • HeFH and HoFH caused primarily by inactivating mutations in LDL Severe Debilitating receptor Dyslipidemia • Early onset cardiovascular disease, HoFH < age 20 Prevalence • 1/200-1/500 HeFH; 1/250,000-1/1,000,000 HoFH • Higher frequency in certain gen
Slide 18: 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
Slide 19: Phase 2 HeFH Clinical Trial Protocol
Phase 2 HeFH Clinical Trial Protocol Study Study Details Drug MGL-3196 Inclusion/Exclusion • HeFH on maximally tolerated statins (typically high dose), ezetimibe Design 2:1 Comparator/Arms • MGL-3196 or Placebo, once daily Stage Ph2 Primary Endpoint # Patients 105 • LDL cholesterol lowering Centers
Slide 20: Potential Near and Long-term Value Drivers
Potential Near and Long-term Value Drivers 2016 2017 2018 Clinical trial initiated: Clinical trial initiations: Potential Data Readouts: • Ph2 in NASH: • Ph2 in HeFH: • Ph2 topline results in NASH (liver 12 week MRI-PDFF with 12-week clinical trial (initiated) biopsy) 36-week liver biopsy • Ph2a in
Slide 21: Madrigal Investment Highlights
Madrigal Investment Highlights MGL-3196: First-in-Class • Phase 2 once-daily oral, liver-directed thyroid hormone receptor-β agonist (THR-β); efficacy THR-ß Agonist and safety profile validated by preclinical and clinical data Large & Underserved Markets in NASH & • Initial indications are NASH and
Slide 22: Thank you
Thank you NASDAQ: MDGL 22 6/5/2017
Slide 23: Back Up Slides
Back Up Slides 23 6/5/2017
Slide 24: NASH: High Prevalence and Significant Mortality
NASH: High Prevalence and Significant Mortality NAFLD is the most common liver disease world-wide ~25% of US population Rapid progression, <2 years 25% of NASH ~5% of the US population has NASH Stage 3 progress to cirrhosis • NASH was coined over 40 years ago, to describe fatty changes with lobular
Slide 25: 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
Slide 26: THR-β: Decreased Liver Fibrosis and Apoptosis
THR-β: Decreased Liver Fibrosis and Apoptosis α β • THR-β -/- mice have increased β liver fibrosis with age α β β • Treatment β with thyroid hormone reduces fibrosis in animal models of liver fibrosis (PNAS β113: 3451, 2016) β β β α β µ ± β • THR-β knockout and hypothyroid ± ´ mice have delayed live
Slide 27: 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
Slide 28: 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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