Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL
Madrigal Pharmaceuticals — Investor Presentation (September 2019)
29 slides from Madrigal Pharmaceuticals's investor presentation, September 2019
Slide 1: Nonconfidential September 2019
Nonconfidential September 2019 1
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: Pipeline: Madrigal has Initiated the Phase 3 in NASH Fibrosis
Pipeline: Madrigal has Initiated the Phase 3 in NASH Fibrosis Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Dyslipidemia Pre- Compound Indication Phase 1 Phase 2 Phase 3 Upcoming Catalysts Clinical Nonalcoholic Steatohepatitis (NASH) Phase 3
Slide 4: NAFLD Ranges from Simple Steatosis to NASH, a Progressive Form of Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD) Ranges from Simple Steatosis (NAFL) to NASH, a Progressive Form of Liver Disease D I NAFLD results from accumulation of NAFLD Spectrum excess fat within the liver (steatosis) S Fat Accumulation E unrelated to alcohol use A Some patients with NAFLD have N
Slide 5: MGL-3196 Development Path Across the Spectrum of NAFLD/NASH
MGL-3196 Development Path Across the Spectrum of NAFLD/NASH NASH/NAFLD Spectrum1 1.3 million F4 Phase 3 NASH study: NASH Resolution (primary), LDL-C, 2.0 million F3 fibrosis (key secondary); Phase 4 (post-approval): CV Benefits cirrhosis and MACE 3.4 million F2 Fatty liver LDL-C F1B ApoB Triglycerid
Slide 6: Resmetirom - High Potential to Resolve NASH, Improve Fibrosis and Provide Cardiovascular Protection
Resmetirom - High Potential to Resolve NASH, Improve Fibrosis and Provide Cardiovascular Protection ◼ Once a day oral ◼ Selective thyroid receptor-β agonist - intrinsically 28 fold 𝛽𝛽 selective relative to 𝛼𝛼 ◼ Liver directed - no exposure outside liver, >99% protein bound, does not cross blood…
Slide 7: Mechanism of Action: The Importance of Liver THR-β in NASH
Mechanism of Action: The Importance of Liver THR-β in NASH Thyroid In humans, thyroid hormone receptor-β (THR-β) agonism: Nuclear THR-α, THR-β Gland Lowers LDL-cholesterol T44 Lowers triglycerides T3 Lowers liver fat, potentially reducing T4, prohormone Liver lipotoxicity, NASH T3, active horm
Slide 8: MGL-3196, First and Best-in-Class Liver-Directed THR-β Agonist
MGL-3196, First and Best-in-Class Liver-Directed THR- β Agonist First bona fide THR-β selective molecule with key advantages Discovery of MGL-3196 utilized a novel in vitro functional assay, 28 fold THR-β selective with virtually no THR-α activity — Other thyromimetic compounds lacked beta selecti
Slide 9: Phase 2 NASH Study Design: Randomized, Double-Blind, Placebo Controlled
Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled MRI-PDFF MRI-PDFF Liver Biopsy PK MRI-PDFF Liver Biopsy MRI-PDFF Screening D1 W2 W4 W12 W36 ExD1 W12 W36 36 Week Main Study Extension Study Comparator/Arms 2:1 MGL-3196 to placebo 125 patients enrolled in USA, 18 sites MGL-319
Slide 10: Study Endpoints
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 co
Slide 11: Baseline Characteristics
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-
Slide 12: Safety
Safety 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, GI Aes not increased in Phase 1 or NASH extension study AEs No lab abnormalities or other AEs were inc
Slide 13: Resmetirom: Potential Improvements in NASH and Fibrosis
Resmetirom: Potential Improvements in NASH and Fibrosis 1. Steatosis: a. Resmetirom, administered at Phase 3 doses (80 or 100 mg/qd) clears more liver fat (MRI- PDFF), than other agents at doses that are adequately tolerated. b. Emerging data indicate ≥30% hepatic fat removal predicts higher rates o
Slide 14: Resmetirom - Fibrosis (continued)
Resmetirom - High Potential to Resolve NASH, Improve Fibrosis and Provide Cardiovascular Protection (continued) 4. Fibrosis: a. Trend favoring resmetirom in Phase 2 (the study was not powered for 1-point improvement in fibrosis); b. 50% of patients who resolved NASH also resolved fibrosis, 61% of NA
Slide 15: Dose-related Sustained Reduction in Liver Fat on MRI-PDFF
Dose-related Sustained Reduction in Liver Fat on MRI-PDFF Relative Fat Reduction (%) Absolute Fat Reduction (%) 36 Week Extension Study Main, 36 Week Study Thirty patients, 14 former placebo patients Sustained statistically significant reduction in were treated with MGL-3196, 80 mg for an hepati
Slide 16: MRI-PDFF Absolute Fat Reduction (%)
MRI-PDFF Absolute Fat Reduction (%) Target FGF19 THR-𝛽𝛽 FXR FGF21 ACC GLP-1 THR-𝛽𝛽 Early Disease NASH NASH NASH NAFLD NAFLD NAFLD Early NAFLD Weeks 12 36 72 16 12 24 12 MGL- GS- VK280 Treatment Pbo NGM28 Pbo MGL- 3196 OCA/pb Pbo Peg Pbo 0976 Lira Pbo 9 2 0 3196 25 0 dose (mg) 0 3 sc (n=3 60/80…
Slide 17: MRI-PDFF Relative Fat Reduction (%)
MRI-PDFF Relative Fat Reduction (%) Target FGF19 THR-𝛽𝛽 FXR FGF21 ACC GLP-1 THR-𝛽𝛽 Early Disease NASH NASH NASH NAFLD NAFLD NAFLD Early NAFLD Weeks 12 36 72 16 12 24 12 MGL- GS- VK280 Treatment Pbo NGM28 Pbo MGL- 3196 OCA/pb Pbo Peg Pbo 0976 Lira Pbo 9 2 0 3196 25 0 dose (mg) 0 3 sc (n=3 60/80…
Slide 18: NASH Resolution: Ballooning = 0; Inflammation = 0,1; No worsening of fibrosis
NASH Resolution: Ballooning = 0; Inflammation = 0,1; No worsening of fibrosis stage 40 Biopsies with resolution (%) 35 30 25 20 37 15 25 10 19 16.7 5 14.9 7.9 9 0 5 6 0 Treatment Pbo OCA Pbo Elafibranor Pbo Aramchol Pbo MGL-3196 3196 PDFF+ 0 mg 25 mg 0 mg 120 mg 0 mg 600 mg 0 mg 60–80 mg 60–80 mg do
Slide 19: NASH Resolution: Non-NASH or Ballooning=0; no worsening of fibrosis
NASH Resolution: ”Non-NASH” or Ballooning=0; no worsening of fibrosis In older studies Inflammation score not considered 100 90 80 Biopsies with resolution (%) 70 60 50 90 40 30 20 47 36 39 10 21 10 9 0 Treatment dose Pbo Pioglitazone Vitamin E Pbo Lira ≥5% wt loss ≥10% wt loss (n) 0 mg 30 mg 800 mg
Slide 20: Correlation of Decrease in Hepatic Fat with Improvement in Ballooning and Inflammation
Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy NASH Resolution (%); Biopsies with MRI-PDFF Week 12, % Relative Change: Both Ballooning and Inflammation Correlation with Change in Improvement Ballooning and Inflammation Scores MGL-319
Slide 21: Week 36: Change in Fibrosis Score on Liver Biopsy
Week 36: Change in Fibrosis Score on Liver Biopsy ≥1 pt reduction in fibrosis SHG Score on liver biopsy (SHG) SHG (qfibrosis) 3 2 1 0 Pathologist Score Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique ar
Slide 22: Phase 3/4: MGL-3196 NASH Trial
Phase 3/4: MGL-3196 NASH Trial Study Overview Study Details Inclusion/Exclusion MGL-3196 NASH on liver biopsy: NAS≥4, high risk F1, F2/3 Drug (resmetirom) Comparator/Arms Blinded MGL-3196 80 or 100 mg or Placebo, once daily Design 1:1:1 Primary Endpoint Phase 3: Liver biopsy at 52 weeks -
Slide 23: Phase 3 Largely Replicates the Phase 2 Design at Higher Doses
Phase 3 Largely Replicates the Phase 2 Design at Higher Doses Phase 2 NASH Phase 3 NASH Liver biopsy confirmed NASH; NAS≥4 F1-3 NAS≥4, F2-F3, primary assessment; F1B MRI-PDFF≥10% fat fraction MRI-PDFF ≥8% fat fraction Enrollment 125 1:2 placebo: resmetirom Enrollment 900 1:1:1 placebo: 2 doses Dose:
Slide 24: Fatty Liver Associates with Overall CVD Mortality
Fatty Liver Associates with Overall CVD Mortality Pisto P et al. BMJ Open 2014;4:e004973. doi:10.1136/bmjopen-2014-004973 24
Slide 25: CV Risk in NASH and NAFLD
CV Risk in NASH and NAFLD ◼ Strong association between NAFLD, particularly NASH fibrosis, and increased risk of CVD events and mortality — Death from CVD much more common than death from liver disease (Angulo, 2015) ◼ Patients with NAFLD have a pro-atherogenic lipid profile: — Increased triglyceride
Slide 26: Week 36: Sustained Robust Lipid Lowering
Week 36: Sustained Robust Lipid Lowering Lipids (% Change from Baseline) ◼MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory approval for dyslipidemia; an also reduces fatty liver, an independent CV risk factor ◼ApoB, not LDL-C is the major risk factor in CV disea
Slide 27: Phase 3: MAESTRO-NAFLD-1
Phase 3: MAESTRO-NAFLD-1 Study Overview Study Details Inclusion/Exclusion Drug MGL-3196 NASH/NAFLD patients not at target on standard care lipid therapy (LDL-C ≥00 or TGs>150; ≥ 70 mg/dL in patients with CV disease, very high risk diabetics) Design 1:1:1:1 Eligibility: fibroscan, ultrasound,
Slide 28: Catalysts: Our Expectations for Development Timing
Catalysts: Our Expectations for Development Timing 2017 2018 2019 Completed Milestones: Initiation of 12-week Phase 2 Positive topline data from Phase 2 Completion of 36 Week NASH trial of MGL-3196 for HeFH trial of MGL-3196 for HeFH Extension Study Positive topline 12-week data Positive 3
Slide 29: Nonconfidential September 2019
Nonconfidential September 2019 29
Madrigal Pharmaceuticals — Investor Presentation (September 2019) on 6ix