Madrigal Pharmaceuticals, Inc. · NASDAQ:MDGL
Madrigal Pharmaceuticals — Technical Presentation (November 2018)
52 slides from Madrigal Pharmaceuticals's technical presentation, Nov 12, 2018
Slide 1: Welcome to the Madrigal Analyst/Investor AASLD KOL Event
Welcome to the Madrigal Analyst/Investor AASLD KOL Event November 12, 2018
Slide 2: Forward-Looking Statements
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;
Slide 3: Agenda
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 I
Slide 4: Phase 2 Trial: MGL-3196 Compared to Placebo Results
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,
Slide 5: 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 6: Study Design: Randomized, Double-Blind, PBO Controlled Trial
Study Design: Randomized, Double-Blind, PBO Controlled Trial 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-3196 or pl
Slide 7: 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 8: 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 9: Week 36: Sustained Reduction in Liver Fat on MRI-PDFF
Week 36: Sustained Reduction in Liver Fat on MRI-PDFF Relative Fat Reduction (%) Absolute Fat Reduction (%) Placebo MGL-3196 (all) MGL-3196 (high exp) ≥30% Fat Reduction (%) Main, 36 Week Study Sustained statistically significant reduction in hepatic fat Week 12 to Week 36 Placebo response gener
Slide 10: Extension Study of 36 Week Phase 2 Trial
Extension Study of 36 Week Phase 2 Trial 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 Ex
Slide 11: Extension Study: Reduction in Liver Fat on MRI-PDFF
Extension Study: Reduction in Liver Fat on MRI-PDFF ≥30% Fat Relative Fat Absolute Fat Reduction (%) Reduction (%) Reduction (%) Main Extension 13
Slide 12: NASH Extension Study
NASH Extension Study MGL-3196 ◼ 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),
Slide 13: Week 36: Sustained Robust Lipid Lowering
Week 36: Sustained Robust Lipid Lowering Lipids (% Change from Baseline) Significant sustained lowering effect in multiple atherogenic lipids Placebo corrected; p value, placebo compared to MGL-3196; MGL-3196, n=79; placebo, n=39 15
Slide 14: Week 36: Liver Enzymes
Week 36: Liver Enzymes Week 36, 40% reduction in ALT in patients with elevated baseline (p=0.01), and all MGL-3196 relative ALT 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-319
Slide 15: Week 36: NASH Liver Biopsy Endpoints
Week 36: NASH Liver Biopsy Endpoints 2-Point NAS Reduction with at least a 1-pt reduction in 2-pt reduction in NAS in ballooning or placebo patients was inflammation correlated with body (% of liver biopsies) weight loss Placebo MGL-3196 (all) MGL-3196 (high exp) MGL-3196, MRI responder NASH Resolut
Slide 16: NAS Endpoint-Defining Dose
NAS Endpoint-Defining Dose Statistically significant dose and exposure dependent improvement in Change in NAS, NAS with low/no effect dose baseline to demonstrated Week 36 MRI Responder; ≥ 30% fat reduction on Week 12 High exposure, n=44; low exposure n=29; based on prespecified exposure groups 18
Slide 17: Correlation of Decrease in Hepatic Fat with Ballooning and Inflammation
Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy NASH Resolution (%) MRI-PDFF Week 12, % Relative Change: Correlation with Change in MGL-3196-treated Ballooning Plus Inflammation Scores Patients who were not MRI-PDFF Responders (≥30%
Slide 18: Week 36: Reduction of Fibrosis Biomarkers
Week 36: Reduction of Fibrosis, Biomarkers ELF BL≥9 CK-18 (M30) U/L Pro-C3 (ng/ml) week % change MGL-3196 (all) MGL-3196 (high exp) F2/F3 ELF, CK-18 and Pro-C3 scores, biomarkers correlated with liver fibrosis stage, were statistically significantly reduced in MGL-3196 treated, especially in patient
Slide 19: 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 20: Safety and Additional Biomarkers
Safety and Additional Biomarkers 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 AEs No lab abnormalities or other AEs were increased in MGL-3196 compared wit
Slide 21: AE Table
AE Table Placebo MGL-3196 n = 41 n = 84 In healthy volunteers 3% (128 Patients with Adverse Events 28 (68.3) 73 (86.9) subjects) reported transient Severe 2 (4.9) 6 (7.1) diarrhea on 100 mg dose, two Moderate 13 (31.7) 27 (32.1) weeks of dosing Mild 13 (31.7) 40 (47.6) Patients with SAEs 2 (4.9) 5 (
Slide 22: Conclusions
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 ◼ Sustain
Slide 23: Phase 3/4: MGL-3196 NASH Trial Design
Phase 3/4: MGL-3196 NASH Trial Design Study Overview Study Details Inclusion/Exclusion Drug MGL-3196 NASH on liver biopsy: NAS≥4, high risk F1, F2/3 Comparator/Arms Design Blinded 2:1 MGL-3196 or Placebo, once daily Primary Endpoint Phase 3: Liver biopsy at 52 weeks - resolution of NASH St
Slide 24: Q&A
. Q&A
Slide 25: The future of cardiovascular disease prevention
The future of cardiovascular disease prevention John JP Kastelein Professor of Internal Medicine Academic Medical Center Amsterdam, the Netherlands
Slide 26: Outline
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
Slide 27: Causative factors versus bystanders
Causative factors versus bystanders Boren J, Curr Opin Lipidol 2016;27:473-483
Slide 28: LDL-C Lowering Therapies Reduce CV Risk
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 the
Slide 29: Outline
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
Slide 30: Genetic versus Therapeutic LDL-c Reduction
Genetic versus Therapeutic LDL-c Reduction
Slide 31: Concept Change I: Start Treatment Early
Concept Change I: Start Treatment Early Less ‘LDL-exposure’ leads to prevention of lesion formation FH Cumulative exposure is important Treat the earlier, the better! Wiegman et al. European Heart Journal, 2015
Slide 32: Concept Change II: Use Combination Therapy
Concept Change II: Use Combination Therapy Ezetimibe induced LDL-c lowering reduces CV-risk 50% Proportional Reduction in Event 40% 30% Rate (SE) CTT-meta-analysis 20% 10% IMPROVE-IT 0% 0.5 1.0 1.5 2.0 Reduction in LDL-C (mmol/L) CTTC. Lancet 2005;366:1267–1278. CTTC. Lancet 2010;376:1670–1681. Cann
Slide 33: PCSK9-antibody on top of statins: FOURIER
PCSK9-antibody on top of statins: FOURIER 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-c ≥70 mg/dL or non-HDL-c ≥100 mg/dL RAND
Slide 34: LDL-c reduction and CV benefit
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 2.5 Placebo HR 0.85 (0.79-0.92) P<0.0001 2.0 59% mean decline P<0.00001 LDL-C (mM) 1.5 Absolute↓1.45 mM (1.42-1.47) 1.0 Evolo
Slide 35: Concept change III: Treat (much more) aggressively
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 50–< 75 75–< 100 100–< 125 125–< 150 150–< 175 ≥ 175 (< 1.29) (1.29–< 1.94) (1.94–< 2.58) (2.58–< 3.23) 3.23– <3.88 (3.88–< 4.52) (≥ 4.52) (n
Slide 36: FOURIER: The lower the better
FOURIER: The lower the better CV Death, MI, or Stroke 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) P = 0.0001 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent LDL-c (mM) at 4 weeks Giugliano RP, Lancet 2017;390:1962-1971
Slide 37: Exploratory analysis of patients with LDL-C <0.26 mM
Exploratory analysis of patients with LDL-C <0.26 mM (10 mg/dL) Efficacy Safety 15 HR 0.69 (0.49-0.97) ≥2.6 mM 30 HR 0.94 (0.74-1.20) ≥2.6 mM P=0.035 P=0.61 <0.26 mM <0.26 mM 11.9 HR 0.59 (0.37-0.92) 25 23.3 22.8 P=0.020 10 20 7.8 7.3 15 HR 1.08 (0.63-1.85) 5 4.4 10 P=0.78 5 3.4 3.6 0 0 CVD, MI, Str
Slide 38: Outline
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
Slide 39: Opportunities Moving Forward
Opportunities Moving Forward • Statin intolerance • Other lipid targets to pursue • Apolipoprotein B • Lp(a) • Apolipoprotein C-III and triglycerides
Slide 40: Other lipid targets to pursue
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 el
Slide 41: Diabetic Dyslipidemia
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
Slide 42: CV Risk in NASH and NAFLD
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 r
Slide 43: Fatty Liver Predicts Risk of CV Events
Fatty Liver Predicts Risk of CV Events **p<0.01 *p<0.05 Pisto P et al. BMJ Open 2014;4:e004973. doi:10.1136/bmjopen-2014-004973
Slide 44: MGL-3196: Lipid Effects in NASH
MGL-3196: Lipid Effects in NASH Lipids (% Change from Baseline) 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 t
Slide 45: MGL-3196: Lipid Effects in FH
confidential MGL-3196: Lipid Effects in FH ◼ 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
Slide 46: MGL-3196: Lipid Effects in FH
confidential MGL-3196: Lipid Effects in FH TGs, ApoCIII Small LDL Particles ◼ MGL-3196 reduces triglycerides, VLDL and LDL-particles, particularly small LDL particles which are highly atherogenic ◼ ApoCIII reduction is likely an hsCRP important mechanism by which MGL-3196 lowers TGs ◼ MGL-3196 reduc
Slide 47: MGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLD
confidential MGL-3196: Potential of a Dyslipidemia Indication in NASH/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 popu
Slide 48: MGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLD
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) 50
Slide 49: MGL-3196: Pivotal Phase III Programme
confidential MGL-3196: Pivotal Phase III Programme Study Overview Study Details Inclusion/Exclusion Drug MGL-3196 NASH/NAFLD, metabolic syndrome, diabetics, primary dyslipidemia patients not at target on current lipid therapy Design 2:1 Fatty liver disease patients Comparator/Arms Stage Ph
Slide 50: Conclusions
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 c
Slide 51: Q&A
. Q&A
Slide 52: Welcome to the Madrigal Analyst/Investor AASLD KOL Event
Welcome to the Madrigal Analyst/Investor AASLD KOL Event November 12, 2018
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