Company Overview. June 2018 NASDAQ: MDGL

Transcription

1 Company Overview June 2018 NASDAQ: MDGL 1

2 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 financing; the estimated size of the market for our product candidates, the timing and success of our development and commercialization of our anticipated product candidates; and the availability of alternative therapies for our target market, are, or may be deemed, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of In some cases, you can identify forward-looking statements by terms such as may, will, could, should, would, anticipate, believe, estimate, continue, design, expect, intend, plan, potential, predict, seek or the negative of these words and similar expressions and their variants may identify forward-looking statements. These forward-looking statements reflect management s current expectations, are based on certain assumptions and involve certain risks and uncertainties, which change over time. Our actual results may differ materially from the results discussed in these forward-looking statements due to various factors. Important factors that may cause actual results to differ materially from the results discussed in these forward-looking statements include, but are not limited to, risks related to securing and maintaining relationships with collaborators; risks relating to our clinical trials; risks relating to the commercialization, if any, of our proposed product candidates (such as marketing, regulatory, product liability, supply, competition, and other risks); dependence on the efforts of third parties; dependence on intellectual property; and risks related to our cash resources and ability to obtain working capital to fund our proposed operations. Further information regarding on the factors that could affect our business, financial conditions and results of operations are contained our filings with the U.S. Securities and Exchange Commission, which are available at These forward-looking statements represent management s expectations as of the date hereof only, and we specifically disclaim any duty or obligation to update forward-looking statements as a result of subsequent events or developments, except as required by law. 2

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

4 Madrigal s Team: Led by an Experienced Management Team with Multiple Successful NDA/MAAs and Marketed Products Paul Friedman, M.D. Chairman and CEO Former CEO of Incyte Former President of R&D at Dupont Pharmaceuticals Rebecca Taub, M.D. CMO, EVP R&D Founder of Madrigal Aided in discover of Eliquis and MGL-3196 at Roche Marc Schneebaum CFO, SVP Former CFO, SVP at Synta Former CEO at Predictive Biosciences 4

5 Pipeline: Madrigal has Two Phase 2 Programs and Is Nearing Potential Phase 3 Initiation Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Familial Hypercholesterolemia (FH) / Dyslipidemia Compound Indication Pre- Clinical Phase 1 Phase 2 Phase 3 Upcoming Catalysts MGL-3196 Thyroid Hormone Receptor-β (THR-β) Agonist Nonalcoholic Steatohepatitis (NASH) FH / Dyslipidemia Phase 3 initiation Potential Phase 3 in FH and/or mixed dyslipidemias MGL-3745 THR-β Agonist NASH and FH / Dyslipidemia 5

6 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 Develops most often in patients with obesity/metabolic syndrome, diabetes and dyslipidemia NASH represents an indication with significant unmet need Estimated to affect 3-5% of the US adult population Expected to be the leading cause of liver transplant There are currently no approved therapies for the treatment of NASH NAFLD is the most common liver disease world-wide ~25% of US population ~3-5% of the US population has NASH Rapid progression, <2 years 25% of NASH Stage 3 fibrosis progress to cirrhosis 6

7 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 T4, prohormone T3, active hormone TSH, thyroid stimulating hormone Nuc Thyroid Hormone Receptor α or β In humans, THR-β agonism: Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially reducing lipotoxicity, NASH No thyrotoxicosis (THR-α effect) Unlike other pathways which raise LDL-cholesterol (FXR, FGF-19) or triglycerides (ACC1 antagonist), THR-β agonism reduces both plasma triglycerides and LDL-cholesterol and may provide CV benefit to NASH patients 7

8 Lipotoxicity: THR-β Agonists May Reduce Lipotoxicity Most hepatic fat derives from external sources, particularly free fatty acids from adipocytes; in NASH, β-oxidation of liver lipids is reduced contributing to lipotoxicity THR-β agonists reduce liver fat through breakdown of fatty acids, and stimulate mitochondrial biogenesis in the NASH liver, thus, we believe, reducing lipotoxicity and improving liver function In human NASH, the liver has relatively low THR-β activity, exacerbating mitochondrial dysfunction and lipotoxicity β-oxidation of fat in mitochondria We believe MGL-3196 has pleiotropic effects characteristic of an ideal NASH drug, with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly) 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 fibrosis as the liver regenerates after cure of HCV) Sinha and Yen Cell Biosci (2016) 6:46 DOI /s ; Autophagy, 11:8, , DOI: /

9 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 companies had done (simple receptor binding assay) Earlier compounds from other companies, purported to be THR-β selective, show no functional selectivity in this assay and, like thyroid hormone, activate the THR-α receptor equally well as the β receptor in vivo data confirm MGL-3196 s high liver uptake and preclinical safety Avoids activity at the systemic THR-α receptor (increased heart rate, osteoporosis) Unlike other company s earlier thyroid receptor agonists, no cartilage findings in chronic toxicology or liver enzyme increases in human studies Tested in more than 180 subjects in Phase 1 studies and 150 patients in Phase 2 studies Phase 2 dosing in humans includes 9 months of treatment in humans with NASH MGL-3196 treated healthy volunteers and patients show normal central thyroid axis and vital signs β/α relative to T more ß selective less α potent α-potency (nm) Thyroid Hormone (T3) MB07811 GC-1 (GC1) MGL-3196 Eprotirome KB J Med Chem. 2014;57(10):

10 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 T3 *** *** *** ** *** *** Thyroid hormone (T3, thyroxine) treatment may cause osteoporosis MGL-3196 p<.05* p<.01** P<.001*** Significantly reduced bone mineral density with T3 *** *** *** *** BMJ 2011;342:d

11 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 ALT ****** ****** Improved Liver Histology All NASH Components Liver Fat (Histology) Control MGL

12 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 Rosi MCP-1/CCL2 MIP-2α/CXCL2 MIP-2ß/CXLCL3 A20/TNFaip3 CRP Annexin 2 SAA1 Fibrosis Collagen 1 Galectin-3 TIMP1 Collagen 4a2 SMA Collagen 4a1 CTGF Keratin 18 Collagen 3 Galectin Bad HFD, lane 1 mean HFD gene expression normalized to mean Lean; Lanes (2-7) mean gene expression normalized to mean of DIO; Rosi (rosiglitazone, 3 mg/kg, 24 wks) Red, higher expression; blue decreased expression Good TIMP1 tissue inhibitor metalloproteinase CTGF connective tissue growth factor SMA smooth muscle actin SAA serum amyloid A CRP C-reactive protein 12

13 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 * * * ** ** *** ** *** ** ** ** *** *** *** *** *** *** p<0.001 ** p<0.01 * p 0.05 p 0.1 * Change from Baseline (CFB) by mean % CFB calculated for each individual subject 24h after 14th dose; baseline value obtained just prior to first dose; ApoB, apolipoprotein B; Chol, total cholesterol; LDL-C, LDL cholesterol directly measured; Non-HDL-C, non- HDL cholesterol; TG, triglycerides (median %CFB) Healthy volunteers with slightly elevated LDL cholesterol (> 110 mg/dl) Well-tolerated, appeared safe at all doses tested No effect on vital signs, heart rate, central thyroid axis, or liver enzymes Once daily oral treatment led to highly statistically significant and dose-dependent up to ~30% reduction of apolipoprotein B (ApoB), total, LDL, non-hdl cholesterol; Strong trends in triglyceride reduction up to 60%; Near maximal effect at 80 mg dose 13

14 MGL-3196: Phase 1 and Long-term Dosing in Humans Completed: Single Ascending Dose (SAD) study Multiple Ascending Dose (MAD) study Phase 1 studies dosing MGL-3196 with statins and mass balance study Phase 1 tablet formulation study of MGL-3196 Number of patients treated Tested in more than 180 subjects in Phase 1 studies and 150 patients in Phase 2 studies MGL-3196 well-tolerated in clinical dosing, normal thyroid axis and vital signs, without liver enzyme increases Lipid lowering Robust, pleiotrophic anti-atherogenic lipid lowering properties In Phase 1 healthy volunteer and Phase 2 heterozygous familial cholesterolemia (HeFH) studies lowered LDL-cholesterol (LDL-C) up to 30%,apolipoprotein B (ApoB) 28%, lipoprotein(a) Lp(a) up to 40%, triglycerides (TGs) up to 40%, and ApoCIII Series of GLP toxicology and CMC studies support all indications Manufacturing and product formulation Chronic toxicology package Phase 3-enabling Atherosclerosis 230 (2013)

15 Phase 2: MGL-3196 Trial Design is Targeted at Highly Relevant Primary and Secondary Endpoints Study Overview Study Details Drug MGL-3196 Design Stage Number of Patients Centers Treatment Duration Blinded 2:1 Phase 2 125, Fully Enrolled ~30, USA 36 Weeks Inclusion/Exclusion NASH on liver biopsy: NAS 4 with fibrosis 10% liver fat on MRI-PDFF Include diabetics, statin therapy Comparator/Arms MGL-3196 or Placebo, once daily Primary Endpoint Reduction of liver fat (MRI-PDFF) at 12 weeks Secondary Endpoints NASH biomarkers and lipids at 12, 36 weeks Repeat MRI-PDFF at 36 weeks Liver biopsy at 36 weeks - reduction/resolution of NASH in patients on drug; reduction of fibrosis Ongoing extension study in a subset of patients who completed the Main 36 week study 15

16 Phase 2: Primary Endpoint Achieved at 12 Weeks ** p< p< *p<0.04 *p<0.02 *p<0.02 p< p< p< p< Primary endpoint was met: Relative change in MRI-PDFF (% change from baseline (median)) and absolute fat reduction were both highly significant Prespecified high exposure MGL-3196 patients achieved a 75% response for 30% liver fat reduction No effect of MGL-3196 on body weight; 5 out of the 7 placebo patients who achieved 30% fat reduction lost 5% body weight *compared with placebo **within group p-value 16

17 Phase 2: Reduction at Week 12 of Liver Enzymes and Markers of Inflammation, Fibrosis Change in ALT (U/L) ** Change in AST (U/L) Decrease in liver enzymes is correlated with improvement in NASH on serial liver biopsy. Significant decrease in ALT, AST (within group MGL-3196); significant decrease in ALT (patients with ALT * elevations at baseline) and AST (p=0.04, 0.02, respectively) compared with placebo in high MGL-3196 patients Pro-C3 and ELF scores have been correlated with the liver fibrosis score on liver biopsy in NASH patients. MGL-3196 significantly decreases ELF and Pro-C3 (up to 40% relative to placebo) fibrosis biomarkers particularly in patients with > normal level at baseline reflective of more advanced baseline liver fibrosis Multiparametric MRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation. Significant decrease in MGL-3196 treated patients. Significant decrease in reverse T3 (p<0.0001), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH *Baseline ALT, >=45 males; >=30 females doi: /en ) Clinical Gastroenterology and Hepatology 2018;16: **within group p-value 17

18 Phase 2: MGL-3196 Achieved Primary and Key Secondary Liver Biopsy Endpoints in NASH at 36 Weeks MGL MGL-3196 MRI- PDFF Responders¹ 36 Week Biopsy Results (Secondary Endpoints) Placebo Number of patients Point Decrease in NAS 56% p= % p= % Sustained, highly statistically significant (p<0.0001) reduction in liver fat compared with placebo on Week 36 MRI-PDFF; mean fat reduction MGL %; placebo, 8.9% Sustained, statistically significant reductions in low-density lipoprotein cholesterol (LDL-C), ApoB, triglycerides, and lipoprotein(a) Well-tolerated: mostly mild and a few moderate AEs, generally balanced between drug treated and placebo NASH Resolution 27% p= % p= % An increase in incidence of transient mild diarrhea in MGL-3196-treated compared with placebo, often a single episode, occurring only early in the course of treatment 7 reported SAEs all unrelated to drug; 5 in MGL-3196-treated, 2 placebo (2-1 randomization) Phase 2 liver biopsy results demonstrate the potential for MGL-3196 to show a clear benefit in patients with NASH, including both reduction and resolution of NASH and improvement in multiple atherogenic lipids ¹ MGL-3196 MRI-PDFF Responders = MGL-3196 treated patients with >=30% relative fat reduction on Week 12 MRI-PDFF. 2 Includes only patients with base line and end-of-study liver biopsies. Does not include one patient whose end-of-study liver biopsy was deemed inadequate. 18

19 Phase 2: MGL-3196 Achieved Primary and Key Secondary Liver Biopsy Endpoints in NASH at 36 Weeks Positive Signals on Fibrosis Statistically significant reductions in fibrosis biomarkers in MGL-3196 treated vs placebo On liver biopsy, fibrosis was reduced by 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo Of the MGL-3196 treated patients that achieved NASH resolution, 50% also achieved fibrosis resolution All MGL-3196 treated patients that achieved NASH resolution also achieved a statistically significantly fibrosis decrease relative to placebo patients Reductions in Liver Enzyme Levels Statistically significant reductions in liver enzymes relative to placebo, with reductions of greater magnitude with longer duration of MGL-3196 treatment Statistically significantly more MGL-3196 treated than placebo patients had normalization of ALT 19

20 FH: In addition to NASH, Madrigal also Targeted Familial Hypercholesterolemia in Phase 2 Trial Severe Debilitating Dyslipidemia HeFH and HoFH caused primarily by inactivating mutations in LDL receptor Early onset cardiovascular disease, HoFH < age 20 Associated with several of potentially severe cardiovascular diseases including coronary heart disease, carotid artery disease, and chronic kidney disease High Genetic Prevalence 1/200-1/500 HeFH; 1/250,000-1/1,000,000 HoFH Higher frequency in certain genetically homogeneous populations High prevalence for a genetic disease Novel Therapeutic Approaches Needed Despite current and newer therapies, HoFH and most HeFH not achieving treatment goals on standard care Significant commercial opportunity for MGL-3196 in HoFH, refractory HeFH 20

21 FH: Phase 2 HeFH Clinical Trial Which Read Out in 2018 Study Overview Drug MGL-3196 Study Details Inclusion/Exclusion HeFH on maximally tolerated statins (typically high dose), ezetimibe Design Stage Number of Patients Centers Treatment Duration 2:1 Phase 2 116, fully enrolled 13, Europe 12 weeks Comparator/Arms MGL-3196 or Placebo, once daily Primary Endpoint LDL cholesterol lowering Secondary Endpoints TGs, Lp(a), ApoB lowering Safety 21

22 Phase 2: MGL-3196 Achieved Primary and Secondary Endpoints in Patients with HeFH ALL MGL Optimal MGL Total patients/mgl /76 76/39 Primary Endpoint: Pbo-adjusted reduction of LDL-cholesterol % p< % p< Baseline characteristics balanced between placebo (pbo) and MGL-3196-treated; 75% taking high intensity statins (20/40 mg rosuvastatin or 80 mg atorvastatin), and about 2/3 of patients also taking ezetimibe Statistically significant improvements in multiple lipid biomarkers (LDL-C, ApoB, Lp(a), triglycerides, ApoCIII) represents a novel and differentiated lipid-management profile with respect to other statin-sparing oral treatments Secondary Endpoints: Pbo-adjusted reduction of Triglycerides ApoB Lp(a) p< for all endpoints -25 to -31% ~-20% -25 to -40% Efficacy in moderate to low/no statin subgroup -28.5% LDL-C lowering (p<0.0001) supports the use of MGL-3196 for HeFH and other high CV risk patients whose LDL-C is not at target despite maximally tolerated lipid-lowering therapies Well-tolerated with mostly mild and a few moderate AEs balanced between placebo and drug-treated groups; 2 SAEs (1 each in pbo and drug-treated group (unrelated to treatment) Efficacy and tolerability profile provide further support for MGL-3196 s overall safety profile and potential for CV benefits in NASH patients, HeFH and other dyslipidemic patients, particularly those on moderate statin doses or intolerant to statins ¹ Data are presented using standard convention for lipid endpoints, as placebo-adjusted or compared to the placebo group, which exhibited ~8% upward LDL drift from baseline during the 12 week study that would occur equally in the drug-treated patients. 2 Prespecified Optimal MGL-3196 group showed drug levels consistent with near maximal lipid lowering effects 22

23 Catalysts: Our Expectations for Development Timing 2016 Completed Milestones: Completion of longterm toxicology studies for MGL-3196 Initiation of 12-week Phase 2 trial of MGL-3196 for HeFH Positive topline data from Phase 2 trial of MGL-3196 for HeFH Completion of Phase 1 trial of MGL-3196 dosed with statins for NASH Initiation of Phase 2 trial of MGL-3196 for NASH Positive topline 12-week data from Phase 2 trial of MGL-3196 for NASH 36-week topline liver biopsy data from Phase 2 trial of MGL-3196 for NASH Upcoming Catalysts: End-of-Phase 2 FDA meeting and Phase 3 initiation in NASH Potential Phase 3 in FH and/or mixed dyslipidemias 23

24 Competitive Position: MGL-3196 is Differentiated in the NASH Landscape Target compound NAS Score Fibrosis Score Liver Lipids NASH Prevention Insulin Sensitivity LDL TGs CV Risk Side Effects FXR, FGF-19 LDL-C Pruritus (BA analogues) Anti-fibrotic?? Unknown PPARαδ?? Well-tolerated Anti-inflam?? Well-tolerated Pioglitazone PPAR CHF, bone, weight MGL-3196 Potential CV Benefit Well-tolerated Potential pleiotropic and cardio-beneficial actions position MGL-3196 as stand alone NASH therapeutic Opportunities for differentiation from other NASH agents Efficacy on NASH and cardiovascular endpoints provide opportunity for MGL-3196 to be used in combination with anti-fibrotic and/or anti-inflammatory agents Lancet 385:956-65; 2015; Gastroenterology Feb ; pii:s (10) Tobira press release July 25, 2016; Ann Intern Med. doi: /m

25 Madrigal Investment Highlights 1 MGL-3196: First-in-Class Thyroid Hormone Receptor (THR)-β Agonist 2 Large & Underserved Markets in NASH & Dyslipidemia 3 Multiple Possible Value-Creating Catalysts over Next 18 Months 4 Seasoned Management Team 25

26 Appendix: Additional Material 26

27 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 fibrosis as the liver regenerates after cure of HCV) THR-β, the operative receptor in hepatocytes, may ameliorate lipotoxicity and resultant local inflammation which lead to hepatocyte dysregulation and apoptosis. These perturbations lead to a profibrotic environment through: Ongoing inflammation Production by the dysregulated / damaged / dying hepatocytes of profibrotic factors, with TGF-β among the most important THR-β may have direct anti-fibrotic effects Thyroid hormone receptor agonism has been shown to dampen inflammation in vivo and to inhibit TGF-β signaling in cell culture and in vivo In animal models of liver fibrosis, the extent of fibrosis is decreased by thyroid hormone administration and increased if thyroid hormone receptors are knocked out PNAS 113: 3451,

28 THR-β Agonism: 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 (PLoS ONE 5(1): e8710, 2010) 28

29 MGL-3196: Agonism of Hepatic THR-β In livers of euthyroid individuals T3 induces about half the maximal transcriptional activity of THRbeta MGL-3196 can further beneficially increase this transcriptional activity as we have shown in euthyroid animal models and humans. Interestingly, systemic hypothyroidism, at the level of the thyroid gland itself, leads to increases in plasma lipids (LDL-C and triglycerides) and increases the risk of nonalcoholic fatty liver disease. In fact, actual NASH is at least twice as common in hypothyroid individuals as in the general population. Further, liver-specific hypothyroidism is present in human NASH, caused by degradation of thyroid hormone (increased deiodinase 3 produced by stellate and inflammatory cells) in the NASH liver In a vicious cycle this liver-specific hypothyroidism increases as NASH progresses Thus, MGL-3196, which is not affected by deiodinases, can increase transcriptional activity over an even broader range than in the non-nash euthyroid state With MGL-3196-induced resolution of NASH, with the concomitant decrease in numbers and level of activation of stellate cells, normalization of hepatic thyroid function should occur. 29

30 MGL-3196: Radiographic Tissue Distribution Liver Kidney (medulla) Kidney (cortex) Skeletal Muscle Heart Pituitary Gland Brain (medulla) Brain (cerebrum) Brain (cerebellum) Bone Marrow Bone (femur) Ratio to Blood 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 heart, bone and brain, further supporting the safety of MGL

31 MGL-3196: 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 (100 or 200 mg) p=.001 Robust lipid lowering was observed (up to 60% LDL-C), subjects reaching an average LDL-C of 70 mg/dl, ApoB of 59 mg/dl p <.0001 p<.003 Consistent with MAD data, subjects with higher MGL-3196 exposures did not demonstrate more lipid lowering. Baseline (BL); triglycerides (TG) (all) or >150 mg/dl at BL; Lp(a) shown only for subjects with measurable BL Lp(a) 31

32 Phase 2: NASH Study Design - Randomized, Double-Blind, PBO Controlled MRI-PDFF Liver Biopsy Screening PK assessment MRI-PDFF MRI-PDFF Liver Biopsy D1 W2 W4 W8 W12 W24 W36 Extension MRI-PDFF W12 Comparator/Arms 2:1 MGL-3196 to placebo 125 patients enrolled in USA, ~30 sites MGL-3196 or placebo, once daily; starting dose 80 mg per day, +-20 mg dose adjustment possible at Week 4 Inclusion/Exclusion NASH on liver biopsy: NAS 4 with fibrosis stage % liver fat on MRI-PDFF Includes diabetics, statin therapy, representative NASH population 32

33 Phase 2: Study Endpoints Primary endpoint Relative reduction of liver fat (MRI-PDFF) at 12 weeks Secondary, exploratory biomarker and imaging endpoints Numbers achieving 30% liver fat reduction at 12 weeks; absolute liver fat reduction NASH, fibrosis biomarkers and lipids at 12, 36 weeks; multi-parametric imaging substudy Repeat MRI-PDFF at 36 weeks Secondary, exploratory liver biopsy endpoints at 36 weeks Reduction (2-point on NAS) or resolution of NASH without worsening of fibrosis in MGL treated compared to placebo One point reduction in fibrosis Reduction in components of NASH Ongoing exploratory endpoint extension study in a subset of patients who completed the main 36 week study 33

34 Phase 2: 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) Mean AST 38.2 (21.2) 35.7 (17.8) Mean LDL-C (30.0) (30.4) Mean TGs (75.2) (82.4) Mean MRI-PDFF* 19.8 (6.7) 20.7 (7.0) Mean NAS 4.8 (1.1) 4.9 (1.0) Fibrosis stage n, % (51.2) 48 (57.1) n, % (48.8) 36 (42.8) * Patients with both baseline and week 12 assessments 34

35 Phase 2: MGL-3196 Study Achieved Primary Endpoint in Interim Readout ALL MGL HIGH MGL- 3196¹ Placebo Number of patients Primary Endpoint: Relative change in MRI- PDFF (% change from baseline, median) Significance relative to placebo Percentage of patients attaining 30% liver fat reduction Significance relative to placebo -36.3% p< % p< % p< % p< % 18.4% Statistically significant improvements in low-density lipoprotein cholesterol (LDL-C), triglycerides and lipoprotein (a) Lp(a)² Statistically significant improvements in liver enzymes in drug-treatment group² Very good all subject tolerability: mostly mild and a few moderate AEs, the numbers of which are balanced between placebo and drug-treated groups; 3 reported SAEs all considered unrelated to drug Two regularly scheduled DSMB meetings held May 2017 and September 2017 to review data from the Madrigal NASH Phase 2 trial. DSMB recommended to continue the trial with no changes to the protocol Growing clinical data set demonstrating correlation between decline in fat content on MRI-PDFF, fibrosis biomarkers and NAS score on biopsy Presentation of 12 week endpoints at EASL 2018 ¹ Prespecified group of patients (44/78) with relatively higher MGL-3196 drug levels ² These beneficial effects are more pronounced in the group of pre-specified patients with higher levels of MGL-3196 Ther. Adv. Gastroenterol. 2016; 9:

36 Phase 2: Fat Reduction Relative to NAS/Fibrosis Stage p=0.02 p=0.002 p=0.001 ** p=0.02 p=0.01 p= p=0.002 p=0.005 MGL-3196 reduces liver fat effectively in both early and advanced NASH fibrosis **within group p-value 36

37 Phase 2: Reductions in Multiple Atherogenic Lipids at 12 Weeks Biomarker Monitoring in Patients: Extension Study Change from baseline ng/dl NA NA % Change from Baseline Significant (p<0.0001) reductions relative to placebo in multiple atherogenic lipids including LDL-cholesterol, Lp(a), Apo B and TGs Average reductions in LDL-C, ApoB and triglyceride reductions not maximal, many patients had drug exposures consistent with half-maximal lipid lowering effect Extension study: Open label study of eligible week 36 completers, all patients on MGL-3196 Dose adjustment based on biomarkers Significant lipid lowering, correlating with sex hormone binding globulin (SHBG) increase ApoB lowering equal to LDL-C, reflects lowering of LDL and VLDL particles; ApoB correlates with CV risk more than LDL-C level Lp(a), % change from baseline, other lipids absolute reductions (ng/ml); LDL-C>100 mg/dl, BL; Lp(a) >10 nmol BL; TGs Week 4, MGL-3196 patients on 80 mg dose; SE shown; ND, not determined; NA, not assessed 37

38 Phase 2: Multiparametric MRI Substudy BL CT1 926 ms Week 12 CT1 840 ms Improvement 44%; deterioration 0% MGL-3196 treated patient (nl CT1 826 ms) Multiparametric MRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation * ** Measures inflammation and liver fat across the whole liver MGL-3196 NASH substudy: evaluation of 17 patients with paired baseline and week 12 multiparametric scans Change in CT1 MGL-3196 treated patients showed statistically significant improvements in MRI-PDFF and CT1 p=0.03 *Liver International. 2017;37: ** within group p-value 38

39 Phase 2: Reduction at Week 12 of Liver Enzymes and Reverse T3, Markers of Inflammation Reverse T3 (inactivated T4, T3 thyroid hormone) NASH Inflammation ** ** Decrease in liver enzymes is correlated with improvement in NASH on serial liver biopsy Significant decrease in ALT, AST (within group MGL-3196); significant decrease in ALT (patients with ALT * elevations at baseline) and AST (p=0.04, 0.02, respectively) compared with placebo in high MGL-3196 patients Significant decrease in reverse T3 (p<0.0001), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH (doi: /en ) Clinical Gastroenterology and Hepatology 2018;16: *Baseline ALT, >=45 males; >=30 females **within group p-value 39

40 Phase 2: Reduction of Fibrosis Biomarkers by MGL-3196 at 12 Weeks ** ** p=0.08 p=0.05 p=0.002 p=0.009 Pro-C3 and ELF scores have been correlated with the liver fibrosis score on liver biopsy in NASH patients* MGL-3196 significantly decreases ELF and Pro-C3 (up to 40% relative to placebo) fibrosis biomarkers particularly in patients with > normal level at baseline reflective of more advanced baseline liver fibrosis BL, baseline; elevated BL Pro-C3>=17.5 ngl/ml; elevated BL ELF >= 9 *Liver Int Feb;35(2):429-37; Journal of Hepatology 2013 vol. 59 j **within group p-value 40

41 Phase 2: 12-Week Safety Results mm Hg ** Study remains blinded, completion of dosing and follow up in 36 week study by end of April 2018 Very good all subject tolerability: mostly mild and a few moderate AEs, the numbers of which are balanced between placebo and drug-treated groups; 3 reported SAEs all unrelated to drug Only 2/9 of the discontinuations were secondary to AEs No THR-αα activity, no change in heart rate or other vital signs; mild, significant decrease in blood pressure in MGL treated consistent with improvement in metabolic syndrome No change in thyroid axis p=0.002 p=0.005 Adverse Events Placebo MGL-3196 Mild n (%) 19 (46.3) 55 (65.5) Moderate n (%) 7 (17.1) 18 (21.4) Severe* 0 0 * Study is blinded; 3 SAEs, all unrelated **within group p-value 41

42 FH: Current Treatment Challenges HoFH Most patients still not reaching LDL-C goal Newer agents, Lomitapide (Juxtapid, MTPi) and Mipomersen (Kynamro, anti-apob) may have safety issues Both carry FDA label warning*, hepatotoxicity Increased ALT and hepatic fat Elevated Lp(a) remains an issue HeFH In HeFH, standard care (statins, ezetimibe) most HeFH still not achieving goal Even with PCSK9 inhibitor, 40% not at target HoFH Lipid Lowering Therapy Conventional LDL decrease Statins Up to 28% Ezetimibe <10% LDL apheresis 20-40% New Treatment Options Lomitapide Up to 50% Mipomersen 25% PCSK9 inh 23% Further treatment opportunities include relative statin intolerance in some and elevated Lp(a) 42

43 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 data) and angiopoietin-like protein 3 ANGPTL3 (gene expression) MGL-3196 lowers LDL in concert with statins in clinical & preclinical studies Thyroid agonists lower cholesterol in LDL receptor knockout mice* In Phase 3 trials in HeFH, an earlier THR agonist lowered LDL cholesterol and Lp(a)** MGL-3196 acts through a mechanism that potentially lowers Lp(a), a severely atherogenic particle that is elevated in FH In FH, we believe MGL-3196 will deliver additional LDL-C and Lp(a) lowering on top of conventional treatment 43