Evercore ISI Presentation- Madrigal
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; the timing or likelihood of regulatory filings and approvals for our product candidates; the timing and success of our development and commercialization of our product candidates; and the potential of our product candidates to achieve clinical benefit and safely treat cardiovascular, metabolic, and liver diseases, including non-alcoholic steatohepatitis and dyslipidemia, are, or may be deemed, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. 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, which are based on certain assumptions and involve certain risks and uncertainties, which could change over time. Actual events or results may differ materially from the events or results discussed in these forward-looking statements due to various factors. Important factors that may cause actual events or results to differ materially from those discussed in these forward-looking statements include, but are not limited to, uncertainties associated with the outcomes, cost and timing of our product candidate development activities and clinical trials; uncertainties inherent in clinical testing; the timing, cost, and uncertainty of obtaining regulatory approvals for our product candidates; our ability to successfully progress or complete further development of our product candidates; our ability to commercialize our product candidates; our ability to protect our intellectual property; our cash resources and ability to obtain working capital to fund our proposed operations; changes in the regulatory landscape, including changes in regulatory policies or positions, or the imposition of regulations that affect our product candidates; our reliance on third-parties to meet our obligations; and other factors that are described in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2017, and subsequent Quarterly Reports on Form 10-Q, including the risk factors set forth in those filings. 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.
MGL-3196: Phase 2 Data and Beyond We believe the Phase 2 results: � Establish a minimum effective dose, once a day oral, for statistically significant NASH resolution with 2 pt reduction in NAS; the endpoint is agreed with Madrigal by FDA for Phase 3 registration study � In the extension study, demonstrated that the higher doses (80, 100 mg) will achieve levels of response similar to the ~39% NASH resolution (MRI-PDFF responders) not 27% which included all MGL-3196 patients dosed, including those with suboptimal exposures � Presented strong fibrosis biomarker and exploratory data, especially in advanced F3 patients, suggesting 3196 has the potential to achieve the 1 -pt fibrosis reduction endpoint in a larger patient data set in Phase 3 � Established MRI-PDFF as a non invasive method to predict NASH Resolution � Demonstrated safety including benefits in liver enzymes � Demonstrated robust lipid lowering, a unique profile, that allows potential benefit in MACE as well as liver endpoints in Phase 4 — Lipid benefits including reduction in liver fat are critical in this population — Reduction in LDL, ApoB (the atherogenic particle)—with add-on of TG, ApoCIII and Lp(a) 3
Power of the Phase 3 for NASH Resolution � The extension study demonstrated that with the Phase 3 doses, 80 and 100 mg, approximately 90% of high risk F2/F3 patients safely achieve an MRI-PDFF response, and average 50% hepatic fat reduction—predicting an overall 35% response on NASH resolution � NASH resolution, no worsening of fibrosis, and at least a 2-point difference in NASH has been accepted by FDA � Even with a very conservative 23% MGL-3196 responder rate relative to 10% placebo for NASH resolution, a 900 patient study is powered >90% to achieve 0.001; in the more likely outcome, MGL-3196>25%, placebo 6% the study is powered 99% � Power assuming drop-outs for 900 patient study: Placebo Response Rate MGL-3196 Response ↓ .21 .22 .23 .24 .25 .06 99 99 99 99 99 .07 99 99 99 99 99 .08 95 97 98 99 99 .09 90 94 97 98 99 .10 82 88 93 96 98 4
Development Path Across the Spectrum of NAFLD/NASH NASH/NAFLD Spectrum F4 Study to show metabolic benefits in cirrhosis, combination .5 million F3 Phase 3 NASH study (Phase 4, both 1.6 million CV Benefits MACE and liver endpoints) F2 2.5 million Fatty liver LDL-C F1B ApoB Triglycerides 5 million F1 Lp(a) Phase 3 Lipid study F0 2 million (no liver biopsy requirement) 15 million NAFLD with dyslipidemia, diabetics, metabolic syndrome Patient Numbers (US) 5
Week 36: Sustained Reduction in Liver Fat on MRI-PDFF Relative Fat Reduction (%) Absolute Fat Reduction (%) Relative Change MRI-PDFF (% ) 12 36 Week 12 36 12 36 Week 12 36 12 36 12 36 0 -1.6 -8 -1 -10 -2.3 -10 Placebo -3 -7.6 -36 MGL-3196 -37 -8.5 -20 -8.8 -42 -9.4 -5 ( all ) -49 MGL-3196 -30 -7 ( high exp ) -40 -9 -50 -11 p<0.0001 p<0.0001 p<0.0001 p<0.0001 ≥30% Fat Reduction (%) Main, 36 Week Study 80 F2/F3 n Sustained statistically significant reduction 60 in hepatic fat Week 40 77 75 12 to Week 36 68 68 60 61 20 n Placebo response 30 22 18 11 generally related to 0 weight loss ≥5% Week 12 36 12 36 12 36 12 36 12 36 p<0.0001 p<0.0001 ND p=0.009 P value, placebo compared to MGL-3196; MGL-3196, n=78; placebo, n=38; 6 prespecified high exposure (High Exp) n=44; F2/F3, placebo, n=19; MGL-3196, n=33
Extension Study of 36 Week Phase 2 Trial Extension Study n The Extension study includes 14 former placebo patients with persistently mildly 40 120 to markedly elevated liver enzymes 30 from the Main 36 Week study, ~ two thirds F2/F3 20 n Noninvasive end points, only Percent Change 10 n To optimize exposure, all patients in the 120 0 Extension study received 80 or 100 mg -21 -23 -29 -31 -21 -33 per day of MGL-3196, a higher average -10 dose than in the 36 Week study to move all patients into the “high exposure” -20 category -30 n Highly significant reduction in lipids -40 including LDL-C, ApoB and triglycerides ApoB LDL-C TGs ALT AST GGT SHBG n Well tolerated, few AEs, improvement in liver enzymes from baseline 7
Extension Study: Reduction in Liver Fat on MRI-PDFF ≥30% Fat Relative Fat Absolute Fat Reduction (%) Reduction (%) Reduction (%) 2 0 100 0.6 - 0 1.9 -10 80 -2 -20 -4 60 -50 -10 -30 -6 87 40 -8 -40 -10 20 -50 -12 7 -60 0 -14 Main Extension 8
Week 36: Sustained Robust Lipid Lowering Lipids (% Change from Baseline) 0 -10 -21.9 -22.3 -36 -36.5 -36.8 -20 -30 -40 -50 LDL-C ApoB TGs Lp(a) ApoCIII (BL>100) (BL>=10) p<0.0001 p<0.0001 p<0.0001 p<0.001 p<0.0001 Significant sustained lowering effect in multiple atherogenic lipids Placebo corrected; p value, placebo compared to MGL-3196; MGL-3196, n=79; placebo, n=39 9
Week 36: Liver Enzymes n Week 36, 40% reduction in ALT in 80 patients with elevated baseline 70 60 (p=0.01), and all MGL-3196 relative 50 to placebo patients (p=0.002) U/L 40 ALT 30 At Week 36, 60% of MGL-3196 n 20 10 patients with ALT <30 vs 37% of 0 placebo (p=0.03) 0 12 36 38 Week 60 50 Week 36, statistically significant n 40 U/L 30 AST reduction in MGL-3196 vs AST 20 placebo (% change and absolute 10 change) p=0.002 0 0 12 36 38 Week 20 % Change 10 Week 36, statistically significant n 0 GGT GGT reduction MGL-3196 vs -10 placebo (% change and absolute -20 change) p=0.002 0 12 36 38 Week Placebo MGL-3196 Statistically significant reductions in ALT, AST and GGT versus placebo; no change in bilirubin or alkaline phosphatase Baseline elevated ALT =45 male, 30 female. GGT shown as % change from baseline, females and 10 males have different normal GGT ranges
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