Evercore ISI Presentation- Madrigal

Transcription

1 Evercore ISI Presentation- Madrigal

2 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 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 1-K for the year ended December 31, 217, and subsequent Quarterly Reports on Form 1-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.

3 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 (8, 1 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

4 Power of the Phase 3 for NASH Resolution The extension study demonstrated that with the Phase 3 doses, 8 and 1 mg, approximately 9% of high risk F2/F3 patients safely achieve an MRI-PDFF response, and average 5% 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 1% placebo for NASH resolution, a 9 patient study is powered >9% to achieve.1; in the more likely outcome, MGL-3196>25%, placebo 6% the study is powered 99% Power assuming drop-outs for 9 patient study: Placebo Response Rate MGL-3196 Response

5 Development Path Across the Spectrum of NAFLD/NASH NASH/NAFLD Spectrum CV Benefits Fatty liver LDL-C ApoB Triglycerides Lp(a).5 million 1.6 million 2.5 million 5 million 2 million 15 million Patient Numbers (US) F4 F3 F2 F1B F1 F Study to show metabolic benefits in cirrhosis, combination Phase 3 NASH study (Phase 4, both MACE and liver endpoints) NAFLD with dyslipidemia, diabetics, metabolic syndrome Phase 3 Lipid study (no liver biopsy requirement) 5

6 Week 36: Sustained Reduction in Liver Fat on MRI-PDFF Relative Fat Reduction (%) Relative Change MRI-PDFF (% ) Week Placebo MGL-3196 (all) MGL-3196 (high exp) Absolute Fat Reduction (%) Week p<.1 p<.1-11 p<.1 p<.1 3% Fat Reduction (%) Main, 36 Week Study n Sustained statistically significant reduction in hepatic fat Week 12 to Week 36 n Placebo response generally related to weight loss 5% Week F2/F p<.1 p<.1 ND p=.9 P value, placebo compared to MGL-3196; MGL-3196, n=78; placebo, n=38; prespecified high exposure (High Exp) n=44; F2/F3, placebo, n=19; MGL-3196, n=33 6

7 Extension Study of 36 Week Phase 2 Trial Extension Study n 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/F n n n n Noninvasive end points, only To optimize exposure, all patients in the Extension study received 8 or 1 mg per day of MGL-3196, a higher average dose than in the 36 Week study to move all patients into the high exposure category Highly significant reduction in lipids including LDL-C, ApoB and triglycerides Well tolerated, few AEs, improvement in liver enzymes from baseline Percent Change ApoB LDL-C TGs ALT AST GGT SHBG 7

8 Extension Study: Reduction in Liver Fat on MRI-PDFF 3% Fat Reduction (%) Relative Fat Reduction (%) Absolute Fat Reduction (%) Main Extension 8

9 Week 36: Sustained Robust Lipid Lowering Lipids (% Change from Baseline) LDL-C (BL>1) ApoB TGs Lp(a) (BL>=1) ApoCIII p<.1 p<.1 p<.1 p<.1 p<.1 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

10 Week 36: Liver Enzymes ALT U/L Week n n Week 36, 4% reduction in ALT in patients with elevated baseline (p=.1), and all MGL-3196 relative to placebo patients (p=.2) At Week 36, 6% of MGL-3196 patients with ALT <3 vs 37% of placebo (p=.3) 6 AST U/L Week n Week 36, statistically significant AST reduction in MGL-3196 vs placebo (% change and absolute change) p=.2 2 GGT % Change Week n Week 36, statistically significant GGT reduction MGL-3196 vs placebo (% change and absolute change) p=.2 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, 3 female. GGT shown as % change from baseline, females and males have different normal GGT ranges 1

11 Week 36: Reduction of Fibrosis, Biomarkers ELF BL 9 CK-18 (M3) U/L Pro-C3 (ng/ml) week p=.9 p=.2 p=.7 p= NS p=.3 p=.4 p=.2-5. Baseline >= 17.5 ng/ml p=.8 p=.7 p=.2 p=.3 p=.1 % change NA -25% -33% -38% -18% -38% -41% -88% -119% 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 patients with advanced fibrosis at baseline BL, baseline; compared with placebo; all, placebo n=38; MGL-3196 n=78; ELF 9 placebo n=21; MGL-3196 n=4; Pro-C3 BL 17.5, placebo n=12; MGL-3196 n=29 11 *Liver Int. 215 Feb;35(2):429-37; Journal of Hepatology 213 vol. 59 j ;

12 Week 36: Change in Fibrosis Score on Liver Biopsy SHG (qfibrosis) A 1B 2 3 Pathologist Score SHG Score % biopsies pt reduction in fibrosis on liver biopsy (SHG) 12 All p=.3 32 Placebo F3 p=.5 47 MGL-3196 n Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen n SHG score was generated and aligned with the pathologist baseline score (baseline, r=.76), (left panel), blinded to treatment code n Using SHG, MGL-3196 treated compared with placebo showed a statistically significant 1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo Week 36 pathology scores and treatment code were not provided to SHG readers.

13 Week 36: NASH Liver Biopsy Endpoints 2-Point NAS Reduction with at least a 1-pt reduction in ballooning or inflammation (% of liver biopsies) NASH Resolution ballooning=, inflammation =, 1 with at least 2-point reduction in NAS (% of liver biopsies) % of biopsies % of biopsies <5% Weight loss p=.9 p=.6 p=.2 p=.2 no fibrosis worsening p=.2 p=.1 p=.3 p=.3 2-pt reduction in NAS in placebo patients was correlated with body weight loss Placebo MGL-3196 (all) MGL-3196 (high exp) MGL-3196, MRI responder In MGL-3196 treated patients with NASH resolution, 5% had fibrosis resolution (F=) MRI Responder; 3% fat reduction on Week 12 MRI-PDFF High Exp,, n=44; 2-pt NAS reduction; MGL-3196, n=73, placebo n=34; NASH Resolution, prespecified endpoint: at least 2-pt reduction in NAS; ballooning=, inflammation=, 1, <9.5% weight loss; 13

14 Diet and Exercise Counseling in NASH trials Phase 2 trial (MGL ) employed mandated diet and exercise counseling at screening and each visit, recorded in the clinical trial record Previous large NASH trials did not have specific diet and exercise counseling at each study visit, and the effect of diet and exercise on NASH endpoints was only known from published literature on NASH endpoints in weight loss trials e.g. Vilar-Gomez Gastroenterology 215;149: Because extensive literature showed that body weight loss reduces and resolves NASH, weight loss subgroups and an exclusion for extreme weight loss were prespecified in MGL statistical analysis plan In Vilar-Gomez, extreme weight loss (1%) and Harrison et al (HEPATOLOGY, Vol. 49, No. 1, 29) >=9% weight loss in NASH patients was correlated with marked reduction in steatosis, ballooning, inflammation on biopsy, resolution of NASH in ~9% In VillarGomez, lesser degrees of weight loss >=5% were associated with NASH improvement MGL prespecified in the statistical analysis plan, evaluation of subgroups with >=5% weight loss on NASH and MRI-PDFF endpoints MGL prespecified in the statistical analysis plan, in the secondary liver biopsy endpoint, elimination of patients with ~1% (>9.5%) weight loss to avoid confounding effects of weight loss on the results to help with powering the Phase 3 Clarification: Patients with extreme weight loss (>9.5%) was an exclusion in the Phase 2 study for NASH resolution, not an endpoint. Patients with weight loss were included in all other analyses of the Phase 2 data, and the Phase 3 endpoint has no exclusion for weight loss 14

15 Weight loss in MGL-3196 Phase 2 Study There were no differences in average weight loss between MGL-3196 and placebo patients All 3 placebo patients with extreme weight loss (>9.5%) and all placebo patients with NASH resolution (6%) came from a single site, resulting in a statistically relevant outlier site that permits removal of the site using standard clinical trial criteria Removal of the single site including all MGL-3196 and placebo patients showed that MGL compared to placebo maintained statistical significance for NASH resolution with no worsening of fibrosis (p=.19), all patients; and p=.1, MRI-responder Inclusion of the site and the 3 patients with weight loss in the NASH resolution post-hoc analysis resulted in p=.15 (all MGL-3196 patients); p=.14, MRI-Responders Since the 3 patients with >9.5% weight loss were placebo patients, in a posthoc analysis, patients with >7% weight loss were also excluded (7% results in NR of ~65%), thus removing a similar number of placebo and 3196 patients (4 each), with no change in the results: Compared with placebo, NASH resolution in all MGL-3196 patients, p=.3-.5; MRI-PDFF responders p=.2-.3 Given the number of sites in Phase 3, unbalanced weight loss or site effects are a non-issue and no patients will be eliminated from analysis for weight loss. Sites will be automatically notified during the study if a patients exceeds 9.5% weight loss or gain so that investigators can review patient behavior and counseling 15

16 NASH Phase 3 Endpoints No NASH biopsy surrogate endpoint is currently validated as reasonably likely to be predictive of clinical benefit, the ultimate arbiter of provisional regulatory approval Clinical benefit based on a NASH endpoint had not been shown Each company negotiates their endpoint and trial design with FDA The definition of NASH resolution (NR) ballooning, inflammation,1 without worsening of fibrosis adopted for Phase 3 by some companies does not require a reduction in NAS. A 2-pt reduction in NAS would, nonetheless, be observed in most NR responders. Unfortunately, we believe this endpoint was not carefully considered and declares NASH resolution in patients who are not actually NASH responders, thereby introducing a lot of noise Madrigal definition, which was prespecified in Phase 2, incorporates the same NASH Resolution definition ballooning, inflammation,1 without worsening of fibrosis with a more stringent requirement for a 2-pt NAS reduction We believe our NASH resolution surrogate endpoint is reasonably likely to predict clinical benefit, and FDA agreed (recent receipt of written agreement) NASH resolution (ballooning, inflammation,1) without worsening of fibrosis and at least a 2-pt reduction in NAS is the endpoint for registration 16

17 Ballooning Reduction Alone Does Not Predict NASH Benefit The less stringent NR definition is only problematic in patients with ballooning=1 inflammation=1 at baseline If a 1- point ballooning reduction is the only change leading to NASH resolution there is no true benefit (allowed in the relaxed NR definition); Ballooning =1, is a few ballooned cells ballooning is highly variable and subject to noise: Liver Fat NAS-4 Steatosis 2 Inflammation 1 Ballooning 1 Liver Fat NAS 3-4 Steatosis 2 or 3 Inflammation 1 Ballooning No improvement in ALT or biomarkers Independent of a weight loss or steatosis reduction, a ballooning reduction does not predict a reduction in NASH components, such as inflammation, or ALT, which has been shown to correlate with histologic response (Loomba et al Gastroenterology Sept 218) Ballooned hepatocyte Inflammation A true NASH resolution response in patients with NAS=4 at baseline: Liver Fat NAS-4 Steatosis 2 Inflammation 1 Ballooning 1 Fat Liver NAS 1-2 Steatosis -1 Inflammation 1 Ballooning ALT, biomarkers improve Literature examples: the NASH response in placebo patients (weight loss, bariatric surgery), FLINT, Pivens, Belfort, LEAN In placebo patients with NR the average residual NAS is <=2, and average decrease in NAS>2 17

18 Importance of Steatosis Reduction in NASH Resolution A growing data set indicates that reduction of hepatic fat in NASH patients leads to histologic response, including NASH resolution Not considering steatosis dismisses the critical role of lipotoxicity in driving NASH fibrosis. Patients with NASH do not have simple steatosis, they have inflammatory fat Based on substantial published data in placebo and drug-treated patients, converting inflammatory fat into noninflammatory fat is not likely. Unless liver fat is reduced via decreased fat production and/or increased breakdown of fat, patients likely still have NASH Evidence in support of the importance of steatosis response in predicting NASH outcome Improvement in steatohepatitis in clinical trials and longitudinal studies is generally associated with a reduction in liver fat (Arun Sanyal, Stephen Harrison) FLINT, LEAN, Belfort, Pivens, placebo patients with weight loss (Vilar-Gomez) Steatosis on biopsy is too crude a measure to predict improvement in other components of NASH. MRI-PDFF is a sensitive measure of hepatic fat that correlates with steatosis score and predicts an NAS response and NASH Resolution Reduction of >=3% liver fat is reasonably called a PDFF responder Reduction of liver fat on MRI-PDFF predicts improvement in ballooning and inflammation (NGM, MGL-3196), not only in drug-treated but in placebo patients with weight loss 18

19 Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy NASH Resolution (%) MGL-3196-treated 37 p=.1 MRI-PDFF Responder 4 MRI-PDFF Non- Responder % Change in MRI-PDFF (Week 12) MRI-PDFF Week 12, % Relative Change: Correlation with Change in Ballooning Plus Inflammation Scores MGL Change in Ballooning Plus Inflammation MGL-3196-treated n Patients who were not MRI-PDFF Responders ( 3% fat reduction) had a low rate of NASH resolution (left panel) n In both MGL-3196 (correlation coefficient.42) (right panel) and placebo (correlation coefficient.58) % relative change in MRI-PDFF was correlated with reduction in ballooning plus inflammation scores on liver biopsy (steatosis score removed) 19