Resmetirom for use in treating cardiomyopathy and / or related heart failure and portal hypertension

Abstract

The present disclosure provides a method of treating cardiomyopathy and / or related heart failure in a human subject (e.g., an adult human subject) in need of such treatment with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirom) or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating portal hypertension in a human subject (e.g., an adult human subject) in need of such treatment with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirom) or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of treating clinically significant portal hypertension (CSPH) in a human subject (e.g., an adult human subject) in need of such treatment with 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (resmetirom) or a pharmaceutically acceptable salt thereof.

Description

Attorney Docket No. 156883.617393 METHODS FOR TREATING CARDIOMYOPATHY AND / OR RELATED HEART FAILURE AND PORTAL HYPERTENSIONCross Reference to Related Applications

[0001] This application claims the benefit of U. S. Patent Application Nos. 63 / 719,257, filed November 12, 2024, 63 / 720,725, filed November 14, 2024, 63 / 721,474, filed November 16, 2024, 63 / 801,986, filed May 8, 2025, 63 / 802,904, filed May 9, 2025, 63 / 804,754, filed May 13, 2025, 63 / 805,404, filed May 14, 2025, 63 / 810,372, filed May 22, 2025, 63 / 839,536, filed July 7, 2025, 63 / 841,809, filed July 10, 2025, 63 / 846,443, filed July 18, 2025, and 63 / 875,184, filed September 3, 2025, the disclosures of all of which are incorporated herein by reference in their entireties.Technical Field

[0002] This disclosure is related to the area of treatment of cardiomyopathy and / or related heart failure. More specifically, this disclosure is related to a method for the efficacious treatment of cardiomyopathy and / or a related heart failure utilizing the thyroid hormone receptor-beta (THR-beta) agonist resmetirom or a pharmaceutically acceptable salt thereof. This disclosure is also related to the area of treatment of treating clinically significant portal hypertension (CSPH). More specifically, this disclosure is related to a method for the efficacious treatment of CSPH utilizing the thyroid hormone receptor-beta (THR-beta) agonist resmetirom or a pharmaceutically acceptable salt thereof. This disclosure is also related to the area of treatment of a fatty liver disease, such as metabolic dysfunction-associated steatohepatitis (MASH), which is also known as nonalcoholic steatohepatitis (NASH), including noncirrhotic MASH with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis, and compensated MASH cirrhosis with stage F4 fibrosisAttorney Docket No. 156883.617393 (stage F4c). More specifically, this disclosure is related to a method for the efficacious treatment of a fatty liver disease (e.g., MASH) utilizing the thyroid hormone receptor-beta (THR-beta) agonist resmetirom or a pharmaceutically acceptable salt thereof.Background

[0003] Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus / pituitary / thyroid (HPT) axis.Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0004] The development of thyroid hormone analogs which avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones would open new avenues of potential treatment for patients w ith metabolic disease such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as liver steatosis and non-alcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, resistance to thyroid hormone and related disorders and diseases.

[0005] Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a fatty inflammation of the liver that can progress to cirrhosis, liver failure, liver cancer, need for liver transplantation, and premature mortality. MASH is expected to become the leading cause of liver transplantation in the U. S. and is already the leading cause of liver transplantation among women. The disease is progressive, starting as steatosis or nonalcoholic fatty liver disease (NAFLD), progressing to an inflamed fatty liver (MASH), and eventually leading to fibrosis and cirrhosis. The disease is generally asymptomatic until severe liver impairment occurs.Attorney Docket No. 156883.617393

[0006] Human subjects with MASH may experience elevated liver volumes, which can be attributed to increased liver fat and fluid retention due to inflammatory processes in MASH. Once patients progress to MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), the risk of adverse liver outcomes increases dramatically: these patients have a 10-17 times higher risk of liver-related mortality as compared to patients without fibrosis. Those who progress to cirrhosis face a 42 times higher risk of liver-related mortality, underscoring the need to treat MASH before complications of cirrhosis develop. MASH is also an independent driver of cardiovascular disease, the leading cause of mortality for patients. As MASH progresses to compensated MASH cirrhosis with stage F4 fibrosis (stage F4c), liver fat decreases as the liver becomes increasingly fibrotic. Liver volume remains elevated in cirrhotic human subjects due to ongoing inflammation and venous congestion associated with portal hypertension. Reducing liver volume in noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis human subjects is important for maintaining perfusion of the diseased liver and reversing disease progression to cirrhosis. Liver volume reduction in MASH and MASH cirrhosis is associated with histopathologic improvement of the liver.

[0007] The prevalence of NAFLD in the U. S. population is about 20-23%, and may be as high as 33%, and the prevalence of MASH in the U. S. population is about 2-3%, corresponding to about 1.5 million patients in the U. S. Some MASH patients will progress to late-stage disease: approximately 15-50% of MASH patients progress to severe fibrosis, and approximately 7-16% progress to MASH cirrhosis. The rate of liver-specific mortality in MASH cirrhosis is approximately 10% per decade. As MASH disease awareness improves and disease prevalence increases, the number of diagnosed patients with MASH with moderate to advanced fibrosis is expected to grow.Attorney Docket No. 156883.617393

[0008] Cirrhotic cardiomyopathy is a syndrome characterized by impaired myocardial contractile response to stress, diastolic dysfunction, and electrophysiological disturbances in patients with liver impairment including portal hypertension, cirrhosis, including those due to MASH. In contrast, metabolic cardiomyopathy is a syndrome characterized by impaired myocardial contractile response to stress, diastolic dysfunction, and electrophysiological disturbances in patients with metabolic disorders including diabetes, obesity, or inherited genetic conditions.

[0009] Cardiomyopathy causes ventricular chambers to become enlarged and weakened, reducing systolic contractility and cardiac output. This can also lead to hypertrophic thickening of the myocardium, which can obstruct blood flow and impair diastolic filling. Stiffening of the ventricular walls can lead to severely limiting ventricular compliance and filling, despite at times preserving systolic function. Over time, these mechanical and functional impairments place a burden on the heart, leading to elevated intracardiac pressures, pulmonary congestion, and ultimately, the clinical syndrome of heart failure.

[0010] Patients often remain asymptomatic until physiological stress reveals cardiac dysfunction. Current therapeutic strategies focus primarily on managing symptoms and slowing progression of disease, with no approved treatments that target the liver related contributions.Summary

[0011] Resmetirom has previously been mentioned in connection with the treatment of a fatty liver disease (see Harrison et al., “Resmetirom (MGL-3196) for the treatment of nonalcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial,” The Lancet, Vol. 394, No. 1021, pp. 2012-2024 (2019), incorporated herein by reference in its entirety), such as metabolic dysfunction-associated steatohepatitis (MASH).Attorney Docket No. 156883.617393 The U. S. Food and Drug Administration (FDA) has recognized the effectiveness of resmetirom by approving REZDIFFRA™ (resmetirom) tablets, in conjunction with diet and exercise, for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis), as reflected in the prescribing information (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2024 / 217785s0001bl.pdf, incorporated herein by reference in its entirety). Embodiments of the present disclosure provide that the use of resmetirom can improve the effectiveness of treating cardiomyopathy. Clinical data demonstrated resmetirom’ s ability to reduce hepatic fat, inflammation, fibrosis, and portal hypertension. By improving portal hypertension and improving hemodynamics along with mitochondrial biogenesis and antifibrotic effects, resmetirom can also improve myocardial function in conditions such as cirrhotic cardiomyopathy or metabolic cardiomyopathy.

[0012] MASH is a chronic and progressive liver disease that may lead to MASH cirrhosis (FIG. 53). Clinically Significant Portal Hypertension (CSPH) is a major consequence of cirrhosis and responsible for its most severe complications, such as ascites, variceal bleeding and hepatic encephalopathy. Fibrosis hardens and stiffens the liver, obstructing normal blood flow to the portal vein, resulting in portal hypertension and an enlarged spleen. An enlarged spleen sequesters platelets (removes from circulation), resulting in a lower platelet count. CSPH is responsible for the most severe and fatal complications of cirrhosis (FIG. 54). Patients with MASH who progress to MASH cirrhosis have a 42 times higher risk of liver-related mortality.

[0013] Disclosed herein is a method for treating or improving cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.Attorney Docket No. 156883.617393

[0014] In particular, disclosed herein is a method of treating cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subject) in need thereof, which comprises: administering to the human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

[0015] Disclosed herein is a method for treating or improving CSPH in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0016] In particular, disclosed herein is a method of treating CSPH in a human subject (e.g., an adult human subject) in need thereof, which comprises: administering to the human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

[0017] Disclosed herein is a method for treating or improving portal hypertension in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0018] In particular, disclosed herein is a method of treating portal hypertension in a human subject (e g., an adult human subject) in need thereof, which comprises: administering to the human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.Brief Description of the Drawings

[0019] The above and further features will be more clearly appreciated from the following detailed description when taken in conjunction with the accompanying drawings.

[0020] FIG. 1 is a graphical representation showing an exemplary' study design.

[0021] FIGs. 2A-2B are graphical representations showing baseline features in NASH genetic populations.

[0022] FIGs. 3A-3B are graphical representations showing baseline triglycerides and MRI-PDFF.Attorney Docket No. 156883.617393

[0023] FIGs. 4A-4B are graphical representations showing NASH genetic background impact on baseline liver enzy mes.

[0024] FIG. 5 is a graphical representation showing the impact of NASH genetic background on NASH resolution.

[0025] FIG. 6 is a graphical representation showing the impact of NASH genetic background on NASH resolution.

[0026] FIG. 7 is a graphical representation showing the impact of NASH genetic risk alleles on liver fat reduction.

[0027] FIG. 8 is a graphical representation showing liver enzy mes responses.

[0028] FIG. 9 is a graphical representation showing FibroScan response.

[0029] FIG. 10 is a graphical representation showing an exemplary study design.

[0030] FIG. 11 is a graphical representation shoyving that GLPs and SGLT2 had no impact on b4. No biopsy response to resmetirom. FIG. 11 also show-s MASH resolution yvith no worsening of fibrosis and fibrosis improvement (reduction by at least one stage with no w orsening of the MASH) in T2DM patients in presence or absence of GLP-1 RA (upper left hand side & upper right hand side) or SGLT2i (lower left hand side & low er right hand side).

[0031] FIG. 12 is a graphical representation shoyving that various diabetes treatments did not impact KRI-PDFF reduction by resmetirom. FIG. 12 also shoyvs relative (median) hepatic fat reduction at Week 52 in various subgroups of patients on resmetirom (80 or 100 mg) or placebo. See Table 25 for Ns.Attorney Docket No. 156883.617393

[0032] FIG. 13 is a graphical representation showing wight loss / resmetirom impact on b4. No biopsy endpoints. FIG. 13 also shows MASH resolution with no worsening of fibrosis and fibrosis improvement (reduction by at least one stage with no worsening of MASH) in patients with (left hand side) or without (right hand side) >5% weight loss.

[0033] FIG. 14 is a graphical representation showing weight loss effect on MRI-PDFF. FIG. 14 also shows relative (median) hepatic fat reduction at weeks 16 and 52 and percentage of patients achieving 30% reduction in hepatic fat in patients on resmetirom (80 or 100 mg) or placebo with >5% weight loss (1stto the left hand side & 2ndto the left hand side) or <5% weight loss (3rdto the left hand side & 4thto the left hand side) at Week 52.

[0034] FIG. 15 is a graphical representation showing an exemplary design for the MAESTRO-NASH study.

[0035] FIG. 16 is a graphical representation showing exposure responses to resmetirom 80 and 100 mg.

[0036] FIG. 17 is a graphical representation showing liver b4. No biopsy responses to resmetirom dose (body weight).

[0037] FIG. 18 is a graphical representation showing liver b4. No biopsy responses to resmetirom dose: effect of BMI (placebo adjusted. ITT).

[0038] FIG. 19 is a graphical representation showing that MRI-PDFF reduction strongly predictive of resmetirom b4. No biopsy responses on fibrosis and NASH.

[0039] FIG. 20 is a graphical representation showing change over time from baseline in ALT and SHBG MAESTRO-NASH Week 52 primary analysis population.Attorney Docket No. 156883.617393

[0040] FIG. 21 is a graphical representation showing C AP / V CTE over time (patients with 3 -year data).

[0041] FIG. 22 is a graphical representation showing VOTE responder analysis at years 1-3.

[0042] FIG. 23 is a graphical representation showing that at baseline, patients receiving statins had lower ALT and AST levels than those not receiving statins. A= all patients with baseline levels >301 / U. B= patients on statin. C= patients not on a statin.

[0043] FIG. 24 is a graphical representation showing ALT levels at baseline and post randomization. A= all patients with baseline levels >30 I / U. B= patients on statin. C= patients not on a statin.

[0044] FIG. 25 is a graphical representation showing AST Levels at baseline and post randomization. A= all patients with baseline levels >30 I / U. B= patients on statin. C= patients not on a statin.

[0045] FIG. 26 is a graphical representation showing GGT Levels at baseline and post randomization. A= all patients with baseline levels >30 I / U. B= patients on statin. C= patients non on a statin.

[0046] FIG. 27 is a graphical representation showing an exemplary MAESTRO-NASH outcomes study design.

[0047] FIG. 28 is a graphical representation showing baseline characteristics by liver b4. No biopsy status.

[0048] FIG. 29 is a graphical representation showing baseline characteristics by liver b4. No biopsy status.Attorney Docket No. 156883.617393

[0049] FIG. 30 is a graphical representation showing baseline: FIB-4, VCTE, ELF, MRE.

[0050] FIG. 31 is a graphical representation showing ALT response at Week 48 in all randomized patients.

[0051] FIG. 32 is a graphical representation showing PDFF reduction in resmetirom treated patients.

[0052] FIG. 33 is a graphical representation showing CAP from BL to Month 36 (mean).

[0053] FIG. 34 is a graphical representation showing VCTE from BL to Month 36 (mean).

[0054] FIG. 35 is a graphical representation showing pharmacokinetics of Atorvastatin with concomitant resmetirom.

[0055] FIG. 36 is a graphical representation showing creatine kinase change from baseline.

[0056] FIG. 37 is a graphical representation showing changes in liver enzymes (ALT). A= all patients (baseline >=30 U / L). B= patients on statins (baseline >=30 U / L). C= patients not on statins (baseline >=30 U / L).

[0057] FIG. 38 is a graphical representation showing efficacy of statins in MAESTRO-NASH. Lipid lowering similar in statin- and non-statin-treated resmetirom patients. Liver b4. No biopsy endpoints achieved in statin- and nonstatin-treated patients on resmetirom.

[0058] FIG. 39 is a graphical representation showing an exemplary trial design - open-label (OL) 52-Week cirrhosis arm of MAESTRO-NAFLD-1 followed by an extension trial.

[0059] FIG. 40 is a graphical representation showing an exemplary trial flow - open-label cirrhosis arm (MAESTRO-NAFLD-1) followed by an extension trialAttorney Docket No. 156883.617393

[0060] FIG. 41 is a graphical representation showing sustained reductions in liver stiffness (LSM) after 2-year treatment with resmetirom.

[0061] FIG. 42 is a graphical representation showing overall shift to lower CSPH risk at Year 1 and Year 2 whether Baveno or a modification of Baveno criteria are used.

[0062] FIG. 43 is a graphical representation showing improvements in portal hypertension risk category with resmetirom.

[0063] FIG. 44 is a graphical representation showing sustained reductions in liver fat and liver stiffness with resmetirom at 2 years.

[0064] FIG. 45 is a graphical representation showing sustained statistically significant improvements in ALT and GGT.

[0065] FIG. 46 is a graphical representation showing reductions in fibrosis and liver injury biomarkers at 2 years.

[0066] FIG. 47 is a graphical representation showing sustained reductions in atherogenic lipids with resmetirom at 2 years.

[0067] FIG. 48 is a graphical representation showing baseline liver fat independent reduction of enlarged MASH cirrhotic livers.

[0068] FIG. 49 is a graphical representation showing normal liver compared to MASLD, MASH, MASH w / fibrosis and cirrhosis (F4) livers. Ascites: abnormal accumulation of fluid in the abdominal cavity; Hepatic encephalopathy: brain disorder caused by liver dysfunction; MASH: Metabolic Dysfunction Associated Steatohepatitis; MASLD: Metabolic Dysfunction-associated Steatotic Liver Disease; Variceal bleeding: bleeding from enlarged veins, usuallyAttorney Docket No. 156883.617393 in the esophagus or stomach; Portal hypertension: increased pressure in the portal vein, which carries blood from the intestines, stomach, pancreas, and spleen to the liver.

[0069] FIG. 50 is a graphical representation showing an exemplary MAESTRO-NAFLD-1 Open-Label Extension (OLE) F4c Study Design.

[0070] FIG. 51 is a graphical representation showing two-year data from MAESTRO-NAFLD-1 OLE (n = 101) that demonstrate potential benefit of Rezdiffra in F4c patients.

[0071] FIG. 52 is a graphical representation showing that a positive outcome is expected to support the full approval of Rezdiffra for noncirrhotic MASH and expand the eligible patient population for Rezdiffra with an additional indication in patients with compensated MASH cirrhosis.

[0072] FIG. 53 is a graphical representation showing that MASH is a chronic and progressive liver disease that leads to MASH cirrhosis.

[0073] FIG. 54 is a graphical representation showing that clinically significant portal hypertension (CSPH) is a consequence of more advanced cirrhosis that leads to lifethreatening liver-related events.

[0074] FIG. 55 is a graphical representation showing that noncirrhotic patients with PDFF response experienced improvements in Abdominal and Worry scores (up to +7%) which were greater than those seen in placebo or non-responders.

[0075] FIG. 56 is a graphical representation showing evaluation of P3NP and Hyaluronic acid (HA) relative to diabetes status and fibrosis stage in patients enrolled in MAESTRO -NASH and MAESTRO - NAFLD.Attorney Docket No. 156883.617393

[0076] FIG. 57 is a graphical representation showing a prescreening and screening flowchart for NCT05500222 trial.

[0077] FIG. 58 is a graphical representation showing an exemplary study schema for NCT05500222 trial.

[0078] FIG. 59 is a graphical representation showing the disposition of subjects / tests in the MAESTRO-NAFLD-1 study of resmetirom.

[0079] FIGs. 60A-60C is a graphical representation showing that subjects were further stratified by HepQuant DuO cutoff of DSI 23. FIG. 60A shows the baseline hepatic impairment in the MAESTRO NAFLD-1 study’s Child-Pugh A cirrhosis population measured by HepQuant DuO disease severity index (DSI) and portal-systemic shunting (SHUNT%), with markers designating their response by Week 48. FIG. 60B shows a correlation heat map of measurements at screening or baseline visits in all subjects with HepQuant DuO testing and other non-invasive assessments. FIGs. 60C and 60D show the responder analysis demonstrating change in hepatic function quantified by DSI (FIG. 60C) and by SHUNT% (FIG. 60D) from baseline to 48 weeks on resmetirom.

[0080] FIGs. 61 A-61B are graphical representations showing the impact of resmetirom on RISK ACE. Solid lines represent the baseline DSI and the probability of clinical outcome prior to treatment with resmetirom. Dashed lines represent the effect at 48 weeks with resmetirom on clinical risk based on the Week 48 DSI measurement. Panel A shows the results for all subjects with follow-up at 48 weeks. Panel B shows the results for all subjects with follow-up at 48 weeks and stratified by baseline DSI, with DSI >23 indicating high risk (red lines), DSI 18.3-23 indicating moderate risk (green lines), DSI ≤18.3 indicating low risk (blue lines).Attorney Docket No. 156883.617393

[0081] FIG. 62 is a schematic representation showing a study population in Example 13.

[0082] FIG. 63 is a graphical representation showing mediation analysis: odds ratios (OR) with 95% confidence intervals for the total effect of resmetirom versus placebo, as well as the direct treatment effect and the indirect effect mediated through the percent change in weight at Week 52 on both MASH resolution and fibrosis improvement.

[0083] FIGs 64A-64B are graphical representations showing absolute Fibroscan VCTE reduction (FIG. 64A) and percentage of patients with achieving a >25% reduction or increase in VCTE (FIG. 64B) in patients with >5% or <5% weight loss at Week 52.Detailed Description

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is intended to describe particular embodiments only and is not intended to limit the scope of the invention.

[0085] As used herein, the following terms have the meaning indicated, unless otherwise specifically noted in context. Unless otherwise defined herein, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0086] As used herein, "‘administering” or “administered to” refers to prescribing a medicine to a human subject, directing others to administer a medicine to a human subject, directing a human subject to self-administer a medicine, and / or the act of physically ingesting the medicine. A medicine containing resmetirom (or a pharmaceutically acceptable salt of resmetirom) and / or a GLP-1 receptor agonist as its active pharmaceutical ingredient, can therefore be administered by a physician or other medical professional who writesAttorney Docket No. 156883.617393 prescriptions for a medicine(s) or otherwise directs a patient to self-administer a prescription, and / or by the human subject who ingests the medicine and / or by a human subject’s caretaker who provides the medicine to a human subject.

[0087] As used herein, the term “cardiomyopathy” refers to structural and / or functional abnormalities of the myocardium, including but not limited to diastolic dysfunction, impaired contractile reserve, and electrophysiological instability.

[0088] As used herein, the term “heart failure” refers to a condition where the heart cannot pump enough blood to meet the human subject’s needs. A heart failure may include heart failure with reduced ejection fraction (HFrEF), referring to a condition where the heart's left ventricle cannot pump enough blood to the rest of the body.

[0089] As used herein, the term “cirrhosis” refers to a late stage (e g., stage F4) of scarring (fibrosis) of the liver caused by many forms of liver diseases and conditions, such as MASH, hepatitis and chronic alcoholism. Cirrhosis may include compensated cirrhosis, which refers to a form of cirrhosis where the liver is damaged but still able to function. The liver fat of a cirrhosis human subject is no more than 5%. A skilled artisan would recognize that MASH cirrhosis is a disease / condition derived from MASH and is distinct from alcoholic cirrhosis. MASH cirrhosis includes compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0090] As used herein, the term “daily” means every day, where each day is defined by a 24-hour period. For the avoidance of doubt, the 24-hour period defining “daily” can bridge two calendar days, for example, Sunday-Monday; Monday-Tuesday; Tuesday-Wednesday; etc.

[0091] As used herein, the term “dose,” “dosage” or “daily dosage” refers to the weight of an active ingredient (e.g., resmetirom and / or the GLP-1 receptor agonist).Attorney Docket No. 156883.617393

[0092] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a formulation that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0093] As used herein, the term “human subject” refers to a human subject who is an adolescent or an adult.

[0094] As used herein, an “adult human subject” refers to a human subject who is 18 years of age or older.

[0095] As used herein, an “adolescent human subject” refers to a human subject who is 12 years of age or older and younger than 18 years of age. A physician’s prescription in connection with the treatment and / or improvement as disclosed herein to a human subject younger than 18 years old is considered to be off-label.

[0096] As used herein, the term “human subject in need thereof,” refers to a human subject having a disease (to be treated) or having an increased risk of developing the disease (to be prevented). A human subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A human subject in need thereof can also be one who has (e.g., is suffering from) a disease or disorder disclosed herein. Alternatively, a human subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a human subject who is predisposed to developing such disorder relative to the population at large). A human subject in need thereof can have a refractory or resistant a disease or disorderAttorney Docket No. 156883.617393 disclosed herein (i.e., a disease or disorder disclosed herein that doesn't respond or hasn't yet responded to treatment). The human subject may be resistant at start of treatment or may- become resistant during treatment. In some embodiments, the human subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the human subject in need thereof received at least one prior therapy.

[0097] As used herein, the term “salt” or “pharmaceutically acceptable salt” refers to a derivative of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxy benzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. Other examples of pharmaceutically acceptable salts include those derived from hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonicAttorney Docket No. 156883.617393 acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. Further examples of pharmaceutically acceptable salts include caffeine, urea, 2-picolinic acid, N-methyl-morpholine, piperazine, benzathine, and L-proline salts. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1: 1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) or co-crystals as defined herein, of the same salt. Some pharmaceutically acceptable salts of resmetirom—and methods for preparing the same— are described in U.S. Patent Application Publication Nos. 2021 / 0122740 and 2023 / 0364099, both of which are incorporated herein by reference in their entireties.

[0098] As used herein, the term ‘‘treating’" or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. That is, “treating” or “treatment” of a state, disorder, or condition therefore includes: (1) delaying the appearance of clinical symptoms of the state, disorder, or condition developing in a human that may be afflicted with the state, disorder, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder, or condition, (2) inhibiting the state, disorder, or condition, i.e., arresting or reducing the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical orAttorney Docket No. 156883.617393 subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0099] As used herein, a “solvate” refers to a crystalline form that includes a solvent (e.g., an organic solvent) chemically incorporated with the parent molecule in various fractional or integral molar ratios.

[0100] As used herein, a “hydrate” refers to a crystalline form that includes water chemically incorporated with the parent molecule in various fractional or integral molar ratios.

[0101] As used herein, a “co-crystal” refers to a crystalline material including at least two, different, molecules in the same crystalline lattice and associated by non-ionic and / or non-covalent bonds in a defined stoichiometric ratio. In some embodiments, the co-crystal includes two molecules which are in natural state. As used herein, this at least one other molecule is referred to as a “co-crystal former.” For example, a co-crystal may be resmetirom with at least one co-crystal former in a defined stoichiometric ratio.

[0102] As used herein, an “amorphous form” refers to a non-crystalline material that lacks long-range order in its structure.

[0103] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.Attorney Docket No. 156883.617393

[0104] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0105] Resmetirom is a compound having the chemical name 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile or 2-[3,5-dichloro-4-((6-oxo-5-(propan-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. Resmetirom has the chemical structure depicted below:HO, N ClN

[0106] It is to be understood that resmetirom or the pharmaceutically acceptable salt thereof can exist in crystalline or amorphous form. It is also to be understood that resmetirom or the pharmaceutically acceptable salt thereof can exist as a hydrate, solvate, or co-crystal. Various forms of resmetirom or the pharmaceutically acceptable salt thereof—and processes for preparing the same—are described in the following patents, applications, and / or publications, all of which are incorporated herein by reference in their entireties:• U.S. Patent No. 9,266,861Attorney Docket No. 156883.617393• U. S. Patent No. 10,376,517• WO 2025 / 171032• U. S. Patent Application Publication No. 2021 / 0122740• U. S. Patent Application Publication No. 2023 / 0416234• WO 2022 / 171200• WO 2025 / 011259• WO 2021 / 063367• CN 115124515A• IN 202241066042 A• U. S. Patent Application Publication No. 2024 / 0423993• CN 118772117A• MSN Laboratories Private Limited, R& D Center, et al, " Solid-state forms of Resmetirom and processes for preparation thereof," found at https: / / www.tdcommons.org / cgi / viewcontent.cgi?article=8898&context=dpubs serie s• U. S. Patent No. 12,428,402• U. S. Patent Application Publication No. 2023 / 0364099• WO 2025 / 172958. WO 2025 / 163672• WO 2025 / 146705. WO 2025 / 083699• CN 120247881 A. CN 120064346 A• CN 119954780A. CN 119143733A• WO 2025 / 202985. IN 202311058349A• IN 202341029959A• IN 202543070290A• CN 119613386A• CN 118772117A• U. S. Patent Application Publication No. 2025 / 0017938Attorney Docket No. 156883.617393 • AU 2025200217 Al

[0107] It is to be understood that resmetirom or the pharmaceutically acceptable salt thereof may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0108] Resmetirom is described, for example, in Examples 4 and 5 of U. S. Patent No.9,266,861 and PCT Pub. No. WO 2014 / 043706. One aspect of the present disclosure relates to methods of treatment or improvement as disclosed herein (e.g., of MASH and / or liver fibrosis) in which one or more solid dosage forms administered to a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement contains resmetirom or a pharmaceutically acceptable salt thereof, and the compound of formula (I), where resmetirom or a pharmaceutically acceptable salt thereof may exist in a morphic form (e.g., an amorphous form, a crystalline form, a solvate, or a hydrate) or a mixture of morphic forms.

[0109] In some embodiments, the resmetirom exists in a crystalline form.

[0110] In some embodiments, the resmetirom exists in an amorphous form.

[0111] In some embodiments, the resmetirom is in the form of a solvate.

[0112] In some embodiments, the resmetirom is in the form of a hydrate.

[0113] In some embodiments, the resmetirom is in the form of a co-crystal along with a co-crystal former as part of the co-crystal.Attorney Docket No. 156883.617393

[0114] In some embodiments, the solvate is selected from 1,1,1-trichloroethane, 1,1,2-trichloroethene, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,3 dioxolane, 1,4-dioxane, 1-butanol, 1-pentanol, 1 -propanol, 2,2,2-trifluoroethanol, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2-methyl-1-propanol, 2-propanol, 3-methyl- 1-butanol, acetic acid, acetone, acetonitrile, acetyl acetone, anisole, benzene, benzyl alcohol, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclohexanone, cyclopentylmethyl ether, di(ethylene glycol) ethyl ether, dibutyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethylene glycol, formamide, formic acid, heptane, hexafluroisopropanol, hexane, isobutyl acetate, isopropyl acetate, methanol, methyl acetate, methyl tetrahydrofuran, methylbutyl ketone, methylcyclohexane, methylethyl ketone, methylisobutyl ketone, MIPK, N, N-dimethylformamide, N, N-dimethylacetamide, nitrobenzene, nitromethane, N-methylpyrrolidone, pentane, propionic acid, propionitrile, propyl acetate, pyridine, sulfolane, tert-butanol, tert-butylmethyl ether, tetrahydrofuran, tetralin, toluene, triethylamine, triflourotoluene, Tween 2.1 wt%, and xylene.

[0115] In some embodiments, the resmetirom is in the form of a hydrate.

[0116] In some embodiments, the resmetirom is in the form of a co-crystal along with a co-crystal former as part of the co-crystal.

[0117] In some embodiments, the co-crystal former is selected from l-(2-hydroxyethyl)pyrrolidine, l-hydroxy-2-naphthoic acid, 4-(2-hydroxyethyl)morpholine, acesulfame, acesulfame potassium, 4-acetamidobenzoic acid, acetic acid, acetoin, acetylsalicylic acid, aconitic acid, adenine, adipic acid, alanine, alitame, alpha tocopherol, aluminum, 4-aminobenzoic acid, 4-aminopyridine, 4-aminosalicylic acid, ammonia, ammonium chloride, anethole, arginine, ascorbic acid, ascorbyl palmitate, asparagine,Attorney Docket No. 156883.617393 aspartame, aspartic acid, benzathine, benzaldehyde, benzamide, benzenesulfonic acid, benzoic acid, beta-cyclodextrin, betaine, betaine HC1, butylated hydroxyanisole, butylated hydroxytoluene, caffeine, calcium, calcium bromide, calcium chloride, camphoric acid, capric acid (decanoic acid), capry lic acid (octanoic acid), carbonic acid, carvone, cholic acid, choline, choline chloride, chrysin, cinnamic acid, citric acid, p-coumaric acid, creatine, creatinine, cyclamic acid, cysteine, cytosine, deanol, dehydroacetic acid, diacetyl, 2,2-dichloroacetic acid, diethanolamine, diethylamine, 2-diethylaminoethanol, 3,4-dihydroxybenzoic acid, dimethyl glycine, 2-dimethylaminoethanol, erythritol, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, ethanesulfonic acid, ethanolamine, ethyl maltol, ethyl paraben, ethyl vanillin, ethylenediamine, eugenol, ferric chloride, folic acid, folinic acid, formic acid, fructose, fumaric acid, gallic acid, genistein, gentisic acid, glucoheptonic acid, gluconic acid, glucosamine, glucosamine hydrochloride, glucose, D-glucuronic acid, glutamic acid, L-glutamine, glutaric acid, glycerin / glycerol, glycine, glycolic acid, guanine, HC1, hippuric acid, L-histidine, 4-hydroxybenzoic acid, hypoxanthine, 1H-imidazole, inositol, D-isoascorbic acid, isobutyric acid, isoleucine, isonicotinamide, ketoglutaric acid, lactic acid, lactitol, lactobionic acid, lactose, lauric acid, L-carnitine, leucine, linoleic acid, lithium, lysine, magnesium, magnesium bromide, magnesium chloride, maleic acid, malic acid, malonic acid, maltitol, maltol, maltose, mandelic acid, manganese chloride, mannitol, meglumine, methanesulfonic acid, methionine, methyl anthranilate, methyl paraben, monosodium glutamate (MSG), mucic (galactaric) acid, naphthalene- 1,5-disulfonic acid, 2-naphthalenesulfonic acid, n-butyric acid, neotame, nicotinamide, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylalanine, phosphoric acid, picolinic acid, piperazine, piperonal, potassium, proline, propionic acid, propyl gallate, propyl paraben, propylene glycol, pyridoxine, pyroglutamic acid, quercetin, resveratrol, retinol, riboflavin, saccharin, sacrosine (N-methylglycine).Attorney Docket No. 156883.617393 salicylic acid, sebacic acid, serine, sodium, sodium chloride, sodium lauryl sulfate, sorbic acid, sorbitol, stannous chloride, stearic acid, succinic acid, sucralose, sucrose, sulfuric acid, tagatose, L-tartaric acid, taurine, theanine, theobromine, theophylline, thiamine chloride, thiamine nitrate, thiocyanic acid, threonine, thymine, p-toluenesulfonic acid, triacetin, tributyrin. triethanolamine, triethyl citrate, triethylamine, tromethamine, tromethamine hydrochloride, L-tryptophan, tyrosine, uracil, urea, valeric acid, valine, vanillic acid, vanillin, xanthine, xylitol, xylose, zinc, and zinc chloride.

[0118] All doses or dosages recited herein for resmetirom or the pharmaceutically acceptable salt thereof are based on the molecular weight of the compound itself, rather than the molecular weight of the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof, or the co-crystal thereof, or any excipients in the composition, unless otherwise stated. For example, administration of resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day means administration of the equivalent of 100 mg of the compound itself per day, not 100 mg of the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof, or the co-crystal thereof, per day.

[0119] In some aspects, the present disclosure provides a method of treating MASH (e.g., noncirrhotic MASH with moderate to advanced liver fibrosis consistent with stages F2 and / or F3 fibrosis, and compensated MASH cirrhosis with stage F4 fibrosis (stage F4c)) in a human subject (e.g., an adult human subject) in need thereof, which comprises: administering to the human subject (e.g., an adult human subject) in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

[0120] In some aspects, the present disclosure provides resmetirom or the pharmaceutically acceptable salt thereof for use for treating MASH (e.g.. noncirrhotic MASH with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis, and / orAttorney Docket No. 156883.617393 compensated MASH cirrhosis with stage F4 fibrosis (stage F4c)) in a human subject (e.g., an adult human subject) in need thereof.

[0121] In some aspects, the present disclosure provides use of resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating MASH (e.g., noncirrhotic MASH with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis, and / or compensated MASH cirrhosis with stage F4 fibrosis (stage F4c)) in a human subject (e.g., an adult human subject) in need thereof.

[0122] In some aspects, the present disclosure provides a method of treating cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subject) in need thereof, which comprises: administering to the human subject (e.g., an adult human subject) in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

[0123] In some aspects, the present disclosure provides resmetirom or the pharmaceutically acceptable salt thereof for use for treating cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subject) in need thereof.

[0124] In some aspects, the present disclosure provides use of resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subj ect) in need thereof.

[0125] In some aspects, the present disclosure provides a method of treating CSPH in a human subject (e.g., an adult human subject) in need thereof, which comprises: administering to the human subject (e.g., an adult human subject) in need thereof resmetirom or a pharmaceutically acceptable salt thereof.Attorney Docket No. 156883.617393

[0126] In some aspects, the present disclosure provides resmetirom or the pharmaceutically acceptable salt thereof for use for treating CSPH in a human subject (e.g., an adult human subject) in need thereof.

[0127] In some aspects, the present disclosure provides use of resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating CSPH in a human subject (e g., an adult human subject) in need thereof.

[0128] In some aspects, the present disclosure provides a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cardiomyopathy and / or a related heart failure in a human subject (e.g.. an adult human subject) in need thereof.

[0129] In some aspects, the present disclosure provides a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating CSPH in a human subject (e g., an adult human subject) in need thereof.

[0130] In some aspects, the present disclosure provides a pharmaceutical composition comprising resmetirom or a pharmaceutically acceptable salt thereof.

[0131] In some aspects, the present disclosure provides a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof for use in treating cardiomyopathy and / or a related heart failure in a human subject (e g., an adult human subject) in need thereof.

[0132] In some aspects, the present disclosure provides use of a pharmaceutical composition comprising resmetirom or a pharmaceutically acceptable salt thereof in theAttorney Docket No. 156883.617393 manufacture of a medicament for treating cardiomyopathy and / or a related heart failure in a human subject (e.g., an adult human subject) in need thereof.

[0133] In some aspects, the present disclosure provides a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof for use in treating CSPH in a human subject (e g., an adult human subject) in need thereof.

[0134] In some aspects, the present disclosure provides use of a pharmaceutical composition comprising resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating CSPH in a human subject (e.g., an adult human subject) in need thereof.

[0135] In some aspects, the present disclosure provides a dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof.

[0136] In some aspects, the present disclosure provides a dosage form comprising a pharmaceutical composition comprising resmetirom or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is administered to the human subject (e.g., an adult human subject) with food. In other embodiments, the dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is administered to the human subject (e.g., an adult human subject) without food.

[0138] In some embodiments, the dosage form is a solid dosage form.Attorney Docket No. 156883.617393

[0139] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof is used in combination with one or more additional compounds or drugs with the same or similar indications.

[0140] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is taken daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly.

[0141] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is taken once or twice daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly.

[0142] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is taken once daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly.

[0143] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been taken without any drug holiday.

[0144] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been taken with one or more drug holidays.

[0145] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been administered for one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks, or for any number of days of weeks therebetween.Attorney Docket No. 156883.617393

[0146] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been administered for longer than 52 weeks.

[0147] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been administered for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months, at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 37 months, at least 38 months, at least 39 months, at least 40 months, at least 41 months, at least 42 months, at least 43 months, at least 44 months, at least 45 months, at least 46 months, at least 47 months, at least 48 months, atAttorney Docket No. 156883.617393 least 49 months, at least 50 months, at least 51 months, at least 52 months, at least 53 months, at least 54 months, at least 55 months, at least 56 months, at least 57 months, at least 58 months, at least 59 months, at least 60 months, at least at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years, or for any number of days, weeks, months, or years therebetween.

[0148] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is or has been administered for at least 2 years.

[0149] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly is about 1 mg to about 200 mg, about 1 mg to about 180 mg. about 1 mg to about 160 mg. about 1 mg to about 140 mg, about 1 mg to about 120 mg, about 1 mg to about 100 mg. about 1 mg to about 80 mg, about 1 mg to about 60 mg. about 1 mg to about 40 mg. about 1 mg to about 20 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg toAttorney Docket No. 156883.617393 about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 200 mg, or any number therebetween.

[0150] In some embodiments, the administering of about 1 mg to about 200 mg, about 1 mg to about 180 mg, about 1 mg to about 160 mg, about 1 mg to about 140 mg, about 1 mg to about 120 mg, about 1 mg to about 100 mg, about 1 mg to about 80 mg, about 1 mg to about 60 mg, about 1 mg to about 40 mg, about 1 mg to about 20 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg,Attorney Docket No. 156883.617393 about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 200 mg, or any number therebetween, daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months, at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 37 months, at least 38 months, at least 39 months, at least 40 months, at least 41 months, at least 42 months, at least 43 months, at least 44 months, at least 45 months, at least 46 months, at least 47 months, at least 48 months, at least 49 months, at least 50 months, at least 51 months, at least 52 months, at least 53 months, at least 54 months, at least 55 months, at least 56 months, at least 57 months, at least 58 months, at least 59 months, at least 60 months, at least at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years, or for any number of days, weeks, months, or years therebetween.Attorney Docket No. 156883.617393

[0151] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly is about 60 mg to about 100 mg.

[0152] In some embodiments, the administering of about 60 mg to about 100 mg. daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months, at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 37 months, at least 38 months, at least 39 months, at least 40 months, at least 41 months, at least 42 months, at least 43 months, at least 44 months, at least 45 months, at least 46 months, at least 47 months, at least 48 months, at least 49 months, at least 50 months, at least 51 months, at least 52 months, at least 53 months, at least 54 months, at least 55 months, at least 56 months, at least 57 months, at least 58 months, at least 59 months, at least 60 months, at least at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years, or for any number of days, weeks, months, or years therebetween.

[0153] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily is about 60 mg to about 100 mg.Attorney Docket No. 156883.617393

[0154] In some embodiments, the administering of about 60 mg to about 100 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

[0155] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily, even’ other day, twice a week, weekly, biweekly, triweekly, or monthly is about 20 mg, about 40 mg, about 60 mg, about 80 mg. about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, or any amount therebetween.

[0156] In some embodiments, the administering of about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg. about 120 mg, about 140 mg, about 160 mg, about 180 mg. about 200 mg, daily, every other day, twice a week, weekly, biweekly, triweekly, or monthly, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, at least 30 months, at least 31 months, at least 32 months, at least 33 months, at least 34 months, at least 35 months, at least 36 months, at least 37 months, at least 38 months, at least 39 months, at least 40 months, at least 41 months, at least 42 months, at least 43 months, at least 44 months, at least 45 months, at least 46 months, at least 47 months, at least 48 months, at least 49 months, at least 50 months, at least 51 months, at least 52 months, at least 53 months, at least 54 months, at least 55 months, at least 56 months, at least 57 months, at least 58 months, at leastAttorney Docket No. 156883.617393 59 months, at least 60 months, at least at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or at least 10 years, or for any number of days, weeks, months, or years therebetween.

[0157] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily is about 60 mg.

[0158] In some embodiments, the administering of about 60 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

[0159] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily is about 80 mg.

[0160] In some embodiments, the administering of about 80 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

[0161] In some embodiments, the amount of resmetirom or the pharmaceutically acceptable salt thereof taken daily is about 100 mg.

[0162] In some embodiments, the administering of about 100 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

[0163] In some embodiments, the dose of resmetirom is determined based on determination of the weight of the adult human subject. For instance, resmetirom or the pharmaceutically acceptable salt thereof is administered at a dosage of 100 mg per day if the human subject is determined to weigh 100 kg or more, or resmetirom or the pharmaceutically acceptable salt thereof is administered at a dosage of 80 mg per day if the human subject is determined to weigh less than 100 kg. The dose of resmetirom can be adjusted once the human subject crosses the 100 kg weight threshold, which can happen with weight reduction.Attorney Docket No. 156883.617393

[0164] In some embodiments, the human subject (e.g., an adult human subject) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is not taking atorvastatin, pravastatin, rosuvastatin, or simvastatin. In some embodiments, the human subject (e.g., an adult human subject) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is taking 20 mg or less rosuvastatin or simvastatin. In some embodiments, the human subject (e.g., an adult human subject) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is taking 40 mg or less atorvastatin or pravastatin.

[0165] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0166] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is administered orally.

[0167] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is administered intravenously.Attorney Docket No. 156883.617393

[0168] In some embodiments, resmetirom or the pharmaceutically acceptable salt thereof, is administered subcutaneously.

[0169] In some aspects, the human subject has a fatty liver disease.

[0170] In some aspects, the fatty liver disease is MASH.

[0171] In some embodiments, the human subject (e.g., an adult human subject) has MASH. It is understood that, in MASH, the fat accumulation may be associated with varying degrees of inflammation (hepatitis) and / or scarring (fibrosis) of the liver. In some embodiments, the fibrosis of the liver is a stage F2 fibrosis. In some embodiments, the fibrosis of the liver is a stage F3 fibrosis. In some embodiments, the fibrosis of the liver is a stage F4 fibrosis and the human subject (e.g., an adult human subject) has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0172] In some embodiments, the human subject (e.g., an adult human subject) has cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has compensated MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c)

[0173] In some embodiments, the human subject (e.g., an adult human subject) has liver inflammation.

[0174] In some embodiments, the human subject (e.g.. an adult human subject) has a disease, disorder, or condition associated with an increased liver volume.

[0175] In some embodiments, the human subject (e.g., an adult human subject) has moderate hepatic impairment.Attorney Docket No. 156883.617393

[0176] In some embodiments, the human subject (e.g., an adult human subject) has autoimmune liver disease. In other embodiments, the human subject (e.g., an adult human subject) does not have autoimmune liver disease.

[0177] In some embodiments, the human subject (e.g., an adult human subject) has moderate to severe hepatic impairment (e.g., Child-Pugh Class B or C). In other embodiments, the human subject (e.g., an adult human subject) does not have moderate to severe hepatic impairment. In other embodiments, the human subject (e.g., an adult human subject) has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c) (e.g., Child-Pugh Class A).

[0178] In some embodiments, the human subject (e.g., an adult human subject) has cardiomyopathy.

[0179] In some embodiments, the human subject (e g., an adult human subject) has a heart failure related to cardiomyopathy.

[0180] In some embodiments, the human subject (e.g., an adult human subject) has cardiomyopathy and cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cardiomyopathy and MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cardiomyopathy and compensated MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cardiomyopathy and compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0181] In some embodiments, the cardiomyopathy is associated with cirrhosis (i.e., cirrhotic cardiomyopathy), metabolic dysfunction (e.g., obesity, MASH), or heart failure including cardiac stress unmasking latent diastolic dysfunction.Attorney Docket No. 156883.617393

[0182] In some embodiments, the human subject (e.g., an adult human subject) has cirrhotic cardiomyopathy and cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cirrhotic cardiomyopathy and MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cirrhotic cardiomyopathy and compensated MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has cirrhotic cardiomyopathy and compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0183] In some embodiments, improvements of cardiomyopathy are assessed through imaging (e.g., echocardiography, cardiac MRI), biomarkers (e.g., NT-proBNP, troponin I, CK-18, PRO-C3), and electrophysiological indicators (e.g., QTc interval).

[0184] In some embodiments, the human subject (e.g., an adult human subject) has cardiac dysfunction with prolonged QTc, elevated NT-proBNP, or imaging-confirmed myocardial stiffness.

[0185] In some embodiments, the administration improves echocardiographic diastolic indices (e.g., E / e’, left atrial volume).

[0186] In some embodiments, the administration reduces QTc interval on ECG.

[0187] In some embodiments, the administration decreases cardiac fibrosis via MRI T1 mapping.

[0188] In some embodiments, the administration reduces biomarkers (e.g., NT-proBNP, troponin I, CK-18, PRO-C3).

[0189] In some embodiments, the human subject (e.g., an adult human subject) has portal hypertension.Attorney Docket No. 156883.617393

[0190] In some embodiments, the human subject (e.g., an adult human subject) has portal hypertension and cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has portal hypertension and MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has portal hypertension and compensated MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has portal hypertension and compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0191] In some embodiments, the portal hypertension is CSPH.

[0192] In some embodiments, the human subject (e.g., an adult human subject) has CSPH.

[0193] In some embodiments, the human subject (e.g., an adult human subject) has CSPH and cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has CSPH and MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has CSPH and compensated MASH cirrhosis. In some embodiments, the human subject (e.g., an adult human subject) has CSPH and compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

[0194] Human subjects can be categorized into certain groups according to Baveno criteria: CSPH, probable CSPH risk, and no / low CSPH risk. In some embodiments, the human subject (e.g., an adult human subject) has CSPH according to Baveno criteria for CSPH. In some embodiments, the human subject (e.g., an adult human subject) has probable CSPH risk according to Baveno criteria for CSPH.

[0195] In some embodiments, the method is of improving portal hypertension.

[0196] In some embodiments, the administration improves portal hypertension over a period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10Attorney Docket No. 156883.617393 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any number of days, weeks, months, or years therebetween.

[0197] In some embodiments, the administration improves portal hypertension over a period of four to 10 weeks.

[0198] In some embodiments, the administration for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, at least 52 weeks, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, or atAttorney Docket No. 156883.617393 least 10 years, or any number of days, weeks, months, or years therebetween, improves portal hypertension.

[0199] In some embodiments, the administration for at least 4 to 10 weeks improves portal hypertension.

[0200] In some embodiments, the method is of improving CSPH.

[0201] In some embodiments, the method is of improving CSPH from CSPH to probable CSPH risk.

[0202] In some embodiments, the method is of improving CSPH from CSPH to no / low CSPH risk.

[0203] In some embodiments, the method is of improving CSPH from probable CSPH risk to no / low CSPH risk.

[0204] In some embodiments, the administration improves CSPH from CSPH to probable CSPH risk over a period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year. 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any number of days, weeks, months, or years therebetween.Attorney Docket No. 156883.617393

[0205] In some embodiments, the administration improves CSPH from CSPH to probable CSPH risk over a period of 4 to 6 weeks.

[0206] In some embodiments, the administration improves CSPH from CSPH to probable CSPH risk over a period of 12 months.

[0207] In some embodiments, the administration improves CSPH from CSPH to probable CSPH risk over a period of 24 months.

[0208] In some embodiments, the administration improves CSPH from CSPH to no / low CSPH risk over a period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any number of days, weeks, months, or years therebetween.

[0209] In some embodiments, the administration improves CSPH from CSPH to no / low CSPH risk over a period of 4 to 6 weeks.

[0210] In some embodiments, the administration improves CSPH from CSPH to no / low CSPH risk over a period of 12 months.

[0211] In some embodiments, the administration improves CSPH from CSPH to no / low CSPH risk over a period of 24 months.Attorney Docket No. 156883.617393

[0212] In some embodiments, the administration improves CSPH from probable CSPH risk to no / low CSPH risk over a period of one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or any number of days, weeks, months, or years therebetween.

[0213] In some embodiments, the administration improves CSPH from probable CSPH risk to no / low CSPH risk over a period of 4 to 6 weeks.

[0214] In some embodiments, the administration improves CSPH from probable CSPH risk to no / low CSPH risk over a period of 12 months.

[0215] In some embodiments, the administration improves CSPH from probable CSPH risk to no / low CSPH risk over a period of 24 months.

[0216] In some embodiments, a human subject (e.g., an adult human subject) in need of the treatment or improvement as described herein can be further instructed (e.g., counseled, instructed or prescribed) to perform diet and / or exercise in conjunction with said administration of a daily dose of resmetirom or the pharmaceutically acceptable salt thereof. In particular, this instruction can be to lose greater than or equal to 5% of their body weight, measured upon initiation of therapy.Attorney Docket No. 156883.617393

[0217] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as described herein administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof will be further instructed (e.g., counseled, instructed or prescribed) to perform diet and exercise in conjunction with said administration of a daily dose of resmetirom or the pharmaceutically acceptable salt thereof. In particular, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as described herein administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof will be instructed (e.g., counseled, instructed or prescribed) to diet and exercise to lose greater than or equal to 5% of their body weight, measured upon initiation of therapy, in conjunction with said administration of a daily dose of resmetirom or the pharmaceutically acceptable salt thereof.

[0218] The pharmaceutical composition can be in a form suitable for oral use. The pharmaceutical composition can be in a form suitable for subcutaneous use.

[0219] In some embodiments, the pharmaceutical composition is formulated in a solid oral dosage form. As used herein, the term “solid dosage form” refers to a dosage form that is in a solid form. As used herein, the term "‘solid oral dosage form” refers to a dosage form that is taken by mouth in a solid form. The solid oral dosage form is designed to be swallowed and later dissolved in the gastrointestinal tract, allowing for systematic delivery of the medication to the human subject (e.g., an adult human subject) who may be in need of the weight reduction as disclosed herein. The solid oral dosage form includes for example, a pill.

[0220] In some embodiments, the pharmaceutical composition is formulated in a pill. As used herein, the term “pill” includes for example, a capsule, a softgel, a sprinkle capsule, a tablet, a chewable tablet, or a caplet.Attorney Docket No. 156883.617393

[0221] In some embodiments, the pharmaceutical composition is formulated in a tablet. As used herein, the term “tablet” refers to a pill that is a solid formulation composed of medication and usually has no outer shell. Typically, the medication is in powder form where the medication and other inactive ingredients are compressed into a solid, smooth form. The tablet can be optionally coated.

[0222] The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0223] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel". or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.Attorney Docket No. 156883.617393

[0224] In some embodiments, the active compounds are prepared with pharmaceutically acceptable excipients that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable excipients.EXAMPLES

[0225] The following Examples are provided by way of illustration and not by way of limitation.

[0226] Example 1; Resmetirom effects on NASH with liver fibrosis in patients with NASH genetic risk alleles

[0227] MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with NASH and fibrosis.

[0228] 966 patients with b4. No biopsy-confirmed NASH were randomized 1: 1: 1 to resmetirom 80 mg, resmetirom 100 mg, or placebo administered once daily.

[0229] Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage reduction in fibrosis with no worsening of NAS (FI).Attorney Docket No. 156883.617393

[0230] In this analysis, the impact of baseline PNPLA3, TM6SF2 and MBOAT7 genotypes on the response to resmetirom on serial liver b4. No biopsy and MRI-PDFF was examined.

[0231] Methods

[0232] Key eligibility criteria of the MAESTRO-NASH trial and a graphical representation showing the study design are shown in FIG. 1.

[0233] SNPs in PNPLA3 rs738409, HSD17B13 (Hydroxysteroid 17-beta Dehydrogenase 13) rs 72613567, TM6SF2 rs58542926, MBOAT7 rs6141738, and SERPINA1 (Alpha-1 Antitrypsin): Variants: Z allele (Glu342Lys) and 8 allele (Glu264Val) were genotyped in patients consenting to DNA collection and genetic testing for the response to resmetirom on serial liver b4. No biopsy and MRI-PDFF.

[0234] Baseline characteristics according to genetic risk markers were assessed.

[0235] B4. No biopsy, MRI-PDFF, and other biomarkers responses were analyzed within each treatment arm, comparing wild type, heterozygote and homozygote for each genetic risk allele.

[0236] Baseline Characteristics

[0237] Across three treatment arms, 740 patients had genotyping and serial liver b4. No biopsy data.

[0238] The minor allele general population frequency is shown in Table 1.Table 1: Minor allele general population frequency.Gene Wildtype Minor Allele Heterozygous HomozygousAttorney Docket No. 156883.617393Frequency*PNPLA3 rs738409 CC 20-46% CG GG TM6SF2 rs58542926 CC 4-8% CT TT MBOAT7 rs641738 CC 20-43% CT TT SERPINA1 Z allele MM 1-2% MZ ZZ (Glu342Lys)HSD17B13 rs7261356 TT 15-33% TA / T TA / TA*Range in normal population

[0239] Allele Frequency in MAESTRO-NASH

[0240] Patient population who consented to genetics and had a Week 52 liver b4. No biopsy is shown in Table 2.Table 2: Allele Frequency in MAESTRO-NASH,Gene Wildtype Heterozygous HomozygousPNPLA3 Non-NASH Population 38% 45% 10.5% MAESTRO-NASH 31.3% 46.2% 22.5% HSD17B13 Non-NASH Population 52-58*% 37*-40% 6*-8.5% MAESTRO-NASH 65% 29% 6% TM6SF2 Non-NASH Population 79-82% 15-21% 0-3% MAESTRO-NASH 80% CT / TT 20% MBOAT7 Non-NASH Population 28-29% 47-50% 21-24% MAESTRO-NASH No effectAttorney Docket No. 156883.617393SERPINA1 Non-NASH Population 90-95% 9-10% 1-2% (AAT) MAESTRO-NASH No effect*PNPLA3 Caucasian (Hispanic, 25%); TM6SF2 Europeans TT, 26%; Hispanic 10%

[0241] PNPLA3 Baseline Characteristics

[0242] Focus was on the 3 genetic markers with the most impact: PNPLA3, HSD. and TM6SF2. A large array of baseline features in the MAESTRO-NASH population were not impacted based on the PNPLA3 genetic background. A few features showed differences (values in bold fond). Results are shown in Table 3.Table 3: PNPLA3 Baseline Characteristics.Characteristic No Mutation Heterozygous Homozygous (N=230) (N=339) (N=165) Age at Informed Consent (years) - 57.3 (9.7) 56.5 (10.9) 55.3 (11.5) Mean (SD)Sex, Male - n (%) 104 (45.2) 156 (46.0) 63 (38.2) Race, White - n (%) 205 (89.1) 306 (90.3) 141 (85.5) Ethnicity, Hispanic or Latino - n (%) 32 (13.9) 76 (22.4) 56 (33.9) Body Mass Index (kg / m2) - Mean (SD) 35.8 (6.6) 35.7 (6.7) 35.1 (6.5) Type 2 Diabetes - n (%) 169 (73.5) 222 (65.5) 99 (60.0) Hypertension - n (%) 193 (83.9) 273 (80.5) 116 (70.3) Dyslipidemia - n (%) 175 (76.1) 239 (70.5) 105 (63.6) Hypothyroidism - n (%) 25 (10.9) 54 (15.9) 18 (10.9) FibroScan VCTE (kPa) at Screening - 13.9 (8.1) 13.1 (6.0) 12.9 (6.1)Attorney Docket No. 156883.617393Mean (SD)Median (Min, Max) 11.9(4.0, 11.6(5.2, 11.1(5.2,75.0) 66.4) 45.6) FibroScan CAP (dB / m) Score at 353.5 (39.8) 350.1 (36.0) 334.7 (40.8) Screening - Mean (SD)Hepatic Fat Fraction (%) by MRI- 17.6 (6.7) 18.2 (6.8) 17.5 (6.7) PDFF at Screening - Mean(SD)Median (Min, Max) 16.9 (2.5, 17.1 (2.8, 16.3 (5.1,35.1) 35.3) 33.8) Stiffness by MRE (kPa) at Screening - 3.6 (1.0) 3.5 (1.0) 3.5 (0.98) Mean (SD)Median (Min, Max) 3.5 (1.8, 9.9) 3.3 (1.9, 9.2) 3.4 (2.1, 6.7) Enhanced Liver Fibrosis Score - Mean 9.7 (0.83) 9.7 (0.82) 9.9 (0.97) (SD)On GLP-1 Therapy 39 (17.0) 48 (14.2) 26 (15.8) On Statin Therapy 122 (53.0) 167 (49.3) 61 (37.0) Baseline Liver B4. No biopsy - n (%)NAS >5 189 (82.2) 287 (84.7) 139 (84.2) Fibrosis 1B 19 (8.3) 13 (3.8) 8 (4.8) Fibrosis 2 72 (31.3) 119 (35.1) 45 (27.3) Fibrosis 3 137 (59.6) 202 (59.6) 110 (66.7)

[0243] Baseline Features in NASH Genetic PopulationsAttorney Docket No. 156883.617393

[0244] Differences in baseline characteristics were explored for patients with and without risk alleles for PNPLA3, HSD17B13 and TM6SF2. Increased Hispanic population was observed in PNPLA3 and HSD risk populations; lower Hispanic population was observed in TM6SF2. In the MAESTRO-NASH population, patients with higher genetic risk had lower metabolic risk factors. Results are shown in FIGS. 2A-2B.

[0245] Baseline Triglycerides and MRI-PDFF

[0246] Decreased plasma triglycerides and no change in MRI-PDFF (liver triglycerides) were observed in the PNPLA3 genetic risk population. Reduced plasma triglycerides and MRI-PDFF were observed in the HSD genetic risk population. Reduced plasma triglycerides and slight increase in liver triglycerides were observed with TM6SF2 genetic markers.Results are shown in FIGS. 3A-3B.

[0247] NASH Genetic Background Impact on Baseline Liver Enzymes

[0248] Increased liver enzymes at baseline were observed in patients with genetic risk alleles for PNPLA3 and HSD relative to patients without genetic risk (FIGS. 4A-4B).

[0249] Impact of NASH Genetic Background on NASH Resolution

[0250] For HSD and TM6SF2 heterozygous and homozygous were combined due to low numbers of patients. In resmetirom-treated patients, the percentage with NASH resolution was not impacted by any NASH genetic risk markers. No apparent impact of genetic risk markers on NASH resolution in placebo population. Results are shown in FIG. 5 and number of patients in Table 4.Table 4 PNPLA3 Baseline Characteristics.Attorney Docket No. 156883.617393Number of pts No mutation Heterozygous Homozygous PNPLA3 230 339 165 HSD 483 214 43 TM6SF2 589 145

[0251] Impact of NASH Genetic Background on B4. No biopsy Fibrosis Improvement

[0252] In resmetirom-treated patients, the percentage with fibrosis improvement on liver b4. No biopsy was not impacted by any NASH genetic risk markers. No apparent impact of genetic risk markers on fibrosis improvement was observed in the placebo population. Results are shown in FIG. 6.

[0253] Impact of NASH Genetic Risk Alleles on Liver Fat Reduction

[0254] In resmetirom-treated patients, the relative percentage reduction in PDFF was not impacted by any NASH genetic risk markers. No apparent impact of genetic risk markers on MRI-PDFF reduction was observed in the placebo population. Results are shown in FIG. 7.

[0255] Liver Enzyme Responses

[0256] Increased liver enzymes at baseline were observed in patients with genetic risk markers for PNPLA3 and HSD relative to patients without genetic risk. Lowering of ALT and AST at Week 48 by resmetirom was robust and independent of genetic risk. Results are shown in FIG. 8.

[0257] FibroScan Response

[0258] Baseline Fibroscan LSM was not different in F2 / F3 NASH patients with genetic risk markers PNPLA3 and HSD compared with patients without genetic risk markers.Attorney Docket No. 156883.617393 Resmetirom compared with placebo lowered LSM at 52 Weeks independent of risk alleles. Results are shown in FIG. 9.

[0259] A significant fraction of patients enrolled in MAESTRO-NASH had genetic risk markers, particularly PNPLA3, HSD17, and TM6SF2 that impacted several baseline features including ethnicity, metabolic features, baseline liver enzyme levels and lipids. Higher genetic risk was associated with lower metabolic risk in this F2 to F3 population. NASH risk alleles were prevalent in the MAESTRO-NASH population did not influence the treatment response to resmetirom on liver b4. No biopsy, imaging or other markers of response.

[0260] Example 2; Effect of Resmetirom or Placebo in NASH Fibrosis Patients with <5% or >5% Weight Loss and / or on Baseline GLP-1 Therapy in the MAESTRO-NASH 52-Week Serial Liver B4. No biopsy Study

[0261] MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with b4. No biopsy-confirmed NASH and fibrosis.

[0262] A total 966 patients with b4. No biopsy-confirmed NASH were randomized 1: 1: 1 to resmetirom 80 mg, resmetirom 100 mg, or placebo administered orally once daily.

[0263] Dual primary endpoints at Week 52 were achieved with both resmetirom doses: NASH resolution with no worsening of fibrosis (NR) or >1 -stage reduction in fibrosis with no w orsening of NAS (FI).

[0264] Histologic end points were assessed after 52 weeks.

[0265] At baseline, 13% to 17% of patients in the treatment groups were on stable GLP-1 therapy (at least 6 months prior to randomization). All patients taking GLP-1 receptorAttorney Docket No. 156883.617393 agonists (GLPs) in MAESTRO-NASH were diabetic. Multiple baseline GLPs were used at diabetes dosages. Other diabetic therapies associated with weight loss included SGLT2s.

[0266] Aims: In MAESTRO-NASH patients, the effects of resmetirom or placebo on GLP-1 baseline therapy were evaluated, and the effect of >=5% weight loss on liver b4. No biopsy¬ end points with or without GLP-1 baseline therapy were evaluated

[0267] Methods

[0268] Key eligibility- criteria of the MAESTRO-NASH trial, a graphical representation showing the study design, and dual primary end point at week 52 are shown in FIG. 10.

[0269] Patients in this serial liver b4. No biopsy trial were counseled on moderate diet and exercise at each study visit. Patients on baseline GLP- therapy with <5% or >5% weight loss at 52 weeks w ere evaluated for achievement of NR and FI liver b4. No biopsy end points or percent change from baseline in MRI-PDFF at Week 52.

[0270] Baseline Characteristics

[0271] In MAESTRO-NASH, baseline GLP-1 therapy had been in place for >6 months. All patients on GLP therapy had diabetes; the most common dose was 1 mg semaglutide or comparable (dulaglutide). At baseline, patients on GLP-1 therapy had a higher % F3 with more metabolic and CV features, more common statin use, and, at baseline, lower LDL and liver enzymes than non-diabetic patients. Patients on GLPs showed no difference in baseline MRI-PDFF or body weight. There were no meaningful differences in baseline characteristics between the patient populations on SGLT2 therapy and / or GLP therapy. The Baseline Characteristics are shown in Table 5.Table 5: Baseline Characteristics.Attorney Docket No. 156883.617393No Diabetes DiabetesAll Diabetes GLP-1 SGLT2 (N=319) (N=647) (N=137) (N=130) Age (years) - Mean (SD) 53.7 (12.3) 58.1 (9.9) 56.2 (9.2) 58.3 (8.6) Female - n (%) 170 (53.3) 372 (57.5) 84 (61.3) 69 (53.1) White n (%) 294 (92.2) 569 (87.9) 123 (89.8) 111 (85.4) Hispanic or Latino - n 63 (19.7) 141 (21.8) 23 (16.8) 30 (23.1) (%)Type 2 Diabetes - n (%) 0 647 (100.0) 137 (100.0) 130 (100.0) Hypertension - n (%) 215 (67.4) 539 (83.3) 116 (84.7) 114 (87.7) Dyslipidemia - n (%) 173 (54.2) 516 (79.8) 117 (85.4) 110 (84.6) Thyroxine Replacement- 40 (12.5) 90 (13.9) 25 (18.2) 17 (13.1) n (%)Statin Therapy - n (%) 97 (30.4) 376 (58.1) 84 (61.3) 86 (66.2) Insulin Therapy - n (%) 0 118 (18.2) 44 (32.1) 38 (29.2) Weight (kg) - Mean (SD) 101.5 (22.8) 100.3 (22.7) 103.7 (24.3) 99.7 (22.4) BMI (kg / m2) - Mean (SD) 35.4 (6.8) 35.8 (6.8) 36.6 (6.9) 35.4 (6.1) HOMA-IR - Mean (SD) 9.4 (8.8) 12.0 (11.7) 12.9 (12.0) 9.3 (5.9) HbAlc (%) -Mean (SD) 5.7 (0.6) 7.0 (1.0) 7.1 (1.0) 7.2 (1.0) 10-year ASCVD Risk 9.5 (7.4) 17.5 (12.7) 14.5 (10.8) 16.0 (10.6) Score - Mean (SD)ELF - Mean (SD) 9.7 (0.9) 9.8 (0.9) 9.5 (0.8) 9.7 (0.8) FibroScan VCTE (kPa) 11.0 (9.1, 14.6) 12.0 (9.7, 12.0 (9.8, 11.2 (9.6, Median (QI, Q3) 15.5) 15.5) 13.9) FibroScan CAP (dB / m)- 342.1 (39.6) 350.3 (36.4) 351.8 (36.2) 348.8 (36.1) Mean (SD)(%) MRI-PDFF- Mean 18.4 (7.0) 17.4 (6.6) 16.5 (6.0) 16.1 (6.5)Attorney Docket No. 156883.617393(SD)MRE (kPa)– Median (Q1, 3.3 (2.7, 3.9) 3.5 (2.9, 4.2) 3.4 (3.0, 4.0) 3.4 (3.0, 4.1) Q3)ALT (U / L) - Mean (SD) 62.1 (36.1) 52.1 (29.0) 45.6 (22.6) 48.3 (23.6) AST (U / L) - Mean (SD) 45.7 (25.9) 38.8 (21.1) 34.3 (16.6) 34.7 (14.3) NAS at Screening, >5 n 263 (82.4) 544 (84.1) 110 (80.3) 101 (77.7) (%)Fibrosis Stage - n (%)IB 16 (5.0) 33 (5.1) 6 (4.4) 4 (3.1) 2 130 (40.8) 189 (29.2) 35 (25.5) 37 (28.5) 3 168 (52.7) 415 (64.1) 93 (67.9) 88 (67.7) 4 5 (1.6) 10 (1.5) 3 (2.2) 1 (0.8)

[0272] GLPs and SGLT2: No Impact on B4. No biopsy Responses to Resmetirom

[0273] Patients with diabetes on resmetirom plus SGLT2 or GLP-1 therapy had equivalent liver b4. No biopsy responses to patients with diabetes not on these therapies. There were no differences in safety or tolerability in patients with diabetes treated with a combination of GLP-1 plus resmetirom. Results are shown in FIG. 11.

[0274] Various Diabetes Treatments Did Not Impact MRI-PDFF Reduction by Resmetirom

[0275] The same response to PDFF-reduction with resmetirom was observed in patients with diabetes exposed to resmetirom and vanous treatments, including GLPs, SGLT2i or insulin. Results are shown in FIG. 12.

[0276] Weight Loss In MAESTRO-NASHAttorney Docket No. 156883.617393

[0277] 17% on 80 mg and 22% on 100 mg in the resmetirom arms achieved >5% weight loss at Week 52 compared to 12% on placebo. Higher weight loss was onserved with resmetirom that was statistically significant (nominal). Median weight loss 7% in the >5% weight loss groups was onserved. GLP-1 treatment in MAESTRO-NASH was not associated with weight loss: 14% of patients with the >5% weight loss were on GLP-1 receptor agonists; 15% of patients with the <5% weight loss were on GLP-1 receptor agonists.

[0278] Weight Loss / Resmetirom Impact on Biopsv Endpoints

[0279] Weigh loss >5% achieved by diet and exercise occurred in about 22% of patients on resmetirom (12% of placebo patients). In resmetirom 100 mg arm, >5% weight loss was associated with increased fibrosis improvement (41%) and NASH resolution (57%) on liver b4. No biopsy; similar improvements in 80 mg arm. Resmetirom maintained the favorable difference on NASH and fibrosis endpoints from placebos with all weight changes (no weight change, >5% wight loss or >5% weight gain). Results are shown in FIG. 13.

[0280] Weight Loss Effect on MRI-PDFF

[0281] PDFF-reduction in patients with >5% weight loss improved at Week 52 relative to Week 16; no change between Week 16 and Week 52 in patients without weight loss.Resmetirom retains separation from placebo in both groups. In resmetirom arm, 98% with >5% weight loss had a 30% PDFF response. Results are shown in FIG. 14.

[0282] In MAESTRO-NASH two thirds of patients had diabetes and many were stably treated with SGLT2i and GLP-1 receptor agonist (GLP-1 RA) therapy. No weight loss above background occurred with GLPs. GLP-1 RA and SGLT2i treated patients with diabetes showed the same NASH resolution and fibrosis improvement rates in combination with resmetirom as patients with diabetes not on these agents. >5% weight loss was observed moreAttorney Docket No. 156883.617393 frequently in resmetirom as compared with placebo treated patients. >5% weight loss was associated with high rates of NASH resolution -60% and fibrosis improvement -40% in resmetirom-treated patients.

[0283] Example 3: Assessment of Resmetirom Efficacy (80 mg vs. 100 mg) Stratified by Baseline Body Mass Index and Weight in Patients from the MAESTRO-NASH trial

[0284] Resmetirom, an oral, liver-directed THR-0 selective agonist, was approved in March 2024 in the United States for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). MAESTRO-NASH is an ongoing 54-month randomized, double-blind, placebo controlled Phase 3 serial liver b4. No biopsy trial evaluating the efficacy & safety of oral, daily 80 mg or 100 mg resmetirom in adults with b4. No biopsy-confirmed NASH (NCT03900429). At week 52, both primary endpoints were met at both clinical doses. The recommended dosage of resmeitrom is based on actual body weight. For patients weighing <100 kg, the recommended dosage is 80 mg orally once daily. For patients weighing >100 kg, the recommended dosage is 100 mg orally once daily.

[0285] In the MAESTRO-NASH study, randomization to 80 mg and 100 mg doses was equal across all body weights. Analyses were conducted to provide additional evidence of a relationship between resmetirom dose, baseline body weight and body mass index (BMI) and safety / efficacy readouts. FIG. 15 shows the number of patients that were discontinued prior to Week 52.

[0286] Results

[0287] MAESTRO-NASH Baseline Characteristics

[0288] MAESTRO-NASH baseline characteristics are provided in Table 6.Attorney Docket No. 156883.617393Table 6: MAESTRO-NASH Baseline Characteristics.Mean (SD) or n (%)Resmetirom 80 mg Resmetirom 100 mg Placebo (N=322) (N=323) (N=321) Age, years, mean (SD) 55.9 (11.5) 57.0 (10.8) 57.1 (10.5) Sex, male 44% 44% 45% Race, White, n (%) 291 (90.4) 291 (90.1) 281 (87.5) Body mass index, kg / m2, 35.5 (6.4) 36.2 (7.4) 35.3 (6.5) mean (SD)Body weight, kg, mean (SD) 100.1 (22.3) 101.9 (22.9) 100.2 (23.1) Type 2 diabetes, n (%) 224 (69.6) 213 (65.9) 210 (65.4) Hypertension, n (%) 243 (75.5) 254 (78.6) 257 (80.1) Dyslipidemia, n (%) 230 (71.4) 236 (73.1) 224 (69.8) Hypothyroidism*, n (%) 39 (12.1) 46 (14.2) 45 (14.0) Baseline liver b4. No biopsy, n (%)NAS >5 266 (82.6) 288 (89.2) 253 (78.8) Fibrosis 1B 16 (5.0) 15 (4.6) 18 (5.6) Fibrosis 2 107 (33.2) 100 (31.0) 112 (34.9) Fibrosis 3 199 (61.8) 208 (64.4) 191 (59.5) FibroScan VCTE / LSM, kPa, 13.3 (6.8) 13.6 (7.1) 12.9 (5.5) mean (SD)FibroScan CAP, dB / m, mean 346.1 (37.2) 349.4 (38.7) 347.2 (37.0) (SD)MRE, kPa, mean (SD) 3.5 (0.9) 3.7 (1.1) 3.5 (1.0)Attorney Docket No. 156883.617393MRI-PDFF, % fat fraction. 18.2 (6.8)mean (SD)

[0289] Discontinuation Rate was Slightly Higher in 100 mg Cohort

[0290] Diarrhea AEs and AE discontinuations were higher in the 100 mg resmetirom group; overall discontinuations at 100 mg were higher in the lower body weight groups (<100 kg). Discontinuations at 80 mg resmetirom were similar to placebo. Discontinuations related to the COVID pandemic (lost to follow up / patient decision) resulted in higher than expected discontinuation at Week 52 in all treatment arms (placebo 11% discontinuation at Week 52). Results are shown in Table 7.Table 7: Discontinuation Rate.Safety Summary Resmetirom 80 mg Resmetirom 100 mg Placebo (N = 321) (Primary Population) (N = 322) (N = 323)EventAdverse event leading 6 (1.9) 22 (6.8) 7 (2.2) to trial discontinuationbefore Week 52Adverse events affecting >10% of patients in any groupDiarrhea 87 (27.0) 108 (33.4) 50 (15.6) Covid- 19 69 (21.4) 54 (16.7) 66 (20.6) Nausea 71 (22.0) 61 (18.9) 40 (12.5) Arthralgia 48 (14.9) 35 (10.8) 40 (12.5) Back pain 35 (10.9) 27 (8.4) 38 (11.8) Urinary tract infection 33 (10.2) 27 (8.4) 27 (8.4) Fatigue 33 (10.2) 26 (8.0) 28 (8.7)Attorney Docket No. 156883.617393Pruritus 26 (8.1) 37 (11.5) 22 (6.9)

[0291] Exposure Responses to Resmetirom 80 and 100 mg

[0292] Pharmacokinetic modeling concluded that higher exposure to resmetirom was associated with higher hepatic target engagement as reflected by higher SHBG responses and higher MRI-PDFF reduction. The only variable that determined exposure to resmetirom in the NASH population was body weight. More patients treated with 100 mg when compared with 80 mg achieved targets for SHBG and PDFF, difference between doses occurred primarily in patients >100 kg. Results are shown in FIG. 16.

[0293] Liver B4. No biopsy Responses to Resmetirom Dose: Body Weight

[0294] Exposure modeling indicated that higher NASH and fibrosis responses on b4. No biopsy were associated with higher exposure to resmetirom. Study median body weight was 100 kg (220 pounds). In the population with both a baseline and Week 52 liver b4. No biopsy equivalent b4. No biopsy responses were achieved in patients who were <100 kg at 80 mg and 100 mg. Lower responses were achieved at 80 mg in the >100 kg patients. Results are shown in FIG. 17.

[0295] Liver B4. No biopsy Responses to Resmetirom Dose: Effect of BMI (Placebo Adjusted, ITT) (FIG. 18)

[0296] MRI-PDFF Reduction Strongly Predictive of Resmetirom B4. No biopsy Responses on Fibrosis and NASH

[0297] All resmetirom treated patients (80 mg and 100 mg combined): Logistic regression model, predicting response on b4. No biopsy as a function of % change from baseline in MRI-PDFF; The graphs (FIG. 19) show that the greater the Week 52 PDFF reduction, the greater likelihood for fibrosis and NASH responses with resmetirom treatment; PDFF reduction inAttorney Docket No. 156883.617393 resmetirom treated patients was highly associated with both NASH resolution and fibrosis improvement; Placebo patients with more PDFF reduction had more NASH reduction but not fibrosis improvement.

[0298] At least a 30% PDFF response was observed in 96% and 88% of resmetirom 100 mg responders for NASH Resolution and Fibrosis Improvement, respectively. The % reduction in PDFF rather than resmetirom dose impacted the response on b4. No biopsy. The response on b4. No biopsy at 80 / 100 mg was equally correlated with the magnitude of PDFF response. Doses were combined in this predictive model.

[0299] Change Over Time From Baseline in ALT and SHBG MAESTRO NASH Week 52 Primary Analysis Population

[0300] Sensitive biomarkers SHBG, PDFF and LDL / ApoB showed a persistent dose response over time with a difference between 80 mg and 100 mg. Other tests like ALT showed an equally high response at both doses, irrespective of baseline body weight.. Results are shown in FIG. 20.

[0301] CAP / VCTE over time (patients with 3-year data)

[0302] VCTE improved over time (1-3 years) years relative to placebo in resmetirom treated patients, both doses showing a similar durable response. Gawreh et al (2024) (Gawrieh S, Vilar-Gomez E, Wilson LA, et al. Increases and decreases in liver stiffness measurements are independently associated with the risk of liver-related events in NAFLD. J Hepatol. Published online May 16, 2024) indicated that less than 10 kpa correlated with less liver related events. CAP was stable over time, both doses showing a similar durable response. Results are shown in FIG. 21.

[0303] VCTE Responder Analysis at Years 1-3Attorney Docket No. 156883.617393

[0304] VCTE Responder analyses at 1-3 years in the MAESTRO-NASH population reflects improvement relative to placebo and <10% resmetirom treated patients had worsening of VCTE. Results are shown in FIG. 22.

[0305] Pharmacokinetic modeling concluded that higher exposure to resmetirom was associated with higher hepatic target engagement as reflected by higher SHBG responses and higher MRI-PDFF reduction. The only variable that influenced exposure to resmetirom in the NASH population was body weight. Resmetirom was well tolerated at both doses with a few more discontinuations in the 100 mg treatment group due to GI AEs. Discontinuations at 100 mg appeared to be slightly higher than 80 mg in patients with baseline body weight <100 kg. Slightly lower rates of fibrosis improvement and NASH resolution on b4. No biopsy were observed in patients who were >100 kg or BMI > 35 in patients treated with 80 mg versus 100 mg. Other biomarkers such as ALT, FibroScan, CAP and VCTE showed similar improvements relative to placebo at 80 mg and 100 mg. Responses on FibroScan in resmetirom treated patients were durable out to 3 years of treatment and showed improvement and less worsening than placebo.

[0306] Example 4; Liver enzymes reductions from baseline over time in resmetirom treated patients in a Phase 3 study, MAESTRO-NASH

[0307] Resmetirom is an orally administered THR-b agonist indicated for the treatment of adults with NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3). Pivotal trial: MAESTRO-NASH (NCT03900429), an ongoing 54-month. randomized, double-blind, placebocontrolled Phase 3 trial in adult patients with b4. No biopsy-confirmed NASH and fibrosis. As patients receiving resmetirom may also be receiving treatment with statins, it is important to determine the effects of resmetirom and statin coadministration on liverAttorney Docket No. 156883.617393function. The objective of this analysis was to evaluate the effects of resmetirom and statins, alone and in combination, on levels of the liver enzymes ALT, AST, and GGT over time.

[0308] Methods

[0309] Patients in MAESTRO-NASH study were monitored for changes from baseline in ALT, AST, and GGT. Enzyme levels were measured at baseline and at 4, 12, 24, 36, and 48 weeks post-randomization. Changes in liver enzymes were assessed according to statin treatment at baseline in each of the study arms.

[0310] Eligible patients have b4. No biopsy-confirmed NASH and fibrosis and an NAFLD activity7score of >4 on a scale of 0 to 8 (higher scores=more severe disease). Prescreening criteria require AST >17 IU (women) and AST >20 IU (men). Patients were excluded if serum ALT was >250 U / L.

[0311] ResultsTable 8Statin Use at Baseline Total Population (N=966) Any Statin, n (%) 473 (49) Atorvastatin 223 (23.1) Lovastatin 7 (0.7) Pitavastatin 3 (0.3) Pravastatin 63 (6.5) Rosuvastatin 114 (11.8) Simvastatin 64 (6.6) High-intensity statin therapy*, % 13 Moderate to low-intensity statin therapy, % 36Attorney Docket No. 156883.617393 *Rosuvastatin 20 mg; atorvastatin 40 mg.

[0312] Effects of Statin Use on Liver Enzyme Levels

[0313] Among patients receiving statins at baseline, a total of 149 (46.2%) patients received resmetirom 80 mg, 166 (51.4%) received resmetirom 100 mg, and 158 (49.2%) received placebo. At baseline, patients receiving statins had lower ALT and AST levels than those not receiving statins (FIG. 23). mild, transient increase in AST and ALT levels (<1.5-fold baseline) was observed at Week 4 in patients receiving statins compared with patients not receiving statins (FIGs. 24-25). This increase did not exceed the level of ALT or AST at Week 4 in patients not receiving statins. Elevations resolved by Week 8, and liver enzyme levels declined thereafter. GGT levels declined from the time resmetirom treatment was initiated (FIG. 26).

[0314] Week 48 Results

[0315] In patients with ALT levels > 30 IU at baseline: ALT declined from baseline by 20% and 24% in the resmetirom 80 and 100 mg arms, respectively, in patients receiving statins (P<0.001 vs placebo); ALT declined from baseline by 37% and 43% in the resmetirom 80 and 100 mg arms, respectively, in patients not receiving statins (P<0.001 vs placebo).

[0316] Liver enzyme levels declined significantly in resmetirom treated patients relative to placebo beginning at Week 12. Transient increases in ALT and AST of <1.3-fold over baseline occurred at Week 4 in patients co-dosed with resmetirom and statins; resmetirom patients not on statins showed <10% increase in liver enzymes at Week 4. Liver enzymes declined below baseline in all patients irrespective of statin after Week 4. Patients receiving statins had lower baseline ALT and AST levels, and elevations at Week 4 were generally not higher than levels in patients not on statins. Lipid lowering, NASH resolution and FibrosisAttorney Docket No. 156883.617393 improvement rates were similar in patients on statins versus not on statins indicating that early liver enzyme excursions do not impact either safety or efficacy. GGT levels declined from the time resmetirom treatment was initiated in all patients.

[0317] Example 5; Baseline characteristics in well-compensated NASH cirrhosis patients diagnosed with or without a liver b4. No biopsy in MAESTRO-NASH-OUTCOMES, a clinical outcome Phase 3 study assessing the effect of resmetirom in well-compensated NASH cirrhosis

[0318] Resmetirom is a thyroid hormone receptor-beta (THR-[3) agonist indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). MAESTRO-NASH-OUTCOMES (NCT05500222) is an ongoing, multinational, multicenter, double-blind, randomized, placebo-controlled study evaluating resmetirom treatment in patients with well-compensated NASH cirrhosis (FIG. 27). Patients are randomly assigned in a blinded manner in a 3: 1 ratio to receive resmetirom 80 mg or matching placebo orally once daily in the morning. Treatment is administered until the required number of Composite Clinical Outcome events are achieved. Composite Clinical Outcome events are defined as any of the following mortality, liver transplant, and significant hepatic events, including potential hepatic decompensation events (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) and confirmed increase of MELD score from <12 to >15. The study comprises an up to 60-day screening period and an approximately 3-year treatment period. The objective of this analysis of data from MAESTRO-NASH-OUTCOMES was to compare baseline factors between patients diagnosed with NASH cirrhosis with and without liver b4. No biopsy.

[0319] MethodsAttorney Docket No. 156883.617393

[0320] Patients were divided into 2 groups: (1) NASH cirrhosis diagnosed with liver b4. No biopsy; (2) NASH cirrhosis diagnosed without liver b4. No biopsy. Baseline factors were compared between groups. Descriptive statistical outputs were generated.

[0321] Subjects: Eligibility criteria

[0322] NASH cirrhosis with b4. No biopsy-confirmed F4 fibrosis with >3 metabolic risk factors, meeting other non-invasive testing and eligibility requirements

[0323] NASH cirrhosis diagnosed non-invasively requiring >2 non-invasive tests for screening (FibroScan VCTE >15 kPa and / or if FibroScan VCTE <15 kPa, > other non-invasive tests (MRE >4.2, platelets <140K, ELF >10.25, FIB-4 >3.

[0324] Other screening tests include blood tests, MRE, MRI-PDFF, and assessments for HCC and ascites, with MELD <12 (except for Gilbert).

[0325] Results

[0326] 566 patients were enrolled in MAESTRO-NASH-OUTCOMES at the time of the analysis. NASH cirrhosis with b4. No biopsy-confirmed F4 fibrosis, n=297. NASH cirrhosis diagnosed non-invasively, n=269.

[0327] Comparison of Baseline Factors Between Groups.

[0328] Baseline factors were generally similar between patients diagnosed as NASH cirrhosis with and without liver b4. No biopsy (Table 9).• Mean age, 63 years• Males, 34-38%Attorney Docket No. 156883.617393• Mean body mass index, 35 kg / m2• Hypertension, 82%• Type 2 diabetes, 73-78%

[0329] Approximately one-third of patients had more advanced disease, based on MRE >6, ELF >11.3, MRI-PDFF <5%.

[0330] A slightly higher percentage of NASH cirrhosis patients diagnosed without a liver b4. No biopsy had baseline characteristics suggestive of more advanced portal hypertension (Platelets <140 K, higher MRE, ELF, and FibroScan VCTE) (FIG. 28 and FIG. 29).Table 9: Baseline factorsPatients with B4. No biopsy Patients without B4. No biopsy (N=392) (N=453) Age, years, mean (SD) 62.6 (8.8) 63.4 (9.4) Sex, male, n (%) 138 (35) 147 (32) Ethnicity, Hispanic / Latino, n (%) 70 (18) 107 (24) Body weight, kg, mean (SD) 94.2 (22.0) 95.0 (21.1) Body mass index, kg / m2, mean (SD) 33.8 (6.7) 34.6 (7.1) Hypertension, n (%) 311 (79) 316 (70) Hypothyroid, n (%) 91 (23) 99 (22) Type 2 diabetes, n (%) 300 (77) 295 (65) Documented ASCVD, n (%) 20 (5.1) 21 (4.6) ELF Test, n 391 388 >11.3, n (%) 102 (26.1) 132 (34.0) <11.3, n(%) 289 (73.9) 256 (66.0) MELD, n 379 387Attorney Docket No. 156883.617393>12, n(%) 12 (3.2) 26 (6.7) 9-11, n (%) 89 (23.5) 122 (31.5) <9, n (%) 278 (73.4) 239 (61.8) MRI-PDFF, n 358 355 <5, n (%) 95 (26.5) 128 (36.1) >5, n (%) 263 (73.5) 227 (63.9) MRI-PDFF, % fat fraction, mean (SD) 8.8 (5.3) 7.6 (5.1) MRE, kPa, n 324 319 >6 94 (29.0) 108 (33.9) <6 230 (71.0) 211 (66.1) MRE, kPa, mean (SD) 5.5 (1.5) 5.8 (1.7) FibroScan VCTE, kPa, mean (SD) 23.0 (11.0) 27.6 (36.6) Fibroscan TE median (Q1, Q3) (kPa) 20.1 (16.2, 26.1) 22.30 (17.4, 30.0) Fibroscan TE < 15 (n,%) 60 (153%) 46 (10.2%) Fibroscan TE 15-20 (n,%) 130 (33.2%) 125 (27.7%) Fibroscan TE 20-25 (n,%) 86 (220%) 104 (23.0%) Fibroscan TE >= 25 (n,%) 115 (29.4%) 177 (39.2%) FibroScan CAP, dB / m, mean (SD) 303.0 (59.1) 304.1 (52.0) Statin use, n (%) 221 (56.4) 220 (48.6) Thyroxine Any, n (%) 98 (25.0) 101 (22.3) GLP-1 use, n (%) 143 (36.5) 125 (27.6) SGLT2 use, n (%) 90 (23.0) 69 (15.2) Other laboratory parameters, mean (SD)FIB-4 2.8 (1.4) 3.3 (1.6) Total bilirubin, mg / dE 0.8 (0.3) 0.9 (0.4) Direct bilirubin, mg / dL 0.2 (0.1) 0.2 (0.1) Platelet count, K 161.6 (58.6) 145.7 (61.2) Albumin, g / dL 4.3 (0.3) 4.2 (0.3) INR 1.2 (0.2) 1.2 (0.1)Attorney Docket No. 156883.617393ELF Test, mg / dL 10.7 (0.9) 10.9 (0.9) ALT, IU / L 42.4 (25.3) 39.1 (23.2) AST, IU / L 41.4 (19.9) 39.9 (19.9) GGT, IU / L 105.7 (122.8) 109.1 (101.3)

[0331] Baseline data from the Phase 3 MAESTRO-NASH-OUTCOMES study demonstrate that non-invasive tests perform similarly to liver b4. No biopsy in identifying patients with well compensated NASH cirrhosis. Patients with NASH Child-Pugh A have a high prevalence of metabolic risk factors, including diabetes, obesity, hypertension, and use of statins for dyslipidemia control. MRI-PDFF <5% was present in approximately 30% of patients with cirrhosis, confirming lower PDFF as a potential indicator of progression to cirrhosis. In NASH cirrhosis patients, while steatosis persists, the concentration of liver fat as measured by PDFF declines due to replacement of liver tissue by fibrosis. Approximately one-third of patients have baseline Fibroscan VCTE and / or other markers ELF, MRE and platelets that are consistent with clinically significant portal hypertension, an important factor.

[0332] Example 6; Use of non-invasive tests to diagnose and follow NASH with liver fibrosis patients treated with resmetirom

[0333] Resmetirom, an oral, liver-directed THR-β-selective agonist, was approved in March 2024 for the treatment of adult patients with noncirrhotic NASH and liver fibrosis consistent with F2 to F3 stages. Approval was based on efficacy demonstrated in MAESTRO-NASH (NCT03900429), an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial in adult patients with b4. No biopsy -confirmed NASH and fibrosis. In MAESTRO-NASH. 966 patients with b4. No biopsy-confirmed NASH were randomly assignedAttorney Docket No. 156883.617393 in a 1:1:1 ratio to receive resmetirom 80 mg, resmetirom 100 mg, or placebo once daily (FIGs. 1 and 10).

[0334] In MAESTRO-NASH, both resmetirom doses achieved either NASH resolution with no worsening of fibrosis or >1 -stage improvement in fibrosis with no worsening of NASH at Week 52. B4. No biopsy is less commonly used in real-world clinical practice due to its invasive nature, procedure-related limitations, and potential for serious complications. As such, the diagnosis of suspected MASH in most patients is based upon clinical, laboratory, and imaging data that are collectively referred to as results of noninvasive tests (NITs) with appropriate exclusion of other liver conditions. This analysis of data from MAESTRO-NASH aimed to assess the accuracy of NASH / fibrosis diagnosis and follow-up of resmetirom-treated patients long-term using real-world, readily available non-invasive testing.

[0335] Methods

[0336] Machine learning models were used to evaluate the relative importance of intrinsic characteristics and screening / baseline biomarkers of patients with fibrosis stages F0 (no fibrosis) to F4 (cirrhosis) on liver b4. No biopsy. The random forest model was selected for its predictive performance. Long-term effects of resmetirom treatment on results of non-invasive tests and biomarkers were evaluated at baseline and at Months 12, 24, and 36 post randomization. 23 baseline clinical characteristics were used. Only readily available tests (FibroScan [VOTE]. ELF, standard blood chemistries) were used to determine the accuracy in diagnosing patients with NASH consistent with F2 to F3.

[0337] Results

[0338] Data from 1247 patients with F0 to F4 on liver b4. No biopsy were analyzed. The F2 to F3 population from MAESTRO-NASH was analyzed.Attorney Docket No. 156883.617393

[0339] In the F2 to F3 population (n=888), FibroScan VCTE was 12 (10, 15) median kPa and ELF was 9.7 (9.2, 10.4). Using 23 baseline clinical characteristics, standard labs, FibroScan, and ELF, the random forest model determined that the most important markers distinguishing F2 to F3 from either F0 / 1 or F4 were FibroScan VCTE, platelets, FIB-4, FAST, and ELF. The AUC (SD) for separation from F0 / F1 or F4 were 0.76 (0.03) and 0.90, respectively.

[0340] Among patients with F2 to F3: 58% were correctly predicted to be F2 / F3; 26% were incorrectly predicted to be F0 / F1; 16% were incorrectly predicted to be F4.

[0341] Among patients with F4: 72% were correctly predicted to be F4; 19% were incorrectly predicted to be F2 / 3.

[0342] The addition of MRE / MRI-PDFF increased diagnostic accuracy for F2 / F3 to 68% and F4 to 81%.

[0343] FIB-4 (FIG. 30) poorly predicts non-cirrhotic NASH fibrosis stage. Including a lower cutoff of VCTE (8.5-10) is important to capture many F2 and F3 patients (FIG. 30): Help to gain confidence in fibrosis staging; A low ELF with a high VCTE suggests repeating the VCTE.

[0344] Week 52 Response to Resmetirom

[0345] Resmetirom showed improvement relative to placebo on multiple responses at Week 52, including MRI-PDFF (the most predictive of a b4. No biopsy response), liver enzymes, lipids, and FibroScan CAP and VCTE. ALT response at Week 48 (FIG. 31) was equivalent at both doses. PDFF reduction in resmetirom treated patients (FIG. 32) was highly associated with both NASH resolution and fibrosis improvement. Placebo patients with more PDFF reduction had more NASH reduction but not fibrosis improvement. At least a 30% PDFFAttorney Docket No. 156883.617393 response was observed in 96% and 88% of resmetirom 80 mg and 100 mg responders for NASH resolution and fibrosis improvement, respectively. The % reduction in PDFF rather than resmetirom dose impacted the response on b4. No biopsy. The response on b4. No biopsy at 80 mg and 100 mg was equally correlated with the magnitude of PDFF response. Doses were combined in this predictive model. Resmetirom responses FibroScan CAP / VCTE (FIG. 33 and FIG. 34) were durable / increased at Months 24 and 36 relative to placebo.

[0346] Reasonably accurate identification of patients with NASH F2 to F3 was achieved with FibroScan VCTE, ELF. and readily available blood tests. In addition to FibroScan VCTE, practitioners may consider expanded noninvasive criteria (ELF. MRE) to help refine fibrosis staging. Patients with fibrosis stage F4 were effectively ruled out. Long-term followup of resmetirom-treated patients with non-invasive tests showed durability of treatment response relative to placebo.

[0347] Example 7: Impact of resmetirom on statin pharmacokinetics safety in Phase 1 and 3 studies; safety and efficacy of resmetirom in patients on statins in MAESTRO-NASH

[0348] Resmetirom, a THR- agonist approved by the US FDA in March 2024, is indicated for the treatment of adults with NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3).

[0349] In MAESTRO-NASH (NCT03900429), the pivotal Phase 3, randomized, placebocontrolled trial of resmetirom that enrolled patients with b4. No biopsy-confirmed NASH and fibrosis:• 49% of enrolled patients were taking statins at baseline (Tables 10 and 11)Attorney Docket No. 156883.617393 • 13% were receiving high-intensity statin therapy (rosuvastatin 20 mg or atorvastatin 40 mg)• 36% were receiving moderate or low-intensity statin therapy.

[0350] As part of the resmetirom clinical development program, four Phase 1 pharmacokinetic studies assessing potential drug interactions of resmetirom with commonly prescribed statins were carried out.

[0351] Methods

[0352] Drug interaction studies of resmetirom with commonly prescribed statins were performed in Phase 1 healthy volunteers. Statin levels were measured in MAESTRO-NAFLD-1, a non-invasively diagnosed NASH population. In MAESTRO-NASH: liver enzymes were assessed in patients on statins and not on statins; assessments of common statin AEs were assessed in MAESTRO-NASH; safety was assessed in patients in MAESTRO-NASH according to statin therapy at baseline. Safety and responses were assessed as a function of statin therapy in MAESTRO-NASH. Data from the Phase 1 pharmacokinetic studies and the Phase 3 study were analyzed to evaluate the potential impact of co-administration of resmetirom and statins on statin pharmacokinetics in healthy subjects and patients with NASH and fibrosis. Safety and efficacy by statin dose in Phase 3 w ere also evaluated.

[0353] Results

[0354] Drug Interaction Studies - Phase 1 and 3Attorney Docket No. 156883.617393

[0355] Phase 1 studies showed generally weak interactions between resmetirom and statins. In Phase 3 patients, the PK of atorvastatin with resmetirom were within the range of normal PK variability' (FIG. 35).Table 10: Patients on Statins in MAESTRO-NASHBaseline Characteristic Statin No Statin (N=472) (N=494)Age (years) - Mean (SD) 593 (94) 54.1 (11.7) Sex, Male - n (%) 223 (47.2) 201 (40.7) 223 (47.2) 201 (40.7) Race, White - n (%) 414 (87.7) 449 (90.9) Ethnicity, Hispanic or Latino - n (%) 94 (19.9) 110 (22.3) Body Mass Index (kg / m2) Mean (SD) 35.9 (6.8) 35.4 (6.7) Type 2 Diabetes - n (%) 376 (79.7) 271 (54.9) Hypertension - n (%) 407 (86.2) 347 (70.2) Dyslipidemia - n (%) 472 (100) 217 (43.9) Hypothyroidism - n (%) 70 (14.8) 59 (11.9) FibroScan VCTE (kPa) Mean (SD) 13.9 (7.4) 12.7 (5.5) Median (Min, Max) 12.0 (3.8, 75.0) 11.4 (4.0, 66.4) FibroScan CAP (dB / m) Mean (SD) 350.5 (36.7) 344.8 (38.4) (%)MRI-PDFF- Mean (SD) 16.8 (6.5) 18.6 (6.9) Stiffness by MRE (kPa)- Mean (SD) 3.6 (1.0) 3.5 (0.98) Median (Min, Max ) 3.5(1.8, 9.2) 3.3(1.9, 9.9) ELF Score -Mean (SD) 9.8 (0.9) 9.7 (0.9) On GLP-1 Therapy - n (%) 84 (17.8) 53 (10.7) Statin IntensityHigh 127 (26.9)Moderate 288 (61.0) —Attorney Docket No. 156883.617393Low 56 (11.9)Baseline Livery B4. No biopsy - n (%)NAS >5 at Screening 393 (83.3) 414 (83.8) Fibrosis 1B 32 (6.8) 17 (3.4) Fibrosis 2 128 (27.1) 191 (38.7) Fibrosis 3 303 (64.2) 280 (56.7)Table 11: Statins and DosesStatin Dose (N=966) %% Patients taking a statin 49.0Atorvastatin 23.1<40 mg 22.7>40 mg 0.4Lovastatin 0.7Pitavastatin 0.3Pravastatin 6.5<40 mg 6.4>40 mg 0.1Rosuvastatin 11.8<20 mg 11.6>20 mg 0.2Simvastatin 6.6<20 mg 6.5>20 mg 0.1

[0356] Creatine Kinase change from baseline (FIG. 36),Attorney Docket No. 156883.617393

[0357] Changes in Liver Enzymes (ALT) (FIG. 37A-37C). FIG. 37A = all patients (baseline >=30 U / L), FIG. 37B= patients on statins (baseline >=30 U / L), FIG. 37C= patients not on statins (baseline>=30 U / L),

[0358] Efficacy of Statins in MAESTRO-NASH

[0359] Lipid lowering was similar in statin- and non-statin-treated resmetirom patients. Liver b4. No biopsy endpoints were achieved in statin- and nonstatin-treated patients on resmetirom. Results are shown in FIG. 38.

[0360] Safety of Statins in MAESTRO-NASH

[0361] No increase in AEs was observed with resmetirom alone or in combination with statins (Table 12A). No change in muscle AEs or no DILI AEs occurred (Table 12B).Table 12A: MAESTRO-NASH Statin Safety (AEs and SAEs)Event Resmetirom 80 mg Resmetirom 100 mg Placebo(N = 322) (N = 323) (N=321) Statin at BL No statin at Statin at BL No statin at Statin at BL No statin at (N = 149) BL (N=166) BL (N=158) BL n (%) (N=173) n (%) (N=157) n (%) (N=163) n (%) n (%) n (%) > 1 adverse 141 (946) 155 (89.6) 149 (89.8) 147 (93.6) 146 (92.4) 152 (93.3) event> 1 SAE 20 (13.4) 15 (8.7) 23 (13.9) 18 (11.5) 23 (14.6) 14 (8.6) Adverse events affecting >10% of patients in any groupDiarrhoea 32 (21.5) 55 (31.8) 52 (31.3) 56 (35.7) 19 (12.0) 32 (19.6) Nausea 29 (19.5) 42 (24.3) 28 (16.9) 33 (21.0) 18 (11.4) 22 (13.5) COVID-19 31 (20.8) 38 (22.0) 27 (16.3) 27 (17.2) 31 (19.6) 36 (22.1)Attorney Docket No. 156883.617393Arthralgia 21 (14.1) 27 (15.6) 19 (11.4) 16 (10.2) 16 (10.1) 24 (14.7) Back pain 21 (14.1) 14 (8.1) 15 (9.0) 12 (7.6) 17 (10.8) 21 (12.9) Pruritus 16 (10.7) 10 (5.8) 21 (12.7) 16 (10.2) 16 (10.1) 6 (3.7) Fatigue 16 (10.7) 17 (9.8) 9 (5 4) 17 (10.8) 15 (9.5) 13 (8.0) Vomiting 14 (9.4) 14 (8.1) 12 (7.2) 23 (14.6) 10 (6.3) 7 (4.3) Abdominal 12 (8.1) 14 (8.1) 13 (7.8) 16 (10.2) 9 (5.7) 9 (5.5) painUTI 12 (8.1) 21 (12.1) 13 (7.8) 14 (8.9) 14 (8.9) 14 (8.6) Headache 10 (6.7) 20 (11.6) 13 (7.8) 12 (7.6) 12 (7.6) 16 (9.8)Table 12B: MAESTRO-NASH Statin Safety (muscle-related events)AE Preferred Resmetirom 80 mg Resmetirom 100 mg Placebo Term (N = 322) (N = 323) (N = 321)n (%) n (%) n (%) Statin No Total Statin No Total Statin No Total Statin Statin Statin Myalgia 2 (1.3) 5 (2.9) 7 (2.2) 3 (1.8) 10 13 5 (3.2) 6 (3.7) 11(6.4) (4.0) (3.4) Myopathy 1 (0.7) 1 (0.4) 1 (0.3) 0 0 0 0 0 0 Myositis 0 0 0 0 0 0 0 0 0 Rhabdomyolysis 0 0 0 0 0 0 0 0 0

[0362] 98% of statin doses already used by NASH patients are recommended in the resmetirom US label; statin exposure level (PK) in Phase 3 patients on resmetirom was within the range of normal PK variability. NASH patients on statins had lower baseline liver enzymes than patients not on statins. Transient increase to approximately 1.3 times baseline at week 4, not generally above the level in patients not on statins, was observed in patients onAttorney Docket No. 156883.617393resmetirom and statins; no significant week 4 elevations were observed in patients on resmetirom not on statins (FIG. 37). Liver enzymes improved relative to baseline over time in resmetirom-treated patients compared with placebo, independent of statin use (FIG. 37). No statin-related safety findings were noted in MAESTRO-NASH patients who took statins. Efficacy measures, including lipid lowering and NASH and fibrosis b4. No biopsy endpoints, were similar and statistically significantly improved in resmetirom-treated patients whether on statins or not on statins (FIG. 38).

[0363] Example 8: Treatment with resmetirom for up to two years led to improvement in liver stiffness, fibrosis biomarkers, fibrosis scores and portal hypertension in 122 patients with compensated MASH cirrhosis

[0364] Resmetirom, an oral, once-daily, liver-directed thyroid hormone receptor β (THR-β) agonist, is the only FDA-approved therapy for MASH (as of 2024). Currently, there are no approved therapies for patients with compensated cirrhosis due to MASH. Cirrhosis (F4) is highly associated with clinical outcomes including hepatic decompensation events, liver failure, liver transplant and mortality’. Therefore, there is an unmet need in MASH cirrhosis.

[0365] Trial Design - Open-Label (OL) 52-Week Cirrhosis Arm of MAESTRONAFLD-1 followed by an Extension Trial (FIG. 39),

[0366] Trial flow - Open-Label Cirrhosis Arm (MAESTRO-NAFLD-1) followed by an Extension Trial (FIG. 40),

[0367] Baseline Characteristics (Table 13),Table 13: Baseline CharacteristicsBL MR1-PDFF > 5%' BL MRI-PDFF < 5%Attorney Docket No. 156883.617393N=93 N=21Age, years 61 (56, 68) 63 (61, 67) Sex, Female 51 (55%) 11 (52%) Ethnicity, Hispanic 28 (30%) 4 (19%) BMI, kg / m234.4 (30.6, 39.1) 33.5 (29.8, 37.9) Type 2 Diabetes 63 (68%) 18 (86%) VCTE, kPa 19.5 (17.1, 29.5) 24.6 (17.1, 39.4) CAP, dB / m 331 (302, 372) 291 (249, 329) MRE, kPa 5.2 (4.0, 6.1) 5.6 (4.9, 7.0) MRI-PDFF, % 9.5 (7.3, 12.6) 3.9 (3.1, 4.4) Liver Volume, mL 2291 (1903, 2737) 2093 (1649, 2473) Spleen Volume, mL 476 (325, 721) 667 (414, 998) ALT, U / L 37 (29, 50) 28 (25, 39) Platelets, 109 / L 139 (112, 193) 110 (90, 141) Albumin, g / dL 4.2 (4.0, 4.4) 4.2 (4.0, 4.5) LDL-C, mg / dL 95 (76, 123) 73 (62, 94) Triglycerides, mg / dL 140 (103, 181) 114 (87, 122) FIB-4 2.3 (1.6, 3.6) 3.5 (2.2, 4.0) ELF Score 10.6 (9.9, 11.4) 11.0 (10.7, 11.7)'Only 114 / 122 patients had baseline MRI-PDFFData are median (QI, Q3) or %

[0368] In MASH cirrhosis lower hepatic fat is associated with more advanced disease.

[0369] Sustained Reductions in Liver Stiffness (LSM) after 2-Year Treatment with Resmetirom

[0370] After 2 years on resmetirom, >50% of patients achieved sustained >25% reduction in LSM by VCTE (FIG. 41).Attorney Docket No. 156883.617393

[0371] Improvements in Portal Hypertension Risk Category with Resmetirom

[0372] Clinically significant portal hypertension (CSPH) predicts liver related outcome events such as ascites, variceal hemorrhage and encephalopathy. Modified Baveno (similar to ANTICIPATE ) requires additional evidence for CSPH in MASH patients with VCTE >25; confirms CSPH risk (Table 14). Overall shift to lower CSPH risk at Year 1 and Year 2 whether Baveno or a modification of Baveno criteria are used (FIG. 42).Table 14: CSPH in MASHRisk of CSPH Baveno Modified Baveno CSPH VCTE > 25 VCTE > 25 plus any one of:- PLT < 150- MRE> 5- ELF> 11.3Probable CSPH 20 < VCTE < 25 & PLT < 150 or 15 < VCTE < 20 & PLT < 110 No / Low CSPH Not meeting above criteria

[0373] Improvements in Portal Hypertension Risk Category with Resmetirom

[0374] High, statistically significant, percentage of patients with probable CSPH and CSPH at baseline shift to lower risk category at Year 1 and Year 2 whether Baveno (shown) or modified Baveno criteria for CSPH are used (FIG. 43).

[0375] Sustained Reductions in Liver Fat and Liver Stiffness with Resmetirom at 2 Years

[0376] Statistically significant improvements in MRI-PDFF, CAP and MRE at 2 Years (FIG. 44).

[0377] Sustained Statistically Significant Improvements in ALT and GGT (FIG. 45),Attorney Docket No. 156883.617393

[0378] Reductions in Fibrosis and Liver Injury Biomarkers at 2 Years (FIG. 46),

[0379] Sustained Reductions in Atherogenic Lipids with Resmetirom at 2 Years.

[0380] Statistically significant atherogenic lipid reductions consistent with non-cirrhotic MASH, independent of liver fat content (FIG. 47).

[0381] MRI-Based Liver and Spleen Volume Assessments.

[0382] Baseline liver fat independent reduction of enlarged MASH cirrhotic livers. Liver volumes are increased in compensated MASH cirrhosis by approximately 40% relative to expected liver size. Liver volume (mean) decrease of 22 to 25% by resmetirom was independent of baseline MRI-PDFF (FIG. 48). MRI was used to measure spleen volume. Platelets and spleen volume, both surrogates of portal hypertension, are inversely correlated (CC= -0.6). Mean spleen volume was reduced by resmetirom at years 1 and 2 in patients with baseline platelets>100K. Spleen volume change correlated with change in platelets (CC= -0.39) and change in VCTE (CC= 0.32).

[0383] Safety Summary after 2-year Open-Label Treatment with Resmetirom

[0384] Safety data were consistent with previous studies. Resmetirom was well-tolerated in this high risk population, low discontinuation rate. All SAEs unrelated to study drug. Overall, 6 / 122 patients experienced decompensation events through two years of treatment.5 / 6 had either elevated baseline MELD and / or baseline platelets <100k. Results are summarized in Table 15.Table 15: Summary of AEsAttorney Docket No. 156883.617393Summary AEs (2 years of treatment) Resmetirom(n=122)Any TEAE 113 (93%)TEAE leading to Trial Discontinuation 3 (2.5%)Death' 2 (1.6%)Common AEs (n=122)2Resmetirom(n=122)AE occurring in >15% of patientsDiarrhea 46 (38%)Covid- 19 38 (31%)Nausea 38 (31%)Urinary Tract Infection 33 (27%)Headache 21 (17%)Arthralgia 19 (16%)Fatigue 19 (16%)Pruritus 20 (16%)Vomiting 18 (15%)1Deaths are Covid and metastatic cancer.2 Common AE safety data extended beyond two years in some patients.

[0385] Resmetirom was well tolerated over 2 years in patients with well-compensated cirrhosis. More than 50% of patients achieved a sustained >25% reduction in LSM; lower VCTEs are associated with less progression to decompensation. Reduced clinically significant portal hypertension risk score was observed based on Baveno and modified Baveno criteria; clinically significant portal hypertension predicts progression to decompensation. Multiple biomarker and imaging evidence of improvement were observed. The present results support the potential clinical benefit of resmetirom in MASH cirrhosis that is being evaluated in the fully enrolled, ongoing MAESTRO-NASH-OUTCOMES trial (n = 845).Attorney Docket No. 156883.617393

[0386] Example 9; Rezdiffra™ (resmetirom) Significantly Improved Imaging Tests, Biomarkers and Portal Hypertension Risk in Patients with Compensated MASH Cirrhosis

[0387] The open-label compensated MASH cirrhosis arm of the Phase 3 MAESTRO-NAFLD-1 trial of Rezdiffra. Patients (n=122) in the study achieved significant improvements from baseline in liver stiffness, liver fat, fibrosis biomarkers, liver volume and risk scores for CSPH.

[0388] Resmetirom demonstrated broad, sustained efficacy across multiple noninvasive parameters at two years of treatment. A high, statistically significant percentage of patients with CSPH or probable CSPH at baseline shifted to lower risk categories. The totality of data in this high-risk population of patients on the cusp of progressing to liver decompensation is highly encouraging as await results are awaited from the ongoing Phase 3 MAESTRO-NASH OUTCOMES trial of Rezdiffra / ’

[0389] CSPH is a major consequence of cirrhosis and is responsible for its most severe complications, including ascites, variceal bleeding and hepatic encephalopathy. Patients with MASH who progress to cirrhosis face a 42 times higher nsk of liver-related mortality (FIG.49).

[0390] MAESTRO-NAFLD-1 included an open-label active treatment arm of patients with compensated MASH cirrhosis. After one year, patients were given the option to enroll in an open-label extension trial; 122 patients enrolled and 113 completed two years of treatment (FIG. 50). At baseline, 35% of patients met Baveno criteria for CSPH, 14% for probable CSPH and 51% for no / low CSPH. The Baveno criteria use a combination of vibration-controlled transient elastography (VCTE) and platelet count to assess CSPH risk.Attorney Docket No. 156883.617393

[0391] Among patients with CSPH at baseline, 65% moved into lower risk categories by year two (42% to no / low CSPH and 23% to probable CSPH). Among patients with probable CSPH at baseline, 57% moved into the no / low CSPH category as compared to 14% who moved into the CSPH category by year two. Improvement in CSPH risk was statistically significant compared to baseline. Similar shifts to lower risk categories were observed in an analysis using a more stringent modified Baveno criteria that incorporates magnetic resonance elastography (MRE) and the Enhanced Liver Fibrosis (ELF) test as additional evidence for CSPH risk.

[0392] Patients achieved a mean 6.7 kPa reduction in liver stiffness at two years, which was statistically significant compared to baseline (FIG. 51). In a responder analysis examining >25% improvement or worsening of liver stiffness, 51% of patients achieved improvement. An improvement of this magnitude has been associated with reduced progression to end-stage liver disease. Rezdiffra helped 35% of patients achieve liver stiffness measurements consistent with F3 fibrosis, suggesting reversal of cirrhosis.

[0393] Safety data were consistent with previous studies and Rezdiffra was well-tolerated with a low rate of discontinuation due to adverse events. The most common adverse events were diarrhea, COVID- 19, and nausea. There were four deaths unrelated to Rezdiffra.

[0394] Lower thyroid-hormone receptor-beta (THR- ) activity in the liver is predictive of hepatic decompensation in patients with MASH, so there is a strong mechanistic rationale supporting the potential of Rezdiffra. a THR-[3 agonist, to improve outcomes in patients with compensated MASH cirrhosis. These two-year open-label data from MAESTRO-NAFLD-1 add important clinical evidence that supports the confidence in the ongoing, fully enrolled Phase 3 outcomes trial of Rezdiffra in compensated MASH cirrhosis.Attorney Docket No. 156883.617393

[0395] Example 10; Improvement in health-related quality of life after treatment with resmetirom in cirrhotic and non-cirrhotic patients with metabolic dysfunction-associated steatotic liver disease; Data from MAESTRO-NAFLD

[0396] Background and Aims: Resmetirom is approved for treatment of F2-F3 metabolic dysfunction-associated steatohepatitis (MASH) in the United States. The aim of this study was to assess health-related quality of life (HRQL) in metabolic dysfunction steatotic liver disease (MASLD) patients with and without cirrhosis treated with resmetirom in MAESTRO-NAFLD clinical trial.

[0397] Methods: MASLD patients with cirrhosis (CP-A) or MASLD without cirrhosis were enrolled in a 52-week, Phase 3 double-blind placebo-controlled study of resmetirom (Period 1 of MAESTRO-NAFLD) and upon treatment completion, were offered to enroll in a 52-week open-label extension study of resmetirom (Period 2). HRQL was assessed using LDQOL, CLDQ-NAFLD and WPAI throughout treatment Period 1 (baseline, week 24, week 52) and treatment Period 2 (day 1, week 12, week 28, week 52). For non-cirrhotic MASLD, PDFF response was defined as a decrease in MRI-PDFF >30% from baseline while for cirrhotic MASLD, it was defined as >20% decrease in MRI-PDFF (if baseline MRI-PDFF >5%).

[0398] Results: MAESTRO NAFLD included 1307 MASLD patients (combined double-blind placebo-controlled mITT and open-label groups). Of these, 193 with cirrhosis (23% with baseline MRI-PDFF <5%) and 1114 were without cirrhosis (baseline MRI-PDFF >8%). At baseline, HRQL scores of patients with cirrhosis were significantly lower (up to -16% of score range) for all 6 domains of CLDQNAFLD. 14 / 17 domains of LDQOL, Activity Impairment of WPAI (p<0.05). Among patients with cirrhosis, there was no significant difference in baseline HRQL scores between those with MRI-PDFF <5% and >5% (all p>0.05). In patients withAttorney Docket No. 156883.617393 cirrhosis, by week 24 of treatment with resmetirom during Period 1, there were improvements in Worry (CLDQ-NAFLD) and Health Distress (LDQOL) up to +4% of score range which sustained by week 52 and throughout Period 2 (day 1, week 12, week 28) (p<0.05). In cirrhotic subjects with MRI-PDFF >5%, PDFF response by Period 1 week 52, there was an improvement in Stigma score (LDQOL): mean change (+4.0 vs. -5.7, p=0.011). By weeks 24 and 52 of treatment, non-cirrhotic patients receiving placebo experienced worsening of HRQL in some physical health-related domains of LDQOL (mean decrease up to -5%; p<0.05) while no decreases were observed in non-cirrhotic patients treated with resmetirom. In addition, non-cirrhotic patients receiving resmetirom experienced improvement in Abdominal and Worry domains of CLDQ-NAFLD and Health Distress of LDQOL (mean increase up to +5% of score range size); no similar improvements were observed in placebo (all p>0.05).Noncirrhotic patients with PDFF response experienced improvements in Abdominal and Worry scores (up to +7%) which were greater than those seen in placebo or non-responders (FIG. 55).

[0399] Conclusions: Patients without or with cirrhosis due to MASLD treated with resmetirom experience sustained improvement in select disease-specific HRQL scores.

[0400] Example 11: Analysis of biomarkers PRO-C3 and ELF in resmetirom-treated patients from the MAESTRO-NASH trial, a 52-week NASH / MASH serial liver b4. No biopsy study

[0401] Background and Aims: MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with b4. No biopsy-confirmed nonalcoholic steatohepatitis (NASH / MASH) and fibrosis. 966 patients with b4. No biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg. or placebo administered once daily. Dual primary endpoints atAttorney Docket No. 156883.617393 Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or >1 -stage improvement in fibrosis with no worsening of NAS (FI). Resmetirom reduced ELF, P3NP and TIMP1 at Week 52 but did not decrease HA. To further explain the effect on ELF, baseline ELF and the 3 components of ELF (TIMP1, P3NP and Hyaluronic acid (HA)) were evaluated relative to diabetes status and fibrosis stage in patients enrolled in MAESTRO-NASH and MAESTRO-NAFLD (NCT04197479; representing stages F0-F4). The correlations betw een ELF / P3NP and PRO-C3 and the effect of resmetirom compared with placebo were evaluated on fibrosis biomarkers PRO-C3 and P3NP / ELF at Week 52.

[0402] Method: Pearson’s correlation was used to examine the association between 2 PRO-C3 ELISA assay methods (ELISA GEN1 and ELISA GEN2, NORDIC BIOSCIENCE) using PRO-C3 baseline data (N=919). The rest of the analyses used the ELISA GEN2 assay. Mean SD or SE and median [QI, Q3] were calculated to summarize PRO-C3 data. ANCOVA was used for comparisons between resmetirom 80 or 100 mg vs. placebo in PRO-C3 change from baseline at w eek 52 (wk52CHG), while controlling for baseline PRO-C3 level. Mean difference with 95% CI and nominal P-values were obtained from the ANCOVA. Scatterplots and Spearman’s correlations with 95% Cis were used to assess the associations between P3NP / ELF and PRO-C3 both at baseline and wk52CHG.

[0403] Results: ELF components TIMP1 and P3NP showed no increase between fibrosis stages F0 and F2, increased by 20% between F2 and F3 / F4; HA was highly variable and higher in diabetics (F0 to F2). HA increased 2.0-fold between F3 and F4, largely explaining the increase in ELF in F4, Baseline P3NP and ELF w ere correlated with PRO-C3 (0.563 and 0.458, respectively) (FIG. 56). At baseline, PRO-C3 was mean (SD)=137 (71.7) ng / ml. At week 52, PRO-C3 wk52CHG for 100 mg resmetirom= -23.05 (4.76), 80 mg= -17.93 (4.61)Attorney Docket No. 156883.617393 and placebo= -0.19, 4.07 with mean difference (95% CI) in PRO-C3 wk52CHG between 80 mg and placebo= -16.9 (-27.0, -6.76; p= 0.0011); 100 mg and placebo= -22.1 (-32.3, -11.84; p < 0.0001). Larger reductions in PRO-C3 mean (SD) on the resmetirom arms were observed in F3 patients: 80 mg= -22.42 (6.38) and 100 mg= -27.42 (6.72) compared with placebo= -0.50 (5.46). The wk52CHG in P3NP was positively associated with wk52CHG in PRO-C3 (0.557, 0.548 and 0.524 for 100 mg, 80 mg and placebo; respectively). A weaker positive correlation between wk52CHG for ELF and PRO-C3 (0.483, 0.484 and 0.487 for 100 mg, 80 mg and placebo, respectively) were also observed.

[0404] Conclusion: The increase in ELF in F3 / F4 patients is explained by the increase in HA, an extracellular matrix protein made outside the liver and metabolized by liver sinusoidal endothelial cells that become dysfunctional in F4 cirrhosis. The reduction in PRO-C3, a marker of liver fibrosis was statistically significantly reduced by resmetirom vs. placebo; the reduction was more pronounced in F3 patients. ELF and PRO-C3 were less strongly correlated than P3NP and PRO-C3.

[0405] Example 12: A Randomized Double-blind Placebo-controlled Phase 3 Study to Evaluate the Effect of Resmetirom on Liver-related Outcomes in Patients with Well-compensated (Child-Pugh A) Non-alcoholic Steatohepatitis (NASH) Cirrhosis (MAESTRO-NASH OUTCOMES) (NCT05500222)

[0406] Objectives:

[0407] Primary Objective:

[0408] To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on patients as measured by time to experiencing a first adjudicated Composite Clinical Outcome (CCO) event, defined as any of the following: all-Attorney Docket No. 156883.617393 cause mortality, liver transplant, and significant hepatic events including hepatic decompensation events (new onset ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) and confirmed increase of Model for End-stage Liver Disease (MELD) score from <12 to >15.

[0409] Key Secondary Objectives:

[0410] To determine the effect of randomized, once daily, oral administration of 80 mg resmetirom versus matching placebo on the:

[0411] 1. Percent change from Baseline to Week 28 in low-density lipoprotein cholesterol (LDL-C).

[0412] 2. Percent change from Baseline to Week 52 in hepatic fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDFF) in patients with baseline MRI-PDFF >5%.

[0413] Secondary Objectives:

[0414] 1. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the time to the first hepatic decompensation event (new onset ascites), hepatic encephalopathy, or gastroesophageal variceal hemorrhage) or confirmed increase of MELD score from <12 to >15.

[0415] 2. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on change from baseline in FibroScan controlled attenuation parameter (CAP) scores as measured at protocol-specified time points.Attorney Docket No. 156883.617393

[0416] 3. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on FibroScan vibration controlled transient elastography (VCTE; kPa) as determined by:• Percent of patients characterized by at least 25% or at least 30% improvement from baseline at the protocol-specified time pointsOR• Percent of patients characterized by at least 25% and at least 30% worsening from baseline at the protocol-specified time points.

[0417] 4. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the change from baseline in Quality of Life(QOL) scores over the course of the study assessed by the Activity / Energy, Fatigue, and Systemic Symptoms domains of non-alcoholic fatty liver disease (NAFLD) / NASH Chronic Liver Disease Questionnaire (CLDQ-NASH), and Activity domain of the Work Productivity and Activity Index (WPAI)-NASH QOL instruments.

[0418] 5. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the:• Percent of patients with at least 19% reduction from Baseline in magnetic resonance elastography (MRE) at the protocol-specified time points.• Percent of patients with at least 19% increase from Baseline in MRE at the protocol- specified time points.Attorney Docket No. 156883.617393

[0419] 6. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo as measured by the percent change from Baseline to Week 16 and 52 and at the protocol-specified time points for:• Liver volume• Spleen volume.

[0420] 7. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the percent change from Baseline to Week 28 in:• Apolipoprotein B (ApoB)• Lipoprotein(a) [Lp(a)] in patients with baseline Lp(a) >10 nmol / L• Triglycerides (TGs) in patients with baseline TGs >150 mg / dL.

[0421] 8. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the percent change from Baseline to Week 52 in:• LDL-C• ApoB• TGs in patients with baseline TGs >150 mg / dL• Lp(a) in patients with baseline Lp(a) >10 nmol / L.

[0422] 9. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the change from Baseline to Week 28 and Week 52 in:Attorney Docket No. 156883.617393 • Triglyceride rich lipoprotein-cholesterol (TRL-C)• Non-high-density lipoprotein cholesterol (HDL-C)• Apolipoprotein C-III (ApoCIII)• Lipoprotein particles• TGs.

[0423] 10. To determine the effect of randomized, once-daily. oral administration of 80 mg resmetirom versus matching placebo on the incidence of treatment-emergent adverse events (TEAEs) through end of study.

[0424] 11. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the incidence of gastrointestinal (Gl)-related TEAEs from baseline to Week 12 as compared to post-Week 12 through end of study.

[0425] 12. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on liver parameters, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), at Week 52 and over time across all patients and in patients with baseline ALT ≥30 IUL / mL.

[0426] 13. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on inflammation and fibrosis biomarkers at Week 52, including:• Reverse T3• Cytokeratin-18 (CK-18)Attorney Docket No. 156883.617393 • Adiponectin• N-terminal type III collagen propeptide (PRO-C3)• Enhanced liver function (ELF) test with 3 direct components, change in ELF, and change in each of the components [ELF baseline >9.8; PIIINP (baseline ≥9 μg / L), TIMP-1 (baseline ≥240 μg / L), HA (baseline ≥50 μg / L)].

[0427] Exploratory Objectives:

[0428] 1. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on patients as measured by time to experiencing a first adjudicated clinical outcome event, defined as any of the following: liver-related and CV mortality,, liver transplant, and significant hepatic events including hepatic decompensation events (new onset ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) and confirmed increase of Model for End-stage Liver Disease (MELD) score from <12 to >15.

[0429] 2. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on the:• Incidence of liver transplant• Incidence of adjudicated hepatic decompensation event:o new onset asciteso hepatic encephalopathyo gastroesophageal variceal hemorrhageAttorney Docket No. 156883.617393 o Incidence of confirmed increase of MELD score from <12 to >15• Incidence of liver-related and CV mortality• Incidence of all-cause mortality.

[0430] 3. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on major cardiac adverse events (MACE) as adjudicated by an independent Cardiovascular Adjudication Committee (CAC) in all patients. MACE includes cardiovascular (CV) mortality, myocardial infarction, and cerebrovascular accident.

[0431] 4. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo (as adjudicated by the CAC) on a composite of: 1) heart failure events, 2) hospitalization for unstable angina, 3) urgent or emergent coronary revascularization.

[0432] 5. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on serious adverse events (SAEs) and adverse events (AEs) leading to the permanent discontinuation of the study drug.

[0433] 6. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on domain and summary scores of various QOL instruments (CLDQ-NASH, Short Form Liver Disease Quality of Life [SF-LDQOL], WPAI-NASH) and overall patient well-being (e.g., hospitalizations and other health career source utilization) at Week 52.

[0434] 7. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on:Attorney Docket No. 156883.617393 • QOL scores with change and / or percent change from baseline in non-invasive tests (e.g., ELF, MRI-PDFF, MRE, VCTE, SHBG, and other relevant endpoints)• Correlation between different QOL instrument scores

[0435] 8. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on change and / or percent change from baseline in metabolic, liver, and CV assessments, including the following:• Markers of insulin resistance and glucose homeostasis, such as homeostasis model assessment-estimated insulin resistance (HOMA-IR), hemoglobin A1c (HbA1c), non- esterified fatty acids (NEFA), glucose, and insulin• Body weight, body mass index (BMI)• Markers of liver function including albumin, ALP, direct and total bilirubin, international normalized ratio (INR)• Osteopenic and osteoporotic risk (T and Z scores) based on bone mineral density(BMD) of hip, spine, and femoral neck in patients with serial BMD measurements on dual energy x-ray absorptiometry (DEXA)• Additional markers of inflammation and fibrosis, including but not limited to high sensitivity C-reactive protein (hsCRP)• Systolic / diastolic blood pressure (SBP / DBP) and heart rate• Sex hormones: total testosterone, free testosterone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH) by sexAttorney Docket No. 156883.617393 • Thyroid hormones (free thyroxine [FT4], free triiodothyronine [FT3], thyroid- stimulating hormone [TSH])• Sex hormone binding globulin (SHBG) combined and by sex• Fibrinogen, ferritin

[0436] 9. To determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on liver assessments, including the following:• Liver events that are adjudicated as drug-induced liver injury (DILI)• Newly detected hepatocellular carcinoma (HCC).

[0437] 10. To determine the pharmacokinetic effect of NASH cirrhosis including severity stage and / or resmetirom treatment on statin levels in patients taking statins, including rosuvastatin, atorvastatin, pravastatin, simvastatin.

[0438] 11. To determine the effect of the results of genetic testing in consenting patients on laboratory criteria (UGT1 alleles), NASH status (NASH SNPs, e.g., PNPLA3 and TM6SF7), or PK (BCRP alleles).

[0439] Study Design:

[0440] This is a multi-national, multicenter, double-blind, randomized, placebo-controlled study in patients with well-compensated NASH cirrhosis. All study subjects must meet specific criteria defined in Pre-Screening Criteria, as well as all inclusion and exclusion criteria for study participation.

[0441] Patients who qualify for study inclusion will be randomized 3: 1 in a blinded manner to receive 80 mg resmetirom or matching placebo given orally once daily in theAttorney Docket No. 156883.617393 morning for the duration of the study (until the required number of events are achieved, approximately 3 years). The randomization will be stratified by 3 factors: (1) baseline Type 2 diabetes (T2D) status (presence / absence); (2) MRI-PDFF (<5%, >5%) or, when MRI-PDFF is unavailable / contraindicated, CAP (<300, >300); and (3) MRE (<6, >6) or, when MRE is unavailable / contraindicated, ELF (<11.3, >11.3).

[0442] Patients (approximately 10%) who are judged to have more progressed disease based on screening criteria (i.e., screening MELD >10 and <12 or the combination of screening MRE >6.5 kPa, screening FibroScan VCTE >25 kPa, AND screening ELF >11.3) will receive 60 mg resmetirom if randomized to resmetirom (NOTE: If a patient does not have a screening MRE, criteria will be based on FibroScan and ELF).

[0443] For all patients, if taking clopidogrel (a moderate CYP2C8 inhibitor):• If randomized to resmetirom and qualified for 80 mg, they will receive 60 mg at baseline• If randomized to resmetirom and qualified for 60 mg dose, they will receive 40 mg average daily dose at baseline (using the 40 mg dosing kit which administers 80 mg qod).

[0444] For patients who initiate treatment with clopidogrel after randomization into the study, identification of clopidogrel use (e.g., the site informs the Medical Monitor (MM) of a change in concomitant medications or new concomitant medications via term search etc.), then the MM will reach out to the site to confirm if clopidogrel treatment is long-term. Once confirmed, the patient will be down titrated in a blinded manner via IRT (e.g, at the next scheduled visit). If a patient previously down titrated to a lower dose of study drug due toAttorney Docket No. 156883.617393 concomitant use of clopidogrel, and discontinues clopidogrel while on study drug, the site will reach out to the MM for blinded up-titration assessment.

[0445] This study comprises an up to 60-day screening period and an approximately 3-year treatment period. However, the study will continue until a sufficient number of confirmed adjudicated CCO events (primary endpoint) have accrued in patients. Study assessments will be performed every’ 4 weeks through the first 16 weeks of the study treatment period, and then every 12 weeks until Week 52 and every 3 months thereafter for the duration of the study. Visits will include safety and efficacy assessments, clinical laboratory assessments, ECG, ultrasound (US), MRI / computerized tomography (CT), MRE, FibroScan, and QOL assessments. Drug dispensation and accountability will be conducted as described in the Schedule of Assessments. Blinded dose adjustments (made by an unblinded monitor) may occur beginning at Week 12 and throughout the remainder of the study.

[0446] Patients who discontinue study treatment (without experiencing an adjudicated CCO event) and do not withdraw consent should continue routine visit assessments at the investigative site, off study drug, until the overall study has concluded. If patients decline further study assessments at the investigative site, they should continue to be followed via telehealth communication at regular study intervals until study completion. At a minimum, patients should be contacted at the conclusion of the study for a final assessment. Note: The patient should also be offered an alternative schedule with flexibility that provides an opportunity for continued participation in the study. A patient will only be considered to have withdrawn participation in the study if all of the alternative options are declined. The research staff should ask each patient to provide contact information for support team members (e.g., relatives, spouse, primary’ caregiver) who can be contacted when there is an issue when tryingAttorney Docket No. 156883.617393 to contact the patient during the study. The research staff should attempt to keep the contact list as current as possible during the conduct of the study.

[0447] If a patient discontinues the study early, without experiencing an adjudicated CCO event, and withdraws consent, they should return to the site for an Early Termination (ET) visit and a 28 Day Follow-up visit

[0448] Safety Monitoring, Stopping Criteria, and Composite Clinical Outcome Event Monitoring.

[0449] Throughout the study, all patients will be monitored for safety and for the occurrence of a CCO event (primary endpoint).

[0450] Certain AEs may result in or require interruption of study drug depending on their severity. Patients will be monitored throughout the study for the occurrence of potential DILI resulting in liver enzyme elevations (AST, ALT, and / or ALP) using standard monitoring criteria.

[0451] Patients will also be monitored for DILI resulting in potential hepatic outcome event such as increased MELD from <12 to MELD >15 or development of new onset ascites, as well as other acute biliary events. For acute biliary events including cholecystitis, obstructive pancreatitis, or any form of acute cholestatic or hepatic impairment, study drug and statin s should be discontinued until the event is resolved.

[0452] Composite Clinical Outcome (Primary Endpoint)

[0453] Composite Clinical Outcome events are defined as any of the following: all-cause mortality, liver transplant, and significant hepatic events, including potential hepatic decompensation events (new onset ascites, hepatic encephalopathy, or gastroesophagealAttorney Docket No. 156883.617393 variceal hemorrhage), and confirmed increase of MELD score from <12 to >15. Suspected liver-related events will be reviewed and adjudicated by a blinded Hepatic Adjudication Committee (HAC).

[0454] During the time period when the potential CCO event is being adjudicated, the patient should remain on study drug, per Principal Investigator discretion in consultation with Sponsor / Medical Monitor. Additional study assessments during this time should include QOL, MRI-PDFF, MRE, FibroScan, and blood collection for biomarker analysis in accordance with the protocol requirements.

[0455] In the event of an adjudicated and confirmed CCO event, the patient will discontinue study drug. The patient should remain in study, at investigator’s discretion, off study drug and continue routine visit assessments for the duration of the trial. Study assessments during this time should include QOL, MRI-PDFF, MRE, FibroScan, and blood collection for biomarker analysis in accordance with the protocol -requirements.

[0456] Once the prespecified number of confirmed adjudicated CCO events (primary endpoint) have accrued, patients will return to the site by the time of their next scheduled study visit for an End of Study (EOS) visit and a 28-Day Follow-up visit to complete their participation in the study.

[0457] Potential Dose Adjustments Throughout the Study

[0458] Post-baseline FT4 and SHBG are blinded to all study personnel, both within Madrigal and the clinical sites, with the exception of the designated unblinded team. Based on pre-defined criteria, an unblinded monitor will implement a dose adjustment in the interactive response technology (IRT) based on the following programmed conditions:

[0459] Dose Adjustments at Week 12:Attorney Docket No. 156883.617393 • A one-time dose increase from 80 mg to 100 mg OR 60 mg to 80 mg will occur in patients with:o A <20% decrease in FT4 at Week 8 labs relative to baseline ANDo An absolute FT4 level >0.9 ng / dL ANDo A <50% SHBG increase at Week 8 labs relative to baseline• A dose decrease from 80 mg to 60 mg or from 60 mg to 40 mg will occur in patients with:o A >30% decrease in FT4 on Week 4 and Week 8 labs relative to baseline AND o An absolute FT4 level below the lower limit of normal (LLN) (<0.7 ng / dL) • A dose decrease from 100 mg to 80 mg, from 80 mg to 60 mg or from 60 mg to 40 mg may occur at any visit if the previous visit showed a >40% decrease from baseline inFT4o NOTE: The 40 mg dosing kit delivers 3 tablets (an 80 mg plus 2 placebotablets) and, on alternate days, 3 placebo tablets.

[0460] Dose Adjustments at Week 16, Week 28, Week 40, Week 52 and Every 3 Months After:• A dose decrease from 100 mg to 80 mg, from 80 mg to 60 mg or from 60 mg to 40 mg will occur in patients when at the 2 most recent consecutive visits, the labs show: o A >30% decrease in FT4 relative to baseline ANDo An absolute level below the LLN (<0.7 ng / dL).

[0461] Blinded Dose Adjustment for Patients with Moderate to Severe Hepatic Impairment due to Advanced CirrhosisAttorney Docket No. 156883.617393

[0462] Enrollment of a small number of patients with moderate to severe hepatic impairment due to more advanced cirrhosis who nonetheless meet protocol specifications for Child-Pugh (CP)-A (CP-A) (Appendix 6) is expected based on the known inaccuracy of CP classifications. In these patients, if randomized to resmetirom 60 mg or 80 mg per day, a significant simultaneous decrease in FT3 and TSH may rarely occur (1% - 3% of total study enrollment); this decrease reflects a high resmetirom level above the target exposure and requires a dose reduction to resmetirom 40 mg per day.

[0463] A dose decrease to every other day dosing should be implemented immediately in patients (including those on thyroid hormone replacement) when:Baseline FT3 is ≥2.0 pg / mL, and• A post Baseline FT3 value is <2.0 pg / mL, and• There is a >25% decrease from Baseline in the post Baseline valueAND• Baseline TSH is >1, and• TSH is decreased by at least 40% and is <1, and / or• Any normal TSH at baseline is decreased by at least 40% and is < LLN

[0464] In a different subset of patients who are not on thyroxine and meet only the postrandomization low FT3 criteria with a normal TSH OR in whom post-randomization TSH < LLN and decreased from baseline (TSH >1) with a normal FT3, a repeat confirmatory lab test should be conducted (while on their current dose of study drug) to determine if both criteria (TSH and FT3) are met. If tests confirm both criteria are met, these patients should dose with their current kit every other day.

[0465] If the TSH / FT3 criteria are met on initial testing or retest and the patient was randomized to resmetirom, the 40 mg dosing kit will be dispensed by IRT by the unblindedAttorney Docket No. 156883.617393 monitor. Once administered the 40 mg dosing kit, patients should return to clinic after two weeks for an unscheduled visit or for the next scheduled study visit, whichever is sooner, for retest of liver chemistries and FT3 / TSH levels. If these labs meet criteria for FT3 / TSH, a 40 mg dosing kit will be issued via IRT by an unblinded monitor.

[0466] DMC, HAC, and CAC

[0467] An unblinded DMC will serve to assess the progress of the clinical study and safety in accordance with the DMC Charter and to recommend to the Sponsor on a regular and ongoing basis whether to continue, modify, or stop the study based on standard safety monitoring. Only the external, independent DMC members, statistician(s), and unblinded team supporting the DMC will have access to unblinded data / comparative results. The DMC is planned to meet quarterly; ad hoc DMC meetings are possible.

[0468] The DMC safety review will include a review of all safety data in accordance with the DMC charter. The DMC will also review information from the blinded CAC and blinded HAC, which includes data for liver decompensation events, DILI episodes, and potential MACE or adjudicated CV events. Other data will be reviewed as mutually agreed upon with the Sponsor.

[0469] Since most components of the primary endpoint of CCO will be SAEs, the DMC will have knowledge of unblinded primary endpoint data. Therefore, the DMC will not provide any recommendations regarding the power assumptions for the study. The DMC will receive strict instructions from the unblinded statistician on the ability / risks to stopping the trial prematurely related to CCO endpoints.

[0470] A safety review of increased incidence of expected SAEs or severe AEs (for example, greater than expected numbers of CV AEs in patients at high CV risk, such asAttorney Docket No. 156883.617393 diabetics) or multiple occurrences of an unexpected SAE will be conducted by the DMC in an unblinded fashion, including potentially ad hoc review by the DMC. The DMC will recommend to stop the trial, modify the trial, or continue, temporarily, while further review is conducted. The DMC may also make a recommendation to stop the trial permanently based on their assessment of the data.

[0471] The blinded CAC and blinded HAC are separate and independent from the unblinded DMC. The blinded HAC will serve to review and adjudicate all CCO events and DILI episodes. The CAC, a separate, blinded adjudication committee, will review potential MACE and other cardiac events. The 2 independent, blinded adjudication committees' reviews are consistent with the definitions and other relevant criteria as defined in their respective Endpoint Adjudication Committee (EAC) Charters.

[0472] Test Product:

[0473] Resmetirom and matching placebo are available as tablets for oral administration. The resmetirom tablet is manufactured in 60, 80, and 100 mg dose strengths along with matching placebo. These dose strengths include all once-a-day dosages (60, 80, or 100 mg) that may be used in the study. Resmetirom (and matching placebo) may also be administered as 40 mg dose using the 40 mg dosing kit.

[0474] Patients will receive resmetirom and matching placebo tablets packaged in blister packs. The pack is designed to help ensure the integrity of each individual dose, as well as the ability to enhance compliance. Each blister pack contains 8 rows of 3 tablets (24 tablets total, sufficient for 8 days). Each row of 3 tablets contains potentially one 60 mg, one 80 mg, one 100 mg-sized tablet or matching placebo. For the resmetirom-treated once-daily patients, two are placebo and one is an active dose. For the placebo-treated patients all 3 tablets areAttorney Docket No. 156883.617393 placebo. Patients will take a full row of 3 tablets, once daily, in the morning for the duration of the treatment period. Four blister packs are packaged together into a drug kit, allowing up to 32 days of dosing.

[0475] A subset of patients may also receive a resmetirom dose of 80 mg every other day and matching placebo tablets packaged in identical blister packs. Each blister pack contains 8 rows of 3 tablets (24 tablets total, sufficient for 8 days). For the resmetirom-treated patients, the 3-tablet row will consist of either one 80 mg tablet and 2 matching placebo tablets or 3placebo tablets. This configuration will alternate by row for the 8-day supply.

[0476] Sufficient kit quantities will be dispensed to a patient to ensure continuous dosing until the next scheduled visit (plus an allowance for unanticipated circumstances which might result in a delay of the scheduled visit). At Baseline and Visits 4 to 12, one drug kit will be dispensed. Starting with Week 16. 3 drug kits will be dispensed, sufficient for up to 96 days.

[0477] Number of Patients (Planned):

[0478] A total of 845 patients are planned for enrollment in this study.

[0479] Diagnosis and Main Criteria for Inclusion:

[0480] Prescreening Criteria:

[0481] All patients screened for the study must have a clinical diagnosis of NASH cirrhosis from site PI or referring physician. To enrich this population for disease etiology and presence of well-compensated cirrhosis, and avoid unnecessary procedures, all study subjects must meet specific criteria ( Pre-Screening Criteria). These criteria include a diagnosis of histologic NASH cirrhosis defined as one of the following: (A) Historic liver b4. No biopsy consistent with NASH cirrhosis. This group is estimated to be approximately 70% ofAttorney Docket No. 156883.617393the study population. (B) Historic b4. No biopsy consistent with NASH with significant fibrosis, now with progression to cirrhosis based on additional prescreening criteria. (C) No historical b4. No biopsy. In this case, clinical picture of NASH cirrhosis is based on prescreening criteria. Combined, (B) and (C) are estimated to be approximately 30% of the study population. To be eligible for this study, patients must meet all prescreening, inclusion and exclusion criteria for study participation.

[0482] All potential patients to be screened for this study will have:• A historical or new diagnosis of well-compensated NASH cirrhosis (CP-A)• No history of a hepatic decompensation event• No historical evidence of untreated or unresolved viral hepatitis or other forms of liver disease that caused cirrhosis• No history of alcohol-related liver disease or history (within 5 years) of excessive alcohol consumption• At least 3 metabolic risk factors, using a modified version of the International Diabetes Foundation (IDF) criteria (Table 16)Table 1: Modified Criteria for Diagnosis of the Metabolic Risk FactorsLarge Waist or Body Mass Index (BMI) >30*Large waist circumference defined as: Men >94 cm (37 in), Women >80 cm (32 in) DyslipidemiaRaised TGs: >150 mg / dL (1.7 mmol / L) OR taking medications to lower TGs DyslipidemiaReduced HDL cholesterol (Men <1.03 mmol / L [40 mg / dL], Women <1.29 mmol / L [50Attorney Docket No. 156883.617393mg / dL])Hypertension>140 / 90 mmHg on 2 occasions OR taking antihypertensive medicationsT2DTaking diabetes medications or clearly documented insulin resistance calculated by the HOMA-IR. This can be derived from the product of the insulin and glucose values divided by a constant - that is, calculated by using the following formula: fasting glucose (mg / dL) x fasting insulin (μU / mL) / 405 (fasting glucose [mmol / L] × fasting insulin [μU / L] / 22.5). The calculation of HOMA-IR from a local laboratory is acceptable. A value >3.8 indicates insulin resistance.NOTE: Determination of metabolic risk factors is based on investigator discretion, and may¬ be based on historic laboratory tests for dyslipidemia or insulin resistance and / or concomitant medication usage for dyslipidemia, diabetes, and / or hypertension.* Asian patients meet criteria for obesity with BMI >27.5 kg / m2.

[0483] Prescreening Liver B4. No biopsy Status1. F4 - By any central reada. Progress to screeningb. No prescreening FibroScan is necessary2. F4 - By local reada. Need prescreening FibroScan >15 kPa (within 12 weeks of prescreening visit) to progress to screeningb. If prescreening FibroScan <15 kPa (within 12 weeks of prescreening visit) need one of the following:i. MRE >4.2 kPa (within the past 6 months prior to prescreening visit)Attorney Docket No. 156883.617393 ii. ELF >10.25iii. Fib-4 >3iv. Platelet count <140,000 mm3a. B4. No biopsy must have been obtained >6 months prior to prescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosisb. If prescreening FibroScan >15 kPa (within 12 weeks of prescreening visit), must also have one of the following at prescreening in order to screen for the study: i. MRE >4.2 kPa (within the past 6 months prior to prescreening visit) ii. ELF >10.25iii. Fib-4 >3iv. Platelet count <140,000 mm3c. If prescreening FibroScan <15 kPa (within 12 weeks of prescreening visit), must also have two of the following at prescreening in order to screen for the study: i. MRE >4.2 kPa (within the past 6 months prior to prescreening visit) ii. ELF >10.25iii. Fib-4 >3iv. Platelet count <140,000 mm34. No biopsya. Presenting at prescreening as clinically cirrhoticb. If prescreening FibroScan >15 kPa (within 12 weeks of prescreening visit), must also have one of the following at prescreening in order to screen for the study: i. MRE >4.2 kPa (within the past 6 months prior to prescreening visit) ii. ELF >10.25Attorney Docket No. 156883.617393 iii. Fib-4 >3iv. Platelet count <140,000 mm3c. If prescreening FibroScan <15 kPa (within 12 weeks of prescreening visit), must also have two of the following at prescreening in order to screen for the study: i. MRE >4.2 kPa (within the past 6 months prior to prescreening visit) ii. ELF >10.25iii. Fib-4 >3iv. Platelet count <140,000 mm3

[0484] Prescreening and Screening Flowchart (FIG.57)

[0485] Inclusion Criteria:

[0486] Patients must meet all Prescreening Criteria to be eligible to provide informed consent and enter the Screening period. Patients who meet all of the following inclusion criteria and none of the exclusion criteria will be eligible to participate in the study.

[0487] Patients who do not initially meet all eligibility criteria may be retested one time, based on Investigator discretion, to determine eligibility for the study.

[0488] Eligible patients:1. Must be willing to participate in the study and provide written informed consent.2. Male and female adults >18 years of age.3. Female patients who:a. Are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use 2 highly effective birth control methods during the studyAttorney Docket No. 156883.617393 b. OR are not of child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]).i. Highly effective birth control methods include condoms with spermicide, diaphragm with spermicide, hormonal and non-hormonal intrauterine device, hormonal contraception (estrogens stable>3 months), a vasectomized male partner, or sexual abstinence (defined as refraining from heterosexual intercourse) from Screening, throughout the study, and for at least 30 days after the last dose of study drug administration.Reliance on abstinence from heterosexual intercourse is acceptable only if it is the patient’s habitual practice.4. Male patients who are sexually active with a partner of child-bearing potential and:a. Are sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure)b. OR practice total abstinence from sexual intercourse as the preferred lifestyle(periodic abstinence is not acceptable)c. OR use a male condom with any sexual activityd. OR agree to use a birth control method considered to be appropriate by the Investigator (such as one of the methods identified above for female patients of childbearing potential) from the time of Screening until 30 days after the last dose of study drug administration.Male patients must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.5. Definitive (by histologic documentation) or probable NASH as causative agent for cirrhosis, following a modified version of the NASH Cirrhosis: Liver Forum ConsensusAttorney Docket No. 156883.617393 Definitions for Clinical Trials, Noureddin 2020.• Historic B4. No biopsy, Tissue availableA. On study centrally read as F4, historic b4. No biopsy is consistent with NASH cirrhosis. i. Continue in screening.B. On study centrally read as consistent with NASH with significant fibrosis.i. B4. No biopsy must have been obtained 6 months or greater prior top rescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis.ii. If screening FibroScan > 15 kPa, must also have one of the following screening results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3iii. If screening FibroScan <15 kPa, must also have two of the following screening results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3• Historic B4. No biopsy, Tissue not availableA. Historical read as F4. If steatosis and ballooning and / or steatosis and inflammation are noted by the local pathologist, then the b4. No biopsy qualifies even if an NAS is not provided.i. Continue in screening.B. Historical read as consistent with NASH with significant fibrosis.Attorney Docket No. 156883.617393 i. B4. No biopsy must have been obtained 6 months or greater prior top rescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis.ii. If screening FibroScan >15 kPa, must also have one of the following screening results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3iii. If screening FibroScan <15 kPa, must also have two of the following screening results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3• No B4. No biopsy - subject must be presenting with clinical cirrhosisi. If screening FibroScan >15 kPa, must also have one of the following results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3ii. If screening FibroScan <15 kPa, must also have two of the followingscreening results:1) MRE >4.2 kP A2) ELF >10.25Attorney Docket No. 156883.617393 3) Fib-4 >34) Platelet count <140,000 mm3• On study (not historic) b4. No biopsy (only obtained in rare instances and with preapproval from the Sponsor), or the b4. No biopsy was obtained less than 6 months prior to the screening date.A. On study (not historic) centrally read as F4, b4. No biopsy is consistent with NASH cirrhosis, i. Continue in screening.B. On study (not historic) centrally read as consistent with NASH with significant fibrosis.i. Need screening FibroScan > 15 kPa.ii. Must also have all of the following screening results:1) MRE >4.2 kPa2) ELF >10.253) Fib-4 >34) Platelet count <140,000 mm3NOTE: When possible, historic biopsies that are used for eligibility will be reviewed and confirmed as consistent with NASH cirrhosis by a central pathologist.o In the event of a conflicting read between historical b4. No biopsy report and central b4. No biopsy read, the central report will be used.NOTE: Infrequently, an on-study screening b4. No biopsy may be performed with prior approval from the Sponsor if the diagnosis of NASH cirrhosis versus other liver diseases is uncertain. This b4. No biopsy will be evaluated by the central pathologist. An on-study b4. No biopsy should not be used to diagnose NASH cirrhosis.6. Well-compensated Child-Pugh A (score of 5-6) cirrhosis at Screening and Baseline AND no history of a hepatic decompensation event.Attorney Docket No. 156883.617393 7. MRI-PDFFa. Obtained during the Screening period, orb. If subject is a re-screen, MRI-PDFF will be valid for up to 12 weeks at the time of randomization, with no weight change >5% in that interval.NOTE: In addition to evaluation of liver fat content, the MRI-PDFF will be evaluated by the MRI Core laboratory for spleen size and liver contour; any notable findings will be reported by the Core laboratory.NOTE: Patients with contraindications to an MRI-PDFF (e.g., metal prosthetics or uncontrolled documented claustrophobia, body weight exceeds limit of machine) examination are eligible for this study if the patient undergoes a FibroScan.8. MRE >4.2 obtained during the screening period (if MRE is <4.2 and >3.7, then an ELF>10.25 OR platelet counts <140K obtained during the screening period is required for eligibility).• NOTE: If MRE is not available, this criterion will not count against enrollment eligibility’.• NOTE: If the MRE appears to be unusually low (<3.7 kPa) despite meeting multiple other criteria for cirrhosis (FibroScan, ELF, platelets), discussion should be held with the Medical Monitor to waive this MRE inclusion criterion.• NOTE: If subject is a re-screen, prior centrally read MRE result will be valid for up to 3 months at the time of randomization.9. ELF >10.25 OR platelet counts <140K obtained during the screening period, ONLY if MRE is unavailable or contraindicated.10. Estimated glomerular filtration rate (GFR) >40 by the Modification of Diet in Renal Disease 6-variable formula (MDRD-6).Attorney Docket No. 156883.617393 11. ALT and AST stability as defined by:a. Screening ALT and AST are within normal limits or showno worsening greater than 50%, for both values, compared to historic ALT and AST obtained within 6 months of start of Screening.b. If greater than 50% worsening with at least one value above the ULN, laboratory¬ tests may be repeated once per PI discretion, with second draw at least 2 weeks after initial screening labs. Re-draw results for each test must be less than a 50% worsening, as compared to screening values or all values below the ULN.c. If no historic labs are available, 2 measurements must be obtained during the screening period at least 2 weeks apart. These must showno worsening of greater than 50% for both ALT and AST. If greater than 50% worsening and at least one value above the ULN, labs may be repeated once per PI discretion, with third draw at least 2 weeks after the second set of labs. The average of first 2 labs should be compared to third laboratory draw for ALT and AST to confirm that there is no worsening of greater than 50% for either ALT or AST or all values below the ULN.

[0489] Exclusion Criteria:

[0490] Patients who meet any of the following exclusion criteria will not be eligible to participate in the study.

[0491] Patients who do not initially meet all eligibility criteria may be retested one time, based on Investigator discretion, to determine eligibility for the study. NOTE: See Exclusion Criterion #2 below for specific guidelines for retesting of elevated MELD.1. Chronic liver diseases other than NASH cirrhosis:a. Primary biliary cholangitisAttorney Docket No. 156883.617393 b. Primary sclerosing cholangitisc. Hepatitis B positived. Hepatitis Ce. History or evidence of current active autoimmune hepatitisf. History or evidence of Wilson's diseaseg. History or evidence of alpha-1-antitrypsin deficiencyh. History or evidence of genetic hemochromatosis (hereditary, primary)i. Evidence of drug-induced liver disease, as defined on the basis of typical exposure and historyj. Known bile duct obstructionk. Suspected or confirmed liver cancer2. MELD score ≥12, due to liver disease at either screening OR baseline.• NOTE: MELD of >12 as the result of liver disease is exclusionary', NOT including isolated laboratory abnormalities such as elevated creatinine due to chronic kidney disease, INR abnormality' secondary to anticoagulants or laboratory error, or bilirubin elevation due to Gilbert’s syndrome. UGT1 Al allele testing to be performed at Screening on all patients (where permitted).• NOTE: A screening MELD of >12 that is likely due to liver disease may only be retested during screening in consultation with the Sponsor because of the possibility that the patient is not well-compensated. If the retest screening MELD is <12 and all other conditions are met, the patient may randomize. If the baseline MELD is >12 in a patient who had a screening MELD >12 (even if the screening retest was <12), the patient must permanently discontinue study drug and exit the Main MGL-3196-19 study.In a patient with a screening MELD <12, if the baseline MELD is >12 and likely dueAttorney Docket No. 156883.617393 to liver disease, the patient must discontinue study drug, and retest MELD within one week of randomization. If repeat MELD is <12, the patient may restart study drug and continue in the study. If the retest shows MELD >12 then the patient must permanently discontinue study drug, but patient may continue in the study off study drug.3. History of hepatic decompensation or impairment at either screening or baseline, defined as presence of any of the following:a. History of gastroesophageal variceal bleeding (NOTE: small to medium (Grade I- II) non-bleeding varices are allowed).b. Ascites due to cirrhosis. Screening MRI or CT shows at least a 2 cm pocket of fluid in at least 2 of 5 abdominal stations, including the four abdominal quadrants and pelvis. NOTE: in situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of ascites.c. Overt hepatic encephalopathy, lactulose treatment, or other treatment for hepatic encephalopathy.d. Serum albumin <3.5 g / dL, except as explained by non-hepatic causes.e. INR >1.4 unless due to therapeutic anticoagulants or laboratory error (NOTE: If laboratory error is suspected, retest to confirm INR <1.4 is required).f. Total bilirubin >2 mg / dL.o NOTE: Patients with genetically confirmed Gilbert’s syndrome are eligible with a total bilirubin >2 mg / dL if reticulocyte count is within normal limits, hemoglobin is within normal limits unless due to chronic anemia and unrelated to hemolysis, and direct bilirubin is <20% of total bilirubin.4. Diagnosis of HCC at Screening or historically.5. Liver Imaging Reporting and Data System (LI-RADS) score >4 at Screening. NOTE: inAttorney Docket No. 156883.617393 situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of hepatocellular cancer.6. Thyroid diseases, as defined by the following conditions:a. Active hyperthyroidism.o NOTE: Patients with a history of hyperthyroidism are eligible to participate. b. Untreated clinical hypothyroidism defined by:o o Thyroid stimulating hormone (TSH ≥7) IU / L with symptoms of hypothyroidism, oro o TSH ≥10 IU / L without symptoms.• NOTE: TSH may be repeated once during Screening, and if still does not meet entry criteria, patients will be considered screen failures. Patients with clinical hypothyroidism newly treated with thyroxine may be rescreened once thyroxine dose is stabilized.• NOTE: Patients with subclinical hypothyroidism or patients on stable thyroxine therapy are eligible to participate. Small adjustments may be made to thyroxine therapy. As per standard of care, adjustments of 12.5 to 25 pg every’ 4 weeks are allowed. Thyroxine dose may be adjusted once during Screening and TSH retested at least 2 weeks prior to randomization.• NOTE: During Screening and the study, patients receiving thyroxine should be on a stable dose for at least 2 weeks prior to randomization, optimally with screening TSH >1 and <5 IU / L. However, these TSH levels are not mandated, rather considered a target for patients who may have underlying CV disease.• NOTE: Recent data suggest that approximately half of patients on thyroxine therapy are treated with too high or too low a dose resulting in exogenous hyper- or hypothyroidism, respectively.Attorney Docket No. 156883.617393 7. Has an active autoimmune disease, including actively treated lupus, rheumatoid arthritis, inflammatory bowel disease, or autoimmune hepatitis that requires systemic treatment within the past 12 weeks or a documented history of clinically severe autoimmune disease, including autoimmune liver disease, or a syndrome that requires systemic steroids or immunosuppressive agents.• NOTE: Patients with vitiligo or resolved childhood asthma / atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators, topical, inhaled, or intranasal corticosteroids, or local steroid injections are not excluded from the study.• NOTE: Patients with autoimmune diseases such as rheumatoid arthritis who are on systemic therapies may be eligible on a case-by-case basis as long as the systemic therapy for the autoimmune disease is not specifically excluded (i.e., steroids or immunosuppressive agents).8. Alcohol consumption of any type, frequency, or amount is not allowed during the screening or treatment phase of the study.9. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.10. History of biliary diversion.11. Uncontrolled hypertension (either treated or untreated), defined as systolic blood pressure >170 mmHg or diastolic blood pressure >100 mmHg at Screening.12. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction <30%.13. Uncontrolled cardiac arrhythmia.14. Screening electrocardiogram (ECG) shows uncontrolled cardiac arrythmia, or not previously diagnosed.Attorney Docket No. 156883.617393 • NOTE: Patient may continue screening or rescreen if arrythmia is controlled (i.e., new onset asymptomatic atrial fibrillation that is appropriately followed up with appropriate treatment such as cardioversion and / or use of anticoagulants).15. Myocardial infarction, unstable angina, emergent percutaneous coronary intervention, coronary artery bypass graft, or stroke within 6 months prior to randomization.16. Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization. 17. Carbohydrate-deficient transferrin (CDT) measured at Screening ≥3.0%, unless another reason for CDT elevation is provided.• NOTE: If CDT is elevated >2.47 and <3.0, additional patient history should be obtained to rule out alcohol consumption inconsistent with the protocol exclusion limit.18. Phosphatidylethanol (PEth) value of ≥20 ng / mL measured at Screening, except in circumstances where investigator and Sponsor believe PEth is the result of a laboratory error or isolated occurrence, based upon patient history.19. HbAlc >9.0%.a. Patients with HbA1c >8.0% and ≤9.0% should have documented efforts to control HbA1C to ≤8.b. If no prior documentation of efforts to control HbA1c, patients with HbA1C>8% and ≤9.0% may be treated with new or higher doses of existing diabetic medication(s) and continue screening.c. If screening HbA1c was >9.0% and a new anti-diabetic therapy was initiated, patient may have a repeat HbA1c 30 days after initiation of the new anti-diabetic therapy.d. Patients must be on stable treatment for all diabetes medications, including any new doses or medications, for ≥30 days prior to randomization.Attorney Docket No. 156883.617393 e. Insulin doses may be altered during the Screening period per standard of care. f. If screening HbA1c >9% and patient has had previous attempts to controlHbA1c, screening HbAlc may be repeated once.g. Modifications of diabetes medications for HbA1C control are allowed during the study.20. Serum ALT >250 U / L.21. Platelet counts <70,000 / mm3at either screening or baseline. If the screening or baseline platelets are 60,000±2000 mm3no repeat is allowed.22. Use of statin therapy exceeding the following doses is not allowed:a. Atorvastatin >20 mg dailyb. Rosuvastatin >20 mg dailyc. Simvastatin >20 mg dailyd. Pravastatin >40 mg dailye. Lovastatin >20 mg dailyf. Pitavastatin >2 mg daily• NOTE: Dose adjustments in statins, consistent with label recommendations for hepatic impairment, cirrhosis or tolerability issues, may be made during the Screening period and during the study.• NOTE: Other dyslipidemia therapies not specifically listed as prohibited, such as PCSK9 inhibitors, fish oils and derivatives, are allowed. Fenofibrate is not allowed in this study.• NOTE: In the case that a lipid lowering medication is discontinued or reduced before randomization, the patient can randomize one week after the discontinuation. An increase in lipid medication dose or a switch in statin (orAttorney Docket No. 156883.617393 other lipid lowering medication) as permitted in the protocol must be stable for at least two weeks prior to randomization.23. Use of high dose vitamin E (>400 lU / day) unless stable for >6 months prior to randomization. Vitamin E can be discontinued or decreased but dose cannot be increased during the study.24. Use of pioglitazone >15 mg per day.• NOTE: Pioglitazone is allowed at doses <15 mg / day if:o The patient has been on pioglitazone for >12 weeks prior to randomization, ANDo The patient is on a stable dose of <15 mg per day for >4 weeks prior to randomization.25. Glucagon-like peptide 1 (GLP-1) agonist therapy for diabetes treatment (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, and albiglutide) must be a stable dose for at least 12 weeks prior to randomization. GLP-1 agonists for weight loss (e.g., semaglutide at doses up to 2.4 mg subcutaneous weekly) must be at stable doses for at least 6 months (including body weight change ≥5% weight loss in the 12 weeks prior to randomization) (please refer to Exclusion Criteria 16 for changes in weight ≥5%).26. Regular use of drugs historically associated with NAFLD, which include, but are not limited to, the following: amiodarone, methotrexate, systemic glucocorticoids, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids except testosterone replacement, valproic acid, and known hepatotoxins for more than 4 weeks within the last 8 weeks prior to the initial Screening.27. Use of illicit drugs within 5 years prior to randomization or a urine drug screen result positive for amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, orAttorney Docket No. 156883.617393 phencyclidine at Screening, unless a prescribed drug accounts for the positive test.28. Active, serious medical disease other than NASH cirrhosis with a likely life expectancy <5 years.29. Participation in an investigational new drug trial (non-NASH therapeutic) in the last60 days or 5 half-lives, whichever is longer, prior to randomization.30. Prior treatment with NASH therapeutics in an investigational trial unless the following criteria are met:a. Follow-up liver b4. No biopsy at the end of trial continued to show NASH cirrhosis meeting eligibility criteria for this trial and they have been off the NASH therapeutic for at least 12 weeks prior to expected randomization.b. OR: Potential NASH therapeutic studied revealed no safety issues, and, in fact, was not an effective NASH therapeutic (no effect on liver b4. No biopsy compared to placebo). Participation may occur 12 weeks or 5 half-lives, whichever is longer, after discontinuation of the therapy.c. OR: Subjects who discontinued from an ongoing NASH cirrhosis study maybe eligible after consultation with Medical Monitor and if they had participated in the study for less than 3 months and if they have been off the NASH therapeutic for at least 6 months prior to expected randomization.d. Note: Any patient who previously took resmetirom is excluded. If a patient participated in a resmetirom clinical trial but was confirmed as randomized to placebo (never received resmetirom), they may be eligible to participate after discussion with the Sponsor as long as other eligibility criteria are met.31. History of major surgery (i.e., surgery involving a risk to the life of the patient; specifically, an operation upon an organ within the cranium, chest, abdomen, or pelvic cavity) within 6 weeks prior to randomization.Attorney Docket No. 156883.617393 32. History' of cancer within the last 5 years (other than treated and believed to be cured basal or squamous cell carcinoma of the skin or resected carcinoma of the cervix).33. Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.34. Known immunocompromised status, including but not limited to individuals who have undergone organ transplantation, who are known to be positive for human immunodeficiency virus (HIV), or who have recurrent or chronic systemic bacterial, fungal, viral, or protozoal infections.35. Hypersensitivity to resmetirom or to any of the excipients including in placebo.

[0492] Duration of Treatment:

[0493] The expected study duration may be approximately 3 years. This study is comprised of a Screening period of up to 60 days, and an approximately 3-year treatment period. However, the study will continue until a sufficient number of confirmed adjudicated CCO events (primary' endpoint) have accrued in patients.

[0494] Reference Product:

[0495] Once daily, oral administration of 80 mg resmetirom or matching placebo in a 3: 1 active versus placebo randomization scheme (40 mg (administered via a 40 mg dosing kit that delivers 80 mg every other day alternating with placebo). 60 mg and 100 mg resmetirom may also be used in some patients).

[0496] Statistical Methods:

[0497] Primary Endpoint:Attorney Docket No. 156883.617393

[0498] The primary endpoint is the effect of once-daily, oral administration of resmetirom versus matching placebo on NASH CP-A patients, as measured by the time to a confirmed adjudicated CCO event.

[0499] The CCO event is composed of all-cause mortality, liver transplant, significant hepatic events including hepatic decompensation events (new onset ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) and confirmed increase of MELD score from <12 to >15.

[0500] Time from the date of randomization to the date of the first CCO event in the Intent-to-Treat (ITT) Population will be compared for all patients randomized to resmetirom and placebo using a stratified log rank test. Patients who terminate the study without an event will be considered censored as of their last day in the study.

[0501] An estimate of the hazard ratio and corresponding 95% confidence interval (CI) will be provided using a Cox proportional hazards model including treatment and the baseline stratification factors. Survival for each arm will be summarized using Kaplan-Meier curves.

[0502] Key Secondary Endpoints:

[0503] There are 2 key secondary endpoints that will be statistically tested while controlling the overall Type 1 error rate:1. Percent change from baseline in LDL-C at Week 282. Percent change from Baseline to Week 52 in hepatic fat fraction by MRI-PDFF inpatients with baseline MRI-PDFF >5%.

[0504] Secondary / Exploratory Endpoints:Attorney Docket No. 156883.617393

[0505] Additional secondary and exploratory endpoints will be defined in a prospectively developed SAP. These endpoints will be assessed descriptively. Nominal p-values may be provided.

[0506] Randomization:

[0507] Patients will be randomized in a 3: 1 allocation to either an initial dose of 80 mg for resmetirom or a matching placebo. Patients (approximately 10%) who are judged to have more progressed disease based on screening criteria (ie, MELD >10 and <12 or the combination of MRE >6.5 kPa, screening FibroScan VCTE >25 kPa, AND ELF >11.3) will be randomized 3: 1 to receive 60 mg resmetirom or placebo (NOTE: If a patient does not have a screening MRE, criteria will be based on FibroScan and ELF). The randomization will be stratified by 3 factors: (1) baseline T2D status (presence / absence); (2) MRI-PDFF (≤5%, >5%) or, when MRI-PDFF is unavailable / contraindicated, CAP (<300. >300); and (3) MRE (<6, >6) or, where MRE is unavailable / contraindicated, ELF (<11.3, >11.3).

[0508] Sample Size and Power

[0509] The following summarizes the sample size requirements for an Alpha = 0.05 (two-sided) primary comparison of resmetirom vs placebo with 90% Power. The assumed event rate per year for the primary endpoint is 10% for placebo and 5% for resmetirom. Sample size estimation was performed using EAST Version 6.5. A 12-month uniform enrollment was assumed. Based on exponential survival, this equates to a hazard ratio of 0.4868. A total of 845 patients will be enrolled and approximately 109 composite clinical events are required.

[0510] There will be no formal interim analysis for this study to establish early benefit. The Sponsor will periodically monitor blinded event rates to understand the plausibility of assumptions that went into the sizing of the study.Attorney Docket No. 156883.617393

[0511] Study Schema (FIG.58).

[0512] Target Population

[0513] This study will include male and female patients >18 years of age with well-compensated NASH cirrhosis (CP-A) and no history of decompensation. The patient population will follow a modified version of the NASH Cirrhosis: Liver Forum Consensus Definitions for Clinical Trials (Noureddin 2020).

[0514] To be considered for screening, patients must meet criteria described herein. This includes: historic b4. No biopsy, clinical criteria for NASH cirrhosis, imaging, labs, no history of alcohol-related liver disease or recent history (within last 5 years) of excessive alcohol consumption and at least 3 metabolic risk factors using a slightly modified version of the International Diabetes Foundation (IDF) criteria.

[0515] Diagnosis of NASH Cirrhosis

[0516] All patients screened for the study must have a clinical diagnosis of cirrhosis, from the site PI or referring physician. To enrich this population for disease etiology and presence of well-compensated cirrhosis, and avoid unnecessary procedures, all study subjects must meet specific criteria (Pre-Screening Criteria). These criteria include a diagnosis of histologic NASH cirrhosis defined as one of the following: (A) Historical liver b4. No biopsy consistent with NASH cirrhosis. This group is estimated to be approximately 70% of the study population. (B) Historic b4. No biopsy consistent with NASH with significant fibrosis, now with progression to cirrhosis based on additional prescreening criteria. (C) No historical b4. No biopsy. In this case, clinical picture of NASH cirrhosis is based on prescreening criteria. Combined, (B) and (C) are estimated to be approximately 30% of the study population.Attorney Docket No. 156883.617393

[0517] To be eligible for this study, patients must meet all prescreening, inclusion and exclusion criteria for study participation.

[0518] Treatment Assignment

[0519] Patients will be randomized 3:1 to receive 80 mg resmetirom or matching placebo.

[0520] Patients (approximately 10%) who are judged to have more progressed disease based on screening criteria (i.e., MELD >10 and <12 or the combination of MRE >6.5 kPa, screening FibroScan VCTE >25 kPa, AND ELF >11.3) will receive 60 mg resmetirom if randomized to resmetirom (NOTE: If a patient does not have a screening MRE, criteria will be based on FibroScan and ELF).

[0521] For all patients, if taking clopidogrel (a moderate CYP2C8 inhibitor):• If randomized to resmetirom and qualified for 80 mg, they will receive 60 mg at baseline.• If randomized to resmetirom and qualified for 60 mg dose, they will receive 40 mg average daily dose at baseline (using the 40 mg dosing kit which administers 80 mg qod).

[0522] Sites will contact the interactive response technology (IRT) to randomize the patient centrally in a 3: 1 manner to receive double-blind 60 mg or 80 mg resmetirom or matching placebo.

[0523] For patients who initiate treatment with clopidogrel after randomization into the study, identification of clopidogrel use (e.g., the site informs the Medical Monitor (MM) of a change in concomitant medications or new concomitant medications via term search etc.), then the MM will reach out to the site to confirm if clopidogrel treatment is long-term. OnceAttorney Docket No. 156883.617393 confirmed, the patient will be down titrated in a blinded manner via IVRS (e.g., at the next scheduled visit). If a patient previously down titrated to a lower dose of study drug due to concomitant use of clopidogrel, and discontinues clopidogrel while on study drug, the site will reach out to the MM for blinded up-titration assessment.

[0524] Dose Adjustment Criteria

[0525] Safety Criteria for Adjustment or Stopping Doses

[0526] Patients will be closely monitored to assess hepatic decompensation events, acute biliary events (including cholecystitis, obstructive pancreatitis, or any form of acute cholestatic or hepatic impairment), MACE and other specified cardiac events, and the potential of DILI resulting in liver enzyme elevations or potential hepatic outcome events. Doses may also be adjusted based on FT4 and SHBG at specific time points.

[0527] Criteria for Dose Adjustment

[0528] Post-baseline FT4 and SHBG are blinded to all study personnel with the exception of the designated unblinded team. Based on pre-defined criteria, an unblinded monitor will implement a dose adjustment in the IRT based on the following conditions:Dose Adjustments at Week 12• A one-time dose increase from 80 mg to 100 mg or from 60 mg to 80 mg will occur in patients with:- A <20% decrease in FT4 at Week 8 labs relative to baseline AND- An absolute FT4 level >0.9 ng / dL AND- A <50% SHBG increase at Week 8 labs relative to baseline• A dose decrease from 80 mg to 60 mg or from 60 mg to 40 mg will occur in patientsAttorney Docket No. 156883.617393 with:- A >30% decrease in FT4 on Week 4 and Week 8 labs relative to baseline AND - An absolute FT4 level below the lower limit of normal (LLN) (<0.7 ng / dL) • A dose decrease from 100 mg to 80 mg, from 80 mg to 60 mg or from 60 mg to40 mg may occur at any visit if the previous visit showed a >40% decrease from baseline in FT4- NOTE: The 40 mg dosing kit delivers 3 tablets (an 80 mg plus 2 placebo tablets) and, on alternate days, 3 placebo tablets.• NOTE: Downward dose adjustments based on low FT4 at Week 12 have occurred in<2% of NASH cirrhosis patients in Study MGL-3196-14.Dose Adjustments at Week 16, Week 28, Week 40, Week 52 and Every 3 MonthsAfter:• A dose decrease from 100 mg to 80 mg, from 80 mg to 60 mg or from 60 mg to40 mg will occur in patients when at the 2 most recent consecutive visits, the labs show: o A >30% decrease in FT4 relative to baseline ANDo An absolute level below the LLN (<0.7 ng / dL)

[0529] Blinded Dose Adjustment for Patients with Moderate to Severe Hepatic Impairment due to Advanced Cirrhosis

[0530] Enrollment of a small number of patients with moderate to severe hepatic impairment due to more advanced cirrhosis who nonetheless meet protocol specifications for Child-Pugh (CP)-A (CP-A) is expected based on the known inaccuracy of CP classifications. In these patients, if randomized to resmetirom 60 mg or 80 mg per day, a significant simultaneous decrease in FT3 and TSH may rarely occur (1% - 3% of total study enrollment); this decrease reflects a high resmetirom level above the target exposure and requires a dose reduction to resmetirom 40 mg per day.Attorney Docket No. 156883.617393

[0531] A dose decrease to every other day dosing should be implemented immediately in patients (including those on thyroid hormone replacement) when:• Baseline FT3 is >2.0 pg / mL, and• A post Baseline FT3 value is <2.0 pg / mL. and• There is a >25% decrease from Baseline in the post Baseline valueAND• Baseline TSH is >1, and• TSH is decreased by at least 40% and is <1, and / or• Any normal TSH at Baseline is decreased by at least 40% and is < LLN.

[0532] In a different subset of patients who are not on thyroxine and meet only the postrandomization low FT3 criteria with a normal TSH OR in whom post-randomization TSH < LLN and decreased from baseline (TSH >1) with a normal FT3, a repeat confirmatory lab test should be conducted (while on their current dose of study drug) to determine if both criteria (TSH and FT3) are met. If tests confirm both criteria are met, these patients should dose with their current kit every other day.

[0533] If the TSH / FT3 criteria are met on initial testing or retest and the patient was randomized to resmetirom, the 40 mg dosing kit will be dispensed by IRT by the unblinded monitor. Once administered the 40 mg dosing kit, patients should return to clinic after two weeks for an unscheduled visit or for the next scheduled study visit, whichever is sooner, for retest of liver chemistries and FT3 / TSH levels. If these labs meet criteria for FT3 / TSH, a 40 mg dosing kit will be issued via IRT by an unblinded monitor.

[0534] Example 13; The Cholate Challenge Test Characterizes Disease Severity in MASH-related Child Pugh A Cirrhosis and Potential Clinical Benefit of ResmetiromAttorney Docket No. 156883.617393

[0535] ABSTRACT

[0536] Background and aims. In this study of MASH-related Child-Pugh A cirrhosis (MASH cirrhosis), the cholate challenge test was used to quantify baseline disease severity and the subsequent impact of resmetirom treatment.

[0537] Methods. Thirty-two subjects enrolled in the Phase 3 open-label MAESTRO-NAFLD-1 trial with MASH cirrhosis underwent baseline dual cholate shunt testing, and 25 had subsequent retesting at 28 and 48 weeks. Blood was sampled from 0 to 90 minutes, serum concentrations measured, and parameters of function (DS1), portal-systemic shunting (SHUNT%). and clinical risk (RISK ACE) were calculated. Responders were defined by >2-point decrease in DSI, stable subjects by a ADSI within ±2. and non-responders by >2-point increase.

[0538] Results. Baseline DSI (22 ± 7) and SHUNT% (36% ± 16%) were consistent with significant functional impairment and portal-systemic shunting. Responder rates were 14% by 28 weeks and 38% by 48 weeks (p=0.0254). After 28 weeks, 87% of subjects were either stable or showed improvement. After 48 weeks, 83% of subjects were either stable or showed improvement, with a significant reduction in mean RISK ACE from baseline (-4.0%, p=0.041). Subjects with the greatest hepatic impairment (n=12, baseline DSI >23) showed the greatest reduction in RISK ACE (-7.5%, p=0.053).

[0539] Conclusions. MASH cirrhosis is characterized by a broad spectrum of hepatic impairment and portal-systemic shunting. DSI, SHUNT%, and RISK ACE may provide early estimates of potential clinical benefit with resmetirom treatment. MAESTRO-NAFLD-1 was registered at ClinicalTrials.gov (NCT04197479).

[0540] INTRODUCTIONAttorney Docket No. 156883.617393

[0541] Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) are the primary contributors to chronic liver disease globally. It is estimated that around 30% of the global population has MASLD,3while MASH affects between 1.5% and 6.5% of the U. S. population, with higher rates among middle-aged individuals. The prevalence of MASH cirrhosis is increasing and is the most common cause for Liver transplant in women. In the U. S., about 4% of patients with MASLD have cirrhosis, and, due to the high prevalence of MASLD (33%), this represents the majority of cirrhosis cases among liver disease etiologies. With the development of new treatments for MASH, there is a pressing need for minimally invasive tools to assess hepatic impairment in MASH cirrhosis and monitor treatment responses.

[0542] Although non-invasive diagnosis and staging of MASH patients have advanced in the past several years, non-invasive tests may not determine the exact stage of advanced F3 to F4 fibrosis / cirrhosis or the degree of hepatic impairment, including clinically significant portal hypertension. Since liver function and portal-systemic shunts are key determinants of liver related health, they are potential new targets for quantifying clinical risk and treatment effects.

[0543] Cholate clearance is a liver-specific function and the basis for the minimally invasive HepQuant platform of tests measuring liver function and portal-systemic shunting. This testing platform has shown utility for assessing risk for varices and other clinical complications, supporting its use in studies of drug therapy of compensated advanced chronic liver disease, such as MASH cirrhosis. The main output of the HepQuant tests is a disease severity index (DSI) which allows estimation of the risk for adverse clinical events (RISK ACE).Attorney Docket No. 156883.617393

[0544] Resmetirom is an oral, once-daily, liver-directed, selective thyroid hormone receptor-β agonist that is FDA-approved for use in MASH with moderate to advanced liver fibrosis (consistent with stage F2 and F3) and is under study for use in cirrhotic MASH.17Primary endpoints from MAESTRO-NAFLD-1 have been reported previously.18 19Herein were reported the results with the oral cholate challenge (HepQuant DuO) test and RISK ACE models from the Phase 3 MAESTRO-NAFLD-1 trial of resmetirom in subjects with well-compensated (Child-Pugh A) MASH cirrhosis.

[0545] METHODS

[0546] Subjects

[0547] The MAESTRO-NAFLD-1 study was a 52-week Phase 3 trial to evaluate the safety and tolerability of resmetirom for the treatment of MASH. The study included an open-label 80 mg once daily resmetirom treatment arm in patients with well-compensated (Child-Pugh A) MASH cirrhosis. The study was conducted between August 7, 2020 and January 6, 2023 at 80 clinical centers in the United States (all sites listed on ClinicalTrials.gov, NCT04197479). The trial consisted of a screening period of up to 8 weeks, a 52-week treatment period, and a4-week follow-up period. Visits were conducted every 4 weeks. Eligibility required at least three metabolic risk factors and MASH cirrhosis diagnosed on liver b4. No biopsy or according to accepted criteria. HepQuant test participants provided written informed consent to participate using an additional informed consent form. An institutional review board or independent ethics committee at each site approved the protocol and all amendments. Central IRB WCG (20192651); local IRB Duke University- Health System (Pro00104842); local IRB Cedars-Sinai Office of Research Compliance and Quality Assurance (STUDY00001571). The study was registered at ClinicalTrials.gov (NCT04197479). The HepQuant study was conducted at 13 centers and tests wereAttorney Docket No. 156883.617393 administered under FDA-issued investigational device exemption, IDE G210024. All authors had access to the study data and reviewed and approved the final manuscript.

[0548] Study procedures

[0549] The details of the HepQuant test procedure have been described previously and are summarized here. Subjects underwent baseline testing and subsequent retesting at 28 and 48 weeks. The test was administered to fasting subjects (overnight or >5 h), and morning medications were held until completion of testing. Dual cholate shunt (HepQuant SHUNT) tests were administered, involving simultaneous dosing of 20 mg [24-13C] (13C) cholate by IV and 40 mg [2.2.4.4-2H] (d4) cholate orally and three (3) mL blood samples collected at 0.5, 20, 45. 60. and 90 min. The results herein are reported for the oral cholate challenge test (HepQuant DuO) which utilized only the oral dose of d4-cholate. followed by blood sampling at 20 and 60 minutes. Serum concentrations of cholate isotopes were quantified using LC-MS / MS. Clinical investigators and study subjects were blinded to the results of the HepQuant test, and HepQuant personnel were blinded to the subjects’ clinical and laboratory’ information.

[0550] HepQuant test parameters and test versions

[0551] The methods for calculating the parameters of all HepQuant test versions and their within individual reproducibility are described in detail in separate publications. The following test parameters were calculated:• Disease Severity Index (DSI) is a score from 0 to 50 indexing a subject’s cholate clearances against maximum clearances of healthy controls.Attorney Docket No. 156883.617393 • Hepatic Reserve (%) ranges from 100% (normal reserve) to 0% (no reserve) and indexes a subject’s cholate clearances against the lower limit of clearances of healthy controls of lean body mass.• Hepatic filtration rates (HFR) are cholate clearances adjusted for body weight.Portal HFR is the clearance of orally administered d4-cholate. and Systemic HFR is the clearance of intravenously administered 13C-cholate. In the oral-only DuO test version, the systemic clearance of 13C-cholate is derived rather than measured.10 11• SHUNT% is the portal-systemic shunt fraction, which is defined as the ratio of the systemic and portal clearances.• RISK ACE scores estimate the probability of adverse clinical events at or before the index time and are calculated using DSI values in Cox proportional hazards regression. Two RISK ACE models were evaluated: the BASELINE model evaluates the risk using the DSI results from a single HepQuant DuO test; the FOLLOW-UP model evaluates the risk at follow-up using the baseline DSI and the rate of change in DSI from baseline and is intended for monitoring applications to track liver function over time.

[0552] The portal cholate clearance is measured using a compartmental model, and systemic clearance was estimated using linear models and noncompartmental analysis. Results with the SHUNT test versions (VI.0, VI.1, and V2.0) are included in the present disclosure.

[0553] Statistical analysisAttorney Docket No. 156883.617393

[0554] The study design and primary and secondary outcome measures of the MAESTRO-NAFLD-1 trial are reported elsewhere. The analyses reported herein represent exploratory objectives for the MAESTRO-NAFLD-1 trial.

[0555] Subject characteristics were compared between those with baseline DSI ≤23 versus >23. In the SHUNT-V pivotal study, the cutoffs of SHUNT% <30% and DSI <18.3 were validated for ruling out large esophageal varices;14,22 DSI <18.3 indicated low risk (<4.7%), DSI 18.3 to <23 moderate risk (<9.4%), and DSI values >23 high risk for varices. For reference, the normal range of DSI was <11.6, defined by results from healthy controls with lean body mass (<25 kg / m2, n=26).

[0556] Responder analysis was completed for baseline to Week 28 (W28) and baseline to Week 48 (W48). Subjects responding to treatment and having a more than 2-point decrease in DSI were defined as responders, stable subjects had ±2 DSI difference, and subjects having more than a 2-point increase in DSI were defined as non-responders. The threshold of 2 DSI units was based on HepQuant’s within individual reproducibility studies of 94 subjects encompassing healthy persons and subjects with MASH, HCV, and primary sclerosing cholangitis, where the minimum detectable difference in DSI was 1.7. Proportions of responders between W28 and W48 were compared using McNemar’s test because the responder proportions are repeated measurements on the same individuals.

[0557] The two RISK ACE models (BASELINE and FOLLOW-UP) were developed from serial studies of 215 subjects with compensated advanced chronic HCV followed for up to 7.9 years. The clinical outcomes for these models included liver-related death, sustained 2-point increase in Child-Pugh score, variceal hemorrhage, ascites, and encephalopathy. In theAttorney Docket No. 156883.617393 BASELINE model, risk for clinical event was directly related to baseline DSL In the FOLLOW-UP model, risk increases with DSI but decreases if DSI is stable or decreased.

[0558] For analysis of the MAESTRO-NAFLD-1 results, RISK ACE scores were calculated using the BASELINE model for baseline DSI and the FOLLOW-UP model for W48 DSL The change in RISK ACE between follow-up and baseline were evaluated for all subjects and by tertiles of baseline DSI (low DSI <18.3. moderate DSI 18.3-23, high DSI >23) with p values calculated from the bootstrapped (n=5000) distribution of the differences in estimated risk for clinical events between W48 and baseline representing the proportion of bootstrapped differences > 0.

[0559] RESULTS

[0560] Subject characteristics, laboratory values, and clinical scores

[0561] The subject / test disposition is shown in FIG. 59. Out of the 32 subjects enrolled and tested at baseline, 28 had evaluable baseline tests, 23 had evaluable W28 tests, and 23 had evaluable W48 tests.

[0562] Baseline subject characteristics, lab values, and clinical scores are shown in Table 17 for all subjects and by subgroups with baseline DSI <23 (n=16) or DSI >23 (n=12). The cohort had an average MELD score of 8.4, consistent with well-compensated CP A cirrhosis. The average age was 60 ±9 years, weight 107 ±26 kg, and BMI 37 ±9 kg m'2. Fifty percent were female, and 21% Hispanic or Latino. Sixty-eight percent had diabetes. Subjects with better liver function at baseline (DSI <23) were more likely to be taking statins (81%) versus those with DSI >23 (25%). Subjects with baseline DSI >23, compared to subjects with baseline DSI <23, had higher kPa by FibroScan (but not by MRE), similar levels of liver fat,Attorney Docket No. 156883.617393and worse results for bilirubin, albumin, platelet count, FIB-4, and MELD score (but not ELF score).Table 17. Baseline subject characteristics, clinical scores, and laboratory values for all subjects and by baseline DSI above or below 23.All Subjects Baseline DSI <23 Baseline DSI >23 n Mean ± SD or n n Mean ± SD or n n Mean ± SD or n (%) (%) (%) CharacteristicsAge 28 60.2 ± 8.9 16 60.4 ± 9.3 12 59.9 ± 8.7 Female 28 14 (50%) 16 8 (50 %) 12 6 (50 %) Hispanic or 28 6 (21%) 16 4 (25 %) 12 2 (17 %) LatinoBody Mass 27 37.3 ± 8.5 16 34.9 ± 5.5 11 40.7± 11.1 Index (kg / m2)Weight (kg) 28 107.1 ± 25.6 16 101.3 ± 21.3 12 114.9 ± 29.5 Diabetes 28 19 (68%) 16 13 (81 %) 12 6 (50 %) Hypothyroid 28 5 (18%) 16 4 (25 %) 12 1 (8 %) Hypertension 28 25 (89%) 16 15 (94 %) 12 10 (83 %) MedicationsStatin 28 16 (57%) 16 13 (81 %) 12 3 (25 %) GLP-1 28 6 (21%) 16 4 (25 %) 12 2 (17 %) Insulin 28 4 (14%) 16 3 (19 %) 12 1 (8 %) SGLT2 28 4 (14%) 16 4 (25 %) 12 0 (0 %) Thyroxine 28 6 (21%) 16 4 (25 %) 12 2 (17 %) Imaging and non-invasive measuresAttorney Docket No. 156883.617393FibroScan 25 30.8 ± 17.2 15 27.1 ± 17.1 10 36.3 ± 16.5 VCTE (kPa)CAP (dB / m) 25 333.6 ± 54.9 15 325.7 ± 55.3 10 345.4 ± 55.0 MRE (kPa) 25 5.6 ± 1.9 15 5.4 ± 2.0 10 5.9 ± 1.7 Hepatic Fat 26 9.2 ± 4.3 16 8.8 ± 3.4 10 9.8 ± 5.7 Fraction byMRI (%)Laboratory values and clinical scoresGlucose 28 130.5 ± 30.7 16 126.4 ± 31.6 12 136.1 ± 29.8 (mg / dL)HOMA-IR 28 14.8 ± 20.8 16 7.6 ± 2.5 12 24.5 ± 29.6 Total 28 0.9 ± 0.6 16 0.7 ± 0.3 12 1.1 ± 0.7 Bilirubin(mg / dL)ALP (U / L) 28 77.4 ± 25.1 16 72.6 ± 24.6 12 83.8 ± 25.5 ALT (U / L) 28 37.1 ± 16.5 16 35.3 ± 17.8 12 39.6 ± 15.2 AST (U / L) 28 36.3 ± 15.8 16 31.4 ± 15.7 12 42.8 ± 14.0 GGT (U / L) 28 119.6 ± 115.1 16 85.4 ± 78.3 12 165.3 ± 142.1 Platelets 27 145.9 ± 77.1 15 175.8 ± 87.6 12 108.6 ± 39.5 (103 / μL)Albumin 28 4.1 ± 0.3 16 4.2 ± 0.3 12 3.9 ± 0.4 (g / dL)PRO-C3 27 53.6 ± 24.2 16 48.4 ± 22.1 11 61.2 ± 26.1 (ng / mL)FIB-4 27 3.2 ± 2.1 15 2.3 ± 1.3 12 4.4 ± 2.2 ELF Score 28 10.5 ± 1.0 16 10.2 ± 0.9 12 10.8 ± 1.1 MELD Score 27 8.4 ± 1.9 15 7.9 ± 1.2 12 9.1 ± 2.4Attorney Docket No. 156883.617393Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CAP, controlled attenuation parameter; DSI, disease severity index; ELF Score, Enhanced Liver Fibrosis score; FIB-4, Fibrosis-4 score; GGT, gamma-glutamyl transferase; GLP-1, glucagon-like peptide- 1 agonists; MELD Score, Model for End-Stage Liver Disease; MRE, magnetic resonance elastography; SGLT2, sodium-glucose cotransporter 2 inhibitors; VCTE, vibration controlled transient elastography.

[0563] HepQuant test results

[0564] Although the results herein are those with the HepQuant DuO test, the results were consistent across all test versions (Table 18).Table 18. HepQuant results for DuO and SHUNT test versions at baseline, Week 28, and Week 48 in subjects taking resmetirom.Test Test Baseline Week 28 Week 48 Version Parameter n Mean ± SD n Mean ± SD n Mean ± SDDuO DSI 28 22.39 ± 7.40 23 22.03 ± 6.94 23 22.76 ± 7.40SHUNT% (%) 28 36.35 ± 15.67 23 36.18 ± 14.41 23 37.13 ± 15.20 Hepatic 28 72.02 ± 18.83 23 72.87 ± 17.70 23 71.12 ± 19.00 Reserve (%)Portal HFR 28 11.31 ± 6.88 23 11.37 ± 6.66 23 10.74 ± 6.05 (mL / min / kg)Systemic HFR 28 3.27 ± 0.83 23 3.36 ± 0.83 23 3.27 ± 0.93 (mL / min / kg)SHUNT DSI 28 23.01 ± 7.00 22 22.83 ± 6.44 23 23.53 ± 7.43Attorney Docket No. 156883.617393VI.0 SHUNT% (%) 28 39.89 ± 17.25 22 41.53 ± 18.30 23 39.68 ± 16.14Hepatic 28 70.69 ± 18.09 22 70.83 ± 16.34 23 69.55 ± 19.27 Reserve (%)Portal HFR 28 10.74 ± 6.21 23 10.96 ± 6.26 23 10.25 ± 5.60 (mL / min / kg)Systemic HFR 28 3.41 ± 0.89 22 3.61 ± 1.40 23 3.37 ± 1.21 (mL / min / kg)SHUNT DSI 28 22.68 ± 7.09 22 22.61 ± 6.50 23 23.27 ± 7.40 VI.1 SHUNT% (%) 28 39.77 ± 17.10 22 40.30 ± 17.36 23 39.44 ± 16.46Hepatic 28 71.07 ± 18.49 22 71.16 ± 16.91 23 69.85 ± 19.38 Reserve (%)Portal HFR 28 10.78 ± 6.32 23 10.99 ± 6.44 23 10.29 ± 5.76 (mL / min / kg)Systemic HFR 28 3.38 ± 0.77 22 3.41 ± 0.80 23 3.28 ± 0.92 (mL / min / kg)SHUNT DSI 28 22.38 ± 7.04 22 22.40 ± 6.48 23 22.87 ± 7.19 V2.0 SHUNT% (%) 28 38.10 ± 17.55 22 38.59 ± 16.27 23 37.57 ± 15.71Hepatic 28 72.19 ± 18.34 22 71.99 ± 16.80 23 71.10 ± 18.69 Reserve (%)Portal HFR 28 11.31 ± 6.88 23 11.37 ± 6.66 23 10.74 ± 6.05 (mL / min / kg)Systemic HFR 28 3.34 ± 0.72 22 3.39 ± 0.82 23 3.27 ± 0.91 (mL / min / kg)Abbreviations: DSL disease severity index; SHUNT%, portal-systemic shunting; HFR, hepatic filtration rate.Attorney Docket No. 156883.617393

[0565] The subjects were further stratified by HepQuant DuO cutoff of DSI 23. Baseline DSI values demonstrated a wide range of functional impairment, and SHUNT% values demonstrated a wide range of portal-systemic shunting (FIG. 60 A). The order, from best to worst, of the correlation coefficients for baseline DSI with other noninvasive markers was: 0.57 for FIB-4; 0.47 for FibroScan; 0.34 for ELF; 0.29 for platelet count; 0.23 for MRE; and 0 for MRI-PDFF (FIG. 60B). The pattern of coefficients, from best to worst, was similar for Hepatic Reserve and SHUNT%. Out of the 28 subjects with baseline DSI, one had DSI <11.6, nine (32%) had DSI 11.6-18.3, six (21%) had DSI 18.3-23, and 12 (43%) had DSI >23. Patients with the highest DSI and greatest SHUNT% had the most improvement in response to treatment (FIGs. 60C-60D).

[0566] There were nonsignificant trends towards improvement in HepQuant DuO test results after 28 and 48 weeks on resmetirom, and similar changes were observed with all test versions (Table 19). The mean DSI (22 ± 7) and SHUNT% (36% ± 16%) were consistent with baseline functional impairment and portal-systemic shunting, and the trends suggested stability or improvement in function and shunting in response to resmetirom treatment.Table 19, Change in HepQuant results for DuO and SHUNT test versions after 28 and 48 weeks on resmetirom.Test Test Parameter Change from W28 - Change from W48 - Version Baseline Baselinen Mean ± SD n Mean ± SDDuO DSI 23 -0.31 ± 2.72 23 -0.93 ± 4.75 SHUNT% (%) 23 0.55 ± 6.38 23 -1.91 ± 11.54Attorney Docket No. 156883.617393Hepatic Reserve (%) 23 0.32 ± 6.60 23 2.17± 12.38 Portal HFR (mL / min / kg) 23 0.54 ± 3.96 23 0.98 ± 4.22 Systemic HFR (mL / min / kg) 23 0.11 ± 0.32 23 0.12 ± 0.56 SHUNT DSI 22 -0.32 ± 2.65 23 -0.57± 3.46 VI.0 SHUNT% (%) 22 1.55 ± 14.44 23 -3.14 ± 11.82Hepatic Reserve (%) 22 0.23 ± 6.61 23 1.56 ± 9.08 Portal HFR (mL / min / kg) 23 0.45 ± 3.67 23 0.80 ± 2.97 Systemic HFR (mL / min / kg) 22 0.23 ± 1.37 23 0.02 ± 0.69 SHUNT DSI 22 -0.13 ± 2.61 23 -0.58 ± 3.32 VI.1 SHUNT% (%) 22 0.10 ± 8.85 23 -2.97 ± 11.93Hepatic Reserve (%) 22 0.02 ± 6.67 23 1.68 ± 9.15 Portal HFR (mL / min / kg) 23 0.43 ± 3.78 23 0.80 ± 3.10 Systemic HFR (mL / min / kg) 22 0.04 ± 0.67 23 -0.01 ± 0.42 SHUNT DSI 22 -0.18 ± 2.62 23 -0.70 ± 4.09 V2.0 SHUNT% (%) 22 0.14 ± 9.37 23 -3.55 ± 14.34Hepatic Reserve (%) 22 0.05 ± 6.74 23 1.87 ± 11.21 Portal HFR (mL / min / kg) 23 0.54 ± 3.96 23 0.98 ± 4.22 Systemic HFR (mL / min / kg) 22 0.08 ± 0.64 23 0.00 ± 0.40Abbreviations: DSI, disease severity index; SHUNT%, portal-systemic shunting; HFR, hepatic fdtration rate; W28, Week 28: W48, Week 48.

[0567] Responder analysis

[0568] FIGs. 60C-60D summarizes the treatment response of resmetirom by DSI. Eighty- three percent of subjects taking resmetirom demonstrated either improvement or stability by W48. Out of the 23 subjects that had baseline and W28 test results, 3 (13%) were responders, 17 (74%) were stable, and 3 (13%) were non-responders. For the 23 subjectsAttorney Docket No. 156883.617393with baseline and W48 results, 9 (39%) were responders, 10 (44%) were stable, and 4 (17%) were non-responders. For subjects with baseline, W28, and W48 results (n=21), the proportion of responders increased three-fold between W28 and W48 (p = 0.0254) (Table 20). Seven of the 9 responders at W48 had baseline DSI >18.3, suggesting that resmetirom had a stronger treatment response in subjects with higher DSI.Table 20, Cross-tabulation of 28- and 48-week response, as defined by a change of 2 DSI units, among the 21 participants with baseline. Week 28, and Week 48 results.Week 48 ResponseWeek 28 Response Non-responder Stable Responder NAaTOTAL Non-responder 0 2 1 0 3 Stable 3 8 4 2 15 Responder 0 0 3 0 3 NAa1 0 1 - - TOTAL 3 10 8 - 21aNA, data not collected for one of either Week 28 or Week 48 visits

[0569] Risk for Adverse Clinical Events (RISK ACE)

[0570] The impact of resmetirom on RISK ACE is shown in FIGs. 61A-61B and Table 21. The estimated risk of clinical outcome for all subjects was 11.0% based on the baseline DSI and 7.0% based on the W48 DSI, representing a 36% reduction in clinical risk after 48 weeks of resmetirom (p=0.0406) (FIG. 61A). The magnitude of improvement in clinical risk was greatest in those with baseline DSI >23, with a 38% risk reduction (20.1% — 12.7%) (Figure 3B). In subjects with baseline DSI between 18.3 and 23, there was modestAttorney Docket No. 156883.617393improvement (47% reduction (3.5% — 1.8%) (p<0.0001)). Subjects with DSI <18.3 who were already at low risk had no significant change in risk (1.9% 1.8%).Table 21, Difference from baseline for DSI and the estimated 48-week RISK ACE at W48 in all subjects and subjects stratified by baseline risk status (DSI).Baseline risk n Change in DSI at W48 Change in 48-week RISK category pairs ACE (%) atW48Mean (SD) p valueaMean (SD) p valuebAll subjects 23 -0.93 (4.75) 0.3598 -3.98 0.0406 (11.88)Low risk (DSI 7 -0.02 (5.43) 0.9936 -0.14 (3.28) 0.3718 <18.3)Moderate risk (DSI 5 0.13 (1.96) 0.8912 -1.66 (0.54) <0.0001 18.3 to 23)High risk (DSI >23) 11 -1.98 (5.29) 0.2421 -7.48 0.0542(16.66)aCalculated from paired t test;bCalculated from the bootstrapped (n=5000) distribution of the differences in estimated risk for clinical events between W48 from baseline representing the proportion of bootstrapped differences > 0; Abbreviations: DSI, disease severity index; RISK ACE, risk of adverse clinical events; W48, Week 48.

[0571] Adverse events

[0572] Adverse events related to the HepQuant test were primarily those that occurred with phlebotomy and venous catheter placement. There were no serious adverse events related to the HepQuant test.Attorney Docket No. 156883.617393

[0573] DISCUSSION

[0574] This study demonstrated that 48 weeks of resmetirom treatment of subjects with MASH cirrhosis was associated with reduction in the estimated risk for clinical outcome as measured by HepQuant RISK ACE.

[0575] A wide range of functional impairment and shunting was observed in this cohort of patients with compensated (CP A) MASH cirrhosis as exemplified in FIG. 60A. CP A subjects in this study, as documented in other studies with similar patient populations, have a spectrum of hepatic impairment and shunting extending from the normal range to severe disease.

[0576] The RISK ACE model was developed from a cohort of chronic hepatitis C patients where both reduction in DSI and stability of DSI were associated with lower risk for clinical outcome. Thus, in the current study even though the overall trend to decrease in mean DSI was nonsignificant, there was an increase in DSI responders between W28 and W48, and 83% of subjects improved or had stable DSI over the 48 weeks of resmetirom treatment. The latter treatment effects contributed to the positive RISK ACE outcome. It is also noteworthy that the improvement in RISK ACE was greatest for those subjects with the highest DSI and SHUNT% at baseline who also showed the greatest decline in DSI.

[0577] Quantitative characterization of the study population and early effects of treatment by HepQuant DuO could allow for more optimal clinical trial design. Improved characterization of the heterogeneity of functional and physiologic impairment at baseline could allow for definitive stratification of subjects by clinical risk. It is noteworthy that the average DSI of 22 for the present study cohort is similar to the threshold of DSI 24 that has been linked to risk for early decompensation in other studies.Attorney Docket No. 156883.617393

[0578] Additionally, early detection of non-responders, stable cases, and responders could improve efficiency in clinical trial design. Both DSI and RISK ACE are new tools that could provide early signals of not only treatment efficacy and the downstream potential for clinical benefit, but also lack of response or even toxicity. An adaptive design using HepQuant DuO could be more time- and cost-effective and require fewer participants than traditional fixed trial designs.

[0579] The significant reduction in the estimated clinical risk by RISK ACE was paralleled by nonsignificant trends in reduction in mean DSI. Other clinical models, MELD and Child-Pugh score, have shown that in comparison to worsening, stability of these scores has been associated with reduced risk for clinical outcome. In this study, this phenomenon was captured by the RISK ACE score despite the overall lack of statistically significant reductions in mean DSI. After 48 weeks of resmetirom, 83% of subjects either showed improvement or stability in their DSI. This is consistent with the mechanism of action of resmetirom, a liver directed thyroid hormone receptor-β agonist, whose immediate effect would reduce intrahepatic triglycerides and inflammation, but in the long-term remodel fibrosis, further reducing DSI.

[0580] One limitation of this study was the lack of a placebo arm. However, two time points were assessed, and the time-related improvements in DSI and RISK ACE do suggest a treatment effect. Another limitation of applying RISK ACE, which was developed from longterm follow-up of patients with chronic hepatitis C (HALT-C), is the potential lack of generalizability to patients with MASH. However, the subjects in the HALT-C Trial had an average BMI of 30 kg / m2, 85% were overweight, 42% were obese, and many were users of alcohol, suggesting potential underlying metabolic dysfunction and / or alcohol-inducedAttorney Docket No. 156883.617393 injury. Nonetheless, additional validation of RISK ACE in larger, diverse populations and liver disease etiologies is warranted.

[0581] In conclusion, a novel set of risk assessment tools were used, DSI and RISK ACE from the HepQuant DuO test, to estimate that 48 weeks of resmetirom in CP A MASH cirrhosis is projected to reduce rates of clinical outcomes in this patient population.

[0582] REFERENCES

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[0584] Younossi ZM, Stepanova M, Rafiq N, et al. Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty' liver disease. Hepatol Commun.2017:1(5).

[0585] Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty' liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4)doi:10.1097 / HEP.0000000000000004.

[0586] Younossi ZM. Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease — Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(l).

[0587] Harrison SA, Gawrieh S, Roberts K, et al. Prospective evaluation of the prevalence of nonalcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort. J Hepatol. 2021;75(2):284-291. doi:10.1016 / j.jhep.2021.02.034.Attorney Docket No. 156883.617393

[0588] Noureddin M, Vipani A, Bresee C, et al. NASH Leading Cause of Liver Transplant in Women: Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol. 2018;113(11): 1649-1659. doi:10.1038 / s41395-018-0088-6.

[0589] Younossi ZM. de Avila L, Racila A, et al. Prevalence and predictors of cirrhosis and portal hypertension in the United States. Hepatology. 2025; inpressdoi: 10.1097 / HEP.0000000000001243.

[0590] Younossi ZM. Loomba R, Rinella ME, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology.2018;68(l).

[0591] de Franchis R, Bosch J, Garcia-Tsao G, et al. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959-974. doi: 10.1016 / j.jhep.2021.12.022.

[0592] McRae MP, Kittelson J, Helmke SM, Everson GT. Within individual reproducibility of a dual sample oral cholate challenge test (DuO) and other simplified versions of the HepQuant test. Clin Transl Sci. 2024;17(4):el3786. doi: 10.1111 / cts.13786.

[0593] McRae MP, Kittelson J, Helmke SM, Everson GT. Advances in noninvasive measurement of liver function and physiology: The HepQuant DuO test. Basic Clin Pharmacol Toxicol. 2024;134(3):385-395. doi: 10.1111 / bcpt.13980.

[0594] Helmke SM, McRae MP, Christians U. Shokati T, Everson GT. A Validated LC-MS / MS Assay for the Quantification of Cholate Isotopes in Human Serum. J Appl Lab Med.2024;9(6): 1028-1039. doi:10.1093 / jalm / jfae094.Attorney Docket No. 156883.617393

[0595] McRae MP, Helmke SM, Burton JR, Jr., Everson GT. Compartmental model describing the physiological basis for the HepQuant SHUNT test. Transl Res. 2023;252:53-63. doi: 10.1016 / j.trsl.2022.08.002.

[0596] Hassanein T, Keaveny AP, Mantry P. et al. Liver function and portal-systemic shunting quantified by the oral cholate challenge test and risk for large oesophageal varices. Aliment Pharmacol Ther. 2024;60(2):246-256. doi: 10.1111 / apt.18054.

[0597] Shiffman M, Reddy KR, Leise MD, et al. Cholate Shunt, Oral Cholate Challenge and Endoscopic Lesions of Portal Hypertension: The SHUNT-V Study. Aliment Pharmacol Ther. 2025;61(l):75-87. doi: 10.1111 / apt.18386.

[0598] Kittelson J, McRae MP, Everson GT. Measuring the risk of clinical adverse events (RISK ACE) by quantifying liver function: A patient-centric model. Eur J Intern Med. 2024;132:160-163. doi:10.1016 / j.ejim.2024.1 1.029.

[0599] Kokkorakis M, Boutari C, Hill MA, et al. Resmetirom, the first approved drug for the management of metabolic dysfunction-associated steatohepatitis: Trials, opportunities, and challenges. Metab Clin Exp. 2024;154doi:10.1016 / j.metabol.2024.155835.

[0600] Harrison SA, Taub R, Neff GW, et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nature Medicine. 2023 / 11 / 01 2023;29(ll):2919-2928. doi:10.1038 / s41591-023-02603-l.

[0601] Harrison Stephen A, Bedossa P, Guy Cynthia D, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024 / 02 / 07 2024;390(6):497-509. doi:10.1056 / NEJMoa2309000.Attorney Docket No. 156883.617393

[0602] Harrison SA, Bashir MR, Guy CD, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394(10213):2012-2024. doi:10.1016 / S0140-6736(19)32517-6.

[0603] Harrison SA, Ratziu V, Anstee QM, et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Then 2024;59(l):51-63. doi: 10.1111 / apt.17734.

[0604] Shiffman M, Reddy KR, Liese MD, et al. Cholate Shunt, Oral Cholate Challenge, and Endoscopic Lesions of Portal Hypertension: The SHUNT-V Study. Aliment Pharmacol Then 2024;in pressdoi: 10.1111 / apt.18386.

[0605] Helmke S, Kittelson J, Imperial JC, McRae MP, Everson GT. The Oral Cholate Challenge Test Quantifies Risk for Liver-Related Clinical Outcomes in Primary Sclerosing Cholangitis. Gastro Hep Advances. 2024;3(7):944-953. doi:10.1016 / j.gastha.2024.07.005.

[0606] Burton JR, Helmke S, Lauriski S, Kittelson J, Everson GT. The within-individual reproducibility of the disease severity index from the HepQuant SHUNT test of liver function and physiology. Transl Res. 2021;233:5-15. doi:10.1016 / j.trsl.2020.12.010.

[0607] Fallahzadeh MA, Hansen DJ, Trotter JF, et al. Predicting clinical decompensation in patients with cirrhosis using the HepQuant SHUNT test. Aliment Pharmacol Then 2021;53(8):928-938. doi: 10.1111 / apt.16283.

[0608] Everson GT, Shiffman ML, Hoefs JC, et al. Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: Results from the hepatitis C antiviral longterm treatment against cirrhosis trial. Hepatology. 2012;55(4): 1019-1029. doi:10.1002 / hep.24752.Attorney Docket No. 156883.617393

[0609] Pallmann P, Bedding AW, Choodari-Oskooei B, et al. Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Med. 2018 / 02 / 28 2018;16(l):29.doi:10.1186 / sl2916-018-1017-7.

[0610] Example 14: Effects of Resmetirom at 52 Weeks in Patients with Metabolic-Dysfunction Associated Steatohepatitis as a Function of Weight Loss or Co-dosing with Glucagon-Like Peptide-1 Receptor Agonists or Sodium-Glucose Cotransporter 2 Inhibitor Therapies

[0611] Abstract

[0612] Background'. MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of resmetirom in patients with b4. No biopsy-confirmed metabolic-dysfunction associated steatohepatitis (MASH) and fibrosis, which achieved both primary endpoints of MASH resolution with no worsening of fibrosis, and >1 -stage improvement in fibrosis with no worsening of MASH at the 52-weeks primary efficacy analysis.

[0613] Aims: The effects of resmetirom (80 or 100 mg) versus placebo were evaluated on Week 52 histological endpoints in patients taking sodium-glucose cotransporter 2 inhibitors, GLP-1 receptor agonists (GLP1-RA) and / or those achieving >5% weight loss.

[0614] Methods: At baseline, 13-17% of b4. No biopsy confirmed FIB, F2, F3 MASH patients (all with T2DM) in the resmetirom treatment groups were on stable GLP-1 RA (doses approved for type 2 diabetes mellitus, for >6 months prior to baseline) or SGLT2i (>30 days prior to baseline) therapy. Changes in liver histology7and MRI-proton density7fat fraction (MRI-PDFF) were examined after 52-weeks of resmetirom or placebo treatment.Attorney Docket No. 156883.617393

[0615] Results'. No additional weight loss above baseline occurred with GLP-1 RA therapy. SGLT2 and GLP-1 RA treated patients with diabetes showed similar rates of MASH resolution and fibrosis improvement in combination with resmetirom as patients with diabetes not on these therapies. In resmetirom-treated patients, weight loss (>5%) compared with weight loss <5% was associated with higher rates of MASH resolution (50-58%), fibrosis improvement (39-42%) and MRI-PDFF reduction (91-98% with >30% PDFF reduction).

[0616] Conclusions'. The efficacy of resmetirom on both histological endpoints was not impacted by background SGLT2i or GLP-1 RA treatment. Small amounts of w eight loss (>5%) enhanced the efficacy of resmetirom.

[0617] Clinical Trial Registration: NCT03900429

[0618] INTRODUCTION

[0619] Metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) is the active, progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty7liver disease [NAFLD]), defined as the presence of 5% or more hepatic steatosis with inflammation and hepatocyte injury (e.g. ballooning), with or without fibrosis. MASH is associated with increased cardiovascular risk, including cardiovascular death. MASH patients with more advanced fibrosis additionally have increased liver related morbidity7and mortality,, especially7in the setting of cirrhosis, where the development of hepatocellular carcinoma, and liver decompensation result in a common indication for liver transplantation. MASH imparts a significant economic burden on the healthcare system, with an estimated 6.65 million patients with MASH in the United States alone. The number of cases of MASHAttorney Docket No. 156883.617393 with clinically significant fibrosis in the United States are expected to increase 11.7 million by 2050.

[0620] Thyroid hormone receptor (THR)-(3 which is preferentially expressed in the liver relative to THR-α mediates beneficial actions in MASH such as de-lipidation of the liver, improvement in hepatic mitochondrial function and biogenesis, and reduction of liver inflammation and fibrosis. Resmetirom, a liver-directed THR-β selective agonist, was approved by the Food and Drug Administration according to subpart H criteria for the treatment of adults with MASH with moderate to advanced liver fibrosis (consistent with F2-F3) based on the resolution of MASH and improvement in liver fibrosis at Week 52 in the MAESTRO-NASH trial. Phase 1, 2, and 3 trials with resmetirom have demonstrated reduction of hepatic and / or circulating lipids in healthy volunteers, familial hypercholesterolemia, MASLD, and patients with MASH. These studies have demonstrated resmetirom’ s safety and that selectivity for THR- and liver targeting led to the absence of toxicities on heart and bone associated with THR-α.

[0621] Glucagon-like peptide- 1 (GLP-1) receptor agonists (RA) such as liraglutide and semaglutide, and other GLP-1 RA combinations (e.g. with glucose-dependent insulinoptropic polypeptide or glucagon receptor agonists) have been investigated in phase 2 trials with positive effects in patients with MASH and fibrosis. Semaglutide recently showed improvements in both resolution of steatohepatitis and fibrosis reduction in a phase 3 trial. Since GLP-1 receptors are not expressed in liver, the potential mechanism of action in MASH relates to indirect actions to reduce body weight, insulin resistance, and metabolic dysfunction. Beneficial effects of weight loss through lifestyle modification on biomarkers and histology' have been shown across the spectrum of MASLD / MASH.Attorney Docket No. 156883.617393

[0622] In this randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of resmetirom in patients with b4. No biopsy-confirmed MASH and fibrosis, a pre-specified analysis of the effects of resmetirom (80 or 100 mg) or placebo on a background of stable GLP-1 baseline therapy (at least 6 months prior to randomization) and the effect of >5% weight loss on liver histology endpoints with or without GLP-1 baseline therapy were evaluated. The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) were also examined.

[0623] METHODS

[0624] Clinical Trial Information

[0625] This study used liver b4. No biopsy samples from the Phase 3, double-blinded, randomized, placebo-controlled MAESTRO-NASH trial (NCT03900429) in adults with b4. No biopsy-confirmed MASH and the primary7analysis population that included 966 patients with statistical analysis plan defined baseline fibrosis stage of FIB, F2, or F3 based on central pathologist scoring from two readers. The design, eligibility' criteria, and results have been reported elsewhere. Of the 966 randomized patients, 647 had type 2 diabetes mellitus (T2DM) and 319 did not. Weight was required to be stable (<5% change in 3 months), and doses of GLP-1 RA were required to be stable for at least 6 months prior to eligibility b4. No biopsy. All patients on GLP-1 RA or SGLT2i were on doses approved for T2DM during the conduct of the trial. The study population is shown in FIG. 62.

[0626] Statistical Analysis

[0627] Descriptive statistics (percentage, mean with standard deviation [SD], median[Ql, Q3], least squared [LS] means with 95% confidence intervals [CI]) were provided to summarize data. A mediation analysis was conducted to separate the contributions of percentAttorney Docket No. 156883.617393 change in weight at Week 52 (an indirect effect) and study treatment (a direct effect) for NASH resolution and Fibrosis Improvement. Odds ratios and 95% confidence intervals were estimated for direct and indirect factors and their combined effect using the logistic regression method described by Samoilenko et al. using the R package, 'ExactMed'. Baseline characteristics are shown for primary population. All other data are shown for the paired b4. No biopsy population.

[0628] RESULTS

[0629] Patients

[0630] The demographic and clinical characteristics of randomized patients (n=966) at baseline according to T2DM and GLP-1 RA / SGLT2i use are shown in Table 5 above. At baseline, 13-17% of patients (all of which had T2DM) in the treatment groups were on stable (for >6 months prior to eligibility b4. No biopsy) T2DM doses of GLP-1 RA (80 mg resmetirom, n=54; 100 mg resmetirom, n=41; placebo, n=42). The most common dose were various doses of liraglutide (-15%); 0.5 to 1 mg semaglutide (-one fourth), 0.75 to 1.5 mg dulaglutide (~ one third). Other T2DM therapies associated with weight loss allow ed in the study included 11-17% of patients on SGLT2i (80 mg resmetirom, n=55; 100 mg resmetirom, n=39; placebo, n=36), with stable treatment (no change in SGLT2i dose >30 days before randomization). In the randomized population, 39 patients were on both a GLP-1 RA and SGLT2i, 34 of w hom had biopsies at Week 52 (B4. No biopsy completers). At baseline, patients on GLP-1 RA or SGLT2i therapy had a higher percentage of F3 patients (67.9 or 67.7 versus 52.7%) with more metabolic (HbAlc: 7.1 or 7.2 versus 5.7%) and cardiovascular features (hypertension: 84.7 or 87.7 versus 67.4%, dyslipidemia: 85.4 or 84.6 versus 54.2%), more common statin use (61.3 or 66.2 versus 30.4%), and, at baseline, lower LDL-C and liver enzymes (ALT: 45.6 or 48.3 versus 62.1 U / L, AST: 34.3 or 34.7 versus 45.7 U / L) thanAttorney Docket No. 156883.617393 non-diabetic patients. There were no differences in baseline body weight (103.7 versus 99.7 kg) or MRI-PDFF (16.5 versus 16.1%), and no meaningful differences in other baseline characteristics between patients on GLP-1 RA or SGLT2i therapy.

[0631] Effects of T2DM treatments on Week 52 histology and MRI-PDFF endpoints

[0632] B4. No biopsy completers were described; an intention-to-treat analysis in which patients with missing Week 52 biopsies were considered non-responders showed consistent relative responses and did not demonstrate an increase in discontinuations in any group. In the 80 and 100 mg resmetirom groups, respectively, patients on GLP-1 RA (n=81) had 26.5% (placebo-corrected %difference [95% CI]. 16.9% [1.9%, 31.9%]) and 39.1% (30.5% [12.8%, 48.3%] response rates for MASH resolution (FIG. 11. upper left hand side. Table 22) compared to resmetirom patients not on GLP-1 RA (n=261), 32.0% (21.3% [12.4%, 30.1%]) and 37.9% (28.3% [19.4%, 37.3%]). Resmetirom patients on GLP-1 RA had 28.6% (18.5% [3.8%, 33.2%]) and 20.3% (10.5% [-4.2%, 25.2%)]) response rates for fibrosis improvement compared to resmetirom patients not on GLP-1 RA 28.9% (14.9% [6.1%, 23.7%] and 31.6% (17.6% [8.8%, 26.4%], FIG. 11, upper right hand side). In the 80 and 100 mg resmetirom groups, respectively, patients on SGLT2i (n=77) had 36.2% (24.3% [6.0%, 42.5%]) and 43.3% (31.1% [11.6%. 50.6%]) response rates for MASH resolution compared to resmetirom patients not on SGLT2i (n=265), 28.5% (18.5% [10.1%, 26.8%]) and 36.9% (28.4% [19.7%, 37.2%], FIG. 11, lower left hand side, Table 23). Resmetirom patients on SGLT2i had 22.3% (3.3% [-13.0%, 19.7%]) and 28.3% (9.2% [-9.1%, 27.5%]) response rates for fibrosis improvement compared to resmetirom patients not on SGLT2i 31.1% (19.3% [10.8%, 27.7%]) and 29.6% (18.1% [9.8%, 26.4%], FIG. 11, lower righthand side). In the 80 and 100 mg resmetirom groups, respectively, patients on insulin (n=93) compared to those not on insulin (n=425) had somewhat lower response rates for MASH resolution (15.6% and 28.1%Attorney Docket No. 156883.617393versus 33.7% and 40.6%) and fibrosis improvement (20.3% and 25.0% versus 30.7% and 30.5%, Table 24).Table 22: Histological responses in T2DM patients on or not on GLP-1 RA at Week 52Enrolled Patients^ — Patients with Diabetes at BaselineGLP-1 RA No GLP-1 RARes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=5 (n=4 (n=4 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 4) 1) 2) (95% CI) (95% CI) 70) 72) 68) (95% CI) (95% CI) MASH 24.1 30.5 7.1 23.0 (7.5, 25.0 28.2 9.2 16.1 (8.7, 19.9 (12.6, resolution (% 38.5) 23.4) 27.2) response)Fibrosis 25.9 15.9 8.3 17.2 (3.6, 7.2 (-5.6, 22.6 23.5 11.6 11.1 (3.8, 12.0 (4.9, response (% 30.9) 20.0) 18.4) 19.2) response)MRI-PDFF -28.0 -47.5 -8.9 -19.1 -38.6 -34.3 -48.0 -6.5 -27.8 -41.5 (LS mean % (-40.0, (-60.1, - (-36.3, - (-50.2, - change from 1.9) 17.1) 19.3) 32.8) BL)n 39 29 27 124 114 117Liver B4. No biopsy Completers - Patients with Diabetes at BaselineGLP-1 RA No GLP-1 RARes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=4 (n=3 (n=3 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 9) 2) 8) (95% CI) (95% CI) 33) 28) 38) (95% CI) (95% CI) MASH 26.5 39.1 7.9 16.9 30.5 32.0 37.9 11.2 21.3 28.3 resolution (% (1.9, 31.9) (12.8, (12.4, (19.4, response) 48.3) 30.1) 37.3) Fibrosis 28.6 20.3 9.2 18.5 10.5 28.9 31.6 14.1 14.9 17.6 response (% (3.8, 33.2) (-4.2, 25.2) (6.1, 23.7) (8.8, 26.4) response)MRI-PDFF -26.0 -48.8 -8.4 -17.6 -40.4 -37.6 -49.8 -6.5 -31.1 -43.2 (LS mean % (-38.6, (-62.2, - (-39.7, - (-52.0, - change from 3.5) 18.5) 22.5) 34.5) BL)n 36 28 27 111 106 107f Randomized F1B / F2 / F3 patients (n=966)Table 23: Histological responses in T2DM patients on or not on SGLT2i at Week 52Attorney Docket No. 156883.617393Enrolled Patients† – Patients with Diabetes at BaselineSGLT2i No SGLT2iRes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=5 (n=3 (n=3 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 5) 9) 6) (95% CI) (95% CI) 69) 74) 74) (95% CI) (95% CI) MASH 30.9 33.3 11.1 20.0 (3.6, 22.2 (5.4, 22.8 27.6 8.3 14.5 (7.5, 20.0 (12.8, resolution (% 36.4) 39.0) 21.4) 27.1) response)Fibrosis 19.1 21.8 16.7 2.2 (-12.4, 5.2 (-10.7, 24.9 22.1 9.8 15.1 (8.0, 12.5 (5.7, response (% 16.8) 21.0) 22.2) 19.3) response)MRI-PDFF -29.0 -46.7 -5.8 -23.2 -40.9 -34.7 -48.4 -7.1 -27.6 -41.4 (LS mean % (-41.1, - (-61.3, - (-36.4, - (-50.2, - change from 5.3) 20.5) 18.8) 32.5) BL)n 42 24 28 121 119 116Liver B4. No biopsy Completers - Patients with Diabetes at BaselineSGLT2i No SGLT2iRes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=4 (n=3 (n=3 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 7) 0) 2) (95% CI) (95% CI) 35) 30) 44) (95% CI) (95% CI) MASH 36.2 43.3 12.5 24.3 (6.0, 31.1 (11.6, 28.5 36.9 10.1 18.5 28.4 (19.7, resolution (% 42.5) 50.6) (10.1, 37.2) response) 26.8) Fibrosis 22.3 28.3 18.8 3.3 (-13.0, 9.2 (-9.1, 31.1 29.6 11.8 19.3 18.1 (9.8, response (% 19.7) 27.5) (10.8, 26.4) response) 27.7)MRI-PDFF -31.0 -48.4 -6.3 -24.7 -42.1 -36.4 -50.0 -7.0 -29.4 -43.1 (LS mean % (-42.8, - (-62.8, - (-38.4, - (-52.1, - change from 6.5) 21.5) 20.4) 34.1) BL)n 40 23 27 107 111 107†Randomized F1B / F2 / F3 patients (n=966)Table 24: Histological responses in T2DM patients on or not on insulin at Week 52Enrolled Population† – Patients with Diabetes at BaselineInsulin No InsulinRes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=4 (n=4 (n=3 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 0) 1) 7) (95% CI) (95% CI) 84) 72) 73) (95% CI) (95% CI) MASH 12.5 22.0 6.8 9.2 (-4.7, 20.5 (5.3, 27.4 30.2 9.2 18.2 21.1 (13.6, resolution (% 23.1) 35.7) (10.8, 28.5)response) 25.5)Attorney Docket No. 156883.617393Fibrosis 16.3 19.5 10.8 4.1 (-9.4, 6.5 (-8.8, 25.0 22.7 11.0 13.9 (6.7, 11.7 (4.7, response (% 17.7) 21.7) 21.2) 18.6) response)MRI-PDFF -25.6 -38.2 -4.6 -21.0 -33.6 -34.9 -50.4 -7.2 -27.7 -43.2 (LS mean % (-38.9, - (-51.4, - (-36.5, - (-52.4, - change from 3.1) 15.7) 18.9) 34.0) BL)tn 26 28 26 137 115 118Liver B4. No biopsy Completers - Patients with Diabetes at BaselineInsulin No InsulinRes Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=3 (n=3 (n=2 and Pbo and Pbo (n=1 (n=1 (n=1 and Pbo and Pbo 2) 2) 9) (95% CI) (95% CI) 50) 28) 47) (95% CI) (95% CI) MASH 15.6 28.1 8.6 11.3 (-5.4, 23.4 (5.4, 33.7 40.6 10.9 22.7 30.6 (21.7, resolution (% 27.9) 41.4) (14.2, 39.5) response) 31.3)Fibrosis 20.3 25.0 13.8 4.6 (-11.7, 7.6 (-10.4, 30.7 30.5 12.9 17.6 (9.2, 17.7 (9.3, response (% 20.9) 25.6) 26.1) 26.1) response)MRI-PDFF -26.1 -43.3 -4.1 -22.0 -39.1 -36.6 -51.0 -7.1 -29.4 -43.9 (LS mean % (-41.0, - (-58.0, - (-38.3, - (-53.1, - change from 2.9) 20.3) 20.5) 34.7) BL)n 24 27 22 123 107 112f Randomized F1B / F2 / F3 patients (n=966)

[0633] Resmetirom’s fibrosis and MASH responses on b4. No biopsy correlate with MRI-PDFF reduction. Comparison of resmetirom’s efficacy to decrease MRI-PDFF in non-diabetics versus T2DM patients, T2DM patients on or not on either GLP-1 RA, SGLT2i, or insulin showed that similar decreases in MRI-PDFF are observed in all comparisons (Fig. 12, Table 25).Table 25: Week 52 MRI-PDFF percent change from baseline in different patient subgroups. Data are presented as median (Q1, Q3)Resmetirom (80 mg) Resmetirom (100 mg) Placebo Group / Subgroup N Median (Q1, N Median (Q1, N Median (Q1,Q3) Q3) Q3) All Patients 210 -42 (-62, -20) 207 -52 (-67, -27) 218 -10 (-28, 10) No T2DM 63 -45 (-63, -25) 73 -51 (-68, -22) 84 -11 (-24, 8) T2DM 147 -41 (-62, -15) 134 -53 (-67, -29) 134 -9 (-31, 11) GLP-1 RA 36 -35 (-55, -14) 28 -53 (-64, -33) 27 -10 (-38, 4) No GLP-1 RA 111 -43 (-63, -17) 106 -53 (-68, -27) 107 -8 (-29, 13) SGLT2i 40 -37 (-58, -10) 23 -53 (-64, -18) 27 -4 (-29, 34) No SGLT2i 107 -41 (-62, -20) 111 -54 (-68, -29) 107 -9 (-33, 10) Insulin 24 -26 (-49, -2) 27 -36 (-60, -25) 22 -11 (-34, 9)Attorney Docket No. 156883.617393 [" No Insulin I 123 | -43 (-62, -20) | 107 | -56 (-69, -31) | 112 | -8 (-30, 12) |

[0634] Safety and tolerability evaluated in patients according to GLP-1 RA therapy

[0635] No notable differences in safety and tolerability were observed. Expected gastrointestinal adverse events such as diarrhea and nausea were generally higher in the resmetirom groups independent of GLP-1 RA use (Table 26).Table 26: Summary of treatment-emergent adverse events (TEAEs) by GLP-1 RA use at baseline (safety population – F1B, F2, F3)GLP-1 No GLP-1MGL- MGL- MGL- MGL- 3196 3196 3196 319680 mg 100 mg Placebo 80 mg 100 mg Placebo Event (n=54) (n=41) (n=42) (n=268) (n=282) (n=279) SAFETY, n (%)Any TEAE 50 (92.6) 40 (97.6) 41 (97.6) 246 (91.8) 256 (90.8) 257 (92.1) Any serious TEAE 3 (5.6) 4 (9.8) 6 (14.3) 32 (11.9) 37 (13.1) 31 (11.1) Maximum severity of TEAEsGrade 1 14 (25.9) 9 (22.0) 7 (16.7) 59 (22.0) 57 (20.2) 70 (25.1) Grade 2 32 (59.3) 27 (65.9) 25 (59.5) 148 (55.2) 156 (55.3) 144 (51.6) Grade 3 4 (7.4) 4 (9.8) 6 (14.3) 37 (13.8) 39 (13.8) 39 (14.0)TEAEs >5% IN OVERALLFREQUENCY, n (%)Diarrhoea 9 (16.7) 20 (48.8) 7 (16.7) 78 (29.1) 88 (31.2) 44 (15.8) COVID-19 12 (22.2) 10 (24.4) 9 (21.4) 57 (21.3) 44 (15.6) 58 (20.8) Nausea 14 (25.9) 10 (24.4) 7 (16.7) 57 (21.3) 51 (18.1) 33 (11.8) Arthralgia 6 (11.1) 4 (9.8) 7 (16.7) 42 (15.7) 31 (11.0) 33 (11.8) Vomiting 5 (9.3) 7 (17.1) 5 (11.9) 23 (8.6) 28 (9.9) 12 (4.3) Constipation 6 (11.1) 3 (7.3) 5 (11.9) 15 (5.6) 25 (8.9) 12 (4.3) Abdominal pain upper 2 (3.7) 9 (22.0) 2 (4.8) 21 (7.8) 18 (6.4) 27 (9.7) Pruritus 5 (9.3) 2 (4.9) 6 (14.3) 21 (7.8) 35 (12.4) 16 (5.7) Fatigue 5 (9.3) 5 (12.2) 2 (4.8) 28 (10.4) 21 (7.4) 26 (9.3) Abdominal pain 4 (7.4) 3 (7.3) 4 (9.5) 22 (8.2) 26 (9.2) 14 (5.0) Urinary tract infection 5 (9.3) 3 (7.3) 3 (7.1 ) 28 (10.4) 24 (8.5) 25 (9.0) Headache 4 (7.4) 3 (7.3) 3 (7.1) 26 (9.7) 22 (7.8) 25 (9.0) Nasopharyngitis 4 (7.4) 3 (7.3) 3 (7.1) 10 (3.7) 17 (6.0) 11 (3.9)Osteopenia 2 (3.7) 3 (7.3) 5 (11.9) 5 (1.9) 1 (0.4) 3 (1.1)Attorney Docket No. 156883.617393GLP-1 No GLP-1MGL- MGL- MGL- MGL- 3196 3196 3196 319680 mg 100 mg Placebo 80 mg 100 mg Placebo Event (n=54) (n=41) (n=42) (n=268) (n=282) (n=279) Hypertension 2 (3.7) 2 (4.9) 4 (9.5) 14 (5.2) 11 (3.9) 21 (7.5) Muscle spasms 1 (1.9) 3 (7.3) 4 (9.5) 13 (4.9) 19 (6.7) 18 (6.5) Upper respiratory tract infection 1 (1.9) 2 (4.9) 5 (11.9) 22 (8.2) 6 (2.1) 12 (4.3) Abdominal distension 4 (7.4) 0 3 (7.1) 10 (3.7) 13 (4.6) 14 (5.0) Back pain 4 (7.4) 0 3 (7.1) 31 (11.6) 27 (9.6) 35 (12.5) Cough 4 (7.4) 1 (2.4) 2 (4.8) 10 (3.7) 17 (6.0) 10 (3.6) Rash 2 (3.7) 2 (4.9) 3 (7.1) 10 (3.7) 19 (6.7) 9 (3.2) Pain in extremity 0 1 (2.4) 4 (9.5) 12 (4.5) 11 (3.9) 19 (6.8)Dizziness 1 (1.9) 0 2 (4.8) 19 (7.1) 19 (6.7) 9 (3.2)

[0636] Impact of weight loss on Week 52 histology, MRI-PDFF, and VCTE endpoints

[0637] Weight loss has been shown to improve responses on liver b4. No biopsy in patients with MASH including patients treated with resmetirom. Reflecting that GLP-1 RA therapy was stable (at least 6 months), the percentage of patients on GLP-1 RA treatment in MAESTRO-NASH with >5% (14%) and <5% (16%) weight loss was equivalent. Week 52 median body weight changes in patients on GLP-1 RA were -1.8%, -1.5%, and -1.9% in placebo, 80 mg, and 100 mg, respectively. Week 52 median body weight changes in patients on SGLT2i were -1.9%, -0.5%, and -2.3% in placebo, 80 mg, and 100 mg, respectively.

[0638] The numbers of patients who lost >5% weight in the study according to treatment were evaluated. The percentage of patients achieving >5% weight loss in the placebo, 80 mg, and 100 mg of resmetirom groups were 12.7% (35 of 276), 17.1% (44 of 258), and 21.4% (53 of 248), respectively. The median weight loss was 7% in the >5% weight loss groups.

[0639] In the 80 and 100 mg resmetirom groups, respectively, patients achieving >5% weight loss had 50.0% (placebo-corrected %difference [95%CI], 22.0% [2.9%, 41.2%]) and 56.6% (28.4% [10.3%. 46.5%]) response rates for MASH resolution (FIG. 13, left hand side,Attorney Docket No. 156883.617393Table 27) compared to resmetirom patients with <5% weight loss who had 27.6% (20.4% [14.1%, 26.7%]) and 33.8% (26.5% [20.1%, 32.9] %) response rates for MASH resolution (FIG. 13, right hand side). In the 80 and 100 mg resmetirom groups, respectively, patients achieving >5% weight loss had 38.6% (11.2% [-6.8%, 29.1%]) and 40.6% (12.0% [-5.0%, 29.0%]) response rates for fibrosis improvement compared to patients with <5% weight loss who had 27.6% (13.0% [6.3%, 19.7%]) and 31.5% (16.7% [9.9%, 23.5%]) response rates for fibrosis improvement. Achieving >5% weight loss in the placebo group resulted in 31.4% and 27.1% response rates for MASH resolution and fibrosis improvement, respectively, compared to placebo patients with <5% weight loss resulted who had 7.9% and 14.9% response rates for MASH resolution and fibrosis improvement, respectively. A mediation analysis revealed that the percent change in weight at Week 52 does not contribute to the benefits of resmetirom relative to placebo on MASH resolution (odds ratio [95% CI], 1.08 [1.00, 1.17]) or fibrosis improvement (1.04 [0.99, 1.09], FIG. 63 and Table 28). Both doses of resmetirom maintained favorable differences on MASH resolution and fibrosis improvement with <5% weight gain (Table 29). The small numbers of patients with >5% weight gain precluded an assessment; however the 100 mg dose appeared to maintain a difference from placebo for MASH and fibrosis improvement.Table 27: Histological responses and the percentage of patients achieving >30% or >50% relative reductions in MRI-PDFF in patients with or without >5% weight loss at Week 52Enrolled Patients’! - Patients with Diabetes at Baseline>5% Weight Loss from Baseline <5% Weight Loss from Baseline Res Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=4 (n=5 (n=3 and Pbo and Pbo (n=2 (n=2 (n=2 and Pbo and Pbo 7) 7) 6) (95% CI) (95% CI) 29) 10) 48) (95% CI) (95% CI) MASH 46.8 52.6 30.6 17.9 (-0.7, 24.6 (6.9, 25.5 31.4 7.7 18.6 24.3 (18.2, resolution (% 36.5) 42.3) (12.6, 30.4)response) 24.6)Attorney Docket No. 156883.617393Fibrosis 36.2 37.7 26.4 9.1 (-8.2, 9.8 (-6.6, 25.5 29.3 14.3 11.4 (5.1, 15.0 (8.5, response (% 26.4) 26.2) 17.8) 21.5) response)Liver B4. No biopsy Completers - Patients with Diabetes at Baseline>5% Weight Loss from Baseline <5% Weight Loss from Baseline Res Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg 100 mg (n=4 (n=5 (n=3 and Pbo and Pbo (n=2 (n=l (n=2 and Pbo and Pbo 4) 3) 5) (95% CI) (95% CI) 12) 95) 39) (95% CI) (95% CI) MASH 50.0 56.6 31.4 22.0 (2.9, 28.4 (10.3, 27.6 33.8 7.9 20.4 26.5 (20.1, resolution (% 41.2) 46.5) (14.1, 32.9) response) 26.7) Fibrosis 38.6 40.6 27.1 11.2 (-6.8, 12.0 (-5.0, 27.6 31.5 14.9 13.0 (6.3, 16.7 (9.9, response (% 29.1) 29.0) 19.7) 23.5) response)n 33 41 27 177 166 190≥30% 90.9 97.6 55.6 9.6 (1.9, 17.1 (2.5, 57.6 66.9 19.5 5.7 (3.5, 8.2 (5.1, relative 47.9) 118.4) 9.1) 13.4) reduction inMRI-PDFF(% n)≥50% 72.7 87.8 37.0 5.8 (1.8, 12.5 (3.4, 35.0 46.4 4.2 14.1 (6.2, 20.4 (9.2, relative 19.4) 46.8) 32.1) 45.3) reduction inMRI-PDFF(% n)f Randomized F1B / F2 / F3 patients (n=966)Table 28: Mediation analysis of the impact of percent change in weight at Week 52 on MASH resolution and fibrosis improvement comparing resmetirom (combined doses) to placebo treatment. N=777. five subjects (two in 80 mg resmetirom and three in placebo) were missing Week 52 body weight dataResmetirom Nominal P-ValueCompared toPlaceboEffect on MASH Resolution OR (95% CI)Weight Loss Independent 4.64 (2.95, 7.31) <0.0001Weight Loss Dependent 1.07 (0.99, 1.15) 0.0762Total Effect 4.97 (3.14, 7.86) <0.0001Effect on Fibrosis ImprovementWeight Loss Independent 2.67 (1.81, 3.93) <0.0001Weight Loss Dependent 1.03 (0.99, 1.07) 0.1340Total Effect 2.76 (1.87, 4.06) <0.0001OR = odds ratio, CI = confidence intervalTable 29: Histological responses in patients with or without >5% weight gain at Week 52Attorney Docket No. 156883.617393>5% Weight Gain from Baseline <5% Weight Gain from Baseline Res Res % Diff % Diff Res Res % Diff % Diff 80 100 Res Res 80 100 Res Res mg mg Pbo 80 mg 100 mg mg mg Pbo 80 mg and 100 mg (n=1 (n=1 (n=1 and Pbo and Pbo (n=2 (n=2 (n=2 Pbo and Pbo 7) 8) 1) (95% CI) (95% CI) 39) 30) 63) (95% CI) (95% CI) MASH 29.4 36.1 22.7 8.9 (-17.7, 12.8 (- 31.6 38.9 10.5 21.6 (15.2, 29.6 (23.0, resolution (% 35.5) 11.4, 37.0) 28.0) 36.2) response)Fibrosis 17.6 38.9 22.7 -2.7 (- 14.5 (- 30.3 33.0 16.2 14.5 (8.0, 17.0 (10.4, response (% 27.3, 10.6, 39.6) 21.1) 23.5)response) 21.9)

[0640] Both doses of resmetirom elicited reductions in MRI-PDFF relative to placebo. independent of weight loss (Table 30). Patients achieving >5% weight loss showed additional reductions in MRI-PDFF between Weeks 16 and 52 irrespective of treatment (FIG. 14, 1stto the left hand side, Table 30), whereas patients who achieved <5% weight loss showed no further reductions in MRI-PDFF at Week 52 compared with Week 16 in any treatment groups (FIG. 14. 3ldto the left hand side). In the resmetirom groups, 90.9 and 97.7% of patients (40 of 44 and 52 of 53 patients in the 80 mg and 100 mg groups, respectively) who achieved >5% weight loss had a >30% reduction in MRI-PDFF (FIG. 14, second to the left hand side). In the resmetirom groups, 72.7-87.8% of patients (32 of 44 and 47 of 53 patients in the 80 mg and 100 mg groups, respectively) who achieved >5% weight loss had a >50% reduction in MRI-PDFF (Table 27) by Week 52.Table 30: Weeks 16 and 52 MRI-PDFF percent change from baseline in patients with or without >5% weight loss at Week 52. Data are presented as median (Q1, Q3).Resmetirom (80 mg) Resmetirom (100 mg) Placebo ≥5% Weight Loss at N Median (Q1, Q3) N Median (Q1, Q3) N Median (Q1, Q3) Week 52Week 16 32 -48 (-68, -28) 39 -52 (-67, -37) 27 -12 (-30, -5) Week 52 33 -64 (-76, -45) 41 -69 (-85, -56) 27 -42 (-60, -9)Resmetirom (80 mg) Resmetirom (100 mg) Placebo <5% Weight Loss at N Median (QI, Q3) N Median (QI, Q3) N Median (QI, Q3) Week 52Week 16 160 -37 (-55, -22) 147 -43 (-57, -22) 174 -6 (-19, 11)Week 52 177 -36 (-58, -14) 166 -46 (-63, -21) 190 -8 (-24, 11)Attorney Docket No. 156883.617393

[0641] Both doses of resmetirom elicited reductions in liver stiffness measurements (VCTE) relative to placebo, independent of weight loss, but percentages with reductions were greater in patients who achieved >5% weight loss (FIG. 64A, Table 31). A responder analysis for patients achieving >5% weight loss showed that 43.9% (18 of 41 patients), 64.7% (33 of 51 patients) and 54.5% (18 of 33 patients) in the 80 mg resmetirom, 100 mg resmetirom, and placebo groups, respectively, achieved a 25% reduction in VCTE (FIG. 64B). For patients achieving <5% weight loss, 43.9% (86 of 196 patients), 44.8% (82 of 183 patients), and 25.3% (56 of 221 patients) in the 80 mg resmetirom, 100 mg resmetirom, and placebo groups, respectively, achieved a 25% reduction in VCTE.Table 31: Summary of Fibroscan VCTE results for patients with or without >5% weight loss at Week 52>5% Weight Loss at Week 52 Resmetirom (80 mg) Resmetirom (100 mg) Placebo Mean (SD) Baseline (kPa) 13.3 (6.4) 14.6 (9.9) 12.1 (3.8) Mean CFB† (SEM) -3.0 (0.9) -6.1 (1.1) -3.5 (0.6) Median CFB (Q1, Q3) -1.9 (-6.5, 0.0) -4.6 (-7.5, -2.0) -2.6 (-4.5, -1.6) <5% Weight Loss at Week 52 Resmetirom (80 mg) Resmetirom (100 mg) Placebo Mean (SD) Baseline (kPa) 13.4 (6.2) 13.2 (6.8) 12.7 (4.9) Mean CFB (SEM) -2.1 (0.4) -2.4 (0.5) -0.5 (0.3)Median CFB (Q1, Q3) -2.2 (-4.9, 0.7) -2.3 (-3.0, 1.8) -0.7 (-3.0, 1.8) fCFB - change from baseline

[0642] DISCUSSION

[0643] In MAESTRO-NASH, 67% of patients had T2DM, 21 % and 20% of which were on stable treatment with GLP-1 RA (for >6 months prior to randomization) or SGLT2i drugs (no change in dose >30 days before randomization), respectively. Consistent with baseline characteristics in our study, about 2 / 3 of patients with b4. No biopsy-confirmed MASH with moderate to advanced liver fibrosis have T2DM. Once MASH progressed to clinically significant fibrosis (stages F2 and F3). the risk of adverse clinical outcomes markedly increased, especially among patients with T2DM. In MAESTRO-NASH, 21% of T2DMAttorney Docket No. 156883.617393 patients were on stable (>6 months) GLP-1 RA treatment yet still had significant MASH (80% had a NAS>5) and clinically meaningful fibrosis (26% were F2, 68% were F3).Baseline hepatic fat content was not different in patients on GLP-1 RA or SGLT2i therapy. Patients in MAESTRO-NASH were on SGLT2i or GLP-1 RA doses used for T2DM (most diabetes doses of semaglutide or dulaglutide per week). No weight loss above background was observed in the GLP-1 RA or SGLT2i treated patients, and GLP-1 RA and SGLT2i treated patients with T2DM showed similar MASH resolution and fibrosis improvement rates and MRI-PDFF responses in combination with resmetirom as patients with T2DM not on these agents. These results demonstrate that the addition of resmetirom to those on GLP-1 RA (T2DM doses) or SGLT2i treatment with stable weight has no additional benefits beyond the significant benefits of resmetirom alone.

[0644] The beneficial effects of weight loss through lifestyle modification on biomarkers and liver histology have been shown across the entire spectrum of MASLD, hence nutrition and exercise counseling remain part of current non-pharmacological recommendations for the treatment of MASLD / MASH. The observations that patients either on placebo or resmetirom with >5% weight loss had higher response rates for both histological endpoints (compared to those with <5% weight loss) are in line with lifestyle modification’s documented histological benefits. Mediation analysis indicated that resmetirom’s improvement in NASH and fibrosis relative to placebo is not mediated by percent change in weight at Week 52. However, in the overall study, >5% weight loss was observed more frequently in resmetirom as compared with placebo treated patients representing approximately 22% of those treated compared with 12% of placebos.

[0645] Within resmetirom groups, a >5% weight loss was associated with higher rates of MASH resolution and fibrosis improvement in resmetirom treated patients compared toAttorney Docket No. 156883.617393 resmetirom treated patients without weight loss, indicating that relatively small amounts (>5%) of weight loss enhance the effects of resmetirom on MASH resolution and liver fibrosis improvement. The effects on MRI-PDFF in >5% resmetirom weight loss patients were also noteworthy, with more than 95% achieving >30% liver fat reduction, a predictive marker for both fibrosis improvement and NASH resolution in resmetirom-treated patients. Non-invasive tests and surrogates for fibrosis also showed robust responses, particularly in patients with >5% weight loss on resmetirom. Although the mechanism of resmetirom-mediated enhancement of weight loss relative to placebo is unknown, hypothetically, a reduction in the hepatic inflammasome that is elevated in MASH patients

[0032] could potentiate weight loss. For example, it is known that anti-inflammatory effects of some diets or medications can help facilitate weight loss.

[0646] Of note, a recently completed 72 week readout of ESSENCE, a phase 3 trial in patients with MASH and F2 / F3 fibrosis, demonstrated that a weekly dose of 2.4 mg semaglutide achieved both NASH resolution and fibrosis improvement endpoints.Approximately 10% weight loss was achieved in the semaglutide arm associated with approximately 50% of patients with 30% reduction of PDFF. In alignment with resmetirom treated patients who had >5% weight loss in MAESTRO-NASH, the combination of resmetirom and higher weight-loss doses of GLP-1 RA may have the potential to achieve additional benefits on MASH with fibrosis compared with either therapy alone.

[0647] The limitations of this study include the small number of subjects, particularly in the groups on resmetirom and either GLP-1 RA or SGLT2i or with weight loss, and, thus, the findings for resmetirom’ s efficacy in T2DM patients in presence or absence of GLP-1 RA or SGLT2i, or patients with >5 / <5% weight loss were exploratory.Attorney Docket No. 156883.617393

[0648] In summary, GLP-1 RA and SGLT2i treated patients with T2DM showed comparable MASH resolution and fibrosis improvement rates in combination with resmetirom as in patients with T2DM not on these agents. Relatively small amounts (>5%) of weight loss enhanced the effects of resmetirom on MASH resolution, liver fibrosis improvement, and non-invasive tests of efficacy suggesting a potential complementary mechanism to increase response rates to resmetirom treatment.

[0649] References

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[0655] Hagstrom, H., et al., Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in b4. No biopsy-proven NAFLD. J Hepatol, 2017. 67(6): p. 1265-1273.Attorney Docket No. 156883.617393

[0656] Noureddin, M., et al., NASH Leading Cause of Liver Transplant in Women:Updated Analysis of Indications For Liver Transplant and Ethnic and Gender Variances. Am J Gastroenterol, 2018. 113(11): p. 1649-1659.

[0657] Younossi, Z.M., et al., Burden of Illness and Economic Model for Patients With Nonalcoholic Steatohepatitis in the United States. Hepatology, 2019. 69(2): p. 564–572.

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[0664] Taub, R., et al., Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis, 2013.230(2): p. 373-80.

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[0679] Huang, D. Q., et al., Fibrosis Progression Rate in B4. No biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study. Gastroenterology, 2023. 165(2): p. 463-472 e5.

[0680] Rinella, M. E., et al., AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology, 2023.Attorney Docket No. 156883.617393

[0681] Csak, T., et al., Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology, 2011. 54(1): p. 133-44.

[0682] Alufer, L., et al., Long-term green-Mediterranean diet may favor fasting morning cortisol stress hormone; the DIRECT-PLUS clinical trial. Front Endocrinol (Lausanne), 2023. 14: p. 1243910.

[0683] Paul, C., et al., Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol, 2015. 173(6): p. 1387-99.

[0684] Edwards, C. J., et al., Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis, 2016. 75(6): p. 1065-73..

[0685] Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the disclosure of the present invention pertains. These patents and publications are herein incorporated by reference for the indicated information to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference for such information. In case of conflict, the present specification, including definitions, will control.

[0686] One skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The present disclosure described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of theAttorney Docket No. 156883.617393 invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention as defined by the scope of the claims.

Claims

Attorney Docket No. 156883.617393CLAIMS1. A method of treating cardiomyopathy and / or a related heart failure, comprising: administering to a human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

2. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating cardiomyopathy and / or a related heart failure, the method comprising:administering to a human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

3. Use of resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cardiomyopathy and / or a related heart failure.

4. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein cardiomyopathy is cirrhotic cardiomyopathy.

5. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein cardiomyopathy is associated with metabolic dysfunction.

6. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 5, wherein the metabolic dysfunction is obesity or metabolic dysfunction-associated steatohepatitis (MASH).

7. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein the related heart failure is associated with cardiac stress unmasking latent diastolic dysfunction.Attorney Docket No. 156883.617393 8. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein the human subject in need thereof has MASH.

9. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 8, wherein the human subject in need thereof has noncirrhotic MASH with moderate to advanced liver fibrosis consistent with stages F2 to F3.

10. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 8, wherein the human subject in need thereof has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

11. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claims 1-8, wherein the human subject in need thereof has liver fibrosis.

12. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 11, wherein the human subject in need thereof has liver fibrosis characterized as fibrosis stage F2.

13. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 11, wherein the human subject in need thereof has liver fibrosis characterized as fibrosis stage F3.

14. A method of treating clinically significant portal hypertension (CSPH), comprising:administering to a human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

15. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating clinically significant portal hypertension (CSPH), the method comprising:Attorney Docket No. 156883.617393 administering to a human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

16. Use of resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating clinically significant portal hypertension (CSPH).

17. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of claims 14-16, wherein the human subject has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

18. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of claims 14-17, wherein the method is of improving CSPH.

19. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of claims 14-18, wherein the human subject has CSPH.

20. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the method is of improving CSPH from CSPH to probable CSPH risk.

21. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the administration for at least 4 to 10 weeks improves CSPH.

22. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the administration improves CSPH from CSPH to probable CSPH risk over a period of 12 months or 24 months.Attorney Docket No. 156883.617393 23. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the method is of improving CSPH from CSPH to no / low CSPH risk.

24. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the administration for at least 4 to 10 weeks improves CSPH.

25. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 19, wherein the administration improves CSPH from CSPH to no / low CSPH risk over a period of 12 months or 24 months.

26. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of claims 14-18, wherein the human subject is characterized as having probable CSPH risk.

27. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 26, wherein the method is of improving CSPH from probable CSPH risk to no / low CSPH risk.

28. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 26, wherein the administration for at least 4 to 10 weeks improves CSPH.

29. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 26, wherein the administration improves CSPH from probable CSPH risk to no / low CSPH risk over a period of 12 months or 24 months.

30. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the precedingAttorney Docket No. 156883.617393 claims, wherein resmetirom or the pharmaceutically acceptable salt thereof is in a solid oral dosage form.

31. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 30, wherein the solid oral dosage form is a tablet.

32. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein the human subject in need thereof is an adult human subject in need thereof.

33. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered once daily.

34. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 60 mg to about 100 mg.

35. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 34, wherein the administering of about 60 mg to about 100 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

36. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of claims 1-33, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg.Attorney Docket No. 156883.617393 37. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of claim 36, wherein the administering of about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, or about 200 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

38. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered for at least 2 years.

39. The method, resmetirom or the pharmaceutically acceptable salt thereof for use, or the use of resmetirom or the pharmaceutically acceptable salt thereof of any one of the preceding claims, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered for longer than 52 weeks.

40. The method of claim 1, wherein the administering comprises administering to the human subject in need thereof a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof.

41. A pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof for use in the method of claim 2, wherein the administering comprises administering to the human subject in need thereof the pharmaceutical composition.

42. Use of a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of the medicament of claim 3.

43. The method of claim 14, wherein the administering comprises administering to the human subject in need thereof a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof.Attorney Docket No. 156883.617393 44. A pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof for use in the method of claim 15, wherein the administering comprises administering to the human subject in need thereof the pharmaceutical composition.

45. Use of a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof in the manufacture of the medicament of claim 16.

46. A method of treating portal hypertension, comprising:administering to a human subject in need thereof resmetirom or a pharmaceutically acceptable salt thereof.

47. The method of claim 46, wherein the human subject in need thereof has compensated MASH cirrhosis with stage F4 fibrosis (stage F4c).

48. The method of claim 46 or 47, wherein the administering for at least 4 to 10 weeks improves the portal hypertension.

49. The method of any one of claims 46-48, wherein the portal hypertension is clinically significant portal hypertension (CSPH).

50. The method of claim 49, wherein the method is of improving CSPH.

51. The method of any one of claims 46-50, wherein the human subject in need thereof has CSPH.

52. The method of claim 51, wherein the method is of improving CSPH from CSPH to probable CSPH risk.

53. The method of claim 52, wherein the administering improves CSPH from CSPH to probable CSPH risk over a period of 12 months or 24 months.

54. The method of claim 52, wherein the method is of improving CSPH from CSPH to no / low CSPH risk.Attorney Docket No. 156883.617393 55. The method of claim 52, wherein the administering improves CSPH from CSPH to no / low CSPH risk over a period of 12 months or 24 months.

56. The method of any one of claims 46-50, wherein the human subject in need thereof is characterized as having probable CSPH risk.

57. The method of claim 56, wherein the method is of improving CSPH from probable CSPH risk to no / low CSPH risk.

58. The method of claim 56, wherein the administering improves CSPH from probable CSPH risk to no / low CSPH risk over a period of 12 months or 24 months.

59. The method of any one of claims 46-58, wherein resmetirom or the pharmaceutically acceptable salt thereof is in a solid oral dosage form.

60. The method of claim 59, wherein the solid oral dosage form is a tablet.

61. The method of any one of claims 46-60, wherein the human subject in need thereof is an adult human subject in need thereof.

62. The method of any one of claims 46-61, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered once daily.

63. The method of any one of claims 46-62, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 60 mg to about 100 mg.

64. The method of claim 63, wherein the administering of about 60 mg to about 100 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

65. The method of any one of claims 46-64, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 60 mg.

66. The method of claim 65. wherein the administering of about 60 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.Attorney Docket No. 156883.617393 67. The method of any one of claims 46-64, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 80 mg.

68. The method of claim 67, wherein the administering of about 80 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

69. The method of any one of claims 46-64, wherein the amount of resmetirom or the pharmaceutically acceptable salt thereof, taken daily, is about 100 mg.

70. The method of claim 69, wherein the administering of about 100 mg, daily, of resmetirom or the pharmaceutically acceptable salt thereof is maintained for at least 12 months.

71. The method of any one of claims 46-70, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered for at least 2 years.

72. The method of any one of claims 46-71, wherein resmetirom or the pharmaceutically acceptable salt thereof is administered for longer than 52 weeks.

73. The method of claim 46, wherein the administering comprises administering to the human subject in need thereof a pharmaceutical composition comprising resmetirom or the pharmaceutically acceptable salt thereof.

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