Methods for treating a fatty liver disease

Abstract

The present disclosure provides a method of treating a fatty liver disease (e.g., non-alcoholic steatohepatitis (NASH)) in a human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) 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 improving liver fibrosis in a human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) 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

METHODS FOR TREATING A FATTY LIVER DISEASECross Reference to Related Applications

[0001] This application claims the benefit of U.S. Patent Application No. 19 / 045,070, filed February 4, 2025, and U.S. Provisional Application Nos. 63 / 550,201, filed February 6, 2024, 63 / 564,803, filed March 13, 2024, 63 / 655,870, filed June 4, 2024, 63 / 719,257, filed November 12, 2024, 63 / 720,725, filed November 14, 2024, and 63 / 721,474, filed November 16, 2024, the disclosures of all of which are incorporated herein by reference in their entireties.Technical Field of the Invention

[0002] This disclosure is related to the area of treatment of a fatty liver disease, such as, for instance, non-alcoholic steatohepatitis (NASH) (e.g., noncirrhotic non-alcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis. In particular, the disclosure relates to method for the efficacious treatment of a fatty liver disease (e.g., NASH) utilizing the thyroid hormone receptor-beta (THR-beta) agonist resmetirom or a pharmaceutically acceptable salt thereof. In addition, the disclosure is related to the area of treatment of stages F2 and F3 liver fibrosis associated with a fatty liver disease. In particular, the disclosure relates to a method for the efficacious treatment of stages F2 and F3 liver fibrosis associated with a fatty liver disease, with improvement of liver fibrosis by up to one or two stages, utilizing resmetirom or a pharmaceutically acceptable salt thereof.Background of the Invention

[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 with 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] Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease in the United States. NASH is a fatty inflammation of the liver and a major cause of fibrosis, cirrhosis and liver failure. The disease is progressive, starting as steatosis or nonalcoholic fatty liver disease (NAFLD), progressing to an inflamed fatty liver (NASH), and eventually leading to fibrosis and cirrhosis. The disease is generally asymptomatic until severe liver impairment occurs.

[0006] Human subjects with NASH may experience elevated liver volumes, which can be attributed to increased liver fat and fluid retention due to inflammatory processes in NASH. As NASH progresses to cirrhosis, 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 livervolume in noncirrhotic non-alcoholic 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 NASH and 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 NASH in the U.S. population is about 2-3%. Some NASH patients will progress to late-stage disease: approximately 15-50% of NASH patients progress to severe fibrosis, and approximately 7-16% progress to cirrhosis. The rate of liverspecific mortality in NASH cirrhotics is approximately 10% per decade.

[0008] Obesity is a common characteristic of both NASH and cirrhosis, due to insufficient weight loss through diet and lifestyle modifications, this patient population is often prescribed interventional surgical procedures (e.g., bariatric surgery). Liver volume reduction immediately prior to surgery is aggressively pursued to improve surgical access to the stomach.Summary

[0009] Resmetirom has previously been mentioned in connection with the treatment of a fatty liver disease, such as NASH. However, it has now been unexpectedly found that the 100 mg dose thereof leads to better outcomes than the 80 mg dose in human subjects that weigh at least 100 kg. The 80 mg dose is optimal for human subjects that weigh less than 100 kg to achieve better outcomes with discontinuation rates based upon adverse results in clinical trials similar to placebo. This weight-based dosing was recognized by the U.S. Food and Drug Administration (FDA) in the approval of REZDIFFRA™ (resmetirom), as reflected in the prescribing information(https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2024 / 217785s0001bl.pdf, incorporated herein by reference in its entirety) and also shown in FIG. 46.

[0010] Disclosed herein is a method of treating or improving a fatty liver disease, such as, for example non-alcoholic steatohepatitis (NASH) (e.g., noncirrhotic non-alcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis) in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0011] In particular, disclosed herein is a method of treating NASH. The method comprises: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

[0012] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0013] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0014] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0015] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl.

[0016] In some embodiments, the method is of improving noncirrhotic nonalcoholic steatohepatitis.

[0017] In some embodiments, the solid oral dosage form comprises resmetirom.

[0018] In some embodiments, the solid oral dosage form is a tablet.

[0019] In some embodiments, the human subject is an adult human subject.

[0020] Also disclosed herein is a method of treating or improving liver fibrosis associated with a fatty liver disease (e.g., NASH) in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0021] In particular, disclosed herein is a method of treating liver fibrosis. The method comprises: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

[0022] In some embodiments, the method is of improving the liver fibrosis.

[0023] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F 1.

[0024] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F2.

[0025] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F3.

[0026] In some embodiments, the method is of improving the liver fibrosis by one stage in the human subject.

[0027] In some embodiments, the method is of improving the liver fibrosis by two stages in the human subject.

[0028] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0029] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0030] In some embodiments, the solid oral dosage form comprises resmetirom.

[0031] In some embodiments, the solid oral dosage form is a tablet.

[0032] In some embodiments, the human subject is an adult human subject.

[0033] Also disclosed herein is a method of treating or improving a fatty liver disease (e.g., NASH) in a human subject (e.g., an adult human subject) who may be in need of suchtreatment or improvement who may also be on a moderate CYP2C8 inhibitor regimen. In this instance, the human subject is administered resmetirom or a pharmaceutically acceptable salt thereof at a dosage that is reduced by 20 mg per day relative to what the same human subject would have otherwise been administered based on the determination of the weight. If the human subject was taking resmetirom or the pharmaceutically acceptable salt thereof prior to using a moderate CYP2C8 inhibitor, then the dose administered to the human subject as determined based on the weight of the human subject would be reduced by 20 mg per day to the reduced dosage, during the concomitant use of the moderate CYP2C8 inhibitor. If the human subject was not taking resmetirom or the pharmaceutically acceptable salt thereof prior to using a moderate CYP2C8 inhibitor, then the human subject would start with the reduced dosage and continue taking the reduced dosage, determined based on the weight of the human subject, during the concomitant use of the moderate CYP2C8 inhibitor.

[0034] In particular, disclosed herein is a method of treating NASH, which comprises: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor.

[0035] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day.

[0036] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day.

[0037] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

[0038] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

[0039] In some embodiments, the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0040] In some embodiments, the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0041] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0042] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with mild liver fibrosis consistent with stage Fl.

[0043] In some embodiments, the method is of improving noncirrhotic nonalcoholic steatohepatitis..

[0044] In some embodiments, the solid oral dosage form comprises resmetirom..

[0045] In some embodiments, the solid oral dosage form is a tablet.

[0046] In some embodiments, the human subject is an adult human subject.

[0047] Also disclosed herein is a method of treating or improving liver fibrosis associated with a fatty liver disease (e.g., NASH) in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement who may also be on a moderate CYP2C8 inhibitor regimen.

[0048] In particular, disclosed herein is a method of treating liver fibrosis, which comprises: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; andwherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

[0049] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising the resmetirom or a pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day.

[0050] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day.

[0051] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

[0052] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

[0053] In some embodiments, the method is of improving the liver fibrosis.

[0054] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F 1.

[0055] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F2.

[0056] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F3.

[0057] In some embodiments, the method is of improving the liver fibrosis by one stage in the human subject.

[0058] In some embodiments, the method is of improving the liver fibrosis by two stages in the human subject.

[0059] In some embodiments, the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0060] In some embodiments, the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0061] In some embodiments, the solid oral dosage form comprises resmetirom.

[0062] In some embodiments, the solid oral dosage form is a tablet.

[0063] In some embodiments, the human subject is an adult human subject.

[0064] Also disclosed herein is resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating nonalcoholic steatohepatitis (NASH), the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

[0065] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0066] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl.

[0067] In some embodiments, the method is of improving noncirrhotic nonalcoholic steatohepatitis.

[0068] Also disclosed herein is resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

[0069] In some embodiments, the method is of improving the liver fibrosis.

[0070] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F 1.

[0071] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F2.

[0072] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F3.

[0073] In some embodiments, the method is of improving the liver fibrosis by one stage in the human subject.

[0074] In some embodiments, the method is of improving the liver fibrosis by two stages in the human subject.

[0075] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0076] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0077] In some embodiments, the solid oral dosage form is a tablet.

[0078] In some embodiments, the human subject is an adult human subject.

[0079] Also disclosed herein is resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating noncirrhotic nonalcoholic steatohepatitis (NASH), the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor.

[0080] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0081] In some embodiments, the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl .

[0082] In some embodiments, the method is of improving noncirrhotic nonalcoholic steatohepatitis.

[0083] Also disclosed herein is resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

[0084] In some embodiments, the method is of improving the liver fibrosis.

[0085] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F 1.

[0086] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F2.

[0087] In some embodiments, the human subject has liver fibrosis characterized as fibrosis stage F3.

[0088] In some embodiments, the method is of improving the liver fibrosis by one stage in the human subject.

[0089] In some embodiments, the method is of improving the liver fibrosis by two stages in the human subject.

[0090] In some embodiments, the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0091] In some embodiments, the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 60 mg per day.

[0092] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

[0093] In some embodiments, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

[0094] In some embodiments, the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine,eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0095] In some embodiments, the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

[0096] In some embodiments, the solid oral dosage form comprises resmetirom.

[0097] In some embodiments, the solid oral dosage form is a tablet.

[0098] In some embodiments, the human subject is an adult human subject.Brief Description of the Drawings

[0099] The above and further features will be more clearly appreciated from the following detailed description when taken in conjunction with the accompanying drawings.

[0100] FIG. 1 is a graphical representation showing the correlation of liver volume reduction and proton density fat fraction (PDFF) reduction in placebo and resmetirom treated patients at 12 weeks in Example 1. "PBO" represents placebo patients and "RES" represents resmetirom-treated patients.

[0101] FIG. 2 is a graphical representation showing change in MRI-PDFF (Magnetic Resonance Imaging-PDFF) in several subgroups of patients treated with 100 mg resmetirom, once daily, for 52 weeks in Example 1. "High SHBG" corresponds with 2 / 3 study patients with the highest increase from baseline in sex hormone binding globulin (SHBG), a biomarker for resmetirom liver exposure.

[0102] FIG. 3 is a graphical representation showing change in liver volume in several subgroups of patients treated with 100 mg resmetirom, once daily, for 52 weeks in Example 1. "High SHBG" corresponds with 2 / 3 study patients with the highest increase from baseline in SHBG, a biomarker for resmetirom liver exposure.

[0103] FIG. 4 is a graphical representation showing resmetirom-mediated changes to the MRI-PDFF and liver volume (LV) at week 52 in Example 1.

[0104] FIG. 5 is a graphical representation showing percentage of patients at week 52 with 10% reduction or 10% increase in spleen volume (SV) in Example 1.

[0105] FIG. 6 is a graph showing the correlation between 52 week liver volume change and spleen volume change in patients who entered the study with baseline PDFF <8% in Example 1.

[0106] FIG. 7 is a graphical representation showing the study design in Example 2. CAP: controlled attenuation parameter; LDL-C: low-density lipoprotein cholesterol; MRE: magnetic resonance elastography; MRI-PDFF: magnetic resonance imaging-proton density fat fraction; VCTE: vibration-controlled transient elastography.

[0107] FIG. 8 is a schematic showing statistical testing process for primary and key secondary endpoints at week 52 in Example 2. LDL-C: low-density lipoprotein cholesterol.

[0108] FIG. 9 is a schematic showing patient disposition in Example 2. AE: adverse event; LTFU: lost to follow up. The primary reasons for screen failure included biopsy, withdraw of consent, MRI-PDFF <8%, HbAlc >9. The exploratory Fl group included baseline Fl A / F1C patients (n = 84) that were considered only for exploratory efficacy and safety analyses. These patients received treatment but as prespecified in the statistical analysis plan, were not included in the primary analysis population.

[0109] FIGS. 10A-10C show primary and Key Secondary End Points in Example 2. The two primary end points at week 52 were resolution of nonalcoholic steatohepatitis (NASH) with no worsening of fibrosis (Panel A, FIG. 10A), and an improvement (reduction) in fibrosis by at least one stage with no worsening of the nonalcoholic fatty liver disease (NAFLD) activity score (Panel B, FIG. 10B). The key secondary end point was the percent change from baseline in the low-density lipoprotein (LDL) cholesterol level at week 24 (Panel C, FIG. 10C). The NAFLD activity score is assessed on a scale of 0 to 8, with higher scores indicating more severe disease; the components of this measure are steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2). NASH resolution was defined as achievement of a hepatocellular ballooning score of 0, a lobular inflammation score of 0 or 1, and a reduction in the NAFLD activity score by at least 2 points. Fibrosis stages range from F0 (no fibrosis) to F4 (cirrhosis). A total of 11 patients had a delay in their week 52 biopsy due to coronavirus disease 2019-related closure of the biopsy site or related reasons and were removed from the primary analysis population for liver-biopsy analyses.

[0110] FIGS. 11A-11D are graphical representations showing subgroup analyses of the dual primary endpoints at Week 52 in Example 2: Resolution of nonalcoholic steatohepatitis (FIG. 11A and FIG. 11C) and improvement in fibrosis (FIG. 11B and FIG. 11D). Data arereported for the primary analysis population (n=955, after removal of the COVID impacted biopsies outside the Week 60 window). Eleven patients had a delay in their Week 52 biopsy due to COVID-19 biopsy site closure or related reasons and were removed from the analysis. Resolution of nonalcoholic steatohepatitis is defined as achievement of a ballooning score of 0, inflammation score of 0 or 1, and >2-point reduction in the nonalcoholic fatty liver disease activity score with no worsening of fibrosis. Fibrosis improvement is defined as achievement of >1 -stage reduction in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score. A 1 -point improvement in fibrosis would be a change to F1A or F1C from F2 (a change of F2 to F1B is not considered a 1-point improvement). Forest plots include prespecified subgroups with minor modifications. Body weight subgroups based on <200, >200 pounds or BMI (Body Mass Index) <35, >35 were not informative. PDFF reduction in resmetirom groups are compared to all placebo patients with any Week 52 PDFF; % SHBG CFB in resmetirom groups is compared to all placebo patients with a Week 52 SHBG. A posthoc subgroup of <100kg, >100 kg is shown in Table 21 that also includes subgroups for >30% PDFF at Week 16, region (US-ExUS), weight gain >5% F2 / F3, FIB. Subgroup analyses by statin use and NAFLD Activity Score (NAS) were post-hoc analyses. Confidence interval widths have not been adjusted for multiplicity and may not be used for hypothesis testing.

[0111] FIG. 12 is a graphical representation showing percentage of patients who were F1B or F2 at baseline with worse (progressed to ≥F3), stable (no change), or improved fibrosis stage at week 52 based on liver biopsy in Example 2. In patients with a baseline and eligible Week 52 biopsy (80 mg, 100 mg: resmetirom). The two pathologists' assessments were similar and were averaged to generate a single output.

[0112] FIG. 13 is a graphical representation showing percent of patients with worsened, stable (no change), or improved individual components of the nonalcoholic fatty liver disease activity score (ballooning, inflammation, steatosis) in Example 2. In patients with a baseline and eligible Week 52 biopsy are shown. The two pathologists' assessments were similar and were averaged to generate a single output.

[0113] FIG. 14 is a graphical representation showing percent change from baseline in lipids and lipoproteins at weeks 24 and 52 in Example 2. ApoB: apolipoprotein B; ApoCIII: apolipoprotein CIII; LDL-C: low-density lipoprotein cholesterol; Lp(a): lipoprotein a; non- HDL-C: non-high-density lipoprotein cholesterol. (80 mg, 100 mg: resmetirom)

[0114] FIGS. 15A and 15B are graphical representations showing percent change from baseline in hepatic fat as measured by magnetic resonance imaging-proton density fat fraction at weeks 16 and 52 (FIG. 15 A), and steatosis as measured by FibroScan controlled attenuation parameter at week 52 (FIG. 15B) in Example 2 (80 mg, 100 mg: resmetirom). Based on observed data, patients with a baseline and week 52 assessment.

[0115] FIG. 16 is a graphical representation showing percentage of patients achieving a >25% reduction from baseline in liver stiffness as measured by FibroScan vibration- controlled transient elastography at week 52 in Example 2. Based on observed data, patients with a baseline and week 52 assessment.

[0116] FIG. 17 is a graphical representation showing improvement or worsening from baseline in liver stiffness as measured by magnetic resonance elastography at week 52 in Example 2. (80 mg, 100 mg: resmetirom) Based on observed data, patients with a baseline and week 52 assessment.

[0117] FIGS. 18A and 18B are graphical representations showing percent change from baseline in liver volume (FIG. 18 A) and spleen volume (FIG. 18B) at weeks 16 and 52 in Example 2. (80 mg, 100 mg: resmetirom) Based on observed data, patients with a baseline and week 52 assessment.

[0118] FIGS. 19A-19C are graphical representations showing change from baseline in the enhanced liver fibrosis score (FIG. 19A), TIMP-1 (FIG. 19B), and P3NP (FIG. 19C) in Example 2. (80 mg, 100 mg: resmetirom) Based on observed data.

[0119] FIG. 20 is a graphical representation showing time to onset of first gastrointestinal adverse event in Example 2.

[0120] FIG. 21 is a graphical representation showing duration of diarrhea: duration of diarrhea reported in first 12 weeks of randomization in Example 2.

[0121] FIG. 22 is a schematic showing prescreening and screening sequence in Example 2.

[0122] FIG. 23 is a schematic showing methodology for central pathologist evaluation of liver biopsies in Example 2.

[0123] FIG. 24A is a graphical representation showing the percentage of patients that achieved >120% increase in SHBG at Week 52 in the resmetirom 80 mg and resmetirom 100 mg groups based on weight in Example 2. FIG. 24B is a graphical representation showing the percentage of patients that achieved >30% reduction in MRI-PDFF at Week 52 in the resmetirom 80 mg and resmetirom 100 mg groups based on weight in Example 2.

[0124] FIG. 25A is a graphical representation showing the percentage of patients that achieved NASH Resolution (ballooning score=0, inflammation score=0 / l, and >2-pointreduction in NAS with no worsening of fibrosis) in the resmetirom 80 mg and resmetirom 100 mg groups based on weight in Example 2. FIG. 25B is a graphical representation showing the percentage of patients that achieved Fibrosis Improvement (≥1-stage improvement in fibrosis with no worsening of NAS) in the resmetirom 80 mg and resmetirom 100 mg groups based on weight in Example 2.

[0125] FIG. 26A is a graphical representation showing the percentage of patients that achieved NASH Resolution (ballooning score=0, inflammation score=0 / 1, and ≥2-point reduction in NAS with no worsening of fibrosis) in the resmetirom 80 mg and resmetirom 100 mg groups based on body mass index in Example 2. FIG. 26B is a graphical representation showing the percentage of patients that achieved Fibrosis Improvement (≥1stage improvement in fibrosis with no worsening of NAS) in the resmetirom 80 mg and resmetirom 100 mg groups based on body mass index in Example 2.

[0126] FIG. 27 is a graphical representation showing the percentage biopsy response for fibrosis improvement and NASH resolution in all resmetirom-treated patients (80 mg and 100 mg combined) and placebo patients based on the percentage change from baseline PDFF at Week 52 in Example 2. The graph shows that the greater the Week 52 PDFF reduction, the greater likelihood for fibrosis and NASH responses with resmetirom treatment.

[0127] FIG. 28 is a graphical representation showing the change over time from baseline to 48 weeks in SHBG in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in the MAESTRO-NASH Week 52 primary analysis population in Example 2.

[0128] FIG. 29A is a graphical representation showing the ALT response at Week 48 in all randomized patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in the MAESTRO-NASH Week 52 primary analysis population in Example 2. FIG. 29B is agraphical representation showing the ALT response at Week 48 where the dose aligned with prescribing information recommended dose for patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in the MAESTRO-NASH Week 52 primary analysis population in Example 2.

[0129] FIG. 30A is a graphical representation showing the change over time in VOTE from baseline to year 3 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg group in Example 2. FIG. 30B is a graphical representation showing the change over time in CAP (dB / M) from baseline to year 3 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in Example 2.

[0130] FIG. 31 is a graphical representation showing the VCTE responder analyses at years 1-3 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in the MAESTRO-NASH population in Example 2.

[0131] FIG. 32A is a graphical representation showing the percentage of patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups that achieved >1 stage fibrosis improvement as determined by qFibrosis and pathologists in Example 2. FIG. 32B is a graphical representation showing the percentage of patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups that had progression of fibrosis as determined by qFibrosis and pathologists in Example 2.

[0132] FIG. 33A is a graphical representation showing the intersection portal tract change from baseline in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2. FIG. 33B is a graphical representation showing the string length portal tract change from baseline in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2.

[0133] FIG. 34A is a graphical representation showing the intersection portal tract change from baseline in pathologist fibrosis responders and non-responders in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2. FIG. 34B is a graphical representation showing the string length portal tract change from baseline in pathologist fibrosis responders and non-responders in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2.

[0134] FIG. 35 A is a graphical representation showing the change from baseline in the number of long strings-portal tract in responders and non-responders in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2. FIG. 35B is a graphical representation showing the change from baseline in the number of short strings zone 2 in responders and non-responders in the placebo and resmetirom (80 mg and 100 mg combined) groups at the F2 and F3 stages in Example 2.

[0135] FIG. 36 is a graphical representation showing the percentage change from baseline in ALT at Week 48 compared to the percentage biopsy response in the patients who achieved resmetirom NASH resolution, resmetirom fibrosis improvement, placebo NASH resolution, and placebo fibrosis improvement in Example 2.

[0136] FIG. 37 is a graphical representation showing the CAP change over time from baseline to year 3 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in Example 2.

[0137] FIG. 38 is a graphical representation showing the percentage change from baseline in CAP at Week 52 compared to the percentage biopsy response in the patients who achieved resmetirom NASH resolution, resmetirom fibrosis improvement, placebo NASH resolution, and placebo fibrosis improvement in Example 2.

[0138] FIG. 39 is a graph showing the percentage change from baseline in PDFF at Week 52 compared to the percentage biopsy response in the patients who achieved resmetirom NASH resolution, resmetirom fibrosis improvement, placebo NASH resolution, and placebo fibrosis improvement in Example 2.

[0139] FIG. 40 is a graphical representation showing the VCTE change over time from baseline to year 3 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in Example 2.

[0140] FIG. 41 is a graphical representation showing the percentage change from baseline in VCTE at Week 52 compared to the percentage biopsy response in the patients who achieved resmetirom NASH resolution, resmetirom fibrosis improvement, placebo NASH resolution, and placebo fibrosis improvement in Example 2.

[0141] FIG. 42 is a graphical representation showing the importance of various response predictors of resmetirom NASH resolution response based on Week 52 data in Example 2.

[0142] FIG. 43 is a graphical representation showing the importance of various predictors of resmetirom fibrosis improvement biopsy response based on Week 52 data in Example 2.

[0143] FIG. 44 is a graphical representation showing the P3NP change vs. the PRO-C3 change at Week 52 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in Example 2.

[0144] FIG. 45 is a graphical representation showing the ELF change vs. the PRO-C3 change at Week 52 in patients in the placebo, resmetirom 80 mg, and resmetirom 100 mg groups in Example 2.

[0145] FIG. 46 is a reproduction of an excerpt of the prescribing information ofREZDIFFRA™ (resmetirom).

[0146] FIG. 47 is an X-ray powder diffractogram (XRPD) pattern of resmetirom Form I.

[0147] FIG. 48 is a differential scanning calorimetry (DSC) diagram of resmetirom Form I.

[0148] FIG. 49 is an XRPD pattern of resmetirom Form λ.

[0149] FIG. 50 is an XRPD pattern of resmetirom Form F.

[0150] FIG. 51 is an XRPD pattern of resmetirom Form L.

[0151] FIG. 52 is an XRPD pattern of resmetirom crystalline Form CSIV.

[0152] FIG. 53 is a thermogravimetric analysis (TGA) diagram of resmetirom crystallineForm CSIV.

[0153] FIG. 54 is a DSC diagram of resmetirom crystalline Form CSIV.

[0154] FIG. 55 is an XRPD pattern of resmetirom Form R3-A.

[0155] FIG. 56 is a solid state13C NMR spectrum of resmetirom Form R3-A (full range 200-0 ppm).

[0156] FIG. 57 is a solid state13C NMR spectrum of resmetirom Form R3-A (200-100 PPm).

[0157] FIG. 58 is a solid state13C NMR spectrum of resmetirom Form R3-A (100-0 ppm).

[0158] FIG. 59 is an XRPD pattern of resmetirom : nicotinamide (Form RC1-A).

[0159] FIG. 60 is a solid state13C NMR spectrum of resmetirom : nicotinamide (Form RC1-A) (full range 200-0 ppm).

[0160] FIG. 61 is a solid state13C NMR spectrum of resmetirom : nicotinamide (Form RC1 -A) (200-100 ppm).

[0161] FIG. 62 is a solid state13C NMR spectrum of resmetirom : nicotinamide (Form RC1-A) (100-0 ppm).

[0162] FIG. 63 is an XRPD pattern of resmetirom : caffeine (Form RC2-A).

[0163] FIG. 64 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-A) (full range 200-0 ppm).

[0164] FIG. 65 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-A) (200-100 ppm).

[0165] FIG. 66 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-A) (100-0 ppm).

[0166] FIG. 67 is an XRPD pattern of resmetirom : caffeine (Form RC2-B).

[0167] FIG. 68 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-B) (full range 200-0 ppm).

[0168] FIG. 69 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-B) (200-100 ppm).

[0169] FIG. 70 is a solid state13C NMR spectrum of resmetirom : caffeine (Form RC2-B)(100-0 ppm).

[0170] FIG. 71 is an XRPD pattern of resmetirom : 2-picolinic acid (Form RC3-A).

[0171] FIG. 72 is an XRPD pattern of resmetirom : urea (Form RC4-A).

[0172] FIG. 73 is an XRPD pattern of resmetirom : N-methyl morpholine salt (Form Rl- A).

[0173] FIG. 74 is an XRPD pattern of resmetirom : piperazine salt (Form R2-A).

[0174] FIG. 75 is a solid state13C NMR spectrum of resmetirom : piperazine salt (FormR2-A) (full range 200-0 ppm).

[0175] FIG. 76 is a solid state13C NMR spectrum of resmetirom : piperazine salt (FormR2-A) (200-100 ppm).

[0176] FIG. 77 is a solid state13C NMR spectrum of resmetirom : piperazine salt (FormR2-A) (100-0 ppm).

[0177] FIG. 78 is an XRPD pattern of resmetirom : benzathine salt (Form R4-A).

[0178] FIG. 79 is a chart depicting weight loss in conjunction with resmetirom therapy’s impact on biopsy endpoints in the MAESTRO-NASH study.

[0179] FIG. 80 is a chart depicting weight loss in conjunction with resmetirom therapy’s impact on MRI-PDFF results in the MAESTRO-NASH study.

[0180] FIG. 81 is an XRPD pattern of resmetirom Form N8.

[0181] FIG. 82 an1H NMR spectrum of resmetirom Form N8.

[0182] FIG. 83 a combined DSC and TGA thermogram of resmetirom Form N8.

[0183] FIG. 84 is an XRPD pattern of resmetirom Form 3.

[0184] FIG. 85 is an XRPD pattern of resmetirom Form 9.

[0185] FIG. 86 is an XRPD pattern of resmetirom Form CSV.

[0186] FIG. 87 is a TGA diagram of resmetirom Form CSV.

[0187] FIG. 88 is an XRPD pattern of resmetirom Form 2.

[0188] FIG. 89 is an XRPD pattern of resmetirom Form 4.

[0189] FIG. 90 is an XRPD pattern of resmetirom Form 6.

[0190] FIG. 91 is an XRPD pattern of resmetirom Form 7.

[0191] FIG. 92 is an XRPD pattern of resmetirom Form 8.

[0192] FIG. 93 is an XRPD pattern of resmetirom Form 10.

[0193] FIG. 94 is an XRPD pattern of resmetirom Form 11.

[0194] FIG. 95 is an XRPD pattern of resmetirom Form 13.

[0195] FIG. 96 is an XRPD pattern of resmetirom Form 14.

[0196] FIG. 97 is an XRPD pattern of resmetirom Form 15.

[0197] FIG. 98 is an XRPD pattern of resmetirom Form 16.

[0198] FIG. 99 is an XRPD pattern of resmetirom Form 17.

[0199] FIG. 100 is an XRPD pattern of resmetirom Form 19.

[0200] FIG. 101 is an XRPD pattern of resmetirom Form 20.

[0201] FIG. 102 is an XRPD pattern of resmetirom Form 21.

[0202] FIG. 103 is an XRPD pattern of resmetirom Form 22.

[0203] FIG. 104 is a solid state13C NMR spectrum of resmetirom Form 20 (full range 200-0 ppm).

[0204] FIG. 105 is a solid state13C NMR spectrum of resmetirom Form 20 (200-100 PPm).

[0205] FIG. 106 is a solid state13C NMR spectrum of resmetirom Form 20 (100-0 ppm).

[0206] FIG. 107 is an XRPD pattern of resmetirom Form CSVI.

[0207] FIG. 108 is a TGA diagram of resmetirom Form CSVI.

[0208] FIG. 109 is an XRPD pattern of resmetirom Form CSVI.

[0209] FIG. 110 is an XRPD pattern of an amorphous resmetirom Form El and / or E2.

[0210] FIG. 111 is an XRPD pattern of an amorphous solid dispersion of resmetirom with copovidone Form E3 and / or E4.

[0211] FIG. 112 is an XRPD pattern of resmetirom Form 3 A.

[0212] FIG. 113 is a TGA diagram of resmetirom Form 3A.

[0213] FIG. 114 is a DSC diagram of resmetirom Form 3 A.

[0214] FIG. 115 is a Fourier Transform Infrared (FT-IR) diagram of resmetirom Form 3 A.

[0215] FIG. 116 is an XRPD pattern of resmetirom Form CSVII.

[0216] FIG. 117 is a TGA diagram of resmetirom Form CSVII.

[0217] FIG. 118 is a DSC diagram of resmetirom Form CSVII.

[0218] FIG. 119 is an XRPD pattern of resmetirom Form Type K65.

[0219] FIG. 120 is an XRPD pattern of resmetirom Form Type K65.

[0220] FIG. 121 is an XRPD pattern of resmetirom Form Type K65 desolvate.

[0221] FIG. 122 is an XRPD pattern of resmetirom Form 4A.

[0222] FIG. 123 is a TGA diagram resmetirom Form 4A.

[0223] FIG. 124 is a1H NMR spectrum of resmetirom Form 4A.

[0224] FIG. 125 is an XRPD pattern of resmetirom Form 7A.

[0225] FIG. 126 is a TGA diagram resmetirom Form 7A.

[0226] FIG. 127 is a1H NMR spectrum of resmetirom Form 7A.

[0227] FIG. 128 is an XRPD pattern of resmetirom Form 9A.

[0228] FIG. 129 is a TGA diagram of resmetirom Form 9A.

[0229] FIG. 130 is a1H NMR spectrum of resmetirom Form 9A.

[0230] FIG. 131 is an XRPD pattern of resmetirom Form BSI.

[0231] FIG. 132 is a DSC diagram of resmetirom Form BSI.

[0232] FIG. 133 is a TGA diagram of resmetirom Form BSI.

[0233] FIG. 134 is an XRPD pattern of resmetirom Form R1.

[0234] FIG. 135 is an XRPD pattern of resmetirom Form R2.

[0235] FIG. 136 is an XRPD pattern of resmetirom Form R3.

[0236] FIG. 137 is an XRPD pattern of resmetirom Form R4.

[0237] FIG. 138 is an XRPD pattern of resmetirom Form R5.

[0238] FIG. 139 is an XRPD pattern of an amorphous solid dispersion of resmetirom with eudragit

[0239] FIG. 140 is an XRPD pattern of an amorphous form of resmetirom reported inIN202241066042 A.

[0240] FIG. 141 is an XRPD pattern of resmetirom Form RL.

[0241] FIG. 142 is an XRPD pattern of resmetirom Form M1.

[0242] FIG. 143 is an XRPD pattern of resmetirom Form M2.

[0243] FIG. 144 is an XRPD pattern of resmetirom Form M3.

[0244] FIG. 145 is an XRPD pattern of resmetirom Form M4.

[0245] FIG. 146 is an XRPD pattern of resmetirom Form M5.

[0246] FIG. 147 is an XRPD pattern of resmetirom Form M6.

[0247] FIG. 148 is an XRPD pattern of resmetirom Form M7.

[0248] FIG. 149 is an XRPD pattern of resmetirom Form Ul.

[0249] FIG. 150 is a combined DSC and TGA thermogram of resmetirom Form U1.

[0250] FIG. 151 is an XRPD pattern of resmetirom Form U2.

[0251] FIG. 152 is a combined DSC and TGA thermogram of resmetirom Form U2.

[0252] FIG. 153 is an XRPD pattern of resmetirom Form U3.

[0253] FIG. 154 is a combined DSC and TGA thermogram of resmetirom Form U3.

[0254] FIG. 155 is an XRPD pattern of resmetirom Form U4.

[0255] FIG. 156 is an XRPD pattern of resmetirom Form U5.

[0256] FIG. 157 is an XRPD pattern of resmetirom Form U6.

[0257] FIG. 158 is a combined DSC and TGA thermogram of resmetirom Form U6.

[0258] FIG. 159 is an XRPD pattern of resmetirom Form U7.

[0259] FIG. 160 is a combined DSC and TGA thermogram of resmetirom Form U7.

[0260] FIG. 161 is an XRPD pattern of resmetirom Form U8.

[0261] FIG. 162 is a combined DSC and TGA thermogram of resmetirom Form U8.

[0262] FIG. 163 is an XRPD pattern of resmetirom Form U9.

[0263] FIG. 164 is combined DSC and TGA thermogram of resmetirom Form U9.

[0264] FIG. 165 is an XRPD pattern of resmetirom Form Cl.

[0265] FIG. 166 is an1H NMR spectrum of resmetirom Form Cl.

[0266] FIG. 167 is a combined DSC and TGA thermogram of resmetirom Form Cl.

[0267] FIG. 168 is an FTIR spectrum of resmetirom Form C1 (bottom) compared to anFTIR spectrum of Resmetirom Form I (top).

[0268] FIG. 169 is a Raman spectrum of resmetirom Form C1 (bottom) compared to aRaman spectrum of resmetirom Form I (top).

[0269] FIG. 170 is an XRPD pattern of resmetirom Form C2.

[0270] FIG. 171 is an1H NMR spectrum of resmetirom Form C2

[0271] FIG. 172 is a combined DSC and TGA thermogram of resmetirom Form C2.

[0272] FIG. 173 is an FTIR spectrum of resmetirom Form C2 (bottom) compared to anFTIR spectrum of Resmetirom Form I (top).

[0273] FIG. 174 is a Raman spectrum of resmetirom Form C2 (bottom) compared to aRaman spectrum of resmetirom Form I (top).

[0274] FIG. 175 is an XRPD pattern of resmetirom Form C3.

[0275] FIG. 176 is an XRPD pattern of resmetirom Form C4.

[0276] FIG. 177 is an1H NMR spectrum of resmetirom Form C4

[0277] FIG. 178 is a combined DSC and TGA thermogram of resmetirom Form C4.

[0278] FIG. 179 is an XRPD pattern of resmetirom Form C5.

[0279] FIG. 180 is an1H NMR spectrum of resmetirom Form C5.

[0280] FIG. 181 is a combined DSC and TGA thermogram of resmetirom Form C5.

[0281] FIG. 182 is an FTIR spectrum of resmetirom Form C5 (bottom) compared to an FTIR spectrum of resmetirom Form I (top).

[0282] FIG. 183 is a Raman spectrum of resmetirom Form C5 (bottom) compared to aRaman spectrum of resmetirom Form I (top).

[0283] FIG. 184 is an XRPD pattern of resmetirom Form C6.

[0284] FIG. 185 is an XRPD pattern of resmetirom 4-aminopyridine salt (Form C7).

[0285] FIG. 186 is an1H NMR spectrum of resmetirom 4-aminopyridine salt (Form C7).

[0286] FIG. 187 is a combined DSC and TGA thermogram of resmetirom 4- aminopyridine salt (Form C7).

[0287] FIG. 188 is an FTIR spectrum of resmetirom 4-aminopyridine salt (Form C7)(bottom) compared to an FTIR spectrum of resmetirom Form I (top).

[0288] FIG. 189 is a Raman spectrum of resmetirom 4-aminopyridine salt (Form C7)(bottom) compared to a Raman spectrum of resmetirom Form I (top).

[0289] FIG. 190 is an XRPD pattern of resmetirom imidazole salt (Form C8).

[0290] FIG. 191 is an1H NMR spectrum of resmetirom imidazole salt (Form C8).

[0291] FIG. 192 is a combined DSC and TGA thermogram of resmetirom imidazole salt(Form C8).

[0292] FIG. 193 is an FTIR spectrum of resmetirom imidazole salt (Form C8) (bottom) compared to an FTIR spectrum of resmetirom Form I (top).

[0293] FIG. 194 is a Raman spectrum of resmetirom imidazole salt (Form C8) (bottom) compared to a Raman spectrum of resmetirom Form I (top).

[0294] FIG. 195 is an XRPD pattern of resmetirom tromethamine salt (Form C9).

[0295] FIG. 196 is an1H NMR spectrum of resmetirom tromethamine salt (Form C9).

[0296] FIG. 197 is a combined DSC and TGA thermogram of resmetirom tromethamine salt (Form C9).

[0297] FIG. 198 is an XRPD pattern of resmetirom Form N1.

[0298] FIG. 199 is an1H NMR spectrum of resmetirom Form N1.

[0299] FIG. 200 is an XRPD pattern of resmetirom Form N2.

[0300] FIG. 201 is an1H NMR spectrum of resmetirom Form N2.

[0301] FIG. 202 is a combined DSC and TGA thermogram of resmetirom Form N2.

[0302] FIG. 203 is an XRPD pattern of resmetirom Form N3.

[0303] FIG. 204 is an1H NMR spectrum of resmetirom Form N3.

[0304] FIG. 205 is an XRPD pattern of resmetirom Form N4.

[0305] FIG. 206 is an1H NMR spectrum of resmetirom Form N4.

[0306] FIG. 207 is a combined DSC and TGA thermogram of resmetirom Form N4.

[0307] FIG. 208 is an XRPD pattern of resmetirom Form N6.

[0308] FIG. 209 is an1H NMR spectrum of resmetirom Form N6.

[0309] FIG. 210 is an XRPD pattern of resmetirom Form N7.

[0310] FIG. 211 i s an1H NMR spectrum of resmetirom Form N7.

[0311] FIG. 212 is a combined DSC and TGA thermogram of resmetirom Form N7.

[0312] FIG. 213 is an XRPD pattern of Resmetirom Form N9.Detailed Description

[0313] 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 belongs. The terminology used in the description is intended to describe particular embodiments only, and is not intended to limit the scope of the invention.

[0314] 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 belongs.

[0315] As used herein, the term "MRI-PDFF" describes proton-density-fat-fraction determined by a magnetic resonance imaging (MRI)-based determination. MRI-PDFF is an MRI-based diagnostic imaging biomarker of the liver. MRI-PDFF is a measure to assess liver fat content and is proposed to be used as non-invasive method used as a pre-screening strategy in an adult population having clinical signs or risk factors suggesting nonalcoholic fatty liver disease, e.g., noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis. MRI-PDFF is also used as a monitoring tool to demonstrate efficacy and reduction in NASH over time. MRI-PDFF is an accurate quantitative imaging biomarker with high repeatability and reproducibility and has provided results from test and validation datasets with MRI-PDFF compared to liver histology to show optimal MRI-PDFF cut-offs in order to reduce the number of unnecessary biopsies.

[0316] As used herein, the term "portal hypertension," refers to an increase in the pressure within the portal vein (the vein that carries blood from the digestive organs (large and small intestines, stomach, pancreas, spleen) to the liver). The increase in pressure is caused by a blockage in the blood flow through the liver.

[0317] As used herein, the term "cirrhosis," refers to a late stage of scarring (fibrosis) of the liver caused by many forms of liver diseases and conditions, such as hepatitis and chronic alcoholism. The liver fat of a cirrhosis human subject (e.g., as measured by MRI-PDFF) is no more than 5%.

[0318] 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) as its active pharmaceutical ingredient, can therefore be administered by a physician or other medical professional who writes 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.

[0319] As used herein, the term "preventing" or "prevent" describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0320] As used herein, the term "daily" means every day, where each day is defined by a24 hour period. For the avoidance of doubt, the 24 hour period defining "daily" can bridgetwo calendar days, for example, Sunday-Monday; Monday-Tuesday; Tuesday-Wednesday; etc.

[0321] As used herein, the term "dose," "dosage" or "daily dosage" refers to the weight of an active ingredient (e.g., resmetirom).

[0322] As used herein, the term "reduced dosage" refers to a dose of resmetirom or the pharmaceutically acceptable salt thereof that is less than the dose that would otherwise be administered to the human subject based on the determination of the human subject’s weight due to concomitant use of a moderate CYP2C8 inhibitor.

[0323] In some embodiments, the human subject who is administered resmetirom or the pharmaceutically acceptable salt thereof is concomitantly on a moderate CYP2C8 inhibitor regimen. Such a human subject is administered a reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof per day compared to the daily dose that would otherwise be administered if this human subject were not on a moderate CYP2C8 inhibitor regimen.

[0324] In some embodiments, the human subject was already taking the moderate CYP2C8 inhibitor prior to being administered resmetirom or the pharmaceutically acceptable salt thereof.

[0325] 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.

[0326] As used herein, the term "human subject" refers to a human subject who is an adolescent or an adult.

[0327] As used herein, an "adult human subject" refers to a human subject who is 18 years of age or older.

[0328] 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.

[0329] 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 disorder 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.

[0330] 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-acetoxybenzoic, 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-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-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 parentcompound 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 reported in U.S. Patent Application Publication Nos. 2021 / 0122740 and 2023 / 0364099, both of which are incorporated herein by reference in their entireties.

[0331] 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 or 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] As used herein, the notation "resmetirom : nicotinamide" refers to a distinct molecular species that includes resmetirom and nicotinamide. Resmetirom : nicotinamide may be a co-crystal of resmetirom and nicotinamide. Alternatively, resmetirom : nicotinamide may be a salt.

[0336] As used herein, the notation "resmetirom : caffeine" refers to a distinct molecular species that includes resmetirom and caffeine. Resmetirom : caffeine may be a co-crystal of resmetirom and caffeine. Alternatively, resmetirom : caffeine may be a salt.

[0337] As used herein, the notation "resmetirom : 2-picolinic acid" refers to a distinct molecular species that includes resmetirom and 2-picolinic acid. Resmetirom : 2-picolinic acid may be a co-crystal of resmetirom and 2-picolinic acid. Alternatively, resmetirom : 2- picolinic acid may be a salt.

[0338] As used herein, the notation "resmetirom : urea" refers to a distinct molecular species that includes resmetirom and urea. Resmetirom : urea may be a co-crystal of resmetirom and urea. Alternatively, resmetirom : urea may be a salt.

[0339] As used herein, the notation "resmetirom : N-methyl-morpholine salt" refers to a distinct molecular species that includes resmetirom and N-methyl-morpholine. Resmetirom : N-methyl-morpholine salt may be a co-crystal of resmetirom and N-methyl-morpholine salt. Alternatively, resmetirom : N-methyl-morpholine salt may be a salt.

[0340] As used herein, the notation "resmetirom : piperazine salt" refers to a distinct molecular species that includes resmetirom and piperazine salt. Resmetirom : piperazine salt may be a co-crystal of resmetirom and piperazine salt. Alternatively, resmetirom : piperazine salt may be a salt.

[0341] As used herein, the notation "resmetirom : benzathine salt" refers to a distinct molecular species that includes resmetirom and benzathine salt. Resmetirom : benzathine salt may be a co-crystal of resmetirom and benzathine salt. Alternatively, resmetirom : benzathine salt may be a salt.

[0342] As used herein, the notation "resmetirom : L-proline" refers to a distinct molecular species that includes resmetirom and L-proline. Resmetirom : L-proline may be a co-crystal of resmetirom and L-proline. Alternatively, resmetirom : L-proline may be a salt.

[0343] As used herein, an "amorphous form" refers to a non-crystalline material that lacks long-range order in its structure.

[0344] 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 inpracticing 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.

[0345] 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.

[0346] 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. Resmetirom has the chemical structure depicted below:

[0347] 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.

[0348] Various forms of resmetirom or the pharmaceutically acceptable salt thereof — and processes for preparing the same — are reported in the following patents, applications, and / or publications, all of which are incorporated herein by reference in their entireties:• U.S. Patent No. 9,266,861• U.S. Patent No. 10,376,517• 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 Application Publication No. 2022 / 0372021• U.S. Patent Application Publication No. 2023 / 0364099

[0349] 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.

[0350] In some embodiments, the resmetirom exists in a crystalline form.

[0351] In some embodiments, the resmetirom exists in an amorphous form.

[0352] In some embodiments, the resmetirom is in the form of a solvate.

[0353] In some embodiments, the solvate is selected from 1,1,1 -tri chloroethane, 1,1,2- trichloroethene, 1,1 -di chloroethene, 1,2-di chloroethane, 1,2-di chloroethene, 1,2- dimethoxyethane, 1,3 dioxolane, 1,4-dioxane, 1-butanol, 1-pentanol, 1-propanol, 2,2,2- trifluoroethanol, 2-butanol, 2-ethoxy ethanol, 2-methoxy ethanol, 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, trifl our otoluene, Tween 2.1 wt%, and xylene.

[0354] In some embodiments, the solvate is 2,2,2-trifluoroethanol, cyclohexanone, methyl acetate, methylethyl ketone, N,N-dimethylformamide, nitromethane, N-methylpyrrolidone, tert-butanol, or xylene.

[0355] In some embodiments, the resmetirom is in the form of a hydrate.

[0356] 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.

[0357] In some embodiments, the co-crystal former is selected from 1-(2- hydroxyethyl)pyrrolidine, 1 -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, 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), caprylic 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- di chloroacetic acid, diethanolamine, di ethylamine, 2-di ethylaminoethanol, 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, naphthal ene- 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), 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.

[0358] In some embodiments, the co-crystal former is 4-aminopyridine, cytosine, 2,2- di chloroacetic acid, diethylamine, dimethyl glycine, 1H-imidazole, pantothenic acid (calcium pantothenate), triethyl citrate, or tromethamine.

[0359] In some embodiments, the co-crystal former is L-proline, caffeine, or 2-picolinic acid.

[0360] In some embodiments, resmetirom exists in a co-crystal form or a salt form including resmetirom : nicotinamide, resmetirom : caffeine, resmetirom : 2-picolinic acid, resmetirom : urea, resmetirom : N-methyl-morpholine salt, resmetirom : piperazine salt, resmetirom : benzathine salt, or resmetirom : L-proline.

[0361] 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 otherwisestated. 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.

[0362] Resmetirom is described, for example, in Examples 4 and 5 of U.S. Patent No. 9,266,861 and WO 2014 / 043706. One aspect of the present disclosure relates to methods of treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) in which a solid dosage form 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, existing in a morphic form (e.g., an amorphous form, a crystalline form, a solvate, or a hydrate) or a mixture of morphic forms.

[0363] In some embodiments, resmetirom exists in Form I. Form I is described in U.S. Patent No. 9,266,861 and WO 2014 / 043706 and can be synthesized as shown, for example, in Examples 6 and 7 of U.S. Patent No. 9,266,861 and WO 2014 / 043706.

[0364] Example 6 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 describes conversion of resmetirom to Form I:

[0365] Purified resmetirom (4802 g) as a 1 : 1 MIBK solvate which was obtained from Int. 8 as described in Example 5 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 above was added into a jacketed, 100 L reactor along with 24 liters of ethanol. The resulting slurry was heated to 80 ± 5 °C (reflux) over 1 h 25 min; the mixture was stirred at that temperature for 4 h 25 min. Analysis of the filtered solids at 2 h 55 min indicated that the form conversion was complete, with the XRPD spectra conforming to Form I. The mixture was cooled to 20 ± 5 °C over 45 min and stirred at that temperature for 15 min. The slurry was filtered and thefilter cake was washed twice with prefiltered ethanol (2 x 4.8 L). The wet cake (4.28 kg) was dried under vacuum at 40 ± 5 °C for 118 h to afford 3390 g of resmetirom Form I.

[0366] The X-ray Powder Diffraction study was performed on different lots of resmetirom m orphic Form I generated by the process described above. XRPD after micronization confirms Form I.

[0367] The data for Form I is provided in the table below and the diffractograms of Form I are provided as FIG. 43.

[0368] Table 11 of U.S. Patent No. 9,266,861 and WO 2014 / 043706

[0369] Form I was found to have a melting onset around 321 °C, followed by decomposition upon melting by DSC (FIG. 44).

[0370] Example 7 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 describes preparation of resmetirom Form I: conversion of resmetirom solvate to Form I:

[0371] A 50 L, jacketed, glass vessel purged with N2 was charged with resmetirom MIBK solvate (2.72 kg) from Example 5 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 above and ethanol (13.6 L). The agitator was started and the batch temperature was adjusted from 16.8 °C to 79.4 °C over 1.3 h. The batch was held at 79.5 °C for 2 h and sampled for XRPD analysis. XRPD indicated Form I, and the batch was cooled to 24.9 °C over 1 h and 10 min. An 18" Nutsche filter equipped with tight-weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 4 min. Ethanol (2.8 L) was charged to the vessel and transferred to the filter cake. The cake was manually resuspended and the liquors were pulled through with vacuum. Ethanol (2.80 L) was charged to the filter cake and the cake was manually resuspended. The liquors were pulled through with vacuum and the cake was conditioned with vacuum and nitrogen for 1 h. The filter cake was transferred to drying pans and dried at 45 °C and 28 " / Hg for one day to give an 89% yield (1.96 kg) of resmetirom as a light yellow solid. HPLC analysis indicated a purity of 99.6%. XRPD analysis is consistent with Form I. Micronization of 300 g of this material on a 2" jet mill gave 284 g (95% yield) of micronized resmetirom. XRPD analysis confirmed that micronized resmetirom remained Form I.

[0372] Resmetirom DMAC solvate can be converted, via the dihydrate and the MIBK solvate, to Form I as described in Example 7 of U.S. Patent No. 9,266,861 and WO 2014 / 043706. Alternatively, the DMAC solvate was converted directly to Form I in 75% yield (yield calculated from Intermediate 8) by heating it with 8 volumes of ethanol to 80 °C for 2 hours followed by cooling to room temperature and filtering. In another reaction, a sample of resmetirom that was a mixture of the DMAC solvate and dihydrate was converted to Form I in 69% yield by heating it with 8 volumes of MIBK to 80°C followed by cooling to room temperature.

[0373] In some embodiments, Form I of resmetirom is characterized by an X-ray powder diffraction (XRPD) pattern including signals (e.g., peaks) at 10.5°±0.2°, 18.7°±0.2°, 22.9°±0.2°, 23.6°±0.2°, and 24.7°±0.2° 29. In some embodiments, the XRPD pattern further includes one or more signals (e.g., peaks) at 8.2°±0.2°, 11.2°±0.2°, 15.7°±0.2°, 16.4°±0.2°, 17.7°±0.2°, 30.0°±0.2°, and 32.2°±0.2° 29. The XRPD pattern of Form I of 2-(3,5-dichloro- 4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro- l,2,4-triazine-6-carbonitrile (resmetirom) is described, for example, in Table 11 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 and FIG. 43.

[0374] In some embodiments, Form I of resmetirom is characterized by a differential scanning calorimetry (DSC) diagram comprising an endothermic peak at 329° C. In some embodiments, Form I of resmetirom is further characterized by an onset melting temperature of 321° C. The DSC diagram of Form I resmetirom is described for example in Example 6 of U.S. Patent No. 9,266,861 and WO 2014 / 043706 and FIG. 44.

[0375] In some embodiments, resmetirom or a pharmaceutically salt thereof exists in a morphic form (e.g., crystalline form), as described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068 (incorporated herein by reference in their entireties).

[0376] In some embodiments, resmetirom is Form λ, which is described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068.

[0377] Form λ can be produced as described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068:

[0378] A suspension of resmetirom and isopropyl acetate was stirred for 2 days then filtered. Heating to 100°C for 1 hour generated the desolvate. (Form λ, FIG. 45).

[0379] In some embodiments, Form λ of resmetirom is characterized by an X-ray powder diffraction pattern including peaks at 10.6°±0.2°, 12.0°±0.2°, 14.3°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 18.0°±0.2°, and 24.3°±0.2° 29, wherein the X-ray powder diffraction pattern is obtained using a CuKα radiation source (1.54 A). In some embodiments, the X-ray powder diffraction pattern of Form λ can further include one or more peaks from Table 29 of U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068. In some embodiments, Form λ has an X-ray diffraction pattern substantially similar to that set forth in FIG. 45.

[0380] Table 29 of U.S. Patent Application Publication No. 2021 / 0122740 and WO2020 / 010068 provides the following data:

[0381] In some embodiments, resmetirom is Form F, which is described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068.

[0382] Form F can be produced as described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068:

[0383] A suspension of resemtirom and ethyl acetate was stirred for 2 days then filtered. Heating to 100°C for 1 hour generated the desolvate (Form F, FIG. 46).

[0384] In some embodiments, Form F of resmetirom is characterized by an X-ray powder diffraction pattern including peaks at 10.1 °±0.2°, 10.4°±0.2°, 11.4°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 16.4°±0.2°, 17.1°±0.2°, 22.0°±0.2°, 23.8°±0.2°, and 29.5°±0.2° 20, wherein the x-ray powder diffraction pattern is obtained using a CuKα radiation source (1.54 A). In some embodiments, the X-ray powder diffraction pattern of Form F can further include one or more peaks from Table 8 of U.S. Patent Application Publication No. 2021 / 0122740 and WO2020 / 010068. In some embodiments, Form F has an X-ray diffraction pattern substantially similar to that set forth in FIG. 46.

[0385] Table 8 of U.S. Patent Application Publication No. 2021 / 0122740 and WO2020 / 010068 provides the following data:

[0386] In some embodiments, resmetirom is Form L, which is described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068.

[0387] Form L can be produced as described in U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068:

[0388] A suspension of resmetirom and acetonitrile was stirred for 2 days then filtered.XRPD analysis indicated the formation of the acetonitrile solvate (Form L, FIG. 47).

[0389] In some embodiments, Form L of resmetirom is characterized by an X-ray powder diffraction pattern including peaks at 10.5°±0.2°, 11.5°±0.2°, 11.9°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 16.0°±0.2°, 16.9°±0.2°, 17.1°±0.2°, 18.4°±0.2°, 18.7°±0.2°, 22.0°±0.2°, 22.8°±0.2°, 23.5°±0.2°, and 26.4°±0.2° degrees 2θ, wherein the x-ray powder diffraction pattern is obtained using a CuKα radiation source (1.54 A). In some embodiments, the X-ray powder diffraction pattern of Form L can further include one or more peaks from Table 13 of U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068. In some embodiments, Form L has an X-ray diffraction pattern substantially similar to that set forth in FIG. 47.

[0390] Table 13 of U.S. Patent Application Publication No. 2021 / 0122740 and WO 2020 / 010068 provides the following data:

[0391] A number of forms of resmetirom have been reported in the art.

[0392] For example, one of the forms is Form CSIV reported in U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465.

[0393] Form CSIV may be characterized, for instance, by the X-ray powder diffraction pattern that comprises characteristic peaks at 2-theta values of 6.3°±0.2°, 18.1°±0.2°, and 25.3°±0.2° using CuKα radiation. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.4°±0.2°, 14.5°±0.2°, 20.6°±0.2°, 24.6°±0.2°, and 28.6°±0.2°2-theta.

[0394] Example 1 of U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465 describes preparation of resmetirom crystalline Form CSIV:

[0395] 145.2 mg of resmetirom solid was weighed into a glass vial. 1.5 mL of acetonitrile was added, and then stirred at room temperature for three days to form a suspension. The suspension was centrifuged to obtain a solid. The obtained solid was dried under vacuum at 100° C. for 3.5 hours to obtain resmetirom crystalline Form CSIV.

[0396] The XRPD pattern of resmetirom crystalline Form CSIV obtained in this example is shown in FIG. 48, and the XRPD data are listed in Table 2 of U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465.

[0397] Table 2 of U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465 provides the following data:

[0398] The TGA curve of resmetirom crystalline Form CSIV is substantially as depicted in FIG. 49, which shows about 0.1% weight loss when heated to 200° C.

[0399] The DSC curve of resmetirom crystalline Form CSIV is substantially as depicted in FIG. 50, which shows an exothermic peak and an endothermic peak. The peak at around 245° C. (onset temperature) is an exothermic peak of crystal transformation, and the endothermic peak at around 334° C. (onset temperature) corresponds to melting.

[0400] The1H NMR data of resmetirom crystalline Form CSIV are:1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.24 (s, 1H), 7.78 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H), 1.20 (d, J=6.9 Hz, 6H).

[0401] Example 2 of U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465 also describes preparation of resmetirom Crystalline Form CSIV:

[0402] A certain amount of resmetirom solid was put in 30 mL of acetonitrile and stirred at -20° C. for about 37.5 h. The obtained solid was separated and dried under vacuum at 50° C. for about 23.5 h to obtain resmetirom crystalline Form CSIV.

[0403] For example, one of the forms is Form CSV reported in WO 2021 / 129465.

[0404] Form CSV may be characterized, for instance, by the X-ray powder diffraction pattern that comprises characteristic peaks at 2-theta values of 11.9°±0.2°, 13.8°±0.2°, and 17.3°±0.2° using CuKα radiation. The X-ray powder diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 19.9°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 24.5°±0.2°, 26.2±0.2°, and 27.0°±0.2° 2-theta.

[0405] Example 3 of U.S. Patent Application Publication No. 2022 / 0372021 and WO 2021 / 129465 describes preparation of resmetirom crystalline Form CSV:

[0406] 2.0742 g of resmetirom solid was weighed into a glass vial, 30 mL of dimethyl carbonate was added, and then stirred at 5° C. for 19 hours to form a suspension. The suspension was centrifugated and the separated solid was dried under vacuum at 50° C. for 4 hours to obtain a dry solid. 54.9 mg of the dry solid was weighed into a glass vial, 1 mL of isopropyl alcohol was added, and then stirred at 5° C. for 1.5 hours to obtain resmetirom crystalline Form CSV.

[0407] The XRPD pattern of resmetirom crystalline Form CSV obtained in this example is shown in FIG. 86, and the XRPD data are listed in Table 3 of U.S. Patent ApplicationPublication No. 2022 / 0372021 and WO 2021 / 129465.

[0408] Table 3 of U.S. Patent Application Publication No. 2022 / 0372021 and WO2021 / 129465 provides the following data:

[0409] The TGA curve of resmetirom crystalline Form CSV is substantially as depicted in FIG. 87, which shows about 0.1% weight loss when heated to 200° C.

[0410] The1H NMR data of resmetirom crystalline Form CSV are:1H NMR (400 MHz. DMSO~d6) 6 13.29 (s, 1H), 12.25 (s, 1H), 7.79 (s, 2H), 7.45 (s, 1H), 3.05 (m, 1H). 1.20 (d, J ==6.9 Hz, 6H).

[0411] For example, one of the forms is Form CSVI reported in U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822.

[0412] Form CSVI may be characterized, for instance, by the X-ray powder diffraction pattern that comprises characteristic peaks at 2-theta values of 9.6°±0.2°, 10.1°±0.2°, and 18.9°±0.2° using CuKα radiation. The X-ray powder diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 11.6°±0.2°, 13.7°±0.2°, 19.5°±0.2°, 20.6°±0.2°, 23.3±0.2°, and 31.9°±0.2° 2-theta.

[0413] Example 1 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 describes preparation of resmetirom crystalline Form CSVI:

[0414] 1.5801 g of resmetirom was weighed into a glass bottle, followed by adding 25 mL of acetonitrile, and then stirred at room temperature for 4 days. The obtained solid was separated by filtration, and then blast dried the obtained solid at 40° C. for 15.5 h to obtain the resmetirom crystalline form CSVI.

[0415] The XRPD pattern of resmetirom crystalline Form CSVI obtained in this example is shown in FIG. 107, and the XRPD data are listed in Table 3 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 .

[0416] Table 3 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 provides the following data:

[0417] The TGA curve of resmetirom crystalline Form CSVI is substantially as depicted in FIG. 108, which shows about 0.2% weight loss when heated to 250° C.

[0418] The1H NMR data of resmetirom crystalline Form CSVI are:1H NMR (400MHz, DMSO-d6) δ 13.28(s, 1H), 12.23(s, 1H), 7.79(s, 2H), 7.44(d, J=0.8Hz, 1H), 3.04 (dq, J=13.5, 6.8 Hz, 1 H). 120 (d. J=6 .9 Hz, 6H).

[0419] Example 2 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 describes preparation of resmetirom crystalline Form CSVI:

[0420] 22.0 mg of resmetirom was weighed into a glass bottle, followed by adding 2.0 mL of the solvent mixture of acetonitrile and water (95:5, V:V), and then dissolved at 50° C., filtered, then the filtrate was stirred at -20° C. for 4 h. The obtained solid was separated by filtration, and then dried the obtained solid at 25° C. under a vacuum for 2 h to obtain the resmetirom crystalline Form CSVI.

[0421] The XRPD pattern of resmetirom crystalline Form CSVI obtained in this example is shown in FIG. 109, and the XRPD data are listed in Table 4 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 .

[0422] Table 4 of U.S. Patent Application Publication No. 2023 / 0416234 and WO 2022 / 052822 provides the following data:

[0423] For example, one of the forms is Form CSVII reported in WO 2025 / 011259.

[0424] Form CSVII may be characterized, for instance, by the X-ray powder diffraction pattern that comprises characteristic peaks at 2-theta values of 6.5°±0.2°, 7.7°±0.2°, and 23.4°±0.2° using CuKα radiation. The X-ray powder diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 12.2°±0.2°, 19.7°±0.2°, 21.1±0.2°, 22.7°±0.2°, 24.2°±0.2°, and 25.4°±0.2° 2-theta.

[0425] Example 1 of WO 2025 / 011259 describes preparation of resmetirom crystallineForm CSVII:

[0426] 527.6 mg of resmetirom was weighed into a glass bottle, followed by adding 15 mL of methyl tert-butyl ether, and then stirred at room temperature for 1 day. The obtained solid was separated by filtration, and then dried under vacuum at 25° C. for 0.5 hour to obtain a dried soled. The partially dried solid was heated to 140° C. at 10° C. / min under the protection of nitrogen and kept warm form 60 minutes, cooled to room temperature to obtain the resmetirom crystalline form CSVII.

[0427] The XRPD pattern of resmetirom crystalline Form CSVII obtained in this example is shown in FIG. 116, and the XRPD data are listed in Table 2 of WO 2025 / 011259.

[0428] Table 2 of WO 2025 / 011259 provides the following data:

[0429] The TGA curve of resmetirom crystalline Form CSVII is substantially as depicted in FIG. 117, which shows about 0.5% weight loss when heated to 100° C.

[0430] The DSC curve of resmetirom crystalline Form CSVII is substantially as depicted in FIG. 118, which shows an exothermic peak near 264° C. and an endothermic peak near 333° C.

[0431] The1H NMR data of resmetirom crystalline Form CSVII are:1H NMR (400MHz, DMSO-d6) δ 12.24(s, 1H), 7.79(s, 2H), 7.44(d, J= 0.7Hz. 1H), 3.13-2.97 (m, = 1 1). 1.19 (d, J 6 9 Hz. 6H).

[0432] For example, one of the forms is Form Type K65 reported in WO 2025 / 011259.

[0433] Example 4 of WO 2025 / 011259 describes preparation of resmetirom crystalline Form Type K65:

[0434] 51.2 mg of resmetirom was weighed into a vial, a mixed solvent (volume ratio of 7: 1) of 1.0 mL of acetonitrile and methanol was added, the mixture was suspended and stirred overnight at room temperature, and centrifugation was performed to obtain the resmetirom crystalline Form Type K65.

[0435] The XRPD pattern of resmetirom crystalline Form Type K65 obtained in this example is shown in FIG. 119, and the XRPD data are listed in Table 5 of WO 2025 / 011259.

[0436] Table 5 of WO 2025 / 011259 provides the following data:

[0437] Example 5 of WO 2025 / 011259 describes preparation of resmetirom crystallineForm Type K65:

[0438] 10.1 mg of resmetirom was weighed into a vial, 0.2 mL of acetonitrile was added, sonicated at room temperature for about 1 minute, and centrifuged to obtain the resmetirom crystalline Form Type K65.

[0439] The XRPD pattern of resmetirom crystalline Form Type K65 obtained in this example is shown in FIG. 120, and the XRPD data are listed in Table 6 of WO 2025 / 011259.

[0440] Table 6 of WO 2025 / 011259 provides the following data:

[0441] For example, one of the forms is Form Type K65 desolvate reported in WO2025 / 011259.

[0442] Example 6 of WO 2025 / 011259 describes preparation of resmetirom crystallineForm Type K65 desolvate:

[0443] The crystalline Form Type K65 obtained in Example 4 was placed in a room temperature environment for about 5 h.

[0444] The XRPD pattern of resmetirom crystalline Form Type K65 desolvate obtained in this example is shown in FIG. 120, and the XRPD data are listed in Table 6 of WO 2025 / 011259.

[0445] Table 6 of WO 2025 / 011259 provides the following data:

[0446] For example, one of the forms is Form R3-A reported in U.S. Patent ApplicationPublication No. 2023 / 0364099 and WO 2022 / 086894.

[0447] The crystalline Form R3-A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 55; an X-ray powder diffraction pattern having peaks at 8.6°±0.2°, 9.3°±0.2°, 10.3°±0.2°,16.9°±0.2° and 18.3°±0.2° 2-theta; a solid state13C NMR spectrum with characteristic peaks at 161.7±0.2, 152.4±0.2, 135.1±0.2, 60.8±0.2 and 46.5±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 174.7 ppm ± 1 ppm: 13.0±0.1, 22.3±0.1, 39.6±0.1, 114.0±0.1 and 128.3±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIGS. 56, 57, or 58; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 16.4°±0.2°, 20.1°±0.2°, 21.9°±0.2°, 24.8°±0.2° and 25.8°±0.2° 2-theta.

[0448] Example 22 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of resmetirom Form R3-A (resmetirom : L-proline Form R3-A):

[0449] Procedure A

[0450] 2-methoxy ethanol (3.5 ml, 26Vol) was added to L-proline (132 mg, 1.15 mmol) to give a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Then, resmetirom (500 mg, 1.15 mmol) was added to the magnetically stirred clear hot solution at 80 °C to obtain a slurry. Next, the slurry was magnetically stirred at 80 °C to give a clear solution and after 15 minutes precipitation occurred. Next, the obtained slurry was cooled to room temperature and was magnetically stirred for 18 hours. Then the solid was filtered by Buchner and dried in vacuum oven at 45 °C for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 53.

[0451] Procedure B

[0452] 2-methoxy ethanol (0.66 ml, 55V) was added to L-proline (12 mg, 0.11 mmol) to give a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain clear solution, followed by a hot mechanical filtration. Then, the obtained clear solution was placed in a 4 ml vial. Next, in another 4 ml vial, 2-methoxy ethanol (0.21 ml, 7V) was added to resmetirom (30 mg, 0.07 mmol) to give a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain clear solution, followed by a hot mechanical filtration. Then, the resmetirom hot solution was added to the 4 ml vial that contained the L-Proline hot solution and the reaction was magnetically stirred at 80 °C for 15 minutes. Then, the clear solution was concentrated by rotor vapor. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom L-proline salt Form R3-A.

[0453] For example, one of the forms is Form RC1-A (resmetirom : nicotinamide) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0454] The crystalline Form RC1-A of resmetirom : nicotinamide may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 59; an X-ray powder diffraction pattern having peaks at 8.7°±0.2°, 18.6°±0.2°, 21.1°±0.2°, 25.3°±0.2° and 26.4°±0.2° 2-theta; a solid state13C NMR spectrum with characteristic peaks at 159.9±0.2, 153.4±0.2, 136.2±0.2, 134.9±0.2 and 119.1±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 170.2 ppm±l ppm: 10.3±0.1, 16.8±0.1, 34.0±0.1, 35.3±0.1 and 51.0±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIG. 60, 61, or 62 ; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 11.5°±0.2°, 12.6°±0.2°,13.9°±0.2°, 20.1°±0.2° and 22.0°±0.2° 2-theta.

[0455] Example 24 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form RC1-A (resmetirom : nicotinamide).

[0456] Procedure A

[0457] Resmetirom (200 mg, 0.46 mmol) was grinded by mortar and pestle with Nicotinamide (56.2 mg, 0.46 mmol, 1 eq.) for 1 minute. Dichloromethane was added to 50 mg of grinding mixture of resmetirom and nicotinamide to give slurry. The obtained slurry was seeded with 0.1-0.5% of resmetirom : nicotinamide Form RC1-A (prepared according to procedure B or C) and was magnetically stirred at room temperature for 18 hours. Then, the solid was separated by centrifuge and dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and the XRPD pattern is presented in FIG. 59.

[0458] Procedure B

[0459] 2-methoxy ethanol (0.25 ml, 5 V) was added to resmetirom (50 mg, 0.115 mmol) to give slurry. The obtained slurry was stirred at 80° C. for 30 minutes to full dissolution of the solid. Next, nicotinamide (14.05 mg, 0.115 mmol, 1 eq.) was added to obtained hot clear solution to give slurry. Then, the obtained slurry was magnetically stirred at 80° C., for 30 min. to full dissolution of the solid. Next, the above mixture was dried in a vacuum oven at 45° C. for 18 hours to obtain yellow solid. Then, Dichloromethane (0.512 ml, 8V) was added to give slurry. The obtained slurry was magnetically stirred at 25° C. for 18 hours. Then the solid separated by centrifuge and dried in vacuum oven at 45° C. for 18 hours. The solid was analyzed by X-ray powder diffraction and characterized as resmetirom : nicotinamide Form RC1-A.

[0460] Procedure C

[0461] Resmetirom (50 mg, 0.115 mmol) was grinded by mortar and pestle with Nicotinamide (14.05 mg, 0.115 mmol, 1 eq.) for 1 minute. The obtained solids mixture was heated in 1.7 ml glass vial at 140° C. (10° C. higher than the melting point of co-former) for 2 hours. Then, the vial was cooled to 120° and heated at this temperature for 1 hour. Next, the vial was cooled to room temperature. The obtained solid was analyzed and characterized as resmetirom : nicotinamide Form RC1-A.

[0462] Procedure D

[0463] Dichloromethane (0.48 ml, 8V) was added to resmetirom methyltetrahydrofuran solvate (50 mg, 0.115 mmol) to give slurry. Next, nicotinamide (14 mg, 0.115 mmol, 1.0 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC1-A. Next, the slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : nicotinamide crystal Form RC1-A.

[0464] Procedure E

[0465] Dichloromethane (0.48 ml, 8V) was added to resmetirom methylethyl ketone solvate (50 mg, 0.115 mmol) to give slurry. Next, nicotinamide (14 mg, 0.115 mmol, 1.0 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC1-A. Next, the slurry was magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solidwas analyzed by X-ray powder diffraction and identified as resmetirom : nicotinamide crystalline Form RC1-A.

[0466] For example, one of the forms is Form RC2-A (resmetirom : caffeine) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0467] The crystalline Form RC2-A of resmetirom: caffeine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 63; an X-ray powder diffraction pattern having peaks at 6.0°±0.2°, 6.8°±0.2°, 10.4°±0.2°, 11.2°±0.2° and 16.4°±0.2° 2-theta; a solid state13C NMR spectrum with characteristic peaks at 139.5±0.2, 118.8±0.2, 106.7±0.2, 34.0±0.2 and 29.6±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 161.0 ppm±l ppm: 21.4±0.1, 42.2±0.1, 54.3±0.1, 127.0±0.1 and 131.4±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIGS. 64, 65, or 66; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 14.6°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2° and 26.9°±0.2° 2-theta.

[0468] Example 25 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form RC2-A (resmetirom : caffeine).

[0469] Procedure A

[0470] 2-methoxy ethanol (0.2 ml, 6.7V) was added to resmetirom (30 mg, 0.07 mmol) to give a slurry. The obtained slurry was stirred at 80° C. during 30 minutes to full dissolution of the solid. Next, caffeine (13.4 mg, 0.07 mmol, 1 eq.) was added to obtained hot clear solution to give a slurry. Then, ethanol (0.2 ml, 6.7V) was added to the obtained slurry and was magnetically stirred at 80° C., for 30 minutes to full dissolution of the solid. The mixturewas dried in a vacuum oven at 45° C. for 18 hours, to obtain yellow solid. Then, isopropanol (0.18 ml, 4V) was added to give slurry. The obtained slurry was magnetically stirred at 25° C. for 18 hours. Then the solid separated by centrifuge and dried in vacuum oven at 45° C. for 18 hours. The solid was analyzed by X-ray powder diffraction and the XRPD pattern is presented in FIG. 63.

[0471] Procedure B

[0472] Iso-propyl alcohol (0.45 ml, 6V) was added to resmetirom methyltetrahydrofuran solvate (50 mg, 0.115 mmol) to give slurry. Next, caffeine (24.2 mg, 0.126 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC2-A. Next, the slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : caffeine crystal Form RC2-A.

[0473] Procedure C

[0474] Iso-propyl alcohol (0.45 ml, 6V) was added to resmetirom methylethyl ketone solvate (50 mg, 0.115 mmol) to give slurry. Next, caffeine (24.2 mg, 0.126 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC2-A. Next, the slurry was magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : caffeine crystalForm RC2-A.

[0475] For example, one of the forms is Form RC2-B (resmetirom : caffeine) reported inU.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0476] The crystalline Form RC2-B of resmetirom: caffeine may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 67; an X-ray powder diffraction pattern having peaks at 8.9°±0.2°, 10.6°±0.2°, 11.2°±0.2°, 14.5°±0.2° and 17.1°±0.2° 2-theta; a solid state13C NMR spectrum with characteristic peaks at 145.9±0.2, 142.7±0.2, 108.7±0.2, 33.5±0.2 and 28.1±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 161.1 ppm±l ppm: 15.2±0.1, 18.45±0.1, 52.4±0.1, 127.6±0.1 and 133.0±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIGS. 68, 69, or 70; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 14.9°±0.2°, 20.0°±0.2°, 21.9°±0.2°, 24.5°±0.2° and 28.2°±0.2° 2-theta.

[0477] Example 26 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form RC2-B (resmetirom : caffeine).

[0478] Procedure A

[0479] 2-methoxy ethanol (0.2 ml, 6.7V) was added to resmetirom (30 mg, 0.07 mmol) to give a slurry. The obtained slurry was stirred at 80° C. for 30 minutes to full dissolution of the solid. Next, caffeine (13.4 mg, 0.07 mmol, 1 eq.) was added to obtained hot clear solution to give slurry. Then, ethanol (0.2 ml, 6.7V) was added to the obtained slurry and was magnetically stirred at 80° C., for 30 minutes to full dissolution of the solid. Next, the above mixture was dried in a vacuum oven at 45° C. for 18 hours, to obtain yellow solid. Then, toluene (0.18 ml, 4V) was added to give slurry. The obtained slurry was magnetically stirredat 25° C. for 18 hours. Then the solid separated by centrifuge and dried in vacuum oven at 45° C. for 18 hours. The solid was analyzed by X-ray powder diffraction and the XRPD pattern is presented in FIG. 67.

[0480] Procedure B

[0481] Resmetirom (200 mg, 0.46 mmol) was grinded by mortar and pestle with caffeine (89 mg, 0.46 mmol, 1 eq.) for 1 minute. Toluene (4 Vol) was added to 250 mg of grinded mixture of resmetirom and caffeine to give a slurry. The obtained slurry was seeded with 0.1- 0.5% of resmetirom : caffeine Form RC2-B (prepared according to procedure example 26, procedure A) and was magnetically stirred at 25° C. for 48 hours. Then, the solid was separated by centrifuge and dried in vacuum oven at 45° C. for 72 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as Form RC2-B.

[0482] Procedure C

[0483] Toluene (0.30 ml, 4V) was added to resmetirom methyltetrahydrofuran solvate (50 mg, 0.115 mmol) to give slurry. Next, caffeine (24.2 mg, 0.126 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom : caffeine Form RC2-B. Next, the slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : caffeine crystal Form RC2-B.

[0484] Procedure D

[0485] Toluene (0.30 ml, 4V) was added to resmetirom methylethyl ketone solvate (50 mg, 0.115 mmol) to give slurry. Next, caffeine (24.2 mg, 0.126 mmol, 1.1 eq.) was added tothe obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom : caffeine Form RC2-B. Next, the slurry was magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : caffeine crystal Form RC2-B.

[0486] For example, one of the forms is Form RC3-A (remetirom : 2-picolinic acid) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0487] The crystalline Form RC3-A of resmetirom: 2-picolinic acid may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 71; an X-ray powder diffraction pattern having peaks at 6.0°±0.2°, 6.8°±0.2°, 12.9°±0.2°, 15.6°±0.2° and 26.9°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 10.4°±0.2°, 14.8°±0.2°, 18.0°±0.2°, 18.5°±0.2° and 24.7°±0.2° 2-theta.

[0488] Example 27 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form RC3-A (resmetirom : 2-picolinic acid).

[0489] Procedure A

[0490] 2-methoxy ethanol (0.375 ml, 7.5V) was added to resmetirom (50 mg, 0.115 mmol) to give a slurry. The obtained slurry was stirred at 80° C. during 30 minutes to full dissolution of the solid. Next, 2-picolinic acid (14.6 mg, 0.115 mmol, 1 eq.) was added to obtained hot clear solution to give a slurry. Then, the obtained slurry was magnetically stirred at 80° C., for 30 minutes to full dissolution of the solid. Next, the above mixture was dried ina vacuum oven at 45° C. for 18 hours, to obtain yellow solid. The solid was analyzed by X- ray powder diffraction and the XRPD pattern is presented in FIG. 71.

[0491] Procedure B

[0492] Dichloromethane (0.5 ml, 8V) was added to resmetirom methyltetrahydrofuran solvate (50 mg, 0.115 mmol) to give slurry. Next, 2-picolinic acid (15.62 mg, 0.126 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC3-A. Next, the slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : 2- picolinic acid crystal Form RC3-A.

[0493] Procedure C

[0494] Dichloromethane (0.5 ml, 8V) was added to resmetirom methyltetrahydrofuran solvate (50 mg, 0.115 mmol) to give slurry. Next, 2-picolinic acid (15.62 mg, 0.126 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC3-A. Next, the slurry was magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifuge and then was dried in a vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : 2- picolinic acid crystal Form RC3-A.

[0495] For example, one of the forms is Form RC4-A (resmetirom : urea) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894. In some embodiments, the molar ratio of resmetirom and urea is about 1 : 1.

[0496] The crystalline Form RC4-A of resmetirom: urea may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 72; an X-ray powder diffraction pattern having peaks at 7.6°±0.2°, 12.6°±0.2°, 15.7°±0.2°, 16.4°±0.2° and 16.9°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 15.2°±0.2°, 19.1°±0.2°, 19.6°±0.2°, 22.0°±0.2° and 23.6°±0.2° 2-theta.

[0497] Example 28 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form RC4-A (resmetirom : urea).

[0498] Procedure A

[0499] Resmetirom (100 mg, 0.23 mmol) and urea (14 mg, 0.23 mmol) were dissolved in 2-methoxy ethanol (0.57 ml, 5.7 Vol) at 80° C. for 30 minutes. The obtained solution was dried in vacuum oven at 50° C. for 18 hours to give a solid and then was dried in vacuum oven at 80° C. for 18 hours. The obtained solid was characterized by X-ray powder diffraction as resmetirom : urea crystal Form RC4-A (FIG. 72).

[0500] Procedure B

[0501] Dichloromethane (0.48 ml, 8V) was added to resmetirom Me-THF solvate (50 mg, 0.115 mmol) to give slurry. Next, urea (7.7 mg, 0.128 mmol, 1.1 eq.) was added to obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and then was seeded with 0.1-0.5% of resmetirom Form RC4-A. The slurry was magnetically stirred at room temperature for 4 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : urea crystal Form RC4-A.

[0502] Procedure C

[0503] Dichloromethane (0.46 ml, 8V) was added to resmetirom methylethyl ketone solvate (50 mg, 0.115 mmol) to give slurry. Next, urea (7.7 mg, 0.128 mmol, 1.1 eq.) was added to the obtained slurry. Then, the obtained slurry was magnetically stirred at room temperature, and was seeded with 0.1-0.5% of resmetirom Form RC4-A. Next, this slurry was magnetically stirred at room temperature for 3 days. The precipitate was separated by centrifuge and then was dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : urea crystal Form RC4- A.

[0504] For example, one of the forms is Form Rl-A (resmetirom : N-methylmorpholine salt) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0505] The crystalline Form Rl-A of resmetirom : N-methylmorpholine salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 73 ; an X-ray powder diffraction pattern having peaks at 8.2°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.6°±0.2° and 21.5°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 10.0°±0.2°, 14.5°±0.2°, 20.2°±0.2°, 22.4°±0.2° and 27.4°±0.2° 2-theta.

[0506] Example 20 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form Rl-A (resmetirom : N-methylmorpholine salt).

[0507] Procedure A

[0508] N-methylmorpholine [4-methylmorpholine] (4.0 ml, 20V) was added to resmetirom (200 mg, 0.26 mmol) to obtain a slurry. The slurry was magnetically stirred atroom temperature over a period of 48 hours. Next the solid was separated by centrifuge and dried in vacuum oven at 45° C. for 18 hours and was then analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 73.

[0509] For example, one of the forms is Form R2-A (resmetirom : piperazine salt) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0510] The crystalline Form R2-A of resmetirom : piperazine salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 74; an X-ray powder diffraction pattern having peaks at 10.7°±0.2°, 15.7°±0.2°, 19.5°±0.2°, 22.0°±0.2° and 23.9°±0.2° 2-theta; a solid state13C NMR spectrum with characteristic peaks at 161.1±0.2, 152.0±0.2, 138.0±0.2, 40.9±0.2 and 39.9±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 164.6 ppm±l ppm: 3.5±0.1, 12.6±0.1, 26.6±0.1, 123.7±0.1 and 124.7±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIGS. 75, 76, or 77; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from 12.0°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 17.1°±0.2° and 21.5°±0.2° 2-theta.

[0511] Example 21 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form R2-A (resmetirom : piperazine salt).

[0512] Procedure A

[0513] 2-methoxy ethanol (4.2 ml, 35.3V) was added to piperazine (119 mg, 1.38 mmol) to give a slurry. The slurry was magnetically stirred at 80° C. over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Then, resmetirom (600 mg, 1.38 mmol) was added to the magnetically stirring clear solution at 80° C. to give slurry.Next, the slurry was magnetically stirred at 80° C. to give a clear solution and after 15 minutes a solid precipitation occurred. Next, obtained slurry was cooled to room temperature and then magnetically stirred at room temperature for 18 hours. Then the obtained solid was separated by centrifuge, dried in vacuum oven at 45° C. for 18 hours and analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 74.

[0514] Procedure B

[0515] 2-methoxy ethanol (0.42 ml, 70V) was added to piperazine (6 mg, 0.07 mmol) to give a slurry. The slurry was magnetically stirred at 80° C. over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Then, the obtained clear solution was placed in a 4 ml vial. Next, in another 4 ml vial, 2-methoxy ethanol (0.25 ml, 8.3V) was added to resmetirom (30 mg, 0.07 mmol) to give a slurry. The slurry was magnetically stirred at 80° C. over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Then, the resmetirom hot solution was added to 4 ml vial that contains the Piperazine hot solution and the reaction was magnetically stirred at 80° C. for 15 minutes. Then, the clear solution was concentrated in vacuum oven at 45° C. for 24 hours. The obtained solid was analyzed by X-ray powder diffraction and identified as resmetirom : piperazine salt form R2-A.

[0516] For example, one of the forms is Form R4-A (resmetirom : benzathine salt) reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0517] The crystalline Form R4-A of resmetirom : benzathine salt may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 78; an X-ray powder diffraction pattern having peaks at8.8°±0.2°, 13.0°±0.2°, 17.6°±0.2°, 20.7°±0.2°, 22.3°±0.2° 2-theta; and combinations of thesedata. The X-ray powder diffraction pattern may have any one, two, three, four or five additional peaks selected from l l. l°±0.2°, 11.4°±0.2°, 17.1°±0.2°, 18.7°±0.2° and 23.7°±0.2° 2-theta.

[0518] Example 23 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form R2-A (resmetirom : benzathine salt).

[0519] Procedure A

[0520] Ethanol (45 ml, 75V) was added to resmetirom (0.6 grams, 1.38 mmol) to give a slurry. The obtained slurry was heated to 75° C. and magnetically stirred at this temperature for 30 minutes to obtain a clear solution, followed a hot mechanical filtration. Then, benzathine (0.663 ml, 2.76 mmol) was added dropwise to the filtrated solution at 75° C. while magnetically stirred. Next, the obtained clear mixture was cooled to room temperature to give slurry and was stirred at room temperature for 18 hours. The obtained solid was filtered by Buchner and then dried in vacuum oven at 45° C. for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 78.

[0521] For example, one of the forms is Form 2 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0522] The crystalline Form 2 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 88; an X- ray powder diffraction pattern having peaks at 6.9°±0.2°, 10.0°±0.2°, 14.1°±0.2°, 19.1°±0.2°, and 21.9°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.0°±0.2°, 15.7°±0.2°, 22.7°±0.2°, 23.3°±0.2°, and 25.2°±0.2° 2-theta.

[0523] Example 2 of U.S. Patent Application Publication No. 2023 / 0364099 and WO2022 / 086894 describes preparation of Form 2.

[0524] Procedure A

[0525] Methyl isopropyl ketone (MIPK) (1.25 ml, 50V) was added to resmetirom (25 mg, 0.06 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C over a period of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, diethyl ether as anti-solvent (5.6 ml) was added dropwise to the stirred clear solution at 80 °C. The obtained clear solution was stirred at 80 °C for 1 hour and then cooled to room temperature. Next, the solution was magnetically stirred at RT over 48 hours to obtain a solid precipitate. The solid was then separated by centrifuge and analyzed by X-ray powder diffraction. The XRPD pattern is presented in FIG. 88.

[0526] Procedure B

[0527] Methyl isopropyl ketone (MIPK) (4.0 ml, 20V) was added to resmetirom (200 mg, and 0.46 mmol) to give a slurry. The obtained slurry was heated to 80 °C and stirred at 80 °C temperature for a period of 48 hours. Then the slurry was cooled to room temperature and separated by centrifuge. Next, the obtained solid was dried in a vacuum oven at 25 °C for 2 hours and was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 2.

[0528] For example, one of the forms is Form 3 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0529] The crystalline Form 3 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 84; an X- ray powder diffraction pattern having peaks at 6.9°±0.2°, 13.8°±0.2°, 15.0°±0.2°, 20.0°±0.2°,and 20.8°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 19.0°±0.2°, and 23.6°±0.2° 2-theta.

[0530] Example 3 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 3.

[0531] Procedure A

[0532] Dioxane (1.7 ml, 57V) was added to resmetirom (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 70° C. and magnetically stirred at 70° C. for a period of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, diethyl ether as anti-solvent (6.8 ml) was added dropwise to the stirred clear solution at 80° C. to obtain a solid precipitate. The obtained slurry was magnetically stirred at 80° C. for 1 hour and then cooled to room temperature with stirring. Next, the obtained slurry was magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifuge and analyzed by XRPD. The obtained XRPD pattern is presented in FIG. 84.

[0533] Procedure B

[0534] Dioxane (2.0 ml, 10V) was added to resmetirom (200 mg, and 0.46 mmol) to give a slurry. The obtained slurry was heated to 80° C. and magnetically stirred at 80° C. for a period of 48 hours. Then, the slurry was cooled to room temperature and separated by centrifuge. The obtained solid was dried in a vacuum oven at 25° C. for 2 hours. The solid was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 3.

[0535] For example, one of the forms is Form 4 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0536] The crystalline Form 4 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 89; an X- ray powder diffraction pattern having peaks at 11.5°±0.2°, 14.2°±0.2°, 18.0°±0.2°, 22.0°±0.2°, and 25.4°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1°±0.2°, 12.5°±0.2°, 15.2°±0.2°, 21.0°±0.2°, and 23.0°±0.2° 2-theta.

[0537] Example 4 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 4.

[0538] Procedure A

[0539] Anisole (4.0 ml, 20V) was added to resmetirom (200 mg, and 0.46 mmol) to obtain a slurry. The slurry was heated to 80 °C and stirred at 80 °C for a period of 48 hours. Then, the slurry was separated by centrifuge. The obtained solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 89.

[0540] For example, one of the forms is Form 6 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0541] The crystalline Form 6 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 90; an X- ray powder diffraction pattern having peaks at 5.4°±0.2°, 8.5°±0.2°, 10.9°±0.2°, 16.4°±0.2°, and 23.9°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 19.1°±0.2°, 19.9°±0.2°, 21.1°±0.2°, 22.3°±0.2°, and 25.7°±0.2° 2-theta.

[0542] Example 5 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 6.

[0543] Procedure A

[0544] N,N-Dimethylformamide (DMF) (1.3 ml, 4.3 V) was added to resmetirom (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C for a period of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, water as anti-solvent (2.6 ml) was added dropwise to the stirred clear solution at 80 °C to obtain a solid precipitate. The obtained slurry was stirred at 80 °C for 1 hour and cooled to room temperature. Next, the slurry was magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifuge and was dried in a vacuum oven at 25 °C for 18 hours. The obtained solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 90.

[0545] For example, one of the forms is Form 7 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0546] The crystalline Form 7 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 91; an X- ray powder diffraction pattern having peaks at 6.1 °±0.2°, 11.8°±0.2°, 14.6°±0.2°, 19.1°±0.2°, and 26.6°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.0°±0.2°, 20.6°±0.2°, 21.2°±0.2°, 23.2°±0.2°, and 25.7°±0.2° 2-theta.

[0547] Example 6 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 7.

[0548] Procedure A

[0549] Acetyl acetone (0.85 ml, 30V) was added to resmetirom (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C over aperiod of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, hexane as anti-solvent (2.55 ml) was added dropwise to the stirred clear solution at 80 °C to obtain a solid precipitate. The obtained slurry was stirred at 80 °C for 1 hour and cooled to room temperature. Next, the slurry was magnetically stirred at room temperature during 18 hours. The solid was then separated by centrifuge analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 91.

[0550] Procedure B

[0551] Acetyl acetone (4.0 ml, 20V) was added to resmetirom (200 mg, and 0.46 mmol) to give a slurry. The obtained slurry was stirred at room temperature over a period of 48 hours. Then, the slurry was separated by centrifuge and dried in vacuum oven at 25 °C for 2 hours. The solid was analyzed by XRPD and identified as resmetirom crystalline Form 7.

[0552] For example, one of the forms is Form 8 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0553] The crystalline Form 8 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 92; an X- ray powder diffraction pattern having peaks at 11.0°±0.2°, 12.2°±0.2°, 17.5°±0.2°, 20.7°±0.2°, and 22.0°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.3°±0.2°, 14.1°±0.2°, 15.4°±0.2°, 23.9°±0.2°, and 25.4°±0.2° 2-theta.

[0554] Example 7 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 8.

[0555] Procedure A

[0556] Acetyl acetone (0.85 ml, 30V) was added to resmetirom (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and was magnetically stirred at 80 °C over a period of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, propionitrile as anti-solvent (3.4 ml) was added dropwise to the stirred clear solution at 80 °C to obtain a solid precipitate. The obtained slurry was magnetically stirred at 80 °C for 1 hour and then cooled to room temperature. Next, the obtained slurry was magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifuge and analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 8.

[0557] Procedure B

[0558] Propionitrile (0.80 ml, 20V) was added to resmetirom (40 mg, and 0.09 mmol) to give a slurry. The obtained slurry was heated to 80 °C and stirred at 80 °C over a period of 48 hours. Then, the slurry was left to cool to room temperature, separated by centrifuge and dried in vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 92.

[0559] For example, one of the forms is Form 9 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0560] The crystalline Form 9 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 85; an X- ray powder diffraction pattern having peaks at 8.7°±0.2°, 13.4°±0.2°, 14.8°±0.2°, 15.5°±0.2°, and 22.8°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 1 l.l°±0.2°,19.8°±0.2°, 20.3°±0.2°, 21.5°±0.2°, and 24.4°±0.2° 2-theta.

[0561] Example 8 of U.S. Patent Application Publication No. 2023 / 0364099 and WO2022 / 086894 describes preparation of Form 9.

[0562] Procedure A

[0563] Nitrobenzene (2.0 ml, 10V) was added to resmetirom (200 mg, and 0.46 mmol) to give a slurry. The obtained slurry was heated to 80° C. and stirred at 80° C. over a period of 48 hours. Then, the slurry was left to cool to room temperature, separated by centrifuge and dried in vacuum oven at 25° C. for 2 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 85.

[0564] For example, one of the forms is Form 10 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0565] The crystalline Form 10 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 93; an X- ray powder diffraction pattern having peaks at 12.5°±0.2°, 14.9°±0.2°, 20.4°±0.2°, 21.1°±0.2°, and 23.4°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 7.4°±0.2°, 13.4°±0.2°, 16.0°±0.2°, 22.5°±0.2°, and 24.8°±0.2° 2-theta.

[0566] Example 9 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 10.

[0567] Procedure A

[0568] Di(ethylene glycol)ethyl ether (2.0 ml, 10V) was added to resmetirom (200 mg, and 0.46 mmol) to give a slurry. The obtained slurry was stirred at room temperature over aperiod of 48 hours. Then, the slurry was separated by centrifuge, analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 93.

[0569] For example, one of the forms is Form 11 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0570] The crystalline Form 11 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 94; an X- ray powder diffraction pattern having peaks at 5.9°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 19.7°±0.2°, and 25.1°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.5°±0.2°, 16.4°±0.2°, 16.8°±0.2°, 17.9°±0.2°, and 22.2°±0.2° 2-theta.

[0571] Example 10 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 11.

[0572] Procedure A

[0573] 1,3 -Dioxolane (1 ml, 33.3V) was added to resmetirom (30 mg, 0.07 mmol) and stirred at room temperature to give a clear solution. The clear solution was mechanically filtered and was left for 4 days for slow evaporation at room temperature. The obtained solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 94.

[0574] For example, one of the forms is Form 13 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0575] The crystalline Form 13 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 95; an X-ray powder diffraction pattern having peaks at 14.4°±0.2°, 17.0°±0.2°, 20.0°±0.2°, 22.7°±0.2°, and 24.5°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 7.3°±0.2°, 13.0°±0.2°, 17.9°±0.2°, 18.7°±0.2°, and 19.0°±0.2° 2-theta.

[0576] Example 11 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 13.

[0577] Procedure A

[0578] Methyl ethyl ketone (3.33 ml, 33.3V) was added to resmetirom (100 mg, 0.23 mmol) to obtain a slurry. The slurry was heated to 60 °C and magnetically stirred at 60 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, di chloroethane as anti-solvent (10 ml) was added dropwise to the stirred clear solution at 60 °C to obtain a solid precipitate. The obtained slurry was stirred at 60 °C for 1 hour and cooled to room temperature. Next, the slurry was magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifuge and dried in vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 95.

[0579] Procedure B

[0580] 2-methoxy ethanol (0.15 ml, 5V) was added to resmetirom (30 mg, 0.07 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, di chloroethane as anti-solvent (0.6 ml) was added dropwise to the stirred clear solution at 80 °C to obtain a solid precipitate. The obtained slurry was stirred at 80 °C for 1 hour and cooled to room temperature. Next, the slurry was magnetically stirred at room temperature for 18hours and was then separated by centrifuge. The solid was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 13.

[0581] For example, one of the forms is Form 14 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0582] The crystalline Form 14 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 96; an X- ray powder diffraction pattern having peaks at 9.8°±0.2°, 11.1°±0.2°, and 23.2°±0.2° 2-theta; and combinations of these data.

[0583] Example 12 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 14.

[0584] Procedure A

[0585] Methyl tetrahydrofuran (3.3 ml, 10V) was added to resmetirom (100 mg, and 0.23 mmol) to give a slurry. The obtained slurry was stirred at 75 °C for 30 minutes to full dissolution of the solid, followed by a hot mechanical filtration. Next, the filtered clear solution was magnetically stirred at 4 °C for 18 hours to obtain a solid precipitate. The solid was then separated by centrifuge and dried in vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray powder diffraction and the obtained pattern is presented in FIG. 96.

[0586] Procedure B

[0587] Methyl tetrahydrofuran (5 ml, 10V) was added to resmetirom (500 mg, and 0.15 mmol) to give a slurry. The obtained slurry was heated to 60 °C and magnetically stirred at this temperature for 48 hours. Then, the slurry was cooled to room temperature and separatedby centrifuge. The solid was dried in vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 14.

[0588] For example, one of the forms is Form 15 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0589] The crystalline Form 15 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 97; an X- ray powder diffraction pattern having peaks at 10.0°±0.2°, 11.6°±0.2°, 13.0°±0.2°, 18.6°±0.2°, and 23.8°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.7°±0.2°, 17.0°±0.2°, 18.2°±0.2°, 22.0°±0.2°, and 23.3°±0.2° 2-theta.

[0590] Example 13 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 15.

[0591] Procedure A

[0592] Propionic acid (15 ml, 50V) was added to Resmetirom (300 mg, 0.7 mmol) to obtain a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, the filtered clear solution was magnetically stirred at 4 °C for 72 hours to obtain a solid precipitate. The solid was then separated by centrifuge and dried in vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 97.

[0593] For example, one of the forms is Form 16 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0594] The crystalline Form 16 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 98; an X- ray powder diffraction pattern having peaks at 8.7°±0.2°, 11.5°±0.2°, 13.3°±0.2°, 14.7°±0.2°, and 26.0°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 10.2°±0.2°, 12.8°±0.2°, 19.5°±0.2°, 25.3°±0.2°, and 26.4°±0.2° 2-theta.

[0595] Example 14 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 16.

[0596] Procedure A

[0597] Propionic acid (15 ml, 50V) was added to resmetirom (300 mg, 0.7 mmol) to obtain a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain clear solution, followed by a hot mechanical filtration. Next, the filtered clear solution was magnetically stirred at 4 °C for 72 hours to obtain a solid precipitation. Next, the saturated solution was separated by centrifuge from the solid and then was concentrated by slow evaporation of the solvent at 80 °C for 48 hours to give a solid. The solid was analyzed by X- ray powder diffraction and the obtained XRPD pattern is presented in FIG. 99.

[0598] For example, one of the forms is Form 17 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0599] The crystalline Form 17 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 99; an X- ray powder diffraction pattern having peaks at 6.8°±0.2°, 8.7°±0.2°, 11.4°±0.2°, 14.5°±0.2°, and 29.7°±0.2° 2-theta; and combinations of these data. The X-ray powder diffractionpattern may have any one, two, three, four, or five additional peaks selected from 10.1°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 19.7°±0.2°, and 20.0°±0.2° 2-theta.

[0600] Example 15 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 17.

[0601] Procedure A

[0602] Methyl ethyl ketone (2 ml, 20V) was added to resmetirom (100 mg, 0.23 mmol) to obtain a slurry. The slurry was magnetically stirred at 72 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, the filtered clear solution was magnetically stirred at 4 °C during 18h to obtain a solid precipitate. The solid was then separated by centrifuge and dried in vacuum oven at 25 °C for 2 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 99.

[0603] Procedure B

[0604] Methyl ethyl ketone (20 ml, 20V) was added to resmetirom (1000 mg, 2.3 mmol) to obtain a slurry. The slurry was magnetically stirred at 72 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, the filtered clear solution was concentrated by rotor vapor to give a solid. The solid was dried in vacuum oven at 25 °C during 18 hours. The solid was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 17.

[0605] For example, one of the forms is Form 19 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0606] The crystalline Form 19 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 100; an X-ray powder diffraction pattern having peaks at 8.5°±0.2°, 9.1°±0.2°, 12.6°±0.2°, 14.5°±0.2°, and 15.2°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.1°±0.2°, 15.7°±0.2°, 20.8°±0.2°, 21.1°±0.2°, and 25.4°±0.2° 2-theta.

[0607] Example 16 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 19.

[0608] Procedure A

[0609] Methyl ethyl ketone (2.0 ml, 20V) was added to resmetirom (100 mg, 0.23 mmol) to obtain a slurry. The slurry was magnetically stirred at 70 °C over a period of 30 minutes to obtain a clear solution, followed by a hot mechanical filtration. Next, toluene as anti-solvent (8 ml) was added dropwise to the stirred clear solution at 70 °C to obtain a solid precipitate. The obtained slurry was stirred at 70 °C for 1 hour and cooled to room temperature. Next, the slurry was magnetically stirred at room temperature for 18 hours. The solid was then separated by centrifuge and dried in vacuum oven at 25 °C for 3 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 100.

[0610] Procedure B

[0611] Dimethylacetamide (DMAc) (2.5 ml, 5 V) was added to resmetirom (500 mg, 1.15 mmol) to obtain a slurry. The slurry was heated to 80 °C and magnetically stirred at 80 °C over a period of 30 minutes to obtain complete dissolution, followed by a hot mechanical filtration. Next, isopropyl alcohol (IPA) as anti-solvent (10 ml) was added drop-wise to thestirred clear solution at 80 °C. The obtained clear solution was stirred at 80 °C for 1 hour and then cooled to room temperature. Next, the solution was magnetically stirred at RT over 18 hours to obtain a solid precipitate. The solid was then separated by centrifuge, dried in vacuum oven at 25 °C for 18 hours.

[0612] Toluene (2.0 ml, 20V) was added to resmetirom obtained above (100 mg, and 0.23 mmol) to give a slurry. The obtained slurry was stirred at 80 °C over a period of 18 hours. Then, the slurry was cooled to room temperature, filtered by centrifuge, dried in vacuum oven at 45 °C during 18 hours and was analyzed by X-ray powder diffraction and identified as resmetirom crystalline Form 19.

[0613] For example, one of the forms is Form 20 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0614] The crystalline Form 20 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 101; an X-ray powder diffraction pattern having peaks at 6.5°±0.2°, 9.6°±0.2°, 10.1°±0.2°, 19.0°±0.2°, and 23.3°±0.2° 2-theta; and combinations of these data; a solid state13C NMR spectrum with characteristic peaks at 161.0±0.2, 155.0±0.2, 151.1±0.2, 145.3±0.2, and 121.8±0.2 ppm; a solid state13C NMR spectrum having the following chemical shift absolute differences from reference peak at 162.4±1 ppm: 1.4±0.1, 7.5±0.1, 11.3±0.1, 17.1±0.1, and 40.6±0.1 ppm; a solid state13C NMR spectrum substantially as depicted in FIGS. 104, 105, or 106; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.6°±0.2°, 16.2°±0.2°, 19.5°±0.2°, 21.8°±0.2°, and 24.9°±0.2° 2-theta.

[0615] Example 17 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 20.

[0616] Procedure A

[0617] Acetonitrile (66 ml, 132V) was added to resmetirom (500 mg, 1.15 mmol) to obtain a slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain a cloudy solution, followed by a hot mechanical filtration. Next, the filtered clear solution was magnetically stirred at room temperature during 18h to obtain a solid precipitate. The solid was then separated by Buchner and dried in vacuum oven at 45 °C for 72 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 101.

[0618] For example, one of the forms is Form 21 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0619] The crystalline Form 21 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 102; an X-ray powder diffraction pattern having peaks at 7.0°±0.2°, 14.1°±0.2°, 15.9°±0.2°, 20.2°±0.2°, and 28.4°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.4°±0.2°, 17.0°±0.2°, 25.1°±0.2°, 25.8°±0.2°, and 29.3°±0.2° 2-theta.

[0620] Example 18 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 21.

[0621] Procedure A

[0622] Acetonitrile (10.8 ml, 120V) was added to resmetirom (100 mg, 0.23 mmol) to obtain slurry. The slurry was magnetically stirred at 80 °C over a period of 30 minutes to obtain clear solution, followed by a hot mechanical filtration. Next, the filtered clear solution was concentrated by rotor vapor to give a solid. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 102.

[0623] For example, one of the forms is Form 22 reported in U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894.

[0624] The crystalline Form 22 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 103; an X-ray powder diffraction pattern having peaks at 5.6°±0.2°, 15.0°±0.2°, 16.6°±0.2°, 17.4°±0.2°, and 23.0°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 11.5°±0.2°, 23.3°±0.2°, 26.1°±0.2°, 27.6°±0.2°, and 28.9°±0.2° 2-theta.

[0625] Example 18 of U.S. Patent Application Publication No. 2023 / 0364099 and WO 2022 / 086894 describes preparation of Form 22.

[0626] Procedure A

[0627] Ethylene glycol (10 ml, 20V) was added to resmetirom (500 mg, 1.15 mmol) to give a slurry. The obtained slurry was stirred at room temperature for 48 hours. Next, the obtained solid was separated by centrifuge and dried in vacuum oven at 45 °C for 18 hours. The solid was analyzed by X-ray powder diffraction and the obtained XRPD pattern is presented in FIG. 103.

[0628] Resmetirom crystalline Forms 2, 3, 5 and 20 may also be used for preparation of resmetirom crystalline Form 22.

[0629] For example, one of the forms is an amorphous Form El reported in U.S. PatentApplication Publication No. 2024 / 0423993.

[0630] The amorphous Form El may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 110.

[0631] Example-1 of U.S. Patent Application Publication No. 2024 / 0423993 describes preparation of the amorphous Form El.

[0632] Methanol (3000 ml) and resmetirom (100 g) were added in RB flask at 25° C. to 35° C. and reaction mass was stirred for 15 to 20 minutes to get clear solution. The reaction mass was assembled in spray dryer. The reaction mass was spray dried under below conditions. The product was collected from cyclone and was further dried at 40° C. to 50° C. under vacuum for 4 hours to get amorphous form of resmetirom.

[0633] For example, one of the forms is an amorphous Form E2 reported in U.S. Patent Application Publication No. 2024 / 0423993.

[0634] The amorphous Form E2 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 110.

[0635] Example-2 of U.S. Patent Application Publication No. 2024 / 0423993 describes preparation of amorphous Form E2.

[0636] Methanol (300 ml) and resmetirom (100 g) were added at 25° C. to 35° C. The reaction mass was stirred for 10 to 15 minutes to get a clear solution. Methanol was distilled out under vacuum below 45° C. from above reaction mass, n-Heptane (500 ml) was added to residue at 25° C. to 35° C. The reaction mass was stirred for 15 to 20 minutes, filtered and washed with n-Heptane (100 ml) to get amorphous form of resmetirom.

[0637] For example, one of the forms is an amorphous solid dispersion Form E3 reported in U.S. Patent Application Publication No. 2024 / 0423993.

[0638] The amorphous solid dispersion Form E3 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 111.

[0639] Example-3 of U.S. Patent Application Publication No. 2024 / 0423993 describes preparation of the amorphous solid dispersion Form E3.

[0640] Methanol (3000 ml), resmetirom (100 g) and copovidone (Kollidone VA 64) (100 g) were added in RB flask at 25° C. to 35° C. and reaction mass was stirred for 15 to 20 minutes to get clear solution. The reaction mass was assembled in spray dryer. The reaction mass was spray dried under below conditions. The product was collected from cyclone and was further dried at 40° C. to 50° C. under vacuum for 4 hours to get amorphous solid dispersion of resmetirom.

[0641] For example, one of the forms is an amorphous solid dispersion Form E4 reported in U.S. Patent Application Publication No. 2024 / 0423993.

[0642] The amorphous solid dispersion Form E4 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 111.

[0643] Example-4 of U.S. Patent Application Publication No. 2024 / 0423993 describes preparation of the amorphous solid dispersion Form E4.

[0644] Methanol (3000 ml) and resmetirom (100 g) were added at 25° C. to 35° C. The reaction mass was stirred for 15 to 20 minutes to get a clear solution, copovidone (KollidoneVA 64) (100 g) was added to the reaction mass and stirred for 15 to 20 minutes and after that reaction mass was filtered out. Methanol was distilled out below 50° C. from above reaction mass. Cyclohexane (400 ml) was added to residue at 25° C. to 35° C. The reaction mass was stirred for 15 to 20 minutes, filtered and washed with cyclohexane (100 ml) to get amorphous solid dispersion of resmetirom.

[0645] For example, one of the forms is Form 3A reported in WO 2022 / 171200.

[0646] The crystalline Form 3 A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 112; an X-ray powder diffraction pattern having peaks at 10.7±0.2°, 16.2±0.2°, 18.0±0.2°, 24.1±0.2° and 24.3±0.2° 2-theta; and combinations of these data; a FT-IR spectrum substantially as depicted in FIG. 115; a FT-IR spectrum with characteristic peaks at 1718 cm-1±2 cm-1, 1190 cm-1± 2 cm-1, 1180 cm-1± 2 cm-1, 908 cm-1± 2 cm-1, and 896 cm-1± 2 cm-1; a FT-IR spectrum with characteristic peaks at 1603 cm-1± 2 cm-1, 1461 cm-1± 2 cm-1, 1406 cm-1± 2 cm-1, 1337cm-1±2cm-1, 1230cm-1±2cm-1, 952cm -1±2cm-1, 908cm-1±2cm-1, and 896cm-1±2cm-1; and combinations of these data. The X- ray powder diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks selected from 11.3±0.2°, 12.0±0.2°, 14.4±0.2° , 15.6±0.2°, 17.3±0.2°, 17.6±0.2 °, 19.5±0.2°, 20.0±0.2°, 22.4±0.2° , 26.7±0.2°, 26.9±0.2° and 28.7±0.2° 2-theta.

[0647] WO 2022 / 171200 provides the following data:

[0648] The TGA pattern of this crystalline Form 3A is substantially as shown in FIG. 113, with a weight loss of 0.3% before 100°C, and a decomposition temperature of 320°C.

[0649] The DSC pattern of the crystalline Form 3 A is substantially as shown in FIG. 114, and the melting point is 324°C.

[0650] Example 1-1 of WO 2022 / 171200 describes preparation of the crystalline Form 3A.

[0651] Take 20 mg of resmetirom to form a suspension in 0.5 mL of n-propanol. After 5 days of crystal slurry at room temperature, centrifuge, and vacuum-dried at room temperature for 24 hours to obtain crystalline Form 3A.

[0652] Example 1-2 of WO 2022 / 171200 describes preparation of the crystalline Form 3A.

[0653] Take 51.80 mg of resmetirom to form a suspension in 1.0 mL of n-propanol. After slurring at room temperature for 2 days, centrifuge and vacuum dry at room temperature for 24 hours to obtain crystalline Form 3A.

[0654] Example 1-3 of WO 2022 / 171200 describes preparation of the crystalline Form 3A.

[0655] 200 mg of resmetirom was taken into 3 mL of n-propanol to form a suspension, and after 3 days of crystal slurry at room temperature, centrifuged, and vacuum-dried at room temperature for 24 hours to obtain crystalline Form 3A.

[0656] Example 1-4 of WO 2022 / 171200 describes preparation of the crystalline Form 3A.

[0657] Take 500 mg of resmetirom, form a suspension in 3.5 mL of n-propanol, slurried at room temperature for 16 hours, filtered, and vacuum-dried at room temperature for 67 hours to obtain crystalline Form 3A.

[0658] Example 2-1 of WO 2022 / 171200 describes preparation of the crystalline Form 3A.

[0659] Dissolve 20.15 mg of resmetirom in 2 mL of n-propanol at 60 °C, filter, add 3 mg of the crystal form 3 prepared in Example 1 as a seed crystal, stir at 4 °C for 1 day, and thencentrifuge. It was dried under vacuum at room temperature for 24 hours to obtain crystallineForm 3A.

[0660] Example 3-1 of WO 2022 / 171200 describes preparation of this crystalline Form 3A.

[0661] 20.92 mg of resmetirom was dissolved in 7 mL of n-propanol by ultrasonic wave, filtered, and 3 mg of crystalline Form 3 prepared in Example 1 was added as a seed crystal, and after 2 days of open volatilization at room temperature, crystalline Form 3 A was obtained.

[0662] For example, one of the forms is Form 4A reported in CN115124515 A.

[0663] The crystalline Form 4A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 122; an X-ray powder diffraction pattern having peaks at 7.2±0.2°, 12.4±0.2°, 13.3±0.2°, 15.0±0.2° and 23.1±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 8.6±0.2°, 13.9±0.2°, 19.6±0.2° , 22.5±0.2°, and 26.2±0.2° 2-theta.

[0664] CN115124515A provides the following data:

[0665] The TGA pattern of the crystalline Form 4A is substantially as shown in FIG. 123, with a weight loss of 10.5% before 150°C, and a decomposition temperature of 327.11°C.

[0666] The1H NMR spectrum of the crystalline Form 4A is substantially as shown in FIG. 124.

[0667] Example 1 of CN115124515A describes preparation of this crystalline Form 4A.

[0668] About 20 mg of resmetirom was sonicated in 2mL of acetone, filtered, 5.4mL of n- heptane was added with stirring to Form a suspension, which was stirred at room temperature for 3 hours, centrifuged, and dried under vacuum at room temperature for 24 hours to obtain crystalline Form 4A.

[0669] For example, one of the forms is Form 7A reported in CN115124515 A.

[0670] The crystalline Form 7A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 125; an X-ray powder diffraction pattern having peaks at 6.9±0.2°, 13.9±0.2°, 15.0±0.2°, 17.8±0.2° and 20.0±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 12.2±0.2°, 16.0±0.2°, 20.9±0.2° , 22.6±0.2°, and 24.8±0.2° 2-theta.

[0671] CN115124515A provides the following data:

[0672] The TGA pattern of the crystalline Form 7A is substantially as shown in FIG. 126, with a weight loss of 19% before 150°C, and a decomposition temperature of 327°C.

[0673] The1H NMR spectrum of the crystalline Form 7A is substantially as shown in FIG. 127.

[0674] Example 2 of CN115124515A describes preparation of the crystalline Form 7A.

[0675] About 20 mg of resmetirom was suspended in 0.6 mL of 1, 4-dioxane / isopropyl ether (v: v2: 1) and stirred at 40 °C for 5 days to obtain crystalline Form 7A.

[0676] Example 3 of CN115124515A describes preparation of the crystalline Form 7A.

[0677] About 20 mg of resmetirom was suspended in 0.5 mL 1, 4-dioxane / n-heptane (v: v4: 1) and stirred at 40 °C for 5 days to obtain crystalline Form 7 A.

[0678] Example 4 of CN115124515A describes preparation of the crystalline Form 7A.

[0679] About 20 mg of resmetirom was dissolved in 1.8 mL of 1, 4-dioxane / water (v: v2: 1) mixed solvent at 60 °C, filtered, transferred to 4 °C and stirred to obtain crystalline Form 7A.

[0680] For example, one of the forms is Form 9A reported in CN115124515 A.

[0681] The crystalline Form 9A may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 128; an X-ray powder diffraction pattern having peaks at 14.5±0.2°, 19.7±0.2°, 22.2±0.2°, 22.4±0.2° and 23.9±0.2° 2-theta; and combinations of these data, The X-ray powder diffraction pattern may have any one, two, three, four, or five additional peaks selected from 6.9±0.2°, 10.6±0.2°, 12.1±0.2° , 22.9±0.2°, and 25.0±0.2° 2-theta.

[0682] CN115124515A provides the following data:

[0683] The TGA pattern of the crystalline Form 9A is substantially as shown in FIG. 129, with a weight loss of 13.2% before 160°C, and a decomposition temperature of 340°C.

[0684] The1H NMR spectrum of the crystalline Form 9A is substantially as shown inFIG. 130.

[0685] Example 5 of CN115124515A describes preparation of the crystalline Form 7A.

[0686] About 20 mg of resmetirom was suspended in 0.5mL butanone and stirred at room temperature for 6 days to obtain crystalline Form 9 A.

[0687] For example, one of the forms is Form BSI reported in CN118772117A.

[0688] The crystalline Form BSI may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 131; an X-ray powder diffraction pattern having peaks at 6.6±0.2°, 7.8±0.2°, 9.7±0.2°, 10.2±0.2°, 13.7±0.2°, 16.3±0.2°, 17.8±0.2°, 18.2±0.2°, 19.0±0.2°, 19.6±0.2°, 20.7±0.2°, 22.0±0.2°, 23.4±0.2°, 24.9±0.2°, 25.8±0.2°, 26.8±0.2°, 27.5±0.2°, 28.0±0.2°, 30.0±0.2°, 31.2±0.2°, 32.0±0.2°, 34.5±0.2°, 36.5±0.2°, 38.3±0.2°, and 42.4±0.2° 2-theta; and combinations of these data.

[0689] The DSC curve of the crystalline Form BSI is substantially as depicted in FIG. 132, which shows an endothermic peak near 334° C. and an exothermic peak near 238° C which is the crystal transition exothermic peak.

[0690] The TGA pattern of the crystalline Form BSI is substantially as shown in FIG. 133, with a decomposition temperature of 340°C.

[0691] Example 1 of CN118772117A describes preparation of Form BSI.

[0692] Taking 1 g of resmetirom, adding 5 mL of acetonitrile and 5 mL of toluene, stirring to form a suspension, stirring at room temperature for 3 days, filtering, and drying ina vacuum oven (90-100 °C) for 6 hours to obtain 0.88g of the resmetirom crystalline formBSI.

[0693] Example 2 of CN118772117A describes preparation of Form BSI.

[0694] Taking 1 g of resmetirom, adding 5 mL of acetonitrile and 5 mL of cyclohexane, stirring to form a suspension, stirring at room temperature for 4 days, filtering, and drying in a vacuum oven (90-100 °C) for 6 hours to obtain 0.93 g of the resmetirom crystalline form BSI.

[0695] Example 3 of CN118772117A describes preparation of Form BSI.

[0696] Taking 1g of resmetirom, adding 5 mL of acetonitrile and 5 mL of n-hexane, stirring to form a suspension, stirring at room temperature for 3 days, filtering, and drying in a vacuum oven (90-100 °C) for 6 hours to obtain 0.90 g of the resmetirom crystalline form BSI.

[0697] Example 4 of CN118772117A describes preparation of Form BSI.

[0698] Taking 1 g of resmetirom, adding 4 mL of acetonitrile, 3 mL of toluene and 3 mL of cyclohexane, stirring to form a suspension, stirring at room temperature for 3 days, filtering, and drying in a vacuum oven (100-110 °C) for 7 hours to obtain 0.87 g of the resmetirom crystalline form BSI.

[0699] For example, one of the forms is Form R1 reported in IN202241066042A.

[0700] The crystalline Form R1 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 134; an X-ray powder diffraction pattern having peaks at 11.18°±0.2°, 12.48°±0.2°, 13.8°±0.2°,15.02°±0.2°, 16.49°±0.2°, and 20.6°±0.2° 2-theta; and combinations of these data. The X-raypowder diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 5.59°±0.2°, 10.56°±0.2°, 22°±0.2°, 22.76°±0.2°, 26.69°±0.2°, and 27.78°±0.2° 2-theta.

[0701] Example 1 of IN202241066042 A describes preparation of Form Rl.

[0702] A mixture of resmetirom (1 g) and formic acid (5 mL) was stirred for 3 days at room temperature. The resulting mixture was dried at room temperature for 2.5 hours followed by drying under VTD dryer for 1 day at 50 °C to obtain crystalline Form Rl.

[0703] For example, one of the forms is Form R2 reported in IN202241066042 A.

[0704] The crystalline Form R2 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 135; an X-ray powder diffraction pattern having peaks at 9.04°±0.2°, 22.56°±0.2°, and 25.5°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, or three additional peaks selected from 9.6°±0.2°, 15.9°±0.2°, and 26.4°±0.2° 2- theta.

[0705] Example 2 of IN202241066042 A describes preparation of Form R2.

[0706] A mixture of resmetirom (1 g) and hexanoic acid (2 mL) was stirred for 20 hours at room temperature. Diisopropyl ether (25 mL) was added to the above mixture and stirred for 2 hours at the same temperature. The solid was filtered under vacuum under nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain crystalline Form R2.

[0707] For example, one of the forms is Form R3 reported in IN202241066042 A.

[0708] The crystalline Form R3 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 136; an X-ray powder diffraction pattern having peaks at 13.18°±0.2°, 27.2°±0.2°, 30°±0.2°, and 31.6°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, or three additional peaks selected from 9.68°±0.2°, 16.99°±0.2°, and 20.57°±0.2° 2-theta.

[0709] Example 3 of IN202241066042A describes preparation of Form R3.

[0710] A mixture of resmetirom (1 g) and sulfolane (2 mL) was stirred for 20 hours at room temperature. Water (25 mL) was added to the above mixture and stirred for 1 hours at the same temperature. The reaction mixture was filtered under vacuum under nitrogen atmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain crystalline Form R3.

[0711] For example, one of the forms is Form R4 reported in IN202241066042 A.

[0712] The crystalline Form R4 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 137; an X-ray powder diffraction pattern having peaks at 7.02°±0.2°, 8.9°±0.2°, 9.35°±0.2°, and 14.09°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, or three additional peaks selected from 16.88°±0.2°, 22.56°±0.2°, and 28.77°±0.2° 2-theta.

[0713] Example 4 of IN202241066042A describes preparation of Form R4.

[0714] A mixture of resmetirom (1 g) and butyric acid (5 mL) was stirred for 2 days at room temperature. Heptane (25 mL) was added to the above mixture and stirred for 2 hours at the same temperature. The reaction mixture was filtered under vacuum under nitrogenatmosphere. The resulting solid was dried at room temperature for 2.5 hours followed by drying at 50 °C for 12 hours using VTD drier to obtain crystalline Form R4.

[0715] For example, one of the forms is Form R5 reported in IN202241066042A.

[0716] The crystalline Form R5 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 138; an X-ray powder diffraction pattern having peaks at 12.0°±0.2°, 14.28°±0.2°, 15.5°±0.2°, and 22.43°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 5.7°±0.2°, 10.6°±0.2°, 20.2°±0.2°, 21.09°±0.2°, 21.44°±0.2°, and 28.82°±0.2° 2-theta.

[0717] Example 5 of IN202241066042A describes preparation of Form R5.

[0718] A mixture of Resmetirom (1 g) and 1,2-Dimethoxy ethane (2.5 mL) was stirred for 24 hours at 40 °C. After 24 hours of stirring at 40 °C, the reaction mixture is cooled to 25 °C. The solid was filtered and dried at under VTD dryer for 2 days at 50 °C to obtain crystalline Form R5.

[0719] For example, one of the forms is an amorphous solid dispersion of resmetirom and eudragit (1 :2) reported in IN202241066042A.

[0720] The amorphous solid dispersion of resmetirom and eudragit may be characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 139.

[0721] Example 6 of IN202241066042A describes preparation of the amorphous solid dispersion of resmetirom and eudragit.

[0722] A mixture of resmetirom (1.5 g) and eudragit (3 g) in methanol (500 mL) was heated 50 °C and stirred for 1 hour. The mixture was filtered and the resulting clear solutionwas subjected to spray drying at 70 °C. The resulting solid was further dried at 40 °C underVTD dryer for 18 hours to obtain the amorphous solid dispersion of resmetirom and eudragit.

[0723] For example, one of the forms is an amorphous form of resmetirom reported in IN202241066042A.

[0724] This amorphous form of resmetirom may be characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 140.

[0725] Example 7 of IN202241066042A describes preparation of this amorphous form of resmetirom.

[0726] A mixture of resmetirom (3 g) and acetone (300 mL) was stirred for 2 hours at 40 °C. The mixture was filtered and the resulting clear solution was subjected to spray drying at 65 °C to obtain this amorphous form of resmetirom.

[0727] For example, one of the forms is Form RL reported in IN202241066042A.

[0728] The crystalline Form RL may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 141; an X-ray powder diffraction pattern having peaks at 18.42°±0.2°, 19.09°±0.2°, and 20.49°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one or two additional peaks selected from 11.24°±0.2° and 17.12°±0.2° 2- theta.

[0729] Example 8 of IN202241066042A describes preparation of Form RL.

[0730] A mixture of resmetirom (1.7 g) and lysine (0.58 g) in acetone (15 mL) was stirred for 2 days at room temperature. The resulting solid was filtered and dried at under VTD dryer for 3 hours at room temperature to obtain crystalline Form RL.

[0731] For example, one of the forms is Form Ml reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.

[0732] The crystalline Form Ml may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 142; an X-ray powder diffraction pattern having peaks at 10.6°±0.2°, 12.0°±0.2°, and 12.7°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, six, or seven additional peaks selected from 10.2°±0.2°, 11.5°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 21.1°±0.2°, 22.4°±0.2°, and 24.2°±0.2° 2-theta.

[0733] Example 1 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form Ml.

[0734] Dissolved resmetirom (0.5 g) in the mixture of acetic acid (12 ml) and ethyl acetate (18 ml) at 40-50°C, cooled the obtained solution to 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound to obtain crystalline Form Ml.

[0735] For example, one of the forms is Form M2 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.

[0736] The crystalline Form M2 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 143; an X-ray powder diffraction pattern having peaks at 5.0°±0.2°, 6.4°±0.2°, 7.7°±0.2°, 15.1°±0.2°, and 23.7°±0.2° 2-theta; and combinations of these data. The X-ray powderdiffraction pattern may have any one, two, three, four, five, or six additional peaks selected from 10.1°±0.2°, 12.1°±0.2°, 14.3°±0.2°, 17.8°±0.2°, 19.6°±0.2°, and 21.8°±0.2° 2-theta.

[0737] Example 2 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form M2.

[0738] Dissolved resmetirom (0.5 g) in cyclohexanol (45 ml) at 60-70°C and filtered for particle free. Obtained filtrate is added to the methyl tertiary butyl ether (80 ml) at 25-30°C and stirred at the same temperature. Cyclohexane (100 ml) added to the mixture at 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to obtain crystalline Form M2.

[0739] For example, one of the forms is Form M3 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.

[0740] The crystalline Form M3 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 144; an X-ray powder diffraction pattern having peaks at 6.9°±0.2°, 8.6°±0.2°, 11.5°±0.2°, 13.9°±0.2°, 24.7°±0.2°, and 30.2°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve additional peaks selected from 9.8°±0.2°, 10.3°±0.2°, 10.7°±0.2°, 12.2°±0.2°, 15.7°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 21.6°±0.2°, 22.7°±0.2°,26.7°±0.2°, and 28.5°±0.2° 2-theta.

[0741] Example 3 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof " describes preparation of FormM3.

[0742] Dissolved resmetirom (0.5 g) in cyclohexanol (45 ml) at 60-70°C, cooled the obtained solution to 25-30°C and filtered for particle free. Obtained filtrate is added to cyclohexane (80 ml) at 25-30°C and stirred at the same temperature. Filtered the solid and dried to obtain crystalline Form M3.

[0743] For example, one of the forms is Form M4 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof.

[0744] The crystalline Form M4 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 145; an X-ray powder diffraction pattern having peaks at 3.9°±0.2°, 18.3°±0.2°, and 19.0°±0.2° 2- theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen additional peaks selected from 9.6°±0.2°, 11.9°±0.2°, 13.2°±0.2°, 14.9°±0.2°, 15.2°±0.2°, 16.9°±0.2°, 17.6°±0.2°, 19.7°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 29.8°±0.2°, and 36.9°±0.2° 2-theta.

[0745] Example 4 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form M4.

[0746] Dissolved resmetirom (0.5 g) in acetic acid (7 ml) at 70-80°C. Obtained solution is added to cyclohexane (60 ml) at 25-30°C and stirred. The mixture was cooled to 0-5°C andstirred the mixture at the same temperature. The mixture was heated to 35-40°C and stirred.Filtered the solid and dried to obtain crystalline Form M4.

[0747] For example, one of the forms is Form M5 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof.

[0748] The crystalline Form M5 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 146; an X-ray powder diffraction pattern having peaks at 6.4°±0.2°, 7.5°±0.2°, 8.2°±0.2°, and 9.5°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, or ten additional peaks selected from 10.0°±0.2°, 11.5°±0.2°, 16.1°±0.2°, 18.8°±0.2°, 19.4°±0.2°, 20.5°±0.2°, 21.7°±0.2°, 23.2°±0.2°, 24.7°±0.2°, and 27.2°±0.2° 2-theta.

[0749] Example 5 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form M5.

[0750] Dissolved resmetirom (0.5 g) and isonicotinamide (0.286 g) in acetonitrile (12 ml) at 75-85°C and filtered for particle free at the same temperature. Obtained filtrate is cooled to 25-30°C and stirred at the same temperature. Filtered the precipitated solid and dried to obtain crystalline Form M5.

[0751] For example, one of the forms is Form M6 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.

[0752] The crystalline Form M6 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 147; an X-ray powder diffraction pattern having peaks at 6.9°±0.2°, 8.5°±0.2°, 11.2°±0.2°, and 14.5°±0.2° 2-theta; and combinations of these data. The X-ray powder diffraction pattern may have any one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or sixteen additional peaks selected from 10.6°±0.2°, 12.1°±0.2°, 13.9°±0.2°, 15.3°±0.2°, 15.9°±0.2°, 16.4°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 19.6°±0.2°, 19.9°±0.2°, 21.4°±0.2°, 22.4°±0.2°, 25.1°±0.2°, 27.5°±0.2°, 29.9°±0.2°, and 32.4°±0.2° 2- theta.

[0753] Example 6 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form M6.

[0754] Dissolved resmetirom (0.3 g) in a mixture (1 : 1) of acetonitrile and tetrahydrofuran (6.0 ml) at 55-65°C and filtered for particle free at the same temperature. Obtained filtrate is cooled to 25-30°C and stirred at the same temperature. Filtered the solid and dried to obtain crystalline Form M6.

[0755] For example, one of the forms is Form M7 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.

[0756] The crystalline Form M7 may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in FIG. 148; an X-ray powder diffraction pattern having peaks at 9.1°±0.2°, 9.5°±0.2°, 10.5°±0.2°, 10.8°±0.2°, and 23.0°±0.2° 2-theta; and combinations of these data. The X-ray powderdiffraction pattern may have any one, two, three, four, five, six, seven, eight, or nine additional peaks selected from 11.9°±0.2°, 15.7°±0.2°, 17.3°±0.2°, 18.8°±0.2°, 19.5°±0.2°, 21.5°±0.2°, 24.3°±0.2°, 24.9°±0.2°, and 28.8°±0.2° 2-theta.

[0757] Example 7 of MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof' describes preparation of Form M7.

[0758] A mixture of isobutyl acetate (15.0 ml) and resmetirom (0.3 g) is stirred at 25- 30°C. Filtered the solid and dried to obtain crystalline Form M7.

[0759] The present disclosure also provides novel, previously unknown morphic forms, co-crystals, and salts of resmetirom, as well as methods for their preparation.

[0760] All XRPD patterns and peak listings for the novel forms described herein are based on a Cu-Ka radiation wavelength (1.54 A). A Rigaku Smart Lab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters are shown in the table below:

[0761] All DSC analyses for the novel forms described herein were carried out using a TA Instruments Q2000 Discovery Series instrument. The instrument temperature calibrations were performed using indium. The DSC cell was kept under a nitrogen purge of about 50 mL per minute during the analysis. Each sample was placed in a standard, crimped aluminum pan and heated from approximately -30°C to 250 / 300°C or -30°C to 350 / 400°C at a rate of 10°C per minute.

[0762] All thermogravimetric analyses (TGA) were carried out using a TA Instruments Q5500 Discovery Series instrument. The instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel. The nitrogen purge was about 10 mL per minute at the balance and about 25 mL per minute at the furnace. The sample was placed into a pre-tared platinum pan and heated from approximately 25 °C to 400 °C at a rate of 10 °C per minute.

[0763] All infrared (IR) spectroscopic analysis for the novel forms described herein was performed using a Thermo Scientific model iS50 Fourier-transform (FT) IR spectrophotometer equipped with a deuterated triglycine sulfate (DTGS) detector, a potassium bromide (KBr) beamsplitter, and a Polaris™ long-life IR source. A diamond attenuated total reflectance (ATR) sampling accessory with a spectral range of 4000 cm-1to 400 cm-1was used for ATR analysis. A SpectraTech drifts (Diffuse reflectance infra-red Fourier transform spectroscopy, DRIFTS) sampling accessory with a spectral range of 4000- 400 cm-1was used for DRIFTS analysis. Each spectrum was the result of 128 co-added scans acquired at 2 cm-1resolution. A single beam background scan of air was ac-quired before the sample scan, allowing presentation of the spectra in log 1 / R units. Wave-length calibration was performed using polystyrene. OMNIC v9.11 software package (Thermo-Nicolet) was used to acquire, process, and evaluate the spectral data.

[0764] All1H NMR spectra for the novel forms described herein were acquired on a Bruker Avance NEO 400 MHz spectrometer. Samples were prepared by dissolving material in DMSO-d6. The solutions were placed into individual 5 mm NMR tubes for subsequent spectral acquisition. Each spectrum was processed using TopSpin version 4.1.4 and referenced to the chemical shift of the residual DMSO-d6 (2.5 ppm) peak.

[0765] All Raman spectroscopic analysis for the novel forms described herein was performed using a Nicolet iS50 Raman module that was equipped with a 1064 nm near- infrared laser. The system was configured with an indium gallium arsenide (InGaAs) detector and a calcium fluoride (CaF2) beamsplitter. Each sample was placed onto the automated XYZ stage and analyzed using a laser power that was adjusted to optimize the signal intensity while avoiding damage to the sample. Raman spectra were collected with 256 signal- averaged scans at a resolution of 2 cm-1over the spectral range from 3700 cm-1to 100 cm Data acquisition and processing were performed using OMNIC v9.11 software.

[0766] Methods for synthesizing resmetirom can be found in U.S. Patent Nos. 7,452,882 and 9,266,861. Resmetirom Form I may be prepared according to the methods of U.S. Patent No. 9,266,861. Resmetirom Form D (acetone solvate) may be prepared according to the methods disclosed in U.S. Patent Application Publication No. 2021 / 0122740 Al. The contents of each of the foregoing are incorporated herein by reference in their entirety.

[0767] One aspect of the present disclosure relates to a morphic form, Form Ul, of resmetirom. Form Ul is a methyl ethyl ketone (MEK) solvate. In some embodiments, Form Ul is characterized by an XRPD pattern including peaks at 10.0°±0.2°, 10.7°±0.2°, 13.8°±0.2°, 23. 5°±0.2°, and 24.5°±0.2° 2-theta. In some embodiments, Form Ul is characterized by an XRPD pattern including any three, four, or five peaks selected from10.0°±0.2°, 10.7°±0.2°, 13.8°±0.2°, 23. 5°±0.2°, and 24.5°±0.2° 2-theta. In someembodiments, the XRPD pattern of Form U1 further includes one or more additional peaks from Table U1 below ±0.2° 2-theta. In other embodiments, Form U1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.149. In other embodiments, Form U1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U1 below ±0.2° 2-theta.TABLE U1

[0768] In other embodiments, Form U1 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 150. In other embodiments, Form U1 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 150. In other embodiments, Form U1 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 150. In other embodiments, Form U1 is also or alternatively characterized by a TGA thermogram comprising a 7.9% weight loss upon heating to about 200 °C. In other embodiments, Form U1 is also or alternatively characterized by a DSC thermogram comprising an endothermic event at about 150 °C and about 334 °C.

[0769] Another aspect of the present disclosure relates to a morphic form, Form U2, of resmetirom. Form U2 is a t-butanol solvate. In some embodiments, Form U2 is characterized by an XRPD pattern including peaks at 12.9°±0.2°, 13.7°±0.2°,16.9 °±0.2°, 23.6°±0.2°, and 29.3°±0.2° 2-theta. In some embodiments, Form U2 is characterized by an XRPD pattern including any three, four, or five peaks selected from 12.9°±0.2°,13.7°±0.2°,16.9 °±0.2°, 23.6°±0.2°, and 29.3°±0.2° 2-theta. In some embodiments, theXRPD pattern of Form U2 further includes one or more additional peaks from Table U2 below ±0.2° 2-theta. In other embodiments, Form U2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.151. In other embodiments, Form U2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U2 below ±0.2° 2-theta.TABLE U2

[0770] In other embodiments, Form U2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 152. In other embodiments, FormU2 is also or alternatively characterized by a TGA thermogram substantially similar to thatset forth in FIG. 152. In other embodiments, Form U2 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 152. In other embodiments, Form U2 is also or alternatively characterized by a TGA thermogram comprising about 5.7% weight loss upon heating to about 200 °C. In other embodiments, Form U2 is also or alternatively characterized by a DSC thermogram comprising an endothermic event at about 136 °C and about 328 °C.

[0771] Another aspect of the present disclosure relates to a morphic form, Form U3, of resmetirom. Form U3 is a N-methyl pyrrolidone solvate. In some embodiments, Form U3 is characterized by an XRPD pattern including peaks at 10.5°±0.2°, 11.2°±0.2°, 16.4°±0.2°, 22.7°±0.2°, and 23.2°±0.2° 2-theta. In some embodiments, FormU3 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.5°±0.2°, 11.2°±0.2°, 16.4°±0.2°, 22.7°±0.2°, and 23.2°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U3 further includes one or more additional peaks from Table U3 below ±0.2° 2-theta. In other embodiments, Form U3 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.153. In other embodiments, Form U3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U3 below ±0.2° 2-theta.TABLE U3

[0772] In other embodiments, Form U3 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 154. In other embodiments, Form U3 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 154. In other embodiments, Form U3 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 154. In other embodiments, Form U3 is also or alternatively characterized by a TGA thermogram comprising about 20.0% weight loss upon heating to about 200 °C. In other embodiments, Form U3 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 169 °C, about 207 °C, and about 329 °C.

[0773] Another aspect of the present disclosure relates to a morphic form, Form U4, of resmetirom. Form U4 is a nitromethane solvate. In some embodiments, Form U4 is characterized by an XRPD pattern including peaks at 8.1°±0.2°, 12.9°±0.2°, 16.3°±0.2°, 23.8°±0.2°, and 29.5°±0.2° 2-theta. In some embodiments, Form U4 is characterized by an XRPD pattern including any three, four, or five peaks selected 8.1°±0.2°, 12.9°±0.2°, 16.3°±0.2°, 23.8°±0.2°, and 29.5°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U4 further includes one or more additional peaks from Table U4 below ±0.2° 2-theta. In other embodiments, Form U4 is also or alternatively characterized by a XRPD patternsubstantially similar to that set forth in FIG.155. In other embodiments, Form U4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U4 below ±0.2° 2-theta.TABLE U4

[0774] Another aspect of the present disclosure relates to a morphic form, Form U5, of resmetirom. Form U5 is an o-xylene solvate. In some embodiments, Form U5 is characterized by an XRPD pattern including peaks at 8.7°±0.2°, 11.1°±0.2°, 15.5°±0.2°, 24.5°±0.2°, and 32.4°±0.2° 2-theta. In some embodiments, Form U5 is characterized by an XRPD pattern including any three, four, or five peaks selected from 8.7°±0.2°, 1 l.l°±0.2°, 15.5°±0.2°, 24.5°±0.2°, and 32.4°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U5 further includes one or more additional peaks from Table U5 below ±0.2° 2-theta. In other embodiments, Form U5 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.156. In other embodiments, Form U5 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U5 below ±0.2° 2-theta.TABLE U5

[0775] Another aspect of the present disclosure relates to a morphic form, Form U6, of resmetirom. Form U6 is a trifluoroethanol (TFE) solvate. In some embodiments, Form U6 is characterized by an XRPD pattern including peaks at 10.6°±0.2°, 11.5°±0.2°,18.8 °±0.2°, 20.0°±0.2°, and 23.5°±0.2° 2-theta. In some embodiments, Form U6 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.6°±0.2°, 11.5°±0.2°,18.8 °±0.2°, 20.0°±0.2°, and 23.5°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U6 further includes one or more additional peaks from Table U6 below ±0.2° 2-theta. In other embodiments, Form U6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.157. In other embodiments, Form U6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U6 below ±0.2° 2-theta.TABLE U6

[0776] In other embodiments, Form U6 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 158. In other embodiments, Form U6 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 158. In other embodiments, Form U6 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 158. In other embodiments, Form U6 is also or alternatively characterized by a TGA thermogram comprising about 18.4% weight loss upon heating to about 150 °C. In other embodiments, Form U6 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 234°C and about 333 °C.

[0777] Another aspect of the present disclosure relates to a morphic form, Form U7, of resmetirom. Form U7 is a solvate comprising multiple solvents. In some embodiments, Form U7 is characterized by an XRPD pattern including peaks at 9.5°±0.2°, 11.5°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 23.8°±0.2° 2-theta. In some embodiments, Form U7 is characterized by an XRPD pattern including any three, four, or five peaks selected from 9.5°±0.2°, 11.5°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 23.8°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U7 further includes one or more additional peaks from Table U7 below ±0.2° 2-theta. In other embodiments, Form U7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.159. In other embodiments, Form U7 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U7 below ±0.2° 2-theta.TABLE U7

[0778] In other embodiments, Form U7 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 160. In other embodiments, Form U7 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 160. In other embodiments, Form U7 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 160. In other embodiments, Form U7 is also or alternatively characterized by a TGA thermogram comprising about 9.7% weight loss between about 100°C and about 150 °C. In other embodiments, Form U7 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 73°C, about 130 °C, and about 320°C.

[0779] Another aspect of the present disclosure relates to a morphic form, Form U8, of resmetirom. Form U8 is a cyclohexanone solvate. In some embodiments, Form U8 is characterized by an XRPD pattern including peaks at 13.9°±0.2°,14.9 °±0.2°, 21.6°±0.2°, 25.1°±0.2°, and 28.2°±0.2° 2-theta. In some embodiments, Form U8 is characterized by an XRPD pattern including any three, four, or five peaks selected from 13.9°±0.2°,14.9 °±0.2°, 21.6°±0.2°, 25.1°±0.2°, and 28.2°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form U8 further includes one or more additional peaks from Table U8 below ±0.2° 2-theta. In other embodiments, Form U8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.161. In other embodiments, Form U8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U8 below ±0.2° 2-theta.TABLE U8

[0780] In other embodiments, Form U8 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 162. In other embodiments, Form U8 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 162. In other embodiments, Form U8 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 162. In other embodiments, Form U8 is also or alternatively characterized by a TGA thermogram comprising about 18.4% weight loss upon heating to about 200 °C. In other embodiments, Form U8 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 192 °C and about 333°C.

[0781] Another aspect of the present disclosure relates to a morphic form, Form U9, of resmetirom. Form U9 is a methyl acetate solvate. In some embodiments, Form U9 is characterized by an XRPD pattern including peaks at 10.5°±0.2°, 11.0°±0.2°, 11.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2° 2-theta 2-theta. In some embodiments, Form U9 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.5°±0.2°, 11.0°±0.2°, 11.8°±0.2°, 19.8°±0.2°, and 24.4°±0.2° 2-theta. In some embodiments, theXRPD pattern of Form U9 further includes one or more additional peaks from Table U9 below ±0.2° 2-theta. In other embodiments, Form U9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.163. In other embodiments, Form U9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U9 below ±0.2° 2-theta.TABLE U9

[0782] In other embodiments, Form U9 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 164. In other embodiments, Form U9 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 164. In other embodiments, Form U9 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 164. In other embodiments, Form U9 is also or alternatively characterized by a TGA thermogram comprising about 13.9% weight loss upon heating to about 175 °C. In other embodiments, Form U9 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 110 °C, about 154°C, and about 333 °C.

[0783] Another aspect of the present disclosure relates to a resmetirom triethyl citrate cocrystal, Form Cl. In some embodiments, Form C1 is characterized by an XRPD pattern including peaks at 7.1°±0.2°, 9.3°±0.2°, 10.1°±0.2°, 12.5°±0.2°, and 23.5°±0.2° 2-theta. In some embodiments, Form C1 is characterized by an XRPD pattern including any three, four, or five peaks selected from 7.1°±0.2°, 9.3°±0.2°, 10.1°±0.2°, 12.5°±0.2°, and 23.5°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C1 further includes one or moreadditional peaks from Table Cl below ±0.2° 2-theta. In other embodiments, Form C1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.165. In other embodiments, Form C1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table Cl below ±0.2° 2-theta.TABLE Cl

[0784] In other embodiments, Form C1 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 167. In other embodiments, FormCl is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 167. In other embodiments, Form C1 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 167. In other embodiments, Form C1 is also or alternatively characterized by a TGA thermogram comprising about 37% weight loss by 250 °C. In other embodiments, Form C1 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 84 °C and about 330 °C.

[0785] In other embodiments, Form C1 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 166. In other embodiments, Form C1 is also or alternatively characterized by an FTIR spectrum substantially similar to the FTIR spectrum of Form C1 set forth in FIG. 168. In other embodiments, Form C1 is also or alternatively characterized by a Raman spectrum substantially similar to the Raman spectrum of Form C1 set forth in FIG. 169.

[0786] Another aspect of the present disclosure relates to a resmetirom cytosine cocrystal, Form C2. In some embodiments, Form C2 is characterized by an XRPD pattern including peaks at 8.7°±0.2°, 10.8°±0.2°, 13.6°±0.2°, 17.6°±0.2°, and 21.6°±0.2° 2-theta. In some embodiments, Form C2 is characterized by an XRPD pattern including any three, four, or five peaks selected from 8.7°±0.2°, 10.8°±0.2°, 13.6°±0.2°, 17.6°±0.2°, and 21.6°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C2 further includes one or more additional peaks from Table C2 below ±0.2° 2-theta. In other embodiments, Form C2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.170. In other embodiments, Form C2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C2 below ±0.2° 2-theta.TABLE C2

[0787] In other embodiments, Form C2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 172. In other embodiments, Form C2 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 172. In other embodiments, Form C2 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 172. In other embodiments, Form C2 is also or alternatively characterized by a TGA thermogram comprising about 0.6% weight loss up to 200 °C. In other embodiments, Form C2 is also or alternatively characterized by a DSC thermogram comprising two major overlapping endothermic events with onset at 283 °C.

[0788] In other embodiments, Form C2 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 171. In other embodiments, Form C2 is also or alternatively characterized by an FTIR spectrum substantially similar to the FTIR spectrum of Form C2 set forth in FIG. 173. In other embodiments, Form C2 is also or alternatively characterized by a Raman spectrum substantially similar to the Raman spectrum of Form C2 set forth in FIG. 174.

[0789] Another aspect of the present disclosure relates to a resmetirom calcium pantothenate cocrystal, Form C3. In some embodiments, Form C3 is characterized by an XRPD pattern including peaks at 5.8°±0.2°, 11.5°±0.2°, 19.2°±0.2°, 20.0°±0.2°, and 23.4°±0.2° 2-theta. In some embodiments, Form C3 is characterized by an XRPD patternincluding any three, four, or five peaks selected from 5.8°±0.2°, 11.5°±0.2°, 19.2°±0.2°, 20.0°±0.2°, and 23.4°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form C3 further includes one or more additional peaks from Table C3 below ±0.2° 2-theta. In other embodiments, Form C3 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.175. In other embodiments, Form C3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C3 below ±0.2° 2-theta.TABLE C3

[0790] Another aspect of the present disclosure relates to a resmetirom dimethylglycine cocrystal, Form C4. Form C4 also contains 0.7 molar equivalents of isopropanol (IPA). In some embodiments, Form C4 is characterized by an XRPD pattern including peaks at 11.3°±0.2°, 14.1°±0.2°, 18.0°±0.2°, 19.7°±0.2°, and 22.7°±0.2° 2-theta. In some embodiments, Form C4 is characterized by an XRPD pattern including any three, four, or five peaks selected from 11.3°±0.2°, 14.1°±0.2°, 18.0°±0.2°, 19.7°±0.2°, and 22.7°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C4 further includes one or more additional peaks from Table C4 below ±0.2° 2-theta. In other embodiments, Form C4 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.176. In other embodiments, Form C4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C4 below ±0.2° 2-theta.TABLE C4

[0791] In other embodiments, Form C4 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 178. In other embodiments, Form C4 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 178. In other embodiments, Form C4 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 178. In other embodiments, Form C4 is also or alternatively characterized by a TGA thermogramcomprising two weight loss steps: 4.4% by 75 °C (about 0.5 Eq IPA) and an additional 2.1% by 125 °C (about 0.2 Eq IP A) In other embodiments, Form C4 is also or alternatively characterized by a DSC thermogram comprising multiple overlapping endotherms with peaks at 68 °C (broad) and 130 °C (double endo-therms), with an apparent onset of decomposition after the last endotherm.

[0792] In other embodiments, Form C4 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 177.

[0793] Another aspect of the present disclosure relates to a resmetirom di chloroacetic acid cocrystal, Form C5. In some embodiments, Form C5 is characterized by an XRPD pattern including peaks at 3.5°±0.2°, 6.9°±0.2°, 10.3°±0.2°, 13.7°±0.2°, and 17.2°±0.2° 2-theta. In some embodiments, Form C5 is characterized by an XRPD pattern including any three, four, or five peaks selected from 3.5°±0.2°, 6.9°±0.2°, 10.3°±0.2°, 13.7°±0.2°, and 17.2°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C5 further includes one or more additional peaks from Table C5 below ±0.2° 2-theta. In other embodiments, Form C5 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.179. In other embodiments, Form C5 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C5 below ±0.2° 2-theta.TABLE C5

[0794] In other embodiments, Form C5 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 181. In other embodiments, Form C5 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 181. In other embodiments, Form C5 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 181. In other embodiments, Form C5 is also or alternatively characterized by a TGA thermogram comprising about 37.8% weight loss by about 200 °C and a subsequent onset of decomposition at 339 °C. In other embodiments, Form C5 is also or alternatively characterized by a DSC thermogram comprising a major endotherm at about 106 °C (onset),a minor broad endotherm at about 186 °C (peak), and a major endotherm at about 319 °C (onset).

[0795] In other embodiments, Form C5 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 180. In other embodiments, Form C5 is also or alternatively characterized by an FTIR spectrum substantially similar to the FTIR spectrum of Form C5 set forth in FIG. 182. In other embodiments, Form C5 is also or alternatively characterized by a Raman spectrum substantially similar to the Raman spectrum of Form C5 set forth in FIG. 183.

[0796] Another aspect of the present disclosure relates to a resmetirom diethylamine cocrystal, Form C6. In some embodiments, Form C6 is characterized by an XRPD pattern including peaks at 10.0°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 22.2°±0.2°, and 22.8°±0.2° 2-theta. In some embodiments, Form C6 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.0°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 22.2°±0.2°, and 22.8°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form C6 further includes one or more additional peaks from Table C6 below ±0.2° 2-theta. In other embodiments, Form C6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.184. In other embodiments, Form C6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C6 below ±0.2° 2-theta.TABLE C6

[0797] Another aspect of the present disclosure relates to a resmetirom 4-aminopyridine salt, Form C7. In some embodiments, Form C7 is characterized by an XRPD pattern including peaks at 4.5°±0.2°, 8.9°±0.2°, 24.5°±0.2°, 27.3°±0.2°, and 16.9°±0.2° 2-theta. In some embodiments, Form C7 is characterized by an XRPD pattern including any three, four, or five peaks selected from 4.5°±0.2°, 8.9°±0.2°, 24.5°±0.2°, 27.3°±0.2°, and 16.9°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C7 further includes one or more additional peaks from Table C7 below ±0.2° 2-theta. In other embodiments, Form C7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.185. In other embodiments, Form C7 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C7 below ±0.2° 2-theta.TABLE C7

[0798] In other embodiments, Form C7 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 187. In other embodiments, Form C7 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 187. In other embodiments, Form C7 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 187. In other embodiments, Form C7 is also or alternatively characterized by a TGA thermogramcomprising about 1.1% weight loss by 100 °C, a further 2.2% weight loss by 225 °C, and the onset of decomposition at 255 °C. In other embodiments, Form C7 is also or alternatively characterized by a DSC thermogram comprising a minor broad endotherm at 76 °C (peak), a minor endotherm at 178 °C (peak) overlapping with an exotherm at 181 °C (onset), followed by a broad endotherm at 216 °C (peak) and a sharp major endotherm at 267 °C (onset).

[0799] In other embodiments, Form C7 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 186. In other embodiments, Form C7 is also or alternatively characterized by an FTIR spectrum substantially similar to the FTIR spectrum of Form C7 set forth in FIG. 188. In other embodiments, Form C7 is also or alternatively characterized by a Raman spectrum substantially similar to the Raman spectrum of Form C7 set forth in FIG. 189.

[0800] Another aspect of the present disclosure relates to a resmetirom imidazole salt, Form C8. In some embodiments, Form C8 is characterized by an XRPD pattern including peaks at 6.3°±0.2°, 7.3°±0.2°, 17.4°±0.2°, 21.9°±0.2°, and 22.3°±0.2° 2-theta. In some embodiments, Form C8 is characterized by an XRPD pattern including any three, four, or five peaks selected from 6.3°±0.2°, 7.3°±0.2°, 17.4°±0.2°, 21.9°±0.2°, and 22.3°±0.2° 2-theta In some embodiments, the XRPD pattern of Form C8 further includes one or more additional peaks from Table C8 below ±0.2° 2-theta. In other embodiments, Form C8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.190. In other embodiments, Form C8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C8 below ±0.2° 2-theta.TABLE C8

[0801] In other embodiments, Form C8 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 192. In other embodiments, Form C8 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 192. In other embodiments, Form C8 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 192. In other embodiments, Form C8 is also or alternatively characterized by a TGA thermogram comprising about 3.1% weight loss by 175 °C, and an additional about 13.4% weight loss by about 275 °C. In other embodiments, Form C8 is also or alternatively characterized by a DSC thermogram comprising endotherms at 150 °C (onset) and at 231 °C (onset).

[0802] In other embodiments, Form C8 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 191. In other embodiments, Form C8 is also or alternatively characterized by an FTIR spectrum substantially similar to the FTIR spectrum of Form C8 set forth in FIG. 193. In other embodiments, Form C8 is also or alternatively characterized by a Raman spectrum substantially similar to the Raman spectrum of Form C8 set forth in FIG. 194.

[0803] Another aspect of the present disclosure relates to a resmetirom tromethamine salt, Form C9. In some embodiments, Form C9 is characterized by an XRPD pattern including peaks at 7.3°±0.2°, 9.0°±0.2°, 20.2°±0.2°, 21.1°±0.2°, and 22.5°±0.2° 2-theta. In someembodiments, Form C9 is characterized by an XRPD pattern including any three, four, or five peaks selected from 7.3°±0.2°, 9.0°±0.2°, 20.2°±0.2°, 21.1°±0.2°, and 22.5°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form C9 further includes one or more additional peaks from Table C9 below ±0.2° 2-theta. In other embodiments, Form C9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth inFIG.195. In other embodiments, Form C9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C9 below ±0.2° 2-theta.TABLE C9

[0804] In other embodiments, Form C9 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 197. In other embodiments, Form C9 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 197. In other embodiments, Form C9 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 197. In other embodiments, Form C9 is also or alternatively characterized by a TGA thermogram comprising about 6.5% weight loss by about 130 °C, followed by onset of apparent decomposition at about 184 °C. In other embodiments, Form C9 is also or alternatively characterized by a DSC thermogram comprising a broad and sharp endotherm at 104°C and 134°C (onset), respectively, preceded by a minor endotherm with peak at 87 °C.

[0805] In other embodiments, Form C9 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 196.

[0806] Another aspect of the present disclosure relates to a morphic form, Form Nl, of resmetirom. Form Nl is a methyl ethyl ketone (MEK) solvate. In some embodiments, Form Nl is characterized by an XRPD pattern including peaks at 10.9°±0.2°, 14.3°±0.2°, 17.0°±0.2°, 21.9°±0.2°, and 24.5°±0.2° 2-theta. In some embodiments, Form N1 is characterized by an XRPD pattern including any three, four, or five peaks selected from10.9°±0.2°, 14.3°±0.2°, 17.0°±0.2°, 21.9°±0.2°, and 24.5°±0.2°. In some embodiments, the XRPD pattern of Form N1 further includes one or more additional peaks from Table N1 below ±0.2° 2-theta. In other embodiments, Form N1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 198. In other embodiments, Form N1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N1 below ±0.2° 2-theta.TABLE N1

[0807] In other embodiments, Form N1 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 199.

[0808] Another aspect of the present disclosure relates to a morphic form, Form N2, of resmetirom. Form N2 is an unsolvated form. In some embodiments, Form N2 is characterized by an XRPD pattern including peaks at 14.5°±0.2°, 15.3°±0.2°, 23.8°±0.2°, 24.6°±0.2°, and 25.3°±0.2° 2-theta. In some embodiments, Form N2 is characterized by an XRPD pattern including any three, four, or five peaks selected from 14.5°±0.2°, 15.3°±0.2°, 23.8°±0.2°, 24.6°±0.2°, and 25.3°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form N2 further includes one or more additional peaks from Table N2 below ±0.2° 2-theta. In other embodiments, Form N2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 200. In other embodiments, Form N2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N2 below ±0.2° 2-theta.TABLE N2

[0809] In other embodiments, Form N2 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 201. In other embodiments, Form N2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 202. In other embodiments, Form N2 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 202. In other embodiments, Form N2 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 202.

[0810] Another aspect of the present disclosure relates to a morphic form, Form N3, of resmetirom. Form N3 is an acetyl acetone solvate. In some embodiments, Form N3 is characterized by an XRPD pattern including peaks at 8.0°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.4°±0.2°, and 13.7°±0.2° 2-theta. In some embodiments, Form N3 is characterized by an XRPD pattern including any three, four, or five peaks selected from 8.0°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.4°±0.2°, and 13.7°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form N3 further includes one or more additional peaks from Table N3 below ±0.2° 2-theta. In other embodiments, Form N3 is also or alternatively characterized by a XRPD patternsubstantially similar to that set forth in FIG. 203. In other embodiments, Form N3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N3 below ±0.2° 2-theta.TABLE N3

[0811] In other embodiments, Form N3 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 204.

[0812] Another aspect of the present disclosure relates to a morphic form, Form N4, of resmetirom. Form N4 is a methyl ethyl ketone (MEK) solvate. In some embodiments, FormN4 is characterized by an XRPD pattern including peaks at 10.0°±0.2°, 10.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, and 24.5°±0.2° 2-theta. In some embodiments, Form N4 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.0°±0.2°, 10.9°±0.2°, 23.5°±0.2°, 24.1°±0.2°, and 24.5°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form N4 further includes one or more additional peaks from Table N4 below ±0.2° 2-theta. In other embodiments, Form N4 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 205. In other embodiments, Form N4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N4 below ±0.2° 2-theta.TABLE N4

[0813] In other embodiments, Form N4 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 206. In other embodiments, Form N4 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 207. In other embodiments, Form N4 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 207. In other embodiments, Form N4 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 207.

[0814] Another aspect of the present disclosure relates to a morphic form, Form N6, of resmetirom. Form N6 is an acetyl acetone solvate. In some embodiments, Form N6 is characterized by an XRPD pattern including peaks at 5.1°±0.2°, 11.9°±0.2°, 19.9°±0.2°,17.5°±0.2°, and 23.6°±0.2° 2-theta. In some embodiments, Form N6 is characterized by an XRPD pattern including any three, four, or five peaks selected from 5.1°±0.2°, 11.9°±0.2°, 19.9°±0.2°, 17.5°±0.2°, and 23.6°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form N6 further includes one or more additional peaks from Table N6 below ±0.2° 2-theta. In other embodiments, Form N6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 208. In other embodiments, Form N6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided inTable N6 below ±0.2° 2-theta.TABLE N6

[0815] In other embodiments, Form N6 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 209.

[0816] Another aspect of the present disclosure relates to a morphic form, Form N7, of resmetirom. Form N7 is a propionic acid solvate. In some embodiments, Form N7 is characterized by an XRPD pattern including peaks at 6.3°±0.2°, 12.7°±0.2°, 19.4°±0.2°, 25.0°±0.2°, and 25.6°±0.2° 2-theta. In some embodiments, Form N7 is characterized by an XRPD pattern including any three, four, or five peaks selected from 6.3°±0.2°, 12.7°±0.2°,19.4°±0.2°, 25.0°±0.2°, and 25.6°±0.2° 2-theta. In some embodiments, the XRPD pattern ofForm N7 further includes one or more additional peaks from Table N7 below ±0.2° 2-theta. In other embodiments, Form N7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 210. In other embodiments, Form N7 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N7 below ±0.2° 2-theta.TABLE N7

[0817] In other embodiments, Form N7 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 211. In other embodiments, Form N7 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 212. In other embodiments, Form N7 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 212. In other embodiments, Form N7 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 212.

[0818] Another aspect of the present disclosure relates to a morphic form, Form N8, of resmetirom. Form N8 is an isopropanol (IPA) acid solvate. In some embodiments, Form N8 is characterized by an XRPD pattern including peaks at 6.9°±0.2°, 14.3°±0.2°, 20.4°±0.2°, 23.0°±0.2°, and 30.1°±0.2° 2-theta. In some embodiments, Form N8 is characterized by an XRPD pattern including any three, four, or five peaks selected from 6.9°±0.2°, 14.3°±0.2°, 20.4°±0.2°, 23.0°±0.2°, and 30.1°±0.2° 2-theta. In some embodiments, the XRPD pattern of Form N8 further includes one or more additional peaks from Table N8 below ±0.2° 2-theta. In other embodiments, Form N8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 81. In other embodiments, Form N8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N8 below ±0.2° 2-theta.TABLE N8

[0819] In other embodiments, Form N8 is also or alternatively characterized by an1H NMR spectrum substantially similar to that set forth in FIG. 82. In other embodiments, Form N8 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 83. In other embodiments, Form N8 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 83. In other embodiments, Form N8 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 83.

[0820] Another aspect of the present disclosure relates to a morphic form, Form N9, of resmetirom. In some embodiments, Form N9 is characterized by an XRPD pattern including peaks at 4.8°±0.2°,10.6 °±0.2°, 16.9°±0.2°, 19.5°±0.2°, and 25.4°±0.2° 2-theta. In someembodiments, Form N9 is characterized by an XRPD pattern including any three, four, or five peaks selected from 4.8°±0.2°,10.6 °±0.2°, 16.9°±0.2°, 19.5°±0.2°, and 25.4°±0.2° 2- theta. In some embodiments, the XRPD pattern of Form N9 further includes one or more additional peaks from Table N9 below ±0.2° 2-theta. In other embodiments, Form N9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.213. In other embodiments, Form N9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N9 below ±0.2° 2-theta.TABLE N9

[0821] The present disclosure provides a method of treating or improving a fatty liver disease (e.g., NASH), the method comprising administering to the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement resmetirom or a pharmaceutically acceptable salt thereof.

[0822] The present disclosure also provides a method of treating or improving liver fibrosis associated with a fatty liver disease (e.g., NASH), the method comprising administering to the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement resmetirom or a pharmaceutically acceptable salt thereof.

[0823] The present disclosure also provides resmetirom or a pharmaceutically acceptable salt thereof for use for treating or improving a fatty liver disease (e.g., NASH) in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0824] The present disclosure also provides use of resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or improving a fatty liver disease (e.g., NASH) in a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement.

[0825] In some aspects, the present disclosure provides a method of reducing liver volume in a human subject (e.g., an adult human subject) who may be in need of such a reduction and / or may be in need of treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis), the method comprising administering to this human subject resmetirom or a pharmaceutically acceptable salt thereof.

[0826] In some aspects, the present disclosure provides resmetirom or a pharmaceutically acceptable salt thereof for use for reducing liver volume in a human subject (e.g., an adult human subject) who may be in need of such a reduction and / or may be in need of treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis).

[0827] In some aspects, the present disclosure provides use of resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing liver volume in a human subject (e.g., an adult human subject) who may be in need of such a reduction and / or the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis).

[0828] In some aspects, the present disclosure provides resmetirom or a pharmaceutically acceptable salt thereof for use in treating or preventing NASH in a human subject (e.g., an adult human subject) who may be in need of such treatment or prevention .

[0829] In some aspects, the present disclosure provides resmetirom or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing NASH in a human subject (e.g., an adult human subject) who may be in need of such treatment or prevention.

[0830] Specifically, the present disclosure provides a method of treating NASH. The method comprises: determining a weight of an adult human subject in need thereof; and based on determination of the weight of the adult human subject in need thereof, administering to the adult human subject in need thereof a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the adult human subject in need thereof is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the adult human subject in need thereof is determined to weigh less than 100 kg.

[0831] In some embodiments, the adult human subject in need thereof is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0832] In some embodiments, the adult human subject in need thereof is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0833] In some embodiments, the solid oral dosage form is a tablet.

[0834] In some embodiments, the solid oral dosage form comprises resmetirom.

[0835] Specifically, the present disclosure also provides a method of improving liver fibrosis. The method comprises: determining a weight of an adult human subject in need thereof; and based on determination of the weight of the adult human subject in need thereof, administering to the adult human subject in need thereof a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the adult human subject in need thereof is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the adult human subject in need thereof is determined to weigh less than 100 kg; and wherein the adult human subject in need thereof has nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0836] In some embodiments, the adult human subject in need thereof is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0837] In some embodiments, the adult human subject in need thereof is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0838] In some embodiments, the method is of improving the liver fibrosis by at least one stage in the adult human subject in need thereof.

[0839] In some embodiments, the solid oral dosage form is a tablet.

[0840] In some embodiments, the solid oral dosage form comprises resmetirom.

[0841] In some embodiments, the adult human subject in need thereof has liver fibrosis characterized as fibrosis stage F3.

[0842] In some embodiments, the adult human subject in need thereof has liver fibrosis characterized as fibrosis stage F2.

[0843] The present disclosure also provides a method of treating or improving a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject (e.g., an adult human subject); and based on determination of the weight of the human subject (e.g., an adult human subject), administering to the human subject (e.g., an adult human subject) a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject (e.g., an adult human subject) is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

[0844] The present disclosure also provides a method of improving a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject who may be in need of such improvement (e.g., an adult human subject); and based on determination of the weight of this human subject, administering to this human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if this human subject is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if this human subject is determined to weigh less than 100 kg.

[0845] The present disclosure also provides a method of treating a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject in need of such treatment (e.g., an adult human subject); and based on determination of the weight of the human subject in need of such treatment (e.g., an adult human subject), administering to the human subject in need of such treatment (e.g., an adult human subject) a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject in need of such treatment (e.g., an adult human subject) is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject in need of such treatment (e.g., an adult human subject) is determined to weigh less than 100 kg.

[0846] The present disclosure also provides a method of treating or improving liver fibrosis associated with a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject (e.g., an adult human subject); and based on determination of the weight of the human subject (e.g., an adult human subject), administering to the human subject (e.g., an adult human subject) a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject (e.g., an adult human subject) is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

[0847] The present disclosure also provides a method of treating liver fibrosis associated with a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject (e.g., an adult human subject) who may be in need of such treatment; and based on determination of the weight of this human subject, administering to this human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if this human subject is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if this human subject is determined to weigh less than 100 kg, and wherein this human subject has liver fibrosis associated with the fatty liver disease (e.g., NASH).

[0848] The present disclosure also provides a method of improving liver fibrosis associated with a fatty liver disease (e.g., NASH). The method comprises: determining a weight of a human subject (e.g., an adult human subject) in need of such improvement; and based on determination of the weight of the human subject (e.g., an adult human subject) in need of such improvement, administering to the human subject (e.g., an adult human subject) in need of such improvement a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject (e.g., an adult human subject) in need of such improvement is determined to weigh 100 kg or more; or(ii) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject (e.g., an adult human subject) in need of such improvement is determined to weigh less than 100 kg, and wherein the human subject (e.g., an adult human subject) in need of such improvement has liver fibrosis associated with the fatty liver disease (e.g., NASH).

[0849] In some aspects, the human subject (e.g., an adult human subject) who may be in need of such treatment and / or improvement (e.g., of NASH and / or liver fibrosis) is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

[0850] In some aspects, the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement (e.g., of NASH and / or liver fibrosis) is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

[0851] In some aspects, the fatty liver disease is NASH. In some aspects, the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement (e.g., of NASH and / or liver fibrosis) may have noncirrhotic non-alcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 and F3 fibrosis. In some aspects, the human subject (e.g., an adult human subject) who may be in need of suchtreatment or improvement (e.g., of NASH and / or liver fibrosis) may have noncirrhotic non- alcoholic steatohepatitis with mild liver fibrosis consistent with stage F1.

[0852] In some aspects, the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement (e.g., of NASH and / or liver fibrosis) is administered the solid oral dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof.

[0853] In some aspects, the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement (e.g., of NASH and / or liver fibrosis) has liver fibrosis characterized as fibrosis stage F2 or F3. In some aspects, the method is that of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

[0854] In some aspects, the method is of improving the liver fibrosis by one stage in the human subject (e.g., an adult human subject) who may be in need of such improvement . The human subject (e.g., an adult human subject) who may be in need of such improvement may have liver fibrosis characterized as fibrosis stage F2. The human subject (e.g., an adult human subject) who may be in need of such improvement may have liver fibrosis characterized as fibrosis stage F3.

[0855] In some aspects, the method is of improving the liver fibrosis by at least one stage (e.g., two stages) in the human subject (e.g., an adult human subject) who may be in need of such improvement. The human subject (e.g., an adult human subject) who may be in need of such improvement may have liver fibrosis characterized as fibrosis stage F2. The human subject (e.g., an adult human subject) who may be in need of such improvement may have liver fibrosis characterized as fibrosis stage F3.

[0856] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a body weight at or greater than 100 kilograms, and the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been administered to such a human subject at a dosage of 100 mg per day.

[0857] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a body weight less than 100 kilograms, and the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been administered to the human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) at a dosage of 80 mg per day.

[0858] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a body weight less than 100 kilograms, and the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been administered to the human subject (e.g., an adult human subject) in need of such treatment (e.g., NASH / improving liver fibrosis) at a dosage of 60 mg per day.

[0859] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is administered to the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) with food. In other embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is administered to the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., NASH and / or liver fibrosis) without food.

[0860] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken daily.

[0861] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken once or twice daily.

[0862] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken once daily.

[0863] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof, is or has been taken without any drug holiday.

[0864] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been taken with one or more drug holidays.

[0865] In some embodiments, the solid oral dosage form comprising 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, 52 weeks, or for any number of weeks therebetween.

[0866] In some embodiments, the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been administered for longer than 52 weeks.

[0867] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) 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) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) 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) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is taking 40 mg or less atorvastatin or pravastatin.

[0868] It was also found that concomitant use of resmetirom or the pharmaceutically acceptable salt thereof and a CYP2C8 inhibitor can increase resmetirom Cmax and AUC. As a result, the daily dose of resmetirom or the pharmaceutically acceptable salt thereof can be reduced to a reduced dosage and yet continue to provide the desired treatment or improvement of a fatty liver disease (e.g., NASH) and / or of fibrosis associated with the fatty liver disease (e.g., NASH) with such concomitant use.

[0869] Specifically, the reduction in the daily dose of resmetirom or the pharmaceutically acceptable salt thereof is 20 mg for a human subject (e.g., an adult human subject) who may be in need of the treatment or improvement of a liver disease (e.g., NASH) or of liver fibrosis associated with such a liver disease as described in this disclosure, who is on a moderateCYP2C8 inhibitor regimen. For instance, if such a human subject would otherwise be administered a dose of 100 mg of resmetirom per day based on the determination that theweight of this human subject is at least 100 kg, then the reduced dosage, due to the use of a moderate CYP2C8 inhibitor by this human subject, is 80 mg per day. If the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) would otherwise be administered a dose of 80 mg of resmetirom per day based on the determination that the weight of this human subject is less than 100 kg, then the reduced dosage, due to the use of a moderate CYP2C8 inhibitor by this human subject, is 60 mg per day.

[0870] If the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., NASH and / or liver fibrosis) was taking a moderate CYP2C8 inhibitor prior to using resmetirom or the pharmaceutically acceptable salt thereof then this human subject would start with the reduced dosage of 80 mg or 100 mg per day, depending on the weight determination. If the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as described herein (e.g., of NASH and / or liver fibrosis) was taking resmetirom or the pharmaceutically acceptable salt thereof at a dose of 100 mg per day or 80 mg per day, depending on the weight determination, but was not taking a moderate CYP2C8 inhibitor prior to using resmetirom or the pharmaceutically acceptable salt thereof then the dose would be reduced from 100 mg per day or 80 mg per day to a reduced dosage of 80 mg or 60 mg per day, respectively, depending on the weight determination, once this human subject is concomitantly using a moderate CYP2C8 inhibitor. If the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as described herein (e.g., of NASH and / or liver fibrosis) was using neither resmetirom or the pharmaceutically acceptable salt thereof nor a moderate CYP2C8 inhibitor prior to their concomitant use, then this human subject would start taking resmetirom or the pharmaceutically acceptable salt thereof with the reduceddosage of 80 mg or 60 mg per day, depending on the weight determination, for this concomitant use.

[0871] Specifically, disclosed herein is a method of treating or improving a fatty liver disease (e.g., NASH or in particular noncirrhotic NASH), which method comprises: determining a weight of a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement; and based on determination of the weight of the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement, administering to this human subject (e.g., an adult human subject) who may be in need of such treatment or improvement a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is determined to weigh 100 kg or more and the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is determined to weigh less than 100 kg and the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is using a moderate CYP2C8 inhibitor.

[0872] Also disclosed herein is a method of treating or improving liver fibrosis, which method comprises: determining a weight of a human subject (e.g., an adult human subject) who may be in need of such treatment or improvement ; and based on determination of theweight of the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement, administering to the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is determined to weigh 100 kg or more and the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is determined to weigh less than 100 kg and the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement is using a moderate CYP2C8 inhibitor, wherein the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

[0873] In some aspects, the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin,troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

[0874] In some aspects, the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, teriflunomide, trimethoprim, and / or pioglitazone.

[0875] In some aspects, the fatty liver disease is NASH.

[0876] In some aspects, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) who is on a moderate CYP2C8 inhibitor regimen is administered the resmetirom compound.

[0877] In some aspects, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) was also previously on a moderate CYP2C8 inhibitor regimen.

[0878] In some embodiments, the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof is 80 mg per day.

[0879] In some embodiments, the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof is 60 mg per day.

[0880] In some embodiments, the method includes reducing the previously used oral dose of resmetirom or the pharmaceutically acceptable salt thereof to the reduced dosage.

[0881] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

[0882] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

[0883] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) uses the moderate CYP2C8 inhibitor concomitantly (e.g., together or on the same day) with the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof. In some embodiments, the moderate CYP2C8 inhibitor is used by the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) daily. In some embodiments, the moderate CYP2C8 inhibitor is used by the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) once daily.

[0884] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof (e.g., a reduced dosage), is not using a strong CYP2C8 inhibitor (e.g., gemfibrozil).

[0885] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof (e.g., a reduced dosage), is not using OATP1B1 (organic anion transporting polypeptide IB 1) or OATP1B3 (organic anion transporting polypeptide 1B3) inhibitors (e.g., cyclosporine).

[0886] In some embodiments, the concomitant use of the moderate CYP2C8 inhibitor is within 24 hours before the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) takes resmetirom or the pharmaceutically acceptable salt thereof.

[0887] In some embodiments, the concomitant use of the moderate CYP2C8 inhibitor is within 24 hours after the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) takes resmetirom or the pharmaceutically acceptable salt thereof.

[0888] In some embodiments, the concomitant use of the moderate CYP2C8 inhibitor by the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) is conducted simultaneously with the administration of resmetirom or the pharmaceutically acceptable salt thereof.

[0889] The reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof may be administered via a solid oral dosage form.

[0890] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of such treatment or improvement as disclosed herein has a disease, disorder, or condition being NASH. It is understood that, in NASH, 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.

[0891] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein has a disease, disorder, or condition being liver inflammation.

[0892] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein has a disease, disorder, or condition being associated with an increased liver volume.

[0893] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein has a disease, disorder, or condition being portal hypertension.

[0894] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein has moderate hepatic impairment.

[0895] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein has autoimmune liver disease. In other embodiments, the human subject (e.g., an adult human subject) who may bein need of the treatment or improvement as disclosed herein does not have autoimmune liver disease.

[0896] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein 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) who may be in need of the treatment or improvement as disclosed herein does not have moderate to severe hepatic impairment.

[0897] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver volume being at least 5% greater, at least 10% greater, at least 20% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, at least 100% greater, at least 150% greater, at least 200% greater, or any number therebetween, compared to the same human subject had this human subject not been affected by the disease, disorder, or condition (e.g., without NASH).

[0898] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) being at least 5% greater, at least 10% greater, at least 20% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, at least 100% greater, at least 150% greater, at least 200% greater, or any number therebetween, compared to the same human subject had this human subject not been affected by the disease, disorder, or condition (e.g., without NASH ).

[0899] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) being at most 200% greater, at most 150% greater, at most 100% greater, at most 90% greater, at most 80% greater, at most 70% greater, at most 60% greater, at most 50% greater, at most 40% greater, at most 30% greater, at most 20% greater, at most 10% greater, or at most 5% greater, or any number therebetween, compared to the same human subject had this human subject not been affected by the disease, disorder, or condition (e.g., without NASH ).

[0900] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) being 50% or less, 40% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or any number therebetween.

[0901] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) being 5% or less.

[0902] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, or any number therebetween.

[0903] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by proton density fat fraction (PDFF)) being greater than 5%.

[0904] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a spleen volume being at least 5% greater, at least 10% greater, at least 20% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, at least 100% greater, at least 150% greater, at least 200% greater, or any number therebetween, compared to the same human subject had this human subject not been affected by the disease, disorder, or condition (e.g., without portal hypertension).

[0905] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is not administered a strong CYP2C8 inhibitor (e.g., gemfibrozil).

[0906] In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof is not administered OATP1B1 or OATP1B3 inhibitors (e.g., cyclosporine).

[0907] In some embodiments, the human subject (e.g., an adult human subject) i who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a daily dose of resmetirom or the pharmaceutically acceptable saltthereof is not administered atorvastatin, pravastatin, rosuvastatin, or simvastatin. In some embodiments, the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) 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) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) administered a reduced daily dose of resmetirom or the pharmaceutically acceptable salt thereof is taking 40 mg or less atorvastatin or pravastatin.

[0908] In some embodiments, the administration eliminates, or reduces the severity of, the disease, disorder, or condition.

[0909] In some embodiments, the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween (e.g., over a period of 12 weeks or 52 weeks).

[0910] In some embodiments, the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween, over a period of 12 weeks.

[0911] In some embodiments, the administration reduces the liver volume by at least 10% over a period of 12 weeks.

[0912] In some embodiments, the administration reduces the liver volume by at least 15% over a period of 12 weeks.

[0913] In some embodiments, the administration reduces the liver volume by at least 20% over a period of 12 weeks.

[0914] In some embodiments, the administration reduces the liver volume by at least 25% over a period of 12 weeks.

[0915] In some embodiments, the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween, over a period of 52 weeks.

[0916] In some embodiments, the administration reduces the liver volume by at least 10% over a period of 52 weeks.

[0917] In some embodiments, the administration reduces the liver volume by at least 15% over a period of 52 weeks.

[0918] In some embodiments, the administration reduces the liver volume by at least 20% over a period of 52 weeks.

[0919] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween (e.g., over a period of 12 weeks or 52 weeks).

[0920] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween, over a period of 12 weeks.

[0921] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 10% over a period of 12 weeks.

[0922] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 15% over a period of 12 weeks.

[0923] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 20% over a period of 12 weeks.

[0924] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 25% over a period of 12 weeks.

[0925] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween, over a period of 52 weeks.

[0926] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 10% over a period of 52 weeks.

[0927] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 15% over a period of 52 weeks.

[0928] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver volume by at least 20% over a period of 52 weeks.

[0929] In some embodiments, the administration reduces the liver fat amount (e.g., as measured by MRI-PDFF) by 60% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or any number therebetween, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration.

[0930] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less, and the administration reduces the liver fat amount (e.g., as measured by MRI-PDFF) by 60% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or any number therebetween, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration.

[0931] In some embodiments, the administration reduces the liver fat amount (e.g., as measured by MRI-PDFF) by 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, or any number therebetween, as compared to the liver volume of the human subject (e.g., an adult human subject) who may be in need of thetreatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration.

[0932] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 60% or less, 50% or less, 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, or any number therebetween, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween (e.g., over a period of 12 weeks or 52 weeks).

[0933] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 40% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 10% (e.g., over a period of 12 weeks or 52 weeks).

[0934] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein(e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 35% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) in n who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 10% (e.g., over a period of 12 weeks or 52 weeks).

[0935] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 30% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 10% (e.g., over a period of 12 weeks or 52 weeks).

[0936] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 40% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) in who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 15% (e.g., over a period of 12 weeks or 52 weeks).

[0937] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein(e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 35% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) in who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 15% (e.g., over a period of 12 weeks or 52 weeks).

[0938] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 30% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) in who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 15% (e.g., over a period of 12 weeks or 52 weeks).

[0939] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 40% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) in who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 20% (e.g., over a period of 12 weeks or 52 weeks).

[0940] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein(e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 35% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 20% (e.g., over a period of 12 weeks or 52 weeks).

[0941] In some embodiments, prior to the administration the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) has a liver fat amount (e.g., as measured by MRI-PDFF) being 5% or less; the administration reduces the liver fat amount (e.g., as measured by MRI- PDFF) by 30% or less, as compared to the liver fat amount of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) prior to the administration; and the administration reduces the liver volume by at least 20% (e.g., over a period of 12 weeks or 52 weeks).

[0942] In some embodiments, the liver volume reduction is dependent from the liver fat amount (e.g., the liver fat amount prior to the administration).

[0943] In some embodiments, the liver volume reduction is independent from the liver fat amount (e.g., the liver fat amount prior to the administration).

[0944] In some embodiments, the liver volume reduction is dependent from the liver fat amount reduction.

[0945] In some embodiments, the liver volume reduction is independent from the liver fat amount reduction.

[0946] In some embodiments, the liver volume reduction is greater than the liver fat amount reduction.

[0947] In some embodiments, the liver volume reduction is at least 5% greater, at least 10% greater, at least 20% greater, at least 30% greater, at least 40% greater, at least 50% greater, at least 60% greater, at least 70% greater, at least 80% greater, at least 90% greater, at least 100% greater, at least 150% greater, at least 200% greater, at least 300% greater, at least 400% greater, at least 500% greater, at least 600% greater, at least 700% greater, at least 800% greater, at least 900% greater, at least 1000%, or any number therebetween, as compared to the liver fat amount reduction.

[0948] In some embodiments, the administration eliminates, or reduces the severity of, liver inflammation.

[0949] In some embodiments, the administration eliminates, or reduces the severity of, portal hypertension.

[0950] In some embodiments, the administration reduces the blood pressure in the portal vein of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis).

[0951] In some embodiments, the administration reduces the blood pressure in the portal vein of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis) by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween (e.g., over a period of 12 weeks or 52 weeks) as compared to before treatment.

[0952] In some embodiments, the administration reduces the spleen volume of the human subject (e.g., an adult human subject) who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis).

[0953] In some embodiments, the administration reduces the spleen volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, or any number therebetween (e.g., over a period of 12 weeks or 52 weeks) as compared to before treatment.

[0954] In some embodiments, the administration reduces the spleen volume by at least 10% or at least 15% (e.g., over a period of 12 weeks or 52 weeks).

[0955] In some embodiments, the administration reduces the spleen volume by at least 10% or at least 15% over a period of 12 weeks.

[0956] In some embodiments, the administration reduces the spleen volume by at least 10% or at least 15% over a period of 52 weeks.

[0957] It has been unexpectedly determined that treatment with resmetirom or a pharmaceutically acceptable salt thereof can significantly improve NASH resolution and / or liver fibrosis if a human subject (e.g., an adult human subject) loses at least 5% of their body weight. Such weight loss can be achieved, for example, as a result of diet and / or exercise. Thus, a human subject (e.g., an adult human subject) in need of the treatment or improvement as described herein (e.g., of NASH and / or liver fibrosis) 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.

[0958] 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 (e.g., of NASH and / or liver fibrosis) 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 (e.g., of NASH and / or liver fibrosis) 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.

[0959] The pharmaceutical composition can be in a form suitable for oral use.

[0960] In some embodiments, the pharmaceutical composition is formulated in a solid oral dosage 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 treatment or improvement as disclosed herein (e.g., of NASH and / or liver fibrosis). The solid oral dosage form includes for example, a pill.

[0961] 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.

[0962] 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.

[0963] 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.

[0964] 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 corn 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.

[0965] 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.

[0966] EXAMPLES

[0967] The following Examples are provided by way of illustration and not by way of limitation.

[0968] Example 1

[0969] Liver Volume Reduction in Resmetirom-treated Non-cirrhotic and Cirrhotic NASH Patients

[0970] Hepatomegaly may cause symptoms (e.g., pain) in NASH patients, and is thought to be driven primarily by high liver fat content. In a 36-week Phase 2 serial MRI-PDFF and liver biopsy study in adults with biopsy-confirmed NASH (NAS≥4, F1-F3) and hepatic fat fraction ≥10%, resmetirom treated patients, compared with placebo, showed statistically significant liver fat reduction that was associated with NASH resolution on liver biopsy. This study was to assess the relationship between liver triglycerides as measured by MRI-PDFF and liver volume (LV) in placebo and resmetirom-treated patients.

[0971] MRI-PDFF and liver volume (LV) were assessed in, (n=117), and a NASH- cirrhotic active resmetirom treatment arm of MAESTRO-NAFLD-1 (n=73), in patients whohad at least baseline and one additional serial PDFF. LV was assessed using a validated artificial intelligence model for segmenting the liver on standard MR images.

[0972] LV at baseline was elevated in non-cirrhotic and cirrhotic NASH patients relative to literature values for healthy controls and was greater than predicted even after accounting for sex and body weight. PDFF correlated with LV at baseline in non-cirrhotic (r2=0.19, p<0.001) and more weakly in cirrhotic NASH (r2=0.079, p=0.01). Reduction in LV (CFB) correlated with reduction in PDFF in placebo (r2=0.25, p=0.001) and resmetirom (r2=0.38, p<0.0001) treated patients at 12 (and 36 (not shown)) weeks (see, e.g., FIG. 1). LV reduction was greater in resmetirom (-18.6 %(1.1), -20.5 %(1.2) compared to placebo (-0.4 %(1.5), 0.1% (1.9) treated at 12 and 36 weeks, respectively (p<0.0001). A higher percentage of resmetirom (69.2%) than placebo (5.3%) patients had a ≥15% reduction in liver volume (p<0.0001) at Week 12, and similarly at Week 36. The relationship between LV reduction and PDFF reduction was proportionately weaker in placebo compared to resmetirom treated non-cirrhotic NASH patients. In cirrhotic NASH patients treated with resmetirom (see FIG. 1), LV reduction was much greater than expected based on the small reduction in PDFF, especially in patients with PDFF≤5% at baseline (LV mean ¾CFB, -16.3% versus PDFF, mean ¾CFB, -2.5% at week 16). Resmetirom treated patients who had NASH resolution and / or fibrosis reduction on biopsy at week 36 all had a PDFF reduction ≥30% and / or LV reduction of ≥15% at week 12.

[0973] Without wishing to be bound by theory, reduction in liver volume in resmetirom treated patients may be explained in part by reduction in liver triglycerides (measured by MRI-PDFF), but it also may be driven by other changes related to its mechanism of action. LV reduction may be associated with histopathologic improvement of NASH that may be further assessed by data from Phase 3 MAESTRO-NASH study,

[0974] Biomarkers, imaging and safety in resmetirom 52 week non-cirrhoticNASH Phase 3 clinical trial, completed open-label arm of MAESTRO-NAFLD-1

[0975] MAESTRO-NASH NCT03900429 and MAESTRO-NAFLD-1 NCT04197479 are 52 week Phase 3 registrational double blind placebo controlled clinical trials to study the effect of resmetirom in more than 2,000 NASH patients. A goal of MAESTRO-NAFLD-1, a 1,200 patient "real life" NASH study is to identify non-invasive markers that correlate with patient response to resmetirom treatment. The 169 patient, 100 mg open label (OL) arm completed the 52 week study in July 2021.

[0976] Eligibility required at least 3 metabolic risk factors (Metabolic syndrome), fibroscan kilopascals (kPa) consistent with ≥F1 fibrosis stage, and MRI-PDFF≥8%. The primary and key secondary endpoints of MAESTRO-NAFLD-1 including safety, relative percent reduction of MRI-PDFF (week 16), LDL cholesterol (LDL-C) (week 24), apolipoprotein B and triglycerides, fibroscan and 52 week endpoints were analyzed in the OL arm.

[0977] Mean age was 55.7 (11.5 Standard Deviation (SD)), female 69%, BMI 35.8 (6.0), diabetes 43%, hypertension 62%, dyslipidemia >70%, atherosclerotic cardiovascular disease (ASCVD) score 11.5%; fibroscan (kPa 7.7 (3.6)), and MRI-PDFF 17% (7%). Statistically significant (p<0.0001) reduction of MRI-PDFF -53% (3.3% (Standard Error)) overall, and in several subgroups were observed at week 52 (see, e.g., FIG. 2). Liver volume (LV) was elevated at baseline (2202 cm3 (535)) by -50% relative to normal controls and -15% after correction for BMI (Euro J of Radiol 106, 2018, 32-37). Resmetirom reduced LV -21% (1.0%), -23% (1.0%) respectively, at weeks 16 and 52 (p<0.0001), in all demographic groups (see, e.g., FIG. 3). LV reduction was 2-3 fold greater than predicted by% reduction in MRI- PDFF, a measure of liver fat content (Clin Gastroenterol Hepatol. 2015 13: 561-568); LY-corrected mean MRI-PDFF reduction was -63% (2.4%). Weight loss >5% occurred in -25% and was linked to resmetirom exposure (SHBG). At week 52, magnetic resonance elastography (MRE) (-0.34, p=0.03); fibroscan controlled attenuation parameter (CAP) (-39 (4.6)) and vibration-controlled transient elastography (VCTE) (-1.87;-20%) (p<0.0001) were reduced relative to baseline. LDL-C (-22% (1.9%), apolipoprotein-B (- 24% (1.6%)), triglycerides (-24% (2.6) were statistically reduced (p<0.0001). Decreases from baseline in liver enzymes were ALT -20 International Unit (IU), aspartate aminotransferase (AST) -11 IU, gamma-glutamyl transferase (GGT) -25 IU (p<0.0001). Significant reductions in inflammatory and fibrosis biomarkers, reverse T3, enhanced liver fibrosis (ELF), and M30 (an apoptotic serum marker), and an increase in adiponectin were observed. No safety flags were identified; Blood pressure (systolic, diastolic) was reduced by -2 mmHg, (p=0.02); bone mineral density (DEXA) was unchanged at 52 weeks.

[0978] In this 52 week Phase 3 OL study, noninvasively identified NASH patients treated with 100 mg per day of resmetirom for up to 52 weeks demonstrated rapid and sustained reduction in (1) hepatic fat and liver volume; (2) fibrosis as assessed by biomarkers, MRE, and fibroscan; (3) LDL and atherogenic lipids; and (4) liver enzymes inflammatory biomarkers, providing support for the use of non-invasive tests to monitor individual NASH patient response to resmetirom treatment.

[0979] Biomarkers., imaging and safety in a well-compensated NASH cirrhotic cohort treated with resmetirom for 52 weeks

[0980] As mentioned above, MAESTRO-NAFLD-1 is a 52-week patient Phase 3 randomized double blind placebo controlled NASH clinical trial that was conducted to study safety and biomarker effects of resmetirom in NASH patients with F1-F4 fibrosis identifiedusing non-invasive biomarkers and imaging (NCT04197479). The study included an open label active resmetirom treatment arm in well-compensated NASH cirrhotic patients.

[0981] Eligibility required at least 3 metabolic risk factors (metabolic syndrome), and NASH cirrhosis diagnosed on liver biopsy or according to accepted criteria. The primary and key secondary end points of the cirrhotic arm include safety, relative percent reduction of MRI-PDFF (week 16), LDL cholesterol (LDL-C) (week 24), Apolipoprotein Band triglycerides, and markers of fibrosis. Patients received 80-100 mg daily dose of resmetirom for 52 weeks.

[0982] 105 well-compensated NASH cirrhotic patients were enrolled in the open label arm, 2 / 3 confirmed by liver biopsy. Demographics include mean age 62.7 (9.0 (SD...

Claims

CLAIMS1. A method of treating nonalcoholic steatohepatitis (NASH), comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

2. The method according to claim 1, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

3. The method according to claim 1, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

4. The method according to any one of the preceding claims, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

5. The method according to any one of the preceding claims, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis.

6. The method according to any one of the preceding claims, wherein the solid oral dosage form comprises resmetirom.

7. A method of treating liver fibrosis comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of80 mg per day, if the human subject is determined to weigh less than 100 kg; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

8. The method according to claim 7, wherein the method is of improving the liver fibrosis.

9. The method according to claim 7 or 8, wherein the human subject has liver fibrosis characterized as fibrosis stage F2.

10. The method according to claim 7 or 8, wherein the human subject has liver fibrosis characterized as fibrosis stage F3.

11. The method according to any one of claims 8-10, wherein the method is of improving the liver fibrosis by one stage in the human subject.

12. The method according to claim 10, wherein the method is of improving the liver fibrosis by two stages in the human subject.

13. The method according to any one of claims 7-12, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

14. The method according to any one of claims 7-12, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

15. The method according to any one of claims 7-14, wherein the solid oral dosage form comprises resmetirom.

16. The method according to any one of claims 1-15, wherein the solid oral dosage form is a tablet.

17. The method according to any one of claims 1-16, wherein the human subject is an adult human subject.

18. A method of treating noncirrhotic nonalcoholic steatohepatitis (NASH), comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor.

19. The method according to claim 18, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day.

20. The method according to claim 18, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day.

21. The method according to claim 19, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

22. The method according to claim 20, wherein, the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

23. The method according to any one of claims 18-22, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

24. The method according to any one of claims 18-22, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

25. The method according to any one of claims 18-24, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

26. The method according to any one of claims 18-25, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis.

27. The method according to any one of claims 18-26, wherein the solid oral dosage form comprises resmetirom.

28. The method according to any one of claims 18-27, wherein the solid oral dosage form is a tablet.

29. The method according to any one of claims 18-28, wherein the human subject is an adult human subject.

30. A method of treating liver fibrosis comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

31. The method according to claim 30, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day.

32. The method according to claim 30, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day.

33. The method according to claim 31, wherein the human subject used the resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

34. The method according to claim 32, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

35. The method according to any one of claims 30-34, wherein the method is of improving the liver fibrosis.

36. The method according to any one of claims 30-35, wherein the human subject has liver fibrosis characterized as fibrosis stage F2.

37. The method according to any one of claims 30-35, wherein the human subject has liver fibrosis characterized as fibrosis stage F3.

38. The method according to any one of claims 35-37, wherein the method is of improving the liver fibrosis by one stage in the human subject.

39. The method according to claim 36, wherein the method is of improving the liver fibrosis by two stages in the human subject.

40. The method according to any one of claims 30-39, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate,spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir, lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

41. The method according to any one of claims 30-39, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

42. The method according to any one of claims 30-41, wherein the solid oral dosage form comprises resmetirom.

43. The method according to any one of claims 30-42, wherein the solid oral dosage form is a tablet.

44. The method according to any one of claims 30-43, wherein the human subject is an adult human subject.

45. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating nonalcoholic steatohepatitis (NASH), the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 80 mg per day, if the human subject is determined to weigh less than 100 kg.

46. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 45, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

47. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 45, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis.

48. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of 100 mg per day, if the human subject is determined to weigh 100 kg or more; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a dosage of80 mg per day, if the human subject is determined to weigh less than 100 kg; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

49. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48, wherein the method is of improving the liver fibrosis.

50. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48 or 49, wherein the human subject has liver fibrosis characterized as fibrosis stage F2.

51. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 48 or 49, wherein the human subject has liver fibrosis characterized as fibrosis stage F3.

52. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 49-51, wherein the method is of improving the liver fibrosis by one stage in the human subject.

53. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 51, wherein the method is of improving the liver fibrosis by two stages in the human subject.

54. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 48-53, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 100 mg per day.

55. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 48-53, wherein the human subject is determined to weigh less than 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.

56. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-55, wherein the solid oral dosage form is a tablet.

57. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-56, wherein the human subject is an adult human subject.

58. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating noncirrhotic nonalcoholic steatohepatitis (NASH), the method comprising: determining a weight of a human subject; and based on determination of the weight of the human subject, administering orally to the human subject a solid oral dosage form comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor.

59. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 58, wherein the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.

60. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 58 or 59, wherein the method is of improving noncirrhotic nonalcoholic steatohepatitis.

61. Resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising:(i) resmetirom or a pharmaceutically acceptable salt thereof at a reduced dosage of 80 mg per day, if the human subject is determined to weigh 100 kg or more and the human subject is using a moderate CYP2C8 inhibitor; or(ii) resmetirom or the pharmaceutically acceptable salt thereof at a reduced dosage of 60 mg per day, if the human subject is determined to weigh less than 100 kg and the human subject is using a moderate CYP2C8 inhibitor; and wherein the human subject has liver fibrosis associated with nonalcoholic steatohepatitis (NASH).

62. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61, wherein the method is of improving the liver fibrosis.

63. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61 or 62, wherein the human subject has liver fibrosis characterized as fibrosis stage F2.

64. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 61 or 62, wherein the human subject has liver fibrosis characterized as fibrosis stage F3.

65. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 62-64, wherein the method is of improving the liver fibrosis by one stage in the human subject.

66. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 64, wherein the method is of improving the liver fibrosis by two stages in the human subject.

67. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-66, wherein the human subject is determined to weigh 100 kg or more and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 80 mg per day.

68. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-66, wherein the human subject is determined to weigh lessthan 100 kg and is administered the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof at the reduced dosage of 60 mg per day.

69. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 67, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 100 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 100 mg per day is reduced to the reduced dosage of 80 mg per day.

70. Resmetirom or the pharmaceutically acceptable salt thereof for use according to claim 68, wherein the human subject used resmetirom or the pharmaceutically acceptable salt thereof at an oral dose of 80 mg per day before starting to use the moderate CYP2C8 inhibitor, and the oral dose of 80 mg per day is reduced to the reduced dosage of 60 mg per day.

71. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-70, wherein the moderate CYP2C8 inhibitor is selected from the group consisting of rosiglitazone, trimethoprim, tamoxifen, irbesartan, quinine, efavirenz, rabeprazole, crisaborole, nabilone, bexarotene, ritonavir, nicardipine, loratadine, eltrombopag, diltiazem, enzalutamide, ketoconazole, fluvastatin, levothyroxine, oxybutynin, medroxyprogesterone acetate, spironolactone, amlodipine, saquinavir, abiraterone, genistein, lenvatinib, pioglitazone, clotrimazole, nilotinib, teriflunomide, topiroxostat, lovastatin, troglitazone, amitriptyline, pirtobrutinib, belinostat, bezafibrate, candesartan, cholecalciferol, cimetidine, colchicine, dabrafenib, deferasirox, diethylstilbestrol, enasidenib, erlotinib, ethinylestradiol, fenofibrate, gemfibrozil, idelalisib, isoniazid, ketoprofen, letermovir,lumacaftor, mefenamic acid, midostaurin, montelukast, nilutamide, opicapone, phenelzine, piroxicam, pyrimethamine, quercetin, raloxifene, repaglinide, rifampicin, rofecoxib, salmeterol, sorafenib, sulfaphenazole, tegaserod, terbinafine, terfenadine, thiazolidinediones, ticlopidine, trametinib, triazolam, troleandomycin, valproic acid, verapamil, vismodegib, clopidogrel, and zafirlukast.

72. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-70, wherein the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and / or pioglitazone.

73. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 45-72, wherein the solid oral dosage form comprises resmetirom.

74. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-73, wherein the solid oral dosage form is a tablet.

75. Resmetirom or the pharmaceutically acceptable salt thereof for use according to any one of claims 58-74, wherein the human subject is an adult human subject.

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