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WO2025171032A1 - Méthodes de traitement d'une stéatose hépatique - Google Patents

Méthodes de traitement d'une stéatose hépatique

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Publication number
WO2025171032A1
WO2025171032A1 PCT/US2025/014625 US2025014625W WO2025171032A1 WO 2025171032 A1 WO2025171032 A1 WO 2025171032A1 US 2025014625 W US2025014625 W US 2025014625W WO 2025171032 A1 WO2025171032 A1 WO 2025171032A1
Authority
WO
WIPO (PCT)
Prior art keywords
resmetirom
human subject
pharmaceutically acceptable
acceptable salt
per day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014625
Other languages
English (en)
Inventor
Rebecca Taub
Dominic LABRIOLA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Madrigal Pharmaceuticals Inc
Original Assignee
Madrigal Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US19/045,070 external-priority patent/US12377104B1/en
Application filed by Madrigal Pharmaceuticals Inc filed Critical Madrigal Pharmaceuticals Inc
Priority to EP25709834.3A priority Critical patent/EP4658275A1/fr
Publication of WO2025171032A1 publication Critical patent/WO2025171032A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • 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.
  • NASH non-alcoholic steatohepatitis
  • 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.
  • TTR-beta thyroid hormone receptor-beta
  • the disclosure is related to the area of treatment of stages F2 and F3 liver fibrosis associated with a fatty liver disease.
  • 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.
  • 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.
  • HPT hypothalamus/pituitary/thyroid
  • 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.
  • 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.
  • NASH non-alcoholic steatohepatitis
  • Non-alcoholic steatohepatitis 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.
  • NASH nonalcoholic fatty liver disease
  • NASH nonalcoholic fatty liver disease
  • NASH nonalcoholic fatty liver disease
  • NASH inflamed fatty liver
  • the disease is generally asymptomatic until severe liver impairment occurs.
  • liver volumes can be attributed to increased liver fat and fluid retention due to inflammatory processes in NASH.
  • liver fat decreases as the liver becomes increasingly fibrotic.
  • Liver volume remains elevated in cirrhotic human subjects due to ongoing inflammation and venous congestion associated with portal hypertension. Reducing liver volume in noncirrhotic 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.
  • NAFLD National Airway disease
  • U.S. population 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.
  • 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.
  • 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)
  • NASH non-alcoholic steatohepatitis
  • a human subject e.g., an adult human subject
  • a human subject e.g., an adult human subject
  • a method of treating NASH 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:
  • 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.
  • 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.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl.
  • the method is of improving noncirrhotic nonalcoholic steatohepatitis.
  • the solid oral dosage form comprises resmetirom.
  • the solid oral dosage form is a tablet.
  • the human subject is an adult human subject.
  • 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.
  • a fatty liver disease e.g., NASH
  • a method of treating liver fibrosis 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:
  • 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).
  • NASH nonalcoholic steatohepatitis
  • the method is of improving the liver fibrosis.
  • the human subject has liver fibrosis characterized as fibrosis stage F 1.
  • the human subject has liver fibrosis characterized as fibrosis stage F2.
  • the human subject has liver fibrosis characterized as fibrosis stage F3.
  • the method is of improving the liver fibrosis by one stage in the human subject.
  • the method is of improving the liver fibrosis by two stages in the human subject.
  • 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.
  • the solid oral dosage form comprises resmetirom.
  • the solid oral dosage form is a tablet.
  • the human subject is an adult human subject.
  • 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.
  • 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:
  • 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.
  • 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.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with mild liver fibrosis consistent with stage Fl.
  • the method is of improving noncirrhotic nonalcoholic steatohepatitis.
  • the solid oral dosage form comprises resmetirom.
  • the solid oral dosage form is a tablet.
  • 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.
  • a fatty liver disease e.g., NASH
  • 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.
  • 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.
  • 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.
  • 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.
  • the method is of improving the liver fibrosis.
  • the human subject has liver fibrosis characterized as fibrosis stage F2.
  • the human subject has liver fibrosis characterized as fibrosis stage F3.
  • 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.
  • 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,
  • the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and/or pioglitazone.
  • the solid oral dosage form comprises resmetirom.
  • the solid oral dosage form is a tablet.
  • the human subject is an adult human subject.
  • 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
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl.
  • the method is of improving noncirrhotic nonalcoholic steatohepatitis.
  • 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:
  • 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).
  • NASH nonalcoholic steatohepatitis
  • the method is of improving the liver fibrosis.
  • the human subject has liver fibrosis characterized as fibrosis stage F 1.
  • the human subject has liver fibrosis characterized as fibrosis stage F2.
  • the human subject has liver fibrosis characterized as fibrosis stage F3.
  • the method is of improving the liver fibrosis by one stage in the human subject.
  • the method is of improving the liver fibrosis by two stages in the human subject.
  • 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.
  • 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.
  • the solid oral dosage form is a tablet.
  • the human subject is an adult human subject.
  • 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
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.
  • the method is of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stage Fl .
  • the method is of improving noncirrhotic nonalcoholic steatohepatitis.
  • resmetirom or a pharmaceutically acceptable salt thereof for use in a method of treating liver fibrosis, the method comprising:
  • 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).
  • NASH nonalcoholic steatohepatitis
  • the method is of improving the liver fibrosis.
  • the human subject has liver fibrosis characterized as fibrosis stage F 1.
  • the human subject has liver fibrosis characterized as fibrosis stage F2.
  • the human subject has liver fibrosis characterized as fibrosis stage F3.
  • the method is of improving the liver fibrosis by one stage in the human subject.
  • the method is of improving the liver fibrosis by two stages in the human subject.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, gemfibrozil, teriflunomide, trimethoprim, and/or pioglitazone.
  • the solid oral dosage form comprises resmetirom.
  • the solid oral dosage form is a tablet.
  • the human subject is an adult human subject.
  • 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.
  • PDFF proton density fat fraction
  • PBO represents placebo patients
  • RES represents resmetirom-treated patients.
  • 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.
  • SHBG sex hormone binding globulin
  • 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.
  • FIG. 4 is a graphical representation showing resmetirom-mediated changes to the MRI-PDFF and liver volume (LV) at week 52 in Example 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • LDL low-density lipoprotein
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the two pathologists' assessments were similar and were averaged to generate a single output.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 20 is a graphical representation showing time to onset of first gastrointestinal adverse event in Example 2.
  • FIG. 21 is a graphical representation showing duration of diarrhea: duration of diarrhea reported in first 12 weeks of randomization in Example 2.
  • FIG. 22 is a schematic showing prescreening and screening sequence in Example 2.
  • FIG. 23 is a schematic showing methodology for central pathologist evaluation of liver biopsies in Example 2.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 a graphical 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 46 is a reproduction of an excerpt of the prescribing information of
  • FIG. 47 is an X-ray powder diffractogram (XRPD) pattern of resmetirom Form I.
  • FIG. 48 is a differential scanning calorimetry (DSC) diagram of resmetirom Form I.
  • FIG. 49 is an XRPD pattern of resmetirom Form ⁇ .
  • FIG. 50 is an XRPD pattern of resmetirom Form F.
  • FIG. 51 is an XRPD pattern of resmetirom Form L.
  • FIG. 52 is an XRPD pattern of resmetirom crystalline Form CSIV.
  • FIG. 53 is a thermogravimetric analysis (TGA) diagram of resmetirom crystalline
  • FIG. 54 is a DSC diagram of resmetirom crystalline Form CSIV.
  • FIG. 55 is an XRPD pattern of resmetirom Form R3-A.
  • FIG. 56 is a solid state 13 C NMR spectrum of resmetirom Form R3-A (full range 200-0 ppm).
  • FIG. 57 is a solid state 13 C NMR spectrum of resmetirom Form R3-A (200-100 PPm).
  • FIG. 58 is a solid state 13 C NMR spectrum of resmetirom Form R3-A (100-0 ppm).
  • FIG. 59 is an XRPD pattern of resmetirom : nicotinamide (Form RC1-A).
  • FIG. 60 is a solid state 13 C NMR spectrum of resmetirom : nicotinamide (Form RC1-A) (full range 200-0 ppm).
  • FIG. 61 is a solid state 13 C NMR spectrum of resmetirom : nicotinamide (Form RC1 -A) (200-100 ppm).
  • FIG. 62 is a solid state 13 C NMR spectrum of resmetirom : nicotinamide (Form RC1-A) (100-0 ppm).
  • FIG. 63 is an XRPD pattern of resmetirom : caffeine (Form RC2-A).
  • FIG. 64 is a solid state 13 C NMR spectrum of resmetirom : caffeine (Form RC2-A) (full range 200-0 ppm).
  • FIG. 65 is a solid state 13 C NMR spectrum of resmetirom : caffeine (Form RC2-A) (200-100 ppm).
  • FIG. 66 is a solid state 13 C NMR spectrum of resmetirom : caffeine (Form RC2-A) (100-0 ppm).
  • FIG. 67 is an XRPD pattern of resmetirom : caffeine (Form RC2-B).
  • FIG. 68 is a solid state 13 C NMR spectrum of resmetirom : caffeine (Form RC2-B) (full range 200-0 ppm).
  • FIG. 70 is a solid state 13 C NMR spectrum of resmetirom : caffeine (Form RC2-B)
  • FIG. 71 is an XRPD pattern of resmetirom : 2-picolinic acid (Form RC3-A).
  • FIG. 72 is an XRPD pattern of resmetirom : urea (Form RC4-A).
  • FIG. 73 is an XRPD pattern of resmetirom : N-methyl morpholine salt (Form Rl- A).
  • FIG. 75 is a solid state 13 C NMR spectrum of resmetirom : piperazine salt (Form
  • FIG. 76 is a solid state 13 C NMR spectrum of resmetirom : piperazine salt (Form
  • FIG. 77 is a solid state 13 C NMR spectrum of resmetirom : piperazine salt (Form
  • FIG. 78 is an XRPD pattern of resmetirom : benzathine salt (Form R4-A).
  • FIG. 79 is a chart depicting weight loss in conjunction with resmetirom therapy’s impact on biopsy endpoints in the MAESTRO-NASH study.
  • FIG. 80 is a chart depicting weight loss in conjunction with resmetirom therapy’s impact on MRI-PDFF results in the MAESTRO-NASH study.
  • FIG. 81 is an XRPD pattern of resmetirom Form N8.
  • FIG. 82 an 1 H NMR spectrum of resmetirom Form N8.
  • FIG. 84 is an XRPD pattern of resmetirom Form 3.
  • FIG. 85 is an XRPD pattern of resmetirom Form 9.
  • FIG. 86 is an XRPD pattern of resmetirom Form CSV.
  • FIG. 87 is a TGA diagram of resmetirom Form CSV.
  • FIG. 88 is an XRPD pattern of resmetirom Form 2.
  • FIG. 89 is an XRPD pattern of resmetirom Form 4.
  • FIG. 90 is an XRPD pattern of resmetirom Form 6.
  • FIG. 94 is an XRPD pattern of resmetirom Form 11.
  • FIG. 95 is an XRPD pattern of resmetirom Form 13.
  • FIG. 96 is an XRPD pattern of resmetirom Form 14.
  • FIG. 98 is an XRPD pattern of resmetirom Form 16.
  • FIG. 100 is an XRPD pattern of resmetirom Form 19.
  • FIG. 101 is an XRPD pattern of resmetirom Form 20.
  • FIG. 102 is an XRPD pattern of resmetirom Form 21.
  • FIG. 103 is an XRPD pattern of resmetirom Form 22.
  • FIG. 104 is a solid state 13 C NMR spectrum of resmetirom Form 20 (full range 200-0 ppm).
  • FIG. 105 is a solid state 13 C NMR spectrum of resmetirom Form 20 (200-100 PPm).
  • FIG. 106 is a solid state 13 C NMR spectrum of resmetirom Form 20 (100-0 ppm).
  • FIG. 107 is an XRPD pattern of resmetirom Form CSVI.
  • FIG. 108 is a TGA diagram of resmetirom Form CSVI.
  • FIG. 109 is an XRPD pattern of resmetirom Form CSVI.
  • FIG. 114 is a DSC diagram of resmetirom Form 3 A.
  • FIG. 122 is an XRPD pattern of resmetirom Form 4A.
  • FIG. 125 is an XRPD pattern of resmetirom Form 7A.
  • FIG. 126 is a TGA diagram resmetirom Form 7A.
  • FIG. 127 is a 1 H NMR spectrum of resmetirom Form 7A.
  • FIG. 129 is a TGA diagram of resmetirom Form 9A.
  • FIG. 130 is a 1 H NMR spectrum of resmetirom Form 9A.
  • FIG. 131 is an XRPD pattern of resmetirom Form BSI.
  • FIG. 132 is a DSC diagram of resmetirom Form BSI.
  • FIG. 133 is a TGA diagram of resmetirom Form BSI.
  • FIG. 134 is an XRPD pattern of resmetirom Form R1.
  • FIG. 135 is an XRPD pattern of resmetirom Form R2.
  • FIG. 136 is an XRPD pattern of resmetirom Form R3.
  • FIG. 137 is an XRPD pattern of resmetirom Form R4.
  • FIG. 138 is an XRPD pattern of resmetirom Form R5.
  • FIG. 139 is an XRPD pattern of an amorphous solid dispersion of resmetirom with eudragit
  • FIG. 140 is an XRPD pattern of an amorphous form of resmetirom reported in
  • FIG. 142 is an XRPD pattern of resmetirom Form M1.
  • FIG. 143 is an XRPD pattern of resmetirom Form M2.
  • FIG. 144 is an XRPD pattern of resmetirom Form M3.
  • FIG. 145 is an XRPD pattern of resmetirom Form M4.
  • FIG. 146 is an XRPD pattern of resmetirom Form M5.
  • FIG. 147 is an XRPD pattern of resmetirom Form M6.
  • FIG. 148 is an XRPD pattern of resmetirom Form M7.
  • FIG. 149 is an XRPD pattern of resmetirom Form Ul.
  • FIG. 150 is a combined DSC and TGA thermogram of resmetirom Form U1.
  • FIG. 154 is a combined DSC and TGA thermogram of resmetirom Form U3.
  • FIG. 155 is an XRPD pattern of resmetirom Form U4.
  • FIG. 156 is an XRPD pattern of resmetirom Form U5.
  • FIG. 158 is a combined DSC and TGA thermogram of resmetirom Form U6.
  • FIG. 159 is an XRPD pattern of resmetirom Form U7.
  • FIG. 160 is a combined DSC and TGA thermogram of resmetirom Form U7.
  • FIG. 162 is a combined DSC and TGA thermogram of resmetirom Form U8.
  • FIG. 163 is an XRPD pattern of resmetirom Form U9.
  • FIG. 164 is combined DSC and TGA thermogram of resmetirom Form U9.
  • FIG. 165 is an XRPD pattern of resmetirom Form Cl.
  • FIG. 166 is an 1 H NMR spectrum of resmetirom Form Cl.
  • FIG. 167 is a combined DSC and TGA thermogram of resmetirom Form Cl.
  • FIG. 168 is an FTIR spectrum of resmetirom Form C1 (bottom) compared to an
  • FIG. 169 is a Raman spectrum of resmetirom Form C1 (bottom) compared to a
  • FIG. 170 is an XRPD pattern of resmetirom Form C2.
  • FIG. 171 is an 1 H NMR spectrum of resmetirom Form C2
  • FIG. 173 is an FTIR spectrum of resmetirom Form C2 (bottom) compared to an
  • FIG. 174 is a Raman spectrum of resmetirom Form C2 (bottom) compared to a
  • FIG. 175 is an XRPD pattern of resmetirom Form C3.
  • FIG. 176 is an XRPD pattern of resmetirom Form C4.
  • FIG. 178 is a combined DSC and TGA thermogram of resmetirom Form C4.
  • FIG. 179 is an XRPD pattern of resmetirom Form C5.
  • FIG. 180 is an 1 H NMR spectrum of resmetirom Form C5.
  • FIG. 181 is a combined DSC and TGA thermogram of resmetirom Form C5.
  • FIG. 182 is an FTIR spectrum of resmetirom Form C5 (bottom) compared to an FTIR spectrum of resmetirom Form I (top).
  • FIG. 183 is a Raman spectrum of resmetirom Form C5 (bottom) compared to a
  • FIG. 184 is an XRPD pattern of resmetirom Form C6.
  • FIG. 185 is an XRPD pattern of resmetirom 4-aminopyridine salt (Form C7).
  • FIG. 186 is an 1 H NMR spectrum of resmetirom 4-aminopyridine salt (Form C7).
  • FIG. 187 is a combined DSC and TGA thermogram of resmetirom 4- aminopyridine salt (Form C7).
  • FIG. 188 is an FTIR spectrum of resmetirom 4-aminopyridine salt (Form C7)
  • FIG. 189 is a Raman spectrum of resmetirom 4-aminopyridine salt (Form C7)
  • FIG. 190 is an XRPD pattern of resmetirom imidazole salt (Form C8).
  • FIG. 191 is an 1 H NMR spectrum of resmetirom imidazole salt (Form C8).
  • FIG. 192 is a combined DSC and TGA thermogram of resmetirom imidazole salt
  • FIG. 193 is an FTIR spectrum of resmetirom imidazole salt (Form C8) (bottom) compared to an FTIR spectrum of resmetirom Form I (top).
  • FIG. 194 is a Raman spectrum of resmetirom imidazole salt (Form C8) (bottom) compared to a Raman spectrum of resmetirom Form I (top).
  • FIG. 195 is an XRPD pattern of resmetirom tromethamine salt (Form C9).
  • FIG. 196 is an 1 H NMR spectrum of resmetirom tromethamine salt (Form C9).
  • FIG. 197 is a combined DSC and TGA thermogram of resmetirom tromethamine salt (Form C9).
  • FIG. 198 is an XRPD pattern of resmetirom Form N1.
  • FIG. 199 is an 1 H NMR spectrum of resmetirom Form N1.
  • FIG. 200 is an XRPD pattern of resmetirom Form N2.
  • FIG. 201 is an 1 H NMR spectrum of resmetirom Form N2.
  • FIG. 202 is a combined DSC and TGA thermogram of resmetirom Form N2.
  • FIG. 203 is an XRPD pattern of resmetirom Form N3.
  • FIG. 207 is a combined DSC and TGA thermogram of resmetirom Form N4.
  • FIG. 208 is an XRPD pattern of resmetirom Form N6.
  • FIG. 209 is an 1 H NMR spectrum of resmetirom Form N6.
  • FIG. 210 is an XRPD pattern of resmetirom Form N7.
  • FIG. 212 is a combined DSC and TGA thermogram of resmetirom Form N7.
  • FIG. 213 is an XRPD pattern of Resmetirom Form N9.
  • 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.
  • NASH noncirrhotic non-alcoholic steatohepatitis
  • 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.
  • 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.
  • 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%.
  • administering 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.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • the term "daily” means every day, where each day is defined by a
  • the 24 hour period defining "daily" can bridge two calendar days, for example, Sunday-Monday; Monday-Tuesday; Tuesday-Wednesday; etc.
  • dose refers to the weight of an active ingredient (e.g., resmetirom).
  • 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.
  • the human subject who is administered resmetirom or the pharmaceutically acceptable salt thereof is concomitantly on a moderate CYP2C8 inhibitor regimen.
  • 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.
  • the human subject was already taking the moderate CYP2C8 inhibitor prior to being administered resmetirom or the pharmaceutically acceptable salt thereof.
  • 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.
  • the term "human subject” refers to a human subject who is an adolescent or an adult.
  • an "adult human subject” refers to a human subject who is 18 years of age or older.
  • 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.
  • 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.
  • 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.
  • the human subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein.
  • the human subject in need thereof received at least one prior therapy.
  • 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.
  • 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,
  • 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.
  • compositions include caffeine, urea, 2-picolinic acid, N-methyl-morpholine, piperazine, benzathine, and L-proline salts.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • 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.
  • 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.
  • treating 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.
  • 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.
  • 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.
  • resmetirom : nicotinamide refers to a distinct molecular species that includes resmetirom and nicotinamide.
  • Resmetirom : nicotinamide may be a co-crystal of resmetirom and nicotinamide.
  • resmetirom : nicotinamide may be a salt.
  • resmetirom N-methyl-morpholine salt
  • Resmetirom N-methyl-morpholine salt
  • Resmetirom : N-methyl-morpholine salt may be a co-crystal of resmetirom and N-methyl-morpholine salt.
  • resmetirom N-methyl-morpholine salt may be a salt.
  • 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.
  • resmetirom : benzathine salt may be a salt.
  • 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.
  • resmetirom : L-proline may be a salt.
  • an "amorphous form” refers to a non-crystalline material that lacks long-range order in its structure.
  • 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:
  • 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.
  • the resmetirom exists in a crystalline form.
  • the resmetirom exists in an amorphous form.
  • the resmetirom is in the form of a solvate.
  • 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 t
  • the solvate is 2,2,2-trifluoroethanol, cyclohexanone, methyl acetate, methylethyl ketone, N,N-dimethylformamide, nitromethane, N-methylpyrrolidone, tert-butanol, or xylene.
  • the resmetirom is in the form of a hydrate.
  • the resmetirom is in the form of a co-crystal along with a co-crystal former as part of the co-crystal.
  • 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-
  • 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.
  • the co-crystal former is L-proline, caffeine, or 2-picolinic acid.
  • 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.
  • All doses or dosages recited herein for resmetirom or the pharmaceutically acceptable salt thereof are based on the molecular weight of the compound itself, rather than the molecular weight of the pharmaceutically acceptable salt thereof, or the hydrate or solvate thereof, or the co-crystal thereof, or any excipients in the composition, unless otherwise stated.
  • 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.
  • Resmetirom is described, for example, in Examples 4 and 5 of U.S. Patent No. 9,266,861 and WO 2014/043706.
  • a solid dosage form administered to a human subject e.g., an adult human subject
  • 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.
  • Form I was found to have a melting onset around 321 °C, followed by decomposition upon melting by DSC (FIG. 44).
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • DSC differential scanning calorimetry
  • 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).
  • resmetirom is Form ⁇ , which is described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068.
  • Form ⁇ can be produced as described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068:
  • Form ⁇ 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 CuK ⁇ radiation source (1.54 A).
  • the X-ray powder diffraction pattern of Form ⁇ can further include one or more peaks from Table 29 of U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068.
  • Form ⁇ has an X-ray diffraction pattern substantially similar to that set forth in FIG. 45.
  • resmetirom is Form F, which is described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068.
  • Form F can be produced as described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068:
  • 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 CuK ⁇ radiation source (1.54 A).
  • 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 WO 2020/010068.
  • Form F has an X-ray diffraction pattern substantially similar to that set forth in FIG. 46.
  • resmetirom is Form L, which is described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068.
  • Form L can be produced as described in U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068:
  • 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 2 ⁇ , wherein the x-ray powder diffraction pattern is obtained using a CuK ⁇ radiation source (1.54 A).
  • 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.
  • Form L has an X-ray diffraction pattern substantially similar to that set forth in FIG. 47.
  • Table 13 of U.S. Patent Application Publication No. 2021/0122740 and WO 2020/010068 provides the following data: [00391] A number of forms of resmetirom have been reported in the art.
  • Form CSIV reported in U.S. Patent Application Publication No. 2022/0372021 and WO 2021/129465.
  • 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 CuK ⁇ 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.
  • Example 1 of U.S. Patent Application Publication No. 2022/0372021 and WO 2021/129465 describes preparation of resmetirom crystalline Form CSIV:
  • Table 2 of U.S. Patent Application Publication No. 2022/0372021 and WO 2021/129465 provides the following data:
  • 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.
  • 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.
  • Example 2 of U.S. Patent Application Publication No. 2022/0372021 and WO 2021/129465 also describes preparation of resmetirom Crystalline Form CSIV:
  • one of the forms is Form CSV reported in WO 2021/129465.
  • 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 CuK ⁇ 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.
  • Example 3 of U.S. Patent Application Publication No. 2022/0372021 and WO 2021/129465 describes preparation of resmetirom crystalline Form CSV:
  • 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.
  • Form CSVI reported in U.S. Patent Application Publication No. 2023/0416234 and WO 2022/052822.
  • 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 CuK ⁇ 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.
  • Example 1 of U.S. Patent Application Publication No. 2023/0416234 and WO 2022/052822 describes preparation of resmetirom crystalline Form CSVI:
  • Table 3 of U.S. Patent Application Publication No. 2023/0416234 and WO 2022/052822 provides the following data:
  • 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.
  • Example 2 of U.S. Patent Application Publication No. 2023/0416234 and WO 2022/052822 describes preparation of resmetirom crystalline Form CSVI:
  • Form CSVII reported in WO 2025/011259.
  • 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 CuK ⁇ 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.
  • Example 1 of WO 2025/011259 describes preparation of resmetirom crystalline
  • Table 2 of WO 2025/011259 provides the following data:
  • 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.
  • 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.
  • Form Type K65 reported in WO 2025/011259.
  • Example 4 of WO 2025/011259 describes preparation of resmetirom crystalline Form Type K65:
  • Table 5 of WO 2025/011259 provides the following data:
  • Example 5 of WO 2025/011259 describes preparation of resmetirom crystalline
  • Table 6 of WO 2025/011259 provides the following data:
  • Form Type K65 desolvate reported in WO
  • Example 6 of WO 2025/011259 describes preparation of resmetirom crystalline
  • Example 4 The crystalline Form Type K65 obtained in Example 4 was placed in a room temperature environment for about 5 h.
  • Table 6 of WO 2025/011259 provides the following data:
  • Form R3-A reported in U.S. Patent Application
  • 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIGS.
  • 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.
  • one of the forms is Form RC1-A (resmetirom : nicotinamide) reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIG. 60, 61, or 62 ; and combinations of
  • Example 24 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form RC1-A (resmetirom : nicotinamide).
  • 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.
  • 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.
  • Procedure C [00461] 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.
  • one of the forms is Form RC2-A (resmetirom : caffeine) reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • the crystalline Form RC2-A of resmetirom 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIGS.
  • Example 25 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form RC2-A (resmetirom : caffeine).
  • Form RC2-A is Form RC2-A.
  • Form RC2-B resmetirom : caffeine
  • 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIGS.
  • 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.
  • Example 26 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form RC2-B (resmetirom : caffeine).
  • 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.
  • 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.
  • 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.
  • 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).
  • Form RC4-A (resmetirom : urea) reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • the molar ratio of resmetirom and urea is about 1 : 1.
  • 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.
  • 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.
  • Example 28 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form RC4-A (resmetirom : urea).
  • 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.
  • 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.
  • 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).
  • 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 at room temperature over a period of 48 hours.
  • 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.
  • Form R2-A resmetirom : piperazine salt
  • U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 is Form R2-A (resmetirom : piperazine salt) reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIGS.
  • 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.
  • Example 21 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form R2-A (resmetirom : piperazine salt).
  • 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.
  • Form R4-A resmetirom : benzathine salt
  • U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 is Form R4-A (resmetirom : benzathine salt) reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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 at
  • 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.
  • Example 23 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form R2-A (resmetirom : benzathine salt).
  • 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.
  • benzathine 0.63 ml, 2.76 mmol was added dropwise to the filtrated solution at 75° C. while magnetically stirred.
  • 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.
  • one of the forms is Form 2 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • MIPK Methyl isopropyl ketone
  • MIPK Methyl isopropyl ketone
  • one of the forms is Form 3 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 3 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 3.
  • 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.
  • Example 4 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 4.
  • one of the forms is Form 6 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 5 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 6. [00543] Procedure A
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 6 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 7.
  • Form 8 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 7 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 8.
  • one of the forms is Form 9 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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°,
  • 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.
  • one of the forms is Form 10 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 9 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 10.
  • one of the forms is Form 11 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 10 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 11.
  • 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.
  • one of the forms is Form 13 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 11 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 13.
  • one of the forms is Form 14 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 12 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 14.
  • one of the forms is Form 15 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 13 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 15.
  • Form 16 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 14 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 16.
  • one of the forms is Form 17 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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 diffraction pattern 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.
  • Example 15 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 17.
  • 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.
  • 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.
  • Form 19 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 16 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 19.
  • 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.
  • 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.
  • 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.
  • 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.
  • isopropyl alcohol (IPA) as anti-solvent (10 ml) was added drop-wise 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.
  • 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.
  • Form 20 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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 state 13 C 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 state 13 C 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 state 13 C NMR spectrum substantially as depicted in FIGS.
  • Example 17 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 20.
  • 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.
  • 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.
  • one of the forms is Form 21 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 18 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 21.
  • Procedure A 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.
  • Form 22 reported in U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894.
  • 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.
  • Example 18 of U.S. Patent Application Publication No. 2023/0364099 and WO 2022/086894 describes preparation of Form 22.
  • 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.
  • 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.
  • Resmetirom crystalline Forms 2, 3, 5 and 20 may also be used for preparation of resmetirom crystalline Form 22.
  • one of the forms is an amorphous Form El reported in U.S. Patent
  • 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.
  • Example-1 of U.S. Patent Application Publication No. 2024/0423993 describes preparation of the amorphous Form El.
  • one of the forms is an amorphous Form E2 reported in U.S. Patent Application Publication No. 2024/0423993.
  • 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.
  • Example-2 of U.S. Patent Application Publication No. 2024/0423993 describes preparation of amorphous Form E2.
  • 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.
  • 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.
  • one of the forms is an amorphous solid dispersion Form E4 reported in U.S. Patent Application Publication No. 2024/0423993.
  • 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.
  • Example-4 of U.S. Patent Application Publication No. 2024/0423993 describes preparation of the amorphous solid dispersion Form E4.
  • one of the forms is Form 3A reported in WO 2022/171200.
  • 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.
  • 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.
  • WO 2022/171200 provides the following data:
  • 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.
  • the DSC pattern of the crystalline Form 3 A is substantially as shown in FIG. 114, and the melting point is 324°C.
  • Example 1-1 of WO 2022/171200 describes preparation of the crystalline Form 3A.
  • [00651] 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.
  • Example 1-2 of WO 2022/171200 describes preparation of the crystalline Form 3A.
  • Example 1-3 of WO 2022/171200 describes preparation of the crystalline Form 3A.
  • Example 1-4 of WO 2022/171200 describes preparation of the crystalline Form 3A.
  • Example 2-1 of WO 2022/171200 describes preparation of the crystalline Form 3A.
  • Example 3-1 of WO 2022/171200 describes preparation of this crystalline Form 3A.
  • one of the forms is Form 4A reported in CN115124515 A.
  • 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.
  • CN115124515A provides the following data:
  • 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.
  • Example 1 of CN115124515A describes preparation of this crystalline Form 4A.
  • one of the forms is Form 7A reported in CN115124515 A.
  • 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.
  • CN115124515A provides the following data:
  • 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.
  • the 1 H NMR spectrum of the crystalline Form 7A is substantially as shown in FIG. 127.
  • Example 2 of CN115124515A describes preparation of the crystalline Form 7A.
  • Example 3 of CN115124515A describes preparation of the crystalline Form 7A.
  • Example 4 of CN115124515A describes preparation of the crystalline Form 7A.
  • one of the forms is Form 9A reported in CN115124515 A.
  • 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.
  • CN115124515A provides the following data:
  • 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.
  • the 1 H NMR spectrum of the crystalline Form 9A is substantially as shown in
  • Example 5 of CN115124515A describes preparation of the crystalline Form 7A.
  • one of the forms is Form BSI reported in CN118772117A.
  • 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.
  • 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.
  • the TGA pattern of the crystalline Form BSI is substantially as shown in FIG. 133, with a decomposition temperature of 340°C.
  • Example 1 of CN118772117A describes preparation of Form BSI.
  • Example 2 of CN118772117A describes preparation of Form BSI.
  • Example 3 of CN118772117A describes preparation of Form BSI.
  • Example 4 of CN118772117A describes preparation of Form BSI.
  • Form R1 reported in IN202241066042A.
  • 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°,
  • the X-ray powder 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.
  • Example 1 of IN202241066042 A describes preparation of Form Rl.
  • Form R2 reported in IN202241066042 A.
  • 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.
  • Example 2 of IN202241066042 A describes preparation of Form R2.
  • Form R3 reported in IN202241066042 A.
  • 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.
  • Example 3 of IN202241066042A describes preparation of Form R3.
  • Form R4 reported in IN202241066042 A.
  • 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.
  • Example 4 of IN202241066042A describes preparation of Form R4.
  • Form R5 reported in IN202241066042A.
  • 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.
  • Example 5 of IN202241066042A describes preparation of Form R5.
  • one of the forms is an amorphous solid dispersion of resmetirom and eudragit (1 :2) reported in IN202241066042A.
  • the amorphous solid dispersion of resmetirom and eudragit may be characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 139.
  • Example 6 of IN202241066042A describes preparation of the amorphous solid dispersion of resmetirom and eudragit.
  • VTD dryer for 18 hours to obtain the amorphous solid dispersion of resmetirom and eudragit.
  • one of the forms is an amorphous form of resmetirom reported in IN202241066042A.
  • This amorphous form of resmetirom may be characterized by an X-ray powder diffraction pattern substantially as depicted in FIG. 140.
  • Example 7 of IN202241066042A describes preparation of this amorphous form of resmetirom.
  • one of the forms is Form RL reported in IN202241066042A.
  • 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.
  • Example 8 of IN202241066042A describes preparation of Form RL.
  • 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.
  • 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'.
  • 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 powder diffraction 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.
  • 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'.
  • 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°,
  • 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.
  • 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.
  • 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.
  • 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.
  • Form M6 reported in MSN Laboratories Private Limited, R&D Center, et al, "Solid-state forms of Resmetirom and processes for preparation thereof'.
  • 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.
  • 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'.
  • 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 powder diffraction 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.
  • the present disclosure also provides novel, previously unknown morphic forms, co-crystals, and salts of resmetirom, as well as methods for their preparation.
  • thermogravimetric analyses 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.
  • IR infrared
  • FT Fourier-transform
  • DTGS deuterated triglycine sulfate
  • KBr potassium bromide
  • PolarisTM long-life IR source a diamond attenuated total reflectance (ATR) sampling accessory with a spectral range of 4000 cm -1 to 400 cm -1 was used for ATR analysis.
  • ATR attenuated total reflectance
  • SpectraTech drifts Diffuse reflectance infra-red Fourier transform spectroscopy, DRIFTS sampling accessory with a spectral range of 4000- 400 cm -1 was used for DRIFTS analysis. Each spectrum was the result of 128 co-added scans acquired at 2 cm -1 resolution. 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.
  • Form Ul is a methyl ethyl ketone (MEK) solvate.
  • MEK methyl ethyl ketone
  • 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.
  • Form Ul is characterized by an XRPD pattern including any three, four, or five peaks selected from
  • the XRPD pattern of Form U1 further includes one or more additional peaks from Table U1 below ⁇ 0.2° 2-theta.
  • Form U1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.149.
  • Form U1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U1 below ⁇ 0.2° 2-theta.
  • 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.
  • Form U2 is a t-butanol solvate.
  • 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.
  • Form U2 is characterized by an XRPD pattern including any three, four, or five peaks selected from 12.9° ⁇ 0.2°,
  • the XRPD pattern of Form U2 further includes one or more additional peaks from Table U2 below ⁇ 0.2° 2-theta.
  • Form U2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.151.
  • Form U2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U2 below ⁇ 0.2° 2-theta.
  • Form U2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 152.
  • Form U2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 152.
  • Form U2 is also or alternatively characterized by a TGA thermogram substantially similar to that set 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.
  • Form U3 is a N-methyl pyrrolidone solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form U3 further includes one or more additional peaks from Table U3 below ⁇ 0.2° 2-theta.
  • Form U3 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.153.
  • Form U3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U3 below ⁇ 0.2° 2-theta.
  • 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.
  • Form U4 is a nitromethane solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form U4 further includes one or more additional peaks from Table U4 below ⁇ 0.2° 2-theta.
  • Form U4 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.155.
  • Form U4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U4 below ⁇ 0.2° 2-theta.
  • Form U5 is an o-xylene solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form U5 further includes one or more additional peaks from Table U5 below ⁇ 0.2° 2-theta.
  • Form U5 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.156.
  • Form U5 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U5 below ⁇ 0.2° 2-theta.
  • Form U6 is a trifluoroethanol (TFE) solvate.
  • TFE trifluoroethanol
  • 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.
  • 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.
  • the XRPD pattern of Form U6 further includes one or more additional peaks from Table U6 below ⁇ 0.2° 2-theta.
  • Form U6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.157.
  • Form U6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U6 below ⁇ 0.2° 2-theta.
  • 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.
  • Form U7 is a solvate comprising multiple solvents.
  • 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.
  • 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.
  • the XRPD pattern of Form U7 further includes one or more additional peaks from Table U7 below ⁇ 0.2° 2-theta.
  • Form U7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.159.
  • Form U7 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U7 below ⁇ 0.2° 2-theta.
  • 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.
  • 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.
  • Another aspect of the present disclosure relates to a morphic form, Form U8, of resmetirom.
  • Form U8 is a cyclohexanone solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form U8 further includes one or more additional peaks from Table U8 below ⁇ 0.2° 2-theta.
  • Form U8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.161.
  • Form U8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U8 below ⁇ 0.2° 2-theta.
  • 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.
  • Form U9 is a methyl acetate solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form U9 further includes one or more additional peaks from Table U9 below ⁇ 0.2° 2-theta.
  • Form U9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.163.
  • Form U9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table U9 below ⁇ 0.2° 2-theta.
  • 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.
  • 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.
  • 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.
  • the XRPD pattern of Form C1 further includes one or more additional peaks from Table Cl below ⁇ 0.2° 2-theta.
  • Form C1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.165.
  • Form C1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table Cl below ⁇ 0.2° 2-theta.
  • Form C1 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 167.
  • Form Cl is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 167.
  • Form C1 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 167.
  • Form C1 is also or alternatively characterized by a TGA thermogram comprising about 37% weight loss by 250 °C.
  • Form C1 is also or alternatively characterized by a DSC thermogram comprising endothermic events at about 84 °C and about 330 °C.
  • Form C1 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 166.
  • 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.
  • 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.
  • 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.
  • 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.
  • the XRPD pattern of Form C2 further includes one or more additional peaks from Table C2 below ⁇ 0.2° 2-theta.
  • Form C2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.170.
  • Form C2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C2 below ⁇ 0.2° 2-theta.
  • 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.
  • Form C2 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 171.
  • 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.
  • 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.
  • 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.
  • Form C3 is characterized by an XRPD pattern including 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.
  • the XRPD pattern of Form C3 further includes one or more additional peaks from Table C3 below ⁇ 0.2° 2-theta.
  • Form C3 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.175.
  • Form C3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C3 below ⁇ 0.2° 2-theta.
  • Form C4 also contains 0.7 molar equivalents of isopropanol (IPA).
  • IPA isopropanol
  • 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.
  • 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.
  • the XRPD pattern of Form C4 further includes one or more additional peaks from Table C4 below ⁇ 0.2° 2-theta.
  • Form C4 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.176.
  • Form C4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C4 below ⁇ 0.2° 2-theta.
  • 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.
  • Form C4 is also or alternatively characterized by a TGA thermogram comprising 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)
  • 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.
  • Form C4 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 177.
  • 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.
  • 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.
  • the XRPD pattern of Form C5 further includes one or more additional peaks from Table C5 below ⁇ 0.2° 2-theta.
  • Form C5 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.179.
  • Form C5 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C5 below ⁇ 0.2° 2-theta.
  • 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.
  • 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).
  • Form C5 is also or alternatively characterized by an 1 H 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.
  • 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.
  • the XRPD pattern of Form C6 further includes one or more additional peaks from Table C6 below ⁇ 0.2° 2-theta.
  • Form C6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.184.
  • Form C6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C6 below ⁇ 0.2° 2-theta.
  • 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.
  • 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.
  • the XRPD pattern of Form C7 further includes one or more additional peaks from Table C7 below ⁇ 0.2° 2-theta.
  • Form C7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.185.
  • 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
  • Form C7 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 187.
  • Form C7 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 187.
  • Form C7 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 187.
  • Form C7 is also or alternatively characterized by a TGA thermogram comprising 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.
  • 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).
  • Form C7 is also or alternatively characterized by an 1 H 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.
  • 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.
  • 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
  • the XRPD pattern of Form C8 further includes one or more additional peaks from Table C8 below ⁇ 0.2° 2-theta.
  • Form C8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.190.
  • Form C8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C8 below ⁇ 0.2° 2-theta.
  • 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).
  • Form C8 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 191.
  • 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.
  • 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.
  • 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.
  • 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.
  • the XRPD pattern of Form C9 further includes one or more additional peaks from Table C9 below ⁇ 0.2° 2-theta.
  • Form C9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in
  • Form C9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table C9 below ⁇ 0.2° 2-theta.
  • 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.
  • 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.
  • Form C9 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 196.
  • Form Nl is a methyl ethyl ketone (MEK) solvate.
  • 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.
  • Form N1 is characterized by an XRPD pattern including any three, four, or five peaks selected from 10.9° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.0° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the XRPD pattern of Form N1 further includes one or more additional peaks from Table N1 below ⁇ 0.2° 2-theta.
  • Form N1 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 198.
  • Form N1 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N1 below ⁇ 0.2° 2-theta.
  • Form N1 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 199.
  • Form N2 is an unsolvated form.
  • 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.
  • 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.
  • the XRPD pattern of Form N2 further includes one or more additional peaks from Table N2 below ⁇ 0.2° 2-theta.
  • Form N2 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 200.
  • Form N2 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N2 below ⁇ 0.2° 2-theta.
  • Form N2 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 201.
  • Form N2 is also or alternatively characterized by a DSC thermogram substantially similar to that set forth in FIG. 202.
  • Form N2 is also or alternatively characterized by a TGA thermogram substantially similar to that set forth in FIG. 202.
  • Form N2 is also or alternatively characterized by TGA and DSC thermograms substantially similar to that set forth in FIG. 202.
  • Form N3 is an acetyl acetone solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form N3 further includes one or more additional peaks from Table N3 below ⁇ 0.2° 2-theta.
  • Form N3 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 203.
  • Form N3 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N3 below ⁇ 0.2° 2-theta.
  • Form N3 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 204.
  • Form N4 is a methyl ethyl ketone (MEK) solvate.
  • Form N4 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.
  • 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.
  • the XRPD pattern of Form N4 further includes one or more additional peaks from Table N4 below ⁇ 0.2° 2-theta.
  • Form N4 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 205.
  • Form N4 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N4 below ⁇ 0.2° 2-theta.
  • Form N4 is also or alternatively characterized by an 1 H 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.
  • Form N6 is an acetyl acetone solvate.
  • 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.
  • 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.
  • the XRPD pattern of Form N6 further includes one or more additional peaks from Table N6 below ⁇ 0.2° 2-theta.
  • Form N6 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 208.
  • Form N6 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in
  • Form N6 is also or alternatively characterized by an 1 H NMR spectrum substantially similar to that set forth in FIG. 209.
  • Form N7 is a propionic acid solvate.
  • 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.
  • 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°,
  • the XRPD pattern of Form N7 further includes one or more additional peaks from Table N7 below ⁇ 0.2° 2-theta.
  • Form N7 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 210.
  • Form N7 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N7 below ⁇ 0.2° 2-theta.
  • Form N7 is also or alternatively characterized by an 1 H 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.
  • Form N8 is an isopropanol (IPA) acid solvate.
  • IPA isopropanol
  • 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.
  • 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.
  • the XRPD pattern of Form N8 further includes one or more additional peaks from Table N8 below ⁇ 0.2° 2-theta.
  • Form N8 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG. 81.
  • Form N8 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N8 below ⁇ 0.2° 2-theta.
  • Form N8 is also or alternatively characterized by an 1 H 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.
  • 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.
  • 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.
  • the XRPD pattern of Form N9 further includes one or more additional peaks from Table N9 below ⁇ 0.2° 2-theta.
  • Form N9 is also or alternatively characterized by a XRPD pattern substantially similar to that set forth in FIG.
  • Form N9 is also or alternatively characterized by an XRPD pattern having peaks substantially as provided in Table N9 below ⁇ 0.2° 2-theta.
  • 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.
  • a fatty liver disease e.g., NASH
  • 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.
  • 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.
  • 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.
  • a fatty liver disease e.g., NASH
  • a human subject e.g., an adult human subject
  • 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.
  • 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).
  • a human subject e.g., an adult human subject
  • 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).
  • 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).
  • a human subject e.g., an adult human subject
  • the treatment or improvement as disclosed herein e.g., of NASH and/or liver fibrosis
  • 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 .
  • 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.
  • a human subject e.g., an adult human subject
  • 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:
  • 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.
  • 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.
  • the solid oral dosage form is a tablet.
  • the solid oral dosage form comprises resmetirom.
  • 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:
  • 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.
  • NASH nonalcoholic steatohepatitis
  • 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.
  • 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.
  • the method is of improving the liver fibrosis by at least one stage in the adult human subject in need thereof.
  • the solid oral dosage form is a tablet.
  • the solid oral dosage form comprises resmetirom.
  • the adult human subject in need thereof has liver fibrosis characterized as fibrosis stage F3.
  • the adult human subject in need thereof has liver fibrosis characterized as fibrosis stage F2.
  • 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:
  • 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
  • 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:
  • 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
  • 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:
  • 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
  • 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).
  • 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
  • the human subject e.g., an adult human subject
  • the solid oral dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof at the dosage of 80 mg per day.
  • the fatty liver disease is NASH.
  • 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.
  • 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 mild liver fibrosis consistent with stage F1.
  • the human subject e.g., an adult human subject
  • the solid oral dosage form comprising resmetirom or a pharmaceutically acceptable salt thereof.
  • the human subject e.g., an adult human subject
  • the method is that of treating noncirrhotic nonalcoholic steatohepatitis with moderate to advanced liver fibrosis consistent with stages F2 to F3.
  • 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
  • the 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.
  • 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
  • the 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.
  • the human subject e.g., an adult human subject
  • 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.
  • the human subject e.g., an adult human subject
  • the treatment or improvement as disclosed herein e.g., of NASH and/or liver fibrosis
  • 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.
  • the human subject e.g., an adult human subject
  • the treatment or improvement as disclosed herein e.g., of NASH and/or liver fibrosis
  • 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.
  • 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.
  • 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.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken daily.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken once or twice daily.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is taken once daily.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been taken without any drug holiday.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been taken with one or more drug holidays.
  • 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.
  • the solid oral dosage form comprising resmetirom or the pharmaceutically acceptable salt thereof is or has been administered for longer than 52 weeks.
  • the human subject e.g., an adult human subject
  • the 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.
  • 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.
  • 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.
  • resmetirom or the pharmaceutically acceptable salt thereof and a CYP2C8 inhibitor can increase resmetirom Cmax and AUC.
  • 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.
  • a fatty liver disease e.g., NASH
  • fibrosis associated with the fatty liver disease e.g., NASH
  • 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 moderate
  • CYP2C8 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 the weight 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.
  • the human subject e.g., an adult human subject
  • the reduced dosage due to the use of a moderate CYP2C8 inhibitor by this human subject, is 60 mg per day.
  • the human subject e.g., an adult human subject
  • the treatment or improvement as disclosed herein e.g., NASH and/or liver fibrosis
  • this human subject would start with the reduced dosage of 80 mg or 100 mg per day, depending on the weight determination.
  • the human subject e.g., an adult human subject
  • the 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.
  • the human subject e.g., an adult human subject
  • the 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
  • this human subject would start taking resmetirom or the pharmaceutically acceptable salt thereof with the reduced dosage of 80 mg or 60 mg per day, depending on the weight determination, for this concomitant use.
  • a method of treating or improving a fatty liver disease 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:
  • 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
  • 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 the weight 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:
  • 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
  • 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).
  • NASH nonalcoholic steatohepatitis
  • 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,
  • the moderate CYP2C8 inhibitor is clopidogrel, deferasirox, teriflunomide, trimethoprim, and/or pioglitazone.
  • the fatty liver disease is NASH.
  • 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.
  • the human subject e.g., an adult human subject
  • the treatment or improvement as disclosed herein e.g., of NASH and/or liver fibrosis
  • the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof is 80 mg per day.
  • the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof is 60 mg per day.
  • the method includes reducing the previously used oral dose of resmetirom or the pharmaceutically acceptable salt thereof to the reduced dosage.
  • the human subject e.g., an adult human subject
  • 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.
  • the human subject e.g., an adult human subject
  • 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.
  • 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.
  • 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.
  • 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.
  • the human subject e.g., an adult human subject
  • the 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) administered a daily dose of resmetirom or the pharmaceutically acceptable salt thereof (e.g., a reduced dosage)
  • a strong CYP2C8 inhibitor e.g., gemfibrozil
  • 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
  • OATP1B1 organic anion transporting polypeptide IB 1
  • OATP1B3 organic anion transporting polypeptide 1B3
  • cyclosporine e.g., cyclosporine
  • 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.
  • 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.
  • the concomitant use of the moderate CYP2C8 inhibitor by the human subject e.g., an adult human subject
  • the human subject who may be in need of the treatment or improvement as disclosed herein (e.g., of NASH and/or liver fibrosis)
  • the administration of resmetirom or the pharmaceutically acceptable salt thereof is conducted simultaneously with the administration of resmetirom or the pharmaceutically acceptable salt thereof.
  • the reduced dosage of resmetirom or the pharmaceutically acceptable salt thereof may be administered via a solid oral dosage form.
  • 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.
  • NASH the fat accumulation may be associated with varying degrees of inflammation (hepatitis) and/or scarring (fibrosis) of the liver.
  • the fibrosis of the liver is a stage F2 fibrosis.
  • the fibrosis of the liver is a stage F3 fibrosis.
  • the human subject e.g., an adult human subject
  • a disease, disorder, or condition being liver inflammation.
  • the human subject e.g., an adult human subject
  • the 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.
  • the human subject e.g., an adult human subject
  • the human subject who may be in need of the treatment or improvement as disclosed herein has a disease, disorder, or condition being portal hypertension.
  • the human subject e.g., an adult human subject
  • the human subject who may be in need of the treatment or improvement as disclosed herein has moderate hepatic impairment.
  • 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 be in need of the treatment or improvement as disclosed herein does not have autoimmune liver disease.
  • 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.
  • moderate to severe hepatic impairment e.g., Child-Pugh Class B or C.
  • 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.
  • 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).
  • 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
  • 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 ).
  • a liver fat amount e.g., as measured by proton density fat fraction (PDFF)
  • PDFF proton density fat fraction
  • 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 ).
  • a liver fat amount e.g., as measured by proton density fat fraction (PDFF)
  • PDFF proton density fat fraction
  • 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.
  • a liver fat amount e.g., as measured by proton density fat fraction (PDFF)
  • PDFF proton density fat fraction
  • the human subject e.g., an adult human subject
  • 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)
  • PDFF proton density fat fraction
  • 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.
  • a liver fat amount e.g., as measured by proton density fat fraction (PDFF)
  • PDFF proton density fat fraction
  • the human subject e.g., an adult human subject
  • 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)
  • PDFF proton density fat fraction

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Abstract

La présente divulgation concerne une méthode de traitement d'une stéatose hépatique (par exemple, la stéatohépatite non alcoolique (NASH)) chez un sujet humain (par exemple, un sujet humain adulte) ayant besoin d'un tel traitement (par exemple, NASH/amélioration de la fibrose hépatique) par le 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile (resmétirom) ou un sel pharmaceutiquement acceptable de celui-ci. La présente divulgation concerne en outre une méthode d'amélioration de la fibrose hépatique chez un sujet humain (par exemple, un sujet humain adulte) ayant besoin d'un tel traitement (par exemple, NASH/amélioration de la fibrose hépatique) par le 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile (resmétirom) ou un sel pharmaceutiquement acceptable de celui-ci.
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Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7452882B2 (en) 2005-07-21 2008-11-18 Hoffmann-La Roche Inc. Thyroid hormone analogs
WO2014043706A1 (fr) 2012-09-17 2014-03-20 Madrigal Pharmaceuticals, Inc. Procédé de synthèse d'analogues de l'hormone thyroïdienne et de ses polymorphes
WO2020010068A1 (fr) 2018-07-02 2020-01-09 Madrigal Pharmaceuticals, Inc. Formes solides de 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile
WO2021063367A1 (fr) 2019-09-30 2021-04-08 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation
WO2021129465A1 (fr) 2019-12-26 2021-07-01 苏州科睿思制药有限公司 Cristal de resmétirom, son procédé de préparation et ses utilisations
WO2022052822A1 (fr) 2020-09-10 2022-03-17 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation
WO2022086894A1 (fr) 2020-10-19 2022-04-28 Teva Pharmaceuticals International Gmbh Formes solides de resmetirom
WO2022171200A1 (fr) 2021-02-10 2022-08-18 杭州领业医药科技有限公司 Forme cristalline de resmétirom, son procédé de préparation et son utilisation
CN115124515A (zh) 2021-04-16 2022-09-30 杭州领业医药科技有限公司 Resmetirom的晶型及其制备方法
CN118772117A (zh) 2024-06-28 2024-10-15 江苏百奥信康医药科技有限公司 一种瑞司美替罗的晶体形式及其制备方法
US20240423993A1 (en) 2023-06-23 2024-12-26 Zydus Lifesciences Limited Amorphous form of resmetirom and process for preparation thereof
WO2025011259A1 (fr) 2023-07-07 2025-01-16 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7452882B2 (en) 2005-07-21 2008-11-18 Hoffmann-La Roche Inc. Thyroid hormone analogs
WO2014043706A1 (fr) 2012-09-17 2014-03-20 Madrigal Pharmaceuticals, Inc. Procédé de synthèse d'analogues de l'hormone thyroïdienne et de ses polymorphes
US9266861B2 (en) 2012-09-17 2016-02-23 Madrigal Pharmaceuticals, Inc. Method of synthesizing thyroid hormone analogs and polymorphs thereof
US10376517B2 (en) 2012-09-17 2019-08-13 Madrigal Pharmaceuticals, Inc. Methods of synthesizing thyroid hormone analogs and polymorphs thereof
WO2020010068A1 (fr) 2018-07-02 2020-01-09 Madrigal Pharmaceuticals, Inc. Formes solides de 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phényl)-3,5-dioxo-2,3,4,5-tétrahydro-1,2,4-triazine-6-carbonitrile
US20210122740A1 (en) 2018-07-02 2021-04-29 Madrigal Pharmaceuticals, Inc. Solid forms 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-1,2,4-triazine-6-carbonitrile
WO2021063367A1 (fr) 2019-09-30 2021-04-08 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation
US20220372021A1 (en) 2019-12-26 2022-11-24 Crystal Pharmaceutical (Suzhou) Co., Ltd. Resmetirom crystal, preparation method for same, and uses thereof
WO2021129465A1 (fr) 2019-12-26 2021-07-01 苏州科睿思制药有限公司 Cristal de resmétirom, son procédé de préparation et ses utilisations
WO2022052822A1 (fr) 2020-09-10 2022-03-17 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation
US20230416234A1 (en) 2020-09-10 2023-12-28 Crystal Pharmaceutical (Suzhou) Co., Ltd. Crystal form of resmetirom, preparation method therefor, and use thereof
WO2022086894A1 (fr) 2020-10-19 2022-04-28 Teva Pharmaceuticals International Gmbh Formes solides de resmetirom
US20230364099A1 (en) 2020-10-19 2023-11-16 Teva Pharmaceuticals International Gmbh Solid state forms of resmetirom
WO2022171200A1 (fr) 2021-02-10 2022-08-18 杭州领业医药科技有限公司 Forme cristalline de resmétirom, son procédé de préparation et son utilisation
CN115124515A (zh) 2021-04-16 2022-09-30 杭州领业医药科技有限公司 Resmetirom的晶型及其制备方法
US20240423993A1 (en) 2023-06-23 2024-12-26 Zydus Lifesciences Limited Amorphous form of resmetirom and process for preparation thereof
WO2025011259A1 (fr) 2023-07-07 2025-01-16 苏州科睿思制药有限公司 Forme cristalline de resmetirom, son procédé de préparation et son utilisation
CN118772117A (zh) 2024-06-28 2024-10-15 江苏百奥信康医药科技有限公司 一种瑞司美替罗的晶体形式及其制备方法

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD) ED - Dufour Jean-Fran�ois; Schwabe Robert F; Terrault Norah; Wong Vincent", JOURNAL OF HEPATOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 81, no. 3, 7 June 2024 (2024-06-07), pages 492 - 542, XP087591250, ISSN: 0168-8278, [retrieved on 20240607], DOI: 10.1016/J.JHEP.2024.04.031 *
CLIN GASTROENTEROL HEPATOL, vol. 13, 2015, pages 561 - 568
EURO J OF RADIOL, vol. 106, 2018, pages 32 - 37
HARRISON STEPHEN A ET AL: "Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial", THE LANCET, vol. 394, no. 10213, 1 November 2019 (2019-11-01), AMSTERDAM, NL, pages 2012 - 2024, XP093198678, Retrieved from the Internet <URL:https://pdf.sciencedirectassets.com/271074/1-s2.0-S0140673619X00513/1-s2.0-S0140673619325176/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEOb//////////wEaCXVzLWVhc3QtMSJGMEQCIC8sOWsbg60wos7hjTd9J6lpHiegmFsgKB931LVA9EirAiBOTUErodke9eV44LEYLbUvUl7A/uK5tR8L0a7YV2QdBiq7BQju//////////8BEAUaDDA1OTAwMzU0N> DOI: 10.1016/S0140-6736(19)32517-6 *
HARRISON STEPHEN A. ET AL: "Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial", NATURE MEDICINE(AUTHOR MANUSCRIPT ), vol. 29, no. 11, 1 November 2023 (2023-11-01), New York, pages 2919 - 2928, XP093198810, ISSN: 1078-8956, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10667098/pdf/41591_2023_Article_2603.pdf> DOI: 10.1038/s41591-023-02603-1 *
SALVATORE PETTA ET AL: "The first MASH drug therapy on the horizon: Current perspectives of resmetirom", LIVER INTERNATIONAL, BLACKWELL MUNKSGAARD, OXFORD, GB, vol. 44, no. 7, 5 April 2024 (2024-04-05), pages 1526 - 1536, XP072652731, ISSN: 1478-3223, DOI: 10.1111/LIV.15930 *
STEPHEN A HARRISON ET AL: "Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis", ALIMENTARY PHARMACOLOGY & THERAPEUTICS, BLACKWELL SCIENTIFIC PUBLICATIONS LTD., CAMBRIDGE, GB, vol. 59, no. 1, 2 October 2023 (2023-10-02), pages 51 - 63, XP072550572, ISSN: 0269-2813, DOI: 10.1111/APT.17734 *

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