Identification
- Summary
Resmetirom is a thyroid hormone receptor-beta agonist used to treat noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis in adults.
- Generic Name
- Resmetirom
- DrugBank Accession Number
- DB12914
- Background
Resmetirom is a thyroid hormone receptor-beta (THR-beta) agonist. On March 14, 2024, it was approved by the FDA as the first treatment of liver fibrosis due to noncirrhotic non-alcoholic steatohepatitis (NASH), which is a form of non-alcoholic fatty liver disease (NAFLD).6
Thyroid hormones directly regulate lipid metabolism in the liver; thus, impaired thyroid function, such as low serum thyroid hormone levels, is often observed in NAFLD.3 Resmetirom works to reduce liver fat by stimulating fatty acid degradation and oxidation.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Resmetirom (DB12914)
- Weight
- Average: 435.22
Monoisotopic: 434.0297083 - Chemical Formula
- C17H12Cl2N6O4
- Synonyms
- 1,2,4-Triazine-6-carbonitrile, 2-[3,5-dichloro-4-[[1,6-dihydro-5-(1-methylethyl)-6-oxo-3-pyridazinyl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-
- 2-[3,5-Dichloro-4-[[1,6-dihydro-5-(1-methylethyl)-6-oxo-3-pyridazinyl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile
- Resmetirom
- External IDs
- MGL 3196
- MGL-3196
- MGL3196
- VIA-3196
Pharmacology
- Indication
Resmetirom is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Its use should be avoided in patients with decompensated cirrhosis.5
This indication is approved under accelerated approval based on the improvement of NASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.5
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Advanced liver fibrosis •••••••••••• ••••• •••••• Adjunct therapy in treatment of Moderate liver fibrosis •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
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Resmetirom is a partial agonist of the thyroid hormone receptor-beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 µM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptor-alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC50 of 3.74 µM.5
Resmetirom decreases liver fat content and the concentrations of free thyroxine (FT4), which is a prohormone.5 Although it is inconclusive, there have been some reports in the literature suggesting that resmetirom may convert thyroxine (T4) to triiodothyronine (T3).3 It increases the concentrations of sex hormone-binding globulin.5
- Mechanism of action
Thyroid hormones, such as FT4 and free triiodothyronine (FT3), are key regulators of lipid metabolism in the liver.1 Thyroid hormone receptor-beta (THR-β) is the major form of the thyroid hormone receptor in the liver,2 and stimulation of this receptor reduces intrahepatic triglycerides.5
Many patients with non-alcoholic fatty liver disease (NAFLD) present with impaired thyroid function, such as hypothyroidism, rendering it a significant risk factor for NAFLD.1,2,3 Hypothyroidism has also been linked to dysregulated adipose tissue lipolysis and increased free fatty acid release from the adipose to the liver, promoting hepatic insulin resistance.1 Increased circulating levels of proinflammatory adipokines, which contribute to hepatic inflammation and fibrosis, may also be observed.1
Resmetirom is a partial agonist of THR-β 5 that promotes lipophagy and hepatic fatty acid β-oxidation, thereby reducing liver fat.3 It is approximately 28 times more selective than FT3 for THR-β versus thyroid hormone receptor-alpha (THR-α), which is mainly expressed in the heart and bones.4
Target Actions Organism AThyroid hormone receptor beta partial agonistHumans - Absorption
The median Tmax is approximately four hours following multiple daily doses of resmetirom 80 mg or 100 mg.5
Concomitant food administration resulted in a 33% decrease in Cmax, an 11% decrease in AUC, and a delay in median Tmax by about two hours compared to an under-fasted condition.5
- Volume of distribution
Resmetirom apparent volume of distribution (Vd/F) at steady-state is 68 (227%) L.5
- Protein binding
Resmetirom is greater than 99% protein-bound.5
- Metabolism
Resmetirom is metabolized by CYP2C8. MGL-3623 is a major metabolite with a 28-times lower potency for THR-β than resmetirom. MGL-3623 represents 33% to 51% of resmetirom AUC at steady-state following administration of 100 mg once daily.5
- Route of elimination
Following oral administration of a 100 mg radio-labeled dose of resmetirom, approximately 67% of the total radioactive dose was recovered in the feces, mostly as metabolites and 24% of the total radioactive dose was recovered in the urine. Unchanged labeled resmetirom was not detected in feces and accounted for 1% of the dose recovered in urine. A metabolite MGL-3623 accounted for 3.3% and 16% of the dose recovered in feces and urine, respectively. Oxalic acid metabolite was observed in plasma but not in urine.5
- Half-life
The median terminal plasma half-life is 4.5 hours.5
- Clearance
The steady state apparent clearance (CL/F) is 17.5 (56.3%) L/h.5
- Adverse Effects
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There is no information regarding the acute toxicity and overdosage of resmetirom.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The metabolism of Resmetirom can be increased when combined with Abatacept. Abiraterone The metabolism of Resmetirom can be decreased when combined with Abiraterone. Acetylcysteine The serum concentration of Resmetirom can be increased when it is combined with Acetylcysteine. Adalimumab The metabolism of Resmetirom can be increased when combined with Adalimumab. Almotriptan The metabolism of Almotriptan can be decreased when combined with Resmetirom. - Food Interactions
- Take with or without food. A high fat meal may reduce Cmax and AUC delay Tmax, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rezdiffra Tablet, coated 80 mg/1 Oral Madrigal Pharmaceuticals, Inc. 2024-03-14 Not applicable US 
Rezdiffra Tablet, coated 60 mg/1 Oral Madrigal Pharmaceuticals, Inc. 2024-03-14 Not applicable US Rezdiffra Tablet, coated 100 mg/1 Oral Madrigal Pharmaceuticals, Inc. 2024-03-14 Not applicable US
Categories
- Drug Categories
- BCRP/ABCG2 Inhibitors
- BCRP/ABCG2 Substrates
- BSEP/ABCB11 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (weak)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- OAT3/SLC22A8 Inhibitors
- OATP1B1/SLCO1B1 Inhibitors
- OATP1B1/SLCO1B1 Substrates
- OATP1B3 inhibitors
- OATP1B3 substrates
- Pyrimidines
- Pyrimidinones
- Thyroid hormone receptor-beta (THR-beta) agonist
- UGT1A4 Inhibitors
- UGT1A9 Inhibitors
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Ethers
- Direct Parent
- Diarylethers
- Alternative Parents
- Phenoxy compounds / Phenol ethers / Dichlorobenzenes / Pyridazinones / Aryl chlorides / 1,2,4-triazines / Heteroaromatic compounds / Lactams / Nitriles / Azacyclic compounds show 3 more
- Substituents
- 1,2,4-triazine / 1,3-dichlorobenzene / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonitrile / Chlorobenzene / Cyanide show 18 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- RE0V0T1ES0
- CAS number
- 920509-32-6
- InChI Key
- FDBYIYFVSAHJLY-UHFFFAOYSA-N
- InChI
- InChI=1S/C17H12Cl2N6O4/c1-7(2)9-5-13(22-23-15(9)26)29-14-10(18)3-8(4-11(14)19)25-17(28)21-16(27)12(6-20)24-25/h3-5,7H,1-2H3,(H,23,26)(H,21,27,28)
- IUPAC Name
- 2-(3,5-dichloro-4-{[6-oxo-5-(propan-2-yl)-1,6-dihydropyridazin-3-yl]oxy}phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
- SMILES
- CC(C)C1=CC(OC2=C(Cl)C=C(C=C2Cl)N2N=C(C#N)C(=O)NC2=O)=NNC1=O
References
- General References
- Hatziagelaki E, Paschou SA, Schon M, Psaltopoulou T, Roden M: NAFLD and thyroid function: pathophysiological and therapeutic considerations. Trends Endocrinol Metab. 2022 Nov;33(11):755-768. doi: 10.1016/j.tem.2022.08.001. Epub 2022 Sep 26. [Article]
- Li L, Song Y, Shi Y, Sun L: Thyroid Hormone Receptor-beta Agonists in NAFLD Therapy: Possibilities and Challenges. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1602-1613. doi: 10.1210/clinem/dgad072. [Article]
- Karim G, Bansal MB: Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, beta-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60. Epub 2023 May 1. [Article]
- Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11. [Article]
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- FDA: FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease [Link]
- External Links
- PubChem Compound
- 15981237
- PubChem Substance
- 347829063
- ChemSpider
- 13112637
- BindingDB
- 50012905
- 2677894
- ChEMBL
- CHEMBL3261331
- ZINC
- ZINC000034842512
- Wikipedia
- Resmetirom
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Non Alcoholic Steatohepatitis (NASH) 1 3 Completed Treatment Fatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD 1 3 Recruiting Treatment Cirrhosis of the Liver / Nash 1 3 Recruiting Treatment Fatty Liver, Non-alcoholic Fatty Liver Disease, NAFLD 1 2 Completed Treatment Heterozygous Familial Hypercholesterolemia (HeFH) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, coated Oral 100 mg/1 Tablet, coated Oral 60 mg/1 Tablet, coated Oral 80 mg/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0126 mg/mL ALOGPS logP 3.6 ALOGPS logP 2.97 Chemaxon logS -4.5 ALOGPS pKa (Strongest Acidic) 5.65 Chemaxon pKa (Strongest Basic) -5.2 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 136.25 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 102.45 m3·mol-1 Chemaxon Polarizability 39.4 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0000900000-d61c515b84b6556167eb Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-2003900000-41867e62596ccd4396cd Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0003900000-5f0547cade512726d8a7 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-02uc-5009800000-7e261824a21b5c1546ce Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-5119300000-56cb83c41baf56a05ccc Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9000000000-1a4cf3d5a21e199cc2a1 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 187.56334 predictedDeepCCS 1.0 (2019) [M+H]+ 189.92134 predictedDeepCCS 1.0 (2019) [M+Na]+ 197.58514 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Partial agonist
- General Function
- Zinc ion binding
- Specific Function
- Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.
- Gene Name
- THRB
- Uniprot ID
- P10828
- Uniprot Name
- Thyroid hormone receptor beta
- Molecular Weight
- 52787.16 Da
References
- Karim G, Bansal MB: Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, beta-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60. Epub 2023 May 1. [Article]
- Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11. [Article]
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Protein homodimerization activity
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
- Gene Name
- UGT1A4
- Uniprot ID
- P22310
- Uniprot Name
- UDP-glucuronosyltransferase 1-4
- Molecular Weight
- 60024.535 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Retinoic acid binding
- Specific Function
- UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1-9
- Molecular Weight
- 59940.495 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
- Gene Name
- SLCO1B3
- Uniprot ID
- Q9NPD5
- Uniprot Name
- Solute carrier organic anion transporter family member 1B3
- Molecular Weight
- 77402.175 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Solute carrier family 22 member 8
- Molecular Weight
- 59855.585 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Transporter activity
- Specific Function
- Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
- Gene Name
- ABCB11
- Uniprot ID
- O95342
- Uniprot Name
- Bile salt export pump
- Molecular Weight
- 146405.83 Da
References
- FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Drug created at October 21, 2016 01:15 / Updated at April 03, 2024 01:15