Resmetirom

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 receptoralpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC₅₀ of 3.74 µM. THR-β is the major form of THR in the liver, and stimulation of THR-β in the liver reduces intrahepatic triglycerides, whereas actions of thyroid hormone outside the liver, including in heart and bone, are largely mediated through THR-α.

Liver Fat Content

Resmetirom decreases liver fat content as measured by magnetic resonance imaging-protein density fat fraction (MRI-PDFF) or FibroScan controlled attenuation parameter (CAP).

Reductions in liver fat content by MRI-PDFF were observed at 16 (the first assessment) and 52 weeks of treatment. Reductions in liver fat content by CAP were observed at 52 weeks of treatment.

Prohormone FT4

Resmetirom decreased concentrations of prohormone FT4 were observed at the first assessment at 4 weeks of treatment. Similar decreases in FT4 were observed during the treatment.

Sex Hormone Binding Globulin (SHBG)

Resmetirom increased concentrations of sex hormone binding globulin (SHBG) were observed at the first assessment at 4 weeks of treatment, and at longer durations of treatment. The clinical significance of this change is unknown.

Cardiac Electrophysiology

At a dose two times the maximum recommended dose, resmetirom does not prolong the QT interval to any clinically relevant extent.

Following once daily doses, steady state is typically reached within 3 to 6 days of dosing. Resmetirom steady state exposure increases in a dose proportional manner between doses of 40 mg (0.5 times the lowest approved recommended dose) and 100 mg. Resmetirom exposure increases in a greater than dose proportional manner between doses of 100 mg and 200 mg (2 times the highest approved recommended dose) by about 5.6-fold. Resmetirom exposure increased 1.5- to 3-fold following once daily dosing; however, the MGL-3623 metabolite does not accumulate. The estimated resmetirom systemic exposure at steady state in NASH patients is summarized in Table 1. Resmetirom exposure is similar between NASH patients with F2 stage fibrosis and F3 stage fibrosis.

Table 1. Resmetirom Estimated Systemic Exposure at Steady State in Patients with NASH with Fibrosis (F2 and F3):

Abbreviations: AUC_tau,ss = area under the concentration-versus-time curve over one dosing interval at steady state; C_max,ss = maximum concentration at steady state; CV = arithmetic coefficient of variation

Absorption

The resmetirom median time to maximum plasma concentration (T_max) is approximately 4 hours following multiple daily doses of resmetirom 80 mg or 100 mg.

Effect of Food

No clinically significant differences in resmetirom pharmacokinetics were observed following administration with a high-fat meal (approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively). Concomitant food administration resulted in a 33% decrease in C_max, an 11% decrease in AUC, and a delay in median T_max by about 2 hours compared to under fasted condition.

Distribution

Resmetirom apparent volume of distribution (Vd/F) at steady-state is 68 (227%) L. Resmetirom is greater than 99% protein-bound.

Elimination

Resmetirom median terminal plasma half-life (t_½) is 4.5 hours and the steady state apparent clearance (CL/F) is 17.5 (56.3%) L/h.

Metabolism

Resmetirom is metabolized by CYP2C8 and is not metabolized by other CYP enzymes in vitro. 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.

Excretion

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.

Specific Populations

No clinically significant differences in the pharmacokinetics of resmetirom were observed based on age (18 to 83 years), sex, race (White, Black, or Asian), or ABCG2 genotype (BCRP p.Gln141Lys, p.Val12Met).

Population PK analyses indicated no clinically significant difference in the pharmacokinetics of resmetirom by mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m², Modification of Diet in Renal Disease (MDRD)). The effect of severe renal impairment (eGFR <30 mL/min/1.73 m², MDRD) on resmetirom pharmacokinetics is unknown.

Body Weight

A clinically significant difference in resmetirom exposure was not observed with the recommended weight-based dosage. However, resmetirom CL/F and Vd/F increase with increasing body weight, resulting in lower resmetirom exposure in patients with higher body weight receiving the same dosage as lower weight patients.

Patients with Hepatic Impairment

Patients with Hepatic Impairment: Following repeated 80 mg once daily dosing of resmetirom for 6 days, resmetirom AUC was 1.3-fold, 2.7-fold and 19-fold higher in patients with mild, moderate and severe hepatic impairment (Child-Pugh A, B and C), respectively compared to subjects with normal hepatic function. Resmetirom C_max was 1.2-fold, 1.7-fold and 8.1-fold higher in patients with mild, moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function (Table 2).

In the same study, MGL-3623 AUC_tau was 1.3-fold, 2-fold and 5.8-fold higher in patients with mild, moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function.

Table 2. Mean (CV%) Resmetirom Systemic Exposure in Subjects with Normal Hepatic Function and Non-NASH Patients with Hepatic Impairment Following Resmetirom 80 mg Once Daily for 6 Days and Exposure Change Relative to Normal Hepatic Function:

^a Exposure parameters presented as Mean (CV%)
^b N=8
Abbreviations: AUC_tau,ss = area under the concentration-versus-time curve over one dosing interval at steady state; C_max,ss = maximum concentration at steady state; CV = arithmetic coefficient of variation

NASH Patients with Mild Hepatic Impairment (Child-Pugh A): Geometric mean AUC and C_max in NASH cirrhosis patients with mild hepatic impairment (Child-Pugh Class A; n=20) were 6% higher and 10% lower, respectively, compared to non-cirrhotic NASH patients following repeated 100 mg once daily dosing of resmetirom for 6 days. The safety and effectiveness of resmetirom have not been established in patients with NASH cirrhosis.

NASH Patients with Mild Hepatic Impairment (Child-Pugh A): Geometric mean AUC and C_max in NASH cirrhosis patients with mild hepatic impairment (Child-Pugh Class A; n=20) were 6% higher and 10% lower, respectively, compared to non-cirrhotic NASH patients following repeated 100 mg once daily dosing of resmetirom for 6 days. The safety and effectiveness of resmetirom have not been established in patients with NASH cirrhosis.

Drug Interaction Studies

Clinical Studies

Moderate CYP2C8 Inhibitors: Resmetirom C_max increased 1.3-fold and AUC 1.7-fold following concomitant use of multiple doses of resmetirom 100 mg/day with clopidogrel (a moderate CYP2C8 inhibitor) at steady-state in healthy subjects.

CYP2C8 Substrates: Pioglitazone (a CYP2C8 substrate) C_max was unchanged and AUC increased 1.5-fold following concomitant use of a single oral dose of pioglitazone (15 mg) with resmetirom at steady state (100 mg/day) in healthy subjects.

Simvastatin: Simvastatin (OATP1B1 and OATP1B3 substrate) C_max increased 1.4-fold and AUC 1.7-fold following concomitant use of a single oral dose of simvastatin (20 mg) with resmetirom at steady state (100 mg/day) in healthy subjects.

Rosuvastatin: Rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate) C_max increased 2.9-fold and AUC 1.8-fold following concomitant use of a single oral dose of rosuvastatin (10 mg) with resmetirom at steady state (at two times the highest recommended dosage) in healthy subjects.

Pravastatin: Pravastatin (OATP1B1 and OATP1B3 substrate) C_max increased 1.3-fold and AUC 1.4-fold following concomitant use of a single oral dose of pravastatin (40 mg) with resmetirom at steady state (100 mg/day) in healthy subjects.

Atorvastatin: Atorvastatin (BCRP, OATP1B1, and OATP1B3 substrate) C_max was unchanged and AUC increased 1.4-fold following concomitant use of a single oral dose of atorvastatin (20 mg) with resmetirom at steady state (100 mg/day) in healthy subjects. Atorvastatin lactone C_max increased 2.0-fold and AUC increased 1.8-fold.

Other Drugs: No clinically significant differences in the pharmacokinetics of R-warfarin or S-warfarin were observed when used concomitantly with resmetirom.

In Vitro Studies

CYP450 Enzymes: Resmetirom is an inhibitor of CYP2C8.

Glucuronidation Enzymes: Resmetirom is an inhibitor of UDP-glucuronosyltransferases (UGTs) 1A4 and 1A9. The clinical relevance of UGT1A4 and UGT1A9 inhibition is unknown.

Transporters: Resmetirom is a substrate for organic anion-transporting polypeptides (OATP) 1B1 and 1B3 and breast cancer resistance protein (BCRP). Resmetirom inhibits OATP1B1, OATP1B3, BCRP, OAT3, and bile salt export pump (BSEP). The clinical significance of OAT3 and BSEP inhibition is unknown.