What is mechanism of action?

mechanism of action is Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA], Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA], Cytochrome P450 2C8 Inhibitors [MoA], Thyroid Hormone Receptor beta Agonists [MoA] or Breast Cancer Resistance Protein Inhibitors [MoA]

Rezdiffra (resmetirom) - Complete Medication Label Info, PA Forms, & Patient Education (2025)

Rezdiffra Prescribing Information

REZDIFFRA 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).

This indication is approved under accelerated approval based on improvement of NASH and fibrosis

[see

14 CLINICAL STUDIES

The efficacy of REZDIFFRA was evaluated based on an efficacy analysis at Month 12 in Trial 1 , a 54-month, randomized, double-blind, placebo-controlled trial. Enrolled patients had metabolic risk factors and a baseline or recent liver biopsy showing NASH with fibrosis stage 2 or 3 and a NAFLD Activity Score (NAS) of at least 4. Efficacy determination was based on the effect of REZDIFFRA on resolution of steatohepatitis without worsening of fibrosis and one stage improvement in fibrosis without worsening of steatohepatitis, on post-baseline liver biopsies collected at 12 months.

The month 12 analysis included 888 F2 and F3 (at eligibility) patients randomized 1:1:1 to receive placebo (n = 294), REZDIFFRA 80 mg once daily (n = 298), or REZDIFFRA 100 mg once daily (n = 296), in addition to lifestyle counseling on nutrition and exercise. Patients were on stable doses of medications for diabetes, dyslipidemia, and hypertension.

Demographic and baseline characteristics were balanced between treatment and placebo groups. Overall, the median (Q1 to Q3) age of patients at baseline was 58 (51 to 65) years, 56% were female, 21% were Hispanic, 89% were White, 3% were Asian, and 2% were Black or African American.

Median (Q1 to Q3) body mass index (BMI) was 35 (31 to 40) kg/m

²

and median (Q1 to Q3) body weight was 99 (85 to 114) kg. Baseline characteristics are presented in Table 7.

Table 7: Baseline Characteristics in Adult Patients with Noncirrhotic NASH with Stage 2 to Stage 3 Fibrosis in Trial 1
^aLess than 5% missingness in these variables is omitted. ^bkPa = kilopascal; Db/M = decibels per meter
Characteristic	Overall N=888
Fibrosis stage, n (%) F2 F3
Fibrosis stage, n (%) F2 F3	328 (37) 560 (63)
Type 2 Diabetes, n (%)	608 (68)
Hypertension, n (%)	700 (79)
Dyslipidemia, n (%)	633 (71)
Statin use, n (%)	434 (49)
Thyroxine use, n (%)	124 (14)
Vibration-controlled Transient Elastography (VCTE) (kPa), Median (Q1, Q3)^{a, b}	12 (10, 15)
Controlled attenuation parameter (CAP) (Db/M), Median (Q1, Q3)^a	349 (320, 378)
Fibrosis Index Based on 4 Factors (FIB-4), Median (Q1, Q3)^a	1.3 (1, 1.8)
Enhanced Liver Fibrosis (ELF), Median (Q1, Q3)^a	9.7 (9.2, 10.4)

Table 8 presents the Month 12 histopathology results comparing REZDIFFRA with placebo on 1) the percentage of patients with resolution of steatohepatitis and no worsening of liver fibrosis and 2) the percentage of patients with at least one stage improvement in liver fibrosis and no worsening of steatohepatitis. Two pathologists, Pathologist A and Pathologist B, independently read the liver biopsies for each patient. Both the 80 mg once daily and the 100 mg once daily dosages of REZDIFFRA demonstrated improvement on these histopathology endpoints at Month 12 compared to placebo. In a statistical analysis incorporating both pathologists’ independent readings, REZDIFFRA achieved statistical significance on both histopathology endpoints for both doses.

Examination of age, gender, diabetes status (Yes or No), and fibrosis stage (F2 or F3) subgroups did not identify differences in response to REZDIFFRA among these subgroups. The majority of patients in the trial were white (89%); there were too few patients of other races to adequately assess differences in response by race.

Table 8: Efficacy Results at Month 12 in Adult Patients with Noncirrhotic NASH with Stage 2 or Stage 3 Fibrosis in Trial 1
Liver fibrosis was evaluated on the NASH Clinical Research Network (CRN) fibrosis score as 0 to 4. Resolution of steatohepatitis was defined as a score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis. No worsening of steatohepatitis was defined as no increase in score for ballooning, inflammation, or steatosis. Estimated using the Mantel-Haenszel method stratified by baseline type 2 diabetes status (presence or absence) and fibrosis stage (F2 or F3). 95% stratified Newcombe confidence intervals (CIs) are provided. Patients with missing liver biopsy at Month 12 are considered a non-responder.
	Placebo N=294	REZDIFFRA 80 mg Once Daily N=298	REZDIFFRA 100 mg Once Daily N=296
Resolution of steatohepatitis and no worsening of liver fibrosis
Response rate, Pathologist A (%)	13	27	36
Difference in response rate vs. placebo (95% CI)		14 (8, 20)	23 (16, 30)
Response rate, Pathologist B (%)	9	26	24
Difference in response rate vs. placebo (95% CI)		17 (11, 23)	15 (9, 21)
Improvement in liver fibrosis and no worsening of steatohepatitis
Response rate, Pathologist A (%)	15	23	28
Difference in response rate vs. placebo (95% CI)		8 (2, 14)	13 (7, 20)
Response rate, Pathologist B (%)	13	23	24
Difference in response rate vs. placebo (95% CI)		11 (5, 17)	11 (5, 17)

Starting at Month 3 and through Month 12, there was a trend of greater reductions from baseline in average ALT and AST in the REZDIFFRA groups as compared to the placebo group.

]

. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use

Avoid use of REZDIFFRA in patients with decompensated cirrhosis

[see

8.7 Hepatic Impairment

Avoid use of REZDIFFRA in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment)

.

Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom C_maxand AUC

[see Clinical Pharmacology (12.3

)], which may increase the risk of adverse reactions.

No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A)

[see Clinical Pharmacology (12.3)]

.

The safety and effectiveness of REZDIFFRA have not been established in patients with NASH cirrhosis.

,

12.3 Pharmacokinetics

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 5. Resmetirom exposure is similar between NASH patients with F2 stage fibrosis and F3 stage fibrosis.

Table 5: Resmetirom Estimated Systemic Exposure at Steady State in Patients with NASH with Fibrosis (F2 and F3)
Abbreviations: AUC_t_au,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
Parameter	Resmetirom 80 mg Once Daily Mean (CV%)	Resmetirom 100 mg Once Daily Mean (CV%)
C_max,ss(ng/mL)^a	778 (41.5)	971 (40.9)
AUC_tau,ss(ng*h/mL)^a	5850 (60.5)	7780 (65.5)

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_maxby 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 (t½) 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

[see Dosage and Administration (2.1)]

.

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_maxwas 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 6).

In the same study, MGL-3623 AUC_tauwas 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

[see Use in Specific Populations (8.7)].

Table 6: 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
^aExposure parameters presented as Mean (CV%) ^bN = 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
Parameter	Normal Hepatic Function (N = 7)	Child-Pugh Class
Parameter	Normal Hepatic Function (N = 7)	A Mild (N = 10)	B Moderate (N = 9)	C Severe (N = 3)
	Resmetirom
C_max,ss(ng/mL)^a	1070 (51.0)	1390 (67.8)	1830 (47.5)	7730 (17.4)
AUC_tau,ss(ng*h/mL)^a	5100 (51.5)	5570 (66.4)	15100 (65.8)^b	97600 (39.0)

NASH Patients with Mild Hepatic Impairment (Child-Pugh A):

Geometric mean AUC and C_maxin 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_maxincreased 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

[see Drug Interactions (7.1)]

.

CYP2C8 Substrates:

Pioglitazone (a CYP2C8 substrate) C_maxwas 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

[see Drug Interactions (7.1)]

.

Simvastatin:

Simvastatin (OATP1B1 and OATP1B3 substrate) C_maxincreased 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

[see Drug Interactions (7.2)]

.

Rosuvastatin:

Rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate) C_maxincreased 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

[see Drug Interactions (7.2)]

.

Pravastatin:

Pravastatin (OATP1B1 and OATP1B3 substrate) C_maxincreased 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

[see Drug Interactions (7.2)]

.

Atorvastatin:

Atorvastatin (BCRP, OATP1B1, and OATP1B3 substrate) C_maxwas 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_maxincreased 2.0-fold and AUC increased 1.8-fold

[see Drug Interactions (7.2)]

.

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.

]

.

The following clinically significant adverse reactions are described elsewhere in labeling:

Hepatotoxicity
[see
5.1 Hepatotoxicity
Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention.
Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests.
]
Gallbladder-Related Adverse Reactions
[see
5.2 Gallbladder-Related Adverse Reactions
In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved
[see Adverse Reactions (6.1)]
.
]

REZDIFFRA (resmetirom) tablets contain resmetirom, a thyroid hormone receptor-beta agonist. The chemical name for REZDIFFRA is 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. The molecular formula is C₁₇H₁₂Cl₂N₆O₄ and the molecular weight is 435.22. The chemical structure is:

Referenced Image

Resmetirom has low aqueous solubility below pH 6 and higher solubility above pH 7 (0.44 mg/mL at pH 7.04).

REZDIFFRA tablets are supplied in 60 mg, 80 mg, and 100 mg strengths for oral administration. Each tablet contains the active ingredient, resmetirom, and the following USP/NF excipients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. REZDIFFRA tablets are film-coated with an Opadry coating comprised of polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, red iron oxide (100 mg tablets), yellow iron oxide (80 mg and 100 mg tablets).

The efficacy of REZDIFFRA was evaluated based on an efficacy analysis at Month 12 in Trial 1 , a 54-month, randomized, double-blind, placebo-controlled trial. Enrolled patients had metabolic risk factors and a baseline or recent liver biopsy showing NASH with fibrosis stage 2 or 3 and a NAFLD Activity Score (NAS) of at least 4. Efficacy determination was based on the effect of REZDIFFRA on resolution of steatohepatitis without worsening of fibrosis and one stage improvement in fibrosis without worsening of steatohepatitis, on post-baseline liver biopsies collected at 12 months.

The month 12 analysis included 888 F2 and F3 (at eligibility) patients randomized 1:1:1 to receive placebo (n = 294), REZDIFFRA 80 mg once daily (n = 298), or REZDIFFRA 100 mg once daily (n = 296), in addition to lifestyle counseling on nutrition and exercise. Patients were on stable doses of medications for diabetes, dyslipidemia, and hypertension.

Demographic and baseline characteristics were balanced between treatment and placebo groups. Overall, the median (Q1 to Q3) age of patients at baseline was 58 (51 to 65) years, 56% were female, 21% were Hispanic, 89% were White, 3% were Asian, and 2% were Black or African American.

Median (Q1 to Q3) body mass index (BMI) was 35 (31 to 40) kg/m

²

and median (Q1 to Q3) body weight was 99 (85 to 114) kg. Baseline characteristics are presented in Table 7.

Table 7: Baseline Characteristics in Adult Patients with Noncirrhotic NASH with Stage 2 to Stage 3 Fibrosis in Trial 1
^a Less than 5% missingness in these variables is omitted. ^b kPa = kilopascal; Db/M = decibels per meter
Characteristic	Overall N=888
Fibrosis stage, n (%) F2 F3
Fibrosis stage, n (%) F2 F3	328 (37) 560 (63)
Type 2 Diabetes, n (%)	608 (68)
Hypertension, n (%)	700 (79)
Dyslipidemia, n (%)	633 (71)
Statin use, n (%)	434 (49)
Thyroxine use, n (%)	124 (14)
Vibration-controlled Transient Elastography (VCTE) (kPa), Median (Q1, Q3)^{a, b}	12 (10, 15)
Controlled attenuation parameter (CAP) (Db/M), Median (Q1, Q3)^a	349 (320, 378)
Fibrosis Index Based on 4 Factors (FIB-4), Median (Q1, Q3)^a	1.3 (1, 1.8)
Enhanced Liver Fibrosis (ELF), Median (Q1, Q3)^a	9.7 (9.2, 10.4)

Table 8 presents the Month 12 histopathology results comparing REZDIFFRA with placebo on 1) the percentage of patients with resolution of steatohepatitis and no worsening of liver fibrosis and 2) the percentage of patients with at least one stage improvement in liver fibrosis and no worsening of steatohepatitis. Two pathologists, Pathologist A and Pathologist B, independently read the liver biopsies for each patient. Both the 80 mg once daily and the 100 mg once daily dosages of REZDIFFRA demonstrated improvement on these histopathology endpoints at Month 12 compared to placebo. In a statistical analysis incorporating both pathologists’ independent readings, REZDIFFRA achieved statistical significance on both histopathology endpoints for both doses.

Examination of age, gender, diabetes status (Yes or No), and fibrosis stage (F2 or F3) subgroups did not identify differences in response to REZDIFFRA among these subgroups. The majority of patients in the trial were white (89%); there were too few patients of other races to adequately assess differences in response by race.

Table 8: Efficacy Results at Month 12 in Adult Patients with Noncirrhotic NASH with Stage 2 or Stage 3 Fibrosis in Trial 1
Liver fibrosis was evaluated on the NASH Clinical Research Network (CRN) fibrosis score as 0 to 4. Resolution of steatohepatitis was defined as a score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis. No worsening of steatohepatitis was defined as no increase in score for ballooning, inflammation, or steatosis. Estimated using the Mantel-Haenszel method stratified by baseline type 2 diabetes status (presence or absence) and fibrosis stage (F2 or F3). 95% stratified Newcombe confidence intervals (CIs) are provided. Patients with missing liver biopsy at Month 12 are considered a non-responder.
	Placebo N=294	REZDIFFRA 80 mg Once Daily N=298	REZDIFFRA 100 mg Once Daily N=296
Resolution of steatohepatitis and no worsening of liver fibrosis
Response rate, Pathologist A (%)	13	27	36
Difference in response rate vs. placebo (95% CI)		14 (8, 20)	23 (16, 30)
Response rate, Pathologist B (%)	9	26	24
Difference in response rate vs. placebo (95% CI)		17 (11, 23)	15 (9, 21)
Improvement in liver fibrosis and no worsening of steatohepatitis
Response rate, Pathologist A (%)	15	23	28
Difference in response rate vs. placebo (95% CI)		8 (2, 14)	13 (7, 20)
Response rate, Pathologist B (%)	13	23	24
Difference in response rate vs. placebo (95% CI)		11 (5, 17)	11 (5, 17)

Starting at Month 3 and through Month 12, there was a trend of greater reductions from baseline in average ALT and AST in the REZDIFFRA groups as compared to the placebo group.

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