Resmetirom

Resmetirom is a weak CYP2C8 inhibitor. Resmetirom increases exposure of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates.

Monitor patients more frequently for substrate-related adverse reactions if resmetirom is co-administered with CYP2C8 substrates where minimal concentration changes may lead to serious adverse reactions.

If resmetirom is used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel), reduce the dosage of resmetirom:

• <100 kg, reduce the dosage of resmetirom to 60 mg once daily.
• ≥100 kg, reduce the dosage of resmetirom to 80 mg once daily.

Concomitant use of resmetirom with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended.

Resmetirom is an OATP1B1 and OATP1B3 substrate. Concomitant use with OATP1B1 and OATP1B3 inhibitors may increase resmetirom C_max and AUC, which may increase the risk of resmetirom adverse reactions.

Concomitant use of resmetirom with OATP1B1 or OATP1B3 inhibitors (e.g., cyclosporine) is not recommended.

Avoid use of resmetirom 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_max and AUC, which may increase the risk of adverse reactions.

Resmetirom increased plasma concentrations of some statins (atorvastatin, pravastatin, rosuvastatin and simvastatin), which may increase the risk of adverse reactions related to these drugs.

Rosuvastatin and simvastatin: Limit daily statin dosage to 20 mg.

Pravastatin and atorvastatin: Limit daily statin dosage to 40 mg.

There are no available data on resmetirom use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus related to underlying NASH with liver fibrosis. In animal reproduction studies, adverse effects on embryo-fetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recommended dose during organogenesis. These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits. No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623. A pre- and post-natal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose (see Data). These effects were associated with marked suppression of maternal T4, T3, and TSH levels.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

There is no information regarding the presence of resmetirom in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for resmetirom and any potential adverse effects on the breastfed infant from resmetirom or from the underlying maternal condition.

Carcinogenesis

In a 2-year study in CD-1 mice, resmetirom produced leiomyoma or leiomyosarcoma in the uterus at a dose of 100 mg/kg/day (51 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in female mice at doses of up to 30 mg/kg/day (14 times the maximum recommended dose based on AUC) or in male mice at doses of up to 100 mg/kg/day (35 times the maximum recommended dose based on AUC).

In a 2-year study in Sprague-Dawley rats, resmetirom produced benign fibroadenoma in the mammary gland of males at a dose of 30 mg/kg/day (6.5 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in male rats at doses of up to 6 mg/kg/day (3.7 times the maximum recommended dose based on AUC) or in female rats at doses of up to 30 mg/kg/day (3.4 times the maximum recommended dose based on AUC).

In a 26-week study in transgenic [CByB6F1-Tg(HRAS)2Jic] mice, the major metabolite of resmetirom, MGL-3623, was not tumorigenic at doses of up to 1500 mg/kg/day.

Mutagenesis

Resmetirom was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, the in vitro micronucleus assay in L5178Y tk+/- mouse lymphoma cells, and the in vivo rat micronucleus assay.

The metabolite MGL-3623 was negative in the in vitro bacterial reverse mutation (Ames) assay and the in vivo rat micronucleus assay. MGL-3623 tested positive in the presence of metabolic activation in the in vitro micronucleus assay with TK6 human lymphoblast cells, with the increase in micronuclei limited to a single concentration that produced 59% growth inhibition.

Impairment of Fertility

Resmetirom had no effects on fertility or reproductive function in male and female rats at oral doses of up to 30 mg/kg/day (6.9 times and 2.6 times the maximum recommended dose in male and female rats, respectively, based on AUC).

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of resmetirom was evaluated in two randomized, double-blind, placebo-controlled trials that enrolled a total of 2019 patients.

Trial 1

Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888).

Adverse Reactions Leading to Discontinuations

The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the resmetirom dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation.

Common Adverse Reactions

Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with resmetirom and were greater than that reported for placebo.

Table 1. Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with Resmetirom in Adult Patients with Noncirrhotic NASH (Trial 1)^a,b,c:

^a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility).
^b Median exposure duration was 68 weeks for placebo, 74 weeks for resmetirom 80 mg once daily, and 66 weeks for resmetirom 100 mg once daily.
^c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively.
^d The EAIR per 100 PY can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 patients are treated for one year.
Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis

Gastrointestinal Adverse Reactions

The incidence of gastrointestinal adverse reactions was higher for the resmetirom drug arms compared to placebo. The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, resmetirom 80 mg once daily, resmetirom 100 mg once daily arms, respectively.

Diarrhea typically began early in treatment initiation and was mild to moderate in severity. The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily arms, respectively.

Median duration of diarrhea was 9 days for placebo compared to 20 days for both resmetirom 80 mg once daily and resmetirom 100 mg once daily dosage arms.

Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily arms, respectively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily arms, respectively. Vomiting and abdominal pain adverse reactions were mild to moderate in severity.

Hypersensitivity Reactions

Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving resmetirom. The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily arms, respectively. The EAIRs for rash were 3 per 100 PY in the placebo and resmetirom 80 mg once daily arms compared to 5 per 100 PY in the resmetirom 100 mg once daily arm.

Gallbladder-Related Adverse Reactions

A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms.

Less Common Adverse Reactions

Additional adverse reactions that occurred more frequently in the resmetirom arms compared to placebo, in less 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding.

Laboratory Abnormalities

Liver Tests

Increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with resmetirom. In both resmetirom dosage arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment.

Table 2 presents the frequency of liver test elevations during Trial 1.

Table 2. Frequency of Liver Test Elevations in Trial 1:

^a TB elevations include patients with Gilbert syndrome.

Thyroid Function Tests

A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, resmetirom 80 mg once daily, and resmetirom 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH. There were no clinical findings associated with FT4 decreases.

Additional Safety Data

The safety evaluation of resmetirom also included an analysis of an additional randomized placebocontrolled safety trial which included 969 patients from a relevant patient population (placebo [n=318], resmetirom 80 mg once daily [n=327], and resmetirom 100 mg once daily [n=324]).

Data from the safety trial was combined with data from NASH patients with F2 and F3 fibrosis at eligibility (n=888) and data from an additional 162 patients from a relevant patient population enrolled in Trial 1. In the combined safety population (n=2019), the median (Q1 to Q3) age of patients at baseline was 58 (50 to 65) years; 55% were female, 28% were Hispanic, 89% were White, 2% were Asian, and 4% were Black or African American.

The safety profile from this combined analysis was similar to that in Trial 1, other than the one case of hepatotoxicity in the safety trial.