First Treatment for Damage Due to Fatty Liver Disease Receives FDA Approval: Resmetirom

On 14 March 2024, the Food and Drug Administration (FDA) in the United States approved Rezdiffra, containing resmetirom and manufactured by Madrigal Pharmaceuticals, for use alongside diet and exercise to treat adults with noncirrhotic nonalcoholic fatty liver disease and moderate to advanced liver fibrosis (scarring, damage).

Previously, no drug could directly address liver damage in patients with nonalcoholic fatty liver disease and significant liver scarring. Rezdiffra's approval will provide these patients, for the first time, with a treatment option alongside diet and exercise.

What Does Nonalcoholic Fatty Liver Mean?

Some people may not have heard of fatty liver, or, more accurately in medical terms, fatty liver disease . However, it would probably be fair to describe it as one of the most common diseases in recent years. This condition is often referred to in English as Nonalcoholic Fatty Liver Disease, meaning "fatty liver not caused by alcohol". It is known that approximately 10 to 46 percent of people in the United States have fatty liver disease. Following advanced fatty liver, the proportion developing liver inflammation or damage is between 3-12 percent.

Compared with a healthy liver, a fatty liver is slightly larger and has lost its characteristic color. Tissue samples show fat deposits characteristic of nonalcoholic fatty liver disease (image on the right).

This liver damage results from the progression of nonalcoholic fatty liver disease, in which liver inflammation leads over time to liver scarring and dysfunction. Nonalcoholic fatty liver disease is often associated with other health problems, such as high blood pressure and type 2 diabetes. In the United States alone, approximately 6-8 million people have moderate to advanced liver scarring due to nonalcoholic fatty liver disease, and this number is expected to rise. Rezdiffra is a partial activator of a thyroid hormone receptor that reduces fat accumulation in the liver.

How Does Rezdiffra Work?

Rezdiffra (resmetirom) is a drug that functions as a thyroid hormone receptor beta (THR-β) agonist. It mainly targets thyroid hormone receptors in the liver to help regulate metabolism and cholesterol levels. The drug was developed particularly for treating dyslipidemia (commonly known as high cholesterol) and other metabolic diseases. Details of its mechanism of action follow:

Mechanism of Action

Rezdiffra acts as an analog of the endogenous form of thyroid hormone. Thyroid hormones have important effects on various metabolic processes in the body. These hormones have two main receptors: thyroid hormone receptor alpha (THR-α) and thyroid hormone receptor beta (THR-β). By specifically targeting THR-β, Rezdiffra mimics the natural effects of thyroid hormone. However, because it has minimal effects on THR-α, it prevents many side effects associated with excessive thyroid hormone activation.

Effects on the Liver

• Cholesterol Metabolism: Rezdiffra increases the expression of LDL (low-density lipoprotein, or bad cholesterol) receptors in the liver. This helps remove LDL cholesterol from the bloodstream more efficiently, thereby lowering total and LDL cholesterol levels.
• Triglyceride Levels: It also helps lower triglyceride levels by increasing fatty acid oxidation in the liver.
• Fatty Liver: By reducing fat accumulation in the liver, it offers potential benefits for treating conditions such as nonalcoholic fatty liver disease.

Effects on Cardiovascular Health

• Rezdiffra has been shown to improve cardiovascular disease risk factors. It may be an important step toward protecting cardiovascular health, particularly in patients with dyslipidemia (abnormal blood lipid levels).

The Clinical Trial Leading to FDA Approval

Rezdiffra's safety and effectiveness were assessed using an interim analysis at month 12 of a 54-month randomized, double-blind, placebo-controlled trial. This interim analysis measured the degree of liver inflammation and scarring. The sponsor is required to conduct a postapproval study to verify and describe Rezdiffra's clinical benefit. This will involve completing the same 54-month trial, which is still ongoing.

To participate in the trial, patients needed a liver biopsy showing moderate or advanced liver scarring due to nonalcoholic fatty liver disease.

In the trial, 888 participants were randomly assigned to receive one of the following once daily: placebo (294 participants), 80 milligrams of Rezdiffra (298 participants), or 100 milligrams of Rezdiffra (296 participants), together with standard care for nonalcoholic fatty liver disease, namely counseling on a healthy diet and exercise.

Results

After 12 months, liver biopsies showed that a higher proportion of participants treated with Rezdiffra had improvement in nonalcoholic fatty liver disease or liver scarring than those receiving placebo.

• Among participants receiving 80 milligrams of Rezdiffra, 26% to 27% experienced resolution of nonalcoholic fatty liver disease without worsening liver scarring, as did 24% to 36% of those receiving 100 milligrams;
• This occurred in 9% to 13% of those receiving placebo and diet and exercise counseling.

The range in responses reflects readings by different pathologists.

Demonstrating these treatment-related changes after only one year is noteworthy, because the disease usually progresses slowly, with most patients showing progression after years or even decades.

Rezdiffra's most common side effects were diarrhea and nausea. Rezdiffra carries certain warnings and precautions, including drug-induced liver toxicity and gallbladder-related side effects.

Rezdiffra should be avoided in patients with decompensated cirrhosis. Patients should stop taking Rezdiffra if signs or symptoms of worsening liver function develop during treatment.

Taking Rezdiffra together with certain other drugs, particularly cholesterol-lowering statins, may cause potentially significant drug interactions. Healthcare providers should consult the full prescribing information for further details on potentially significant interactions with Rezdiffra and recommended dosage and management changes.

For drugs that treat serious conditions and address an unmet medical need, the FDA permits earlier approval through its accelerated approval pathway. Rezdiffra was approved through this route, based on interim findings that reasonably predict clinical benefit. The required, ongoing 54-month trial will assess Rezdiffra's clinical benefit after 54 months.