By Tinsay Ambachew Woreta, MD, MPH, with Keri Wiginton
Dr. Woreta is assistant professor of medicine and program director for gastroenterology and transplant hepatology fellowships at Johns Hopkins University School of Medicine in Baltimore. The information here represents her research and knowledge as a medical professional; Dr. Woreta was not involved in the development of or clinical trials for resmetirom (Rezdiffra).
Metabolic dysfunction-associated steatohepatitis (MASH) is a condition where excess fat builds up in the liver. MASH, previously known as non-alcoholic steatohepatitis (NASH), is a subtype of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD).
Along with high levels of fat in the liver, people diagnosed with MASLD have at least one of five cardiometabolic risk factors. This may include overweight or obesity, prediabetes or diabetes, high blood pressure, high triglycerides, or low HDL (the “good” cholesterol).
MASLD is a common cause of liver disease that affects around 30% of people worldwide. Among adults in the United States, 1.5% to 6% have MASH. This means you also have inflammation in your liver that can lead to scarring, which is what we call fibrosis.
MASH raises your risk of having liver complications such as permanent scarring, liver failure, liver cancer, or death. Up to now, no medications were approved to specifically target liver damage caused by the disease.
But this is an exciting time for people with MASH, because we now have a drug approved to treat it and many more medications in the pipeline.
Who is this treatment for?
Resmetirom (Rezdiffra) is approved to treat adults with MASH who have moderate to advanced liver scarring, or stages F2 and F3 fibrosis. We know from multiple studies that it’s this inflammation and fibrosis that drives the risk of health complications and death in people with MASH.
Fibrosis ratings go from F0 to F4, with the lowest meaning no scarring and the highest showing evidence of permanent liver scarring. In a key clinical trial for resmetirom, researchers included those with fibrosis stages F1B, F2, or F3.
While resmetirom isn’t approved to treat people with cirrhosis, a severe scarring of the liver that doesn’t go away, there’s ongoing research into the safety and benefits of the medication in this population. But we don’t have that data yet.
How is this treatment different and how does it work?
This drug is a breakthrough for the field of hepatology, not because it’s so effective but because it’s the first drug approved to target the underlying cause of liver damage caused by MASH.
Previously, the mainstay of treatment has been lifestyle interventions, including following a Mediterranean-style diet and getting regular cardiovascular exercise. People with overweight or obesity tend to have better liver function when they lose at least 10% of their body weight. But only a small number of people can achieve these goals, and it’s been frustrating not to have something else to offer them.
We still recommend diet and exercise along with medication. But resmetirom works in a unique way: by targeting a thyroid hormone receptor in the liver. This changes how fat cells are processed by the body. And there’s good data to show that stimulating this hormone decreases excess fat in the liver and reverses fibrosis in some people.
How effective is this treatment? How soon does it work?
In the most recent study, researchers found that the medication led to a resolution of MASH (meaning there was no evidence of inflammation) and no worsening of fibrosis in about 26% to 30% of people who received the drug, compared to about 10% of those who only got lifestyle counseling (the placebo group.
For around 25% of people in the study, the scar tissue in their liver decreased by at least one stage of fibrosis, compared to 14% of people in the placebo group. That’s a statistically significant benefit.
Researchers looked at an overall benefit in fibrosis after 1 year. But if you take this drug and respond to it, you might get other health benefits before that. You may see improvement in certain inflammation markers (according to liver enzyme tests) within 3 months of treatment.
Studies also show that people who got the drug had a significant reduction in LDL cholesterol, compared to those who didn’t receive the medication, and they saw that benefit after 6 months of treatment. (LDL is generally considered the “bad” kind of cholesterol that’s associated with increased risk of heart disease.)
We don’t currently have a way to predict who’ll respond to this medication. But even if resmetirom only works for 1 in 4 people with MASH, that is still reason for hope. And if you have moderate to advanced liver scarring, it’s tremendous to finally have a treatment that may lessen the chances you’ll get liver cancer, need a liver transplant, or have other liver complications.
Is this treatment safe?
According to clinical trials so far, this drug seems reasonably safe and well-tolerated. While resmetirom does come with a warning about the possibility of drug-related liver damage and gallbladder issues, the overall risk is low.
It’s important to note that liver toxicity can be seen with any medication, and this drug is no exception. But your doctor will keep a close eye on your liver enzymes once you start treatment.
You’ll need to stop the drug if your lab tests show signs of liver injury. But tell your doctor right away if you get certain warning signs of serious side effects, including symptoms such as yellowing of the skin (jaundice), fatigue, nausea, vomiting, upper right-side pain, or a rash.
What are the common side effects of this treatment and are there ways to prevent or manage them?
In clinical trials, the most common side effects were diarrhea and nausea at the start of treatment. These symptoms were usually mild and self-limiting, meaning they went away on their own without medical treatment.
Other side effects might include constipation, belly pain, dizziness, itching, or throwing up.
Always tell your doctor about any symptoms that bother you even if you don’t think they’re serious. You can meet with someone on your supportive care team to find the best way to manage your side effects or to find out if you need to stop or adjust your treatment plan.
How is this treatment taken? Is follow-up testing or monitoring needed? Is it a long-term treatment?
This is a once-daily pill you can take with or without food. The tablets come in strengths of 60 milligrams, 80 milligrams, and 100 milligrams. The recommended dose for you depends on your body weight.
When you start treatment, expect close monitoring of your liver enzymes. If everything looks normal after the first month or two, you might be able to space out the lab tests to every 3 to 6 months. Your doctor will let you know what’s right for you.
More research is needed to find out if this will be a long-term treatment or something you only take for a short while.
Who shouldn’t take this treatment?
Resmetirom isn’t recommended for people with decompensated cirrhosis. This is a type of cirrhosis where you have severe scarring and your liver doesn’t function well. If your liver doesn’t work the way it should, you could get unsafe levels of the drug in your body.
Pregnant people or those who are breastfeeding shouldn’t take this medication. More research is needed to know if the drug is safe for this group.
Resmetirom may interact with certain medications, including statins. These are common drugs used to lower cholesterol. Your doctor will let you know if you need to stop or adjust the dose of any of your medications.
What are the costs of this treatment? Will insurance cover it, and are there cost assistance programs?
Madrigal Pharmaceuticals, the company that makes resmetirom (Rezdiffra), set the price around $47,000 a year. But it’s our understanding that commercial insurance providers, like the kind you get through your job, will cover it.
If you have private health insurance and your provider doesn’t pay all the costs, Rezdiffra can be as little as $10 a month with a copay card. There’s also a patient assistance program (PAP) from the drugmaker to help people without health insurance get the drug.
When will this treatment be available?
You could get a prescription today, but resmetirom is available only from a limited number of specialty pharmacies. Since the drug is new, we’re not sure how fast or easy the rollout will be. Your doctor should be able to help you find ways to get the medication if you need it.
How can I learn more about whether this is a good treatment option for me?
If you have MASH and moderate to advanced liver scarring, you could be a good candidate for resmetirom, especially if you have overweight or obesity and you’re having trouble losing weight through lifestyle interventions alone.
Your primary care doctor can be a good person to start the conversation with, but they may not be familiar with this medication or the criteria for treatment. But they can refer you to a gastroenterologist or another liver specialist (hepatologist) who treats people with MASLD or MASH.
If you already have a relationship with a doctor who treats MASH, make an appointment solely to talk about the pros and cons of the medication and whether it’s right for you.
As I mentioned before, this treatment is approved to treat people who have MASH with stage 2 or stage 3 fibrosis. If you’re not sure if that’s you, your doctor can run some tests to figure out if you have liver scarring and how serious it is.
Lab tests can rule other causes of liver disease. But to diagnose or evaluate MASH, you might need a liver biopsy or less invasive tests such as an ultrasound, CT scans, or magnetic resonance elastography (MRE).
Even if you decide not to start therapy or you don’t qualify, check in with your doctor at least every 6 months to monitor your liver health. While MASH tends to worsen slowly over time, some people progress quicker than others.
How carefully was this drug studied?
There’s robust data from several clinical trials showing this drug’s safety and efficacy in more than 2,000 people. And from the evidence we have so far, I’d say this drug has been carefully studied and meets an unmet medical need, which is why the FDA granted accelerated approval.
And as hepatologists, we see this need daily, as our clinics fill with an increasing number of patients with MASLD and MASH. And the absence of any treatment until now has been problematic.
But a growing number of people have MASH or will develop it in the future, which means potentially hundreds of thousands of people could be on this drug. It’s possible that we could see other side effects or complications appear when the medication is studied in larger groups.
Obviously, we don’t have long-term safety data yet. Those trials are ongoing. And final FDA approval depends on the results of future studies, which should verify and confirm that the drug is safe and has a proven medical benefit.
