FDA Approves Rezdiffra, the First Drug for NASH, a Form of Fatty Liver Disease
Rates of a serious form of liver disease have grown, but there have been no medications to treat it—until now. In March, the U.S. Food and Drug Administration (FDA) approved a pill called resmetirom, sold under the brand name Rezdiffra™, for NASH (nonalcoholic steatohepatitis).
NASH is a subtype of one of the most common types of liver disease, nonalcoholic fatty liver disease (NAFLD), a term used to describe a spectrum of conditions marked by a buildup of fat in the liver that is not caused by heavy alcohol use.
NAFLD ranges from fatty liver disease, which has little or no liver inflammation—and often no symptoms—to NASH, where there is inflammation (hepatitis) and possible scarring (fibrosis) of the liver. In its most advanced stage, NASH can lead to cirrhosis (permanent scarring of the liver) and even liver failure.
Rezdiffra is approved for adults with NASH who have moderate to advanced scarring of the liver, which is the case for an estimated 6 to 8 million Americans. Chronic overnutrition is a major contributor to the development of NASH, says Wajahat Mehal, MD, director of the Yale Metabolic Health & Weight Loss Program. Overnutrition is a type of malnutrition (imbalanced nutrition) that means a person is taking in an excessive number of nutrients, causing body fat to accumulate and leading to negative health consequences.
Obesity, type 2 diabetes, and metabolic syndrome (a group of conditions, including high blood pressure and abnormal cholesterol levels, that can lead to serious health problems) are also risk factors.
About 42% of American adults have obesity, a number that continues to rise, which then also contributes to the increasing number of people with fatty liver disease. And while weight loss can help reverse both NAFLD and NASH (in early stages), it may not reverse the fibrosis caused by NASH. This new medication, however, has been shown to improve scarring in about 25% of people who take it.
Dr. Mehal says he hopes the drug’s approval “energizes” the field and leads to more treatment advances. In fact, there are several different types of NASH medications in late-stage clinical trials, he adds.
“Now that the FDA has approved a drug for NASH, pharmaceutical companies will have a better understanding of the thresholds they must meet to get future approvals,” Dr. Mehal says. “This makes them more enthusiastic about continuing drug development in this area. And there are many promising medications coming along.”
Below, we talk more with Dr. Mehal about NASH and what this development means for patients.
Why is NASH dangerous?
It’s helpful to think of fatty liver disease as progressive and, as mentioned above, largely driven by overnutrition. “Particularly with chronic overnutrition, the body stores fat in many places, including the liver,” Dr. Mehal says. “Most people with obesity or overweight are going to have high levels of fat in their liver, and that means they have NAFLD. But, over time, about a quarter of people with NAFLD will start to experience liver damage. That’s when NAFLD transitions to NASH.”
With NASH, the liver scarring is a threat to your health, he says.
The level of damage is measured via biopsy and is graded in four stages from 0 (no scarring) to 4 (cirrhosis). However, because NASH is a progressive disease, fibrosis can eventually develop into liver cirrhosis.
At that point, a liver transplant might be the only treatment for cirrhosis, and even that is not always effective—or attainable, Dr. Mehal says.
How are NAFLD and NASH diagnosed?
Because NAFLD and NASH often don’t have symptoms, it is difficult to diagnose. Doctors rely on a medical history, a physical examination, and tests, including imaging tests, blood tests, and liver biopsies.
NAFLD might be suspected if you have elevated levels of certain liver enzymes, for example, found during routine blood work for an annual physical.
“It’s important to note, however, that most cases of NASH can be diagnosed with blood tests and imaging. A liver biopsy is necessary in about 10% of patients,” says Dr. Mehal.
How effective is Rezdiffra for NASH?
Rezdiffra, made by Madrigal Pharmaceuticals, is a daily pill that activates a thyroid hormone receptor that reduces liver fat accumulation.
Results from an ongoing Phase III clinical trial were published in The New England Journal of Medicine. Resmetirom, which was tested at two dose strengths, was shown to resolve NASH without a worsening of fibrosis in 26% (at the lower dose) and 30% (at the higher dose) of patients compared to 10% in the placebo group. The trial also showed that the drug improved fibrosis by at least one stage in 24% (at the lower dose) and 26% (at the higher dose) of the patients, compared to 14% in the placebo group.
The medication was granted accelerated approval; final approval is contingent on the results of the ongoing study.
What are the side effects of Rezdiffra?
Diarrhea and nausea are the most common side effects of Rezdiffra. The drug also comes with warnings and precautions about drug-induced liver toxicity and side effects related to the gallbladder. It may also have “potentially significant drug interactions” with certain other drugs, including statins for lowering cholesterol, the FDA notes.
Can anti-obesity medications help people with NAFLD?
Typically, if NASH patients lose 10% to 11% of their body weight, their liver condition improves, Dr. Mehal says. “But, of course, that can be difficult to achieve, and before this drug came along, we would give other medications that could help with weight loss,” he says.
Anti-obesity medications, such as semaglutide (Wegovy) and tirzepatide (Zepound), can help treat fatty liver disease and potentially stop it from advancing to NASH, but once someone has NASH, these drugs have not yet been proven to reverse it, Dr. Mehal says. However, clinical trials are ongoing, and the early data is very encouraging that these medications will be effective for NASH, he adds.
Dr. Mehal says he expects insurance carriers to cover the cost of Rezdiffra and, once it becomes available, he will offer it to his patients with NASH who fit the criteria.
“Rezdiffra is meant for adults with NASH who have well-developed, but not extremely severe scarring in their liver, and it should be used along with a healthy diet and an active lifestyle,” says Dr. Mehal.
Editor’s note: NAFLD and NASH were recently renamed MASLD (metabolic dysfunction-associated steatotic liver disease) and MASH (metabolic dysfunction-associated steatohepatitis), respectively. However, this article follows the nomenclature used in the FDA approval of Rezdiffra, the trial published in NEJM, and Rezdiffra's website.
