The Food and Drug Administration on Thursday approved Rezdiffra, or resmetirom, as the first medication specifically authorized to treat adults with noncirrhotic nonalcoholic steatohepatitis and moderate-to-advanced liver fibrosis. The decision ends years of failed drug-development efforts in a progressive liver disease associated with obesity, type 2 diabetes and other metabolic disorders and creates the first pharmacologic option aimed directly at reducing liver injury before cirrhosis develops.

The FDA granted accelerated approval for Rezdiffra to be used with diet and exercise in adults with fibrosis consistent with stages F2 to F3. The agency estimates that roughly 6 million to 8 million people in the United States have NASH with moderate-to-advanced liver scarring, although only a fraction have been formally diagnosed and identified for treatment.

A first approval in a disease with repeated drug failures

NASH develops when excess liver fat is accompanied by inflammation and cellular injury, which can progressively produce fibrosis, cirrhosis, liver failure and liver cancer. The condition is now also called metabolic dysfunction-associated steatohepatitis, or MASH, under terminology adopted by international liver societies last year. Until this week, treatment centered on weight loss, exercise, management of diabetes and cardiovascular risk, and surveillance for progression because no drug had received FDA approval specifically for the disease.

Rezdiffra is a selective thyroid hormone receptor-beta agonist. Activating that receptor in the liver is intended to increase fat metabolism and reduce accumulation of liver fat while limiting effects on other tissues. Madrigal Pharmaceuticals, the drug’s developer, said in its March 14 announcement that the approval represents the culmination of more than 15 years of work on the mechanism.

The significance is magnified by the history of the field. Several compounds have reached late-stage development only to fail because they did not sufficiently improve fibrosis, did not resolve NASH, raised safety concerns or could not demonstrate an acceptable benefit-risk profile. The absence of an approved treatment has left hepatologists managing a large and growing disease burden largely through metabolic risk reduction.

MAESTRO-NASH provides the surrogate evidence for accelerated approval

The approval rests on interim pathology results from the ongoing Phase 3 MAESTRO-NASH trial. The New England Journal of Medicine published the primary 52-week results in February. Patients with biopsy-confirmed NASH and fibrosis were randomly assigned to once-daily resmetirom at 80 milligrams, 100 milligrams or placebo, with the trial designed to evaluate both disease resolution and improvement in fibrosis.

For the FDA’s efficacy analysis, 888 patients were included: 298 in the 80-milligram group, 296 in the 100-milligram group and 294 receiving placebo. Depending on the pathologist reading the biopsies, NASH resolution without worsening of fibrosis occurred in 26% to 27% of patients taking 80 milligrams and 24% to 36% taking 100 milligrams, compared with 9% to 13% on placebo. Improvement in fibrosis without worsening of NASH occurred in 23% of the 80-milligram group and 24% to 28% of the 100-milligram group, compared with 13% to 15% of placebo patients.

Those are surrogate histologic endpoints rather than direct proof that the drug prevents cirrhosis, liver failure, transplantation or death. That distinction is why the FDA used the accelerated approval pathway. Madrigal must complete the ongoing outcomes portion of the 54-month study to verify clinical benefit. If the longer-term trial does not confirm benefit, the approval could be reconsidered.

The label avoids a mandatory liver-biopsy requirement

One of the most consequential practical elements of the approval is what the prescribing information does not require. Madrigal says the label contains no requirement that clinicians obtain a liver biopsy before prescribing Rezdiffra. That matters because biopsy is invasive, expensive and impractical as a screening tool for the millions of Americans who may have clinically significant fibrosis.

Reuters reported that specialists viewed the absence of a mandatory biopsy as important for adoption. Clinicians can increasingly use combinations of blood-based fibrosis scores, elastography and imaging to identify patients likely to have F2 or F3 disease, although determining who falls within the approved population will still require careful clinical judgment.

The Philadelphia Inquirer reported that the approval is especially significant because metabolic liver disease has risen alongside obesity and diabetes. Many patients are asymptomatic until fibrosis is advanced, so the availability of a treatment may increase pressure on health systems to identify disease earlier rather than waiting for complications of cirrhosis.

Safety, interactions and patient selection will shape early use

Rezdiffra is an oral, once-daily medication, but the approval does not make it appropriate for all fatty-liver disease. The indication is limited to adults without cirrhosis who have moderate-to-advanced fibrosis. The FDA advises against use in patients with decompensated cirrhosis and includes warnings regarding drug-induced liver injury and gallbladder-related events.

The most common adverse reactions in the clinical program included diarrhea and nausea. Drug interactions are another important issue because many patients with NASH also have cardiovascular disease and take statins. The FDA warns that resmetirom can increase exposure to certain statins, requiring clinicians to follow dose limits and monitor patients for adverse effects.

The disease itself also complicates treatment decisions. Patients often have obesity, insulin resistance, hypertension, dyslipidemia or type 2 diabetes, meaning a liver-directed drug will usually become one component of a broader metabolic treatment strategy rather than replacing weight management or cardiovascular risk reduction.

A new therapy may force a new care pathway

The American Liver Foundation called the decision a major milestone for patients who previously had no approved medical therapy. Its response also underscores an implementation challenge: millions may have the disease, but the healthcare system does not yet have a standardized national pathway for finding, staging and referring all patients who might benefit.

Primary-care physicians, endocrinologists and cardiologists frequently encounter patients with metabolic risk factors long before they reach hepatology clinics. With an approved therapy now available for selected fibrosis stages, noninvasive testing could become more consequential because a positive result can lead to an intervention rather than only risk counseling.

Madrigal expects Rezdiffra to become commercially available in April through a specialty-pharmacy network. Pricing, payer authorization criteria and requirements for documentation of fibrosis will determine how quickly patients can access the drug. Because the approval is accelerated, insurers and clinicians will also be watching the continuing MAESTRO-NASH outcomes trial for evidence that biopsy improvements translate into fewer clinical liver events.

By Saturday, however, the threshold change is clear. A disease that has long had no FDA-approved medication now has its first liver-directed therapy. Rezdiffra does not eliminate the need for diet, exercise, metabolic risk control or long-term evidence, but it gives clinicians a treatment that has demonstrated measurable improvement in NASH resolution and fibrosis in a Phase 3 trial. The next test is whether those short-term tissue changes lead to durable reductions in cirrhosis, liver failure and transplantation as the confirmatory study continues.