A Breakthrough in MASH Treatment: FDA Approval of Rezdiffra & What it Means for Payers
By: Emily Crisano, PharmD. and Jason Peterson, R.Ph.
What is NASH—Now Known as MASH?
Non-Alcoholic Steatohepatitis (NASH), recently renamed as Metabolic Dysfunction Associated Steatohepatitis (MASH) by the American Association for the Study of Liver Diseases (AASLD), is a severe stage of liver disease characterized by fatty buildup, inflammation, and damage, potentially leading to cirrhosis—severe liver scarring. Part of the broader spectrum of non-alcoholic fatty liver diseases (NAFLD), now called Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD), MASH primarily affects individuals who consume little to no alcohol.
Often, MASH is a silent disease, discovered incidentally through elevated liver enzyme tests or imaging that shows fatty deposits in the liver. Symptoms like fatigue, weight loss, and weakness might not appear until the disease advances. While early stages of liver fibrosis in MASH are reversible, progression to cirrhosis is permanent, necessitating treatments aimed at slowing disease progression or, in severe cases, a liver transplant.
MASH patients, whether with cirrhosis or not, face an elevated risk of developing liver cancer (hepatocellular carcinoma, HCC). Studies reveal that over eight years, about one-fifth of patients may advance to cirrhosis, with 13% progressing directly to HCC. The incidence of MASH-related HCC has notably increased, climbing from 8.3% in 2002 to 13.5% in 2012, highlighting a growing health concern often undetected due to the typically asymptomatic nature of early-stage MASLD and MASH.
Who is at Risk?
Individuals with MASLD and additional metabolic risk factors—such as obesity (BMI ≥ 25kg/m^2), diabetes, dyslipidemia, and hypertension—are at greater risk of advancing to MASH. The main suspected cause of MASLD involves insulin resistance, which is believed to lead to liver steatosis and potentially steatohepatitis.
In the U.S., between 1.5% and 6.5% of adults are estimated to have MASH, translating to about 6–8 million people with at least moderate to advanced liver fibrosis. Moreover, approximately 25% of adults with MASH may develop cirrhosis, underscoring the significant health challenge posed by this condition.
Challenges and Methods in Screening and Diagnosis of MASLD and MASH
Currently, official guidelines do not recommend routine screening for MASLD or MASH, largely due to the absence of FDA-approved treatments and the questionable cost-effectiveness of existing screening methods. Here’s how it’s currently diagnosed:
Typically, suspicion of MASH arises following the detection of elevated liver enzymes, with ultrasound serving as the initial diagnostic test.
Definitive diagnosis of MASH is achieved through a liver biopsy, with subsequent histological analysis.
Liver fibrosis is then staged using the METAVIR scoring system, which ranges from F0 (no fibrosis) to F4 (cirrhosis), based on the level of inflammation and damage observed.
In addition to biopsy, fibrosis can be assessed using non-invasive techniques such as VCTE (vibration-controlled transient elastography), commonly known as FibroScan, and magnetic resonance elastography (MRE).
The Enhanced Liver Fibrosis (ELF) test, which measures three molecules involved in liver matrix metabolism, can also provide a fibrosis severity score.
Other non-invasive diagnostic methods include the NAFLD Fibrosis Score (NFS) and the Fibrosis 4 (FIB4) index, which calculate fibrosis risk based on various biomarkers.
Disease Management
Historically, without a dedicated treatment for MASH, the following approaches focus on both prevention and targeted interventions to mitigate progression and improve quality of life:
Lifestyle and Supportive Care: Effective management of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) involves abstaining from alcohol and ensuring vaccination against hepatitis A and B to prevent further liver damage. Additionally, controlling associated conditions like cardiovascular disease is crucial for overall health.
Weight Management: Central to MASLD treatment is weight loss, especially for those with a BMI of 25kg/m^2 or higher. Studies show that losing at least 5% of body weight can improve liver steatosis, while a 7% weight loss can reduce liver inflammation and disease severity. Lifestyle modifications such as diet and exercise are key, with bariatric surgery considered for patients unable to meet weight loss targets through conventional means, although it may pose risks of worsening fibrosis.
Pharmacologic Interventions: For patients struggling to achieve weight loss goals with lifestyle changes alone, pharmacological treatments are an option. GLP-1 agonists like Wegovy (semaglutide) and Saxenda (liraglutide) are commonly used off-label for individuals with biopsy-proven MASH and significant fibrosis (stage ≥F2), helping to target a weight loss of 7% to 10% of baseline body weight.
2024—The Year of a Breakthrough in MASH Treatment: FDA Approval of Rezdiffra
The FDA approved Rezdiffra (resmetirom) in March 2024 as the first treatment specifically for patients with MASH who have moderate to advanced liver fibrosis (stages F2 to F3). Taken orally once daily in 80mg or 100mg doses based on body weight, Rezdiffra acts as a thyroid hormone receptor-beta (THR-beta) agonist. This mechanism targets the liver's ability to process fats more effectively, distinguishing it from effects on other organs mediated by THR-alpha receptors.
The drug's accelerated approval stemmed from promising results in the Phase 3 MAESTRO-NASH trial. This study involved 888 participants with biopsy-confirmed MASH, randomized to receive Rezdiffra or a placebo alongside lifestyle modifications. After 12 months, significant improvements were noted in liver health among Rezdiffra users compared to the placebo group, with up to 36% achieving MASH resolution without worsening scarring.
Despite potential side effects like diarrhea and nausea, the treatment marks a pioneering step towards addressing the underlying causes of MASH. Rezdiffra's full approval depends on ongoing studies, including a 54-month confirmatory trial, to validate long-term benefits and safety. This treatment offers new hope for those suffering from this slow-progressing, often asymptomatic liver disease, enhancing standard care with a focused approach to managing the disease.
Other Drugs in the Pipeline
While Rezdiffra may be the first drug to enter the U.S. market for MASH treatment, there are several other agents in Phase II to Phase III development, some of which seek to target novel mechanisms of action:
Two fibroblast growth factor (FGF) analogues, efruxifermin and pegozafermin, are in development by Akero and 89bio/Teva, respectively. Both agents are developed as subcutaneous injections and have shown a reduction of MASH and improvement of fibrosis after 24 weeks in Phase II trials. FGFR21 analogs aim to target lipid and carbohydrate metabolism within the liver.
Other manufacturers are focusing on gaining approval for GLP-1 and/or GIP co-agonists alone or in combination with other mechanisms for MASH. Novo Nordisk is currently investigating semaglutide and Lily is investigating tirzepatide, both in Phase II-III trials. Semaglutide provided a 59% improvement in MASH resolution but did not improve fibrosis in the Phase II trial. Tirzepatide 15mg demonstrated no further worsening of liver scarring or fibrosis after one year for 74% of the trial population.
Boehringer Ingelheim and Zealand Pharma have developed a GLP-1/glucagon co-agonist, survodutide, that has demonstrated an 83% improvement in liver biopsies and showed an improvement in fibrosis.
Novo Nordisk is working on a combination therapy for Stage-4 MASH with cirrhosis with a subcutaneous/oral therapy containing semaglutide, cilofexor, and firsocostat. Cilofexor is a non-steroidal agonist of farnesoid X receptor (FXR) which works to inhibit fat production, sugar production from fats, and bile acid synthesis. Firsocostat is an acetyl-coenzyme A carboxylase (ACC) inhibitor which reduces new fat production generated from the liver.
GLP-1 agonists, GIP co-agonists, and glucagon co-agonists provide the advantage of weight loss and weight maintenance for patients that are obese while also targeting the underlying pathophysiology of MASH to reduce symptoms and fibrosis burdens. The other mechanisms under investigation aim to target MASH at different moments in the pathophysiology cascade to prevent, delay, or slow down the overall disease progression.
Financial Implications for Payers with the Launch of Rezdiffra
Introduced in early April, Rezdiffra, priced at $47,000 per year, is the first FDA-approved treatment for MASH and is available exclusively through a select specialty pharmacy network. It is likely that most payers will implement stringent prior authorization requirements. These may include mandatory liver biopsy confirmation of diagnosis, as was required in the Rezdiffra clinical trials, and adherence to the FDA-approved indication which restricts use to patients with fibrosis scores of F2 or F3, those at increased risk of progressing to cirrhosis (F4).
Coverage is generally expected to exclude patients at the extremes of the fibrosis scale (F0, F1, and F4). The introduction of Rezdiffra is anticipated to raise MASH diagnosis rates and, consequently, the use of off-label GLP-1 agonists, particularly among patients with obesity or type 2 diabetes, as these drugs also target related comorbidities.
Payers also face uncertainties regarding the optimal duration of Rezdiffra therapy, as clinical trials have not yet determined when treatment can be discontinued. This will likely necessitate further guidance from future trials or updates to AASLD treatment guidelines to clarify long-term management strategies. This evolving landscape suggests that payers need to stay informed and adaptable as new data emerges.
Anticipating a Surge in MASH Awareness and Treatment
With the market introduction of the first FDA-approved treatment for MASH, experts anticipate a notable shift in the landscape of this condition. Increased physician awareness and the potential development of less invasive diagnostic alternatives to liver biopsy are expected to lead to more widespread and systematic screening programs. This is likely to result in a significant rise in diagnosed cases of MASH.
As the pharmaceutical market welcomes additional FDA-approved treatments, the financial implications for payers could be profound, particularly if newer drugs are perceived as improvements over existing options, potentially driving up prices. Moreover, with GLP-1 agonists also being explored for MASH, heightened awareness campaigns are on the horizon. These initiatives are set to elevate public and medical understanding of a condition previously obscure to many in the U.S., signaling a new era of recognition and management for MASH.
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