Naim Alkhouri, M.D., on MASH: Exploring New Treatments for a Silent Epidemic

Naim Alkhouri, M.D.

Credit: Arizona Liver Health

Metabolic dysfunction-associated steatohepatitis (MASH), previously called nonalcoholic steatohepatitis (NASH), is a chronic liver disease marked by fat buildup, inflammation and scarring. It often goes undiagnosed and untreated but can lead to severe complications, like cirrhosis or liver cancer.

In an interview with The Educated Patient, Naim Alkhouri, M.D., chief medical officer, chief of transplant hepatology and director of the Fatty Liver Program at Arizona Liver Health, discusses the results of recent trials evaluating treatment with pegozafermin to treat this condition, which were presented at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting.

The drug shows promise, with significant improvement in liver health markers and fibrosis reduction over time. Unlike existing treatments, pegozafermin has demonstrated both safety and effectiveness, making it a potential cornerstone for MASH therapy. Early diagnosis and evolving treatments like pegozafermin could improve outcomes and quality of life for many patients.

Why is it important for patients to be aware of this condition?

Naim Alkhouri, M.D.: By 2030, an estimated 27 million people in the United States will have MASH, of whom 7.5 million will have advanced fibrosis. Raising awareness of MASH is critical because despite its prevalence, people living with this “silent” disease may have no symptoms.

How does MASH impact a patient’s overall health and quality of life, and what are the main goals of treatment?

NA: The impact of MASH can be extensive, including severe liver-related complications, such as cirrhosis, liver failure and hepatocellular cancer. The primary treatment goal for patients with MASH at all stages is reversal of liver fibrosis and to prevent progression to more severe liver-related complications. With only one recently approved medicine, treatment options have relied on lifestyle changes such as diet and exercise and managing comorbidities with medications to induce weight loss and improve glycemic control. However, patients with advanced MASH require active medical intervention, namely a treatment that can specifically and quickly address fibrosis.

Can you explain what the phase 2b ENLIVEN trial studied and why the results are significant for people living with MASH?

NA: The phase 2b ENLIVEN trial evaluated the efficacy and safety of pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21 (FGF21), in MASH patients with biopsy-proven F2/F3 fibrosis. The trial evaluated 219 adult patients for 24 weeks of whom 192 had biopsy-confirmed fibrosis stages F2/F3 MASH. In this study, participants achieved improvements in key noninvasive markers of liver inflammation and results also showed quick reversal of fibrosis after just 24 weeks of treatment. In addition, after the main study, patients began a 24-week blinded extension phase for a total of 48 weeks of treatment. At week 48, pegozafermin demonstrated statistically significant improvements across key markers of liver health. The benefits observed at week 48 were consistent with the results observed at week 24, indicating sustained benefits over time. The reversal of fibrosis is significant because fibrosis can ultimately lead to death in patients with MASH. Pegozafermin’s efficacy, safety, tolerability and convenient dosing suggest that it could become a mainstay of MASH treatment.

What makes pegozafermin different from other treatments currently available for MASH?

NA: Pegozafermin addresses the drivers of MASH occurring both inside and outside of the liver and in clinical trials has demonstrated direct antifibrotic and anti-inflammatory effects on the liver. Pegozafermin has also shown a favorable safety and tolerability profile, with few gastrointestinal side effects. This is important in MASH, which requires chronic treatment, as poor tolerability could negatively impact quality of life, resulting in poor adherence and clinical outcomes. Additionally, because pegozafermin can be self-administered once every week or every other week, it could offer a convenient and preferred option for people that may already be on multiple medicines due to comorbidities.

What were the most important findings from the new analyses presented at the AASLD Liver Meeting? How might these findings impact the future of MASH treatment?

NA: The post hoc analyses presented at the AASLD Liver Meeting demonstrate the potential of noninvasive tests (NITs) like FAST and AGILE3+ to identify high-risk patients, potentially reducing the need for liver biopsy. In addition, results show that pegozafermin not only improved patients’ FAST scores but also achieved both MASH resolution and fibrosis improvement, indicating its potential as a treatment option for patients with advanced MASH.

Can you discuss the implications of the new data on fibrosis in MASH patients? Why is targeting fibrosis so critical in the treatment of liver diseases like MASH?

NA: The primary treatment goal for patients with MASH is reversal of liver fibrosis to prevent progression to more severe liver-related complications. The post hoc analysis of the phase 2b ENLIVEN trial evaluating pegozafermin in MASH patients with advanced fibrosis showed that pegozafermin treatment reduced the proportion of F3 patients progressing to cirrhosis (F4) at week 24. In addition, the treatment group in F3 patients showed improvement in histological disease activity and multiple liver-related NITs, suggesting clinical benefits even in patients with fibrosis progression. These results show that pegozafermin may prevent noncirrhotic patients from progressing to cirrhosis, which is a much more serious stage of the disease.

What are the next steps in the development of pegozafermin after these trial results?

NA: Based on these phase 2b results, 89bio is advancing the clinical development of pegozafermin and evaluating its safety and efficacy in two ongoing global, randomized, double-blind, placebo-controlled phase 3 trials: the ENLIGHTEN-Fibrosis trial in patients with noncirrhotic MASH with fibrosis (F2-F3) and the ENLIGHTEN-Cirrhosis trial in patients with MASH with compensated cirrhosis (F4).

What role does early diagnosis play in managing MASH, and how might new treatments like pegozafermin change the outlook for patients?

NA: Early diagnosis of MASH is critical because it gives patients time to make lifestyle changes and explore treatment options to prevent disease progression. Therapies, like pegozafermin, could offer patients potent antifibrotic effects, favorable safety and tolerability profile, and convenient dosing schedules, which could potentially provide benefits to patients by addressing the liver pathology in a convenient, well-tolerated way that would support them staying on therapy.

What advice would you give to someone who has been recently diagnosed with MASH and is feeling overwhelmed about managing their condition?

NA: For this first time, MASH treatment is making progress. Following the first approval of a therapeutic option earlier this year, there are additional treatment options being studied in enrolling clinical trials that not only offer antifibrotic effects and improve outcomes but that also ensure tolerability and dosing convenience making it easier for patients to stay on treatment. People with MASH should feel empowered to talk to their doctors about options beyond lifestyle modifications.