Q&A: MASH experts emphasize using noninvasive tests to assess response to Rezdiffra
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Key takeaways:
- Experts recommend confirming MASH diagnosis by assessing steatosis via ultrasound or FibroScan.
- MRI-proton density fat fraction reduction alone may confirm treatment response.
With the FDA label for Rezdiffra excluding the need for liver biopsy, experts proposed recommendations to “fill the gap” on how to leverage noninvasive tests to assess treatment response in metabolic dysfunction-associated steatohepatitis.
This landmark subpart H FDA approval of Rezdiffra (resmetirom, Madrigal Pharmaceuticals) in March for the treatment of patients with MASH and stage 2 or 3 fibrosis was largely based on successful data from the ongoing phase 3 MAESTRO-NASH trial. Despite the huge win this approval represents, Mazen Noureddin, MD, MHSc, professor of medicine, hepatologist and director at Houston Methodist Hospital, told Healio it also presents prescribers with certain challenges and questions.
“It became clear that liver biopsy was not required, which left a vacuum in the community, practices and the field about what to do in terms of noninvasive tests,” he said. “We wanted to fill that gap with investigators in [the phase 3 MAESTRO-NASH] trial, as well as other trials that have been studying MASH for over a decade, so people can adapt in clinical practices.”
As part of an expert panel, Noureddin and colleagues in Clinical Gastroenterology and Hepatology outlined clinical application recommendations for initiating and monitoring patients treated with resmetirom for MASH and moderate to noncirrhotic advanced fibrosis. Recommendations included guidance on how to identify the intended treatment population, assess treatment response and safely discontinue treatment among applicable patients.
In a Healio interview exclusive, Noureddin weighs in on the most significant takeaways from the expert panel recommendations, upcoming research and what the future of MASH treatment looks like.
Healio: What are the key takeaways from these expert recommendations?
Noureddin: I just want to emphasize that we relied on the MAESTRO-NASH phase 3 data published in The New England Journal of Medicine in terms of our recommendation. This came with a focus on the FDA label and supporting this evidence with recent data, such as the NIMBLE study published in Nature Medicine. There are variations in noninvasive tests that are still debatable and there is always room for gray areas.
The first step in considering Rezdiffra is you need to confirm that the patient has metabolic dysfunction-associated steatotic liver disease. This is usually done by steatosis assessment via ultrasound or FibroScan and ruling out all other causes of liver disease, in particular alcohol-related liver disease as well as autoimmune hepatitis. The next step is to tease out if the patient has significant and advanced fibrosis. At the same time, we are ruling out cirrhosis using noninvasive tests.
One of most obvious tests is transient elastography between 10 kPa and 20 kPa, due to its availability and price. We emphasize between 10 kPa and 20 kPa, especially between 15 kPa and 20 kPa, because you have to make sure that patients are not cirrhotic and especially that they do not have portal hypertension. Using a platelet count of less than 140 – an exclusion criterion in the MAESTRO-NASH trial – can be a hint of these advanced cases.
We also use other biomarkers such as the Enhanced Liver Fibrosis (ELF) and composite scores as well as published scores (e.g. FAST and MAST) based on AASLD guidelines.
Healio: How should providers select their target population?
Noureddin: The sweet spot is patients who have what we call at-risk MASH or significant and advanced fibrosis. If there is a historical biopsy within the last 3 years showing F2 or F3, you can treat this patient, making sure they are not cirrhotic. If biopsy is not available in these MASLD/MASH patients, the money is where their [liver] stiffness is.
This should be assessed in all cases based on noninvasive tests. If you can confirm they have an equivalent of F2 to F3 fibrosis, they should be treated.
Healio: Who should not be treated with Rezdiffra?
Noureddin: This should not be used in cirrhotic patients, especially those with portal hypertension. This is not because it is contraindicated, but because we do not have data on them. Indeed, the MAESTRO outcome study is ongoing right now to see if these patients will benefit from Rezdiffra.
There are light cautions with some medications, such as gemfibrozil because of the enzyme inhibitions, but overall it’s a very safe and well-tolerated drug that we feel comfortable giving to our patients.
Healio: How is treatment response assessed and what markers confirm treatment is working?
Noureddin: We emphasize using noninvasive tests, and hepatologists and gastroenterologists have made clinical judgment over the years whether patients are improving or not. Luckily, because of the use of transient and MR elastography, we gain a lot of experience.
We use alanine aminotransferase dropped by 20% or two less than 17 units, transient elastography stiffness dropped by 30% and MRI-proton density fat fraction (PDFF) reduction by 30%; MRI-PDFF was the best predictor of response. I also want to emphasize that CAP, which measures steatosis in transient elastography, is also helpful and has shown correlation with histology in the MAESTRO-NASH trial. In general, PDFF by itself could be sufficient; otherwise, you might want to use two noninvasive tests to confirm that patients are improving.
I want to caution people to be a little bit careful with the transient elastography and ALT and make sure you have a clear picture. There were some patients who improve in histology, but they did not have such improvement on transient elastography or ALT, so combining noninvasive tests or using hierarchy such MRI-PDFF is also important.
Healio: What safety considerations should providers keep in mind and in what scenario should treatment be discontinued?
Noureddin: I have tried the medicines throughout the clinical trials, including in patients with cirrhosis in certain trials where we enrolled large number of patients. We have not seen safety signals, but I want to mention a couple of things in the drug label.
There was a case mentioned of hepatic toxicity: One case out of 2,000 patients but there was no black box warning. In my opinion, it was a case that was entered from one of the studies that did not require liver biopsy and that case was likely autoimmune hepatitis, which led to some concerns.
There was a slight increase in gall bladder side effects, but in a range similar to what I see in other MASLD patients.
Healio: What additional research is planned or currently ongoing for Rezdiffra?
Noureddin: There are two main studies: MAESTRO-NASH is still ongoing, which is why we are telling physicians to not jump and stop treatment because the current phase 3 study is going to continue until 54 months. The MAESTRO outcome study is the cirrhotic study.
The most important data that is going to be updated periodically are response data. Stay tuned for that.
Healio: What advice would you give to providers caring for this patient population?
Noureddin: It is an exciting time and the future is bright as this is the first FDA-approved liver-directed therapy.
I often get questions about glucagon-like peptide-1 agonists, their use and if they should be using GLP-1s as a first-line therapy for MASH. My answer is not at the current time. GLP-1s are making their way and they still have to show that they can improve fibrosis in phase 3 studies. I think they will be great to add to the current therapies, as well as other promising ones like Fibroblast growth factor-21.
The future will probably lead to combination therapy, but right now Rezdiffra is the only FDA-approved drug for directed therapy. It’s safe and you don’t need a liver biopsy. We finally have an option for our patients.
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