MASH candidates make a splash after first drug approval

Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease that can become life-threatening when paired with other metabolic diseases like diabetes. After years of failed clinical trials, U.S. regulators finally approved the first drug to tackle MASH earlier this year. Now, more clinical advancements have been pouring in.

American biopharma Madrigal Pharmaceuticals’ drug Rezdiffra received accelerated approval for the treatment of MASH from the U.S. Food and Drug Administration (FDA) after a phase 3 trial saw statistically significant improvement compared to the placebo. There was a reduction in non-alcoholic fatty liver disease (NAFLD) activity score – a measure to evaluate MASH treatment response – and fibrosis improved in patients. These two endpoints were consistent in the 1,759 patients regardless of age, gender, type 2 diabetes status, or fibrosis stage.

How does MASH affect people?

When the body begins to store fat in the liver, it can cause inflammation resulting in liver disease. MASH is the advanced form of liver disease. Chronic inflammation can scar the tissues, which can lead to cirrhosis (liver damage), and even liver failure.

“Most people don’t really know what metabolic means even if you’re in the scientific field but it is the more accurate term to define disease. When people talk about non-alcoholic steatohepatitis or NASH, you’re adding some level of qualifier or value or judgment.”
Tania Kamphaus, associate vice president of Science Partnerships and director of Patient Engagement at the Foundation for the National Institutes of Health (FNIH)

As the progressive disease affects more than 115 million people worldwide, the FDA nod is a step up towards treating the condition. While the exact cause is unknown, it is often linked to high cholesterol levels, insulin resistance, obesity, and high blood pressure. And 20% of those who have metabolic dysfunction-associated steatotic liver disease (MASLD) – chronic liver disease that affects a quarter of the adult U.S. population – will develop MASH.

From NASH to MASH: what’s up with the name change?

Only recently was the term MASH rebranded from NASH – nonalcoholic steatohepatitis – by the scientific community.

“Most people don’t really know what metabolic means even if you’re in the scientific field but it is the more accurate term to define disease,” said Tania Kamphaus, associate vice president of Science Partnerships and director of Patient Engagement at the Foundation for the National Institutes of Health (FNIH). “When people talk about non-alcoholic steatohepatitis or NASH, you’re adding some level of qualifier or value or judgment.”

The term ‘non-alcoholic’ is inaccurate as well since “some amount of alcohol is permissible,” because there is a certain threshold, explained Kamphaus. The word ‘metabolic’ more accurately defines the disease.

“The patient perspective on this is slightly different because most patients understand ‘non-alcoholic’ easily but everybody doesn’t understand what metabolic-associated dysfunction is; it needs an extra explanation. I think from a lay perspective, the name change is a little bit challenging and would require some level of adoption and understanding of what the disease is,” said Kamphaus. “But from the scientific rigor perspective, it was voted on by a few societies as the most accurate way to describe the disease.”

Could Viking Therapeutics’ VK2809 beat Rezdiffra?

To overcome MASH symptoms, Rezdiffra reduces fat in the liver as it is a thyroid hormone receptor-beta (THR-beta) agonist. An agonist is a drug that imitates a hormone when it binds to the hormone’s specific receptor. THR-beta is a hormone responsible for lowering cholesterol levels.

California-based Viking Therapeutics has also come up with a pill that works like Rezdiffra to treat MASH. When treated with VK2809, 69% of patients had their condition resolved in a phase 2 trial, compared to the 29% who received a placebo. More than half of those who were given the drug saw an improvement in their fibrosis scores and 44% had MASH resolution as well as improvement in fibrosis. This is significantly higher than in the placebo group, where 34% and 20% of patients saw changes respectively.

Moreover, Viking’s drug seems to have beat Rezdiffra when it came to fibrosis improvement. These results confirm top line data released a month ago that stated that up to 85% of the patients experienced at least 30% relative decline in liver fat.

GLP1 agonists survodutide and tirzepatide progress to treat MASH

Meanwhile, GLP1 agonists have joined the race to defeat MASH. GLP1 agonists, which work by mimicking the hormone glucagon-like peptide 1 to stimulate insulin production, and in turn, lower blood sugar, have gained popularity in recent times as a treatment for diabetes and obesity.

The GLP1 drug survodutide, born out of Zealand Pharma’s collaboration with German multinational Boehringer Ingelheim, demonstrated a 64.5% improvement in fibrosis in patients with F2 and F3 stages of fibrosis – which result in moderate to advanced scarring – in a phase 2 trial. This data was presented at the European Association for the Study of the Liver Congress (EASL) 2024 in Italy, less than two weeks ago.

“There are lots of new medicines and treatment regimens coming down the pike. There are many other drugs that are going to come up for approval, which are showing promising results.”
Tania Kamphaus

As for pharma giant Lilly’s tirzepatide, which has long been in the GLP1 game since it bagged the FDA nod for diabetes and obesity, unveiled phase 2 results recently. 51.8% of the patients who took 5 mg of the drug “achieved an absence of MASH” by the end of 52 weeks. 62.8% and 73.3% of those who were given 10 mg and 15 mg of the drug respectively, were also cured of the disease compared to 13.2% of patients in the placebo cohort.

U.S. clinical trials of efruxifermin, pegozafermin, and ION224 aim to reverse MASH

That’s not all. California-based Akero Therapeutics is also in pursuit of MASH drug success. Its candidate efruxifermin (EFX) has been engineered to mimic fibroblast growth factor 21 (FGF21), a hormone that regulates multiple metabolic pathways. The drug met the primary endpoint in a phase 2b study when fibrosis in 75% of patients improved by at least one stage compared to 24% of patients who took the placebo. This is a comeback from a failed study late last year.

However, three patients left the study after 15 “serious adverse events” were reported during the trial.

Another California-based biopharma that is developing a drug for MASH is 89bio. Its phase 3 candidate pegozafermin is similar to Akero’s EFX. It is an FGF21 analog that has been engineered with mutations that are designed to activate the FGF21 hormone. 48-week data was presented at EASL. Hank Mansbach, chief medical officer (CMO) of 89bio said that the results “highlight the observed long-term efficacy, tolerability, and sustained improvement in key liver health markers,” which will be validated in phase 3, in a press release.

RNA-targeted therapeutics company Ionis Pharmaceuticals’ drug has a slightly different approach to agonists. Its drug ION224 is designed to decrease the production of the enzyme diacylglycerol acyltransferase 2 (DGAT2), which aids in fat deposition in the liver.

A phase 2 trial met its primary endpoint of liver histologic improvement and its secondary endpoint of MASH resolution. 44% of patients treated with 120 mg of the drug had at least a 50% relative reduction in fat buildup in the liver compared to 3% who were given the placebo.

These clinical advancements are a stark improvement from how things were looking for people with MASH only a while ago. When American biotech Intercept’s Ocaliva – a drug that controls bile enzyme production – was struck down by the FDA last year due to safety and efficacy concerns for the second time, it was a blow to the MASH community as Intercept had been the closest to the finish line for a long time.

FNIH’s NIMBLE project sets out to improve MASH diagnosis

Besides, finding ways to better diagnose MASH has been challenging too. People are typically expected to get a biopsy done, which is an invasive, painful, and expensive method. To add to that, biopsies have a screen failure rate that crosses 80%. Researchers at the FNIH have been working on shifting to a less invasive means with the help of blood and imaging biomarkers.

The NIMBLE project aims to validate and test biomarkers that can detect the disease in patients as well as tell what stage a patient is in.

“Our goal was very clear from the beginning that we really wanted to move the needle forward; not to discover something new but to generate enough evidence that would be good for the FDA to consider qualifying these biomarkers under their Biomarker Qualification program. So that’s how we set it out,” said Kamphaus, who is a part of the study.

If doctors were able to test patients for MASH with the help of an ultrasound or a magnetic resonance imaging (MRI) scan, it could either eliminate the need for a biopsy or at least narrow down the patient population that would need a biopsy.

Promising data from the study calls for further biomarker research. The different biomarker tests including the enhanced liver fibrosis (ELF) blood test, which checks for three molecules that signal fibrosis, and OWLiver, were able to detect MASH in patients who had the disease and were at-risk for developing it.

“Some biomarkers are really good at looking at fibrosis stages, so the more fibrotic, the better the biomarker’s ability to predict it. And some biomarkers are better at looking at at-risk MASH – F2 AND F3. So, different biomarkers depending on what they are testing and what they’re looking at, are good at predicting the stage of the disease. That is a really good outcome from this because we can use them in combination to really isolate a particular population or stage of MASH,” said Kamphaus.

As NIMBLE gears up for stage two of the project where the biomarkers will be tested in people with a range of metabolic disorders to confirm the results of the first phase, Kamphaus thinks that Rezdiffra’s FDA win is one for the books.

“We’ve been waiting for this for a long time to come,” said Kamphaus. “There are lots of new medicines and treatment regimens coming down the pike. There are many other drugs that are going to come up for approval, which are showing promising results. So, this is a really good time for MASH therapeutics.”