With diagnostics being integral in the detection, confirmation, and monitoring of disease, the lack of adequate and available diagnostics for metabolic dysfunction-associated steatohepatitis (MASH) studies can make aspects of a trial more laborious and cripple the conduct of a clinical study.
MASH is a culmination of steatosis, inflammation, and fibrosis, and is also associated with comorbidities such as obesity and diabetes. With distinct mechanisms being required to address each facet of the disease, MASH can be complicated to treat.
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In March 2024, Madrigal Pharmaceuticals’ Rezdiffra (resmetirom), a type of thyroid hormone receptor beta (THR-beta) agonist, became the first and only approved therapy that does not require a liver biopsy for the treatment of patients with MASH and Stage 2–3 fibrosis.
Other approaches that are in development include fibroblast growth factor (FGF) mimetics such as FGF21-targeting candidates like Akero Therapeutics’ efruxifermin and 89bio’s pegozafermin, as well as glucagon-like peptide-1 receptor agonists (GLP-1-RAs) like Eli Lilly’s retatrutide, which also targets GIP and glucagon.
The consensus among experts is that the treatment of MASH will require the use of combination therapies. Though the therapeutic landscape is small, with only one approved drug to date, studies are ongoing and inching closer toward filling the treatment landscape despite the obstacles faced in trial design.
Distinguishing the stages of fibrosis
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By GlobalDataThe presence of comorbidities like obesity, diabetes, and hypertension, and their significant overlap with MASH creates challenges with clinical study design, such as inclusion and exclusion criteria, says Dr. Mohammad Derakhshan, associate medical director at Parexel.
Patients with MASH have different underlying pathophysiologies and their categorisation has not extended beyond grouping them as those with lean MASH and patients with other types of MASH. For example, patients in the Hispanic community have higher frequencies of the PNPLA3 gene, which leads to the “pineapple phenotype,” says Pol Boudes, CMO at Cambridge, Massachusetts-based Rectify Pharma. These patients are predisposed to a higher risk of progression and cirrhosis, which leads to a higher risk for decompensation, he elaborates.
Furthermore, the lack of visible symptoms particularly when it comes to determining the stage of fibrosis is a challenge with MASH, says Boudes. Most patients are not aware that they have stage 4 fibrosis at diagnosis, and this comes down to a lack of awareness about the symptoms, he explains. “In terms of medical need, the most pressing need would be to better differentiate F4 and F3 [stages of fibrosis],” says Boudes.
The barrier of requiring a liver biopsy
While there is ongoing research to develop better tools like biochemical markers to differentiate fibrosis stage in MASH patients, the only standard currently used in MASH clinical studies involves liver biopsies at the time of diagnosis. Experts agree this can be strenuous and difficult for the participant and the physician.
“It is not so much that the biopsy is difficult, but it depends on your patient,” says Boudes. Biopsies can be difficult for obese patients and those at an advanced stage of fibrosis.
Requiring a liver biopsy is a significant barrier in clinical trials, particularly when it comes time to take the second biopsy at the end of the study, says Dave Happel, CEO of Sagimet Biosciences. Moreover, while it is well understood that requiring a liver biopsy creates a barrier, it is still the best way to understand if the disease has progressed or regressed, Happel explains.
Happel says patients often drop out from trials when they require additional liver biopsies. “And I think that is why you overpower these studies so significantly: in anticipation of people dropping out because they don’t want to get the biopsy,” says Happel. Furthermore, it is why Sagimet has designed its Phase III FASCINATE-3 study (NCT06594523) of fat inhibitor denifanstat to include an 18-month enrollment period, he explains.
Alan Baldridge, senior development director in Hepatology at ICON, says the field is between a rock and a hard place when it comes to the need and use of liver biopsies in MASH studies. “It [liver biopsies] is uncomfortable, invasive, and it has some risks associated with it so our patients don’t particularly care for it,” he says.
Additionally, liver biopsies are associated with high variability, in terms of intra and inter-reader variability, the “waxing and waning” nature of the disease, and variability depending on where the liver sample is taken, Baldridge explains.
With industry consensus on the limitations of liver biopsy, there have been advances in non-invasive or minimally invasive markers, such as serum biochemical markers or imaging markers of fibrosis, which can provide more information about the liver.
Minimally invasive and non-invasive tests such as magnetic resonance imaging (MRI) scans are more sensitive in MASH because a physician can see a more holistic picture of the liver as opposed to a segment of the liver collected through biopsy, says Baldridge. The drawback, however, is that regulatory bodies are “less keen” on validating these markers for clinical trials, he adds.
The use of liver biopsy is ultimately a question of context, says Boudes. “As a clinician coming back to a standard case [of MASH], an endocrinologist will not push for liver biopsy because it makes no sense to your medical practice,” says Boudes. Baldridge agrees, noting that in clinical care, less than 10% of MASH patients will get liver biopsies to confirm their diagnosis.
However, it is important to distinguish that while standard practice would gravitate towards the minimally invasive FibroScan or MRI diagnostics, clinical trials are and must be biopsy-driven by necessity, says Baldridge.
