Liver biopsy—a process whereby a small piece of liver tissue is extracted via a needle—is the reigning gold standard to measure the efficacy of nonalcoholic steatohepatitis (NASH) drug candidates in clinical trials. However, the procedure’s invasive nature is one of the main challenges in developing therapies for this liver condition. Moreover, it leaves room for a more straightforward way to diagnose patients in the real world.
There is growing momentum and a sense of inevitability that biopsies will be replaced, notes Dr Scott Friedman, chief of the division of liver diseases, Icahn School of Medicine at Mount Sinai. “We are pushing hard to go away from biopsies,” adds Dr Jean-François Dufour, director, Digestive Disease Centre in Lausanne, Switzerland.
While there is a wide variety of noninvasive NASH tests available and under investigation, it is unlikely a single approach will take over biopsies, Friedman notes. This is due to NASH being intensely multifactorial—it starts off as fat accumulating in the liver, which triggers liver inflammation and ballooning, and can progress to fibrosis and then cirrhosis. There are many questions yet to be answered: what is the best way to mix and match the different tests, and do we have enough data to make these decisions?
Three types of noninvasive NASH tests
GlobalData’s Medical Intelligence Center Clinical Trials database tracks nine medical device studies in NASH at the clinical research stage and three that are being planned. There are three types of noninvasive tests. The first uses some type of clinical algorithm to produce a score, taking into consideration a patient’s medical record, says Inova Medicine Services president Dr Zobair Younossi. One example is the FIB-4 scoring system that uses a combination of a patient’s age and platelet counts, as well as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels.
But FIB-4 might be best as a test at the population level rather than for individuals, says Antwerp University Hospital division of gastroenterology and hepatology chairman Dr Sven Francque. FIB-4 relies on four parameters that can fluctuate based on the day, and depends on which laboratory is running the test, he adds.
The second group is noninvasive tests that are radiologic, which measures liver stiffness, Younossi says. Elastography measures liver stiffness, which can correlate to the stage of fibrosis, he explains. Transient or shear wave elastography is based on ultrasound, while magnetic resonance elastography (MRE) is based on MRI-based imaging. But liver stiffness is not fibrosis, and is affected by various elements like nutritional status, Francque notes.
But liver stiffness is not fibrosis, and is affected by various elements like nutritional status.Sven Francque
Imaging approaches measure stiffness and liver fat, Younossi adds. Here, controlled attenuation parameter (CAP) is an example of an ultrasound-based approach, and MRI Proton Density Fat Fraction (PDFF) is an example of an MRI-based approach. The issue is that liver fat is not the most important metric in NASH—it is liver inflammation and ballooning, which can lead to fibrosis, Francque explains.
Iron corrected T1 (cT1) is an MRI-based diagnostic imaging biomarker of the liver under investigation for NASH. It has a logical mechanism in that it uses an oxidant and oxidative stress to measure liver values, Dufour explains. But so far, this approach has only been seen in some Phase II trials as a secondary endpoint, he notes. cT1 has value in measuring inflammation and some indication of ballooning, but is ideal in combination with MRI-PDFF, he says.
Serum-based noninvasive NASH test an option
The final group of noninvasive tests are serum-based. One example is the Enhanced Liver Fibrosis (ELF) test that measures components of fibrogenesis and fibrolysis, Younossi says. “ELF tests are excellent and easy to use,” he adds. While getting payer coverage can be challenging, a bigger difficulty with ELF tests is the need to raise awareness about their use, he notes. While ELF tests have been available in Europe and Asia, they only arrived in the US in the past year, he explains.
A combination approach is key. According to Younossi: “When you look at these three test types individually, they offer a good negative predictive value to exclude cirrhosis, but they have poor positive predictive value. These tests can be taken as a part of an algorithm that starts with FIB-4 and is followed by transient elastography or ELF. These combinations can optimise both positive and negative predictive values to include or exclude cirrhosis.”
But since NASH is so multifactorial, not just a couple, but four or five noninvasive tests might be needed to paint a fuller picture of a patient’s disease status and progress, Francque says. “[Using] one or two parameters can give the wrong conclusion.”
Functional tests under investigation
Outside these three groups are functional tests. Their advantage is that they can measure liver function even before there’s any notable change in fibrosis, Francque explains. “As seen in pulmonology, when you look at what drugs receive regulatory support, they are drugs that improve clinical outcomes or function and not scarring,” Friedman adds.
Friedman points to a functional test that centres on c13 substrates. The quicker this substrate is broken down, the healthier the liver, he explains. But there are technical limitations to functional tests, such as factors like intestinal absorption, that can impact data, Francque says.
Breath tests are also being investigated as a functional test for NASH, where they measure different molecules in the breath. The key is finding the compound associated with NASH, Dufour says. But there are questions if a breath test will provide robust information compared to a blood sample, he adds. It is likely that breath tests will be used at a specialised level, and not designed for diagnostic convenience, Francque notes.
Biopsies are imperfect
Liver biopsies have several issues. They are associated with bleeding and pain, and could lead to other complications, Younossi says. Not only is the procedure expensive, but the need for pathologists to analyse samples adds to the cost, he notes. A sample’s positive or negative reading can also depend on where the needle was injected. Moreover, there is variability among pathologists in their pathologic readings to diagnose NASH.
Some studies are investigating the potential for artificial intelligence (AI) to take over the analysis. AI can help demonstrate whether any change in the patient’s biopsy sample is real, rather than being subject to pathologist variability, Younossi notes. AI allows standardised analysis across trials, Francque adds.
But the key with AI is that it needs to have high amounts of data to be quantitative and objective, Friedman says, adding AI does not remove biopsies from the diagnostic process. Pathologists will still be needed to “train the machines” about pathologic features of NASH, Younossi notes. “We don’t know yet if a digital method will remove some of the bias from sample variability,” Friedman adds.
In the realm of clinical trials, biopsy-related measures will still likely be critical primary endpoints in Phase III trials, at least for now, Friedman says. That said, the FDA will want a drug that improves how a patient feels in addition to improved organ function, which can lead to better survival, he adds. And this is beyond the realm of what a biopsy can offer.
If a NASH drug is approved based on biopsy data, the approval will likely be conditional, Friedman says. This means that the company will have to keep reporting data on quality of life, length of life, and reduced disease complications once it reaches the market, he explains.
Alongside the hunt for improving noninvasive NASH tests, the sector needs to find ways to improve the amount of information it can extract from biopsies. “[These tests] give a direct insight in the liver, and we are not exploiting all the information we can get,” Francque says. “We have a huge amount of data, but only simplistic analysis methods.”
Many questions remain
Finding ways to optimise efficacy of noninvasive tests is critical in NASH research, and the eventual rollout of approved drugs. Noninvasive tests can stage a patient’s NASH status, which can then allow clinicians to provide a prognosis. They can diagnose the fibrosis stage of a patient’s liver, and monitor progression or improvement of their liver disease, Younossi explains.
Perhaps the biggest challenge at present is that none of the noninvasive tests have definitive data to show they can be reliably used to monitor patients, Younossi adds. Further, there is the need for more outcomes data to find the best combination of tests and measure robustness, he says.
None of the noninvasive tests have definitive data to show they can be reliably used to monitor patients.Zobair Younossi
“We [also] don’t have a reliable diagnostic tool yet for NASH,” Dufour adds. NASH is complicated in that fibrosis tells the patient’s prognosis but does not add to the diagnosis of NASH, he explains. But, Younossi notes fibrosis is key as it is the most important predictor of mortality in NASH—patients at Stage 2 or higher have increased risk of mortality.
While there are still gaps and limitations to existing noninvasive tests, this does not mean they should not be used today. Awareness is key; FIB-4 is the first step that general practitioners and endocrinologists can use for their patients they suspect might have NASH, and other noninvasive tests can follow, Younossi says.
As for noninvasive test developers, a common mistake among them is overhyping their approach, Friedman says. Data from a small population size may not correlate to clinical outcomes, he adds. Indeed, in terms of finding a biopsy replacement, it is not so much finding a single needle in a haystack but discovering which combinations of approaches offer the best alternative.
- There are several types of noninvasive NASH tests, but not a single approach will replace biopsies. It will be a combination of analyses to paint a full picture of a patient’s disease status. While noninvasive tests are imperfect, it is not a reason to not use them to seek disease insight.
- AI can be an option in addressing pathologist variability in analysing biopsy samples. But the strength of the approach will depend on the volume of data, and pathologists still having to establish standards.
- In clinical trials, biopsies will remain essential for an investigational drug to reach the market. But regulatory bodies are likely to seek real-world data for the candidate to secure full approval.