Beyond biopsy how noninvasive NASH tests can move the needle

 The current gold standard for evaluating the efficacy of nonalcoholic steatohepatitis (NASH) drug candidates in Ultrasound Systems Market, which involves extracting a small piece of liver tissue with a needle. However, one of the main obstacles to developing treatments for this liver condition is the invasive nature of the procedure. In addition, it permits a more straightforward method of diagnosing patients in the real world.

Dr. Scott Friedman, chief of the division of liver diseases at Mount Sinai's Icahn School of Medicine, asserts, "There is a sense of inevitability that biopsies will be replaced." Dr. Jean-François Dufour, director of the Digestive Disease Centre in Lausanne, Switzerland, adds, "We are pushing hard to go away from biopsies."

Friedman makes the observation that it is highly unlikely that any one method will replace biopsies, despite the fact that a wide range of noninvasive NASH tests are currently available and being studied. This is because NASH is extremely multifactorial: it can start as fat accumulation in the liver, which causes inflammation and ballooning in the liver. It can then progress to fibrosis and cirrhosis. There are numerous unanswered questions: Do we have sufficient data to make these decisions, and what is the most effective method for combining the various tests?

There are three types of noninvasive NASH tests that are tracked by GlobalData's Medical Intelligence Center Clinical Trials database. There are nine clinical research studies about medical devices in NASH, and there are three planned. Noninvasive tests come in three varieties. According to Dr. Zobair Younossi, president of Inova Medicine Services, the first uses a clinical algorithm to generate a score based on a patient's medical record. The FIB-4 scoring system, which takes into account a patient's age, platelet counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, is one example.

However, according to Dr. Sven Francque, chairman of the division of gastroenterology and hepatology at Antwerp University Hospital, FIB-4 might be more appropriate as a test for a population than for an individual. He adds that the four parameters used in FIB-4 can change from day to day and from laboratory to laboratory.

According to Younossi, the second category includes radiologic noninvasive tests that measure liver stiffness. He explains that elastography measures liver stiffness, which may be correlated with the stage of fibrosis. Ultrasound is used in transient or shear wave elastography, whereas MRI-based imaging is used in magnetic resonance elastography (MRE). However, according to Francque, liver stiffness is not fibrosis and is influenced by a variety of factors, such as nutritional status.

However, liver stiffness is influenced by a variety of factors, including nutritional status, and is not fibrosis.

Younossi adds that Sven Francque Imaging techniques measure liver fat and stiffness. Controlled attenuation parameter (CAP) and MRI Proton Density Fat Fraction (PDFF) are two examples of ultrasound-based approaches in this case. Francque explains that liver inflammation and ballooning, which can result in fibrosis, is the most important metric in NASH, not liver fat.

An MRI-based diagnostic imaging biomarker of the liver called iron corrected T1 (cT1) is being studied for NASH. Dufour explains that it uses an oxidant and oxidative stress to measure liver values, which is a logical mechanism. He points out, however, that this strategy has only been used as a secondary endpoint in a few Phase II trials up to this point. He asserts that although cT1 is useful for measuring inflammation and providing some indication of ballooning, it performs best when used in conjunction with MRI-PDFF.

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A possibility for a serum-based noninvasive NASH test The final class of noninvasive tests is serum-based. According to Younossi, one example is the Enhanced Liver Fibrosis (ELF) test, which measures aspects of fibrogenesis and fibrolysis. He adds, "The ELF tests are excellent and simple to use." He points out that the need to raise awareness about the use of ELF tests is a bigger challenge than getting payer coverage for them. He explains that although ELF tests are available in Europe and Asia, they have only recently arrived in the United States.

The key is a combination strategy. Younossi claims that: When taken as a whole, each of these three types of tests has a low positive predictive value but a high negative predictive value for excluding cirrhosis. These tests can be included in an algorithm that begins with FIB-4 and ends with ELF or transient elastography. In order to include or exclude cirrhosis, these combinations can maximize both positive and negative predictive values.

However, Francque asserts, because NASH is so multifactorial, a patient's disease status and progression may require as many as four or five noninvasive tests to get a complete picture. One or two parameters can lead to an incorrect conclusion.

Functional tests under investigation exist outside of these three categories. Francque explains that one of their advantages is that they can measure liver function before fibrosis has changed significantly. Friedman adds, "As can be seen in pulmonology, the drugs that receive regulatory support are those that improve clinical outcomes or function and do not cause scarring."

Friedman cites a c13 substrate-centered functional test. He explains that the liver is healthier the faster this substrate is broken down. However, according to Francque, data can be affected by technical limitations of functional tests, such as factors like intestinal absorption.

Additionally, breath tests, in which various molecules in the breath are measured, are being investigated as a functional test for NASH. According to Dufour, locating the compound associated with NASH is essential. However, he adds, there are concerns regarding the accuracy of a breath test in comparison to a blood sample. Francque makes the observation that breath tests are likely to be utilized at a specialized level and are not intended for diagnostic convenience.

Liver biopsies are imperfect for a number of reasons. According to Younossi, they can cause pain, bleeding, and other complications. He points out that not only is the procedure expensive, but pathologists are also needed to analyze the samples, which increases the cost. The location of the needle that was injected can also affect whether a sample gives a positive or negative reading. In addition, the pathologic readings that pathologists use to diagnose NASH vary widely

Credit: Shutterstock A number of studies are looking into the possibility that analysis could be taken over by artificial intelligence (AI). Younossi says that AI can show whether a change in the patient's biopsy sample is real instead of being affected by pathologist variability. Francque adds that AI enables standardized trial analysis.

Friedman asserts that in order for AI to be quantitative and objective, it must have a large amount of data, but AI does not eliminate biopsies from the diagnostic process. According to Younossi, pathologists will still be required to "train the machines" about the pathologic characteristics of NASH. Friedman adds, "We don't yet know if a digital method will remove some of the bias from sample variability."

Biopsies are essential Friedman asserts that, at least for the time being, biopsy-related measures will likely continue to be crucial primary endpoints in Phase III clinical trials. However, he adds that the FDA will want a drug that not only improves organ function but also improves a patient's mood, which may increase their chance of survival. Additionally, a biopsy cannot provide this.

According to Friedman, the approval of a NASH drug based on biopsy data is likely to be conditional. He explains that as soon as the product reaches the market, the company will be required to continue reporting data on quality of life, life expectancy, and reduced disease complications.

The industry needs to find ways to increase the amount of information it can extract from biopsies in addition to the search for improved noninvasive NASH tests. Francque asserts, "We are not utilizing all of the information we can get because these tests] give a direct insight into the liver." We have a lot of data, but only simple methods for analyzing it.

There are still a lot of unanswered questions. It is crucial for NASH research and eventually the introduction of approved drugs to find ways to improve the efficacy of noninvasive tests. A patient's NASH status can be staged with noninvasive tests, allowing clinicians to offer a prognosis. Younossi explains that they are able to diagnose the fibrosis stage of a patient's liver and monitor the progression or improvement of their liver disease.

According to Younossi, the fact that none of the noninvasive tests currently have definitive data demonstrating that they can be used to reliably monitor patients is perhaps the greatest obstacle at the moment. He adds that additional outcomes data are required to determine the optimal test-measure robustness combination.

There are no conclusive data demonstrating that any of the noninvasive tests can be used to reliably monitor patients.

Zobair Younossi Dufour adds, "We also don't have a reliable diagnostic tool yet for NASH." He explains that fibrosis does not increase the likelihood of a diagnosis of NASH, making NASH more complicated. However, Younossi points out that fibrosis is crucial because it is the most significant indicator of mortality in NASH—patients in Stage 2 or higher are more likely to die.

Even though there are still holes and limitations in the noninvasive tests that are available, this does not mean that they should not be used right now. The key is awareness; According to Younossi, FIB-4 is the first noninvasive test that general practitioners and endocrinologists can use on patients they suspect may have NASH. Other tests can follow.

Friedman asserts that one of the most common mistakes made by developers of noninvasive tests is exaggerating their approach. He adds that clinical outcomes may not be correlated with data from a small population. In point of fact, locating a biopsy replacement is not so much a matter of finding a single needle in a haystack as it is of determining which approaches offer the most effective alternative.