Why Are So Many Promising NAFLD Treatments Failing in Clinical Trials?

Nancy S. Reau, MD


April 17, 2023

It is estimated as much as 40% of the world could be affected by nonalcoholic fatty liver disease (NAFLD), among whom some are at risk for the progressive form nonalcoholic steatohepatitis (NASH). The ever-growing incidence of NAFLD has corresponded with the development of several therapeutic agents meant to treat it, none of which have yet been approved. In fact, most of these investigational products do not progress to phase 3 trials, failing to achieve the endpoints approved by regulatory agencies.

To better understand what has hindered the development of treatments in this disease space, Medscape contributor Nancy S. Reau, MD, chief of the hepatology section at Rush University Medical Center in Chicago, spoke with Vlad Ratziu, MD, PhD. In addition to serving as a professor of hepatology at the Sorbonne Université and the Hôpital Pitié-Salpêtrière Medical School in Paris, France, Dr Ratziu is co-editor of the Journal of Hepatology and has written of the promise and challenges inherent to developing treatments for NAFLD.

What's Behind the Failure of Investigational Treatments?

Multiple drugs have been evaluated for the treatment of NAFLD. Why do most agents fail to progress from phase 2 to phase 3 trials? Or from phase 3 to approval?

There are several reasons why some of these drugs had to be stopped during clinical development. Obviously, a lot were stopped because the results of the phase 2 trials were negative or not considered sufficiently positive. There are a few instances where the drugs were stopped despite clear hints of efficacy. The priorities for the drug companies that develop these products were suddenly changed and reoriented to other diseases.

An important reason why some phase 2 trials failed to show sufficient efficacy is because they were either underpowered in terms of sample size or too short in duration to show some effects. This is a slowly evolving disease, and it likely takes a long time for fibrosis to disappear. It's therefore probably overly optimistic to believe that anything shorter than 1 year would result in meaningful histologic improvement.

Now, there might be some intrinsic reasons why the compounds failed, which has to do with the drugs themselves or their mechanism of action. It is also clear that some of these compounds were rushed into later phases of development without having gone through a very thorough demonstration of their efficacy in well-conducted, earlier-phase trials.

What other trial design limitations have hindered drug development for NAFLD?

Another limitation is the way we measure drug efficacy, which for the moment is based on histologic evaluation using conventional histology. Conventional pathologic reading comes with certain caveats, not the least of which being that there is insufficient clarity in the definition of the lesions that are supposed to be improved.

Then there are issues of variability between readers and also within readers (ie, intraobserver variability). This creates uncertainty in the way we assess the histologic effects of a compound, and whether we view a drug as positive or not. There are several examples where drugs that were probably efficacious were deemed ineffective in clinical trials because of the pathologic tools we're using to demonstrate efficacy.

Another important limitation is that the measurements we use for assessing histologic efficacy are based on semi-quantitative and rather insensitive histologic classifications.

There is hope that by integrating digital pathology into clinical trials, it will help us define tools that are much more sensitive to change and much more reliable and precise, as well as operator independent and automated. That will certainly help us observe histologic effects that otherwise cannot be shown using the semi-quantitative histologic classification, particularly when dealing with underpowered or short-duration trials.

Building Better NAFLD Trials

Do you think there are other ways to change clinical trials that can address these limitations outside of pathology interpretation?

At this point, I think the most impactful way to change clinical trials would be to gather sufficient information from the literature and current trials, so that in the future, we can convince the regulatory bodies that we can use noninvasive testing both for trial inclusion and for measuring a treatment effect.

Clearly, noninvasive methods would significantly speed up recruitment in these trials. In turn, this means that you can complete the trial faster, get the information required to move forward, or optimize the subsequent trials in a more reliable way, thereby contributing to the overall success of a development program.

Noninvasive tests would also provide the ability to measure drug efficacy with methods that are hopefully more sensitive to change than current histologic classifications.

Until then, biopsy will still be necessary. And although pathologists will not be replaced, artificial intelligence-powered digital pathology should provide an automated and quantitative method that is operator-independent, improving on some of the drawbacks of current pathology readings.

At least in my experience, I often see patients whom I think are good candidates get excluded because their histology doesn't support the entrance criteria. Do you think that's still going to be a problem if we eliminate histology from this process?

NASH is a complex, multifaceted disease intertwined with other comorbidities, and therapeutic trials have a rigid framework. So, patients will still screen-fail in NASH trials. But if you eliminate histology, you discard the main reason for screen failure in most, if not all, trials, so that will be certainly a big advance.

In fact, it is not eliminating the histology that is most important; patients will still be required to have a certain level of severity that will be assessed by other methods. It is eliminating the uncertainty around the histologic reading that will be progress. We have examples where the same baseline slides were read by the same pathologist, typically at the end of the trial, and there is a notable proportion of patients who are no longer deemed to be eligible based on that reread, so that clearly shows that there is an issue.

In terms of speed of recruitment, there are clear issues with the need for biopsy, because many patients do not easily accept the procedure. These are also contributing factors to the screen failure rate and the overall problems of the trials not moving fast enough when recruiting. Replacing the need for a biopsy with noninvasive tests would clearly improve an important aspect of screen failure. Biomarkers have false-negatives and false-positives, but so does the biopsy, if one takes the liver in its entirety, and not a core fragment, as the reference standard.

The agents that didn't progress in clinical trials were not excluded because of adverse events, but rather lack of efficacy. Do you think that means they actually may have a role in NAFLD?

It's entirely speculative. We can't say for sure. It might be that, fundamentally, these drugs were still not efficient enough, because most probably if a drug is very efficient, you would see histologic improvement despite all the issues related to liver biopsy sampling vulnerability and reader variability.

We cannot expect, in this disease or in any other, to have miracle drugs from the beginning of the discovery process. Improvements in efficacy will be incremental.

Not having accurate, reproducible, and sensitive ways to measure treatment effect does not help. Defining the histologic efficacy in a very stringent way (eg, total disappearance of steatohepatitis instead of improvement in disease activity) may be self-defeating as well. There is controversy regarding how valuable stabilization of fibrosis (ie, no progression) is as an endpoint vs the usually recommended one-stage reduction. Moreover, some drugs may have slower or indirect (rather than rapid and liver-directed) beneficial histologic effects, which are not visible in short-term trials. There are also data for some drugs pointing to their possible efficacy that could have been masked by some of these issues. To what degree this suggests that those compounds could be effective, in the end, is very hard to determine.

Impact of New Guidelines and Treatment Pathways

The American Association for the Study of Liver Diseases recently released updated guidelines for the diagnosis and management of NAFLD. Do you think that this will help clinical trials, either in their design or identification and recruitment?

In my view, the two are not necessarily related. Clinical practice guidelines are designed to help practitioners worldwide manage patients with NAFLD. They're not designed for improving any of the aspects of a clinical trial.

Very indirectly, they may have positive consequences on clinical trials. If they increase awareness and subsequently increase the diagnostic rate, then you bring more patients to specialist care. As a consequence, that ultimately may result in more patients being included in clinical trials.

But let's remember that these clinical trials are done in a very small number of highly specialized centers, which usually don't rely on clinical practice guidelines to operate. Additionally, even if more patients arrive to these centers, you still must pass through all the issues related to screen failure that we've discussed.

So, I don't think this will be the reason there's an increase in the efficiency or chances of success of clinical trials. They can help, however, because there clearly is a need not only to raise awareness but also to propose a simple way to identify patients at risk for severe forms of disease in the larger community (particularly those with metabolic risk factors) and to design pathways for care and treatment strategies.

Clinical practice guidelines do serve other purposes that are just as important. They familiarize practitioners with a basic understanding of the disease, they set a consensual way for investigations and monitoring and treatment in clinical practice, and they help convey the needs for patient management at the relevant institutions regulating public health.

My last question addresses these clinical care pathways, several of which help providers identify high-risk patients with NAFLD who should be referred to hepatology for consultation. These tend to focus on significant fibrosis. Do you think this is going to be a problem as we get therapeutics approved for NAFLD, because they're going to be tailored toward the patients who are felt to need them the most?

It would be ideal to identify patients with significant or advanced fibrosis as well as those with active disease not yet at the advanced fibrosis stage but who might get there soon because of the disease activity and a high fibrotic potential — in other words, patients at an early stage but at risk for disease progression. Should these patients be treated with drugs once they are available?

This may be decided on a case-by-case basis; it may depend on the drug profile and cost. Conversely, one can argue that there might not be an immediate necessity or urgency to do that, in the sense that this is a slowly evolving disease.

If they get to higher stages of fibrosis, you will diagnose them a few years later if you have good markers. You won't necessarily lose these patients if you're able to monitor them and have them come back to the clinic. But that can be a big "if" in some circumstances.

So, ideally, yes, it would be good to diagnose people with active disease at an earlier fibrosis stage because they have a high fibrogenic potential, but we can't do that with the current tools.

The second point is, will the current referral pathways that aim at identifying patients with significant fibrosis help deliver medication to the largest number possible of patients who need it? I think that concentrating on advanced or significant fibrosis will already do us a big service. Because, in the end, if these new drugs get to the market, the indication will be to use them in patients who have advanced fibrosis. Cost-effectiveness analyses will probably confirm that.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.