Surfing the MASH Tsunami

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On September 18-19, the FDA hosted a workshop to update key stakeholders on the state-of-the-art use of biomarkers and noninvasive tests (NITs) based on recent advances in NASH/metabolic dysfunction associated steatohepatitis (MASH) clinical trials. In this episode, Surfing NASH  reviews highlights from the workshop in three seperate interview sessions with guests Naim Alkhouri, Laurent Castera and Veronica Miller. Each guest participated in some form at the meeting and shares slightly differing but incredibly insightful perspectives with Surfers Jörn Schattenberg, Louise Campbell and Roger Green. Naim elaborates on the limitations of current pathways and the possibilities of combination NITs and conditional approval. Laurent discusses "inflammation as disease a driver, liver fibrosis as a killer and steatosis as a marker." Veronica shares thoughts around collaboration and expanding this conversation on NITs to move the field forward. Additionally, plenty more ideas are explored as this is a very fascinating and pivotal workshop which covers a range of topics on NITs with presentations by the some of the field's most innovative and knowledgable contributors. Listen to the full episode to gain a richer understanding than can be described in this summary. If you have questions or comments around the workshop, NITs, drug development or any other themes addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

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[Meeting Information from the FDA Website]

Use of Biomarkers for Diagnosing and Assessing Treatment Response in Noncirrhotic NASH Trials

Drug development for NASH/MASH with liver fibrosis has increased substantially and there is growing interest in developing NITs to detect the presence of fibrosis, and to accurately classify different stages of fibrosis as well as cirrhosis. Candidate NITs include both blood tests (circulating biomarkers) and imaging tests. In recent years, most data regarding use of NITs have been collected from NASH/MASH clinical trials. However, there are limited published data for use of NITs across the spectrum of the affected population that would be encountered in routine clinical care, including patients without fibrosis. This workshop will assist the FDA in identifying current knowledge gaps for using NITs as diagnostic biomarkers and reasonably likely surrogates, as well as provide a framework for additional data that are needed to fill these knowledge gaps. Ultimately, the FDA seeks to learn whether expert stakeholders have evidence to indicate currently available NITs are adequate to meet the Agency evidentiary standard for assessing primary evidence of clinical efficacy. The primary focus of this workshop is “non-cirrhotic NASH/MASH population with advanced (i.e., Stage 2 or Stage 3) liver fibrosis”. The workshop will not address the use of biomarkers for treatment trials in cirrhosis due to NASH/MASH, however, the workshop will discuss identification of “progression to cirrhosis” using biomarkers.

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Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This wrap-up conversation starts with Roger asking the panelists what other important/intriguing questions we have not yet covered which arose in the meeting. Scott discusses interesting talks on genetics. Laurent concurs and adds that he was struck by a talk about pediatric NASH, which is more likely to be endogenous since these young patients do not consume alcohol, but also confounded by how pediatricians are trained (or rather, not trained) to conduct biopsies and otherwise assess patients. Jörn discusses a statistical method for comparing disparate options known as DOOR – Desirability of Outcome Rankings. Lastly, Louise and Roger raise a couple of additional questions. Listen on to hear what they are.

This episode and its conversations cover a range of fascinating insights stemming from yet another impactful Paris NASH meeting. If you have questions or comments around Paris NASH, NITs or any other themes addressed, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected]. 

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Send us Fan Mail

Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This conversation starts with a question from Louise about whether utilizing CAP would provide added insight in light of what the group has discussed around NITs in the preceding conversations. Laurent responds that CAP is more related to inflammation and steatosis than to fibrosis, and Scott agrees. Laurent suggests that MRI-PDFF would be an ideal test for addressing this issue, but it is not cost-effective for regular practice. Therefore, he uses VCTE measures, including CAP, because the numbers he provides are motivating to patients. Louise asks how activation of stellate cells depends on disease and Scott notes that most stellate cell activation is driven by inflammation, not fat. However, this raises two challenges: whether lipotoxic mediators drive fibrosis directly or act through inflammation and, more broadly, that current clinical tools for measuring fat are quite broad. On this point, Jörn notes that as the liver progresses toward cirrhosis, it loses fat and thus makes  the entire issue more complex. Roger raises the question whether patient compliance and adherence might be affected negatively by uncertainty about the meaning of results. The rest of this conversation centers around Scott’s comment about the complicated impact of using GLP-1s and other incretins to treat obesity will have on Steatotic Liver Disease (SLD) and challenges in treating and assessing adequately. 

This episode and its conversations cover a range of fascinating insights stemming from yet another impactful Paris NASH meeting. If you have questions or comments around Paris NASH, NITs or any other themes addressed, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This conversation begins with Jörn discussing his topic from Paris NASH. His notes stem from a topic he received from the organizers: once a drug is available in the clinic, which test will you use to decide if the patient gets the drug. Jörn notes quickly that he will use neither biopsy nor FIB-4. He then notes that FAST was designed for this purpose, but that no current test makes sense today. Scott raises the parallel question: once you commit a patient to therapy, how will you determine whether the patient is responding or not? Jörn notes that most of the data we see today is aggregate, rather than the individual patient data we will need to assess how each patient performs on these tests. Laurent notes that there is not much data on this issue and then goes on to discuss the one study that does exist. He also describes a two-stage decline in test scores over time, with a more robust early decline and a slower decline later. That said, he questions whether the reduction in stiffness results from a decline in inflammation or fibrosis.

As the conversation winds down the floor goes back to Scott and Jörn. Scott notes that while the question is interesting, declines in inflammation or fibrosis both correlate with improved outcomes. He also notes that currently developing fibrosis-specific markers like ProC3 may help answer this question. Jörn says that the answer he gave in the meeting is a form of “it depends” – in this case, possibly on the starting level of drug, whether the decline is early or late stage and the starting fibrosis level.

This episode and its conversations cover a range of fascinating insights stemming from yet another impactful Paris NASH meeting. If you have questions or comments around Paris NASH, NITs or any other themes addressed, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This session starts with questions to Laurent from Jörn and Louise about his comments on NITs from the preceding conversation. Jörn concurs with Laurent’s statements on the value of FIB-4, particularly if the provider conducts sequential tests. Louise asks whether we are looking solely at liver disease, given the high levels of non-liver mortality among patients with F1-F3 fibrosis. Laurent notes that the primary purpose so far has been to identify F3 and F4 NASH, but more recently methods such as FAST, MAST, MEFIB and MASEF, which was discussed on the podcast in S4E39, seek to define disease stages with greater specificity. He then goes on to discuss the importance of the context of screening on test performance. Laurent notes that in higher prevalence populations there will be a larger percentage of false positives. Thus, he notes, FIB-4 works well in initial screening based on strong NPV performance, but has less value in a disease-enriched population.

This episode and its conversations cover a range of fascinating insights stemming from yet another impactful Paris NASH meeting. If you have questions or comments around Paris NASH, NITs or any other themes addressed, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This conversation starts with Scott discussing the session he shared with Fabio Marra which investigates the link between fibrosis and regeneration. Scott points out that the liver’s ability to regenerate is unique among organs and a pivotal question for which a new answer arises every ten years, none of which turns out to cover the topic adequately. He goes on to note that injured livers are less likely to regenerate and that regenerative livers are less likely to create scar. He suggests that while we do not know which one comes first, the answer is likely to have broad implications not only for liver disease but also a range of other organs. In response to a question from Roger, Scott says he considers it more likely that regenerating liver tissue sends a message to break down scarring. This inclination is based on thorough experience of observing the natural history of treating viral hepatitis. Jörn asks about the degree to which the underlying etiology of disease causes this response. Scott states that the response is fairly common across etiologies but, as he notes, the devil is in the details.

The rest of this conversation is devoted to Laurent and his session with Dr. Mark Muthiah about the use and limitations of NITs. This talk evolved from a case study about an individual patient. Laurent’s point, in a nutshell, is that we need a range of tests depending on the question we are trying to answer – initial screening vs. staging vs. monitoring - but that the entire issue runs the risk of overwhelming front-line treaters who are not aware of these issues. In this context, he sites the value of FIB-4, and also its major drawback related to ages and cutoffs. 

This episode and its conversations cover a range of fascinating insights stemming from yet another impactful Paris NASH meeting. If you have questions or comments around Paris NASH, NITs or any other themes addressed, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Along with NASH-TAG, Paris NASH is one of two famously small, science-based and publicly available events every year for the liver community. Given the depth of topics and ideas explored in Paris, the event in its entirety would be nearly impossible to cover in a single conclusive episode. That said, the Surfers (Jörn Schattenberg, Louise Campbell and Roger Green) are joined by two presenting KOLs, Scott Friedman and Laurent Castera, for a neatly packaged conversation to capture some of the key dynamics of the meeting. Particularly, the group hone in on developments in the landscape around NITs.

This episode begins with Scott discussing the session he shared with Fabio Marra which investigates the link between fibrosis and regeneration. Scott points out that the liver's ability to regenerate is unique among organs and the question of how it does so is readdressed seemingly each passing decade without clear explanation. He goes on to note that injured livers are less likely to regenerate than healthy ones and that regenerative livers are less likely to scar. While we do not know which of these phenomena comes first, the answer is likely to have a broad range of implications not only for liver disease but also a range of other organs in addition.

Next, Laurent shares thoughts from his session with Mark Muthiah about the use and limitations of NITs. In a nutshell, Laurent explains why we need a range of tests to choose from depending on the question which we are looking for an answer. The reoccurring theme on the podcast around the importance of frontline education and training is addressed by Laurent here. Further, he underscores the value and simplicity behind FIB-4 as a simple frontline testing tool while also discussing its drawbacks. From here, Jörn and Louise ask relevant and interesting questions around what Laurent has discussed.

Jörn moves on to discuss the question that goes once a drug is approved, which test will you use to determine whether a patient receives that therapy or not? Jörn promptly notes that he will use neither biopsy nor FIB-4 then comments that FAST was designed for this purpose, but doesn't rise to the level he would hope to find. Scott raises a parallel question that goes once you commit a patient to drug, how will it be determined that the patient is responding or not? The conversation continues to look into how to assess data at an individual level and learn more about how each patient variably responds to tests.

For a wrap up question, Roger asks for any other important or intriguing questions yet to be covered that arose in the meeting. Scott shares some interesting talks on genetics, while Laurent adds that he was struck powerfully by a talk on pediatric NASH. Jörn goes a different direction and discusses a statistical method for comparing disparate options known as DOOR, or desirability of outcome rankings, and its effect on how to compare drugs and different options in unique patient situations.

This conversation covers many more fascinating elements of another insightful Paris NASH meeting. Listen to the full episode and dive into this weekend's conversation to gain a richer understanding than can be described in this summary. If you have questions or comments around Paris NASH, NITs or any other themes addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

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Surfing NASH returns to its regular program with a fresh episode and some fascinating and progressive ideas around non-invasive testing. Mazen Noureddin joins co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to discuss serum identification of at-risk MASH and the Metabolomics-Advanced Steatohepatitis Fibrosis Score (MASEF). In late July, Mazen co-authored a paper on the subject which was published in Hepatology.

This final conversation starts with Louise’s curiosity on whether any socioeconomic differences were clear between those considered at-risk. Mazen responds with his belief that there would be much to benefit from studying a larger prospective cohort with multiple different ethnic groups. Before moving on to final thoughts, Roger asks Mazen whether there are any populations yet to be considered that might benefit from this work going forward. Mazen responds by highlighting the importance of continued and persistent testing and reiterates that the next steps have more to do with response to therapy and correlation with outcomes. Jörn lastly mentions that the cirrhotic patient population would benefit from a test to which Mazen offers a clarifying response on when and why this group was included in the study. 

In closing, Roger asks the group, starting with Mazen, to envision the practical use of MASEF two years from today. Each panelist provides a thought-provoking answer - surf on to learn more.

If you have questions or comments around MASEF, metabolomics or any other ideas considered in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected]. The Surfing the NASH Tsunami will be back next week with more original content.

Stay Safe and Surf On!

Send us Fan Mail

Surfing NASH returns to its regular program with a fresh episode and some fascinating and progressive ideas around non-invasive testing. Mazen Noureddin joins co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to discuss serum identification of at-risk MASH and the Metabolomics-Advanced Steatohepatitis Fibrosis Score (MASEF). In late July, Mazen co-authored a paper on the subject which was published in Hepatology.

This conversation begins with Louise’s focus on pediatric cohorts and whether MASEF can be applied to younger populations. Mazen states that while it has yet to be applied in this way, he would be very interested to learn more and invites anyone interested to reach out. From here Roger steers the discussion towards the future MASEF and what Mazen would like to have happen next in terms of its progress. Mazen notes the surprisingly fast commercial uptake of metabolomics tests and talks about how it might soon roll out in the US. Ultimately, he hopes if proven to be a good test that this will help replace biopsy. 

The remainder of the conversation considers a question from Louise around how MASEF could be adapted for the newly classified Met-ALD (those with MASLD who consume greater amounts of alcohol per week).

If you have questions or comments around MASEF, metabolomics or any other ideas considered in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected]. The Surfing the NASH Tsunami will be back next week with more original content.

Stay Safe and Surf On!

Send us Fan Mail

Surfing NASH returns to its regular program with a fresh episode and some fascinating and progressive ideas around non-invasive testing. Mazen Noureddin joins co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to discuss serum identification of at-risk MASH and the Metabolomics-Advanced Steatohepatitis Fibrosis Score (MASEF). In late July, Mazen co-authored a paper on the subject which was published in Hepatology.

This conversation begins with Louise’s initial response around the setting of application for MASEF. She poses a question that leads the group to explore possible pros and cons of different approaches and the potential impact each might have in terms of cost effectiveness. For example, Jörn wonders how feasible it will be for non-experts to administer. Mazen suggests that its application will be relatively easy before explaining how to navigate the caveat of a gray zone similar to that of VCTE. After a few more comments on sequential pairing with FIB-4, Mazen next teases the possibility of demonstrating therapeutic efficacy in the drug development space. 

Louise returns to a question around cohorts and asks whether variables like age or sex has an impact on the test’s capabilities. She then asks whether this sort of work has the potential to inform retrospective cardiac studies. After Mazen and Louise go back and forth with a few ideas in response, Roger makes the comment that he is struck by the wide breadth of application and describes the platform as “elegant.” As the conversation winds down, the group discusses a few comparisons between different blood-based markers. 

If you have questions or comments around MASEF, metabolomics or any other ideas considered in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected]. The Surfing the NASH Tsunami will be back next week with more original content.

Stay Safe and Surf On!