Surfing the MASH Tsunami

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Our week of "Greatest Hits" episodes from the vault continues with this conversation from the episode announcing the launch of the NAIL-NIT consortium. Stephen Harrison and Mazen Noureddin discuss the thinking behind their new consortium and its targets. In this conversation, they discuss challenges with the NAS score.

The early part of 2022 had several episodes discussing the increasing need to move beyond biopsy (yes, semi-quantitative, but even AI-assisted at some levels) to a future shaped by NITs. One pivotal issue that emerged regarded ballooned hepatocyte evaluation and its impact on NAS scores. 

As I wrote: The first section focuses mostly on what we can and cannot learn from a NAS score, and implications of its shortcomings on the drug development process. After this, Stephen Harrison notes the complex role the liver plays in energy transfer throughout the entire metabolic process. This suggests that the effects of Fatty Liver disease vary among individual patients and, as a result, drug development and patient diagnosis and treatment should provide sufficient insight to optimize each patient's therapy. As the conversation closes, Mazen Noureddin is responding to a question from Louise Campbell about what we will learn about optimal testing strategy. Mazen suggests there is unlikely to be a single "winning" test but, instead, a combination of NITs probably will be necessary to answer all the questions necessary to optimize therapy.

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Our week of "Greatest Hits" episodes from the vault continues with our second most popular conversation ever, which came from the wrap-up episode for AASLD2021. In this episode, Manal Abdelmalek, Jörn Schattenberg and Ian Rowe joined Stephen Harrison, Louise Campbell and Roger Green to recap NAFLD and NASH-related insights from AASLD2021 TLMdX and specifically to focus on how NITs will help, in the words of Stephen Harrison, "put a big, fat dent in Fatty Liver disease."

As I wrote at the time: The conversation starts with the group congratulating Manal Abdelmalek on her wrap-up NAFLD talk at the 2021 TLMdX. From there, the group focuses on the shortcomings of using biopsy as the clinical trial gold standard and how strategic clinical trial design and interpretation of existing NIT data can build a bridge from biopsy through MRE/biopsy correlations to a total NIT future.

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Our week of "Greatest Hits" episodes from the vault continues with our most popular conversation ever, as Stephen Harrison and Jörn Schattenberg synopsize the Basic Science segment of the recent Paris NASH meeting. This segment, which focuses largely on a state-of-the-art look at fibrosis, is by far our most downloaded conversation every, with more volume than the next four posts combined!

As I wrote at the time: Paris NASH is a meeting for basic science and interdisciplinary thinking. Since Stephen Harrison was drafted into co-chairing the session titled "Deep Dive into Fibrosis," he led this conversation. The session included three presentations with a powerful collective message about stellate cells: that different stellate cell subtypes perform in unique ways in terms of how they function, the process(es) through which they become modified and what this represents in terms of performance. This description does not do Stephen and Jörn's comments justice. It's a short session, so listen for yourself...

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Our week of "Greatest Hits" episodes from the vault continues with Scott Friedman's fascinating presentation on precision medicine in the context of senescent stellate cells and fibrosis, first posted in October 2021. Scott combines erudition and unparalleled knowledge of the subjects he is discussing with a storyteller's ability to paint clear pictures and make complex issues both simple and lively.

Scott, known to some as the "Father of Fibrosis," starts this discussion talking about his own history in fibrosis research and then the history of the stellate cell and its role in where precision medicine is heading. The rest of the episode touches on issues ranging from the importance of omics in learning about the disease and the future of precision medicine to target disease to today, specifically, the downside of being, as Scott puts it, "yoked to biopsy." In the aftermath, listeners (including other leading KOLs) described this episode as a "coup," a "treasure" and "something you can find only at Surfing the NASH Tsunami." If you missed this episode the first time around, download it now and make it your weekend (or vacation week) listen.

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Our week of "Greatest Hits" episodes from the vault starts with Jörn's first featured episode, which we posted in November 2020. The episode focused on a recent article he co-authored looking at why so many NASH drug trials fail. One key issue: proper utilization of Phase 2 trials. At the time, we wrote:

Jörn Schattenberg joins Stephen, Donna, Louise and Roger to discuss his recent article "The Nonalcoholic Steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future successes." The discussion starts with lessons from failed trials, focusing on the importance of utilizing Phase 2 trials to test hypotheses and establish appropriate targets. From there, Surfers went on to discuss commercial and patient-focused definitions of what makes a clinical trial successful.

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Surfing the NASH Tsunami posted on Buzzsprout for the first time on July 23, 2020. Over the past two years, NASH Tsunami has posted 132 episodes and close to 400 posts when we include both episodes and conversations. This week, Jörn Schattenberg and Roger Green review some of the podcast's high points and set the stage for a week of resharing "Greatest Hits" episodes and conversations from the Vault of old postings.

The conversation starts with Jörn and Roger reminiscing about Jörn's first couple of appearances on the podcast, first helping to review the digital ILC 2020 and then coming on a couple of months later to discuss a paper Jörn had recently published looking at why NASH drug trials fail. Jörn and Roger discuss come of the lessons from the paper and how those have translated into changes in drug development and clinical trial strategies.

One interesting side note: Roger asks Jörn about feedback from the original paper. He comments that the authors rarely get feedback, especially those who are not the correspondent author (which Jörn was not for this paper). He commented that he receives more feedback from the discussions on NASH Tsunami, either on the podcast or in subsequent conversations with friends and colleagues who have heard the episode. 

Roger goes on to note that while the "Why Trials Fail" paper touched on challenges around biomarkers and conditional endpoints, we were only at the beginning of learning how many flaws existed in the system of semi-quantitative reads. This serves as a bridge to the specific conversations NASH Tsunami will repost from the Vault during this anniversary week. They address topics ranging from stellate cell activation to the role of NITs to the importance of patient advocacy. As they move from post to post, Jörn and Roger provide context on where each one fits in the history of the podcast and what they learned or experienced as a result. 

Of course, a podcast without Stephen or Louise can provide only so much of the podcast's history and key moments, but for listeners, this episode will give you an opportunity to reflect on your own intellectual journey with NAFLD and NASH and to ask yourself which of the older episodes and conversations you might want to revisit. As we noted earlier, we will post two episodes and six conversations we like to revisit in the week ahead.

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his week, Surfing the NASH Tsunami returns to a subject we have explored from time to time over the past two years: helping patients with cirrhosis. While the immediate stimulus for doing so was the semaglutide late-breaker at #ILC2022, our more general interest is that many patients with cirrhosis will start to decompensate and decline in a fairly short period of time. This conversation brings together key threads from earlier in the episode, focusing significantly on providing better cirrhosis patient support as a key element in improving NASH cirrhosis therapies.

As this final conversation starts, Jörn Schattenberg and Lars Johansson are discussing two points: (i) the idea that even when a patient is diagnosed, this might not make it into that patient's medical record or become a focus of therapy, and (ii) the idea that the 30,000-patient study Lars has mentioned is focusing on deriving outcomes without biopsying patients. Louise Campbell joins in to endorse both these ideas, focusing more on capturing patients' NAFLD, NASH or NASH cirrhosis in the medical record and making it actionable. In particular, she notes that the investment necessary to improve communication will be far lower than what will be necessary to create or dramatically enhance drugs and diagnostic technologies.

This leads to Roger Green's closing question about a likely area for short-term improvement in a treatment area the panelist touches every day. Panelists' answers are diverse and thought-provoking.

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This week, Surfing the NASH Tsunami returns to a subject we have explored from time to time over the past two years: helping patients with cirrhosis. While the immediate stimulus for doing so was the semaglutide late-breaker at #ILC2022, our more general interest is that many patients with cirrhosis will start to decompensate and decline in a fairly short period of time. This conversation focuses on what Roger Green describes as a "pincer movement" in technological development: high-end technology to empower better diagnosis, staging and treatment and low-end technology to capture more patients, capture them earlier in disease and keep them engaged in the process.

The conversation starts with Roger posing a question of whether the major need in improving cirrhosis diagnosis and treatment is a human systems or a medical technology issue. After some conversation, the answer turns out to be "both."

Louise Campbell responds first. She focuses on human systems needs: send the right letter, engage the patient and provide the proper and necessary information to educate the patient and keep them involved. She goes on to note that (i) these needs appear to be global in scope although the challenge takes different forms in different countries; and (ii) for patients with progressive disease, "not feeling worse" is an outcome they will pursue aggressively. 

This observation, coming after earlier discussions about medical treatment issues, leads Roger to make his "pincer movement" comment. Jörn Schattenberg agrees that there is a "disparity" between investment in high-end medical technologies and physician and hospital office systems that rely on older technology and inadequate systems. He states that he considers it important to invest in health structure improvements as well as advancing technologies.

Roger asks Lars what role high-end technologies will play in advancing patient care. Lars suggests that technology's major role will be in driving better decisions about which drugs to develop and how. He goes on to state that advances in clinical practice need to be simple, affordable and practical. The example Lars gives is an effort years ago to persuade Swedish patients with dyslipidemia and cardiovascular disease to focus on Apo B instead of LDL. The task became impossible because, in spite of more compelling data on Apo B, the concept of LDL-lowering as the therapeutic target was so well embedded that it proved impossible to dispel, or even modify meaningfully. 

As this conversation winds down, Roger asks Lars to describe work he is doing that will benefit patients. Lars talks about exploring the effects of cirrhosis on other organ systems, specifically the heart and kidney. Jörn follows up with a question about deploying standard imaging (his example is back pain) to identify previously undiagnosed liver issues. Lars responds by discussing an AI-aided study he is working on with 30,000 patients looking at multi-organ imaging issues using CT. He suggests that in the future, simply having a section of liver in the CT will provide this kind of guidance.

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This week, Surfing the NASH Tsunami returns to a subject we have explored from time to time over the past two years: helping patients with cirrhosis. While the immediate stimulus for doing so was the semaglutide late-breaker at #ILC2022, our more general interest is that many patients with cirrhosis will start to decompensate and decline in a fairly short period of time. This conversation focuses on a specific question: where is the next breakthrough in cirrhosis patient management likely to come?

This conversation starts with Roger reflecting on a comment Lars had made during a previous appearance on the podcast, that we should spend more time focusing on what should be happening in the liver instead of what shouldn't. Lars notes one reason for this: when we look at other organ systems (heart or kidney, for example), we focus on how the organ functions. With the liver, we read static biopsies that do not measure actual function. He goes on to note that researchers are developing functional tests, many of which require labeled compounds and then record how they move through the body. 

At this point, Roger shifts the discussion by asking the panel where members anticipate the next major breakthrough in improving cirrhosis diagnosis and treatment. Louise responds first by noting the need to pick up patients earlier in the course of the disease as they move through the healthcare system. She envisions that this may come by adding. FIB-4 to every patient coming through the system or perhaps to something like the iLFT that John Dillon described at the Barcelona meeting. Even there, she notes, the system picks up only 50% of diseased patients. Jörn describes the need to improve diagnostic performance, both in terms of better tests and better ability to deliver both testing and results to patients. Lars questions whether the answer lies in providing imaging tests for every patient. Instead, he suggests, we need to link imaging results more closely to liquid biomarkers and then drive universal, early use of these less expensive liquid tests. As the conversation ends, Louise agrees with this point but notes again that we are assuming a level of patient communication and provider follow-through that does not exist today.

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This week, Surfing the NASH Tsunami returns to a subject we have explored from time to time over the past two years: helping patients with cirrhosis. While the immediate stimulus for doing so was the semaglutide late-breaker at #ILC2022, our more general interest is that many patients with cirrhosis will start to decompensate and decline in a fairly short period of time. This conversation begins to explore the ability of currently available medications to cause fibrosis regression in patients with cirrhosis.

This conversation starts with Lars posing a question to Jörn: does he believe that a "drug like sema[glutide]" can inhibit the progression of fibrosis, even though the #ILC2022 late-breaker showed no significant level of fibrosis regression over a 48-week period. Jörn replies that the study demonstrated that semaglutide was safe and demonstrated some effects (on transaminase levels, for example), but nothing on fibrosis. He then turns the question back to Lars to ask what metabolic or systemic effects we might measure as a precursor to fibrosis regression or even lack of progression. Lars points to subclinical signs of possible portal hypertension as one place to look. In this context, he notes that increases in spleen volume as modest as 20-30% can be linked to increasing fibrosis levels and possibly changes in portal pressure. As a result, he suggests, looking at changes in portal pressure might be a fruitful area for exploring the ability of a medication to regress fibrosis or even just to stop progression. Lars notes this could be reduced inflammation that has not yet translated into fibrosis regression. As he points out, bariatric studies show it can take years to regress fibrosis. 

Roger asks the group which parameters they consider signs of fibrotic stabilization or regression. Jörn notes Lars's earlier comment about HVPG and asks which measures correlate with it. He mentions varices and ascites as signs to watch as the disease progresses. Finally, he asks about how well patients with compensated cirrhosis perform on other performance metrics.

Lars answers that performance is "not that bad in terms of other effects" and goes on to describe some of the other measures he and others are exploring. As the conversation ends, Lars points out that reducing activation of stellate cells would be a good thing in itself, regardless of whether or how long it takes to lead to fibrosis regression.