Surfing the MASH Tsunami

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This week's Vault looks back to the EASL Congress 2023 and includes Aleksander Krag, Sven Francque and all three surfers: Jörn Schattenberg, Louise Campbell and Roger Green. The focus of this conversation revolves around program design. The original conversation came with a robust description:

This conversation starts with Roger’s question to Sven around his role as Educational Councillor and the various educational opportunities embedded within the program. Sven first describes a postgraduate course that focuses on the link between NAFLD and cancer. He goes on to describe a plethora of activities which each embody different levels of education and participation for different stakeholder groups. Notably, he underscores the goal of broadening education to reach parties external to specialist hepatology groups. This is not only about raising awareness, but also engaging communities with the concept of liver health from a very young age. Roger asks what the balance is between virtual and onsite attendance and Aleksander suggests people are trending back to onsite participation. The group discusses why in-person attendance is especially positive for the previously described educational elements. From here Roger asks Aleksander and Sven for their lists of “3 things you can’t miss” for different participating groups. First, he asks what’s not to be missed for a recently minted transplant hepatologist. Next, he shifts focus to what’s not to be missed for attending students.

The conversation shifts to questions from Louise and Jörn which focus on how the program was put together. It becomes clear that this is a multifaceted event that combines the experiences of education, networking, science development and much more. Aleksander likens the meeting to a giant dinner party whereby the organizers are chefs who have taken a year to prepare an extravagant meal for thousands to enjoy. For the remainder of the session, Louise leans in on a comment Aleksander makes about allied health and points out that there are some very good and important sessions around health literacy.

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This final conversation from SurfingMASH's EASL Congress 2024 preview includes two final papers, one covering MASLD drug development, and a diverse set of answers to Roger Green's closing question.

Jörn Schattenberg discusses a paper he will present on a completely new concept to treat MASLD, a Phase 2a trial of a transglutaminase inhibitor, a compound originally developed for Celiac disease. Aleksander Krag describes as "exciting" the idea that this concept came from Celiac disease.

Michelle Long discusses a late-breaker abstract, which means it is embargoed, and she cannot share many details. This is another "really good use" of a big data set, in this case data from an array of Novo Nordisk trials.

With all the abstracts presented, Roger Green observes that this is the first major Congress preview SurfingMASH has done where the discussion focused on anything other than drug development, in this case, data development. 

Roger asks for a "big picture" lesson each panelist will leave Milano with. Michelle notes that while she likes Roger's comment about focus, she views Big Data development as driving a new, broader phase of drug development. The group agrees.

Beyond that, the panelists' closing comments vary in scope and focus but share themes that have emerged throughout the discussion.

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This conversation revolves largely around two Big Data presentations Hannes Hagstrom's team is sharing at the EASL Congress. Every other panelist has at least one meaningful comment to make about the future of Big Data in MASLD.

Hannes describes two big data studies of his own, "very much Big Data, but it's not omics." One examined 860,000 residents of Stockholm who took a liver test between 2010-2022 seeking to estimate liver and cardiovascular risk. It relied on a tool from Stefano Romeo's group called the Fibrotic Mass Index. The results demonstrated the prediction of liver-related and cardiovascular-related outcomes.

The other study relied on the same dataset to build a prediction model for liver-related outcomes in the general population. Instead of relying on a dedicated test like FIB-4, which has false results on both sides, this assimilates five simple parameters (ALT, AST, GGT, ender, age) and proves to be far more accurate at risk assessment than FIB-4. The study team will also present a small, web-based calculator "where people can go to estimate the risk." The tricky part, Hannes notes, is where to set a tolerable risk threshold. 

Jörn, thinking about the 860,000 sample, asks, "How much data is big enough?" Hannes notes that if the sample is big enough, we need not worry about statistical tests because we have true population-level data. 

Michelle considers the overarching implications of Hannes's comments: "I think a risk-based view of this disease makes a lot of sense." Aleksander and Roger concur that using a risk-based screening approach is preferable, in large part because it should allow a far larger share of resources to be devoted to those with significant disease. 

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This conversation starts with Jörn Schattenberg joining the conversation. The main points are two abstracts, one reviewed by Jörn and the other by Aleksander Krag.

As Hannes finishes discussing his abstract, Jörn joins the podcast. While Michelle looks for an abstract she highlighted on which Jörn is an author, Jörn discusses a panel that Hannes will chair on the future of hepatology, at which Jörn will speak about artificial intelligence. Hannes shares his excitement about a session that looks to take a peak into the future, framing it in the context of the EASL vision and mission.

The abstract Michelle selects for Jörn is titled The cause of death, mortality rates and the role of sociodemographic risk factors and biomarkers in metabolic dysfunction-associated steatohepatitis in more than 18,000 real-world patients from the United States. Jörn shares the group's enthusiasm for large sample sets of "real-world" patients, this one obtained through the Optum health registry, and discusses some of the outputs of the research, notably including the association with EGFR and some "very nice" genetics aspects.

Roger asks the panel each to discuss one of their own abstracts they consider important.  Aleksander describes a Galaxy consortium database of 900 people with a range of steatotic liver disease severity. The "true multi-omics" study incorporated "18 layers of omics" and also host genetic factors. He goes on to discuss the way the group dove into this massive set of data and how the results of this study and others like it will open a "new, new world of biomarkers." He describes the immense analytical needs for a data set with 900 cases and 18 layers of omics, which required analysis of "10 to the 11th power" to analyze." In the end, the data set identified 500 "highly significant" variables.

Jörn notes that while the data is extremely complex, it reaffirms the value of some of the pathways we have been studying. The challenge, Jörn notes, is to make it "easy" for the clinician. To Aleksander, "that's the thing...we need to bring" if studies like these are to become actionable. Roger comments that in complexity theory, complexity can produce simplicity if analysts do not seek too high a level of granularity. Aleksander sees the solution in creating tools based on host genetics, which are stable for life and which "everybody has."

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This conversation starts and ends with thoughts from Michelle Long. Her first comment praises the expanded networking opportunities in the program, and her last comment focuses on the quality of the MASLD abstracts (really, all abstracts) and the importance of reviewing them in advance. 

Michelle starts by commenting on the networking sessions that EASL is sponsoring around the large consortia and other projects. "It really speaks to how... open this community is to exploring different ideas and getting people together." She notes that these sessions have particular value for two groups: people just getting into the field and those looking for a potential collaborator. Aleksander describes these sessions as helping to support the big consortia by tying them into the networking sessions. It also demonstrates the way that academia, companies and public funders align on pivotal projects.

Roger comments that this is consistent with the generally high level of collegiality he sees in the hepatology community. In response, Aleksander states that the meeting will revisit EASL's mission and vision, which speaks to the many ways the organization can advance liver care.

Roger asks Michelle what else she anticipates eagerly about the Congress. Her reply? "Don't sleep on the abstracts." She starts reviewing the abstract book and quickly highlights 75 of interest, and then states there are far more than just those 75 that have high-level value.  She notes that our fellow day Surfers, Aleksander, Hannes and Jörn, are authors of some of these. She describes the themes of linking and collaboration as coming through the abstracts. Finally, she recommends poster sessions as a place to dig into what lies behind the document for some pivotal pieces of research. 

Roger invites Michelle to choose one abstract from her 75 with Aleksander, Hannes and Jörn as authors so that the three can describe their work.

The first abstract Michelle highlights has Aleksander as an author and is titled Longitudinal changes in liver stiffness measurements in a population-based screening cohort of 5,517 participants. Without revealing conclusions or interpretations, Aleksander describes the work his group did and then shifts focus to advocate that all listeners and attendees review abstracts extensively before coming to the meeting.

The second abstract Michelle highlights has Hannes as an author and is titled The validation of the Baveno Rule of 5 in a real-life multicenter cohort of patients with metabolic dysfunction-associated steatotic liver disease. Like Aleksander, Hannes does not share data, but discusses how valuable a multicenter cohort can be in answering pivotal questions as compared to single-sample studies, "which cannot be replicated elsewhere."

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This first conversation from our EASL Congress 2024 preview starts with EASL Secretary General Aleksander Krag offering his vision for next week's meeting in Milano, after which Hannes Hagstrom shares some of his thoughts about the meeting design. 

Aleksander starts by discussing the preparation that has gone into this Congress since the Vienna meeting closed last August. The goals are ambitious, but he feels EASL has, by and large, succeeded. Aleksander mentions that 7,000+ people have registered, including 80+ companies and 25+ patient groups.  and that researchers submitted 3,000 abstracts, 2,000 of which have been accepted. "Almost 300 different types of sessions" with 450 faculty members focus on: 

• The one approved MASLD drug and nine others in late-stage development, including "several Phase 2 studies"
• Breakthroughs on non-invasive tests 
• An update on the "one-year baby" nomenclature, including a look at alcohol in the context of ALD and MetALD
• Enhanced understanding of the underlying disease.

He also highlights the EASL Studio as a "relaxed" place to listen to important discussions. Finally, he praises Milan's charms, particularly its food and wine. 

Hannes describes the scale of the program as "like going to a place with a lot of good restaurants, but you only have one stomach," with not only research presentation sessions but also an array of meetings. He also commends the design element that places young researchers in prominent positions. Aleksander notes that some choices of chairs and events are designed specifically to move the public dialogue beyond "the usual suspects." 

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Next week, 7,000+ hepatology stakeholders will convene in Milano, Italy, to consume 2,000+ posters and presentations, including an extensive set of MASLD studies, at EASL Congress 2024. EASL Secretary General Aleksander Krag, Hannes Hagstrom, and Michelle Long join Jörn Schattenberg and Roger Green to preview the program.

00:00:00 - Surf's Up: Season 5 Episode 17
Standard lead-in, including quotes from panelists.

00:02:40 - Introduction
Roger describes the structure of this episode.

00:04:21 - Groundbreaker 
Good personal and professional news from the panelists. 

00:08:04 - A 10,000m look at the EASL Congress 2024
Aleksander discusses the preparation that has gone into this Congress, resulting in 2,000 accepted abstracts presented in  "almost 300 different types of sessions" from 450 faculty members. Many focus on the range of key MASLD issues.

Hannes commends the design, which prominently positions young researchers. 
Michelle says the networking sessions that EASL is sponsoring around the large consortia and other projects " really speak to how open this community is to exploring different ideas and getting people together."

00:21:01 - Michelle praises abstract quality and selects abstracts for colleagues to review
Michelle advises, "Don't sleep on the abstracts;" she quickly highlighted 75 of interest.  She recommends poster sessions as a place to dig into what lies behind some pivotal pieces of research. 

Roger invites Michelle to choose one abstract from her 75 that have her fellow panelists as authors, so that the three can describe their work. 

Aleksander and Hannes both choose to describe the work their groups did on the various abstracts, but both describe methods and overall benefits. 

00:26:41 - Jörn Schattenberg joins panel
As Hannes makes his statement, Jörn joins the podcast. He starts by discussing a panel  Hannes will chair on the future of hepatology at which Jörn's will focus on AI. Hannes shares his excitement about a session that looks to take a peak into the future.

Jörn describes the abstract Michelle selects for him as a Big Data study of "real-world" U.S. patients, which he sees as having great benefit compared to looking at the patients he treats.  

00:30:25 - Panelists each choose an abstract to discuss
Roger asks each panelist to discuss an abstract. Aleksander and Hannes each describe Big Data studies, but these are quite different. Aleksander's relies on massive computing power to analyze 12 levels of omics data for 900 patients,  while Hannes's two are based on 860,000 residents of Stockholm who received a liver test between 2010 and 2022. 

One study from Hannes demonstrated that five simple parameters proved far more accurate than FIB-4 in assessing risk. To MIchelle, "a risk-based view of this disease makes a lot of sense." Aleksander and Roger concur that such an approach will probably yield a far more efficient use of resources. 

Jörn discusses a drug development paper reporting on a Phase 2a trial of a transglutaminase inhibitor. Michelle mentions an embargoed late breaker abstract that she describes as a "really good use" of a big data set from an array of Novo Nordisk trials.

00:48:31 - Closing comments and wrap-ups to discuss
Roger asks each panelist for a "big picture" lesson they will take from Milano. Closing comments from the panelists vary in scope and focus but share themes that have emerged throughout the discussion.

00:54:55 - Question of the Week  
This week's question of the week asks which sources of insight will drive the next generation of MASLD research.

00:55:44 - Business Report  
This week's news on how SurfingMASH will cover the EASL Congress, our new private community, some of its new features and a description of the vault episode.

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In this excerpt from last July, Stephen Harrison shares results of the FASCINATE-2 study as part of SurfingMASH's larger coverage of exciting drug trials presented at The EASL Congress. 

The original writeup reads:

This month, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from June's two major conferences: the 2023 EASL Congress in Vienna and the American Diabetes Association's 83rd Scientific Sessions meeting in San Diego. This is the second session focusing on drug development, and specifically, on several presentations for exciting drugs in development. In doing so, the Big Band of Surfers (Stephen Harrison, Jörn Schattenberg, Louise Campbell and Roger Green) are joined by Mazen Noureddin for a fascinating conversation which covers plenty of compelling clinical trial data.

Jörn preludes this discussion by noting just how much important drug development research was released at this year's EASL Congress. Stephen proceeds from here to detail positive Phase 2b FASCINATE-2 clinical trial interim data for fatty acid synthase (FASN) inhibitor, denifanstat, as presented at EASL Congress by Rohit Loomba. In the process, Stephen elucidates why the idea of a FASN inhibitor is so exciting. It blocks de novo lipogenesis, which means it can have effects on inflammation and possibly direct fibrosis inhibition. Previously in Season 4, Episode 32, it was discussed why inflammation, which is tied to liver volume, might be a critical component to better understand for therapuetic development and the wider scope of liver health. From here, Stephen goes on to describe the trial, starting with basic design and sharing the MRI-PDFF and biomarker data that was presented at the EASL Congress. He finishes with safety and efficacy data and a general comment that the trial demonstrated, 'the drug is doing what it's intended.'

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This is the second half of Roger Green's conversation with Dimitar Tonev. It focuses largely on some of the elements of Stephen's personality that made him so unique and a role model within the community. 

Dimitar discusses one more innovation Stephen brought to MASLD clinical trials: recruiting in neighborhoods that received lower levels of medical care and then, within those communities, recruiting within families. Roger harkens back to the recruitment issue to tell the story that Stephen and he started SurfingMASH to educate sponsors and sites about the ability to keep trials running in a site network like Summit. 

To Dimitar, one thing that made Stephen special was his "enormous capacity to work long hours," to the degree that left Dim "wondering how this is even humanly possible." He mentions early clinic starts, 4 a.m. text messages, and other related of-hours items. Roger shares a story he heard at the funeral about Stephen stating that he didn't sleep much but slept"very efficiently." Dimitar and Roger agree about the energy and enthusiasm Stephen devoted to everything he did. 

Dimitar tells a story about Stephen flying over the Atlantic with his family. You'll have to listen to learn it. He goes on to discuss Stephen's passion for working on minor diseases that were unlikely to ever pay off in terms of money or prestige and, finally, how Stephen boosted Dim's self-image by presenting a couple of Dim's slides during a presentation at a major meeting.

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The conversation shares the first half of Roger Green's interview with Dimitar Tonev, whose tribute comment to Stephen Roger shared in a recent SurfingMASH weekly newsletter. 

Because this is Dimitar's first appearance on SurfingMASH, he starts by telling the audience a bit about his history, including the fact that he came to know Stephen from the viral hepatitis days. As his "one unique thing," Dimitar mentions his proficiency as a skier, which leads Roger to ask about his description of Stephen in the SurfingMASH note as a "clumsy skier." Dim states that Stephen's form wasn't the best but that he skied with energy and passion. He goes on to tell a different story about how he broke Stephen's glasses the first time they met and how Stephen was able to laugh about it with him.
 
Dimitar describes the "really impressive way" Stephen developed his process for recruiting patients into what were then called NASH studies through the "first iterations of Summit," the idea of a site network. In response to a question from me, he described the pre-screening pathway as one element of the "secret sauce," and the use of portable FibroScan devices as another. He goes on to describe that Stephen's sites could recruit 8x as many patients per month as a typical CRO, which is why the Summit network has become a preferred provider to many CROs and why no one has yet been able to replicate his success.