Surfing the MASH Tsunami

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Surfing the MASH Tsunami continues its 2023 wrap-up conversations with HistoIndex Chief Scientific Officer Dean Tai, along with co-hosts Jörn Schattenberg and Roger Green. The conversation focuses on growth in the use of AI in Steatotic Liver Disease and some of the insights the profession is developing as a result. 

The conversation starts with Dean Tai and Jörn Schattenberg discussing the many promising advances in artificial intelligence over the past year. The two leaders agree both that the advances are providing exceptional new insights already, and will provide even greater insight when we can link AI to outcomes. Roger Green also notes how important it is that we improve the insights we develop from biopsy and, at the same time, the quality of non-invasive tests and suggests that AI has the ability to help on both issues. Finally, from the patient perspective, Louise Campbell suggests that anything that reduces the number of patients we biopsy or the number of biopsies per patient is a significant advance. 

To be more specific, Dean points out that some of the newer clinical trials are yielding decreases of 30-70% in liver fat density, along with significant decreases in liver volume. Since these measures reduce faster than fibrosis, AI is now giving us the ability to learn more about the process of fibrosis reduction in the aftermath of density and volume declines. Jörn notes that one important issue here involves differences in how pathologists and AI read changes in fibrosis. Specifically, we sometimes overread fibrosis levels in the presence of fast liver fat reductions. He also notes that we can combine these findings with direct fibrosis measures to learn even more and faster. Louise anticipates that this will provide additional benefits if we can fit patient quality-of-life metrics with this data to pinpoint when in the disease treatment process patients begin actually to feel better. 

Dean goes on to a second point. AI allows researchers to explore reductions in different regions of the liver in terms of how different regions relate to outcomes. He also points out that in Steatotic Liver Diseases, we see that fibrosis continues in parallel with fibrolysis, which researchers now need to consider in the context of overall disease. Roger mentions two items: that Dean has said in private conversation that in AI-based studies, placebo response usually occurs in ~1/3 of patients and, separately, that bariatric studies suggest that one level of regression might require five years. Dean responds by saying that AI allows us to determine when underlying disease is resolving even if the pathologist considers the patient as presenting with regressive disease. 

Roger asks whether AI can be used to assure patients how thoroughly we have studied these drugs and how much we have learned and, separately, to demonstrate more value to payers than we believe using "naked eye" data. Dean suggests the keys will be to simplify the data we present and also to generate a joint statement from the entire community on these issues. 

Looking at 2024, Dean anticipates more and richer data than we have. He also cautions that we should shift from biopsy to NITs in clinical trials before we have developed deeper knowledge on how the liver works and what NITs must capture. In this process, he envisions 2024 as a "proof-of-concept" year before we can move to totally non-invasive monitoring in 2025 or 2026. Jörn, who had dropped off the conversation for a few moments, suggested that AI will improve clinical practice over time as well. 

In closing, Dean states his concern for 2024 is that we shift too quickly from biopsy to NITs. Louise comments that we cannot discredit biopsy (at least, not yet) and that providers can explain to patients why it is necessary.

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Surfing the MASH Tsunami continues its 2023 wrap-up conversations with hepatology researcher and key opinion leader Naim Alkhouri of the Arizona Liver Health Institute, along with co-hosts Louise Campbell and Roger Green. The conversation focuses on viewing the year's major events in drug development, non-invasive tests (NITs) and clinical care pathways.

This conversation starts with Roger asking Naim his reaction to 2023. Naim starts by mentioning his disappointment that OCA did not get approved but shares his vision that the data presentation did not support approval and his hope and belief that resmetirom will fare better. From there, he shifts quickly to discuss being "a little bit disappointed" at the implementation of the AACE and AGA guidelines. In practical terms, he has not seen a single referral from primary care practices (PCP) for elevated FIB-4. He notes that this will require better education of PCPs, but also expresses concern that the guidelines might not be practical for them. In the effort "not to miss a single patient," he believes, authors have created a system with too many patients screened, found negative, and sent back to the PCP. Instead, he suggests, guidelines should have a more realistic goal (reducing unidentified patients from 95% to 80%) and rely on higher FIB-4 cutoffs until PCPs have integrated the concept of MASH screening into their practices. Wrapping up his view of 2023, he describes it as a "good year," although unfortunately one in which drug approval and increased pathway use did not occur.

Roger suggests that the same phenomenon -- worrying more about making things perfect than making them implementable -- applied to the original rollout of the new nomenclature as well as pathways, and goes on to discuss what he sees as the behavioral psychology implications of the pathway guidelines. Naim responds with two suggestions: raise the minimum PIB-4 score at which patients are referred to 2.67 and, in the US, reflex to an ELF test before sending patients to specialists. Louise notes that ELF is not as readily available in the UK as Americans might assume. Roger adds that it might be of value to educate PCPs on the value of FIB-4 as predictive of MACE and other forms of mortality.

Roger asks Naim to describe the "biggest wins" of 2023. Naim starts by citing specific advances in NITs, specifically mentioning NIS-2+ and MASEF (discussed in S4 E39). In terms of medications, he discussed the double- and triple-incretin agonists and their ability to support patients in defatting their livers and notes that, of course, resmetirom's positive Phase 3 results are the biggest story. His third item is the expansion of multi-specialty meetings that educate other specialties on SLD, why it matters, and what roles the other specialties can play in diagnosing and managing MASH patients. 

Roger's next question is about disappointments. Naim wishes FDA had moved further and faster in alternate drug approval pathways and metrics, but sees progress in terms of their openness to exploring NITs and, more exciting, their recently stated willingness to grant full approvals in cirrhosis based on histology. Roger asks how AI fits into the emerging picture. Naim states that AI analyses can teach a great deal about the disease, but is not practical for patient treatment. 

The last question: his most optimistic picture for 2024 starts with resmetirom approval, goes on to mention several exciting potential drug development results and then discusses creating MASL Centers of Excellence relying on robust NITs for diagnosis and management. 

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Surfing the MASH Tsunami continues its 2023 wrap-up conversations with patients and patient advocates Mike Betel of the Fatty Liver Alliance (Canada) and Tony Villiotti of NASH kNOWledge (Pittsburgh, PA), along with co-hosts Jörn Schattenberg and Roger Green. The conversation focuses on viewing the year's major events and upcoming priorities from a patient advocate's point of view. 

The conversation starts by looking at the roles that patient advocates in different countries have played in the global mix. The conversation starts by focusing on highlights and not-so-highlights of the year, with the first group including the return of face-to-face conferences with active patient involvement and education, the second group including the complete response letter for obeticholic acid and the new nomenclature seen as generally positive but somewhere in the middle.

The conversation's first deep dive comes around the new nomenclature. Mike notes that this was an important initiative for every stakeholder in the MASLD/NAFLD community during the year. Tony describes himself as originally having been opposed because of all the re-work it will require for his organization and also because at a 1:1 level, it becomes hard to envision a physician explaining this disease to patients without raising the concept of "fat." They start by discussing liquid tests, but Mike then shifts to VCTE and the idea that Canadian patients wait six months for VCTE, which is not tenable in the long-run. Mike discusses having gone to the Canadian parliament this past spring and that he learned how little members know about MASLD. He sees increased meetings and conversations, particularly with patients telling their own stories, as critical to building government support. 

In response to a question from Roger, both Tony and Mike consider the new nomenclature background noise that will not meaningfully affect how patients and their providers communicate. Jörn notes that in German, he cannot discuss metabolic disease or steatosis because they will mean nothing to the patient, so he uses the term "fat liver," which is the literal German translation. 

The conversation shifts to the concept of "stigma", with Jórn starting by noting that the phrase "fat liver" has little stigma. Tony and Jörn agree that framing the issue properly can overcome any perceived stigma on the part of patients. The group agrees that it will take time for stakeholders to adopt the nomenclature, but, as Mike says, "it's here" and everyone will need to get used to it. 

In response to a question from Roger, both Mike and Tony highlight increased use of and access to non-invasive testing (NITs) as a primary advocate goal for 2024.  They also discuss gaining access to VCTE on a timely basis. 

Roger asks what listeners should consider about working more effectively with patient advocate groups. Mike starts by asking that manufacturers and sponsors bring patients into the clinical trial design process far earlier. He also notes that patient advocate groups need financial support from all sources including manufacturers, to support education. Tony mentions the importance of working with children, going into schools to educate children, and, through them, to reach the parents. 

Advocates' hopes for 2024 start with the idea of resmetirom being approved. Mike looks to learn more about what primary care physicians in Canada are doing now and how he can motivate them to do more. Mike and Roger discuss strategies for working with industry.  Tony mentions the importance of motivating patients to seek their own care. The last comments are around the availability of multi-lingual materials in the two countries. 

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Surfing the MASH Tsunami kicks off its 2023 wrap-up conversations with Jeff Lazarus, the 2023 winner of the Distinguished Scientific Achievement Award from the American Liver Foundation. He discusses three core MASLD-related opportunities for which he played a key role in 2023: the Research in Action initiative, the new MASLD nomenclature process and the Healthy Livers, Healthy Lives coalition.

Most of this discussion focuses on Jeff's work leading the Research in Action coalition. As Jeff notes, this was the first time the MASLD "field has set its own agenda." Absent governmental or not-for-profit agencies driving the discussion, a group that has grown to over 400 collaborators published its own action agenda in AASLD and EASL publications. Jeff discusses the process through which he built this consensus, focusing on domains identified in earlier meetings: (i) treatment and care; (ii) models of care; (lll) increased awareness; and (iv) leadership. Jeff feels the legitimacy of this activity comes from "casting the net wide" with a series of Wilton Park meetings and from demonstrating how far MASLD lagged behind other non-communicable diseases in terms of goal development, structured support and public presence. Another key element in the initiative's success was a side event at the World Health Assembly led by the four major hepatology organizations, including not only AASLD and EASL but also APASL, and ALEH. Efforts to create parity with other non-communicable diseases will result in increased funding and "massive" increases in awareness.

Today, the other NCDs mention other related metabolic diseases but not MASLD or MASH. Another example of the lack of urgency around MASLD: NIH just put out a call for funding for HIV, which Jeff notes might not be as high a priority in 2024 as MASLD.

At this point, Jörn Schattenberg joins the conversation to congratulate Jeff on his recognition and award and also to discuss how important it is to the entire community that Jeff plays the role he does. In response, Jeff comments that one benefit of the Award is that it ratifies the importance of the kinds of consensus building and application of public health initiatives in MASLD space.

From here, Jeff and Jörn step further forward to discuss the importance of funding prevention and education programs, done by governments in the EU and perhaps public or private players in the US. Jörn discusses the multidisciplinary nature of the Barcelona meeting they co-chair and how it provides outreach beyond hepatology. Jeff continues the thought to discuss the importance of social determinants of health (for example, food insecurity) in a world where healthy foods cost far more than more common alternatives (basmati rice costs 3x basic white rice).

Roger asks how the new nomenclature is proceeding. Jeff says it is doing quite well in that there is significant global buy-in. Major centers around the world are adopting the new nomenclature for their meetings and clinics, but, Jeff notes, it is difficult for physicians to explain the disease to patients without using the words "fat" or "fatty."

As the conversation winds up, Jeff notes the importance of bringing primary care to the education and outreach processes and the goal of doubling the number of patients screened over the next four years. The conversation closes on this note: much that must be done, but confidence that the energy to achieve these big goals is coalescing properly.

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This Vault conversation stems from the wrap-up to TLM2022. In the episode, the panel (Jörn Schattenberg, William Alazawi, Naim Alkhouri, Laurent Castera, Ken Cusi, Wayne Eskridge and Roger Green) addresses several topics from the program. This one focuses largely on NITs. 

This conversation focuses on several papers of interest to Laurent. The first is a prospective screening study on patients with diabetes seen in either primary care or a diabetes clinic in the US. Using NITs to screen for NASH and MRE to screen for advanced disease, they identified 65% with NAFLD, 14% with advanced fibrosis and 5% with cirrhosis. When 164 of these patients moved into biopsy, they identified 61% with NAFLD, 30% advanced NASH and 9% cirrhosis. Laurent contrasts these results to a similar study conducted in a French diabetes clinic-treated cohort with transaminase greater than 20 in women and 30 in men. This yielded 58% NASH, 38% advanced fibrosis and 10% cirrhosis.

The panelists then explore the implications of both studies in terms of how screening should be conducted today. Laurent estimates that we might miss ~25% of advanced patients using current VCTE cutoffs without additional parameters. He also notes that neither duration of diabetes nor A1c levels were predictive. The group concludes that, as Ken puts it, studies like these push the needle toward action in both primary care and diabetes settings.

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This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers a pivotal session on the new MASLD nomenclature, plus what the panelists found exciting and important about the developing class of triple agonists, at TLM 2023. 

This conversation starts with Roger stepping gently into the topic of the new MASLD nomenclature by discussing a Saturday morning session chaired by Maru Rinella and Meena Bansal. The session took a broad, fairly detailed view of progress in knowledge and implementation of this nomenclature. Roger's point: two of the three obvious potential downsides to the new nomenclature are now rendered resolved. First, George Makar of FDA stated that the agency now uses the terms “MASH” and “NASH” or “MASLD” and “NAFLD” interchangeably, which means that the nomenclature will cause no delays or rework around drug and device clinical trials. Second, Quentin Anstee and Arun Sanyal reported from the LITMUS and NIMBLE databases that the patient overlap when mapping against the two definitions was 95-98%, which means there should be no dispute around the impact on how we define patient populations. In this regard, Roger notes that Gregory Gores, editor-in-chief of Hepatology, said the journal believes this issue is over and will not accept more publications on the subject. 

The third item is the perceived stigma around the word “fat.” Roger quotes NASH kNOWledge founder and patient advocate Tony Villiotti, who points out that while we may describe a specific medical event as a myocardial infarction, the doctor still tells the patient "You had a heart attack." Similarly, the concept of “fat on the liver” will be essentially to explain what is going on to the patient, whatever the nomenclature says. This leads Laurent to discuss the paper on stigma presented at the conference which suggests that "fatty liver" is far less stigmatizing in general than "obesity" or "diabetes," and some specific nuances of the paper. When he is done, Scott and Roger comment on vastly different moments in history and regions in the world where obesity was actually considered a sign of something positive. 

This entire discussion leads Scott to remember a presentation on Eli Lilly's triple agonist retatrutide and the remarkable impact this class of drugs is likely to have on how we manage obesity, diabetes and liver disease. Roger notes that Altimmune and Merck/Hanmi have similar agents in development. He goes on to note that these drugs demonstrate levels of weight loss found with bariatric surgery and asks Laurent and Scott whether they believe the drugs will have impact similar  to surgery. Both say it is too early to tell. Louise follows this by mentioning a study showing that allied health professionals are proficient at motivating patients to lose weight, maintain that loss, and do so in healthy ways.

Roger's wrap-up question asks what will be different at TLM2024 next year in San Diego. You’ll have to listen to hear the answers.

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This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about liver science, VCTE, regulatory approvals using NITs or AI, and other issues at TLM 2023. 

It starts with Roger sharing his belief that regulators are likely to approve NITs only if a small battery of tests (or ideally, a single test) prove valuable in assessing all agents, or at least all agents, for a stage of disease or segment of the market. Scott notes his frustration that biopsy is an expensive and poorly-graded measure and hopes that FDA will move past semi-qualitative biopsy. 

Roger asks Scott what we learned about basic science in the meeting. Scott discusses advances in single-cell technologies as pivotal in helping us understand underlying disease better, and goes on to mention several presentations on senescent cells that provided insight but, he felt, little for basic drug development. 

Roger then asks Louise what in the meeting she found most interesting. She points to two posters regarding VCTE. The first looks at liver stiffness and controlled attenuation parameter, or CAP in patients after transplantation. Louise describes this as the first time she has seen CAP used as an independent predictor. She mentions a second poster on methotrexate using VCTE as having similar promise to expand VCTE as a research tool.

Louise then goes on to discuss a poster addressing the evolving impact of allied providers in hepatology. In this poster, the authors projected a roughly 1/3 growth in hepatology patients by 2023 requiring treatment, coupled with a roughly 1/3 decline in the number of hepatologists available to treat them. Allied providers in hepatology showed a similar trend. To Louise, this signaled clearly that all countries need to boost the number of allied providers if these patients are to receive the care they will need. As the conversation winds down, Louise and Roger discuss the high level of patient presence and energy suffusing the entire event.

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This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations covering NITs, artificial intelligence and bariatric surgery at TLM2023. 

The conversation starts with Roger discussing a presentation in which Stephen Harrison shared HistoIndex data from the MAESTRO-NASH trial for resmetirom. HistoIndex’s proprietary methods produced results suggesting 34% improvement in the placebo group vs. 54% in the treatment group. More interesting, Dean Tai from HistoIndex suggested to Roger in a private conversation that this 1/3 placebo success rate holds fairly common across trials using these methods. Given that bariatric surgery studies suggest a five-year gap from successful surgery to fibrosis regression, the one-year standard requested by FDA for conditional approval might lead us to understate drug efficacy for resmetirom and later New Drug Applications submitted under these criteria.

Laurent discusses a study from Phillipe Mathurin’s group in France that demonstrates among bariatric surgery patients, MASH resolution and fibrosis regression lead to improved outcomes. His point: it is important that this study confirms the idea that MASH resolution and fibrosis regression do, in fact, lead to fewer Major Adverse Liver Outcomes, or MALO.

The conversation shifts to NITs and the value of biomarkers in proving that a drug is working. Laurent notes that no single market is sufficiently reliable and that we will need a cluster of tests to evaluate any given drug. As an example, he cites the impact of BMI on liver stiffness as a confounder that does not exist in other tests like ELF. Scott asks about HepQuant; Laurent has limited experience but finds the idea conceptually appealing. Scott notes that the slow rollout and low budget might be responsible for the lack of market and academic interest. 

Laurent focuses on a specific poster looking at a database of 16,000 patients over two years. The study shows that an increase in liver stiffness, AGILE-3 or AGILE-4 score all correlate with MALOs.  What the study doesn’t address, and Laurent points up will be key to learn, is whether declines in these measures correlate with improved outcomes among declining patients. 

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This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations of clinical trial results at TLM2023.  

Instead of focusing immediately on MASH drugs, Scott suggested we should not overlook the idea that elafibranor is preparing to come to market in the US as a novel medication for PBC with good efficacy and safety from patients who do not respond well to ursodiol or obeticholic acid. I note that elafibranor is only one of two PPARs speeding toward market in PBC with exciting data given what we all heard in the late-breaker presentation on seladelpar. Scott also mentions to integrin antagonist from Pliant in PSC, a disease with no available solutions today. Laurent agrees with Scott that the rare disease drug advances were more exciting than the advances in more common liver diseases.

I bring up papers addressing the value of FGF-21 and FGF-19 agents in cirrhosis, which showed some promise for compensated cirrhotic patients. Scott politely disagrees, feeling that while these agents might hold disease steady, they do not address the challenges and mechanisms necessary to meaningfully regress disease. We agree there is a benefit to any agent that slows or reverses the course of disease even slightly in that this buys the patient more time to be treated with more exciting medications still in the pipeline. 

Scott notes that for Hepatitis C, a far simpler disease it took 25 years from discovery to cure on a path of incremental process. Scott notes that drug development successes are keeping investors interested, which is encouraging in a challenging environment for investment. 

Laurent returns to the issue of cirrhosis, noting that there are multiple challenges and concomitant bad behaviors like alcohol consumption. He points out that where good studies exist, these are short studies with small samples. Scott points out that MASH is less like hepatitis and more like inflammatory diseases like IBD, where causes of underlying disease are difficult to determine and there is no single pathway in drug development. He buttresses this by noting that in clinical trials, resmetirom provided benefit to only 25% of patients. 

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This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers the four panelists’ general impressions of TLM2023, both the good and bad of it. 
Scott starts with a simple statement: “It was good to be at an AASLD that felt like an AASLD. Specifically, Scott is talking about the energy and excitement associated with the meeting. He also approves of Boston as a meeting location. 
Scott’s meeting worst was the meeting app. The group elaborates on why they all agree. 
Laurent Castera agrees with Scott: bad app; excellent meeting with a great deal of colleague interaction. 
As a virtual attendee, Louise felt her own unique pain with the app. In addition, only 20% of sessions were live, and many were Zoom, which meant ‘Zoom in the US.’ She describes this as the most disappointing meeting experience, and she notes that some people paid $1,200 for it. 
I make two other points: the patient tracks were broad in coverage and highly well-attended, and Saturday night’s Diwali celebration. Scott, Laurent and I agree that the meeting was genuinely crowded and hot…but worthwhile. 
My final comment: tremendous excitement and anticipation about March 14, resmetirom’s PDUFA date at the FDA.