Surfing the MASH Tsunami

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The 2022 NAFLD Summit presented a range of perspectives and insights on fatty liver and metabolic diseases. Program speakers Mazen Noureddin, Sven Francque and Hannes Hagström join Surfer Roger Green, on-site from Dublin to review their reactions immediately after the conference ended. 

In this episode, the panelists discuss presentations and sessions they found particularly compelling. The group notes Session 7 from Day 2 as an attractive line of topics covering overlooked issues in clinical trials. While difficult to quantify the impact on clinical trials, the data supports approximately 10% of patients with NAFLD underreport alcohol consumption. Hannes’ own presentation at the NAFLD Summit covered this subject. However, his concern lies in possible patient reluctance to enter a clinical trial in response to ‘the elephant in the room.’ Roger and Mazen are optimistic that simpler, faster biomarkers will help overcome this challenge. Mazen also shares his interest in Sven’s presentation which provided an introduction to cardiovascular comorbidities within the same theme of Session 7.

Next, Sven focuses on the strengths of consulting with non-hepatologists on how the treatment of comorbidities affects NAFLD. They provide different, more holistic perspectives than one typically hears in a hepatology-centric event. Recently, this podcast has begun to focus on multi-organ metabolic effects more frequently. Patients rarely face NAFLD or NASH as an isolated liver problem. More often, other metabolic diseases ride along with it. Sven emphasizes that the researcher must keep the entire scope in focus when designing and executing NASH trials.

This episode is sponsored by Resoundant, a Mayo Clinic company and the developers of Magnetic Resonance Elastography. MRE is widely available with over 2000 locations worldwide, and can be done as a low-cost, rapid exam in just 5 minutes. Together with PDFF, this quantitative exam is called an Hepatogram – a powerful non-invasive alternative to liver biopsy in many cases. For more information, visit www.resoundant.com on the web.

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The 2022 NAFLD Summit presented a range of perspectives and insights on fatty liver and metabolic diseases. In this episode, program speakers Mazen Noureddin, Sven Francque and Hannes Hagström join Surfer, Roger Green, on site from Dublin to review their thoughts and key takeaways immediately after the conference ended. Roger starts by asking each to choose and elaborate on one presentation or session of particular interest. Hannes is the first responder, establishing Session 7 from Day 2 as an attractive line of topic covering overlooked issues in clinical trials. While difficult to quantify the impact on clinical trials, the data supports approximately 10% of patients with NAFLD underreport alcohol consumption. Hannes’ own presentation was tied to this subject. However, his concern lies in possible patient reluctance to enter a clinical trial in response to ‘the elephant in the room.’ Roger and Mazen commend Hannes on the presentation, noting the optimism that simpler, faster biomarkers lend to the matter. Mazen extends commendations to Sven also, for his introduction and exploration of cardiovascular comorbidities within the same theme of Session 7. 

Next, Sven introduces his interest in two sessions from Friday afternoon. Specifically, he contemplates the strengths of consulting with non-hepatologists on how the treatment of comorbidities affects NAFLD. Moreover, some of those participating endocrinologists, bariatricians and other specialists possess long-standing expertise in metabolic diseases, but not necessarily NASH. They provide more holistic perspectives than one typically hears in a hepatology-centric event. As the group notes, patients rarely face NAFLD or NASH as an isolated liver problem. More often, other metabolic diseases ride along with it.

The conversation continues to highlight what differentiates NAFLD Summit from other major liver meetings. Mazen states that both the NAFLD Summit and NASH-TAG allow for a deeper dive into more provocative discussions around how to advance the field. Then, Hannes proposes the group consider stability of fibrosis worthy of investigation as an outcome. Mazen replies that preventing decompensation and associated outcomes can serve as a goal that makes fast Phase 3 cirrhosis trials possible.

Next, the group assesses Session 9 from Friday, a series of case studies on why trials fail. The panel agrees that the presentations on three failed Phase 3 trials were richly valuable and that each offered its own clear lessons for researchers.

Following, the group examines weight change and lifestyle modification, referencing insights from the obesity and diabetes fields. Roger plays the role of Louise, elucidating the immediate impact FibroScan has on illustrating results and influencing patient motivation. Improvements in patient management do have a role in contributing to better outcomes. On the other hand, there is also the pressure of minimizing placebo rates in trials. Mazen is confident in the existing data and analyses that set precedent for placebo response rates. 

Finally, Roger calls attention to a debate around NITs that took place on the opening day. Mazen Noureddin revisits what he has described on this podcast as the coming “combo-combo” world. However, Sven utters a word of caution: it is still important to evaluate the limitations of NITs. The episode concludes with a round of final reflections. Tune in and surf on for the full review.

This episode is sponsored by Resoundant, a Mayo Clinic company and the developers of Magnetic Resonance Elastography. MRE is widely available with over 2000 locations worldwide, and can be done as a low-cost, rapid exam in just 5 minutes. Together with PDFF, this quantitative exam is called an Hepatogram – a powerful non-invasive alternative to liver biopsy in many cases. For more information, visit www.resoundant.com on the web.

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In Season 3, Episode 19, the content focus looks at what the retrospective analysis from the NAIL-NIT consortium can achieve in terms of moving the shift beyond the biopsy in NASH diagnostics forward.

This conversation starts with Stephen discussing how challenging it was to develop initial FDA test criteria for evaluating NASH drugs. Many years later, he notes, we have learned how flawed these criteria were, several in ways we cannot fix, but we need to do better. He relates this to what the British author Rupert Sheldrake describes as “morphic resonance” or mysterious telepathy type interconnections between organisms and collective memories within species. One thing leading hepatologists have learned is that you can look at a liver or liver data and get a clear since you are looking at NASH, but it is harder to generate and vet consistently clear data on this point. He points to the REGENERATE trial as a place where specific data analysis did not reflect the gestalt impression and says, “that is what we need to get beyond.”

Louise Campbell interjects a very different kind of question, asking whether the NAL-NIT analyses can include questions that patients answer on initial screening in pursuit of AI-driven analyses of these questions to screen patients into or out of further tests..an idea that draws an immediate, enthusiastic response from Naim Alkhouri. In the end, the discussion turns light-hearted and focuses on how many papers the panelists will have to produce in the first year of the program.

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In this episode, the group covers the Day Two program and offers final thoughts on the Paris NASH 2022 review.

The conversation starts with Louise introducing the discussion around estrogen replacement therapy and fatty liver in post-menopausal women. She notes this an area of opportunity for improving women’s health.

Next, Arun Sanyal’s science lecture on NITs is discussed. The lecture is noted to be less about groundbreaking science and more so a clear description of the thinking behind developing an NIT diagnostic pathway. This pathway starts with FIB-4 and goes into more accurate (and expensive) tests for patients that FIB-4 does not rule out.

From there, the conversation shifts to one last discussion about the ways that liver disease is central in the cluster of chronic non-communicable metabolic diseases. Finally, Roger offers the closing question. Each responds with their feelings toward the future of NASH, NAFLD, metabolic disease, and interdisciplinary collaboration.

Listen on for the Surfer’s, and Jeff McIntyre’s, final thoughts on Paris NASH 2022.

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This episode addresses the other talks in Session 5 focusing on clinical trial innovation, after Frank Anania’s opener.

Roy Sabo presented a cogent, comprehensible discussion of the value of adaptive trial strategies. Roger relates the presentation to a conversation on the NASH Tsunami last month with Stephen Harrison. Stephen introduced an example of adjusting FibroScan thresholds to boost the number of patients who could enter clinical trials. Roger commends Sabo on the “wizardry Bayesian statistics.”

The following two talks discussed organizing patient databases in ways that simplified trial recruitment and had the potential to reduce screen fail rates. Lastly, the group explores the pros and cons of educating patients on improving self-care. The benefit is that it creates a larger, ready-made patient pool and improves overall health. The drawback is that it increases placebo rates in clinical trials, thereby requiring drugs to perform better to demonstrate statistical difference. However, in a world of well-informed patients practicing aggressive health self-management, there should be the expectation that drugs offer better performance.

The conversation finishes with covering the rest of the day one program.

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The episode starts with Louise sounding an alarm about the rate of growth for cirrhosis and bridging or advanced cirrhosis. She is concerned that as more data is collected, an increasing number of lives fail to be served with the passage of time. She then mentions a talk by Oxana Drapkina from Session 1 about how the Russian system operates. On the surface, this sounds to be more efficient than Western approaches.

Next, Jeff and Jörn share their thoughts and satisfaction on the closing session, in which both participated. The diversity of regional challenges and the varied positions of the panelists led to a lively and far-reaching discussion. In response to a question from Jörn, Jeff expands on what he learned while working on food policy in the Obama White House.

In the final part of this episode, Roger raises a few issues of interest. He discusses the ability to educate and work more quietly in Congress than in public venues. He also mentions the value of educating physicians to think of Fatty Liver issues when treating other metabolic patients. Louise joins to consider the idea that while different specialties look down organ silos, reality often presents an integrated metabolic challenge.

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The episode begins with the panelists - Jörn, Louise, Jeff McIntyre of GLI and Roger - discussing one thing each found particularly striking at the recent Paris NASH meeting.

Most comments centered around three themes:

1. A general appreciation of the quality and diversity of talks at Paris NASH.
2. Disappointment with the regulatory response from Frank Anania of FDA on the question of moving beyond biopsy and changing the shape of conditional drug approvals.
3. The “dynamic tension” between forces pushing for rapid progress vs. forces slowing pace of development.

The group further considers the influence of providers, manufacturers and patients versus that of regulators and payers. Jeff and Roger agree that payers are likely to present the last- and likely highest- barrier to rapid progress on prescription medicines and testing.

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The importance of integrating the NAFLD and NASH field within a wider scope of metabolic health was emphasized at the 8th Paris NASH Meeting. Last week, Surfers Roger Green, Louise Campbell and Jörn Schattenberg were in attendance alongside patient advocate and episode guest, Jeff McIntyre.

The conversation starts with Roger asking the group about one thing each found particularly striking from the meeting. Jörn responds first, noting his many appearances across the history of the event. He thinks this year’s dominating theme to be the engagement of regulatory questions that address moving beyond biopsies and conditional drug approval. Jeff joins to echo this takeaway, adding that he is intrigued by the multinational dynamics of the meeting. Next, Louise recalls a more specific crux. In response to an industry roundtable, she suggests that with the wealth of data provided from clinical trials it is now time to consider changing endpoints. Lastly, Roger offers his general thoughts on witnessing the shifting tensions between the scientific and patient advocate positions and the regulatory and payer responses. The group then compares the American and European positions on moving the field toward a more metabolic perspective. They consider where this pressure comes from in terms of regulators, patients, payers, politicians and employers.

Moving on, Roger asks the group for an example of one particular talk or panel that grabbed their imagination and why. Louise returns to the statistics surrounding NASH. She reminds that while the field searches for more data, an expected rise of 110-125% in advanced liver disease and mortality by 2040 is underway. Given the influence of obesity on this rise, Louise highlights the role of allied health professionals in providing lifestyle guidance to mitigate disease progression from an earlier stage.

In the closing session, both Jörn and Jeff reflect on participating in discussions surrounding the role of the patient voice and developing a global strategy for NASH. This leads the group to explore the potential for public advocacy in the field of NAFLD and NASH. Afterwards, Roger brings focus to educating physicians and other healthcare professionals on the nature of metabolic disease. By developing an understanding of the multifaceted application of many drugs in a metabolic context, the wait for an F1 or NAFLD drug approval can be possibly eliminated altogether. Louise adds that a pivot is required to move away from organ-centric thinking.

Next, the group provides their thoughts on Session 5, starting with response adaptive trial design to pick the best dose. Roger and Jörn share ideas on clinical trial criteria and the use of Bayesian priors in enrichment strategies. Jeff also revisits the role of patient involvement in this topic.

Roger then suggests the four go through and connect missing dots between sessions covered in the conversation thus far. After that, the final response:

Louise looks toward a bright future with metabolic coordination. She believes patients are key in developing person-centric approaches. 

Jörn believes that addressing multiple organ systems is the way forward and that it is necessary to partner with other disciplines. 

Jeff feels grateful for his participation as a patient advocate. He says he is looking for the experience of the science, which in the end feels positive to him. 

Roger reiterates the importance of investigating these discussions as Paris NASH does. “One thing that became clearer to me in this meeting than it's ever been before, is that this is all about metabolic disease.” He is hopeful. 

Surf on for the full review.

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This week, Surfing the NASH Tsunami discusses a preview of the 8th Paris NASH Meeting taking place on September 8th & 9th, 2022. Paris NASH is a meeting for basic science and interdisciplinary thinking. Key opinion leaders from both sides of the Atlantic come together to present pivotal learnings and host exciting discussions on fatty liver diseases.

In this conversation from September, 2021, Jörn Schattenberg, Stephen Harrison and Roger Green review some highlights from last year’s Paris NASH conference. This conversation is the summary of conference high points and lessons. From the second day, Jörn chose to mention several talks he felt made particularly important points. This includes a session, “NASH Around the World,” that demonstrates the scale of the global challenge by looking at major countries around the world. Finally, Stephen and Roger join Jörn in selecting one key takeaway from the meeting and their conversation together.

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Roger starts by asking Jeff to describe his role in the NAFLD Summit and to discuss any other presentations of interest outside of his own. Jeff shares that he will be talking about evolving models of care and future implications. His interest in the session stems not just from his presenting, but from the session title, "Epidemiology, Disease Modifiers and Models of Care," and the opportunity it presents to, as Jeff puts it, "hammer home" the importance of integrated care and pathways. He also mentions the importance of the sessions covering NITs, which are pivotal to the way forward, new approaches to lifestyle modification and drug clinical trials and development. 

The conversation shifts Jeff's other activity in Dublin: meeting with industry and other colleagues to build momentum for an upcoming meeting at Wilton Park to build on the momentum of the 2021 global consensus statement on NAFLD. (This was the topic of Season 2, Episode 59.)  

The conversation veers into two other topics of relevance. First, Jeff draws a link between the importance of viewing liver disease in a truly multi-disciplinary context with the broadening of presentation topics at major meetings. He points out that if we want colleagues from other medical specialties to join in efforts to contain the coming NAFLD pandemic, medical meeting agendas must include enough topics of interest to them to broaden the prospective set of attendees. The second issue involves engaging the WHO to incorporate liver disease into its global health priorities.