Surfing the Nash Tsunami

The last month has witnessed several major Fatty Liver conferences and others that touch on NAFLD in the context of metabolic disease. One common theme has been the need for different specialties to align in treating the complete range of non-communicable metabolic diseases. In this episode, Roger Green, Jörn Schattenberg and Louise Campbell propose factors that have the potential to dramatically shift the force around fatty liver disease over the next six months.Jörn starts the conversation with a personal example of a larger trend: he attended last month's EASD meeting for the first time. Historically, few hepatologists attend this meeting, but Jörn believes his attendance is indicative of a trend: hepatologists and endocrinologists working together on diabetes and NAFLD. Louise echoes the sentiment that liver health is gaining traction as a critical function of holistic patient management, although cardiology appears to be slow on the uptake.Roger links this collaborative energy to a completely different kind of energy formation: capital investment. He notes Akero's recent filing for $230 million in equity to help bring efruifermin to market based on Phase 2b results. If this effort succeeds, Roger suggests that it may signify that the financial markets are becoming more optimistic about NASH drugs after several years of extreme skepticism.Next, Jörn returns to his original theme to discuss how endocrinologists have received the concept of liver disease as part of multimorbidity management in patients living with T2DM. He reports that endocrinologists have been enthusiastic about the idea and eager to learn the liver testing tools and metrics they should use.The group then responds to the AACE guidelines promoted last May. The guidelines recommend that front-line physicians not screen their T2DM patients for NAFLD, since 80+% will test positive. Instead, guidelines recommend using a FIB-4 test to identify patients at risk due to current fibrosis. Roger asks whether these will move into actual practice. Louise and Jörn each state that in their countries, front-line treaters are not required to perform liver enzyme blood work. These tests are pivotal for early liver screening. Louise doubts that change will come until after an expensive drug is approved, at which point there will be economic motivation to test. Jörn is more hopeful that with simple tests, he and other hepatologists can educate endocrinologist colleagues on the reasons to adopt this testing strategy over time.The conversation shifts to speculation as to whether prescribers or payers will be the source of bottleneck in patient care pathways at the outset of a drug approval. The group generally agrees that pushback will come from the payers and that healthcare systems are not yet ready. They then look towards the social and political will to take action on the crisis. In response to Roger's question, the group acknowledges the immense hurdles present in changing provider behavior over the next 6-12 months while stressing the importance of provider education and patient empowerment.Finally, the group discusses the future of the recently coined “combo-combo world,” where correct diagnosis will require a combination of biomarker tests and treatment may require a combination of therapies. At the end, Roger asks what changes each member envisions. Surf on to find out.

The 2022 NAFLD Summit presented a range of perspectives and insights on fatty liver and metabolic diseases. In Season 3, Episode 46, program speakers Mazen Noureddin, Sven Francque and Hannes Hagström join Roger Green on-site from Dublin to review their reactions immediately after the conference ended. The panelists note the impact of weight change and lifestyle modification in clinical trials while utilizing insights from the bariatric and diabetes fields.In this episode From the Vault, Roger Green, Stephen Harrison, Ali Aminian and Wayne Eskridge discuss how weight loss and GLP-1s or Double/Triple Agonists in relation to SPLENDOR. This conversation comes from Season 2, Episode 61.3.Season 3, Episode 46 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.

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. This final conversation begins with Roger calling attention to a debate around NITs that took place on the opening day of the meeting. Mazen revisits what he has described on this podcast as the coming “combo-combo” world. The group generally agrees that biomarkers in primary care ought to be simple, cost effective and accessible. However, Sven utters a word of caution: while acknowledging the positive potential of NITs, it is still important to evaluate its limitations.The episode concludes with a round of final reflections. Roger asks for panelists to forecast the most important thing that will have changed between now and when we return for the NAFLD Summit 2023. Surf on to find out what the panel predicts.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.

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 Roger Green on-site from Dublin to review their reactions immediately after the conference ended. In this conversation, the panelists examine the impact of weight change and lifestyle modification in clinical trials while utilizing insights from the bariatric and diabetes fields.This conversation continues the issue of Hawthorne effects in trial design. Hannes starts by noting we can learn from obesity trials – and also from TV shows like “Biggest Loser” – that people regain weight without continued support. Roger shares a thought he believes might have come from absent co-host Louise Campbell, recalling the immediate impact FibroScan has on illustrating results and influencing patient motivation. Sven notes that the issue of lifestyle management in a NASH trial has been a significant issue for the Liver Forum and other supportive groups in terms of trial design and also the power calculations that shape trial size. Mazen closes the discussion by stating that recent meta-analyses show that placebo rates tend to run around 20% and that this might be the right placebo result for power calculations. As the conversation winds down, he shares his guiding principle for these issues: “Prepare for the worst and hope for the best.”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.

The 2022 NAFLD Summit presented a range of perspectives and insights on fatty liver and metabolic diseases. In this conversation, the panelists explore issues around clinical trial design, focusing specifically on the value of Phases 2a and 2b and whether improvement in patient self-management during trials is a research artifact or a replication of reality. This conversation addresses two issues in clinical trial design. First, Roger Green draws on the Session 9 discussion of failed trials to ask which is the right way to proceed when a drug in a Phase 2b trial fails to reach its primary endpoint but a subanalysis reveals a second possible path to Phase 3. He notes that this was the case with elafibranor, one of the Session 9 case studies, as well as obeticholic acid, a drug whose Phase 3 trials met its efficacy endpoints but is not yet approved due to regulators' seeming perception that it lacks an acceptable cost:benefit ratio. The group points to reasons these may have been solid decisions before noting that the market and scientific community both expect higher performance from drugs today than they did several years ago. Mazen Noureddin asks whether exceptionally promising drugs might consider moving directly from Phase 1b to Phase 3; the group agrees that Phases 2a and 2b will have value for virtually every drug at this time. The final question comes from Roger, who asks whether improvements in patients' diet and lifestyle during the clinical trial constitute a “Hawthorne effect,” as some stated on Saturday morning. He notes that in the literature, a Hawthorne effect is a change that might affect clinical trial results but will have no meaning in day-to-day practice. By that standard, improvements in patients' diets and lifestyles do not constitute a Hawthorne effect since we want to effect these behaviors in all patients. Mazen Nouredin disagrees, noting that after trials, patients' behaviors tend to revert to pre-trial levels, thus making improved behavior a confounding factor in analyzing trial results. The group comes to no clear consensus on this issue.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.

The 2022 NAFLD Summit uniquely 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. At the outset of this episode, the group discusses the benefits of participating in a smaller conference more focused on the challenges presented by the field of NAFLD. Mazen likens the NAFLD Summit to NASH-TAG, asserting that these specific conferences advance the field and address deeper layers around the issues that matter most.Mazen goes on to raise the issue of glycemic control and the impact of glycemic control on NASH drug performance. This bleeds into a brief point about the value of simply stopping fibrosis progression instead of the need to prove regression. He then identifies two sessions he considered particularly valuable: the Saturday morning autopsy of failed Phase 3 trials and therapeutic discussion about drugs at different stages in development. This segues into a discussion of optimism derived from the recent Akero and Altimmune results. In terms of Altimmune, Mazen asks whether the drug should go directly from Phase 1b to Phase 3. The panel generally believes that Phases 2a and 2b have value for virtually all development drugs. Further, 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.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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Roger Green starts this interview with Jeff Lazarus by asking what Jeff has been focusing on since the Barcelona conference in May. Jeff describes his extensive daily efforts to develop and garner support for a global consensus strategy on COVID-19, similar to his work on a global consensus statement on Fatty Liver disease. (This was the topic of Season 2, Episode 59.) Like the Fatty Liver work, his COVID-19 consensus work included representatives from over 200 countries with an array of public, academic and not-for-profit portfolios. However, he suggests that the high levels of agreement and, sometimes, virtually unanimity evident in the Fatty Liver work was impossible to match on an issue as immediate and terrifying as COVID-19.Roger then asks about the NAFLD Nomenclature Conference. Jeff describes the conference as a midway point for a Delphi process to explore the prospect of assigning a new name(s) in the description of fatty liver diseases. Jeff describes the six principles any name change must achieve:AffirmativeAccurate Adaptable Adoptable Applicable Able.The rest of this conversation covers prospects for success of the Nomenclature effort and the nature of the challenges ahead.

The group concludes the preview of the upcoming Paris NASH conference after taking a thorough look at the diversity of topics in Session 5. Roger Green poses the closing question: What insights or energy would you like to see come out of this event? What is the immediate response, and what's going to stick after 3 to 5 years?Jörn Schattenberg indicates his interest in the future of drug development and what implications this meeting will have on it. In a more immediate sense, he notes an interest in the more recent learnings of disease biology covered in Scott Friedman's basic science sessions.Louise Campbell anticipates an immediate integrated response as a result from this meeting. She suggests a joint meeting between specialists to tease out the implications of liver health in a holistic outcome. “We don't try and repair a car without opening the bonnet to look at the engine - but we're trying to solve diabetes, cardiovascular disease and all of the other linked metabolic diseases without taking the lid off the liver.”Rachel Zayas looks for a joint response across specialities to activate steps to break down thinking in terms of “organ silos.”Roger provides his final thoughts by way of a double entendre on the word “global.”. Global refers to how widely NAFLD-associated challenges vary in different parts of the world, but it also refers to the liver as part of a holistic web of non-communicable metabolic diseases. He concludes, “We need to understand how we're going to address this in different parts of the world, but as the challenges vary, we also need to understand how we're going to address the whole body in the context of the liver.”

This conversation picks up focusing on the program's opening session: Epidemiology and Public Health. Roger, Louise and Jörn begin to unpack the field of NASH in terms of adopting a holistic, metabolic approach. Roger asks, “How much of NASH are we thinking about in a holistic metabolic sense versus how much do we pay lip service to that, but really focus on the liver?”In response, Rachel poses a strong question for the surfers. “What do you hope to get out of this session with an integrated approach between specialties? And how is that going to move the field forward?” Jörn takes the first shot. He suggests that data and insights might point the field toward pathway refinement and help identify where patients are lost on this journey. Louise agrees, noting one specific point of challenge: liver patients frequently present too late in the journey.Next, Roger offers his take. “One of the problems the liver has always had is that nobody knows how to measure fatty liver disease.” How will the field move forward? He suggests the way to appreciate the importance of fatty liver disease is to demonstrate how many metabolic diseases and deaths it contributes to, using direct links. “If anybody can provide data that says, if you see this in the heart, the kidney, wherever, that's likely to be a liver issue or more likely to be a liver issue.” From here, the field can start to broaden the context of liver health in a more holistic sense.Rachel then provides her answer. She is looking for strategies to link fatty liver with cardiovascular disease. Suggesting the establishment of if, then statements, Rachel looks to elucidate what actionable results can be taken with those links.

In this conversation, Roger Green, Louise Campbell, Jörn Schattenberg and Rachel Zayas share their particular interests in what's to come from the 6 sessions hosted at this year's Paris NASH Meeting.Rachel identifies a presentation in Session 2: Clinical Aspects, titled Controversy: are HIV infected patients more at risk of NASH? She notes the specific challenges faced by HIV patients and shares her hope the prompt leads to speculation on how to improve patient stratification. Rachel also brings forth a concept of moving beyond ideas of personalized medicine to what she describes as a more “intentional approach.”Staying in Session 2, Jörn draws anticipation toward a talk by Cyrielle Caussy titled, Type 2 diabetes sub-populations with varying outcome profiles. He is curious to learn something about which type two diabetes patients are more severely liver diseased. Jörn also mentions an interest in the last remaining presentation in Session 2, with Kris Kowdley discussing the natural history and clinical outcomes in adults with NAFLD - lessons from cohort studies and placebo arms of trials.Next, Louise calls attention to the opening session and her interest in the integration of the liver under cardiometabolic health. This topic will be presented by Faiez Zannad. Additionally, Louise mentions NASH PASS. In Session 5, Marcus Hompesch discusses three years of data & experiences on a metabolic disease focused patient registry and biobank supporting biomarker and drug development research.Also in Session 5, Frank Anania of the FDA presents on a subject recently explored in last week's episode 43: How to approach combination therapies for NASH. Following, Roy Sabo discusses response adaptive trial design to pick the best dose. This piques Roger's interest.The tone of this conversation conveys a sense of excitement about what this meeting will bring.

The 8th Paris NASH Meeting takes place on September 8th & 9th, where key opinion leaders from both sides of the Atlantic come together to present pivotal learnings and host exciting discussions on fatty liver diseases. Surfers Roger Green, Louise Campbell, and Jörn Schattenberg are joined by Rachel Zayas to discuss this year's program and provide preview commentary on talks and sessions of interest.Roger opens the floor by asking everyone to highlight what specifically stands out to them on the program to look forward to. “Brave one go first.”Rachel notes a presentation in Session 2: Clinical Aspects, titled Controversy: are HIV infected patients more at risk of NASH? Emerging data and insights will be discussed as to why the prevalence of NAFLD, NASH and subsequently fibrosis present higher in HIV-infected patients in comparison to the general population. Rachel hopes the prompt leads to speculation on how to improve patient stratification. She suggests the field is moving beyond ideas of personalized medicine to what is described as a more intentional approach. Jörn echoes Rachel's interest in this topic. There is the need to address not only individuals, but also a group of overlooked patients that call for an intentional and stratified investigation into potentially shared biomarkers. Session 2 also features a discussion on type 2 diabetes sub-populations with varying outcome profiles, solidifying the Clinical Aspects leg as a ‘can't miss' for the whole group.Next, Louise calls attention to the opening session and her interest in the integration of the liver under cardiometabolic health. “That's where we're going to find the breadth and depth of patients for future NASH studies.” She asserts that a larger recruitment to clinical trials will be required in the next 3 to 5 years to move the field forward.Roger relates the relevance of last week's episode on finding the right combinations for NASH therapy. Friday afternoon features a look into the current status and future directions in NIT-based drug development and clinical management of NASH.The conversation shifts to comparative outcomes of the Barcelona meeting and its focus on pathways before transitioning into part 2 of this episode: a one on one interview with Prof. Jeff Lazarus. Much of Jeff's summer was spent working in preparation for the impact COVID will have on the northern hemisphere this autumn. However, he also managed to attend the NAFLD Nomenclature Conference in Chicago. The conference is described as a midway point for a Delphi process that explores the prospect of assigning a new name(s) in the description of fatty liver diseases. What was determined is that should a name change occur, it needs to be organized through global consensus and consistent with the following 6 principles:AffirmativeAccurateAdaptableAdoptableApplicableAbleRoger believes that the meeting was successful at strengthening consensus on this topic. He then asks Jeff to describe his role in the NAFLD Summit and to mention any other presentations of interest outside of his own. Jeff shares that he will be talking about evolving models of care and future implications. Specifically, he is also interested in attending discussions and panels around the impact of NITs in addition to the topic of personalized medicine. Likewise, Roger expresses an interest in emerging technologies before offering a final question - or, rather, a request for commitment. Will Jeff return to the podcast to disclose what occurred at the Wilton Park meeting this October? It seems he might, after a few weeks digestion. Stay tuned, stay safe and surf on.

This conversation from The Vault - Season 3, Episode 25.3 is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg. It starts with Louise Campbell asking whether design and management of the ongoing trials will provide sufficient granularity on matching patient types to medications or drug classes. Stephen Harrison notes that we have not paid sufficient attention to this issue historically. In fact, he notes a range of key variables we do not explore at baseline: genotype disease markers like PNPLA3, microbiome and non-Caucasian population segments, to name three. He also notes that some promising drugs have been killed because of trial design issues. In the end, he returns to core positive concepts: combination therapies, looking for agents with multiple positive metabolic effects and safety.At this point in the conversation, Stephen's transmission starts to fail. Eventually, he leaves the conversation and focus shifts to cirrhosis.This episode from the Vault is sponsored by Madrigal Pharmaceuticals. 

The group investigates potential for different combination packages, beginning with Roger's suggestion for an oral semaglutide. Naim notes that there are other combination trials in the works that may provide more insight.The episode then wraps up with Roger's final question: in seven years, what percentage of patients being treated for NASH fibrosis, non-cirrhotic then cirrhotic, will be treated using combination therapies? Naim thinks the majority of patients with NASH cirrhosis will be on combination therapy, and the majority of patients with F2 or F1 fibrosis will be on monotherapy. He also thinks F3 will see a trend of adding more agents over time to prevent progression to cirrhosis. Mazen suggests in seven years we will not get to combo for NASH patients because of regulation, partnership, and logistics. Louise settles for a position between Naim and Mazen. Jörn highlights that many hurdles remain, especially in identifying these patients. Roger agrees that these diagnostics will be hard to scale over the next seven years. He also imagines there to be less combination packages and more step therapy.

This conversation begins with a broader look at the strategies behind developing combination agents and the role these combination therapies will play in what Mazen Noureddin describes as the coming “combo-combo” world.The group agrees that 2 or 3 agents are the most they can see in a combination therapy at this time. They all agree that some patients will require combination therapies while others will succeed with monotherapies. This will be linked with disease severity. Naim also shares another long term study he is working on.

The discussion shifts to the challenges behind collaborating in a field that, as Naim puts it, “no one has figured out what to do with.” Mazen calls on the “larger companies” to work with the smaller ones to make these studies more common, noting that the economics and risk profiles of smaller companies require them to focus on getting a single drug to market as quickly as possible. Naim notes that precedent has taken form in Hepatitis C. It was very difficult to treat and different companies' drugs were combined for a while until each company figured out their own combination and that collaboration stopped.A debate next emerges when Naim describes LEGEND, a trial combining the promising PPAR agonist with the SGLT-2 agent, empagliflozin. Naim describes empa as an excellent agent to counteract potential weight gain with lani. Mazen shares his belief that the trial should have combined lani with a drug that provides greater weight loss, possibly a GLP-1 agonist or dual agonist. Roger suggests it depends on the target: liver and metabolic disease targeting might lead to a PPAR/GLP-1 combination, while a more holistic look at metabolic outcomes might prefer SGLT-2s for their proven beneficial effects on kidney and cardiovascular diseases.

Naim opens this conversation with his hope for finding eventual combination therapies that begin to realize a cure for NASH in some patients. In particular, he is encouraged to see so many patients achieve greater than 30% relative fat reduction in such a short study. Louise notes that the ability to show patients “real-world results” quickly will motivate them to maintain therapy and lifestyle modification.The discussion shifts to the inclusion of NITs in these combination therapies, and the need for sound pricing strategies. Naim proposes a 6-month “futility” standard: if the drug does not provide results in 6 months, discontinue. Roger notes the importance of combination therapy in a disease that has so many theoretical target points and pathways within the liver.

This discussion begins with Naim offering an in-depth look into the mechanics of the recently published combination study. He explains that “semaglutide hits every point” in terms of effects on metabolic syndrome, cardiovascular outcomes, obesity and liver fat, but it has not yet been proven in monotherapy to regress fibrosis. Gilead Sciences had three agents whose potential anti-fibrotic effects the company wanted to explore fully, so Gilead and Novo Nordisk, which owns semaglutide, formed a partnership to develop these drugs.One agent, selonsertib, turned out to be ineffective, but the other two, the FXR agonist cilofexor and the ACC agent firsocostat proved efficacious in combination with semaglutide. Naim goes on to describe the mechanics of the study and presents results demonstrating that even in a six-month trial, the triple therapy proved efficacious with a favorable side effect profile.Jörn notes one very important aspect of combination agents: by requiring lower levels of each individual agent, they have the potential to exhibit superior safety and side effect profiles that a higher-dose monotherapy might.The rest of this conversation features additional comments by Mazen, namely addressing the short duration of the study. He suggests that if extended, the study quite possibly had more positive results to be shown, namely, through further weight loss. Mazen also raises an intriguing prospect with an interesting acknowledgment: this is an open-label study with neither biopsies nor a placebo arm. However, he suggests, this kind of design will become far more prevalent in a future when one agent in the study has already been approved and is widely used with patients.

This episode explores the future of combination agents in NASH Therapy. First author Naim Alkhouri and last author Mazen Noureddin join the Surfers to discuss their recently published article, Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial (JHEP, 2022). While the conversation starts by focusing on this article, the discussion itself takes a far broader look at the strategies behind developing combination agents, the likely role these combination therapies will play in treating patients, and, more generally, what Mazen Noureddin describes as the coming “combo-combo” world.At the outset, Naim notes that while this study was published in 2020, it was first presented at AASLD in 2020. The rationale? As he explains, “semaglutide hits every point” in terms of effects on metabolic syndrome, cardiovascular outcomes, obesity and liver fat, but has not yet been proven in monotherapy to regress fibrosis. Novo Nordisk and Gilead Sciences had formed a partnership to develop NASH drugs, and Gilead had two agents with anti-fibrotic effects, the FXR-agonist cilafexor and the ACC agent firsocostat, that might regress fibrosis.This conversation is dense with excellent questions and important observations. Here are some of them:Jörn notes one very important aspect of combination agents: by requiring lower levels of each individual agent, they have the potential to exhibit superior safety and side effect profiles that a higher-dose monotherapy might. In agreeing, NAIM notes with particular enthusiasm how many patients achieved greater than 30% relative fat reduction in such a short study.Mazen raises an intriguing prospect by starting with an interesting acknowledgment: this is an open-label study with neither biopsies nor a placebo arm. However, he suggests, this kind of design will become far more prevalent in a future when one agent in the study has already been approved and is widely used with patients.Louise notes that the ability to show patients “real-world results” quickly will motivate them to maintain therapy and lifestyle modification.Naim proposes a 6-month “futility” standard: if the drug does not provide results in 6 months, discontinue.Roger notes the importance of combination therapy in a disease that has so many theoretical target points and pathways within the liver.Mazen calls on the “larger companies” to work with the smaller ones to make these studies more common, noting that the economics and risk profiles of smaller companies require them to focus on getting a single drug to market as quickly as possible.A debate emerges when Naim describes LEGEND, a trial combining the promising PPAR agonist with the SGLT-2 agent, empagliflozin. Naim describes empa as an excellent agent to counteract potential weight gain with lani. Mazen shares his believe that the trial should have combined lani with a drug that provides greater weight loss, possibly an GLP-1 agonist or dual agonist. Roger suggests it depends on the target: liver and metabolic disease targeting might lead to a PPAR/GLP-1 combination, while a more holistic look at metabolic outcomes might prefer SGLT-2s for their proven beneficial effects on kidney and cardiovascular diseases. The group agrees that 2 or 3 agents are the most they can see in a combination therapy at this time. They all agree that some patients will require combination therapies while others will succeed with monotherapies. This will be linked with disease severity.There are more observations here and a raft of supporting data points and arguments. We lack sufficient space to cover all these in this summary, so read and enjoy yourself!

Louise Campbell convenes liver nursing and nurse educator experts Kathryn Jack, Michele Clayton, Pam O'Donoghue and Patrizia Kunzler to consider where liver nurses and advanced nursing practitioners should fit into treatment and communication paradigms and what support they will need. Stephen Harrison joined to offer a different viewpoint.This conversation explores the need for and value of patient education in the NASH Patient Care process. It starts with almost a tangential request that some of the money budgeted for expensive systemic HCC therapies in the UK be rededicated to patient education earlier in the treatment process.From there, the conversation shifts to consider the value of the need for early-stage treatment strategies in poorer countries that are never likely to be able to afford the expense of drugs or treatment modalities. In the end, each panelist describes a change she would like to see in the next 2-3 years.

Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.This final conversation of Season 3 - Episode 42 discusses the power of education to place liver disease on a higher agenda. Louise notes that liver health is not engaged with at a school level. She suggests that liver health as an outcome be incorporated from an earlier age. This familiarity could fundamentally assist the more ‘generalist' approach that Stephen promotes. Michelle mentions potential pushback and the group revisit the need for more patient resources. Beyond access to affordable nutrition, communities need safe spaces and opportunities for exercise.Next, the group expresses their eagerness for building an inclusive, robust framework for a NAFLD pathway. Michelle reiterates her position that the success of such a framework requires the contributions of nurses and allied health professionals. Robert also hopes to see uniform action on this pathway to tap into an immense knowledge base. Stephen enjoyed his first podcast feature and is looking to translate successful strategies from previous pathways to the liver space. Jörn is appreciative of joining this conversation on inclusion, placing a great value on honest and open feedback.

Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD.Louise begins this conversation by asking Stephen about a successful HIV pathway that he had contributed to, and how it may be applicable to liver disease. Stephen maintains that “it's about identifying the most important measures across a pathway.” A pathway can be measured both stepwise and incrementally by indicators within the larger framework. Stephen provides an example of application through the aforementioned HIV pathway. Next, Robert explores the gamification of digital health, and what that may provide in terms of patient empowerment. This movement appeals to Jörn because it can help define goals. Both patients and health professionals are working under mutual motivators.

Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.This conversation begins by discussing the role of patients in the scope of allied health. Louise prompts the question, where do they fit into the pathway? Robert identifies the many touch points and opportunities presented for patient inclusion. He also suggests that patients tend to communicate in terms of quality of life issues - not in the language of diagnostic scores. Michelle joins to highlight the importance of nurses and allied health professionals in the context of patient interactions. Nurses and allied health professionals can offer conversational insights that promote liver health. However, Jörn expresses the shared concern that a lack of funding tends to stretch nursing resources thin.The discussion shifts to promoting liver health in a wider professional setting. Stephen speaks to the reality that “everyone is fighting their own corner” in advocacy and diagnostics. The group then explores ways by which more generalist testing can identify and capture at-risk patients earlier in the pathway. Patients presenting comorbidities need more than one therapy, more than one organ monitored, and more than one answer to their questions.

Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.Earlier this year, Jörn co-authored a paper titled, A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach (2022). Jörn talks about the process and intention behind the paper. He recalls that leading author, Jeff Lazarus, sought to incorporate the SDG and its applicable targets to the challenges posed specifically by NAFLD. The group identifies a lack of representation in authorship and discusses how to improve on this. It is agreed that developing a pathway requires the contribution of nurses, patients and patient advocates, and other allied health professionals.

Surfers Louise Campbell and Jörn Schattenberg are joined by patient advocate Robert Mitchell-Thain, liver nurse Michelle Clayton, and healthcare consultant Stephen Callaghan to talk about their unique perspectives in the process of pathway development for NAFLD. In doing so, the group looks for ways to incorporate the 17 Sustainable Development Goals (SDG) established by the United Nations - an urgent call for action on health, economy, and starvation amongst other human rights issues.Earlier this year, Jörn co-authored a paper titled, A sustainable development goal framework to guide multisectoral action on NAFLD through a societal approach (2022). Louise begins by asking Jörn about the process and intention behind the paper, and how it champions the SDG. Jörn recalls that leading author, Jeff Lazarus, sought to incorporate the SDG and its applicable targets to the challenges posed specifically by NAFLD. The paper is formulated by consensus using The Delphi Process, whereby two rounds of interdisciplinary discussion decided on 16 deliverable targets relevant to NAFLD. It aims to determine what is important to be addressed by politics and those involved with research funding.Michelle notes this paper is absent of nurses, patient advocates or other allied professional contributors. Robert joins to reframe Michelle's concerns, asking how do we do it better next time? He seeks a more genuine multisectoral representation in what could only then be dubbed as a truly societal approach. Jörn acknowledges these shortcomings and agrees that, as the paper stands, it can be seen as a physician's viewpoint. Louise reckons that the paper serves a foundation and that if it were to be further developed, now is the time to introduce different perspectives.The conversation turns to the next steps of establishing such a framework. Stephen Callaghan provides an anecdote from his time contributing to the development of a pathway for HIV. The driving message is that not every stakeholder comes from a clinical environment. As such, the group agrees that herein lies the importance of communication. Robert states that most patients are relating in terms of describing symptoms and other quality of life issues. Some of the more complex metrics understood by specialists may not translate outside of the professional circle. Michelle then highlights the critical role of nurses positioned as a more conversational contact with the ability to identify risk factors and promote liver health. Both points resonate with Jörn. He explains that the SDG paper emphasizes a need for funding for nurses. He also shares Robert's concern surrounding the power gap that can negatively impact the patient's ability to contribute pathway development.Next, Stephen speaks to the reality that “everyone is fighting their own corner” in advocacy and diagnostics. Robert relates, stating the matter is complex and that the community should come together to offer more than one answer to patient questions. Jörn alludes to Stephen's position as a generalist to combat this issue. The conversation then shifts to education. Louise notes that liver health is not engaged with at a school level. She suggests that liver health as an outcome be incorporated from an earlier age. This familiarity could fundamentally assist the more ‘generalist' approach. Michelle mentions potential pushback and the group revisit the need for more patient resources. Beyond access to affordable nutrition, communities require safe spaces and opportunities for exercise.Final thoughts are shared and each expresses their eagerness for building an inclusive, robust framework. The success of such a framework requires many players, and Stephen hopes to translate strategies from past successful pathways to place liver disease on a higher agenda.

Jörn speaks about co-authoring an article, “The Nonalcoholic Steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future successes.” In doing so, he discusses areas for improvement he feels clinical trial strategy and design will require. Joining the conversation is Stephen Harrison and Global Liver Institute Founder and CEO, Donna Cryer. Both Stephen and Donna approach the conversation from the patient and patient advocate perspectives. This episode From the Vault provides an amazing and complementary comparison to how far this topic has come in just two years. Notably, much has developed in the space of NITs since this paper in 2020. In this week's Surf, Season 3 - Episode 41, Roger, Louise, Stephan and Jörn reflect on what has improved in the intervening time period, what has not, and where this space is headed.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group speculates what can still be accomplished. This conversation begins with Roger suggesting that tertiary care research universities that have their own primary practice be utilized as an accessible point of referral. The group agrees that while a good idea, this may not translate to the European system.Roger poses the closing question: what is there to look forward to in the space of NASH clinical trials and improving screen fail rates in the next 6 months to a year? Louise is looking for the approval of FibroScan for primary care in the UK. Jörn is hoping for an opportunity to offer health care services through referral systems. Stephen talks about getting a drug approved. In response to the latter, Roger finishes with a Stephen quote: is the juice worth the squeeze? This "juice" takes forms of cash and optimism, and it will be worth the squeeze if a drug sees successful development.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that researchers are making progress in reducing screen fail rates, but not in the critical issues of accessibility and equity.In this excerpt, Jörn asks whether these new, more focused approaches might lead to investigators overfitting patients. The positive of this outcome, he notes, is that sweet spot patients will be in a position to respond to drug. Louise takes on an additional issue: what is the affect of patient lifestyle mitigation on these trials. Her concern: patients who work hard enough to improve their liver condition after learning they have the disease may be so successful that they no longer qualify by the time they would be called for biopsy. The conversation strays into discussing the high value of bring artificial intelligence assists into histopathological interpretation before Stephen returns to the question of recruiting more patients. He notes that the goal is not merely to pull more patients into the first stages o recruitment ("the top of the funnel") but to improve our distribution of different kinds of minorities and subpopulations with high rates of NASH. He points out the fallacy of treating only mainstream Caucasian Americans and assuming results of these trials will hold true for everyone given what we now know about the important of genotyping and mutations tied to race or ethnicity. As this conversation ends, Stephen outlines potential solutions based on shifting recruitment out of brick-and-mortar trial sites and to recruiting and testing at primary care offices or even patients' homes.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. Large metropolises are identified as missed opportunities. Stephen starts this conversation by shifting focus from issues surrounding trial criteria to the challenge of finding the right patients for these trials. He notes that of the millions of patients with NASH in the U.S. today, only a small fraction might ever realistically find their way to a NASH trial. The biggest factor is that they can only find their way to a trial if they live with  clear access to a trial center. This is not simply a question of rural and exurban residents having too far to travel. He cites Chicago as a city that contributes minimal patient enrollment, despite being a large cites whose population  suffers from high levels of metabolic disease. Jörn adds that while we might believe that European countries with more socialized, government-centered systems would not exhibit this maldistribution in where trial patients live, that belief would be wrong. Roger suggests that the U.S. system, with its highest levels of investment in medical technologies and broader distribution of care sites, might actually be better equipped to attack this issue. At that point, Roger returns to an earlier comment to ask Stephen addresses how mid-trial reassessment of screening criteria works and why it improves screen fail rates. Stephen's answer takes up the rest of this conversation.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that while non-invasive techniques (NITs) have made a significant contribution to patient enrolment, there remains reliant on additional screening methods.This conversation opens with Jörn's observation that NITs are not always part of the protocol when assessing patients for their inclusion or exclusion in clinical trials. However, he states, experienced researchers will rely on these tools along with presence or absence of other metabolic diseases to decide which patients should not progress to biopsy due to high likelihood of screening out of the study anyway. Stephen concurs, adding that by considering these other risk factors, the clinical trials benefit from a more enriched patient population. and fewer unnecessary biopsies. From here, Stephen goes on to discuss two other pivotal issues: advance in strategies for reading biopsies and the impact of high screen fail rates on staff morale. On the first point, he states that good drugs have been lost in development because the strategy for reading biopsies, which relied on a single pathologist to read, created interpretative barriers that led to trials failing or being discontinued. This has led to a place today where all trial design incorporate consensus histopathology reads. On the second, he contrast staff performance for two studies on the same drug: an obesity study with a 25% screen fail rate and a NASH study with an 80% rate. He describes the palpable difference how staff feels about working on each of these projects. As the conversation ends, Louise comments on changing FibroScan thresholds for admission to some trials and Stephen describes how inclusion thresholds might vary from trial to trial and ways he uses other NITs to complete his assessments.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. After Roger Green sets the stage for this conversation, Jörn reflects back on the 2020 paper he co-authored with Joost Drenth and considers important changes in patient screening since then.  In his own words, “The way we use biomarkers and AI to augment outcomes has changed the field dramatically.” Whereas biopsy used to be the core method used to recruit patients, Jörn notes that many practitioners now rely on NITs to assess the patient's likelihood of screening into a trial before conducting a biopsy. The result is a significant reduction in non-essential biopsies. Stephen follows Jörn by discussing ways his own practice has benefitted greatly from the developing a prescreen strategy that relies heavily on NITs. Instead of doing "five biopsies a day, maybe 25 or 30 a week," he now starts with FAST scores and cT1 and, if these seem promising, moves to multiparametric MRI before deciding who to biopsy. Specifically, his practice is now able to utilize VCTE (FibroScan) and other NITs to mine data in real time and refer patients to the proper clinical trial as a result. As the episode winds down, Stephen alludes to the idea of "mid-trial corrections" in pre-biopsy NIT screening criteria and advances in how biopsies are read in trials today as other areas where procedure has improved markedly.

THE NASH Tsunami audience came to know Jörn Schattenberg in the Fall of 2020 when he shared a paper he had recently co-authored on why NASH drug trials failed. This week, the same group that discussed that paper – Jörn, Stephen Harrison, Louise Campbell and Roger Green – reflect on what has improved in the intervening time period and what has not. The group suggest that researchers are making progress in reducing screen fail rates, but not in the critical issues of accessibility and equity. As the conversation begins, Jörn harkens back to the 2020 paper and reflects on improvements in cost-effectiveness and duration of the trial process since. “The way we use biomarkers and AI to augment outcomes has changed the field dramatically.” Yet clinical trials are still reliant on the same endpoint. A surrogate is required for conditional drug approval. Roger asks for the most important improvements that have resulted from conversations around patient selection for a trial. Jörn recalls the past reliance on biopsies and compares today's focus on non-invasive techniques (NITs). Stephen joins to highlight improvements in the way practices utilize VCTE (FibroScan) and other NITs to mine data in real time and refer patients to the proper clinical trial. One idea Stephen mentions: evaluating NIT values during the recruiting process to reset cutoff levels. He also discusses expanding screening criteria to include non-hepatic metabolic risk factors such as obesity and diabetes. Both approaches to patient refinement are contributing to more successful studies and limiting unnecessary biopsies. With fewer screen failures, sites remain engaged. Louise Campbell agrees that mitigating screen fail rate is key to fighting study fatigue. The conversation shifts to finding patients for these trials. Stephen notes that major metropolises still do not have access to NASH clinical trials. "We're putting almost zero NASH patients in clinical trials out of a city as large as Chicago that has high rates of obesity, diabetes and metabolic syndrome.” NITs like the FibroScan are unavailable in large swaths of the country. Even where they are available, a lack of education around NASH diagnostics tests remains a barrier. Jörn adds that multiple hurdles prevent patients from accessing NASH trials in socialized healthcare systems. Roger believes the US system may have a better shot than Europe at broadening recruitment processes because the technology developed under larger U.S. budgets means that some pivotal technologies are more widely available.Next, Roger comments that for as long as screen fail rate has been discussed on this podcast, we had never discussed the idea of mid-trial adjustments. Stephen gives an example of adjusting FibroScan thresholds mid-trial to boost the number of eligible patients. Jörn shares his belief that the use of NITs outside the formal qualification criteria has helped reduce screen fail rates.Stephen shifts focus to a bigger issue: equity in the representation of underserved patients in these trials. There is an issue of decentralized trials, whereby at-risk groups are under-referred due to several factors. Stephen outlines potential solutions. Roger suggests tertiary care research universities that have their own primary practice as suitable to become an accessible point of referral. He notes this may not translate to the European system and Louise agrees. What is there to look forward to in this space in 6 months to a year? Louise is looking for the approval of FibroScan for primary care in the UK. Jörn is hoping for an opportunity to offer health care services through referral systems. Stephen says we'll hopefully be a step closer to getting a drug approved. Roger finishes with a Stephen quote: is the juice worth the squeeze? This "juice" takes forms of cash and optimism, and it will be worth the squeeze if a drug sees successful development.

Episode 40 focuses on lean NASH, and Michelle Long notes that many patients with lean NASH are diagnosed in the Emergency Department when they present with symptoms of decompensating cirrhosis. This conversation from November 2021 considers cirrhotic patients from a different perspective: their uniquely valuable role in clinical trial strategy as the world evolves beyond biopsy as gold standard.Mazen Noureddin notes during this week's episode that when he identifies lean NASH patients, he encourages them strongly to participate in clinical trials. This conversation also looks at the value of cirrhosis studies in clinical trial design, although from a quite different perspective.From the initial description of this conversation: In this conversation, Stephen Harrison starts by pointing out that non-cirrhotic NASH trials and NASH cirrhosis trials differ significantly in goals, endpoints and patient severity. From there, he dives into the NASH cirrhosis trial group with his review of REVERSE, which Vlad Ratziu presented at AASLD. Jörn Schattenberg and Mazen Noureddin also comment on design of this trial. The conversation focuses on two issues: who is the optimal patient for a NASH cirrhosis trial and what is the most appropriate attainable endpoint and, therefore, clinical design? On the optimal patient issue, the group agrees the ideal patient is a well-compensated cirrhotic, because the presence of portal hypertension makes the entire healing issue so much more complex. There was less agreement on the optimal design question.

As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those with "normal" BMI levels (BMI

As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those with "normal" BMI levels (BMI

As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those with "normal" BMI levels (BMI

As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those with "normal" BMI levels (BMI

As the NASH pandemic grows in the number and diversity of patient cases, one patient group receiving increased notice includes patients with "lean NASH," those whose BMI levels are "normal." Last month, Gastroenterology published Best Practice recommendations for diagnosing and treating lean NASH. Two of the authors, Drs. Michelle Long and Mazen Noureddin, were good enough to come on the podcast to share the thinking behind this article along with its key observations and recommendations.This conversation starts with Roger Green asking Michelle and Mazen how they came to write this piece and how the paper came together working with co-author, Dr. Joseph Lim. First, as Michelle notes, "we had to all get on the same page," on the issue of the highest BMI that would be considered lean or, more precisely, not overweight. From there, the team outlined 15 Best Practices based on clinical experience, and set out to refine these based on relevant literature and recommendations from colleagues and reviewers. The co-authors note that while little of what they learned while preparing this paper was surprising, it forced them to focus on creating a fairly simple set of stepwise goals for clinicians to follow.  Louise Campbell joins the conversation to praise the simplicity and clarity of the Best Practices chart the co-authors created. After noting that this algorithm is not very different from others,  Mazen goes on to mention "a couple of things...that we're proud of:" identification of high-risk patients based on age (over 40) or presence of Type 2 diabetes. He also notes that they provided greater clarity around more advanced non-invasive tests like ELF, MAST, FAST, MEFIB, MRI, and cT1.The conversation shifts to focus on the recommendation to retest every 6 or 12 months. Louise notes this approvingly. The group agrees that screening T2D patients annually using FIB-4 is not very different than screening annually for eye, kidney or neurological complications. Roger Green joins the conversation to suggest a 3-5 year follow-up recommendation is not patient-centric, but might calm payers concerned about skyrocketing costs of treating Fatty Liver disease. Mazen shares his expectation that yearly evaluation will be cost-effective and patient-centric. Roger shares an informal belief he has developed that whether due to later stage diagnoses or different disease pathogenesis, lean NASH patients might be more costly because patients progress to cirrhosis more quickly after the original diagnosis. Michelle tends to agree but notes that more research is needed on this.Next, the conversation shifts toward diagnostic approaches. Roger mentions the possible benefit of the "Fibrosis First" method that Ian Rowe discussed the previous week (S3, E39), particularly appropriate when primary care providers observe danger signs in lean patients. Mazen points to extremely elevated liver enzyme levels (ALT of 80 or 90). Michelle agrees, but notes that most of her lean NASH patients are diagnosed in an ED with complications of cirrhosis. The group then spends time asking what might make primary care providers comfortable testing for fibrosis, even if only to pass the patient on to the appropriate specialist.  Roger asks what different groups can learn from this paper. Michelle states that this is a clear call for more research. Mazen points to Table 2 in the paper, which lists other diseases that hepatologists should consider when evaluating these patients. He continues to state that the document is helpful for non-hepatologists and hepatologists alike. Finally, he points out that clinical trials are pivotal for these patients. The last several moments focus on how to ask patients about alcohol consumption and then the closing question. Michelle notes the importance of using lists and tables in the paper to guide the special issues in treating these patients. 

This week's "Conversation from the Vault" comes from September 2021, when Anthony Villiotti of NASH kNOWledge joined Louise Campbell and Roger Green to discuss what he considered the "biggest Fatty Liver story of the summer."In his answer, Tony pointed to two studies published during the summer. The San Antonio Military Medical Center study confirmed work done a decade earlier that suggested overall NAFLD and NASH incidence in a population of asymptomatic middle-aged Texans (37% NAFLD and 14% NASH) might be far higher than the most common publicly quoted numbers (25% and 5,6%, respectively). As we wrote in our conversation synopsis at the time, "Tony and Louise Campbell agree on the importance of educating children starting in their early years of schooling. Tony also comments on his belief in grass-roots education and hopes that as the COVID-19 pandemic abates, he will have more opportunities to do so. Louise talks about the need to educate/motiave primary care practitioners and related specialists to test more frequently and learn about the role the liver plays in non-communicable metabolic diseases they treat more frequently."

One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.As this conversation starts, Louise Campbell notes that John Dillon reported in Barcelona that slightly over half of patients identified as having Fatt Liver via iLFT never returned for their appointments. Ian Rowe points out that this will reduce the costs in the model due to missed diagnoses but questions whether this cost reduction is truly beneficial since missed patient visits translate into non-treatment. More important, he reminds us that iLFT is under constant improvement so that data collected earlier in its lifecycle might not accurately reflect its costs and benefits today.Upon Roger Green's invitation for other questions Louise Campbell asks whether "we" (presumably the UK NHS) should do a better job supporting positive diet and exercise activity for healthcare professionals inside the system. On a more serious note, this leads Ian and Louise to focus on the policy issues that can support patients better (particularly those in the workforce). Ian points out that alcohol is issue #1 for many of these patients. He and Louise go on to point out the importance of public policy around things like soda and sweet food advertising in shifting consumers' focus or craving for bad foods. Roger suggests that this is a two-element issue: stopping advertising for soda and sweets will reduce disease over time but we also need to treat patients who already have developed disease. As he puts it, policy can "put your foot on the hose," but even if we stop the in-flow of new Fatty Liver and metabolic patients, we still have "the patients in the hose" and they will need therapy. As a final thought before wrap-up, Ian shares his belief (which Louise also holds) that VCTE might be more effective in causing changes in patient behavior than blood tests, even if they point up the exact same patient need. The difference: feedback from VCTE comes in real-time where patients get face-to-face feedback and respond, whereas bloodwork results comeback to the patient several days later and delivered impersonally. From here, the group moves to the wrap-up question, which addresses research we should be doing and action steps/changes in behavior we should be promoting. You will have to listen for yourself to hear Surfers' answers.

One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.This conversation centers around challenges related to early diagnosis and NASH Patient Management. As Roger Green notes, listeners to NASH Tsunami might recall a significant number of conversations in which patients and advocates complain about doctors telling them "not to worry" about their Fatty Livers for years until the condition progresses to cirrhosis. Louise Campbell focuses on a different challenge: that of NASH patient management when patients are dealing with other metabolic diseases that are better known or where approved treatments exist.

One of the most important challenges facing Fatty Liver stakeholders involves improving early diagnosis for patients with clinically relevant or advanced fibrosis (F2/3). Today, a significant percentage of patients learn they are living with cirrhosis in the Emergency Department during a decompensating event. Four in ten of these patients in the UK do not leave the hospital. Episode 39 reviewed a model that Ian Rowe and Richard Parker developed to determine the most cost-effective strategy for F2/3 diagnosis.This conversation starts with Louise Campbell agreeing with the vision that led Ian and Richard to build this model. She notes recent data she heard that 85% of all US patients with cirrhosis (and 55% in the UK) learn their diagnoses for the first time in an Emergency Department, which suggests the need to improve earlier diagnosis. She notes that some UK programs are widely cited as examples of good (or best) practice, but, more important, notes that these have been cited as examples for a long time, but also notes that other regions and hospitals have not emulated them. She goes on to ask how the efficiency and number of patients captured in the model would increase if the target expanded to include all patients with metabolic disease. Ian notes that these patients were not included in the model and also suggests that the question reflects a larger question about the goal of this kind of screening.