Surfing the MASH Tsunami

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Hepatology researchers and key opinion leaders Profs. Laurent Castera and Scott Friedman join Louise Campbell and Roger Green in the final element of our review coverage of TLM 2023. This far-ranging conversation moves beyond MASLD/NAFLD and MASH/NASH to consider an array of topics.

The episode starts with Roger asking the other guests for their general impressions of the meeting. Three key insights: 

1.    "Pre-pandemic" levels of interaction and discussion among attendees

2.     Online meeting app was a "fail", becoming a topic of conversation in its own right while fostering confusion

3.    In the "frenzy" about the anticipated resmetirom approval and other MASH drugs approaching market,  we shouldn't overlook that patients with PBC will soon have two new exciting PPAR agents, elafibranor and seladelpar. As Scott notes, we also learned about promising modes of action for PSC so, overall, a promising meeting for rare cholestatic diseases. 

The rest of this discussion covers multiple topics, key among them: 

 ·      Impact of FGF-21 and FGF-19 agents on patients with compensated cirrhosis. Roger is optimistic that agents might provide improvement. Scott is more pessimistic because we do not have agents addressing the unique mechanistic challenges in cirrhosis vs. advanced fibrosis. Both agree that agents on the horizon can buy time until curative or regressive medications arrive. 

·      AI-based analysis. Roger bridges to Stephen Harrison’s presentation of HistoIndex analysis of resmetirom that produces an estimate of 54% efficacy vs. 34% placebo. He comments that given this analysis and that bariatric surgery studies tell us fibrosis regression may take five years, the FDA one-year standard might be so stringent as to be misleading. 

·      Bariatric surgery. Laurent refers to a presentation from Phillippe Mathurin's group demonstrating that in patients post-bariatric surgery, MASH resolution and fibrosis regression clearly lead to improved outcomes. 

·      NITs. Laurent discusses a poster from a multi-country 16,000-patient cohort that did not confirm liver stiffness as leading to a decline in MALO over a two-year period but anticipates more robust findings over time. 

·      VCTE-based analysis. Louise discusses two posters with analyses based on FibroScan. The first, from the Virginia Commonwealth University and the VA, found that liver stiffness correlates with success in liver transplant and that CAP can predict the risk of future MI in these patients. She notes that CAP of 270 served as "its own parameter" in predicting time to mortality. 

·      Nomenclature. Roger notes that a Saturday morning session resolved the two most pivotal outstanding issues about the effect of nomenclature change on scientific development. FDA signaled that the agency views old and new nomenclature terms as interchangeable. NIMBLE and LITMUS analysis determined that patient mapping is also interchangeable.

·      Impact of triple-agents. Presentations at this conference confirm that triple agents addressing GLP-1, glucagon and GIP can have bariatric surgery-level impact on liver fat and reduce the entire disease burden. 

Interspersed between these topics are a range of insights on cirrhosis disease models, regulatory slowness in moving on from current conditional efficacy metrics, treater supply vs. patient demand, "stigma", and basic science. This is a high-level view of an information-dense conversation. Listen to learn more and hear all the details. 

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Fatty Liver Alliance President and Founder Mike Betel, a leading patient advocate for MASLD/MASH patients, joins Roger Green in our continuing review coverage of TLM 2023. Mr. Betel discusses presentations and events he found most valuable to patient advocates. He also discusses the new MASLD nomenclature and Fatty Liver Alliance's upcoming 2nd Annual Primary Care NAFLD & NASH Summit.

The conversation starts with Mike paying the event a profound but slightly backhanded compliment. He comments that interest in some sessions was so strong that organizers did not leave sufficient space for everyone who wanted to attend. As he pointed out, even the "overflow rooms" were overflowing for some sessions! Mike then paid the event a profound complement: the content of the sessions, coupled with his ability to interact with Key Opinion Leaders, made for a meeting that provided him with insight and enthusiasm into where the field is heading. 

Mike shifts focus slightly to praise Madrigal Pharmaceuticals for the Public Service Announcement the company premiered at this event. He describes himself as "blown away" by the 2:30 video. Mike notes, and Roger agrees,  that virtually everyone he spoke with at the conference who saw the PSA felt the same way. In response to Roger's question, Mike offers that what makes the PSA so special is that it focuses on "a real person and a real community interacting" in ways that portray real-life with humor and, at the same time, commitment. He mentions a couple of specific items he particularly likes and goes on to note that as of the end of conference, the video had already received 500,000 views online. 

Mike goes on to discuss one scientific paper he found compelling, a presentation by Prof. Arun Sanyal about the Eli Lilly incretin triple-agonist retatrutide. He cites Arun's comment that in over 90% of the obese patients in this study, the drug reduced liver fat so much that patients' fat levels were defined as "normal." Roger goes on to note that there are three triple-agonists in development, the other two being Altimmune's pemvidutide and Merck/Hanmi's efinopegdutide.  

Shifting focus, Mike congratulates Dr. Jeff Lazarus on being recognized with the Distinguished Scientific Award from the American Liver Foundation. jeff's work over his career has spanned major public health efforts in HIV, Hepatitis C, COVID-19 and Fatty Liver diseases, but his most recent effort was spearheading the Delphi process around the nomenclature change. Roger commends the work that Jeff, Ken Cusi and a few others have made in reaching across specialties and countries to foster and promote clinical care pathways. Mike commends a presentation by Jeff and Mazen Noureddin  talking about "a united voice for liver health." 

Next, the conversation shifts to discuss the new nomenclature, which received significant attention at TLM 2023. Mike comments that while nomenclature is moving ahead, widespread change will hinge on endorsements from regulators, professional organizations and the pharmaceutical industry. Roger notes two specific steps forward: a comment from George Makar of FDA that the agency sees the terms of interchangeability and reports from Profs. Sanyal and Quentin Anstee that the old and new definitions map identically for 95-98% of patients. 

The last part of the discussion focuses on Fatty Liver Alliance's upcoming primary care event. Mike discusses some highlights of the conference and tells listeners how to find it. The podcast ends with a call to action for community-wide engagement in liver health, underscoring the necessity for collaborative efforts to broaden the understanding of liver disease, enhance patient care, and adapt to the evolving medical landscape.

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Dr. Tim Jobson of Predictive Health Intelligence joins Roger Green in our continuing review coverage of TLM 2023. Dr. Jobson discusses the studies he presented at the meeting and other work related to population-level screening for metabolic diseases, the importance of providing better care in areas with lower socio-economic status residents and the global value of population health management.

The conversation starts with Tim discussing the major impact that new medicines like resmetirom and new indications for GLP-1s will have on the entire treatment framework for MASLD and MASH, starting with increased interest in screening coming from physicians who will have medications they can use to treat patients. Roger identifies the ability to predict which patients will proceed from MASLD to MASH as a major area for improvement, which serves as a segue to Tim to discuss PHI's work. 

PHI presented two posters at TLM2023, mostly focusing on deploying PHI's medical record-based case finding approach to identify specific patients badly in need of care but not receiving it. This is particularly crucial in what Tim describes as "areas of deprivation," with residents of lower socio-economic status. One poster addressed identification of untreated patients with Hepatitis B. The other focused on liver disease in these areas: similar rates of disease but far higher rates of advanced disease.  

Tim's is particularly excited about population-level risk stratification and the ability to identify a "five-fold" increase in the people we can target early in adulthood based on their propensity to develop non-communicable disease later in life. This study will target 7% of the population, which he expects will make the program economically viable. Tim reports he has seen tremendous interest in this idea at the meeting, strikingly among US physicians, allied professionals and payers.

The conversation shifts from Tim's work to other issues in the meeting he found fascinating. He was powerfully struck by some of the data and drugs becoming available in Primary Biliary Cholangitis (PBC) and findings about modes of action in Primary Sclerosing Cholangitis (PSC), two rarer diseases vitally in need of better therapies. 

Tim also asks where AI will fit into the emerging care paradigms.  In this regard, one of his concerns regards the intrinsic biases in existing datasets when we try to predict which patients have more urgent need for a liver transplant among those on the list. Tim and Roger return to the issue of biases in the current dataset, and agree the biases are probably too "hard-wired" to eliminate, which means researchers will need to find ways to adapt...and, Tim believes, they will do so.

Looking at another issue that interested Tim, the discussion shifts to asking what the meeting is telling us about Hepatitis B and Hepatitis C. Tim notes that we are unlikely to meet the ambitious elimination goals we have set. Doing better will involve improved patient identification and motivation, which has two tiers of challenge. In developing countries, the data and data structures necessary to target patients simply do not exist. Even when they do exist, as in the UK, the system reaches only half-to-two-thirds of patients with clear signs of serious disease. 

The right strategy for the solution is to pilot in a narrow swath of population, then go broader. As the conversation ends, Tim notes that the technology is here or will be shortly to achieve this goal.

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Dr. Zobair Younossi joins Roger Green to kick off our review coverage of TLM 2023. Dr. Younossi discusses the studies he presented at the meeting and other work related to patient quality-of-life, the economics of screening and treatment, and how stigma affects patients and providers.
The conversation starts with Zobair listing the topics on which he and his group will present data at the TLM2023 meeting. The first of these is an oral presentation regarding health disparities in adolescents. The thrust of this work is that food insecurity is leading to dramatic, increasing rates of MASLD and MASH among adolescents. Food insecurity, which correlates with lower incomes and living in "food deserts" -- primarily urban areas where stores sell ultra-processed foods at high prices -- emerges from the NHANES database as a correlation and likely cause of MASLD and even MASH with fibrosis in these younger patients. 
Zobair cites alarming statistics about the underestimated prevalence of liver diseases in children and teens. Standard estimates put MASLD in children at 10%, but Zobair believes that number to be closer to 18%, with adolescents as high as 24% and the adult US population at 38%! In parallel, there has been a striking increase in liver disease among type 2 diabetics, which was previously estimated at 55%, but he now estimates at 68%! He notes that "food deserts" also tend to be "activity deserts" without facilities that support a healthy lifestyle.
Roger notes that an increase in patients with Type 2 diabetes and MASH will have significant economic implications: they are more likely to develop cardiovascular disease and obesigenic cancers before they progress to cirrhosis. Also, they are more likely to go from advanced fibrosis to cirrhosis than people with MASH and no diabetes. These social and economic realities emphasize the need for cost-effective screening strategies similar to those recommended by professional societies. Zobair mentions another paper he is presenting at TLM that demonstrates cost-effectiveness for screening in all intermediate-risk patients even before MASH drugs come to market. 
From here, the conversation focuses on the factors that make MASLD and MASH so costly. Zobair focuses on fatigue, which affects 30-40% of MASLD patients. Many patients consider fatigue something they live with, not an effect of disease, but MASLD can lead to "brain fog," or cognitive impairment. 
Zobair and Roger go on to explore the issue of stigma in the context of conference presentations and Zobair's own work. After noting that stigma was a significant reason for the recent nomenclature change, Zobair reports that it seems less of an issue for patients (8%) than providers, where the number is higher. Roger notes his experiences in marketing research, where providers frequently blamed patients for their disease and expressed frustration or even contempt that patients could not take better care of themselves. Zobair notes that this translates to patients, who express more significant frustration and sadness about being blamed for the disease than simple name-related stigma. Zobair makes two more points on stigma: (i) patients who feel stigmatized have lower quality-of-life scores, and (ii) to patients, obesity and Type 2 diabetes are far more stigmatizing than "fatty liver disease."
The final portion of this conversation focuses on cultural differences. Zobair notes that the stigma associated with obesity and MASH is a Western-world phenomenon and a relatively recent one. In much of the world, obesity can appear as a sign of prosperity because the obese person has enough wealth to buy large quantities of food. They conclude that understanding these nuances is crucial for improving patient-provider communication and addressing factors beyond individual control, such as social determinants and health disparities, which heavily influence health outcomes. 

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Last week's posting consisted of 1:1 interviews with four KOL from different spheres, each talking with Roger Green about what they are looking forward to seeing at this week's The Liver Meeting 2023. This week, two of those KOLs, co-host Jörn Schattenberg and hepatology KOL Naim Alkhouri, join Roger and co-host Louise Campbell, FRCP, in a free-wheeling review of key abstracts that will be presented at TLM2023.
The discussion begins with Jörn spotlighting the first item in the abstract book, a presentation titled MASH Resolution Without Fibrosis Worsening After Bariatric Surgery Improves Long-Term Survival. Jörn spotlights this study for demonstrating survival benefits, a significant benchmark for drug approval processes. This study of bariatric patients with concomitant MASH and fibrosis reveals that MASH resolution often comes before fibrosis regression. This suggests that MASH resolution itself might predict improved long-term outcomes, contrasting with earlier beliefs that only linked fibrosis regression to positive prognoses. Louise comments that reducing inflammation should logically lead to fibrosis regression, comparing it to the treatment of hepatitis C. Naim agrees, emphasizing the liver's remarkable ability to heal if the initial injury stops, such as with alcohol cessation or hepatitis treatment. However, he points out challenges in clinical definitions and trial inclusions based on the current focus on MASH histology.
The conversation shifts as Naim shares his excitement that both the ENLIVEN trial with FGF-21 agent pegozafermin and the ALPINE-4 trial with FGF-19 agent aldafermin demonstrate the potential for these agents to reduce fibrosis one level (and occasionally even two!) in patients with cirrhosis. The group agrees that treating cirrhosis is the most urgent challenge facing MASLD hepatology today because patients are close to decompensation and antifibrotic pharmacotherapy does not exist. This leads Roger to ask whether the presence of these agents will drive more aggressive screening for cirrhosis patients and for the group to list the benefits early screening will offer.
Louise shares two papers she intends to follow, both of which focus on gender disparities in liver health. She reminds the group of Roberta Forlano's research (shared in S4 E44) and comments during that discussion that women in liver failure experience higher rates of death that man -- they do not fare as well  on liver transplant lists and exhibit higher rates associated with hepatic renal syndrome. The group concurs that this disparity needs more attention and fits into a broader issue of inequality in medical treatment based on gender and other demographic factors.
Roger shares two posters on lanifibranor with an eye toward how payers are likely to assess agents when they come to market. As the group discussed in earlier episodes, there are significant challenges identifying which patients are likely to succeed prospectively on a MASH drug and another on determining in a reasonable timeframe whether the medication is working. Of the two lanifibranor posters, one suggests that changes in adiponectin levels can predict level of therapeutic success, while the other shows that presence of a mutated PNPLA3 gene has minimal or no impact on the likelihood of therapeutic success.
The group discusses a few other papers and concepts. One paper of note came from the NAIT-NIT consortium and suggests that biopsy can lead to an overestimation of liver fat levels compared to MRI-PDFF. Naim and Jörn comment on behavioral or attitudinal constructs from hepatologists that might lead to this result.
Finally, the group comments on the importance of late-breakers as a vital conduit or cutting edge research and each member notes one other paper or session at the meeting they find intriguing.

STAY SAFE AND SURF ON!

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This week on Surfing NASH, host Roger Green embarks on a series of one on one interviews with KOLs and patient advocates to talk about the Liver Meeting 2023 (held in Boston from November 10 - 14) and much more. In this conversation, friend of the podcast, Naim Alkhouri, joins to discuss this highly anticipated event as well as offer a glimpse into his current work and research interests.

The Liver Meeting is known for its exceptional educational content and amazing presenters. This year will be no exception and, if you can't make it to Boston, the state-of-the-art lectures will also be available online. If you have questions or comments stemming from this conversation, the Liver Meeting, or our interview series in general, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

This week on Surfing NASH, host Roger Green embarks on a series of one on one interviews with KOLs and patient advocates to talk about the Liver Meeting 2023 (held in Boston from November 10 - 14) and much more. In this conversation, Key Opinion Leader, Scott Isaacs, joins to discuss this highly anticipated event as well as offer a glimpse into his current work and research interests.

The Liver Meeting is known for its exceptional educational content and amazing presenters. This year will be no exception and, if you can't make it to Boston, the state-of-the-art lectures will also be available online. If you have questions or comments stemming from this conversation, the Liver Meeting, or our interview series in general, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

This week on Surfing NASH, host Roger Green embarks on a series of one on one interviews with KOLs and patient advocates to talk about anticipations around the Liver Meeting 2023 (held in Boston from November 10 - 14) and much more. In this session, President of the Fatty Liver Alliance, Michael Betel,  joins to discuss this highly anticipated event, plus some additional key ideas around patient advocacy.

The Liver Meeting is known for its exceptional educational content and amazing presenters. This year will be no exception and, if you can't make it to Boston, the state-of-the-art lectures will also be available online. If you have questions or comments stemming from this conversation, the Liver Meeting, or our interview series in general, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

This week on Surfing NASH, host Roger Green embarks on a series of one on one interviews with KOLs and patient advocates to talk about the Liver Meeting 2023 (held in Boston from November 10 - 14) and much more. In this first conversation, Jörn Schattenberg joins to discuss this highly anticipated event as well as offer a glimpse into his current work and research interests.

The Liver Meeting is known for its exceptional educational content and amazing presenters. This year will be no exception and, if you can't make it to Boston, the state-of-the-art lectures will also be available online. If you have questions or comments stemming from this conversation, the Liver Meeting, or our interview series in general, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

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In continuation of the Surfing NASH interview series, Roger Green talks to Professor Oren Shibolet, Head of Gastroenterology and Hepatology at the Tel Aviv Medical Center. This is a powerful discussion which touches on the Hamas invasion on October 7 and its aftermath on the Israeli people and the practice of medicine today.

This conversation From the Vault reprises our earlier interview from June with Tetiana Deshko, Director of Programs for the Alliance for Public Health in Ukraine. Dr. Deshko shared her own experience with the challenges of providing health for patients in the midst of an invasion, particularly in occupied and battleground areas.

Think of this From the Vault episode as a dramatically expanded  weekly business report, in which Roger discusses the situation in Ukraine. Dr. Deshko's description is powerful and provokes emotions that words cannot describe. You can support her vital public health work by making  donation to the Alliance for Public Health, one of the largest non-governmental organizations in Ukraine, (click this link to donate and read more about their important work).

If you have any question or interests around the event or Ms. Deshko's  experiences in Ukraine, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On! Перемагаймо разом!