Surfing the MASH Tsunami

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00:00:00 - Surf's Up: Season 6 Episode 4 

Surfing the MASH Tsunami concludes its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on pivotal messages that attendees took away from the conference and what messages they would like to share with listeners. Our newsmaker, Fatty Liver Alliance and CEO Mike Betel, discusses the lessons he has taken from being invited to a far wider swath of conferences this year and shares the messages he delivers to these new audiences. Finally, our expert, hepatology research and key opinion leader Mazen Noureddin, discusses recent advances in drug development, focusing on agents in Phase 3 trials.

00:04:24 - Introduction

Host Roger Green briefly describes this episode's three sections and one key lesson from each.

00:06:03 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 4

This is the concluding portion of our Emerging Trends Conference Roundtable. The group focuses on key lessons they have learned and messages they would like listeners to take from this conversation.  The pivotal idea is that SLD is a spectrum running from MASLD through MetALD to ALD. Researchers and treaters will all do best in developing and implementing therapies and guidelines with this thought in mind. Aleksander Krag stresses this idea and notes that, with several different classes of drugs demonstrating positive impact, it will be an exciting decade ahead as we learn how to apply these drugs along the spectrum. Jenn Jones and Alex Lalos note the importance of identifying MetALD, although Jenn noted that it does not seem wise to conduct trials solely with MetALD patients at this time.  

00:22:04 - Newsmaker: Mike Betel on the Increased Visibility of Patient Advocates

This week's newsmaker, Mike Betel, has experienced a significant increase in the number of conferences at which he is invited to speak or appear on a panel. This discussion centers around the reasons Mike believes this is happening and the message(s) he delivers. To Mike, his most important contribution lies in the amount of information he sends back from each event, many of which surpass 30% download rates (and some even hit 50%). He discusses his value in diabetes, endocrinology and obesity meetings, where he brings a "liver" perspective and co-education opportunity to these events. The entire experience has taught him about the need not to stigmatize patients and reinforced his belief in the importance of tailoring care to patients' needs and personalities. 

00:49:28 - Expert: Mazen Noureddin on the Exciting MASLD Drug Development Environment

Hepatologist and Key Opinion Leader Mazen Noureddin joins Roger to discuss major advances in drug development over the past year. He covers a range of different drug classes, focusing on stages of development and the range of options within each class. Specifically, he discusses the FGF-21 agents, the range of patients for whom they might be appropriate, how efruxifermin's 96-week results may make the idea of "induction therapy" less appropriate,  and the exciting early data on cirrhosis patients. He provides some detail on the various incretin agonist options, why hepatologists are particularly excited about combinations that include a glucagon agent, and what kinds of results we might expect in upcoming trials. He goes on to discuss the pan-PPAR lanifibranor, the FASN inhibitor denifenstat, and notes ongoing work on new classes and combination therapies. In general, he paints, I think, not a rosy, but an extremely optimistic picture of what the future will be for patients who need to be treated for fatty liver.

01:09:38 - Business Report 

Roger discusses the next Roundtable and provides some details on SurfingMASH's coverage of the upcoming EASL Congress.

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This week's Expert is Jeff McIntyre, Vice President, Liver Programs at the Global Liver Institute. His major topic is how recent high-level FDA job cuts might affect MASH drug and diagnostics development. He also shares reactions to FibroSIGHT, HistoIndex's new digital pathology service for clinical practice. 

Highlight: Recent job cuts at the FDA will produce chaos in government and slow response to any emerging crises.

Second Highlight: Patient self-advocacy becomes even more important in this environment.

The conversation takes place on April 1, which lends context to Jeff's opening comment about the rate and nature of change in Washington, DC. He and Roger quickly focus on high-level job cuts at the FDA. 

Jeff believes that the clearest outcome from these changes is that the government will be less able to respond promptly and in a medically appropriate manner to future health crises. Jeff agrees with former FDA Commissioner Rob Califf's comment that the FDA as we know it "is dead," and that we have little idea what the future holds. 

A slower-moving, more chaotic government with a Secretary of HHS who minimizes pharmacotherapies for alternative therapies presents a challenge for all SLD patients. Jeff states that patients need to become more vigilant self-advocates (even more than they are today). He also identifies patient advocacy organizations like GLI as a place patients can go to seek the guidance and support they need from patient advocates. 

Finally, the conversation turns to discuss FibroSIGHT. Jeff describes FibroSIGHT as "exactly where we should be and should not be at the same time," a technology that takes a significant step forward in understanding and patient support, but one that ties us to biopsy as a standard for clinical care. Jeff and Roger agree this issue will play out over the coming years. 

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This week's newsmaker, Yukti Choudhury, Director of Clinical Development at HistoIndex, joins Roger Green to discuss FibroSIGHT, a new HistoIndex service that allows clinicians to use HistoIndex's Second Harmonic Generation (SHG) technology and analytics to determine specific CRN fibrosis level for patients with inconclusive NIT results.  

One reason FibroSIGHT is worthy of attention: This is the first time an in-depth analysis of clinical trial biopsy results is being placed at the service of clinical treatment. 

Another reason: Yukti states that demand for this technique could equal 163,000 cases this year, rising to one million by 2028. 

The interview starts with Yukti sharing information on her own academic and commercial background and how she came to this role. She describes FibroSIGHT, a service that will provide a highly accurate CRN fibrosis level for patients whose NIT results suggest no clear or consistent finding. 

Yukti provides practical cues on ordering the test and its reimbursement. 

Roger shares his long-standing respect for SHG and the clarity it produces. He notes the economic benefit of determining whether a patient has F2 fibrosis, which is indicated for pharmacotherapy, vs.F1, which is not indicated. He sees clear benefit in this analysis. 

Roger goes on to express concern that any option requiring more biopsies will reduce the number of patients treated, particularly if having this tool encourages payers to require a biopsy as a prerequisite to treatment. He asks whether, over time, HistoIndex might be able to develop a companion analytic to improve these estimates without requiring biopsy. 

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Surfing the MASH Tsunami continues its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. 

This week, the panelists focus on what studies on bariatric surgery and drugs in development can tell us about future treatment and explore some clinical trial questions. Guest Surfers include Professor Aleksander Krag of the University of Southern Denmark, the current Secretary-General of EALS, hepatologist Alexander Lalos of Robert Wood Johnson hospital, and Jenn Leigh Jones, founder of the Society for Sober Livers Survival, now part of the Fatty Liver Foundation. 

Aleksander Krag starts by discussing a presentation on what we can learn from bariatric surgery in terms of fibrosis reduction and why pharmacotherapies work (or not). He envisions a day where we have multiple treatment options and understanding how each works for specific types of patients, leading to robust, cost-effective, patient-specific treatment algorithms.  

Alex Lalos describes how presentations on FGF-21s in advanced fibrosis and cirrhosis have whetted his appetite and Jenn Jones asks questions regarding ALD patient trial selection and assignment and clinical endpoints for cirrhosis trials. 

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00:00:00 - Surf's Up: Season 6 Episode 3

Surfing the MASH Tsunami continues its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on what studies on bariatric surgery and drugs in development can tell us about future treatment and explore some clinical trial questions. Our newsmaker, HistoIndex Director of Clinical Development Yukti Choudhury, introduces us to FibroSIGHT, which provides clinicians with highly precise biopsy analysis. Finally, our expert, Global Liver Institute Vice President, Liver Programs Jeff McIntyre, discusses the implications of recent US government job cuts on future MASH treatment options and patient care.

00:04:35 - Introduction

Host Roger Green briefly describes this episode's three sections and one key lesson from each.

00:05:45 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 3

This portion of our Emerging Trends Conference Roundtable looks at how therapy might evolve over time. Aleksander Krag starts by discussing a presentation on what we can learn from bariatric surgery in terms of fibrosis reduction and why pharmacotherapies work (or not). He envisions a day where we have multiple treatment options and understanding how each works for specific types of patients, leading to robust, cost-effective, patient-specific treatment algorithms.  

Alex Lalos describes how presentations on FGF-21s in advanced fibrosis and cirrhosis have whetted his appetite and Jenn Jones asks questions regarding ALD patient trial selection and assignment and clinical endpoints for cirrhosis trials. 

00:16:55 - Newsmakers: FibroSIGHT Brings Clinical Trial Analytics to Clinical Practice Use of Biopsy

Yukti Choudhury, Director of Clinical Development at HistoIndex, joins Roger Green to discuss FibroSIGHT, a new HistoIndex service that allows clinicians to use HistoIndex's Second Harmonic Generation (SHG) technology to determine specific CRN fibrosis level for patients with inconclusive NIT results.  Yukti states that demand for this technique could equal 163,000 cases this year and rising to one million by 2028. She provides practical cues on ordering the test and its reimbursement. 

Roger shares his long-standing respect for SHG and the clarity it produces. He notes the economic benefit of determining whether a patient has F2 fibrosis, which is indicated for pharmacotherapy, vs.F1, which is not indicated. He sees clear benefit, but expresses concern that any option requiring more biopsies will reduce the number of patients treated.

00:41:49 - Patient Advocate and Policy Expert Jeff McIntyre Discusses the Implications of FA/NIH Job Cuts on MASLD Patient Care

Global Liver Institute Vice President, Liver Programs Jeff McIntyre joins Roger to discuss the April 1 job reductions at the FDA, explore implications for the entire MASLD community, and to ask what patients can and should do. Jeff and Roger note that the job changes will create significant uncertainty and probably reduce the government's ability to respond to future health crises. Jeff notes former FDA Commissioner Rob Califf's comment that the FDA as we know it "is dead," and that we have little idea what the future holds. According to Jeff, patients need to become even more vigilant self-advocates and also seek the guidance and support they need from patient advocacies. 

Finally, the conversation turns to discuss FibroSIGHT. Jeff describes FibroSIGHT as "exactly where we should be and should not be at the same time," a technology that takes a large step forward in understanding and patient support, but one that ties us to biopsy as a standard for clinical care. Jeff and Roger agree this issue will play out over the coming years. 

01:09:18 - Business Report

Roger thanks listeners quoting a letter from one of them, and describes the next round of episodes. 

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00:00:00 - Surf's Up: Season 6 Episode 2

Surfing the MASH Tsunami continues its coverage of the AASLD Emerging Trends Conference on MASLD, MetALD and ALD. This week, the panelists focus on disease epidemiology and what it can teach us about the relative importance of alcohol and diet on disease progression. Our newsmaker, hepatology KOL and frequent Surfer Hannes Hagstrom, discusses what a recent paper demonstrates about the impact of MASLD on 15-year mortality and cause of death and how this information can improve patient care. Finally, our Expert, Shelbyville, Indiana internist Emily Ann Andeya, discusses her path from practicing internal medicine to focus on liver health (HINT: the common theme is insulin resistance).

00:04:40 - Introduction

Host Roger Green briefly describes this episode's three sections and one key lesson from each.

00:05:49 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 2 

The second portion of our Roundtable focuses on relative impact of alcohol and diet on disease progression and overall mortality and morbidity. It starts with Aleksander Krag sharing the highlights of his epidemiology presentation at the Emerging Trends Conference. Dr. Krag points out that while the vast majority of SLD patient live with MASLD, the vast majority of hospitalized patients and those living with late-stage cirrhosis live with ALD. Similarly, for the average patient, living with MetALD is more lethal than living with MASLD. Aleksander points out another challenge in defining where a patient lives on the ALD -> MetALD -> MASLD spectrum: patients' level of alcohol consumption is likely to change over time and many ALD or MetALD cirrhosis patients stop drinking altogether. The rest of this section considers the importance of stigma in correctly classifying patients and why genetics may become key to a message that minimizes patient stigma.

00:25:50 - Newsmaker: Hepatology Researcher and KOL Hannes Hagstrom of the Karolinska Institute joins Roger to discuss cause-specific mortality in Swedish MASLD patients

On March 24, the Journal of Hepatology posted a paper titled Cause-specific mortality in 13,099 patients with metabolic dysfunction-associated steatotic liver disease in Sweden. Co-author Hannes Hagstrom joins Roger to discuss the paper's key findings and implications for care. The key finding: living with MASLD leads to a significant increase in 15-year mortality. The most frequent cause of death among MASLD patients is cardiovascular disease, but the greatest increases in relative risk were due to HCC (HR ~ 35) and extra-hepatic cancers (HR ~ 26). Hannes points out that these results can serve as the beginning of a process where physicians can compute the risk at which individual patients place themselves through diet or alcohol patterns, which can aid patient understanding of the disease.

00:44:22 - Experts: Internist Emily Ann Andeya discusses how she developed the commitment to treating liver disease that made her a "unicorn" in the words of one AASLD panelist and also brought her to attend the Emerging Trends Conference last month

Roger first met Emily Ann Andeya when she asked a question at a session of last fall's The Liver Meeting, and again at the Emerging Trends Conference, where Emily and her colleagues were likely the only primary care physicians in the room. Emily describes the path by which she went from wanting to be a cardiologist during medical school in the Philippines through years of nursing in the US to primary care practice and, how, focus on the liver as a key to overall metabolic health. Listen as Emily explains the importance of understanding insulin resistance in her transition, and how her vision affects the way she and her colleagues practice, the goals they set, and the exceptional levels of care they achieve.

01:08:56 Business Report

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00:00:00 - Surf's Up! Season 6 Episode 1

SurfingMASH kicks off our sixth season in our new format, with three major elements to each episode. This week's Roundtable and Newsmakers segments focused on two recent conferences that took a multispecialty perspective on the range of medical and psychological issues affecting steatotic liver disease (a new concept specialty: steatology.") Our Expert this week is our co-host Jörn Schattenberg, discussing the educational and conceptual challenges of readying Europe for the EMA approval of resmetirom later this year.

00:03:58 - Introductions and Groundbreakers

Host Roger Green describes the new v2.0 format. He introduces the guests for this month's Roundtable discussion of the AASLD Emerging Trends conference: co-host Louise Campbell, hepatology KOL and EASL Secretary-General Aleksander Krag, Alcohol Use Disorder and Alcohol Liver Disease patient advocate and Sober Livers patient support organization co-founder Jenn Leigh Jones, and clinical hepatology Alexander Lalos. 

00:15:46 - Roundtable: Highlights from the AASLD Emerging Trends Conference, Part 1

The first portion of our Roundtable focuses on the emerging recognition throughout hepatology that MASLD, MetALD and ALD are best described as a disease spectrum, rather than discreet diseases. This has implications for the medical specialties involved in treatment and the entire way we look at this diseases.

00:32:35 - Newsmakers: Arizona Liver Health Institute Chief Medical Officer Naim Alkhouri and Fatty Liver Alliance Founder Mike Betel Discuss the 2025 Deser Liver Conference

Now in its fourth year, the Arizona Liver Health Institute's Desert Liver Conference has become a major multispecialty event on the Winter conference agenda. Arizona Liver Health Chief Medical Officer and hepatology KOL Naim Akhouri and patient advocate and Fatty Liver Alliance Founder Mike Betel join Roger Green to discuss the conference, including what makes it unique. Listen to Naim introduce a new description of the science of SLD.

00:55:21 - Experts: SurfingMASH co-host and hepatology KOL Jörn Schattenberg joins Roger Green to discuss how Europe is preparing for the launch of resmetirom and his own focus on this issue

Our third co-host, Jörn Schattenberg, could not join the February roundtable discussion. Here, he joins Roger to update listeners on his activities over the past six months. Most of the discussion centers around the necessary steps for Europe to prepare for the launch of resmetirom (anticipated to occur later this year), particularly given that the overall environment is more "siloed."

01:11;15 - Wrap-up: Roger presents "the shortest Business Report ever"

Roger discusses one continuing feature of Business Reports in the future from today and leaves all his other topics for next week.

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In this episode, Naim Alkhouri, Mike Betel, Michelle Long and Jeff McIntyre join Jörn Schattenberg and Roger Green to look back at The Liver Meeting 2024. This conversation reviews two sessions promoting healthy livers and asks panelists what they anticipate for #TLM2025.

This last conversation starts with Jeff describing the session that moved him most and praising a panel that Mike co-chaired on Lifestyle Management of MASLD and MASH. Jeff spoke on this panel, and he describes the breadth and quality of speakers and topics. While Jeff spoke about social determinants of health, others discussed commercial, regulatory and lifestyle determinants, all intermixed with practical advice on managing patients' lifestyle issues. Finally, he comments on a presentation from Meena Bansal discussing several concurrent posters in the meeting that aligned with the discussion in the session. 

After Jeff shares the content of the meeting, he comments on the large number of providers and industry executives who attended this patient-centered session. Roger notes a similar distribution of attendees at the Health Livers, Healthy Lives session on building momentum for prevention. 

In wrapping up the session, Roger does not share another presentation but notes how many modes of action have produced successful Phase 2/3 trial results. He notes that we may have 4-5 different modes of action available five years from now. 

In the rest of the session, panelists describe what they believe will be different and exciting at #TLM2025. Answers vary, but most focus on advances in drug development and/or NITs.

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In this episode, Naim Alkhouri, Mike Betel, Michelle Long and Jeff McIntyre join Jörn Schattenberg and Roger Green to look back at The Liver Meeting 2024. This conversation considers the role of patient advocacy in replacing biopsy in clinical trials with NITs and reviews a session on the foundational principles for patien-centric clinical trials.

This conversation picks up at the end of Michelle's discussion of the FDA Corner session. Jeff starts by identifying this specific issue - replacing biopsy in clinical trials with NITs - as a place topic on which he believes patients must play a pivotal role in this discussion. He notes that patient advocacy has been involved already but anticipates this role will grow as the discussion progresses. After Michelle agrees how vital this issue is for patients and notes that manufacturers are
"taking on this increased workload" for that reason, Jeff shares what he considers the key issue: FDA is not only a scientific agency but also a political one, and patients can serve as the "tip of the spear" toward political ends here.

Mike describes a poster he presented (and was lead co-author), titled Patient Voice in MASH Initiatives:  Foundational Principles for the Conduct of Patient-Centric MASH Research. He lists the groups participating in this broad effort and describes the goal as "reimagin[ing] clinical trials for MASH and how they're designed and delivered... focusing on what matters the most for patients." The outcomes were a set of patient-centric principles:

• Transparency in explaining trial-related issues. Mike gave the example of placebos, how they are used, and what happens to a patient in the placebo cohort at the end of the trial.
• "Whole person focus," including not only the medical issues but also emotional and practical issues that can emerge throughout the trial as patients' needs and life situations change.
• "Patients as partners," treating them as collaborators instead of subjects.
• Family and caregiver awareness, noting how deeply involved family members are through the trial process.
• Responsiveness to patient needs through surveys and checkpoints throughout the process.

Mike closed his comments by stating that all these points "put the patient at the center of the process," which meant considering not only diversity and inclusiveness in the trial population but also knowing and acting on what diversity will be in the context of these five principles.

Speaking from their perspectives as researchers, Michelle and Jörn were both highly supportive of the principles (Michelle called them "fantastic.") Jörn noted that the entire trial process starts with patient-centricity since the research is inherently designed to benefit patients.

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In this episode, Naim Alkhouri, Mike Betel, Michelle Long and Jeff McIntyre join Jörn Schattenberg and Roger Green to look back at The Liver Meeting 2024. This conversation reviews the late-breaker presentation on efimosermin, a q4w FGF-21 agent and the "FDA Corner" session. 

Jörn begins the discussion by highlighting a paper from the later breaker session on efimosfermin alfa, an FGF-21 agent dosed q4w. He notes that after only six doses (24 weeks), efimosfermin alfa demonstrated significant increases in fibrosis regression and lowering NAS score. To Jörn, this result, coupled with others on efruxifermin and pegozafermin, suggest that FGF-21s are likely to play a significant role in MASH therapy once approved. After Roger and Mike note their enthusiasm about the drug class and this study, Jörn mentions a study with 96-week efruxifermin that data demonstrates prolonged efficacy. As he points out, this matters because while studies of an earlier FGF-21 candidate suggested that antibodies might develop in FGF-21 therapy, that does not appear to be an issue here. 

Mike asks the group why they feel placebo performs so well in clinical trials. Jörn suggests that working with a compassionate clinical care team in dealing with the patient leads to better performance on diet and exercise and, as a result, increased placebo response to what we might find in general community practice.

Michelle praises the FDA Corner session, particularly the agency's transparency and willingness to engage industry and academia in finding paths to move away from biopsy. She also notes some of the practical challenges inherent of moving away from biopsy using data from earlier trials with an outmoded histology reader setup. She is optimistic about the scientific community coming together to address these issues. Jeff praises the agency for an "amazing" session.