Surfing the MASH Tsunami

00:00:00 - Surf's Up: Season 5 Episode 25
On July 20, Clinical Gastroenterology and Hepatology released the paper, Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to non-cirrhotic Advanced Fibrosis. Corresponding author Maru Rinella joins the Surfers to share key points from the recommendations and offer her thoughts on what lay behind them.

00:02:26 - Introduction and Groundbreaker
The highlight was Louise's groundbreaker: having become a full Fellow in the Roal College of Physicians.

00:06:28 - Introducing the paper
Roger starts by discussing the importance of this paper and listing the questions the panel will address during the episode. Maru provides a history of developing the paper. Jörn praises its timeliness. 

00:08:59 - Treating the "Right" patients; Using the "Right" tests
Jörh asks why the authors changed the patient definition from a histological one to at-risk MASH patients confirmed by NITs. Maru said the authors sought to follow the FDA guidance on NITs and patient targets. They considered adding liver enzymes or confirmatory VCTE to the protocol, but demurred because not every clinical could execute such a recommendation. 

Jörn asks whether the authors considered requiring three metabolic risk factors. Roger notes that this question implies a need to prioritize patients, which is a factor in Europe but not the U.S. This paper takes a more U.S-based perspective, which is to set a threshold for use.  

00:14:21 - The Decision Not to Discuss Cost
The authors did not address costs because they anticipated steep reductions over time. The panel compares the MASH case to HCV. In HCV, the combination of high drug costs and large number of warehoused patients drove prioritization over time. 

00:16:34 - Relative paucity of warehoused MASH patients 
Maru suggests relatively few MASH patients are warehoused. Louise asks whether many U.S. insurers are controlling access by requiring liver biopsy. Maru reports she has not encountered this personally and  estimates it might affect ~5% of cases so far. 

00:19:05 - Rationale for Patient Selection
Maru explains the rationale for an F2 threshold for patient selection: patients with fibrosis >= F2 show a demonstrable decline in long-term survival. The rationale for excluding cirrhosis patients? Resmetirom is not yet proven to help patients with cirrhosis. Jörn notes, the MAESTRO-OUTCOMES trial is running and will generate consequential data on cirrhosis. 

00:22:11 - Value of Stabilizing Disease without Improvement
Maru notes that the paper focused strongly on how to stabilize patients because the drug is safe and stabilization has real-world benefits.. She points out that patient advocates strongly recommend this focus. All this led to the paper's recommendation to discontinue only upon progression.  

00:25:12 - The importance of incremental learning
The group agrees that these recommendations comprise a base that will be strengthened over time as individual providers gain experience with the drug. 

00:30:06 - Wrapping up
Panelists touch briefly on the value of loose discontinuation rules, how patients feel about starting therapy, how to handle drug interactions, and how the paper is used in the US vs. other countries. In closing, the group remembers Stephen Harrison's unique contributions one more time.

00:37:55 - Question of the Week
Which of the paper's two striking recommendations -- using multiple NITs to qualify patients and continuing therapy unless and until a patient shows signs of disease progression -- will have greater impact on how physicians treat patients?

00:38:44 - Business Report
Summer schedules, value of the business report, the vault discussion.

Two weeks ago, the SurfingMASH Question of the Week asked, "What structural or educational changes do you anticipate will significantly improve Provider-Patient communication? Will these changes require more from the provider and more from the patient?" Today, S5 E23 panelists Mike Betel and José Willemse join Roger Green to review the three answers we received. 

Of the three questions from audience members, one from a patient/patient advocate suggested greater honesty, better listening, and, if possible, either longer appointments or better care team engagement. The second, from another patient, discussed being more honest about the Quality of Life impact of immunological drugs, along with ways to manage these drugs better. The third, from a public health official in Argentina, discussed increasing the use of multidisciplinary teams to educate and empower individuals around healthy habits and lifestyles. 

To Mike, these answers all convey the need for "tailored care," a care and engagement process suited to each patient's individual situation in terms of disease(s) and quality of life needs and issues. He also suggests that pharmaceutical companies help educate physicians on these issues while discussing the disease and use of their medicines. 

José notes that it might not be possible to get more time for a visit, but the physician could improve the visit immensely by asking patients true open-ended questions about their feelings and concerns and then actively listening to their answers. She also suggests that physicians not act like they are time-compressed. If physicians act more leisurely, patients will be more comfortable, even if they do not take up more time. 

Roger suggests that the format of physician protocols and instructions might be part of the problem. If the physicians are evaluated by their employers based on their ability to work through an entire checklist in 15 minutes, they will focus first on the clock and second on the checklist. This will not leave time for patient questions and, even worse, will leave the patient afraid to take up any more of the physician's time than is necessary. Thus no true communication develops. 

Mike goes back to a point that José made during the original episode: physicians should close their computer screens and look at the patients. Roger goes back to the question about immunosuppressants to ask whether providers can assess patients' abilities to manage medications that cause or exacerbate depression and then offer advice and perhaps antidepressants as appropriate. 

Given all these emotive patient needs, José suggests that patient support groups have tremendous value, and Roger notes the presence of online support structures like HOPE from Sober Livers (Season 5 Episode 18). After asking where to find resources for these kinds of activities (particularly in less wealthy parts of the world), the conversation ends.

In the second half of Roger Green's interview with Global Liver Institute Vice President, Liver Programs Jeff McIntyre, Jeff discusses the implications of his key EASL Congress takeaways for GLI and other patient advocacy groups.  

To Jeff, this trend makes patient advocates a more valuable player in the clinical trial design process, particularly when coupled with the FDA's increasing focus on diversity in trial populations. This will become particularly important because, today, the major use of incretin agonists like semaglutide and tirzepatide is in anti-obesity, where payers are frequently declining to pay for the drugs. Advocates like GLI will be pivotal in ensuring that patients who need MASLD drugs will still get the drugs they need, particularly at earlier stages of fibrosis. This discrimination may allow patients to receive incretin agonists during the pre-fibrosis stage based on diabetes and anti-obesity medications and reserve the fibrosis drugs for patients with more advanced MASH. The entire scenario of early metabolic, later MASH treatment with different agents is at least 4-5 years in the future. In the meantime, Jeff sees a need to advocate for underserved groups in the population while at the same time laying the foundation for the longer-term case. In this context, the United Nations General Assembly side effect (covered in S5, E22) is an exciting and vital event.

This conversation contains the first half of Roger Green's interview with Global Liver Institute Vice President, Liver Programs Jeff McIntyre, during which the two discuss what Jeff considered the key strategic takeaways for GLI from the various EASL Congress presentations, abstracts and discussions. 

Jeff focuses on the "overriding sense of optimism" coming from the multiple pieces of positive drug data. He cites the data on Boehringer Ingelheim's survodutide, the follow-up work on Madrigal's resmetirom, an anticipated presentation on semaglutide at the AASLD in November, and strong FGF-21 results as proof that we are beginning to develop multiple robust, safe and effective modes of action for drugs to treat (at least pre-cirrhotic) MASH. His second positive point is that due to the drug trials and nomenclature change, GLI and other advocates are starting to have "more enlightened discussions" about MASLD in the context of the whole patient and related metabolic conditions. As a result, he comes to the third point, which is that multiple modes of action will teach us why what works in one patient might not in another and, ultimately, reshape clinical trials so that the target might not be fibrosis (or at least not only fibrosis), but instead exactly how each drug works. Jeff envisions this line of inquiry as a step down the path away from requiring biopsy. 

In the second half of Roger Green's interview with PharmaNest Founder and CEO Mathieu Petitjean, Matt discusses the implications of his key EASL Congress takeaways for PharmaNest.  

Matt starts this discussion with a simple question: Will biopsy-based analyses become part of a surrogate endpoint? As he points out, they are not today, and creating the necessary data might require a significant effort. If not, they are unlikely to remain relevant to the large, Phase 3 trials. Regardless of the answer to this question, Matt believes digital pathology will still be important in pre-clinical work and other efforts to define underlying liver structures and faults better. Also, he notes, digital pathology is valuable in an array of other liver diseases and in non-hepatological markets, notably including pathology. One way or another, he is confident PharmaNest will continue to make contributions to hepatology and grow as a business.

This conversation contains the first half of Roger Green's interview with PharmaNest Founder and CEO Mathieu Petitjean. After Matt tells the audience a little about his background and PhramaNest, the two discuss what Matt considered the key strategic takeaways for PharmaNest from the various EASL Congress presentations, abstracts and discussions. 

Before answering the question, Matt describes the core services his company offers: "PharmaNest specializes in digital pathology. Four years ago, we put down the hypothesis that the histological phenotype of fibrosis should be quantified in a high-resolution, sophisticated way." He goes on to state their core proposition for MASLD: "The big idea here is that fibrosis equals phenotype." He proceeds to describe his offerings in greater detail before offering the underlying value of computed histology: fibrosis is a continuous variable that is scored in discrete categories under the NASH-CRN model that drives FDA analysis. With this as context, he answers the question by describing three kinds of MASLD clinical trial designs. The first, earliest trials had a single pathologist reading histological slides. The method is not precise, but the drugs were not very good, and none were ultimately approved. The second set of trials relied on more rigorous methods for pathologists to read histology slides, with multiple readers and robust adjudication systems. Also, the drugs in this second set of trials were more efficacious, so that NASH-CRN, while a blunt instrument, could adequately assess efficacy. For the third set of trials, Matt believes non-invasive tests (NITs) are likely to suffice.

00:00:00 - Surf's Up: Season 5 Episode 24 
This week's episode on MASLD lessons from the EASL Congress 2024 includes three separate elements: individual interviews with PharmaNext Founder and CEO Mathieu Petitjean and Global Liver Institute Vice President of Liver Programs Jeff McIntyre,  followed by a discussion with patient advocates Mike Betel of the Fatty Liver Alliance and José Willemse from the Netherlands, now supporting EASL. 

00:02:45 - Introduction
Roger explains the episode format, including the two key questions for Mathieu and Jeff: (i) what were their key takeaways from the EASL Congress, and (ii) how have those takeaways changed how they do their jobs or plan for the future? Roger also sets up the Question of the Week discussion that is today's third section. 

00:04:04 - Meet Mathieu Petitjean
This is the SurfingMASH debut for Mathieu Petitjean, Founder and CEO of PharmaNest. He tells the audience a bit about his background and his love of Harleys.

00:07:10 - First question to Matt
Matt begins by describing the core services Pharmest, a digital pathology company, offers MASH drug developers. Then he answers Roger's question by describing three phases in MASLD clinical trial designs. His point is that over time, drugs have gotten better, and histology requirements have become more onerous. At some point in the not-too-distant future, Matt believes non-invasive tests (NITs) are likely to suffice in large Phase 3 trials of the future.

00:21:01 - Second question to Matt
Matt starts the answer with a conditional: if biopsy-based analyses become part of a surrogate endpoint, the role is large and clear. If not, they are unlikely to remain relevant in Phase 3 trials. Regardless of the answer to this question, Matt believes digital pathology will remain important in pre-clinical work and in other continuous liver diseases with less-defined targets. Also, he says, digital pathology is valuable in an array of non-hepatological markets, notably including pathology. 

00:29:11 - First question to Jeff
Jeff describes an "overriding sense of optimism" he felt due to the many positive drug trials presented in Milano. This suggests that the MASLD community is developing safe and effective MASH drugs with many different modes of action. This is allowing GLI and other advocates to start to have "more enlightened discussions" about MASLD in the context of the patient's overall metabolic state. All this means that what works in one patient might not in another. This can reshape clinical trials so that the endpoint target might not be change in fibrosis but impact against specific NIT targets. Jeff envisions this line of inquiry as a possible step away from biopsy. 

00:39:34 - Second question to Jeff
Concurrently, FDA is beginning to require greater diversity in clinical trial populations. To Jeff, all this makes patient advocates like GLI more valuable to the clinical trial design process and pivotal in ensuring that metabolic and advanced MASH patients will still get the drugs they need. Starting today, Jeff sees advocates as championing underserved groups in the population while at the same time laying the foundation for the longer-term case. 

00:55:20 - Discussing previous "Question of the Week"
This is a 15-minute discussion of the Question of the Week we posed at the end of S5 E23. This section will constitute S5 E24.5, which we will post in the next day or two. A more complete summary will appear there. 

01:11:23 - Question of the Week
The Question of the Week is the first question Roger asks Matt and Jeff during this episode.

01:12:58 - Business Report
Previewing Episode 25, with Maru Rinella discussing the recently-published expert recommendations on use of resmetirom, along with comments on office hours the reason we will not have a vault conversation this week.

This week, Surfing the MASH Tsunami looks back on interviews Roger Green conducted during the EASL Congress itself. This conversation with SurfingMASH co-host and Tawazun Health Founder and Clinical Director Louise Campbell took place on the last day of the Congress This portion of the conversation was not included in the original S5 E19 but instead was reserved for a special conversation at a later time (now).

The specific focus of this conversation is on how practice patterns and guidelines are likely to change over the next several years. One driving factor involves the need to get primary care not only involved but actively committed to playing a leading role in treatment, given how quickly the identified patient population might grow. Louise points out that the overall rate of growth might be one longer-term issue, but in the short term, dramatic increases in the number of patients with cirrhosis will be a more immediate concern. She questions how staffing and training will address both challenges, with more patients being diagnosed in earlier-stage MASLD patients, coupled with more late-stage fibrosis and cirrhosis. She speaks specifically about a poster looking at liver disease as a factor for cardiac arrhythmias and the seemingly confounding idea that play three, while a genetic target to predict muscle, might also be cardioprotective within the muscle population. However, it has no effect on muscle progression or other just related diseases. This leads Louise to one more optimistic conclusion this time that we will see broader collaboration between specialties over time as we appreciate the scope and complexity that comes from viewing muscle as part of the broader metabolic disease continuum.  

This week, Surfing the MASH Tsunami looks back on interviews Roger Green conducted during the EASL Congress itself. This conversation with Hepatology Key Opinion Leader and EASL Educational Councillor Sven Francque took place 90 minutes after the EASL Congress closed. The discussion focuses on plans and hopes for the future, both the future of MASLD diagnosis and treatment and of the EASL Congress itself.

The conversation starts with Sven discussing all the positive energy coming from the Congress, not only for MASLD but for the entire Liver community. He describes the ambiance of the meeting as feeling "vibrant," and with a lot of interaction. He goes on to discuss the CPG guideline committee on which he was a member. (See Season 5 Episode 21 for a fuller discussion of CPG). Sven goes on to share the vision of disease that led to this broad, forward-looking guideline update.

From there, we discuss positive results from a set of early-stage clinical trials, with Sven commenting specifically on tirzepatide, efruxifermin and an array of positive phase two trials, one of which is lanifibranor, which presented its results previous year. Sven also finds two studies that use different methodologies but evaluated the prognostic value of liver stiffness to be important. He discusses the value of the new nomenclature and how it allows researchers to look more broadly at the entire steatotic liver disease category. We close by talking once more about the positive body of drug development studies, which Surfing MASH discusses in greater detail in Season 5 Episode 20.

This week, Surfing the MASH Tsunami looks back on interviews Roger Green conducted during the EASL Congress itself. This conversation with SurfingMASH co-host and Tawazun Health Founder and Clinical Director Louise Campbell took place on the last day of the Congress.

This conversation centered on three major topics addressed at the EASL Congress, each of which made Louise "quite enthusiastic."

The first of these was the presentation of the new EASL/EASD/EASO Clinical Practice Guidelines and their practical implications (Season 5 Episode 21). Louise described this session as having "blown her mind" with its forward-thinking style and recommendations. She termed it a "leap of faith" that we all need to think differently about diabetes and obesity given how quickly incidence is growing. Her favorite items? The guidelines mentioned resmetirom even before it was approved in Europe.   Also, the guidelines described ways to use several drugs that have not been approved for MASLD to treat patients with other metabolic conditions that are linked to MASLD. Louise also expressed enthusiasm at which three organizations partnered on this document.

Roger suggested that this aligned broadly with the various drug presentations in the Late Breaker and General sessions. Collectively, those presentations highlighted an array of drugs with different modes of action and strengths across the metabolic continuum.  More generally, the two agreed that we are looking at a world where, in just a few years, we will have multiple drugs, most with unique modes and all with specific patient targets.

Roger asked whether Louise believes that over time, the diagnostic focus would stay with liver stiffness and CAP or switch to in-office PDFF. Louise suggested that in a world where clinical trials may not require biopsy, it would be difficult to build a sufficiently robust data set for any new tests.