COVID CHAOS: The 2nd Wave - Ep 39

This conversation comes from our first look at MASEF, last September, when lead author Mazen Noureddin joined the Surfers to discuss his recent breakthrough paper on this new NIT.  The original conversation had a robust write-up:

Mazen Noureddin joins co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to discuss serum identification of at-risk MASH and the Metabolomics-Advanced Steatohepatitis Fibrosis Score (MASEF). In late July, Mazen co-authored a paper on the subject which was published in Hepatology.

This conversation begins with Louise’s initial response around the setting of application for MASEF. She poses a question that leads the group to explore possible pros and cons of different approaches and the potential impact each might have in terms of cost effectiveness. For example, Jörn wonders how feasible it will be for non-experts to administer. Mazen suggests that its application will be relatively easy before explaining how to navigate the caveat of a gray zone similar to that of VCTE. After a few more comments on sequential pairing with FIB-4, Mazen next teases the possibility of demonstrating therapeutic efficacy in the drug development space. 

Louise returns to a question around cohorts and asks whether variables like age or sex has an impact on the test’s capabilities. She then asks whether this sort of work has the potential to inform retrospective cardiac studies. After Mazen and Louise go back and forth with a few ideas in response, Roger makes the comment that he is struck by the wide breadth of application and describes the platform as “elegant.” As the conversation winds down, the group discusses a few comparisons between different blood-based markers. 

If you have questions or comments around MASEF, metabolomics or any other ideas considered in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at questions@SurfingNASH.com. The Surfing the NASH Tsunami will be back next week with more original content.

After some final discussion about GLP-1s, this conversation entails Roger Green summarizing what he has heard in the episode so far and testing for confirmation or correction. It goes fast and covers significant ground. 

Naim Alkhouri starts this conversation by discussing patients for whom he would prescribe resmetirom vs. GLP-1s. Lean MASH patients are likely to receive resmetirom. Earlier fibrosis patients are more likely to receive semaglutide. A multimorbid F3 patient might receive both. 

Roger asks how things might change with tirzepatide, since it is a dual agonist with strong MASH-lowering effects. Naim expresses doubt that tirzepatide will be antifibrotic, since neither GLP-1 nor GIP have direct liver effects. He has more faith in the glucagon dual- and triple-incretin agonists. 

The rest of the conversation involves Roger stating themes he has heard earlier and asking for confirmation or amendment. It moves pretty fast, covers a lot of territory, and receives some agreement and some correction.

This conversation touches on two important subjects: the impact of different potential resmetirom prices on the size and structure of the treatable MASH population, and the impact GLP-1s are having (and will have) on clinical trial recruitment and basic patient treatment. 

It starts with Naim Alkhouri expressing concern over the $39-52K price he has heard for resmetirom, which ICER has deemed cost-effective. He mentions another paper that says a price of $19,000 would be cost-effective. To Naim, this magnifies a question that is already quite widely considered: when to prescribe resmetirom vs. a GLP-1 agent. He discusses some patient factors that might go into his decision. 

Naim describes ways that GLP-1 use, which can be sporadic or episodic, is affecting clinical trial recruitment. Ian Rowe discusses the current use of GLP-1s in the UK and suggests that if the price for resmetirom is high enough, GLP-1s will receive significant use. 

Naim Alkhouri shifts direction slightly, from discussing current GLP-1s to exciting recent clinical trial report. He focuses on two: survodutide from Boehringer Ingelheim and efruxifermin from Akero Therapeutics. Recent exciting results from BI and Akero suggest to Naim and others that the future for drugs is bright. 

Ian Rowe anticipates a significant amount of co-prescription of GLP-1s and resmetirom in this population. GLP-1s have already demonstrated clear cardiovascular, weight loss, and HbA1c-lowering benefits. To Ian, that creates sufficient motivation to prescribe GLP-1s to multimorbid patients with diabetes, obesity and most likely MASLD or MASH. To him, the price of resmetirom will have a tremendous impact on how often UK physicians rely on GLP-1s alone.

This conversation focuses more tightly on the specific challenges with the current approaches that use NITs to diagnose and stage advanced MASH fibrosis and explores several newer options and ways of thinking about the challenge.

Roger Green notes that recent papers discuss the failure to predict accurately with FIB-4. He asks how we can improve predictive performance. Louise Campbell notes some specific challenges, after which Jörn Schattenberg praises John Dillon's work in automating lab detection algorithms. He also reiterates his view that repeat testing will be pivotal in good test protocols. Ian Rowe rejoins the conversation (from a faulty Internet connection) to comment that our inability to stage patients reliably will lead to government payers like NHS believing that they will need biopsy to stage patients accurately and treat them cost-effectively. Jörn says Germany will work differently and if EMA approves it, it will launch in Germany.

Roger asks about new tests on the horizon and specifically whether there is sufficient improvement in diagnosis, staging or treatment. He refers specifically to MASEF and Naim Alkhouri's earlier comments about four scan vendors at his conference. Ian says there are tests that can rise to this task, but they are not produced in sufficient quantity and cost too much to become a first-line option. Naim notes that the most exciting tests are a couple of years away. Ian returns to Jörn's earlier point about the value of sequential testing vs an individual test. Louise suggests that device size will be pivotal for primary care.

This conversation explores the challenges with using the current non-invasive tests (NITs) to diagnose patients with F2/F3 advanced MASH fibrosis. If tests today cannot achieve the requisite level of precision, panelists explore other ways to define patient targets.

Roger Green starts by recalling that in a recent episode (Season 5 Episode 2), Jeff McIntyre suggested that in the US, the initial patient population may be as small as a few hundred thousand people. Ian Rowe states that current tools are incapable of placing these patients in a narrow diagnostic or therapeutic window. Jörn Schattenberg takes a "pragmatic" approach to defining the patient he is certain to treat; test results are a small part of his calculus.

Naim Alkhouri shifts the discussion to focus on VCTE cutoff points for cirrhosis. The interplay between Naim and Ian suggests that different practices and guidelines carry with them different cutoffs. Jörn expresses gratitude that the can watch the US and learn from that experience. He notes the tension between wanting a cost-effective system and large numbers of patients clamoring for the new medicine. The need to rule some patients out is obvious, the way to do so is challenging.

Asking, "What can we do besides scan" or use conventional tests, Naim discusses some newer options, starting with the metabolomics-based MASEF score discussed in Season 4 Episode 39. He also mentions the LiverFast test. Jörn describes factors that can render a test inappropriate for a particular patient. Louise suggests the right test will depend on the specific question the provider is trying to answer.

This conversation explores why proper use of non-invasive tests (NITs) will play a pivotal role in increasing the number of patients diagnosed and treated for MASH. It becomes particularly pivotal if, as expected, the first MASH drug is approved later this month.

Roger Green starts this conversation by describing why he considers NIT use and adoption one of the two pivotal patient treatment issues for 2024. Jörn Schattenberg notes that he has not received any referrals from PCPs or endocrinology based on elevated FIB-4, which would happen if enough front-line treaters were adopting the new clinical care pathways. Educational efforts have begun, but do not seem to be changing behavior yet. As Jörn puts it, "We're still preaching, and I haven't seen it in much activity."

Naim Alkhouri states that his experience is the same as Jörn's. He reminds us that we covered some of these issues in a 2023 end-of-year conversation (S4 E50.3). He reiterates his concern with FIB-4 as a standalone first-line test and states his preference for combining it with an in-office scan. He comments that at the recent Desert Liver Conference, four companies displayed these devices, each with a different price point and convenience factor. 

Ian Rowe describes the British experience as being different: "every patient with elevated ALT in the context of metabolic risk factors has a FIB-4 and now has a FibroScan." His biggest concern is that tests are insufficiently precise. If we have top-end and bottom-end cutoffs, he fears, "you're going to end up excluding a lot of patients who would be potentially eligible for treatment."

In 2024, the two major areas for change in diagnosing and treating MASH  are new drug approval and changes in use of NITs. Naim Alkhouri and Ian Rowe join Jörn Schattenberg, Louise Campbell and Roger Green to consider what might change with NITs and how having an approved drug might change thinking on this issue.

00:00:00 - Surf's Up: Season 5 Episode 5
Opening introduction, including brief quotes taken directly from the episode discussion.

00:02:36 - Introduction and Groundbreaker
Panelists congratulate Naim on the recent, highly successful Desert Liver Conference. In the groundbreaker, each panelist shares one piece of good news from the previous week.

00:06:36 - Why Focus on NITs?
Roger describes why he considers this issue worthy of an episode. Naim and Jörn both state that they have received no referrals from PCPs or endocrinology based on elevated FIB-4 tests. Ian notes that the UK has guidelines and pathways built into some protocols; these make it challenging to stage a patient as F2 vs F3 vs early compensated cirrhosis.

00:13:06 - NITs and treating F2/3 MASH patients 
Ian says that current tools are incapable of defining the small nitial target patient population Jeff McIntyre suggested in Season 5 Episode 2.  patients clearly enough to place them in a narrow diagnostic or therapeutic window. Jörn takes a "pragmatic" approach to defining the patient he is certain to treat; test results are a small part of his calculus. Naim shifts the target patient to focus on VCTE cutoff points for cirrhosis. There is no clear cutoff.

00:18:45 - Tests worth using beyond the widely discussed options
Asking "What can we do besides scan" or use conventional tests, Naim discusses some the new blood-based tests. Jörn describes factors that can render a test inappropriate for a particular patient. Louise suggests the right test will depend on the specific question the provider is trying to answer.

00:22:59 - Improving on FIB-4
Roger notes that recent papers discuss failure to predict accurately with FIB-4. In the conversation that follows, panelists agree that automating test results and using a series of tests instead of a single event will both have real value.

00:28:27 - New Devices and Blood-Based Tests for Use in Office
Roger asks about new tests on the horizon and specifically whether there is sufficient improvement in diagnosis or treatment. Naim notes that the most exciting tests are a couple of years away. Ian returns to Jörn's earlier point about the value of sequential testing vs an individual test. Louise suggests that device size will be pivotal for primary care.

00:35:30 - Impact of Resmetirom Price
Naim expresses concern over the $39-52K price he has heard for resmetirom. Roger states that price reflects size of target market. At that point, the discussion veers toward factors that drive drug prices higher.

00:40:22 - Impact of GLP-1s on treatment and resmetirom
Roger asks the group what the impact of consumer-driven GLP-1 use is likely to be on US prescribing of MASH drugs. Ian discusses use of GLP-1s in the UK and suggests that if the price for resmetirom is high enough, GLP-1s will receive significant use. Recent exciting results from BI and Akero suggest to Naim and others that the future for drugs is bright.

00:47:16 - Final question
This entails Roger summarizing what he has heard in the conversation and testing for confirmation or correction. It goes fast and covers significant ground.

00:53:26 - Question(s). of the Week
The question is what else will change, besides prescribing, once a drug is improved and what the industry can to do optimize change.

00:54:06 - Business Report
News on audience metrics, the upcoming Question of the Week, future episodes and this week's Vault co

Two years ago, Surfing the MASH Tsunami conducted two episodes with Chris Estes, then the chief modeler for the Center for Disease Analysis Foundation exploring issues around CDAF's then-recent publication of a NASH/MASH disease model. This conversation centers on issues of advanced fibrosis. We thought it might be interesting to look back at that episode in lieu of today's topic. Here are the summary notes from 2022:

This conversation starts with Chris Estes describing the processes he and his colleagues at the Center for Disease Analysis Foundation have used to build a disease model for NAFLD and NASH prevalence in 15 countries. Chris discusses some of the unique challenges that modeling NASH presents. Among other items, these include (a) spontaneous regression of disease; (b) "excess" mortality (mortality not from liver disease where NASH is a contributing factor); and (c) interplay of demographics (gender, age, race, etc.) and co-morbidities (most notably Type 2 diabetes) with disease.

When Chris ends his initial comments, Jörn Schattenberg asks about the viability of using obesity as the anchor for increasing prevalence estimates instead of diabetes, noting the varying definitions of BMI across countries. Chris notes that obesity is imperfect but adds that we have robust, stable, long-term obesity data bases in most countries, whereas diabetes estimates are newer and many people with diabetes to not recognize they have the disease.

The last element in this conversation starts with Alina Allen noting that for clinical trial development, researchers test patients with a range of diagnostics. As a result, they do not need to develop estimates based on (or even linked directly to) obesity or diabetes. Alina asks what models can tell us that can help bring down high placebo rates in double-blinded, placebo-controlled clinical trials. Chris mentions meta analyses as recently as seven years ago that exhibited negative disease progression over time and adds that any assessment of F3 (or even F2) fibrosis is affected by concomitant disease.

This conversation 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.

As the episode comes to an end, the group winds up focusing on the need for better, more frequent MASH education as a pivotal need if we are to flatten the growth curve of the MASLD pandemic. In the process, the discussion returns to the risk for women and the important role they can play. 

Louise Campbell starts this conversation by harkening back to the issue of post-menopausal women. As she notes, women provide most of the hands-on care in health system, and also do most of the cooking and food shopping for the home. To Louise, targeting women also targets children, so educating women will have multiple derivative benefits.

Zobair Youonossi agrees completely, particularly for the low SDI countries. I suggest that slowing prevalence and disease has two elements: fewer patients at the starting line (or with early MASLD) and better therapies and programs for patients who already live with the disease. I also ask whether the consumer uptake of GLP-1s might have an impact in the US.

Zobair states that educating children is the key long-term driver and that the effect of consumer medical behaviors like taking GLP-1s is likely to be minimal. He also believes that MASLD requires more attention from global and national governmental and non-governmental players…NOW!

This episode does not have a formal closing question, but the rest of this conversation offers a wrap-up of each panelist’s perspective.

This conversation focuses largely on the work of the Global NASH Council, an effort of over 200 stakeholders in more than 50 countries to address a range of macro issues in the MASLD space.

Zobair Younossi, who is the Global NASH Council Chair, starts this conversation by discussing a specific Global NASH Council project on how to implement guidelines for different specialties across regions. He offers two reasons this is such an important project.

1. In general, Zobair notes, 90% of the content in guidelines is virtually identical, but the other 10% might vary widely. The goal of the Global NASH Council is to identify this last 10%, understand the reasons for these differences, and seek to align them better.
2. As he points out, guidelines are worthless without effective implementation. The second goal of this project is exactly that: to improve implementation.

Zobair goes on to discuss other Global NASH Council projects, ranging from shared biopsies to the previously mentioned modeling activities. He notes its growth in size and expresses gratitude to the other global MASLD leaders, including Jörn Schattenberg, who are part of one of more of the Council's major projects.

Roger Green asks Zobair to put the guidelines project and the Council's policy focus in the context of his earlier comments about high SDI vs. low SDI countries. He describes differences in what food insecurity means between the two types of nations and how that should affect each country’s pursuit of policy and guidelines. He also suggests that it will be more important to provide patient and provider information for specific low SDI countries.