Surfing the MASH Tsunami

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Mazen Noureddin and Naim Alkhouri join Jörn Schattenberg and Roger Green to discuss the tirzepatide late-breaker at the EASL Congress 2024 and other "Twin-cretins," all of which are GLP-glucagon combinations. 

"Twin-cretins" is the name Jörn has coined for agents with a GLP-1 agonist plus another incretin effect. Tirzepatide is a GLP/GIP agent, while survodutide and the agents discussed last year, pemvidutide and efinopegdutide, are GLP/gluagons. 

Naim reviews the results of the tirzepatide late-breaker presentation. As expected, it showed high rates of MASH resolution. Naim does not feel it answered the question whether an incretin-agonist can achieve significant fibrosis regression without a direct liver effect, since it relied on a completer analysis that treated 3 of 10 non-completers as a success (in ITT, that would have been 0 out of 10). Again, glucagon has a direct effect; GIP does not.

This takes Naim back to the question of whether a GLP/GOP can have a meaningful effect on fibrosis. He notes that Stephen believed firmly that it could not, but there is a paradox in that bariatric surgery can produce a reduction in fibrosis. Naim notes that conclusive data will arrive later this year, so no one needs to decide now. 

Mazen praises tirzepatide's effect on weight loss and safety and could prescribe it now, but the completer analysis has not persuaded him to prescribe to regress fibrosis, particularly given the lack of a dose response. He notes that "while I don't want to compare apples to oranges," he is more confident in the glucagon effect found with survodutide, pemvidutide and efinopegdutide. Jörn agrees.
 
Roger asks how prescribing decisions will change in a market where a significant share of US patients will have been prescribed semaglutide or tirzepatide before coming to the hepatologist. Naim comments that many of his MASH patients have been on GLP-1 already.  He notes that since glucagon increases blood sugar, the ratio of GLP-1:glucagon is a key issue and difference between the three GLP/glucagon agents. 

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Naim Alkhouri and Mazen Noureddin join Jörn Schattenberg and Roger Green to discuss some of the new research on resmetirom at the EASL Congress 2024.

Mazen begins this discussion by covering a paper he presented on Stephen's behalf, looking at dose-response with resmetirom. The analysis indicated that PDFF and histology improvements at the 100mg dose were greater than at the 80mg dose. Mazen speculates that the higher dose might provide a greater anti-fibrotic response as well, although, in a world where biopsy is not required for prescribing, he doubts the study will ever be done.  Jörn notes that the most important element of the study might be a demonstration of effect lasting at least 36 months. 

As an aside, Mazen mentions a study from Samer Gawrieh demonstrating that dropping liver stiffness to <10kPa correlates with a 75% reduction in clinical liver events. He reports that resmetirom was a bit higher than 10 in Year 1, but dropped below for those patients continuing to Years 2 and 3.
 
 At this point, Naim shifts slightly to compare modes of analysis: Completer Analysis vs. Intent to Treat. 
His point is that Intent to Treat, which scores all non-completers as failures, will produce lower rates of response than a "completer" or "modified Intent to Treat" analysis, which either eliminates non-completers or assigns placebo-level response to them. 

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00:00:00 Surf's Up, Season 5 Episode 20
Naim Alkhouri and Mazen Noureddin join co-hosts Jörn Schattenberg and Roger Green to discuss major drug development stories from the EASL Congress 2024. They pay tribute to Stephen Harrison and proceed to groundbreakers.

00:08:16 - Presentations on Resmetirom
Mazen shares a paper he presented looking at resmetirom dose-response. The 100mg dose performed better than the 80mg dose. Jörn notes that the most important element of the study might be the demonstrated 36-month effect. 

00:14:19- Implications of Different Analytical Modes
Naim compares different modes of analysis. Intent to Treat, which treats all non-completers as failures, will produce lower rates of response than a "completer" or "modified Intent to Treat" analysis, which either eliminates non-completers or assigns them placebo-level response.

00:16:12 - The "Twin-Cretins"
Jörn coined  the name "Twin-cretins" for agents with GLP-1 agonism plus another incretin effect. Tirzepatide is a GLP/GIP while survodutide, pemvuditide, and efinopegdutide, are GLP/glucagons. Naim reviews the tirzepatide late-breaker presentation, which showed high rates of MASH resolution, but, as a completer analysis, might not have proven whether a GLP/GIP can achieve significant fibrosis regression.  Naim notes that Stephen doubted strongly this was possible, but that bariatric surgery's effect creates a paradox. Mazen concurs, and states he is more confident in the GLP/glucagon agents. Jörn agrees.

00:23:09 - Implications of widespread GLP use
Roger asks how widespread prior patient use of incretins will affect prescribing. Naim states that many of his Rezdiffra MASH patients have been on GLP-1 already.  He describes a key difference between the three GLP/glucagon agents in development.

00:24:20 - The previous GLP/glucagon studies
Naim expresses his excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed a further reduction in liver fat compared to the GLP-1 agent.
 
00:26:44 - Safety of survodutide in cirrhosis
Jörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He reviews survodutide data from the NEJM article.
 
00:29:41 - FGF-21s, starting with efrux data
Focus shifts to FGF-21s. Mazen shares data from the efruxifermin late-breaker, a 96-week, triple biopsy study showing dramatic, sustained one- and two-level fibrosis improvement. Jörn notes the design demonstrates durability, which Roger finds particularly encouraging given the pegbelfermin experience. Naim  adds that a sustainable two-stage drop in fibrosis might position FGF-21 as induction therapy before long-term oral maintenance. 
 
00:35:28 - Is a drug-based MASH "cure" possible?
Mazen wonders whether sustained FGF-21 efficacy might return livers to their "normal" state, almost like a "cure." Jörn briefly discusses pegozafermin, and Mazen notes that a third FGF-21 is in development. 
 
00:42:22 - Wrap-up
The panel covers three other agents: the FASN inhibitor, denifenstat, Ionis's DGAT-2 antisense inhibitor, ION224, and Takeda's TAK-227, a TG2 inhibitor, plus the results of SPECIAL, a study evaluating the effect of bariatric surgery on people with cirrhosis. After these, Roger asks Mazen and Jörn what they consider likely to be the biggest story at AASLD in November.
 
00:53:03 - Question of the Week
Given this discussion, Roger asks what are likely to be the three most prescribed medications for MASH five years from now.
 
00:53:36 - Business Report
The next EASL Congress review episodes, how to attend recording sessions live, and a vault discussion from last year's EASL Congress wrap-up. 

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00:00:00 - Surf's Up: Season 5 Episode 19
During EASL Congress 2024, US-based Roger Green, conducted interviews with Mike Betel, Louise Campbell (twice) and Sven Francque from Milano. These interviews focused on the major MASLD themes and presentations at the event. 

00:04:14 - Conversation with Mike Betel begins
On Wednesday, the first afternoon of the meeting, Mike Betel joined Roger from the convention center. 

The first part of the conversation centered  on the Patient Advocate session that Mike chaired with Shira Zelber-Sagi. The session's goal was to discuss barriers to addressing unmet needs in a clinical setting and explore potential solutions. Mike's key takeaway: patients around the world are having challenges getting personal attention and time from their treaters. 

The rest of this interview touched briefly on other sessions Mike attended. 

00:15:23 - First conversation with Louise Campbell 
Roger's first interview with Louise took place late on Thursday. She described the "really nice vibe" of the meeting, dampened by the fact that Stephen Harrison is no longer with us.

The first session Louise chose to discuss was the previous day's Patient Advocate session. To her, the key point was to learn a key question that every provider should share with every patient once a year. 

She briefly mentioned the one presentation from the day's General Session she was able to attend:  analysis of the predictive value of VCTE.

00:19:53 - Philosophically important presentations
Louise discussed two sessions that delivered powerful, somewhat novel messages. The first was a symposium sponsored by Novo Nordisk about how SLD treatment could "manage the cardiometabolic side...rather than focusing on liver disease." The second was the "Healthy Livers, Healthy Lives" presentation which presented "very startling figures" about SLD impact on US healthcare costs and productivity and how and why India has targeted this disease aggressively. 

00:26:29 - Building momentum and energy around AI 
Louise and Roger both observed that momentum is building in MASLD and mentioned why they believe this is happening, 

00:33:05 - Second conversation with Louise begins
Two days later, Louise and Roger conducted a second conversation, which focused on her enthusiasm for the updated Clinical Practice Guidelines and their practical implications. 

00:36:12 - CPG session implications
Louise said this session had "blown her mind" with its forward-thinking style and recommendations. Her favorite point? The guidelines mentioned resmetirom even before it was approved in Europe.   

00:44:07 - Thoughts about medications
Roger suggested that CPG aligned broadly with the drug presentations in the Late Breaker and General sessions. Collectively, those highlighted drugs with an array of modes of action and strengths across the metabolic continuum.  

00:46:09 - Thoughts about devices
Roger asked whether Louise believed that, over time, the diagnostic focus would shift from liver stiffness and CAP to in-office PDFF. Louise discusses why this might be difficult.

00:51:48 - Conversation with Sven begins
This conversation, which took place 90 minutes after the final gavel, started with Sven praising the "vibrant hepatology community" evident at the meeting. 

From there, the discussion covered the Clinical Practice Guidelines, major drug development presentations and other categories. The conversation is fairly short, but packed with information and insight. 

01:06:42 - Question of the Week
Roger asks what kinds of support and education primary care will need to step into a leading role in treating SLD.

01:07:13 - Business Report
Plans for the next month, growth of the SurfingMASH Community, a special surprise instead of the Vault.

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In this final conversation, Sober Livers leaders Jenn Jones and Beth Lehman share what they hope listeners will take from this discussion of HOPE (Healing Others with Peers and Education) and how they can help this unique support program grow. 

The conversation starts with Roger asking what Sober Livers and/or transplant centers can do to help patients learn how to find a living donor. Beth says one key is to make "living liver" synonymous with transplantation, "as with donating a kidney, right?" Jenn adds that an individual who sought a live donor plans to help Sober Livers educate HOPE members on using social media more effectively. She adds that through HOPE, Sober Livers needs to make people who are less social media savvy aware of options and how to pursue them. Also, from a policy perspective, living donor surgery is considered elective for the donor. Until this changes, the process will be exceptionally expensive -- usually prohibitive -- for the donor. 

In closing, Roger asked what issues the conversation missed. Beth asks that everyone remember the website soberlivers.org. Jenn comments that the organization does not yet have the funding it needs to expand during the first year. She notes that it is a 501(c)3 whose books are completely independent of the Fatty Liver Foundation and states that moving the program from Zoom to a more secure platform and covering all first-year expenses will cost $60,000. With that, the conversation ends.

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Sober Livers leaders Jenn Jones and Beth Lehman join Roger Green to discuss HOPE, their new support community for people who have harmed themselves through AUD (Alcohol Use Disorder). This conversation focuses on plans and hopes for the future.

Roger starts this conversation by sharing a story from his own experience about the pressure caregivers struggle with and asks how HOPE (Healing Others with Peers and Education) will address caregivers and their needs. Beth acknowledges that this need is legitimate and that caregivers for these people may need a program of their own. The group wrestled with this issue when considering their original offering, but decided the organization needed to meet the needs of people living with this situation before offering services to caregivers. Jenn elaborates that the reason not to include caregivers in the initial group population is that it may limit the items and issues that HOPE's core constituency is willing to discuss. She says that creating a parallel caregiver program will be a pivotal next step once the target group is up and running. 

Next, Roger asks what else Sober Livers would like to implement over time to enhance the program. Jenn notes that the organization plans to create benchmarks and conduct qualitative and quantitative research to ensure that “this is an effective community that’s actually helping people.” They will share this data and a resulting strategic plan with HOPE’s WHAC (Whole Health Advisory Council) and prospective sponsors, including one healthcare products company that has already committed to a starter grant.

In practical terms, Jenn mentions starting a second meeting at a different time of day, possibly one more suitable for West Coast residents with jobs. They plan to recruit transplant centers to make information available so that appropriate patients will enroll and even make initial contact during first hospitalization. They would like to educate the people living with disease on options they might not have considered and scientific advances.  At one point, Beth mentions a desire for in-person meetings in cities with major transplantation centers.  

In terms of education, Jenn mentions liver perfusion and finding a living donor as two areas Sober LIvers would like to provide support.

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In this conversation, Society of Sober LIvers leaders Jenn Jones and Beth Lehman describe the HOPE (Healing Others with Peers and Education) program. They go on to discuss  why version 1.0 does not include specific support for caregivers.

Jenn describes the program's core elements, starting with a monthly video call that is a support meeting one month and an educational program the next.  The program will include a Facebook group where individuals can continue their conversations in private, plus a weekly blog and an array of educational resources. Beth adds that stopping drinking and addressing addictive behavior are not necessarily the same thing and that HOPE will help individuals address their overall behavior, not merely their AUD. Jenn adds that Sober Living is addressing issues holistically and anticipates that ideas and activities will "bubble up" from members. She also anticipates scaling up in time as interest grows.

Roger asks how a provider can help patients find their ways to Sober Livers and HOPE. Beth says the key is for the group to deliver educational materials to the offices where patients go. After Roger shares the group's e-mail address (soberlivers.org), Jenn notes that the Zoom address for the support meetings will not be publicly available. People must enroll to be invited. While enrolling on the Sober Livers website, they can learn more about the organization and its other resources.

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This conversation focuses on the target population of patients with AUD (Alcohol Use Disorder) with decompensated cirrhosis and asks why this group needs a support community like HOPE (Healing Others with Peers and Education).

Roger asks what makes people who have harmed their bodies through AUD a unique community as compared to other communities providing support for people trying to change their behaviors. Beth and Jenn explain that the lifelong medical challenges associated with being post-transplant or living with cirrhosis create unique needs and challenges that traditional recovery programs do not address. 
 
Roger describes a friend who was found on his bathroom floor vomiting blood and asks whether this person is a good candidate for the program. Jenn describes why that case is so serious and indicates the answer is "Yes." Beth adds that this person might not have addressed the behavior patterns that led him to overconsume alcohol, which would put him at risk of relapse and, therefore, in need of support. 

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This conversation re-introduces us to Sober Livers Founder/Visionary Jenn Jones and introduces us to Beth Lehman, Principal Strategic Advisor to Sober Livers and HOPE, a multi-element patient support program for people who have harmed their livers though AUD (Alcohol Use Disorder).

As this conversation starts, we meet Beth Lehman, Principal Strategic Advisor for Sober LIvers, who discusses her disease background and personal history and adds one thing we might not know about her otherwise.

After we meet Beth, Roger introduces the topic by discussing how the new nomenclature has broadened stakeholders' view of liver disease by incorporating AUD into the vision of steatotic liver disease through ALD and MetALD. In the aftermath of the new nomenclature uptake, Sober LIvers joined forces with the Fatty Liver Foundation and came to SurfingMASH's attention this way.

Jenn introduces HOPE, which stands for Healing Others with Peers and Education, an organization that provides peer support for people who have harmed their bodies due to  AUD, while simultaneously advocating for "people to understand the disease better."  Some peers will be living with cirrhosis, while others will be post-transplant. Patients may have other metabolic system issues.  

After sharing how hard it was for her to confront her truth, Beth notes that while she has been involved in several different programs, none have had subgroups for people who harmed their bodies through AUD...which is why she believes this group is needed so badly.

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Roger Green is joined by Sober Livers Founder/Visionary Jenn Jones and Principal Strategic Advisor Beth Lehman to discuss HOPE, a support program launching June 11 for people who have harmed their bodies through ALD and its consequences. 

00:00:00 - Surf's Up: Season 5 Episode 18
Standard lead-in, including quotes from panelists

00:02:07 - Introduction
Roger describes the episode structure.

00:03:44 - Meet Beth Lehman
Beth Lehman, Principal Strategic Advisor for Sober LIvers, discusses her disease background and personal history,

00:08:45 - Groundbreaker
One good thing in the past week, personal or professional.

00:11:28 - Introducing HOPE
Roger starts the conversation by discussing how the new nomenclature has incorporated alcohol into the vision of steatotic liver disease. It was the new nomenclature that led Sober LIvers to link with the Fatty Liver Foundation.

Jenn introduces HOPE, (Healing Others with Peers and Education) an organization providing peer support for people living with active or remission Alcohol Use Disorder (AUD) while advocating for "people to understand the disease better." Peers will be living with cirrhosis or post-transplant. 

Beth notes that while she has been involved in several different programs, none have had subgroups for people who harmed their bodies through consumption of alcohol...which is why she believes this group is needed so badly.

00:15:38 - Why patients who have harmed themselves have different needs
Roger asks what makes people who have harmed their bodies through alcohol abuse unique. Beth and Jenn explain that the lifelong medical challenges associated with being post-transplant or living with cirrhosis create unique needs and challenges. 

Roger asks whether a friend who was found vomiting blood is a good candidate for the program. Jenn describes why the answer is "Yes." Beth adds that this person might not have addressed the behavior patterns that led him to overconsume alcohol, which would put him at risk of relapse.

00:22:22 - What the HOPE program includes
Jenn describes the program's core elements, starting with a monthly video call that is a support meeting one month and an educational program the next. Beth adds that HOPE's goal is to help individuals address their overall behavior, not merely their drinking. Jenn anticipates that ideas and activities will "bubble up" from members.

00:28:16 - Questions about providers and caregivers
Roger asks how a provider could help patients find their ways to Sober Livers and HOPE. Beth says the key is for the group to deliver educational materials to the offices where patients go. Jenn notes that the Zoom address for the support meetings is not publicly available. People must enroll to be invited.  While enrolling, they can learn more about the organization and its other resources.

Roger asks about support for caregivers. Beth notes that Sober Livers plans to provide support over time, because "care partners are going through a lot." At the same time, she notes that people living with the disease may have things to say that they would not share with caregivers. 

00:33:43 - Future plans, budget and wrap-up
Roger asks what else Sober Livers would like to implement over time to enhance the program. Jenn answers and then, In response to a question from Roger, estimates what it costs to run the program for a year. Sober Livers has raised some funds, but seeks more.

00:44:47 - Question of the Week 
Roger asks listeners what other patient or stakeholder groups might benefit from a program like HOPE.

00:45:19 - Business report 
The business report discusses SurfingMASH's EASL coverage, the high level of interest in the private community and the reason the vault is taking a week off.