Surfing the MASH Tsunami

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This conversation centers around the different kinds of impact that in-office scanning can have on MASLD therapy, both in terms of improved prognostics and better overall outcomes. 

Roger Green starts by suggesting that the recent commercialization of a second VCTE in the U.S. (specifically, Hepatoscope from e-Scopics), coupled with increased promotion of the scanning device Velacur from Sonic Incytes, will increase education and promotion dramatically and lead to significant increases in patients scanned and scan frequency. I then note the downside to this issue: increased presence of scanning devices, coupled with the fact that FDA approved Rezdiffra without requiring biopsy, might make it more difficult to recruit patients to biopsy-based clinical trials.

The group demurs whether this might motivate the FDA or EMA to move toward NITs sooner but is highly confident that it will lead to improved liver health coupled with increased access to training for prescribers and advanced providers and, separately, sensible reimbursement structures.

Jörn Schattenberg shifts to discuss LiverAIM, a new EU consortium with the goal of demonstrating that testing affects outcomes by comparing matched cohorts of 50,000 patients each. If this demonstrates the cost-effectiveness of screening, it will address reimbursement and the speed of device purchase. Louise asks whether LiverAIM will include a brief interventional therapy and conversation, two elements she finds vital in treating liver patients.  Jörn states this is not the primary study objective but might occur. She asks how the study will address cultural and governmental differences between countries. Jörn expresses hope that these can fall out in analysis.

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This conversation explores why different nutrition interventions might help MASLD patients improve their overall liver health and what lessons treaters and researchers can learn from this. 

It starts with Louise Campbell discussing a recent publication of a pilot study from Armandi et al. (including Jörn Schattenberg as a co-author) evaluating the ability of short-term dietary gluten reduction to reduce metabolic dysfunction as measured in CAP (controlled attenuation parameter) scores. The study shows that even a short-term intervention can have a meaningful impact. The results confirm Louise’s experience with sugar-rich foods and suggest that several different diet interventions can produce valuable results. It leads to a discussion with Louise, Jörn and Hannes Hagstrom asking which change actually drives the lower CAP: gluten, associated high fructose and sugar content in the gluten-rich products, or overall calorie reduction.  To Louise, the most important idea is that interventions work best with frequent VCTE tracking and multiple diet options for patients to choose. Jörn and Roger Green concur.

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This conversation focuses on the role of VCTE in diagnosing, staging and treating MASLD patients, both in terms of prognostic ability of VCTE when compared to biopsy and separately as a therapeutic adjunct.

It starts with Hannes Hagstrom and Jörn Schattenberg discussing a study from Vincent Wong and a large group of co-authors, including Hannes,, that compares the abilities or VCTE and biopsy to predict outcomes. After Hannes mentions the studies and makes the key point that VCTE might be sufficient to predict the risk of outcomes in clinical trials or other events, Jörn describes the study in greater detail and goes on to ask a basic question, if a patient comes into a referral center with a VCTE-supported score of 10.2 kilopascals, what does that tell the physician about how to treat? Hannes notes a further complication: this is a tricky test to do properly, particularly in obese patients. He asks whether high kilopascal scores on VCTE should be repeated. Jörn responds that he often does the retest himself, and goes on to suggest that unlike all other tests, a repeat VCTE test four weeks later might serve a therapeutic purpose while also validating earlier results.

Louise Campbell comments that frequent retesting can have two different types of impact. During holiday season, it can inform the patient on exactly how much change increased eating and drinking has caused the liver. During more normal or therapeutic times, it can show the patient how quickly improved behavior might translate into improved liver health.                                                                                                                                                    

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Hannes Hagstrom joins Jörn Schattenberg, Louise Campbell and Roger Green to discuss recent research panelists have conducted. This content-dense conversation focuses initially on the impact of VCTE and other forms of in-office monitoring and branches out from there.

00:00:00 - Surf's Up: Season 5 Episode 9
Opening comments from the panel, including brief quotes taken directly from the episode.

00:02:04 - Introduction and groundbreaker
Each panelist shares one piece of good news from the previous week.

00:06:02 - Introducing Topic
Roger invites panelists to share research they either participated in over the past couple of months or found particularly important.

00:06:57 - VCTE scores predict liver-related events as well as or better than biopsy
Hannes discusses a recent paper in which he participated (Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease; H. Lin et al., JAMA Online, 21MAR 2024.) This paper suggests that, in Hannes's words, "[VCTE] may be enough if you want to predict the risk of outcomes." 

00:09:41 - The value of repeat measures 
Panelists comment on the value and discrete benefits of taking frequent repeat measures for in-office scanning tests.

00:12:15 Changing gluten vs. reducing sugar: impact for patients
Louise mentions a recent study by Armandi et al. looking at the impact of changing gluten content on MASLD. The group discusses the benefits of offering patients multiple behavioral options. 

00:20:33 Impact of increased access to in-office scanning
Roger asks whether an increased focus on overall in-office scanning may speed the replacement of biopsy with scan results in clinical trials, at least in the U.S. Panelists describe other possible benefits.

00:23:48 LiverAIM
Jörn discusses the LiverAIM consortium and its goal to improve that testing improves outcomes. The group asks whether prognostic value can provide a rationale for broader screening. Jörn suggests that LiverAIM might answer some of these questions. 

00:28:56 Primary care as triage
Roger focuses the discussion on how various healthcare systems will manage the tsunami of patients likely to come to physicians' offices once a drug is available and patients are aware. Hannes describes a role for primary care that Roger describes as "triage." 

00:31:05 Is VCTE a simple enough solution?
Roger asks whether VCTE can become the easy-to-interpret test that motivates primary care to engage. Jörn suggests we will need a simpler, potentially automated algorithm, possibly something like the Fibrotic NASH Index ("FIB-4 on steroids"). 

00:37:30 Predictive biomarkers and commercial success
Hannes notes that we will need a way to determine whether a given drug works for a particular patient. To Jörn, this raises the general question of predictive biomarkers for individual drugs or drug classes., which the group agrees will take years to sort out.

00:41:19 Diet and exercise
Louise suggests that the label statement that Rezdiffra is adjunctive to diet and exercise will require prescribers to monitor the efficacy of lifestyle intervention. Jörn and Roger note that this is standard in the U.S. language and requires little real monitoring. 

00:44:20 - Closing question
Roger asks each panelist what we might achieve over the next two years to improve our ability to get the right patients to therapy.

00:49:15 - Question of the Week
The question asks what role you envision office scanning techniques like VCTE and 3D ultrasound playing in the future of patient screening and the development of clinical care pathways compared to computed tests.

00:50:04 - Business report
This week's news on audience metrics, our upcoming 4th anniversary and this week's Vault conversation.

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With Louise Campbell and Jörn Schattenberg both on Easter Week vacations, Fatty Liver Alliance Founder Mike Betel joins Roger Green to continue a brief conversation they began in a post from the Fatty Liver Alliance last weekend. This conversation focuses largely on how patient incentives to participate in MASH clinical trials might need to change now that Rezdiffra is approved. 

00:00:00 - Introduction
Roger explains why Louise and Jörn are not available for this conversation and welcomes Mike to a dialogue on issues they are considering in the aftermath of Liver Forum 16.

00:01:22 - The importance of convergence 
Mike elaborates slightly on a comment he made in a Friday FattyLiver/SurfingMASH post on LinkedIn about the importance of thoughtful convergence between all the stakeholder groups to identify and resolve issues and why he considers the Liver Forum a great place to do this. Roger shares his understanding of the unifying challenge underlying the Forum's remit and the issue it chooses to address.

00:03:15 - Including patients in clinical trial design 
Roger asks Mike what role he believes patient advocates should play in clinical trial design and bringing regulatory issues forward. Mike elaborates on the importance of including patients in clinical trial design. 

00:04:47 - Three issues to consider around placebo, biopsy and clinical trials
Roger lists three issues he considers critical to consider in the aftermath of having an approved drug for advanced MASH patients: (i) requiring biopsies for trial when they are not required for treatment; (ii) willingness of patients to participate in trials when the Control group option remains placebo despite an approved drug; and (iii) maintaining trial patients on placebo to the end of Phase 4.

00:05:20 - Keeping placebo patients in clinical trials 
To Mike, a key challenge for BioPharma companies will be what to offer placebo patients when they finish a clinical trial or the trial transitions to Phase 4. Roger suggests the challenge will become easier in future trials once a Standard of Care replaces placebo in the control group. 

The conversation meanders through the various issues related to placebo in terms of trial assignment and continuation in Phase 4.

00:09:19 - The benefit of having the Liver Forum

To Mike, the Liver Forum brings tremendous benefit in terms of providing a forum for all stakeholders to consider these issues together. Roger points to a different benefit: the ability of companies to pool resources in situations where the cost might be too much for one company to assume. He cites the example of the Placebo Arm Database Project (discussed in Season 3 Episode 57). 

00:10:52—Is the performance of a placebo group in clinical trials the same as that of untreated patients worldwide? 
 
Mike asks whether study results for patients in the placebo control arm of a clinical trial are similar to results we would find in the practice of medicine outside the trial setting. Roger remembers an early lipids trial in which the effect of counseling overwhelmed  drug impact. They discuss how complicated (if not impossible) it would be to design a trial that accurately compares the effect of a "standard treatment" group to the trial control and active groups.

00:13:28 - Can we ensure that patients in general practice get the same level of support as patients in a clinical trial?
Mike suggests that a multi-stakeholder event like the Forum should address ways to ensure that patients in everyday practice get the same support as patients in clinical trials. Roger suggests this goal may be unachievable given the limited amount of time primary care physicians can devote to a typical patient visit. 

00:15:32 - Signoff 
After a brief signoff, the conversation ends.

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So far, this conversation has focused on Rezdiffra approval and its many forms of impact on MASLD patient advocates. This conversation considers their recommendation for others. 

The conversation starts with Roger Green's final question. He asks each panelist to identify a stakeholder group that can take a valuable lesson from this episode and what that lesson should be. 

Wayne Eskridge goes first. Wayne focuses on the need for Madrigal and the various professional societies to increase education and information support for the gastrointestinal community. 

Mike Betel and Jenn Jones hope the Rezdiffra approval will lead to greater research investment and a broader, deeper focus for their investments. Louise Campbell returns to the need for provider education, this time for medical nursing and allied health professionals. She also believes organizations need to recruit greater nursing capacity. 

Jeff McIntyre asserts that if nutrition and physical activity are critical adjuncts to drug therapy, the entire healthcare community needs to advocate for access and reimbursement to dieticians, physical therapists, exercise specialists, and other supportive professionals. Tony Villiotti returns once more to education, mentioning the need to increase scale. He also discusses some specific topics that will merit more focus. 

Finally, Roger Green discusses two different forms of optimism: optimism among patients that they can be treated and, separately, optimism among investors that increasing the scale and scope of their investments will provide good returns.  

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This conversation asks what impact Rezdiffra patient education might have on a U.S. healthcare system in which 38% of American adults live with some form of MASLD and 15% live with MASH. 

Louise Campbell starts off by saying she is “slightly fed up” with the idea that we cannot proceed too quickly for fear of overwhelming the system. Louise would rather flip focus to push systems to build the capacity they will need to handle the flow of patients that will certainly grow over time. Mike Betel agrees and discusses two Fatty Liver Alliance activities in Canada, one of which is a survey of 27,000 primary care physicians. 

Roger Green pushes back slightly on Louise’s comment about overwhelming the system. He suggests that building capacity may be easier in countries with government-run healthcare systems, where one group can make and implement national decisions, than in the fragmented private US system where everything is measured in terms of short-term profit.  Jeff McIntyre agrees with Louise’s point in that we can’t think in terms of “don’t burden the provider anymore.” He then discusses an innovarite solution the US Veterans Administration is implementing.

Louise points to the importance of systems solutions in view of her belief that most patient management in MASLD will fall to primary care within the next 5-7 years. This stresses the importance of systems enhancements and growing the population of advanced providers. 

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This conversation focuses on how the role of MASLD patient advocates might change and expand in the aftermath of Rezdiffra being approved.  

To Wayne Eskridge, this “raises an entirely new field of education and outreach,” because now advocates can do more than merely be supportive emotionally. Advocates can, quoting again, “refresh our message and have broader perspectives and share a more hopeful outlook to the future” and talk about clinical trial participation and other drugs coming down the line. Also, he notes that advocates can provide the education to bring new patients into the system and help deliver the information providers will need to know in order to treat them. Jeff McIntyre adds that this will raise a new set of questions for advocates to ask companies and the healthcare system in terms of support for patients with cirrhosis, more patient-friendly dosing, reimbursement…a range of issues. 

Roger Green shifts focus to ask how advocates can help slow the flow of patients into the system by reducing the rate of MASLD growth. Tony Villiotti says education is key and notes how NASH kNOWledge starts by educating children. Jenn Jones adds that education and promotion can give hope to patients with alcohol-related liver disease and those with the new category MetALD. She also notes that the label gives advocates new leverage to stress the importance of nutrition and physical activity. 

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This conversation focuses on the steps that patient advocates took to educate the FDA on what patients wanted in a MASH drug label, in this case for Rezdiffra. 

It starts with Jeff McIntyre reflecting on apparent changes in how the FDA thinks about labeling since the initial obeticholic acid Complete Response Letter in 2020. His specific point: since that first CRL, GLI has worked closely with patient advocates, including those on this call, to educate the FDA on what their endpoints and considerations were around safety and efficacy and to help get Rezdiffra approved in the way that brings maximum benefit to patients. He points to biopsy as one proof point. More important, he believes the advocacy from patients has led to an approval process and label that “de-risks” the MASLD space for future investment. 

The other panelists agree. Wayne Eskridge points back to biopsy as a particularly critical issue. Jenn Jones believes the collective effort has improved accessibility as well. Tony Villiotti acknowledges a concern that the FDA had been “dismissive” during the Obeticholic Acid Advisory Committee last year and describes himself as “pleasantly surprised” by the patient centricity of the final Rezdiffra label. Louise Campbell says this label might become a “game changer” if it signals that Madrigal will help MASH patients, most of whom live with co-morbidities, get support in navigating their array of issues.

As the conversation ends, Roger Green makes a specific point that Madrigal’s offer to support medical exceptions signifies a deep understanding of the actual challenges to early uptake and a commitment to do better than companies in the past.

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This conversation focuses on advocates' reactions throughout the day on Thursday, March 14, the day Rezdiffra became the first MASH drug approved in the U.S. 

Specifically, panelists discuss their thoughts and feelings as they reflected on Rezdiffra’s approval in the context of their personal experience. While no panelist is eligible to receive Rezdiffra as indicated, some thought back that day on their earlier patient experiences, while others thought of the patients for whom they advocate. 

During the day, all the panelists describe themselves as having reflexively refreshed their screens, waiting for news, and a few described real concern over seeing the announcement that morning from AASLD withdrawn a little while later. Once the announcement came out officially, reactions varied.

Wayne Eskridge was the first to reflect on his reactions. He recalled his initial diagnosis in 2014 or 2015, a “very emotional” event in his office because, at that time, the diagnosis sounded like a death sentence. Tony Villiotti says the approval did not resonate with his experience, but that he felt a surge of hope for those who might benefit today and in the years ahead. Mike Betel seconds his statement, mentioning that the lack of a biopsy requirement was an excellent benefit for patients. Jenn Jones likes the idea that the drug is non-invasive and believes "this is the start of a new era" for MASLD patients of all kinds.