Surfing the MASH Tsunami

Michael Charlton and the Surfers discuss two issues: defining therapeutic futility for Rezdiffra and describing some advances in MASLD translational medicine. The conversation starts by continuing the topic of therapeutic futility. Louise Campbell asks Michael how he plans to determine therapeutic futility with Rezdiffra in terms of side effects or efficacy. Michael indicates that he will continue patients on Rezdiffra as long as their disease does not progress. While he would prefer a more robust approach, he describes the scale of challenge in defining futility for a drug where FibroScan and transaminase levels did not provide strong prediction.Roger Green asks what percentage of patients are taking concomitant GLP-1 therapy. This leads to a brief sideline discussion on levels of therapeutic adherence.Roger asks Michael what he find exciting in translational medicine these days. Michael cites the LiverRisk score, a developing test he describes as "substantially superior" to other biomarkers. His group is currently working with NHANES data to see whether this is predictive for patients who had transient elastography and met MASH criteria. He particularly wants to determine whether this is a dynamic test. Michael goes on to discuss the work his group is doing on the microbiome, where he and others are finding potentially valuable insights. The challenge continues to be how to translate these insights into clinically meaningful interventions.

In this initial conversation, Michael Charlton describes some ways that the presence of Rezdiffra has affected practices and procedures in his clinic and shares issues he and his colleagues are discussing. As the conversation begins, Michael hails Rezdiffra as proof that as a species, "we can be capable of amazing things in a good way," a drug approved by FDA to reverse fibrosis in a significant number of patients with the world's most common liver disease. From there, he goes on to discuss the challenges his metabolic live disease clinic faces in prescribing the drug. The first issue: the label provides "tremendous latitude" in defining the target F2/F3 patient properly.Jörn Schattenberg asks about the patients coming to his clinic and how much knowledge they possess of the disease and medication. He also asks how Michael discusses Rezdiffra with them. Michael describes a clinic with hepatology and endocrinology, nutrition support and a group of nurses all of whom can do elastography.  Some patients want medication, others seek to care for themselves first through nutrition and physical activity plans. In all cases, the clinic takes a holistic approach, particularly because most patients have at least one more metabolic complication.Michael shifts to a second issue: futility. The label does not include information on treatment-stopping criteria.  He alludes briefly to a leading KOL group that is creating "something to help the field" decide which patients to treat and when to stop therapy, among other issues. Jörn asks whether the clinic is setting up a new panel of test for these patients, Michael states that the clinic relies mostly on standard tests: FIB-4, ELF, FibroScan, and, for patients above a certain threshold, MRI. 

Michael Charlton joins Jörn Schattenberg, Louise Campbell, and Roger Green for a far-reaching conversation that covers ways Rezdiffra is already impacting MASH patient treatment, exciting recent studies and broader issues in clinical trial recruitment.  00:00:00 - Surf's Up: Season 5 Episode 11Opening comments from the panel, including brief quotes taken directly from the episode. 00:02:32 - IntroductionOpening comments (re)introducing listeners to Michael Charlton00:04:34 - GroundbreakersEach panelist shares one piece of good news from the previous week.00:06:56 - Impact of Rezdiffra launch on Michael's clinic Michael hails Rezdiffra as "an amazing thing" in terms of its global impact. He goes on to discuss the challenges his clinic faces in properly defining the target F2/F3 patient. 00:14:40 - Defining positive response and treatment futility In response to a question from Louise, Michael indicates that he will continue patients on Rezdiffra as long as they do not progress. 00:19:44 - LiverRISK scoreThe conversation shifts to focus on progress in translational medicine. The first item Michael cites is LiverRIsk, which he terms "substantially superior" to other biomarkers. Next, he mentions his group's work on the microbiome and the challenges in translating items like these into clinically meaningful interventions.00:23:15 - Low-dose aspirin as anti-MASH medicine Michael discusses the recent JAMA publication of a small RCT suggesting benefits from use of low-dose aspirin in biopsy-confirmed MASLD patients.  He and Jörn agree that while the sample size was small, the "highly promising" results might be worthy of discussion with patients.00:26:29 - Jörn and Louise share their items of interestJörn discusses his excitement about the upcoming Innovations in SLD Think-Tank 2024 and its new format. Louise discusses a study indicating correlation between the Dietary Inflammation index score and kilopascal levels. 00:33:27 – Questions about the Dietary Inflammation Index Louise and Jörn speculate on ways to incorporate this kind of result into multifactorial care. Michael asks whether alcohol figured in the index given that many MASH patients consume alcohol. 00:35:38 - Roger on patient feedbackRoger asks how panelists feel about MD columnists recommending that MASH patients  "go to your doctor and ask for an ultrasound."  Michael and Louise agree that given how few patients are treated today, any such public acknowledgment is positive.00:38:11 - Excitement and questions surrounding FGF-21sMichael discusses the emerging excitement around the FGF-21 class. "emerging as highly potent" and asks questions its use and long-term value to patients. The group discusses adherence challenges with a q1w injectable therapy. 00:41:26 Therapeutic models for MASH prescribing Roger asks whether prescribing for FGF-21s might align with an "oncology" model, with FGF-21 as induction drug and Rezdiffra as maintenance drug. Michael suggests that benefits from FGF-21s are likely to fade once therapy is discontinued. 00:43:08 - Challenges in clinical trial recruitment and adherenceJörn, Michael and Roger all agree on the growing challenge of keeping patients in the long-term clinical trials necessary to achieve hard outcomes.00:47:24 - Closing questionRoger asks participants what they believe are exciting studies likely to come to light over the next three months. 00:49:33 - Question of the WeekThe question asks how much value old standard drugs like aspirin or pioglitazone are likely to bring to MASH or MASLD patient treatment.00:50:22 - Business ReportThis week's news on audience metrics, SurfingMASH sponsorship, spring events and this week's Vault conversation.

This episode is a follow-up to Season 4, Episode 5, where we met Tim Jobson. His company, Predictive Health Intelligence (PHI), takes a unique approach to identifying and monitoring MASLD patients using basic EHR data and analytics. This session explores PHI's work over the past years and considers implications for several liver-related health challenges. 00:00:00 - Surf's Up: Season 5 Episode 10Opening comments from the panel, including brief quotes taken directly from the episode. 00:02:04 - Introduction and GroundbreakerEach panelist shares one piece of good news from the previous week.00:07:02 - New projects from TimTim discusses the three major activities that PHI has undertaken since our last visit.00:12:46 - Sequential testingRoger Green asks Tim to state one key lesson he would like to share with a global audience. Tim speaks of the value of sequential testing and the value of collecting data that will support this effort. 00:15:33 - Data governance and privacyLouise Campbell asks Tim about privacy issues and GDPR status for these types of basic health information. Tim states that the number of cases where patients have exhibited concerns when they learn the data is helping them get/stay healthier is virtually nil.00:22:31 - Most and least helpful data itemsTim states that "factual data" (e.g., lab tests) are more valuable than "coded data" reflecting a treater's point of view. 00:25:21 - Thoughts on patient gender and age In response to Louise's questions, Tim shares that his group creates separate analyses by gender, strongly prefers creating risk thresholds to "measures of normality and abnormality," and already is seeing a trend of patients needing MASLD care at younger ages. 00:30:23 - Differences between MASLD and HCVTim discusses some differences in the challenge of bringing in-need HCV patients into the healthcare system compared to in-need MASH patients. HCV patients tend to live at lower socio-economic status, and some who lead high-risk lives may be homeless. MASH patients are more likely simply to lack knowledge and more likely to come to a physician visit once identified. 00:38:38 - Specific challenges in the USIn response to Roger's questions, Tim identifies two differences in the US today: greater clinician motivation due to Rezdiffra coming to market and a greater need for an inexpensive way to target the right patients and then track whether the drug appears to be working.00:41:49 - Keeping data import simpleTim comments that these kinds of activities are challenging enough when data sets and needs are fit to goal and fairly simple, let alone if researchers or policymakers inflate the dataset unnecessarily. This is particularly important because the system can probably locate so many untreated patients using simple data. 00:47:18 - Seeking high-value patients more effectively and final questionLouise and Tim consider what might be the "sweet spot" when patients are ill enough to appreciate that they need treatment but still hardy enough that therapy has time to work. From there, Roger asks a final question about how all stakeholders can contribute to the goal of aggregating large-scale basic sequential data.00:52:52 - Question of the WeekThe question asks what help listeners' organizations or others like them can offer in providing data or otherwise helping enrich data sources for assessing the value of repeat measures. 00:53:37 - Business ReportThis week's news on audience metrics, post-Rezdiffra episode ideas and this week's Vault conversation.

This conversation comes from our coverage of The EASL Congress, 2023, when Sven Francque and Ian Rowe joined Jörn Schattenberg and Roger Green to consider primary care screening at the top of the Clinical Care Pathway. The original conversation had a robust write-up: Ian starts this conversation by pointing to unmet needs in the primary care setting for disease identification. He refers to a related presentation of interest from Vincent Wong titled A clinical care pathway to detect advanced liver disease in patients with type 2 diabetes through automated fibrosis score calculation and electronic reminder messages: a randomized controlled trial. Ian suggests that this study proves both the value of working to identify more patients and the considerable amount of work remaining in this area. The group goes on to discuss what the implications of this study are for treatment in primary care both now and into the future of patient care. In particular, Jörn elucidates the value of FIB-4 not only as a screening tool for liver-related outcomes, but also as a predictor of cardiovascular risk and all-cause mortality. Secondly, Jörn notes that when a NASH therapy becomes available, "the granularity of picking up those patients will be higher" and physicians will be more motivated to take action provided that they have both a screening tool and available treatment to prescribe. This leads to discussion around the differences between hepatology and private medicine practices and management of a population-level disease. Ian raises the question around how frequent should testing be performed in the primary care setting for different pathways. 

This conversation focuses on how the need for biomarkers will evolve in an era of in-office screening and MASH drugs and ends with answers to Roger Green's closing question. Hannes Hagstrom starts this conversation by noting that one challenge as MASH drugs become available involves knowing when to discontinue or add to therapy since, as he points out, Rezdiffra will not be efficacious for all patients. This leads Jörn Schattenberg to the need for predictive biomarkers that will be specific to drugs or modes of action. These have not been studied much to date. Jörn is confident these will not be today’s biomarkers, but is unclear about whether they should point to genotype, mode of action or something else. After some byplay about how quickly this can come about (years vs. decades), Roger Green suggests that one key to commercial success will be the identification of this exact type of biomarker.Louise Campbell broadens the group's focus somewhat by noting that since changes in nutrition and physical activity will be part of any regimen we need to assess the impact of these as compared to the drug itself. Jörn describes this vision as “kind of scary” but notes that diet and exercise labeling is standard for drugs in the US, exactly as it is with Rezdiffra, and these are not monitored closely. From there, we consider the kind of study one might do to assess nutrition and physical activity independently and why that might be extremely hard.From there, the discussion moves on to Roger's final question, in which he asks what steps each panelist believes will take place in the next two years to support improved triaging and patient management through the system. Four active minds produce more than four answers. Listen to learn.

This conversation explores the implications of increased access to economically viable in-office screening, particularly when primary care practices begin to use the new scanning devices.Roger Green begins this conversation by recalling a concern Naim Alkhouri expressed during S4 E50.3, that primary care reliance on FIB-4 can flood the pathways with many “wrong” patients, which might lead to confusion within the channels. Hannes Hagstrom describes a role for primary care at the top of the funnel if practitioners have clear guidance and training. Roger suggests this approach will make primary care providers triagists. The group agrees as long as primary care has clearer guidance based on a limited set of reliable, widely used tests and algorithms. In this context, Jörn Schattenberg suggests that while VCTE might be the first point-of-care test, perhaps EHR-based algorithms can be created and deployed to identify the optimal number and types of patients to bring into the system.This reliance on algorithms can create another challenge. Hannes notes that many algorithms are being published but none are becoming the standards that will be key to primary care assuming a triage role. Louise Campbell feels that the fact that VCTE is fundamentally non-discriminatory between modes of action makes it a good tool as part of this, but we have lots of screening and education before bringing protocols or devices into a primary care setting. As the conversation wraps up, Hannes notes that we will need to keep some patients out of the pathway due to age or low level of disease to identify two qualifiers and that when we have multiple drugs and different lines of therapy or treatment patterns, that will recast the issue once again. algorithms are being published but none are becoming standards, and standards will be key to the primary care as triage approach. Louise Campbell feels that the fact that VCTE is fundamentally non-discriminatory between modes of action makes it a good tool as part of this, but that we have lots of screening and education to do before bringing protocols or devices into a primary care setting. As the conversation wraps up, Hannes notes that we will need to keep some patients out of the pathway due to age or low level of disease to identify two qualifiers and that when we have multiple drugs and different lines of therapy or treatment patterns, that will recast the issue once again. 

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.

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.

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.                                                                                                                                                    

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 9Opening comments from the panel, including brief quotes taken directly from the episode.00:02:04 - Introduction and groundbreakerEach panelist shares one piece of good news from the previous week. 00:06:02 - Introducing TopicRoger 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 biopsyHannes 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 patientsLouise 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 scanningRoger 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 LiverAIMJörn 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 triageRoger 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 successHannes 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 exerciseLouise 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 questionRoger 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 WeekThe 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 reportThis week's news on audience metrics, our upcoming 4th anniversary and this week's Vault conversation.

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 - IntroductionRoger 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 trialsRoger 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 ForumTo 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.

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.  

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. 

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. 

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.

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.

This conversation focuses on two issues: (i) identifying the right target MASH patients for Rezdiffra, and (ii) the extensive Madrigal patient support program for Rezdiffra.It starts with Roger Green asking the group how the current set of target patients is defined. Jeff McIntyre points out that these are the patients currently treated for F2 or F3 MASH in the US healthcare system. Roger asks if this is analogous to the idea of “warehoused” patients observed in Hepatitis C. Jeff suggests these are quite different from warehoused patients in that warehoused patients are not being treated at all, whereas all the target MASH patients are engaged in some form of treatment. Next ,Roger notes that Wayne Eskridge published a long post earlier in the day about the extensiveness of the Madrigal patient support program. Wayne discusses the program in some detail, in the process explaining why this process appears likely to be more engaged, interactive and helpful than the typical patient portal program.

Last Thursday, March 14, Rezdiffra (resmetirom) became the first drug approved in the US for MASH. Five leading North American MASLD patient advocates join the Surfers to discuss their feelings about this approval along with the opportunities and challenges that lie ahead.00:00:00 - Surf's Up: Season 5 Episode 7Opening introduction from an excited, enthusiastic panel, including brief quotes taken directly from the episode discussion.00:05:55 - GroundbreakersEach panelist shares one piece of good news from the previous week.00:11:19 - Advocates recall March 14As March 14 progressed, advocates' attitudes moved from excited anticipation to anxiety to deep happiness. 00:17:41 - Advocates describe their feelings as patientsNone of these advocates are Rezdiffra candidates themselves, but each reflected on their personal experiences with MASLD and what the future holds for patients who are or will be candidates for Rezdiffra.00:22:33 - Identifying target patientsThis conversation starts with Roger Green asking the group to describe where the number "315,000 target patients" came from. After the group replies, Jeff McIntyre and Louise Campbell explain how this is different from a "warehoused" patient population, and Wayne Eskridge discusses the exciting, progressive Madrigal patient support program.00:29:53 - The advocate's role todayJeff begins this discussion by emphasizing the role GLI has shepherded and advocates have played in informing FDA about patients' key concerns for the label. He describes how these are reflected in the approval decision and label, with biopsy being the most obvious example. The other advocates agree, with Mike Betel emphasizing how closely the leading advocates co-ordinate with GLI and each other. Louise suggests it will be a "game changer" if FDA takes a similar view to labels for other metabolic diseases. Roger points to Madrigal's discussion of medical exception as proof of their commitment.00:37:10 - The advocate's role tomorrowAdvocates agree that this approval creates new, broader opportunities for education and outreach. To Jeff, the approval will allow advocates to ask bigger questions on emerging needs. He offers treatment for cirrhosis and drug reimbursement as two such areas. 00:41:22 - Slowing the patient flowRoger asks what steps advocates can take to slow the flow of patients through the progressive stages of MASLD. Tony Villiotti notes that this is the primary goal of NASH kNOWledge, starting with childhood education. Jenn Jones states that publicity about Rezdiffra may lead patients with MetALD or ALD to explore how they can protect their own livers and seek early detection. 00:46:15 - Overwhelming the systemLouise describes herself as "slightly fed up" at individuals who  fear "overwhelming the system." Instead, she says, systems should build capacity to reflect the scale of the disease. Roger notes this may be harder to execute in the US than in countries where governments control their healthcare systems. Jeff points to the US Veterans Administration as a possible model for ways to build capacity.  00:52:21 - Emerging role of primary careLouise states that much treatment will shift to primary care over the next 5-7 years.  Roger agrees and seconds Jeff's comments about the role the VA can play.00:54:55 - Closing question Roger asks each panelist to identify a healthcare stakeholder group that needs to take a lesson from the issues discussed today. Answers vary widely. 01:02:06 - Question of the WeekThe question asks what good ideas listeners have for other stakeholder groups in the aftermath of Rezdiffra's approval.01:02:54 - Business reportThis week's news on audience metrics, future episodes and why there will be no Vault conversation again this week

As the conversation wound down, Roger Green offered panelists to address any issue pertaining to Rezdiffra, the first MASH drug, that had not come up in the hour-long conversation. The seven panelists raised eleven exceptionally diverse issues between them. Rather than provide a simple list of issues, the co-hosts invite you to listen to this short conversation to gain a fuller appreciation of each point.