Surfing the MASH Tsunami

On April 23, the global MASLD community lost one of its giants when SurfingMASH Co-founder Stephen Harrison passed away unexpectedly. Co-hosts Louise Campbell and Roger Green and guests Jeff McIntyre and Mike Betel each share a memory of Stephen. Jeff McIntyre starts this conversation by remembering Stephen as a fellow Southerner and, in addition to his many professional accomplishments, a person who could cut through high-level discussions with a "pithy little West Texas saying" that would make a complex or abstract concept clear. Mike Betel starts his comments by talking about Stephen's older brother, Ken, who wrote personal messages back to every comment he could find on social media, which was a remarkable task in its own right. Mike discusses how often he heard Stephen speak and how many times he interviewed Stephen for various Fatty Liver Alliance posts or events. Mike concludes with a story about Stephen talking for five minutes while Mike's audio was malfunctioning and then doing a second take remarkably similar to the first. Louise discusses being on the podcast with Stephen for years and regrets that he will never cook her a deep-fried turkey. She recalls his hobby of building elaborate sand structures on the beach with his family while he ran around the world, putting a large dent in MASLD. Roger starts by describing the first time he saw Stephen at NASH-TAG 2019 and how his larger-than-life presence and exceptional energy suffused a room of 200 people. He continues by using a favorite "Harrisonism" about being thankful that they didn't stop after WD-39 because WD-40 was the 40th effort to create the product we know today, and comments that for Stephen as Principal Investigator, Rezdiffra was his WD-40. Finally, Roger says he "just lost it" when reading the Walt Whitman poem "O Captain, My Captain," which Scott Friedman posted on LinkedIn as a tribute to Stephen.After the personal comments, Roger says that next week's episode will be a tribute to Stephen from some of his closest friends in the global MASLD community.

Fatty Liver Alliance Founder and President Mike Betel and Global Liver Institute Vice President for Liver Programs Jeff McIntyre join Louise Campbell and Roger Green to preview the premier MASH event for patient advocates, now known as Global Fatty Liver Day, which falls on June 13.00:00:00 - Surf's Up: Season 5 Episode 13 Episode introduction, including brief quotes taken directly from panelists. 00:02:37 - Introduction/Remembering Stephen HarrisonRoger introduces the podcast. Each panelist shares a memory of Stephen Harrison.00:11:44 - Groundbreaker Each panelist shares one piece of good news from the previous week.00:15:18 - Jeff Discusses Global Fatty Liver Day Jeff starts by discussing how GLI came to its 2024 theme:  "Act Now. Get Screened." Roger comments that this will require health systems to expand in scale and sophistication and shares Naim Alkhouri's critique (Season 4, Episode 50.3) of the current approach. He asks if US reimbursement policy is sufficiently developed and what patients can do. Jeff replies, "Get Screened."00:25:46 - Fatty liver and obesity Jeff notes the popularity and widespread discussion around anti-obesity medications, which also have effects on MASH. He expresses concerns that all this will lead to reduced focus on the liver. 00:26:43 - UK and AUSLouise discusses activities in her two homes.  Rather than focusing on liver disease, she prefers "poor liver health," which leads to cardiovascular disease and extra-hepatic cancers. 00:31:10 - Scanning patients as educational toolMike asks Louise to comment on scanning as an educational activity. Louise discusses the ability to generate an effective description and activate conversation when she delivers scan results right at the time of the patient visit. She then discusses the next steps if the first one doesn't work.00:35:40 - Challenges and barriers for patients To Jeff, the previous conversation between Louise and Michael provides "a really great synopsis" of the challenges and barriers to patient diagnosis and care. He announces that the GLI is planning to release its first Best Practices in Policy report.  These challenges are more complex due to the need to find solutions for diagnosis and health system follow-through that will work around the world. 00:43:10 - Battles around healthy lifestyle policies Jeff describes two challenging US health policy cases: the VA's decision (later reversed) to require biopsy for Rezdiffra and giant food companies lobbying to include added sugar as a healthy food item. Louise links the sugar question to "a big to-do" in the UK about children's teeth and access to dentists because poor dental health drives a 7x increase in the risk of liver cancer and advocates for generalized dietician training. 00:47:56 - The liver as elephant Roger cites the parable of the blind people touching the elephant as a metaphor for a myopic view of liver health. He advocates teaching "the whole elephant" to healthcare professionals. Louise proposes an action point of "rule the liver out" before testing for related diseases. Roger suggests this is a dual mandate. For patients: Act Now. Get Screened. For providers, Rule the Liver Out. 00:51:21 - Initiatives for Global Fatty LIver Day and wrap-up In lieu of a final question, Roger asks panelists to describe one specific initiative that is part of Global Fatty Liver Day. Mike and Jeff each describe screening activities.00:58:13 - Question of the Week Roger asks what listeners can do in their work to support the two simple mandates: act now, get screened, and rule the liver out. 00:58:44 - Business ReportThis week's news on audience metrics, future episodes and this week's Vault conversation.

One theme in this week's episode involves different ways to use NITs in drug development and assessing the value of older drugs in MASH. This conversation, from our review of last September's FDA workshop on NITs, considers two additional roles that NITs might play in drug development. The conversation includes Jörn Schattenberg, Louise Campbell, Roger Green, and guest Laurent Castera. The original post has an excellent description:This conversation begins with a discussion of a point from a previous episode in 2022 about the difference between NITs to qualify patients for trials versus to evaluate the efficacy of drugs. This point stems from the idea that the way disease regresses may not be the same way it progresses. Laurent notes that NIMBLE and LITMUS have demonstrated important results with large data over the last two years. Jörn comments on the limits of using transaminase as a key NIT and Laurent replies by discussing a study over time that shows faster early declines on liver stiffness and slow declines over time as therapy might shift from reducing inflammation to regressing fibrosis. Louise shifts focus to ask about the relationship between kilopascal drops related to lifestyle change, specifically to ask whether these are false positives or real effects. Laurent notes that BMI is a confounder for liver stiffness and that CAP might help assess this issue. Finally, in response to a question from Louise, Laurent answers that we do not know about some of the key changes in test scores, and need to know more.Plenty more ideas are explored as this is both a fascinating and pivotal workshop which covers a range of topics on NITs with presentations by the some of the field's most innovative and knowledgable contributors. If you have questions or comments around the workshop, NITs, drug development or any other themes addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse.

This wrap-up conversation about MASH Drug Development covers two issues: combination therapies with old drugs and using NITs to speed and smooth the path to approval.Louise Campbell starts this final conversation by asking whether we are paying sufficient attention to old drugs that might have value in MASH. She points to a recent study demonstrating that low-dose aspirin significantly affects liver fat and suggests that we are not thinking broadly enough about use of older agents in MASH. Jörn Schattenberg comments that without robust NITs, it will be difficult to prove these effects, particularly, as Roger Green adds, for a drug that will not produce sufficient revenue for BioPharma to conduct a larger trial.After a brief digression over whether we know how to shorten the time to drug approvals (short answer: not until we have better approaches to using NITs), Roger asks his closing question: how will having a drug approved affect the conduct of trials going forward? Answers vary and present a complex picture. You'll have to listen to learn

This conversation starts by focusing on the impact of concomitant metabolic therapies in MASH drug development and patient treatment and then moves on to explore some major implications of the earlier conversations. Roger Green begins this conversation by returning to the issue of metabolic drugs. Specifically, he mentions a recent tirzepatide Phase 3 trial that demonstrated efficacy against symptoms of obstructive sleep apnea. Louise Campbell points out that sleep apnea correlates highly with SLD as well as obesity. She suggests this is one more point proving that we need to educate more physician specialties on liver health and educate them more effectively. Will Alazawi agrees with Louise's comment, citing a talk he and a colleague gave at the Diabetes UK conference the previous week that was part of an academic session on liver disease, noting that the session itself was well-attended. Will emphasizes applauding Diabetes UK for arranging and promoting this kind of multidisciplinary academic session of MASLD and MASH. Roger shifts focus by asking what insights investors or other professionals who listen to the episode should take from this discussion. Jörn Schattenberg starts with the most important point: we now know how to get a drug approved. Considering other drugs in development, he adds that the drugs we are studying now may be potent enough to overcome issues that challenged earlier agents. Sven Francque adds that in future years, prior use of incretin double-agonists and triple-agonists will change the nature of the MASH patient population and make drugs like Rezdiffra that have liver-specific modes of action more important and valuable.   

This conversation includes two sections: one optimizing efficacy endpoints to reflect clinical practice and a second looking back at what has improved in MASH drug development since 2020.The first part of this discussion explores the idea that MASH drug development should reflect the clinical use of the target drug. Sven Francque starts by discussing how much larger the drug effect for Rezdiffra looks if we add lack of fibrosis progression to regression in creating the efficacy endpoint. Will Alazawi agrees but notes that the level of other metabolic diseases will also have an impact on how to assess a drug’s performance and that we do not adequately control for this in trials today. Jörn Schattenberg and Will discuss the value and meaning of stabilizing Type 2 diabetes in relevant patients.  Sven points out that the purpose of a clinical trial is different than the goal of clinical practice. Will agrees but wonders whether this might be a reason that some trials fail.Roger Green shifts the focus of the conversation by asking Jörn Schattenberg what we have learned since the article he co-authored in 2020. Jörn points to two specific areas where the field has improved: greater consistency in reading biopsy results, and a tendency back then to rush agents into clinical trials without sufficient consideration of pre-trial data and even complex Phase 1 or 2a results. Will notes that trials that reported in 2020 were designed in the early or mid-10s, which means they could not take advantage of the innovations described in the 2020 paper. He goes on to point out that the failed trials produced data that provided the foundation for analyses from consortia and other groups. Sven commends the companies that produced this data for "digging deep" into results to find insights.

In this conversation, the panel discusses challenges in MASH Drug Development that are centered around efficacy endpoints and NAS scoring.This conversation starts with Will Alazawi suggesting that the MASH clinical trial field suffers from the previous experience with Hepatitis C, where medications became capable of eradicating disease in a fairly linear fashion. He suggests that MASH trials undervalue the value of simply preventing progression, which leads Sven Francque to note that preventing progression to cirrhosis is now accepted by regulators as an endpoint. Roger Green refers to last week's episode (S5 – E11), in which Michael Charlton said he would continue Rezdiffra therapy for any patient exhibiting a lack of progression, and that a clinically valuable efficacy measure must be applicable to true clinical practice. Roger goes on to recall Sven’s earlier comment that having the NAS score as a co-endpoint complicates the challenge of proving efficacy because the scale is relatively blunt and not well suited to the task at hand. He suggests that an activity score focused on inflammation and ballooning might function better than one including steatosis. Jörn Schattenberg suggests that this depends on the drug's Mode of Action. Sven reminds the group that Stephen Harrison presented a paper at AASLD suggesting the approach Sven describes: splitting NAS into separate steatosis and activity scores, with the activity score based on lobular inflammation and ballooning. Roger asks whether the widely reported challenges in coding ballooning will render this method less valuable. Sven says it might, and states the challenge stems from the lack of detail in the scoring system. Louise Campbell suggests that in addition to stabilizing MASH, endpoints might look at related metabolic diseases that poor liver health can affect. Will agrees, noting that many patients may be on other metabolic agents at the outset of a trial or, more challenging, the definition of "good practice" might change during the trial, which can add variability to the sample. He wonders whether differences in placebo rates can provide insight on this issue. Roger recalls a comment from Dean Tai of HistoIndex (S4 - E50.4) that some HistoIndex AI-driven analyses produce consistent placebo rates of ~33%, with efficacy rates far higher. 

In this initial conversation, Sven Francque shares some of the key messages from the MASH Drug Development graveyard paper he co-authored in 2023. Jörn Schattenberg and Will Alazawi comment. This conversation explores key points from Learnings from the Graveyard of Phase 2 and 3 Nonalcoholic Steatohepatitis Trials, which Sven Francque co-authored in 2023 with Aleksander Krag and Mazen Noureddin on lessons from recent clinical trial failures and the reasons to be more hopeful about the future. Sven starts by noting how different the world is now than when he co-authored this paper in 2023, and the reason why: we now have an approved drug.  He goes on to describe three key issues the paper discussed that are still relevant: regression of fibrosis is a "high bar" for efficacy; researchers and trial sites cannot optimize heterogeneous patient samples to create samples that are more rigorously stratified, and the complexity of physiology leaves some attractive modes of action insufficiently efficacious.Jörn Schattenberg goes back to the first issue: regressing fibrosis vs. simply stopping progression. He comments that if the challenge is to stop progression, the researcher needs to manage the trial and control groups. If the control group has disease that is too stable, the test group will likely fail to differentiate, but if the test group progresses too rapidly, it might not perform well enough. Sven agrees on the opportunity and the challenge if patients’ disease is too active.As the conversation ends, Will Alazawi uses the metaphor of the hamburger to describe how finely balanced this kind of patient recruitment and assignment must be. The punchline: you need to hold the hamburger tight enough, but not too tight.

In this conversation, Sven Francque and William Alazawi join Jörn Schattenberg, Louise Campbell, and Roger Green to review papers co-authored by Sven in 2023 and Jörn in 2020 to discuss what failure has taught us about future MASH drug development.00:00:00 - Surf's Up: Season 5 Episode 12Roger comments briefly on Stephen Harrison's passing and explains why this episode will be more sedate than usual.00:01:45 - IntroductionOpening comments from panelists.00:02:28 - GroundbreakersEach panelist shares one piece of good news from the previous week (NOTE: This was recorded before Stephen's death.)00:05:10 - Sven Francque on the State of the Graveyard in 2023Sven starts by noting how different the world is now than when he co-authored this paper in 2023. He goes on to describe three key issues in successful trials that are as relevant now as when the episode was written.00:10:59 - Efficacy endpoint challengesThe group discusses an array of challenges: that fibrosis regressions is a high bar, that patient heterogeneity presents a dilemma for trial recruitment, and that NAS score presents its own challenges. 00:18:29 - Thinking more broadly about metabolic valuesLouise suggests that in addition to stabilizing MASH, endpoints might look at related metabolic diseases that poor liver health can affect. The group considers whether placebo rates can provide guidance and reconsiders the regression and response rate issues, noting the differences between RCT patients and those in usual clinical practice.  00:28:05 - Lessons from 2020 Graveyard articleRoger asks what we have learned since 2020. Jörn points to improved consistency in reading biopsy results and greater diligence in analyzing pre-clinical data before rushing into larger late-stage trials. 00:31:49 - Implications for metabolic agents on MASH therapies Roger returns to the issue of complex drug effects, noting a recent tirzepatide Phase 3 trial on dual agonist's effect on obstructive sleep apnea. Louise notes that apnea correlates highly with SLD. Louise and Will discuss the importance of educating more physician specialties about liver health. Will discusses a presentation he made to an academic session on MASH at the Diabetes UK conference the previous week and noted that it was well-attended.00:36:05 - Looking aheadRoger asks what insights investors and others might take from this discussion. To Jörn,  (i) we now know how to get a drug approved, and (ii) drugs in development today may be potent enough to overcome issues that challenged earlier agents. Sven adds that in future years, the use of incretin double-agonists and triple-agonists will change the nature of therapy. 00:42:23 - Wrap-up and closing questionLouise asks whether we are thinking broadly enough about older agents in MASH, using a recent study on low-dose aspirin (S5 - E11.) . Jörn and Roger each raise a practical challenge for such a trial.  After a brief digression, Roger asks his closing question: how will having a drug approved affect the conduct of trials going forward. Answers vary and present a complex picture. you'll have to listen to learn00:51:45 - Question of the WeekThe question asks for the greatest hurdle left to overcome that will improve the percent of MASH agents achieving approval and, separately, speed approval times.00:52:14 - Back-end reportThis report includes Roger's usual weekly comment on Ukraine and Israel, followed by a tribute to Stephen Harrison. This episode was recorded the day before Stephen Harrison's untimely passing. His influence on this entire podcast was massive. Three years after he ended his co-hosting stint, there are at least two references to his research, insights, or what we called "Stephenisms" during our first anniversary episode.

Earlier in this episode, the panel discusses different prescribing models for MASH drugs, triggered by Roger Green's question about whether MASH prescribing will resemble an oncology model. This conversation, from the EASL Congress 2023 wrap-up episodes, takes a very different view of the relationship between MASH and oncology.The conversation includes Jörn Schattenberg, Stephen Harrison and Roger Green. The original post has an excellent description:This conversation starts with a discussion about the importance of treating early stage cirrhosis patients. Jörn suggests that with new agents in place we may soon be looking to treat other patient populations such as, for example, those with HCC. In such instances NASH drugs will become adjuvant therapy to improve treatment against the primary disease target. Stephen agrees, noting that we will need a better test to diagnose HCC and, once available, there will be fewer presentations of advanced HCC because we will have treated more of them earlier with better agents and adjuvant therapies. Again, all this will await the approval of NASH and ideally cirrhosis drugs in the future. Roger asks how to identify the 20 to 30% of HCC patients who develop cancer before NASH. Stephen suggests it depends largely on NIT development. From there the panelists each share final thoughts around what the session has yet to cover that is important. Stephen comes up with a new idiom and Jörn speculates a new concept. Listen to the session to find out what they are.

This final conversation starts by considering prescribing models for other diseases and how they might work here, shifts to discussing the challenges of keeping a patient enrolled in a long-term clinical trial (or even participating in a trial in the first place), and moves on to the final question for the episode. The conversation picks up on the FG-21 conversation, particularly how FGF-21 might be prescribed alongside Rezdiffra. Roger Green starts by asking whether and how this prescribing pattern might fit in an "oncology" model, where FGF-21 might be an induction drug and Rezdiffra a maintenance drug. Michael Charlton suggests that benefits from FGF-21s are likely to fade once therapy is discontinued, which would make this model suboptimal.Jörn Schattenberg raises the issue of keeping patients in the long-term clinical trials necessary to achieve hard outcomes. Jörn advocates keeping his patients in trials but notes that long-term compliance will become increasingly challenging as more therapeutic options become available and the patient may not be improving. Michael suggests we will find similar challenges in recruitment for new trials if patients have to accept the possibility of receiving a placebo. Roger notes that biopsy requirements increase this challenge. As the episode winds down, Roger asks participants what they believe are exciting studies likely to come to light over the next three months. Their answers vary. You'll have to listen to learn. 

This conversation sees the end of the "hot topics" discussion, followed by Michael Charlton discussing issues and excitement around the FGF-21 class.As we begin, Louise Campbell and Jörn Schattenberg speculate on ways to incorporate metrics like the Dietary Inflammation Index into multifactorial care. Michael asks whether alcohol is figured in the index, given its pro-inflammatory nature, and celebrates the fact that we can now evaluate MetALD patients as a group instead of removing them from classical MASH clinical trials. Louise, who raised the issue in the first place, does not know. As she notes, she first found the issue within the last week. One key question for her is how we can use this in 5-10 years when primary care becomes a key player in MASLD and all metabolic diseases. Roger Green's hot topic involves "Ask the MD" columns in US newspapers and magazines. He gives "two cheers" for help columns in which MDs recommend that MASH patients  "go to your doctor and ask for an ultrasound."  He asks whether the PCP is the right destination and whether "ultrasound is the test to seek. However, he appreciates that all this brings MASH badly-needed visibility in the public eye. Michael and Louise agree that given how few patients are treated today, any such public acknowledgment is positive.Michael discusses the emerging excitement around the FGF-21 class. The recent agents from Akero and 89bio are "emerging as highly potent" in terms of PDFF change and transaminase responses. While we need to learn more, he asks how this will fit in with Rezdiffra and, more generally, how long we can give a patient a "potent" growth factor and what will happen if/when the patient needs to discontinue therapy. Jörn and Michael note adherence challenges with this therapy; Roger comments that even with daily oral drugs, adherence can be a challenge.

After Michael Charlton finishes discussing research he finds compelling, Jörn Schattenberg and Louise Campbell each describe one item they have been focusing on recently. Michael mentions the recent JAMA publication of a small, randomized controlled trial exploring the use of low-dose aspirin in biopsy-confirmed MASLD patients, which he describes as "a tremendous result." The results suggest benefits in terms of both fat fraction (PDFF) and transaminase levels. Jörn provides more detail about the trial. While the sample size was small, the results were highly promising. There is much to learn here from a larger RCT and also from understanding the biological mechanism better, but the group agrees this is a promising development.Roger Green asks his fellow Surfers to discuss one item that has attracted their attention in the past week. Jörn Schattenberg goes first and discusses the upcoming Innovations in SLD Think Tank 2024. He expresses excitement that changes in format should yield unique, high-value benefits. Roger notes that Jörn and his co-chair Jeff Lazarus will discuss the think tank's results during the episode posting on May 15. Louise mentions her constant pursuit of finding ways to improve prediction with FibroScan.  In doing so, she found a study indicating correlation between the Dietary Inflammation index score and kilopascal level on FibroScan testing. Investigators are exploring the use of this index in an array of non-liver diseases related to metabolic syndrome or chronic kidney disease, but the correlation with kilopascals is fairly clear. Louise would like to see research looking at controlled attenuation parameter, since she can usually "see a fat change faster than a stiffness change." 

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.