tlm2023

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers a pivotal session on the new MASLD nomenclature, plus what the panelists found exciting and important about the developing class of triple agonists, at TLM 2023. 

This conversation starts with Roger stepping gently into the topic of the new MASLD nomenclature by discussing a Saturday morning session chaired by Maru Rinella and Meena Bansal. The session took a broad, fairly detailed view of progress in knowledge and implementation of this nomenclature. Roger's point: two of the three obvious potential downsides to the new nomenclature are now rendered resolved. First, George Makar of FDA stated that the agency now uses the terms “MASH” and “NASH” or “MASLD” and “NAFLD” interchangeably, which means that the nomenclature will cause no delays or rework around drug and device clinical trials. Second, Quentin Anstee and Arun Sanyal reported from the LITMUS and NIMBLE databases that the patient overlap when mapping against the two definitions was 95-98%, which means there should be no dispute around the impact on how we define patient populations. In this regard, Roger notes that Gregory Gores, editor-in-chief of Hepatology, said the journal believes this issue is over and will not accept more publications on the subject. 

The third item is the perceived stigma around the word “fat.” Roger quotes NASH kNOWledge founder and patient advocate Tony Villiotti, who points out that while we may describe a specific medical event as a myocardial infarction, the doctor still tells the patient "You had a heart attack." Similarly, the concept of “fat on the liver” will be essentially to explain what is going on to the patient, whatever the nomenclature says. This leads Laurent to discuss the paper on stigma presented at the conference which suggests that "fatty liver" is far less stigmatizing in general than "obesity" or "diabetes," and some specific nuances of the paper. When he is done, Scott and Roger comment on vastly different moments in history and regions in the world where obesity was actually considered a sign of something positive. 

This entire discussion leads Scott to remember a presentation on Eli Lilly's triple agonist retatrutide and the remarkable impact this class of drugs is likely to have on how we manage obesity, diabetes and liver disease. Roger notes that Altimmune and Merck/Hanmi have similar agents in development. He goes on to note that these drugs demonstrate levels of weight loss found with bariatric surgery and asks Laurent and Scott whether they believe the drugs will have impact similar  to surgery. Both say it is too early to tell. Louise follows this by mentioning a study showing that allied health professionals are proficient at motivating patients to lose weight, maintain that loss, and do so in healthy ways.

Roger's wrap-up question asks what will be different at TLM2024 next year in San Diego. You’ll have to listen to hear the answers.

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about liver science, VCTE, regulatory approvals using NITs or AI, and other issues at TLM 2023. 

It starts with Roger sharing his belief that regulators are likely to approve NITs only if a small battery of tests (or ideally, a single test) prove valuable in assessing all agents, or at least all agents, for a stage of disease or segment of the market. Scott notes his frustration that biopsy is an expensive and poorly-graded measure and hopes that FDA will move past semi-qualitative biopsy. 

Roger asks Scott what we learned about basic science in the meeting. Scott discusses advances in single-cell technologies as pivotal in helping us understand underlying disease better, and goes on to mention several presentations on senescent cells that provided insight but, he felt, little for basic drug development. 

Roger then asks Louise what in the meeting she found most interesting. She points to two posters regarding VCTE. The first looks at liver stiffness and controlled attenuation parameter, or CAP in patients after transplantation. Louise describes this as the first time she has seen CAP used as an independent predictor. She mentions a second poster on methotrexate using VCTE as having similar promise to expand VCTE as a research tool.

Louise then goes on to discuss a poster addressing the evolving impact of allied providers in hepatology. In this poster, the authors projected a roughly 1/3 growth in hepatology patients by 2023 requiring treatment, coupled with a roughly 1/3 decline in the number of hepatologists available to treat them. Allied providers in hepatology showed a similar trend. To Louise, this signaled clearly that all countries need to boost the number of allied providers if these patients are to receive the care they will need. As the conversation winds down, Louise and Roger discuss the high level of patient presence and energy suffusing the entire event.

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations covering NITs, artificial intelligence and bariatric surgery at TLM2023. 

The conversation starts with Roger discussing a presentation in which Stephen Harrison shared HistoIndex data from the MAESTRO-NASH trial for resmetirom. HistoIndex’s proprietary methods produced results suggesting 34% improvement in the placebo group vs. 54% in the treatment group. More interesting, Dean Tai from HistoIndex suggested to Roger in a private conversation that this 1/3 placebo success rate holds fairly common across trials using these methods. Given that bariatric surgery studies suggest a five-year gap from successful surgery to fibrosis regression, the one-year standard requested by FDA for conditional approval might lead us to understate drug efficacy for resmetirom and later New Drug Applications submitted under these criteria.

Laurent discusses a study from Phillipe Mathurin’s group in France that demonstrates among bariatric surgery patients, MASH resolution and fibrosis regression lead to improved outcomes. His point: it is important that this study confirms the idea that MASH resolution and fibrosis regression do, in fact, lead to fewer Major Adverse Liver Outcomes, or MALO.

The conversation shifts to NITs and the value of biomarkers in proving that a drug is working. Laurent notes that no single market is sufficiently reliable and that we will need a cluster of tests to evaluate any given drug. As an example, he cites the impact of BMI on liver stiffness as a confounder that does not exist in other tests like ELF. Scott asks about HepQuant; Laurent has limited experience but finds the idea conceptually appealing. Scott notes that the slow rollout and low budget might be responsible for the lack of market and academic interest. 

Laurent focuses on a specific poster looking at a database of 16,000 patients over two years. The study shows that an increase in liver stiffness, AGILE-3 or AGILE-4 score all correlate with MALOs.  What the study doesn’t address, and Laurent points up will be key to learn, is whether declines in these measures correlate with improved outcomes among declining patients. 

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers what the panelists found exciting, important or striking about the presentations of clinical trial results at TLM2023.  

Instead of focusing immediately on MASH drugs, Scott suggested we should not overlook the idea that elafibranor is preparing to come to market in the US as a novel medication for PBC with good efficacy and safety from patients who do not respond well to ursodiol or obeticholic acid. I note that elafibranor is only one of two PPARs speeding toward market in PBC with exciting data given what we all heard in the late-breaker presentation on seladelpar. Scott also mentions to integrin antagonist from Pliant in PSC, a disease with no available solutions today. Laurent agrees with Scott that the rare disease drug advances were more exciting than the advances in more common liver diseases.

I bring up papers addressing the value of FGF-21 and FGF-19 agents in cirrhosis, which showed some promise for compensated cirrhotic patients. Scott politely disagrees, feeling that while these agents might hold disease steady, they do not address the challenges and mechanisms necessary to meaningfully regress disease. We agree there is a benefit to any agent that slows or reverses the course of disease even slightly in that this buys the patient more time to be treated with more exciting medications still in the pipeline. 

Scott notes that for Hepatitis C, a far simpler disease it took 25 years from discovery to cure on a path of incremental process. Scott notes that drug development successes are keeping investors interested, which is encouraging in a challenging environment for investment. 

Laurent returns to the issue of cirrhosis, noting that there are multiple challenges and concomitant bad behaviors like alcohol consumption. He points out that where good studies exist, these are short studies with small samples. Scott points out that MASH is less like hepatitis and more like inflammatory diseases like IBD, where causes of underlying disease are difficult to determine and there is no single pathway in drug development. He buttresses this by noting that in clinical trials, resmetirom provided benefit to only 25% of patients. 

This conversation between Scott Friedman, Laurent Castera, Louise Campbell and Roger Green covers the four panelists’ general impressions of TLM2023, both the good and bad of it. 
Scott starts with a simple statement: “It was good to be at an AASLD that felt like an AASLD. Specifically, Scott is talking about the energy and excitement associated with the meeting. He also approves of Boston as a meeting location. 
Scott’s meeting worst was the meeting app. The group elaborates on why they all agree. 
Laurent Castera agrees with Scott: bad app; excellent meeting with a great deal of colleague interaction. 
As a virtual attendee, Louise felt her own unique pain with the app. In addition, only 20% of sessions were live, and many were Zoom, which meant ‘Zoom in the US.’ She describes this as the most disappointing meeting experience, and she notes that some people paid $1,200 for it. 
I make two other points: the patient tracks were broad in coverage and highly well-attended, and Saturday night’s Diwali celebration. Scott, Laurent and I agree that the meeting was genuinely crowded and hot…but worthwhile. 
My final comment: tremendous excitement and anticipation about March 14, resmetirom’s PDUFA date at the FDA.  

Hepatology researchers and key opinion leaders Profs. Laurent Castera and Scott Friedman join Louise Campbell and Roger Green in the final element of our review coverage of TLM 2023. This far-ranging conversation moves beyond MASLD/NAFLD and MASH/NASH to consider an array of topics.

The episode starts with Roger asking the other guests for their general impressions of the meeting. Three key insights: 

1.    "Pre-pandemic" levels of interaction and discussion among attendees

2.     Online meeting app was a "fail", becoming a topic of conversation in its own right while fostering confusion

3.    In the "frenzy" about the anticipated resmetirom approval and other MASH drugs approaching market,  we shouldn't overlook that patients with PBC will soon have two new exciting PPAR agents, elafibranor and seladelpar. As Scott notes, we also learned about promising modes of action for PSC so, overall, a promising meeting for rare cholestatic diseases. 

The rest of this discussion covers multiple topics, key among them: 

 ·      Impact of FGF-21 and FGF-19 agents on patients with compensated cirrhosis. Roger is optimistic that agents might provide improvement. Scott is more pessimistic because we do not have agents addressing the unique mechanistic challenges in cirrhosis vs. advanced fibrosis. Both agree that agents on the horizon can buy time until curative or regressive medications arrive. 

·      AI-based analysis. Roger bridges to Stephen Harrison’s presentation of HistoIndex analysis of resmetirom that produces an estimate of 54% efficacy vs. 34% placebo. He comments that given this analysis and that bariatric surgery studies tell us fibrosis regression may take five years, the FDA one-year standard might be so stringent as to be misleading. 

·      Bariatric surgery. Laurent refers to a presentation from Phillippe Mathurin's group demonstrating that in patients post-bariatric surgery, MASH resolution and fibrosis regression clearly lead to improved outcomes. 

·      NITs. Laurent discusses a poster from a multi-country 16,000-patient cohort that did not confirm liver stiffness as leading to a decline in MALO over a two-year period but anticipates more robust findings over time. 

·      VCTE-based analysis. Louise discusses two posters with analyses based on FibroScan. The first, from the Virginia Commonwealth University and the VA, found that liver stiffness correlates with success in liver transplant and that CAP can predict the risk of future MI in these patients. She notes that CAP of 270 served as "its own parameter" in predicting time to mortality. 

·      Nomenclature. Roger notes that a Saturday morning session resolved the two most pivotal outstanding issues about the effect of nomenclature change on scientific development. FDA signaled that the agency views old and new nomenclature terms as interchangeable. NIMBLE and LITMUS analysis determined that patient mapping is also interchangeable.

·      Impact of triple-agents. Presentations at this conference confirm that triple agents addressing GLP-1, glucagon and GIP can have bariatric surgery-level impact on liver fat and reduce the entire disease burden. 

Interspersed between these topics are a range of insights on cirrhosis disease models, regulatory slowness in moving on from current conditional efficacy metrics, treater supply vs. patient demand, "stigma", and basic science. This is a high-level view of an information-dense conversation. Listen to learn more and hear all the details. 

Fatty Liver Alliance President and Founder Mike Betel, a leading patient advocate for MASLD/MASH patients, joins Roger Green in our continuing review coverage of TLM 2023. Mr. Betel discusses presentations and events he found most valuable to patient advocates. He also discusses the new MASLD nomenclature and Fatty Liver Alliance's upcoming 2nd Annual Primary Care NAFLD & NASH Summit.

The conversation starts with Mike paying the event a profound but slightly backhanded compliment. He comments that interest in some sessions was so strong that organizers did not leave sufficient space for everyone who wanted to attend. As he pointed out, even the "overflow rooms" were overflowing for some sessions! Mike then paid the event a profound complement: the content of the sessions, coupled with his ability to interact with Key Opinion Leaders, made for a meeting that provided him with insight and enthusiasm into where the field is heading. 

Mike shifts focus slightly to praise Madrigal Pharmaceuticals for the Public Service Announcement the company premiered at this event. He describes himself as "blown away" by the 2:30 video. Mike notes, and Roger agrees,  that virtually everyone he spoke with at the conference who saw the PSA felt the same way. In response to Roger's question, Mike offers that what makes the PSA so special is that it focuses on "a real person and a real community interacting" in ways that portray real-life with humor and, at the same time, commitment. He mentions a couple of specific items he particularly likes and goes on to note that as of the end of conference, the video had already received 500,000 views online. 

Mike goes on to discuss one scientific paper he found compelling, a presentation by Prof. Arun Sanyal about the Eli Lilly incretin triple-agonist retatrutide. He cites Arun's comment that in over 90% of the obese patients in this study, the drug reduced liver fat so much that patients' fat levels were defined as "normal." Roger goes on to note that there are three triple-agonists in development, the other two being Altimmune's pemvidutide and Merck/Hanmi's efinopegdutide.  

Shifting focus, Mike congratulates Dr. Jeff Lazarus on being recognized with the Distinguished Scientific Award from the American Liver Foundation. jeff's work over his career has spanned major public health efforts in HIV, Hepatitis C, COVID-19 and Fatty Liver diseases, but his most recent effort was spearheading the Delphi process around the nomenclature change. Roger commends the work that Jeff, Ken Cusi and a few others have made in reaching across specialties and countries to foster and promote clinical care pathways. Mike commends a presentation by Jeff and Mazen Noureddin  talking about "a united voice for liver health." 

Next, the conversation shifts to discuss the new nomenclature, which received significant attention at TLM 2023. Mike comments that while nomenclature is moving ahead, widespread change will hinge on endorsements from regulators, professional organizations and the pharmaceutical industry. Roger notes two specific steps forward: a comment from George Makar of FDA that the agency sees the terms of interchangeability and reports from Profs. Sanyal and Quentin Anstee that the old and new definitions map identically for 95-98% of patients. 

The last part of the discussion focuses on Fatty Liver Alliance's upcoming primary care event. Mike discusses some highlights of the conference and tells listeners how to find it. The podcast ends with a call to action for community-wide engagement in liver health, underscoring the necessity for collaborative efforts to broaden the understanding of liver disease, enhance patient care, and adapt to the evolving medical landscape.

Dr. Tim Jobson of Predictive Health Intelligence joins Roger Green in our continuing review coverage of TLM 2023. Dr. Jobson discusses the studies he presented at the meeting and other work related to population-level screening for metabolic diseases, the importance of providing better care in areas with lower socio-economic status residents and the global value of population health management.

The conversation starts with Tim discussing the major impact that new medicines like resmetirom and new indications for GLP-1s will have on the entire treatment framework for MASLD and MASH, starting with increased interest in screening coming from physicians who will have medications they can use to treat patients. Roger identifies the ability to predict which patients will proceed from MASLD to MASH as a major area for improvement, which serves as a segue to Tim to discuss PHI's work. 

PHI presented two posters at TLM2023, mostly focusing on deploying PHI's medical record-based case finding approach to identify specific patients badly in need of care but not receiving it. This is particularly crucial in what Tim describes as "areas of deprivation," with residents of lower socio-economic status. One poster addressed identification of untreated patients with Hepatitis B. The other focused on liver disease in these areas: similar rates of disease but far higher rates of advanced disease.  

Tim's is particularly excited about population-level risk stratification and the ability to identify a "five-fold" increase in the people we can target early in adulthood based on their propensity to develop non-communicable disease later in life. This study will target 7% of the population, which he expects will make the program economically viable. Tim reports he has seen tremendous interest in this idea at the meeting, strikingly among US physicians, allied professionals and payers.

The conversation shifts from Tim's work to other issues in the meeting he found fascinating. He was powerfully struck by some of the data and drugs becoming available in Primary Biliary Cholangitis (PBC) and findings about modes of action in Primary Sclerosing Cholangitis (PSC), two rarer diseases vitally in need of better therapies. 

Tim also asks where AI will fit into the emerging care paradigms.  In this regard, one of his concerns regards the intrinsic biases in existing datasets when we try to predict which patients have more urgent need for a liver transplant among those on the list. Tim and Roger return to the issue of biases in the current dataset, and agree the biases are probably too "hard-wired" to eliminate, which means researchers will need to find ways to adapt...and, Tim believes, they will do so.

Looking at another issue that interested Tim, the discussion shifts to asking what the meeting is telling us about Hepatitis B and Hepatitis C. Tim notes that we are unlikely to meet the ambitious elimination goals we have set. Doing better will involve improved patient identification and motivation, which has two tiers of challenge. In developing countries, the data and data structures necessary to target patients simply do not exist. Even when they do exist, as in the UK, the system reaches only half-to-two-thirds of patients with clear signs of serious disease. 

The right strategy for the solution is to pilot in a narrow swath of population, then go broader. As the conversation ends, Tim notes that the technology is here or will be shortly to achieve this goal.