Surfing the MASH Tsunami

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In this conversation, Jeff McIntyre leads with his impressions on the pan-society presentation of NAFLD nomenclature consensus process. He begins with an objective account of the parameters around an extensive Delphi process. Notably, Jeff points out that the discussion appears to be shifting away from the phrase “metabolic.” This is important because in many cultures and settings, “metabolic” may be no easier to explain to patients than “non-alcoholic,” although the specific challenges differ. Jeff also highlights that discussion appears to be moving away from redefining the target patient population. Any change in patient definition threatens to set back the ongoing clinical development work on drugs and diagnostics by a matter of years. Such a setback is clearly not in the interest of patients.

Jeff then engages in a critique of process elements that he felt were not supportive of patients. While every statement needed to surpass a two-thirds “supermajority” threshold to be incorporated in the consensus document, the group comprised more than 70% clinical researchers. If clinical researchers supported a statement heavily enough, no other group input would matter. He also notes the general sense of intimidation felt by patient advocates in the audience of the public debate. While the debate included 5-minute statements from GLI CEO, Donna Cryer, and PBC Foundation CEO, Robert Mitchell-Thain, advocates in the audience didn’t feel welcome to make any statements.

At this point in the conversation, panelists Stephen Harrison, Sven Francque, Jörn Schattenberg, Ian Rowe and Roger Green join to offer their perspectives:

Stephen describes Jeff’s passion as a breath of fresh air. Sven, who was quite involved in the process, responds with his experience and outlook. Jörn acknowledges this to be a complex challenge for the field and that there is no model to measure the potential consequences. Ian voices concern for “a real risk” in having alternate definitions without genuine consensus. Roger responds from his unique position of being neither a patient nor a physician.

Overall, the reactions are unique, interesting and varying. Surf on to hear their full takes.

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Recorded onsite in Washington DC, Scott Friedman, Jörn Schattenberg, Rachel Zayas and Roger Green discuss takeaways from the first three days at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). The group encapsulates the dynamic, vibrant energy of returning to this momentous event which welcomed back over 7,000 in-person attendees.

Jörn starts this conversation by introducing a paper titled, The Effect of a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist, Cotadutide, on Serum Metabolome in Biopsy-Proven Non-Cirrhotic NASH with Fibrosis. He describes Cotadutide followed by the study design which added metabolomic analyses to more standard liver NITs. Serum metabolomics is an emerging non-invasive tool that may identify novel biomarkers for disease stratification and treatment efficacy. Jörn advocates for drug developers to consider adding metabolomic assessments to clinical trials.

Scott shifts focus to note that while our community is liver-centric, Fatty Liver disease is complex and therapies can affect other organs. He wonders how the benefit of these therapies may accrue from effects outside the liver, particularly muscle and adipose tissues. Rachel cautions that emerging gene therapies ought to evaluate the potential off target effects that might be introduced by silencing a gene expression in the liver. In agreement, Scott aptly responds that gene therapy has arrived. In an example from the COVID-19 pandemic, he highlights the development of finely tuned lipid nanoparticle carriers. Roger suggests there is considerable value in the approach of finding a solution, fixing the problem and then figuring out what happened.

The group continues on to discuss an abstract presented by Amrik Shah titled, Histologic Endpoints in NASH Clinical Trials: The Emperor Has No Clothes. This paper evaluated the effects of the imprecision of histologic reading and the consequent effects in therapeutic trials. Scott asserts the need for digital pathologies to enter the mainstream as endpoints in clinical trials. This sparks comments around Arun Sanyal’s redefinition of the REGENERATE data in Late Breaking Oral Abstract, Session 2. As the session winds down, Scott notes the licensing board in the US is no longer requiring liver biopsy as part of gastroenterology or liver training. “People are voting with their feet whether someone wants a claim to biopsy or not. It's only a matter of a generation.” 

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Recorded onsite in Washington DC, Scott Friedman, Jörn Schattenberg, Rachel Zayas and Roger Green discuss takeaways from the first three days at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). The group encapsulates the dynamic, vibrant energy of returning to this momentous event which welcomed back over 7,000 in-person attendees.

In this conversation, Rachel injects fascinating new considerations to the podcast through her lens from the microbiome. She begins by highlighting a poster presented by Curtis Gabriel. The study, titled Diabetic Persons with HIV and Hepatic Steatosis Have Reduced Intestinal Microbial Diversity, links intestinal dysbiosis and hepatic steatosis in patients with HIV. Rachel notes the topic to be compelling yet underexplored. Her curiosity questions, what does the normal microbiome look like initially and how does this change over time? Scott suggests society-wide changes in our food and use of antibiotics are important indices to investigate. Discussion digresses to other related phenomena as antibiotics are not the only agent society has introduced to ecosystems.

Scott distills what he determined to be an eye-opening theme of the meeting in saying, “the Devil is in the details.” He describes himself as always looking to reduce complex topics to main, big picture themes. Contrarily, this meeting made clear to him how complex NAFL-D really is. He regards the complexities and differences in cell backgrounds, microbiota and treatment patterns as components of a longer-term challenge. Despite this challenge, he is confident the disease will yield to therapies incrementally and effectively.

NAFLD is noted to be a complex disease with a set of interrelated issues. Scott provides several examples of this, including Stephen Harrison’s presentation on a fatty acid synthase inhibitor (discussed in a later conversation). Jörn points out that a drug does not have to affect every key target to have an impact on the disease. This leads Rachel to ask in addition to what is driving disease, what are the protective mechanisms? Do they lie in epigenetics? Scott concurs and provides an example based on hyperlipidemia and the PCSK9 class. As this session winds down, Roger comments that we might not need to know exactly why an agent or therapeutic approach works to know that it does work. Instead, we can expect to solve the why as reverse engineers.

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This week attendees from around the world convened at the 73rd Annual AASLD Liver Meeting  for a lively and momentous event in Washington DC. On the final morning, Stephen Harrison, Sven Francque, Jörn Schattenberg, Ian Rowe and Jeff McIntyre join Roger Green to discuss key takeaways.

Sven is first to expand on a presentation that struck notable interest. He chooses to highlight a presentation by Laurent Castera, which Mazen Noureddin anticipated in our preview coverage. This focuses on a prospective head-to-head comparison of the different non-invasive tests in a large cohort of T2D patients with NAFLD. The paper concluded that F-AST and MAST scores outperformed MEFIB, FIB-4 and NFS for identifying fibrotic NASH in T2D patients with NAFLD. Stephen broadens Sven’s analysis by noting F-AST as a standout test that is generally available for multiple different applications. The group puts forth commentary on the cost effectiveness and accuracy of these tests within enriched populations. As this subject winds down, Ian points to the particular challenge of selecting patients for treatment. The reality, he says, is that it’s not a one size fits all approach.

The conversation transitions from diagnostics to the topic of drugs. Stephen  walks through his presentation on the efficacy and safety of Akero’s lead product candidate efruxifermin (EFX) in patients with clinically relevant NASH (F2-F3). The results point to EFX significantly improving liver histology, liver fat content and noninvasive markers of liver injury, fibrosis, and glucose and lipid metabolism in patients with F2/F3 fibrosis due to NASH. Stephen shares his optimism for this particular FGF-21 agonist while Sven agrees that “not all FGF-21’s are created equal.” The group explores the science behind the structure of the EFX compound before Roger recalls the question of where the right use for such a drug might exist. It’s been previously suggested on this podcast that a medication not entirely suited for long-term therapy due to cost, dosing or side effects might serve best as induction therapy. With this in mind, the group addresses the dynamics of what happens when disease regresses to a point where there is far less liver damage. From here, Roger introduces a brief assessment of Arun Sanyal’s presentation of topline results from a new analysis of the REGENERATE Trial.

The last major theme in this episode involves the Nomenclature session. Jeff offers an objective account of how this subject reported before disclosing some concerns from the patient perspective. His primary concern lies in coming to a decision that causes regulatory agencies to require new clinical trials, thereby slowing approvals by several years. The other panelists respond with their impressions and the consensus is that virtually nobody is in favor of a name change at this point in time if it stands in the way of progressing drugs and diagnostics.

The breadth, quality and novelty of this conversation reflects yet another exceptional and positive Liver Meeting, this time back in person.

In lieu of the typical business report, Roger and Stephen conduct a special interview with Michael Cooreman from Inventiva. The three discuss the work of this clinical-stage biopharmaceutical company and its relevance to Fatty Liver. Inventiva develops novel and differentiated oral small molecule therapies for patients suffering from diseases with significant unmet medical need. The discussion centers mostly around clinical trial development for the pan-PPAR lanifibranor.  

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In an insight-laden conversation recorded on site from Washington DC, Scott Friedman, Jörn Schattenberg, Rachel Zayas and Roger Green discuss takeaways from the first three days at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). The group encapsulates the dynamic, vibrant energy of returning to this momentous event in person:

Scott illustrates how progress in the field of Fatty Liver is more a journey of many milestones and not an all-in-one blockbuster conclusion.

Rachel injects fascinating new considerations to the podcast through her lens from the microbiome.

Jörn investigates the mechanistic components of compelling research stories emerging from this conference.

Stay tuned and surf on for the full coverage!

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Manal Abdelmalek, Jörn Schattenberg and Ian Rowe join Stephen Harrison, Louise Campbell and Roger Green to recap NAFLD and NASH-related insights from TLMdX 2021, the AASLD annual liver meeting. This conversation focuses on crafting the most robust efficient pathway to shift the gold standard of drug development from semi-quantitative biopsy reads to intelligent use on non-invasive techniques.

Opinions diverge about everything from how easy it will be to replace biopsy to exactly what that pathway might look like. What is clear is that everyone in this discussion believes with a hot passion that biopsy is a critical impediment to getting drugs approved.

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In a follow-up preview, Jörn Schattenberg, Louise Campbell, Mazen Noureddin, Ian Rowe and patient advocate Jeff McIntyre join Roger Green to discuss key presentations and posters of interest at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). On November 4th-8th in Washington DC, as many as 10,000 attendees will convene in an effort to advance and disseminate the science and practice of hepatology, and to promote liver health and quality patient care. 

Ian leads with a reference to the preceding conversation on a poster that describes ways to utilize AI or other analytics of items in basic medical charts to predict NAFLD. He endorses the idea of putting as few barriers in the way of primary care as possible, speaking to FIB-4 as an excellent front-line tool for primary care initial triage. He discusses the value of BMI as being a superior predictor to more complex measures and recalls Stephen Harrison’s KISS principle as a goal. He notes that patients will be referred for obesity if their BMIs are high enough regardless of whether they exhibit proven NAFLD. Next, he describes the process the NHS used in the UK to select reimbursed programs. He suggests that while there are questions regarding diet and rate of weight loss relevant to the Fatty Liver community, patients with obesity should be treated for weight loss as a simple solution. From here the other panelists provide final thoughts and closing comments on what the field can do to drive NAFLD care and screening to primary care providers. Surf on for their response, and stay tuned for more 2022 AASLD coverage.

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In a follow-up preview, Jörn Schattenberg, Louise Campbell, Mazen Noureddin, Ian Rowe and patient advocate Jeff McIntyre join Roger Green to discuss key presentations and posters of interest at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). On November 4th-8th in Washington DC, as many as 10,000 attendees will convene in an effort to advance and disseminate the science and practice of hepatology, and to promote liver health and quality patient care.

Continuing from the previous conversation, Roger starts by questioning what the right long-term commercial model for remote patient wellness management companies might be. He recalls the early successes of Jenny Craig or Nutrisystem, achieved from selling food and Weight Watchers by branding other companies’ white-or black-labled food products. Is there the potential for these companies to marry strong coaching to services offering high-quality, pre-cooked foods for an integrated offering? Jeff agrees and refers to his own experience working with groups on medically-tailored meals. He briefly notes the push he sees to get these meals paid for by Medicare or private insurers. Louise mentions that the kinds of programs described exist at Safari parks as part of a full-wellness program for the animals. From a different perspective, she notes the importance of patient volition in program success and that volitional assessments are not included in trial design. The app Tawazun Health recently launched adds a volitional element.

Roger returns to a comment made in the first preview episode.  He had talked about finding improved primary care screening tools that might serve a dual purpose by also educating front-line providers how NAFLD often sits at the core of the galaxy of metabolic diseases. Two abstracts for posters are described that address this issue. The first of which is a meta-analysis of 121,975 patients. This study looked at significance of the odds and hazard ratios of the TyG index, computed based on triglyceride and glucose levels. It also investigated the ability over time for that ratio to predict disease. All results were highly significant and clinically meaningful. The second poster  is titled Performance of Artificial Intelligence Enabled Electrocardiogram and the Prediction of Fatty Liver Disease. This paper showed that an AI analysis of ECG results based on a convolutional neural network produced an area under the curve far superior to FIB-4. It also showed to be superior or equal to BMI and simple metabolic parameters. Roger’s general point: using these metrics can improve on FIB-4 while, at the same time, focusing on the links between NAFLD and other metabolic diseases. As the conversation winds down, Mazen and Jörn agree with a few additional comments.

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In a follow-up preview, Jörn Schattenberg, Louise Campbell, Mazen Noureddin, Ian Rowe and patient advocate Jeff McIntyre join Roger Green to discuss key presentations and posters of interest at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). On November 4th-8th in Washington DC, as many as 10,000 attendees will convene in an effort to advance and disseminate the science and practice of hepatology, and to promote liver health and quality patient care.

Jörn starts this conversation by noting his anticipation for Parallel 12: NASH therapeutics and OMICs. Specifically, he points to an abstract titled Novel Mobile Health Delivered Lifestyle Intervention Program (Noom Health Weight) in Patients with NASH: a randomized controlled proof of concept study. This is a small trial in patients with NASH and obesity. The study sought to measure weight loss alongside weekly engagement with the Noom Healthy Weight app. 70% of patients met the engagement goal and lost an average of 5.3 kg over 16 weeks. Patients undergoing a more typical lifestyle management lost an average of 1 kg. Jeff joins to highlight the potential of a remote technology to generate 70% weekly engagement. He also finds this data promising in terms of providing a program that patients can use to measure health and manage fatty liver disease. By contrast, Jeff discusses recent conversations with a patient recently diagnosed with NAFLD who was not maintaining successful self-management due to obscurity of direction. Roger cautions that while this trial reported “no adverse event,” it consisted of a small sample size and short study duration. He also raises questions around the commercial model buttressing this study: who is paying and for how long can they maintain motivation? He envisions a more viable approach will be supported by commercial payers, who in return are investing in health care data. Given this may take some time to play out, Roger casts a third suggestion: FDA-approved digital therapeutic apps. He predicts this to be fertile grounds for patient empowerment over the next few years.

As this session winds down, Jeff responds to several of Roger’s comments and notes the turbulent impact of a pandemic on participation in wellness apps. This topic extends into the next conversation.

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In a follow-up preview, Jörn Schattenberg, Louise Campbell, Mazen Noureddin, Ian Rowe and patient advocate Jeff McIntyre join Roger Green to discuss key presentations and posters of interest at the 73rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). On November 4th-8th in Washington DC, as many as 10,000 attendees will convene in an effort to advance and disseminate the science and practice of hepatology, and to promote liver health and quality patient care.

Louise leads this conversation with commentary carrying over from last week’s discussion on FibroScan as an essential test. Her hope remains that FibroScan be utilized in the early screening process, noting that many patients with poor liver health are still captured much too late in the process. She agrees with the consensus that, while imperfect, FIB-4 currently has the potential to improve patient capture rates. Mazen follows up with a comment on the nature of PPV being highly subjective to both test accuracy and patient population.

Ian suggests that some of the preceding conversation anchors performance of these tests to biopsy. Interested in moving beyond biopsy, he points out presentations which compare outcomes of patients according to either biopsy or associated noninvasive tests. The first paper he notes is titled Prognostic Value of Non-Invasive Tests in Patients with NAFLD. This study looks at outcomes for 1,700 patients with various non-invasive tests and demonstrates the value of each in predicting outcomes. Ian explains the conclusion is that NITs should be accepted as surrogate tests for clinical trials. He then looks at a presentation by Samer Gawrieh which correlates VCTE values with progression to cirrhosis and clinical events. He believes this to be the direction in which the field should move.

Mazen agrees with the idea that as data accumulates around NITs, we can better understand how longitudinal changes impact outcomes. He then briefly describes other presentations and posters at this meeting that address similar topics. His final comments describe the FDA’s interest in NITs: how do we give meaning to improvements in the efficacy of NITS and how do these improvements translate into better outcomes.