Surfing the MASH Tsunami

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This month, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from June's two major conferences: the 2023 EASL Congress in Vienna and the American Diabetes Association's 83rd Scientific Sessions meeting in San Diego. This is the second session focusing on drug development, and specifically, on several presentations for exciting drugs in development. In doing so, the Big Band of Surfers (Stephen Harrison, Jörn Schattenberg, Louise Campbell and Roger Green) are joined by Mazen Noureddin for a fascinating conversation which covers plenty of compelling clinical trial data.

Jörn preludes this discussion by noting just how much important drug development research was released at this year's EASL Congress. Stephen proceeds from here to detail positive Phase 2b FASCINATE-2 clinical trial interim data for fatty acid synthase (FASN) inhibitor, denifanstat, as presented at EASL Congress by Rohit Loomba. In the process, Stephen elucidates why the idea of a FASN inhibitor is so exciting. It blocks de novo lipogenesis, which means it can have effects on inflammation and possibly direct fibrosis inhibition. Previously in Season 4, Episode 32, it was discussed why inflammation, which is tied to liver volume, might be a critical component to better understand for therapuetic development and the wider scope of liver health. From here, Stephen goes on to describe the trial, starting with basic design and sharing the MRI-PDFF and biomarker data that was presented at the EASL Congress. He finishes with safety and efficacy data and a general comment that the trial demonstrated, 'the drug is doing what it's intended.'

The following excerpt is from the Sagiment Biosciences press release on this topic:

The Phase 2b FASCINATE-2 study is a 52-week randomized, double-blind, placebo-controlled trial evaluating the safety and histological impact of a 50mg daily oral dose of denifanstat compared to placebo in 168 biopsy-confirmed NASH patients with moderate-to-severe fibrosis (stage F2 or F3). The primary efficacy endpoint is histological (liver biopsy) improvement at week 52 in nonalcoholic fatty liver disease (NAFLD) activity score (NAS) without worsening of fibrosis or resolution of steatohepatitis without worsening of fibrosis. Secondary endpoints include biomarkers of inflammation, fibrosis and liver injury.

• Denifanstat was well-tolerated and met primary endpoint in planned interim readout with 67% of treated patients achieving ≥30% reductions in liver fat at week 26 compared to 18% placebo (p<0.001) as assessed by MRI-PDFF
• Denifanstat statistically significantly decreased LDL cholesterol in treated patients and improvements in the circulating blood lipid profile were observed
• Topline week 52 liver biopsy results expected in the first quarter of 2024

Each conversation covers a lot of ground on drug development, analysis of trial results, and the upcoming increases in importance of omics and artificial intelligence. If you have questions or comments around the EASL Congress or ADA meetings, or the themes and data discussed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

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This month, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from June's two major conferences: the 2023 EASL Congress in Vienna and the American Diabetes Association's 83rd Scientific Sessions meeting in San Diego. This is the second session focusing on drug development, and specifically, on several presentations for exciting drugs in development.

This session kicks off with a twist as co-host Jörn Schattenberg introduces the episode and its panelists because Roger Green is late (he will join later with a bit of birthday banter). Joining this in-depth discussion around the latest drug development stories to emerge from the EASL and ADA meetings is Stephen Harrison, Mazen Noureddin and Louise Campbell.

Stephen starts the episode by discussing findings from the Phase 2b FASCINATE trial of the FASN inhibitor denifanstat, as presented at the EASL Congress by Rohit Loomba. After describing key efficacy and safety findings, Stephen notes that denifanstat does pretty much what observers expected it to do. Mazen follows up with a series of questions noting that denifanstat's efficacy does not appear equal to the FGF-21s efruxifermin and pegozafermin, and asks whether it will become a "front-line" or "add-on" agent. In response, Stephen suggests we will need a plethora of modes of action, that orals and injectables will each have a place depending on the type of patient, and that this will compete for front-line use in less severe patients and maintenance use in more severe patients with the other oral agent classes. From here, the conversation moves on to discuss the increasing importance of omics and epigenetics, and the role these may play in the future.

This is the point at which Roger joins the discussion. Because Mazen has to leave, Roger asks him a broad question about markers for the future; Mazen bases his answer on the anticipated future approval of resmetirom. After he leaves, Stephen presents results from the Phase 2b study for the dual GLP-1/glucagon agonist pemvidutide, which wanders into the importance of the actual GLP-1-to-glucagon impact ratio, potentially significant safety signals that remain to be fully studied, and the subject of how much lean muscle mass these agents produce. This leads Louise Campbell into a brief but fascinating comment on the psychological impacts of lean muscle mass on different patients.

In the final question, Roger asks the group what we have learned in the previous month that might affect research design or disease strategy thinking going forward. The answers vary widely, and each has value.

If you have questions or comments around the EASL Congress or ADA meetings, the discussed therapeutics, new nomenclature, or any other topic addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

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The first three days of the 2022 program focused on a range of issues, with specific emphasis on non-invasive tests (NITs) and their role at different stages in diagnosis and treatment. This conversation From the Vault touches on two issues: use of AI to better understand the meaning of liver volume and elements of morphology and, relatedly, how much more sophisticated a view we take of NAFLD and NASH than we did even five years ago.

The issues around AI and liver morphology arise from Jörn Schattenberg’s comment that consistent with Stephen Harrison’s “KISS” (Keep It Simple, Stupid!) principle, researchers are starting to explore the meaning of changes in liver volume. Ultimately, Jörn notes, pairing these kinds of measures to AI-supported histopathology can yield tremendous benefits. Roger comments on a breakfast he attended that morning that suggested that AI and NITs each provide different, important information on individual liver health: NITs can address collagen burden but not structure, while AI can identify changes in structure but not link them to the impact on the patient. Zobair ends this part of the conversation by noting that companies are starting to use AI in these ways.

The second part of this conversation stems from Roger’s observation that we know far more about the disease than we did 3-4 years ago. He goes on to describe how the environment is more collaborative and open-minded than it might have been if, in fact, we saw drug approvals at that time. Zobair takes this observation to a different plane, noting that 5-10 years ago, “some very important experts” believed that we all understood the etiology of Fatty Liver disease, so why spend more time? He goes on, “we could not have been more wrong,” observing that what we have learned about progression and regression in placebo arms suggests a far more complex disease than something that progresses linearly, or even constantly in one direction. He goes on to add that the multiple drug trial failures is that targeting drugs to a single solution based on animal models is likely to fail because this is a multiple mode of action disease. His third point: the “source” of the disease is visceral obesity and insulin resistance, which all viable solutions must address. This identifies two targets for treatment, while simultaneously demonstrating that therapy will be chronic, lifelong and with behavioral elements. The rest of the conversation addresses the challenges with shaping this kind of lifelong, multi-target therapy in the US today.

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Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress and the American Diabetes Association's 83rd Scientific Sessions. For this feature, Sven Francque (University of Antwerp) and Ian Rowe (University of Leeds) join Jörn Schattenberg and Roger Green to discuss a range of fascinating topics to emerge at the EASL Congress meeting held in Vienna.

This final conversation begins with Sven's choice to discuss another paper by Vincent Wong that correlated liver stiffness with risk of decompensation and HCC. It is noted that the study relied on repetitive MRE readings over time and could not be performed in many different countries. This leads to comments around the plausibility of shifting from biopsy to NITs and insights around the cost effectiveness and the frequency of testing. On the flip side, Ian next underscores a study that investigates identification of a gene signature that will accurately predict the risk of decompensation and, ultimately, determine how to make better use of the biopsy tissue received in research. Finally, the session winds down with a closing question around what to expect in next year's meeting.

If you have questions or comments around the EASL Congress meeting, new nomenclature, discussed papers or any other ideas addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress and the American Diabetes Association's 83rd Scientific Sessions. For this feature, Sven Francque (University of Antwerp) and Ian Rowe (University of Leeds) join Jörn Schattenberg and Roger Green to discuss a range of fascinating topics to emerge at the EASL Congress meeting held in Vienna.

This conversation begins with Roger's note of a population study from South Korea looking to identify patients with steatotic liver disease, but not cirrhosis, that will progress to HCC over a ten year period. After sharing the study details, both Ian and Jörn express common concern around the relatively small size of the identified patient group. Jörn shares his hope that with new disease classification which combines metabolic and alcoholic components we will be able to study these issues more broadly in populations that might be more finely tuned for the study aims. Next, Jörn highlights a paper that leads the group to unpack how little is known about the mechanisms of fibrosis resolution beyond the idea that there are clear differences between the progression and regression processes.

If you have questions or comments around the EASL Congress meeting, new nomenclature, discussed papers or any other topics addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress and the American Diabetes Association's 83rd Scientific Sessions. For this feature, Sven Francque (University of Antwerp) and Ian Rowe (University of Leeds) join Jörn Schattenberg and Roger Green to discuss posters and presentations that they find critical and/or compelling.

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 randomised 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. 

If you have questions or comments around the EASL Congress meeting, new nomenclature, discussed papers or any other topics addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress and the American Diabetes Association's 83rd Scientific Sessions. For this feature, Sven Francque (University of Antwerp) and Ian Rowe (University of Leeds) join Jörn Schattenberg and Roger Green to discuss a range of fascinating topics to emerge at the EASL Congress meeting held in Vienna.

This conversation focuses on the outcome of the nomenclature process, a three-stage Delphi process that produced new names and classification for what had previously been known as fatty liver disease and henceforth will be known as the steatotic liver disease (SLD). Sven, who was actively involved in the entire exercise, gives a concise summary of the process by which the new classifications were developed and how the new terminology will work. The rest of the conversation focuses on three issues. First, excitement that we will now have the opportunity to study patients whose disease has both metabolic and alcohol-based components. Second, the processes by which the three clinicians, Sven, Ian and Jörn are starting to share the new structure with their patients with varying degrees of success. One interesting observation emerges here from Sven: the English language terms do not translate equally into Dutch, so there is a patient advocate-led effort to create a new set of terms in Dutch. Third, Roger raises concerns about implementation planning for the new nomenclature. One concern is around the possible impact on drug or diagnostic development and the other about the kinds of communication issues covered earlier episodes. Sven, who again worked more closely on the process, states with confidence that the change will not have impact on drug or diagnostic trials. Read more about the switch to steatotic liver disease (SLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) here.

If you have questions or comments around the EASL Congress meeting, new nomenclature, discussed papers or any other topics addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!

Send us Fan Mail

Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress and the American Diabetes Association's 83rd Scientific Sessions. For this feature, Sven Francque (University of Antwerp) and Ian Rowe (University of Leeds) join Jörn Schattenberg and Roger Green to discuss a range of fascinating topics to emerge at the EASL Congress meeting held in Vienna.

The episode begins on the subject of new NAFLD/NASH nomenclature. Sven provides a cogent summary of the background, processes and decisions related to the name changes. The other panelists respond with varying perspectives and expand on the  following ideas that emerge:

• the changes reflect an opportunity to study metabolically at-risk populations that consume more than little-to-no alcohol
• the adoption of more neutral scientific terms  - steatotic rather than fatty -destigmatizes the condition
• In general, improved clarity around definition of disease is a positive step forward in putting a major dent in the pandemic 

The conversation shifts to practical considerations around how to implement the changes in different settings and with patients. Read more about the switch to steatotic liver disease (SLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) here.

The group refocuses on posters and presentations that they find critical and/or compelling. Ian points to a presentation 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 randomised 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. Roger next mentions a population study from South Korea looking to identify patients with steatotic liver disease, but not cirrhosis, that will progress to HCC over a ten year period. After the group comments on this study, Jörn highlights a paper which unpacks how little is known about the mechanisms of fibrosis resolution beyond the idea that there are clear differences between the progression and regression processes. Sven then chooses to discuss another paper by Vincent Wong that correlated liver stiffness with risk of decompensation and HCC. This leads to comments around the plausibility of shifting from biopsy to NITs and insights around the cost effectiveness and the frequency of testing. On the flip side, Ian underscores a study that investigates identification of a gene signature that will accurately predict the risk of decompensation and, ultimately, determine how to make better use of the biopsy tissue received in research. Finally, the session winds down with a closing question around what to expect in next year's meeting. 

If you have questions or comments around the EASL Congress meeting, new nomenclature, discussed papers or any other ideas addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

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In 2022, roughly 5,000 liver community stakeholders gathered in London for the 2022 International Liver Congress (#ILC2022,) the first major hepatology Congress to be held in person since the start of the pandemic (smaller, but very valuable, meetings like NASH-TAG, LiverCONNECT and Paris NASH have taken place with an in-person component, but the International Liver Congress and The Liver Meeting have not). On the last full day of the program, several vitally important drug development studies were presented during the late-breaker and dedicated sessions. 

This particular conversation From the Vault focuses on the semaglutide cirrhosis late-breaker and, more broadly, what panelists consider the presentation from this Congress most likely to effect change over the next 2-3 years.

Because Stephen Harrison needs to depart, the episode starts with him answering a question about the most consequential paper in the Congress. He focuses on the resmetirom late-breaker, which presages potential drug approval within the next 18 months. Jörn Schattenberg takes a different tack, identifying the semaglutide cirrhosis late-breaker instead. Jörn notes that the study did not achieve its primary endpoint of 1-level fibrosis reduction in 48 weeks, but cites other studies and experiences to suggest this is very, very hard to achieve for any drug. Jörn continued to suggest that semaglutide’s safety level combined with ability to help patients lose weight and reduce their HbA1c levels means this can be a valuable drug for Fatty Liver patients as well as diabetics and people with obesity, the currently indicated patient populations. From here, the group provides answers to the “most consequential presentation” question and the conversation comes to an end.

If you have questions or comments around the topics addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

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Throughout the month of July, Surfing NASH embarks on a series of episodes dedicated to takeaways emerging from a busy past month at both the 2023 EASL Congress in Vienna and the American Diabetes Association's 83rd Scientific Sessions meeting in San Diego. To reflect on the insight-laden occasion, Stephen Harrison and Jörn Schattenberg join Roger Green to explore emerging drug development stories in detail.

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.

If you have questions or comments around the EASL Congress or ADA meetings, the discussed therapeutics, new nomenclature, or any other topic addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse. Alternatively, you can write to us directly at [email protected].

Stay Safe and Surf On!