Surfing the MASH Tsunami

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In a thematic debut, Jörn Schattenberg and Roger Green host interviews with three listeners from the Surfing NASH community to discuss takeaways from NASH-TAG 2023 and the future of Fatty Liver. The four prominent questions of each session focus around:

• the “straightjacket” of biopsy
• how we think about “tests” when not classed as "NITs" as compared to biopsy
• how do we all become better centered on patient needs
• the idea of combination therapy

In this first installment, the co-hosts are joined by Pamela Danagher, Senior Vice President for Regulatory Affairs at Terns Pharmaceuticals. This conversation explores the ways that biopsy has, as Pamela puts it, constrained and restrained drug development. Not surprisingly, she also offers strong viewpoints and tremendous insights about uses of testing and combination therapy - two issues pivotal to Terns. Finally, Pamela comments briefly on what Donna Cryer described in a recent episode as “regulatory science” and how the entire community can communicate in ways that support approval of resmetirom and OCA. 

Each guest in these fully-featured interviews shares on-ground experiences which collectively cast invaluable light on how the information featured in Surfing the NASH Tsunami is digested and applied in everyday life. As the podcast enters its fourth season, and embarks on affiliated journeys like the Rising Tide series, we hope to grow our community engagement. If you enjoy our content, we kindly ask that you submit a review wherever you download our episodes. We also encourage our audience to write us questions and look forward to integrating your on-ground experiences and perspectives in the weekly discourse. Most important of all, we whole-heartedly thank you for your continued support as we set out to put a major dent in Fatty Liver disease in 2023 and beyond.

Stay safe and surf on!

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In a thematic debut, this episode comprises three interviews held with our very own listeners from the Surfing NASH community to discuss their takeaways from NASH-TAG 2023 and the future of Fatty Liver. 

Respectively, Pamela Danagher (Terns Pharmaceuticals), Jerry Mabary (Chronwell) and Caitlin Schneider (Sonic Incytes) join Jörn Schattenberg and Roger Green to explore four prominent questions around:

• the “straightjacket” of biopsy
• how we think about “tests” when not classed as "NITs" as compared to biopsy
• how do we all become better centered on patient needs
• the idea of combination therapy

Each guest shares insights which collectively cast invaluable light on how the information featured in Surfing the NASH Tsunami is digested and applied in everyday life. 

As the podcast enters its fourth season, and embarks on affiliated journeys like the Rising Tide series, we hope to grow our community engagement. If you enjoy our content, we kindly ask that you submit a review wherever you download our episodes. We also encourage our audience to write us questions and look forward to integrating your on-ground experiences and perspectives in the weekly discourse. Most important of all, we whole-heartedly thank you for your continued support as we set out to put a major dent in Fatty Liver disease in 2023 and beyond.

Stay safe and surf on!

Send us Fan Mail

In an exclusive interview, Co-Founder and Chief Scientific Officer of HistoIndex, Dr. Dean Tai, joins Fatty Liver Researcher Prof. Dr. Jörn Schattenberg on Surfing the NASH Tsunami podcast with host, Roger Green. The trio discuss pertinent questions stemming from data derived from Phase 2 trial results of aldafermin and resmetirom whereby liver volume reduction was achieved in a considerably abbreviated period. HistoIndex was able to subsequently investigate fibrosis reduction in these studies by conducting AI-assisted histologic assessment to gather a deeper understanding of fibrosis dynamics on a continuous scale.

Jörn introduces the corresponding poster held at NASH-TAG 2023, which reviews the application and compelling results of the qFibrosis® and qSteatosis® products. Dean then elucidates how AI-assisted zonal mapping of the liver delivers a targeted and statistically-improved assessment of fibrosis reduction. Interestingly, two distinctly different fibrosis regression patterns emerged between the aldafermin and resmetirom cohorts. The implication: highly-precise assessment of liver slides is sparking a spate of new questions surrounding therapeutic possibilities. Jörn offers two cogent observations. First, these technologies can drastically improve understanding of how much change in fibrosis really occurs. He points out that while many different MOAs are trialed in comparable populations, it may be that not all drugs are affecting fibrosis regression by the same mechanism. With the technology implemented by HistoIndex, researchers can now begin to assess the nuances of how and where these drugs act.

A different, but critically important idea emerges: patients deserve to have the fullest extent of utility extrapolated from their donated tissue. There is also noted to be a plethora of existing data containing what Dean describes as “a gold mine” for retrospective analysis. The group continues on to explore and compare the myriad of potential future applications of these tools. It becomes clear that advancements in AI-based digital pathology are paving a path for an entirely new, imaginative line of thinking for the Fatty Liver field. Listen to the full feature for more on this illuminating topic.

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NASH-TAG 2023 proved to be a watershed moment for Fatty Liver disease as exciting drug development readouts, powerful academic work on non-invasive tests and the willingness to dive into the toughest questions aligned in Deer Valley, Utah. In this weekend’s conversation series, Surfing NASH reviews its diverse coverage of the conference by showcasing key excerpts across six recordings with various KOLs, patient advocates and stakeholders.

This conversation consists exclusively of an exchange between Donna Cryer and Roger Green. The session begins by Donna noting that while the data is cause for enthusiasm, she is concerned that this alone does not guarantee an inevitable approval. In addition to good data, she suggests, is the need for good regulatory science. As she points out, Intercept hit its endpoints in 2020, yet no approval was gained at the time. “Good regulatory science” is, in her words, conclusive, granular and contains a simplified message. Roger asks for an example of what might not constitute good regulatory science. This leads Donna to recall that the fireside chat, although titled regulatory, focused more on clinical trial designs than how to prepare for advisory committees, health technology assessments and Phase 4 trials. She notes that during this discussion, a good question surfaced regarding how equipoise will change once drugs are approved. The implication: what FDA is currently seeking in Phase 4 becomes unrealistic once drugs reach the market. At this point, Roger returns to Scott Friedman’s comment about the “straitjacket of biopsy” and how that impacts thoughts around trial design and “proof.” Donna adds that real-world evidence is the up-to-date approach these days, and it will be available once we have more experience with the medicines. 

As the session winds down, Roger goes back to the adiponectin analyses predicting non-response as being his favorite part of the meeting and explains why. Donna shares that one of her favorite moments came when Claude Sirlin, a radiologist, asked how they can become more involved here. Roger responds that radiology may succeed biopsy as a “hard standard” of efficacy. In the final moments, Donna discusses some of the presented data and questions that embodied a public health perspective. 

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NASH-TAG 2023 proved to be a watershed moment for Fatty Liver disease as exciting drug development readouts, powerful academic work on non-invasive tests and the willingness to dive into the toughest questions aligned in Deer Valley, Utah. In this weekend’s conversation series, Surfing NASH reviews its diverse coverage of the conference by showcasing key excerpts across six recordings with various KOLs, patient advocates and stakeholders.

This conversation with Naim Alkhouri, Amy Articolo and Jörn Schattenberg begins with Naim illustrating some of the high points of the meeting. First, he recaps the resmetirom data. He then highlights that Intercept’s study of patient response to obeticholic acid (OCA) revealed improvements among the F3 population. He concludes that in the wake of these aforementioned results, there remains plenty of opportunity to improve and other biotechs “are still in the game” with the energy to back them. Jörn notes the high level of engagement from academia in supporting development through the consortia, NIMBLE and LITMUS. Amy credits the collaborative spirit of the meeting and the milestones achieved in improving the field’s understanding of how best to utilize NITs to provide insight and serve patient needs. 

Roger Green steers conversation toward the challenges of payers and gaps in therapeutic efficacy for certain populations. He connects these ideas to slides presented by Naim on AI-driven zonal analysis developed by HistoIndex. The assessment provides a geographic vantage point that offers perspective on how to combine agent benefits and trial emerging opportunities. Amy agrees that some of the complex analytics will help pharma build its case for patients. Naim questions what we call “futility” – if patients stay the same, are they futile? He suggests that AI can help us determine whether people who do not reduce fibrosis are actually benefiting from therapy. Roger notes that Naim outlined three categories: patients whose fibrosis regressed, others who progressed and a third group somewhere in the middle yet to be defined. Naim agrees and underscores that with the non-invasive tests available, we can learn far more than what’s known today. Amy responds with questions around how tests will be used practically, noting that stacked tests are pivotal to the story. As the conversation ends, Jörn notes biopsy is only one way to generate a conditional endpoint for drug approvals.

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NASH-TAG 2023 proved to be a watershed moment for Fatty Liver disease as exciting drug development readouts, powerful academic work on non-invasive tests and the willingness to dive into the toughest questions aligned in Deer Valley, Utah. In this weekend’s conversation series, Surfing NASH reviews its diverse coverage of the conference by showcasing key excerpts across six recordings with various KOLs, patient advocates and stakeholders.

This conversation includes analysis by Scott Friedman, Rachel Zayas, Jörn Schattenberg, Louise Campbell and Roger Green. Roger leads by asking the group to detail the “sit up and take notice” moment of the meeting. Scott immediately describes the “800-lb gorilla in the room,” the resmetirom data, which casts a positive light around everything within the meeting at large. He goes on to discuss other key points, namely, compelling results for other drugs in earlier stage trials and NITs. Rachel agrees with Scott, stating that “the narrative has changed.” She also mentions Mary Rinella’s nomenclature talk and the discussion of combination therapies. Jörn praises the high energy level and well-rounded nature of the talks. Louise points to previously unpublished efruxifermin data from the HARMONY trial that suggested to her we can place drugs in primary care practices if we also ensure they have appropriate tools and tests to monitor patients.

Scott underscores perhaps the most staggering number in the meeting: only 3% of patients treated for NASH are treated by a hepatologist. Jörn concurs with this observation, adding that this casts light on the importance of using the NITs at hand to identify patients. Scott then referred back to Will Alazawi’s presentation on pathways and a brief presentation from Siemens evaluating four different test strategies in terms of lowest cost and highest prediction. Roger comments that the wealth of NIT data is actually starting to point to simple strategies for using them in clinical trials and treating patients. The uses may vary, but the paths seem clear. For Roger, Fagan’s nomogram, which Mike Charlton presented, was the moment at which the paths became clear. He next asks Scott to describe what he considers most pivotal here. Scott goes on to discuss the need to identify non-responders better and figure out how to best manage them. Jörn agrees in the profundity of this analysis and, in that context, calls into question whether our definition of “response” might change from fibrosis regression to something more broadly metabolic. As the talk winds down, Louise notes that we have seen some promising data about combination therapies. Lastly, Scott notes that we have far more scientific ways to approach combination therapy than simply seeing what drugs a company has in its portfolio.

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NASH-TAG 2023 proved to be a watershed moment for Fatty Liver disease as exciting drug development readouts, powerful academic work on non-invasive tests and the willingness to dive into the toughest questions aligned in Deer Valley, Utah. In this weekend’s conversation series, Surfing NASH reviews its diverse coverage of the conference by showcasing key excerpts across six recordings with various KOLs, patient advocates and stakeholders.

This conversation featuring Stephen Harrison, Mazen Noureddin and Jörn Schattenberg begins with Mazen describing how exciting and informative the new sessions on non-invasive tests were. Specifically, he details his own surprise at how much LITMUS and NIMBLE were able to share. Jörn’s main point: we will find more NITs, but do not need them to be able to push treatment far forward today. Roger Green suggests that correct classification metrics (based on the percentage of patients classified correctly) might be more important in practical treatment than other tests which have better positive or negative predictive values but have large “indeterminate zones” of patients the test does not predict for at all. Stephen compliments the NIT discussion and commends Mazen’s observation that NASH is not the only disease area working its way through predictive non-invasive tests. Mazen shifts discussion onto the next session, where Vlad Ratziu, Rohit Loomba and Stephen Harrison investigate important areas in clinical trial design. Vlad discussed combination therapies, Rohit discussed gene SNPs and Stephen discussed cirrhosis.

Stephen refocuses on the idea that by providing continuous scoring, NITs appear to provide better guidance on whether drugs are “working” or not. Mazen agrees, pointing out how high the bar is to label a patient treated with drug a success. As the talk winds down, Jörn notes that Intercept and Madrigal are providing data we can dive into for years. Lastly, Stephen describes the high value that AI-based digital pathology will provide in sorting out how many patients are improving using continuous measures.

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NASH-TAG 2023 proved to be a watershed moment for Fatty Liver disease as exciting drug development readouts, powerful academic work on non-invasive tests and the willingness to dive into the toughest questions aligned in Deer Valley, Utah. In this weekend’s conversation series, Surfing NASH reviews its diverse coverage of the conference by showcasing key excerpts across six recordings with various KOLs, patient advocates and stakeholders.

This conversation features our patient advocate discussion with NASH kNOWledge founder, Tony Villiotti, and Fatty Liver Alliance Founder and CEO, Michael Betel. Tony and Michael begin by describing the high levels of enthusiasm that began at AASLD and carried through to NASH-TAG as it became clear that there are drug trials appearing to meet all criteria for approval. Louise Campbell extends this sentiment further, commenting that new medications combined with greater awareness of the breadth of integrated metabolic disease is leading to a surge in collaboration with other specialists. Specifically, she refers to the involvement of cardiology and endocrinology specialists as a “game changer.” 

Mike shifts focus to the idea that patients with diabetes and/or obesity might be taking GLP-1s or dual glucagon agents for those diseases. He points out that should new NASH drugs be approved, this might lead to de facto combination therapy. Louise suggests reasons why this might be a double-edged sword. The remainder of the episode focuses on things we do not know about the drugs – how they interact, how long they will work and what downsides may be. Louise offers a final thought which emphasizes the importance of providing professional and patient education and training to make sure the new medicines are used properly.

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For our look back at NASH-TAG 2023, Jörn Schattenberg and Roger Green are joined by Amy Articolo and Naim Alkhouri for a discussion which dives into the therapeutic efficacy of recently announced data on resmetirom, NITs, bariatric surgery and more. Adjoining this session is a bonus interview with Donna Cryer on her impressions and key takeaways which largely look into the movement of regulatory science. In combination, this two-part episode encompasses contrasting and thought-provoking perspectives on addressing the opportunities and challenges in moving the Fatty Liver field forward.

Naim opens the first conversation by noting the positivity emitted, echoing Scott Friedman’s position that momentum from Madrigal’s emerging data on resmetirom animated the wider program. In addition, he highlights that granularity around Intercept’s study of patient response to obeticholic acid (OCA) revealed improvements among the F3 population. For Naim, OCA is a drug he has envisioned to be applied toward advanced disease and serves undermet needs of F3 patients. He concludes that in the wake of these aforementioned results, there remains plenty of opportunity to improve and other biotechs “are still in the game” with the energy to back them.

At this point, Jörn underscores the strong presence of academia and involvement of various consortia as further evidence of progress. Amy joins to comment on the vibrant and dynamic discussions around NITs and how to enrich trials. She suggests that the dialogue has reflected the advancements of the field and how work can be enhanced with collective contribution. This leads to thoughts on pharmacodynamic change and demonstrating value to payers. Roger distills a main idea: if only 24% of patients show a one-level regression of fibrosis in a given period of time, there is much to learn about the other 76%. Conversation continues around narrowing the indeterminate zone and improving biomarker concordance in NITs. After exploring considerations in moving beyond biopsy, the group investigates the role of bariatric surgery. While recognizing the validity of bariatric surgery as a treatment option, Naim points to a brighter future of preventative hepatology whereby action precedes BMI levels of 50 and higher. At the end of the session, Roger asks each panelist for one unexpected thing that might happen in the next year.

In the following interview, Donna opens with a powerful statement: hope is not a strategy, and optimism is not inevitability. Specifically, she is determined to match the trajectory of regulatory science to that of the momentous energies emerging from clinical science. In doing so, relationships and open lines of communication are key for meeting agreed endpoints. Next, the two talk about addressing the indeterminate zone in a different context and opportunities for harnessing real-world evidence. As this conversation moves forward, it becomes clear that Donna is committed to connecting patients to care today, and not only after a drug approval. In closing, she fields the same question as the preceding panelists, but offers a very different answer. Surf on to find out. 

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In Part 2 of our real time coverage of the highly anticipated NASH-TAG 2023 conference, friends of the podcast Scott Friedman and Rachel Zayas join Louise Campbell, Jörn Schattenberg and Roger Green to review key takeaways from Friday and Saturday in Deer Valley. Following this session, Jörn, Louise and Roger review high points from the Saturday night “Potpourri” and “Regulatory Fireside Chat” sessions. The final feature of this episode is an enthralling and exclusive interview with HistoIndex Co-Founder and Chief Scientific Officer, Dean Tai, who shares captivating data from an AI-assisted histologic assessment of Phase 2 trials on aldafermin and resmetirom.

Scott opens the leading session with a concise summary of his highlights distilled from an event burgeoning with impressive moments. His main suggestion is that the positive momentum of the recent Madrigal announcement energized the wider program. Rachel echoes the idea that “the narrative has changed” as the field enters a promising New Year. Next, Louise points to her interest in the presentation of previously unreleased Phase 2 results from the HARMONY Trial on efruxifermin. And finally, Roger speaks to the evolving roles that NITs play in clinical trial and primary care settings. As analysis advances, Scott nails down an important question: what are the factors that distinguish the responders from the non-responders in the resmetirom trial? This leads the group down a compelling line of interrogation. The question also proves pertinent later in the episode as Dean teases tools to uncover the nuances of how and where these drugs act in the liver and beyond. Other topics explored in the opening session include insights on combination therapy, covert alcohol use, bariatric surgery, nomenclature, NITs, genetics and more.

In the second conversation, Jörn, Louise and Roger dive deeper into Saturday’s session. A major theme: the increasing focus on the role of bariatric surgery in liver disease. Jörn also underscores discussion around moving the field forward with an NIT that predicts outcome as an acceptable surrogate for conditional drug approval. Roger comments that addressing how drugs get used - not how they get approved - shifts focus from the needs of regulators to those of the payers.

Lastly, Dean joins Jörn and Roger to investigate fibrosis dynamics on a continuous scale using AI-based analysis and quantification of NASH features for treatment efficacy. The main idea: highly-precise assessment of liver slides has arrived, sparking a spate of new questions surrounding therapeutic possibilities. It becomes clear that advancements in AI digital pathology are paving a path for an entirely new, imaginative line of thinking for the Fatty Liver field. Surf on to the full feature for more on this illuminating topic.

This episode of Surfing the NASH Tsunami, including the accompanying discussion on zonal and liver-volume corrected analysis of fibrosis and steatosis, is sponsored by HistoIndex, the world’s leading specialist in stain-free imaging for NASH clinical trials. HistoIndex is transforming diagnostic standards and drug development for NASH with its second harmonic generation based AI digital pathology solution.