Surfing the MASH Tsunami

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The Liver Forum aims to advance the regulatory sciences for the treatment of NAFLD/NASH and liver fibrosis by providing a neutral, independent venue for ongoing multi-stakeholder dialogue. Their work facilitates the best science-based decisions on how to study efficacy and safety in real-time by using collective knowledge and experience with therapies for advancing liver disease. In this conversation, Executive Director Veronica Miller describes how she arrived to the field of NAFLD and the history of the Liver Forum.

Veronica begins by sharing the story of her background, originating in primary research in immunology. This led to her landing in Washington DC to assume leadership of the Forum for Collaborative HIV Research. Veronica recalls this experience as setting precedent for the potential that a forum could be and accomplish. The idea of the HIV Forum was for all stakeholders - patients, drug developers, physicians, investors, regulators and government agencies - to convene for a collaborative approach to research in a safe, egalitarian environment. For Veronica, it was a major switch from presenting her own data to masterminding and leading this collective approach to deal with addressing research gaps. Notably, the role required her to bring disparate groups together, including HIV patient activists, who were extremely knowledgeable and at times challenging. Critically, the forum experience leant patient voice to the arena for the first time. Within a few years, that same approach was expanding to other disease areas, including Hepatitis C. Through the Hepatitis C Forum, Veronica worked to resolve the issue of creating a clinical trial without standard controls. After attending a meeting at FDA about clinical trial endpoints, she ventured into the field of Fatty Liver disease. The session concludes with her note that NAFLD is unique from other diseases in that Fatty Liver does not have a pathogen to target.

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The Liver Forum aims to advance the regulatory sciences for the treatment of NAFLD/NASH and liver fibrosis by providing a neutral, independent venue for ongoing multi-stakeholder dialogue. Their work facilitates the best science-based decisions on how to study efficacy and safety in real-time by using collective knowledge and experience with therapies for advancing liver disease. In this episode, Executive Director Veronica Miller joins guest Manal Abdelmalek and co-host Jörn Schattenberg (both Steering Committee members) to discuss the Liver Forum and its valuable work.  

Veronica details her fascinating, well-traveled background and the path she has taken from HIV research to the HIV Forum - an experience that defined what a forum could be and do - to work on HCV and eventually NAFLD. After Veronica describes her path to the Liver Forum, Manal and Jörn share theirs. Each panelist is attracted to this opportunity to pool insights and ponder the deepest, most challenging questions in liver disease with colleagues from across a broad range of stakeholder organizations. 

The conversation shifts from how the Liver Forum came to be to its ongoing activities and programs of today. Veronica believes the striking challenge of the NASH paradigm to be surmounting sufficient evidence to move beyond the liver biopsy. Recalling the precise and dynamic developments of biomarkers for HCV and HIV, she notes the fatty liver field struggles in absence of a pathogen. There remains a new set of complexities regarding disease etiology and pathophysiology, the natural course of disease and the resulting divergent strategies for therapeutic approaches. However, she points enthusiastically to the emerging field of omics for its potential to illuminate a myriad of patient-specific biomarkers.

As we all move beyond the logistical limitations imposed by the COVID-19 pandemic, stakeholders can now come together to sieve through huge quantities of emerging data and distill them into lessons that will shape how we diagnose and treat Fatty Liver patients and then monitor the outcomes of these activities. As the panel notes, data collaboration is a key component for such a paradigm shift. Veronica introduces the Placebo Arm Database Project, co-chaired by Manal, whereby completed trials are studied in an effort to determine what predicts the stability of disease versus progression or improvement. Manal elaborates on the efforts made toward understanding placebo cohorts in totality, including predictors of responsiveness and adherence amongst other sources of variability. By pooling a wider net of datasets, she hopes to draw stronger conclusions, assessments and even benchmarks to power and design more effective trials in the future. Jörn comments that while he is interested in the influence of background care, he wonders whether by combining two histologic endpoints, fibrosis regression and NASH resolution, placebo response is effectively reduced. Manal suggests the field needs either an all-encompassing drug or to make allowances to tease out the risks, benefits and alternatives of unique therapies. She then expands on how an understanding of placebo arms can optimize patient selection for trials. From here, Veronica bridges the conversation to include the influence these insights might have on driving drug development before venturing into the imminent future of clinical trial design.

This episode offers a very special glimpse into the conversations and considerations taking place in the background of putting a dent in fatty liver disease. The session ultimately exposes a fascinating window into the creative thinking applied to the varied, complex challenges facing the field. 

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This episode From the Vault follows Season 2, Episode 43 in discussing the possible role of NASH cirrhosis clinical trials in the transition from biopsy as gold standard to a post-biopsy world. Terns Pharma CEO Sen Sundaram joins this conversation from the audience to ask whether the term “cirrhosis” is medically helpful or might warrant replacement with “end stage liver disease.” After vigorous discussion on this point, Sen departs and Stephen Harrison leads the group through a review of four ongoing NASH cirrhosis trials. The discussion veers into the issue of which analytics methods designers are specifying and why. At one point, Naim Alkhouri, frequent guest and principal investigator on the Gilead combination agent trial, comments before the session ends. His specific contribution: MRE was not included in the Gilead trial largely for cost reasons.

The most striking fact to emerge from this conversation relates to the “beyond the biopsy” question. MRE is emerging as a highly reliable NIT that appears to produce reliable results regardless of mode of action and is generating correlations and ratios to fibrosis level decreases and other key metrics, yet it is not included in the designs of any ongoing NASH cirrhosis trial. Stephen describes this as the “stovepiping” of data. Companies consider the data they need, not ways it can be aggregated with other trials to solve larger issues. This issue bears further exploration in later episodes.

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Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Alongside this rich discussion are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green.

This final conversation starts with Jörn  recalling Shira's statement that “diet is every day.” He notes that for patients whose serious medical issues are related to poor diet and lifestyle choices, behavior and diet can play an integral role in improved patient self-care and overall health. Roger highlights that a combination of medications and self-management can be a powerful, reinforced and effective treatment solution. This leads Shira to provide a step-by-step vision of how to work with patients on improving bad habits. In the end, she notes, clinicians and leaders need to appreciate the importance of policy in supporting clinical goals. The conversation continues with the group discussing what Louise calls “fun facts” about common unhealthy foods. For the final question, Roger asks the panelists for one piece of advice to be utilized by providers seeking to push behavioral change in their patients. Surf on for their key takeaways. 

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Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Surfing alongside this rich discussion are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green.

Ken begins this conversation by extending his ideas around the need for US insurance companies to support integrated solutions. Louise asks Ken whether he believes things will change when new anti-NASH drugs are approved. Ken states that in his dealings over the years with insurance companies, obesity management has been regarded as an expense, not an investment. He notes Western democracies in general have neglected to invest in obesity management.

Roger revisits the theme of finding value in apps and digital interventions. Shira believes that while they can be a helpful tool for many, they cannot replace human interaction. Ken agrees and elaborates that while an app can catalyze momentum, motivation often wanes after several months. Those trying moments are exactly when Ken envisions human intervention to be critical. Jörn returns to the idea that patients need to develop the habit of regular dietician visits. He says he might adopt Shira’s “haircut” metaphor, whereby maintenance visits are conducted every month or two. As the conversation winds down, Louise and Shira discuss the idea that while allied providers do not have the time for full-fledged behavioral therapy, they can provide information and support that helps patients improve.

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Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Surfing alongside this rich discussion are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green.

Roger prompts this conversation by stating that everyone eventually makes poor dietary choices. The group agrees through various examples that the key is to not let a momentary shortcoming deter progress along the wellness journey. Shira emphasizes that relapse is part of the process and ought to be factored into patients' long-term plans. She goes on to disclose her love for chocolate and how patients can still have some of their favorite foods in their new diet. This leads Ken to describe diet as simply one aspect of a full-life balancing act. For him, perfectionism is the enemy. The group goes on to consider the psychology of decision making around diet in similar terms to that of addiction treatment. Louise notes that while the field of NAFLD deals with areas requiring immense psychological support, those resources are lacking for patients. In addition to including a dietician on the team, she adds emphasis to the benefit of cross-training physicians with education on mental health support. Ken agrees and comments that the US insurance system makes it hard for patients to get the collateral support they need.

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Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Surfing alongside are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green to discuss effective goal setting and dietician visits as life-long therapy. 

This conversation continues on the subject of weight reduction for NASH resolution. Previously, Jörn, Ken and Louise walked through their ideas on strategies around long-term self-management in implementing a healthy diet. Shira begins by describing her own approach, termed weight-inclusive, which focuses on holistic coaching measures that extend to all facets of a happy and healthy lifestyle. By including tools like exercise with all other reachable means of positive feedback, patients are relieved from becoming too fixated on weight-loss. This approach also integrates setting and driving realistic goals, and dietician visits as a life-long therapy. Shira relates visits to the dietician to be as simple as returning for a haircut every month or two. Jörn comments on the value of biofeedback and highlights the ability to drive better health through digital tools. Shira is optimistic about the potential, but cautions negative feedback can also be detrimental to progress. As the session winds down, she describes the power of relationships formed between dieticians and patients on their wellness journey towards regression. 

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Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Surfing alongside are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green to discuss weight reduction for NASH resolution, and strategies for long-term adherence to lifestyle modifications.

Shira leads this conversation by introducing the topic of weight reduction as a first line of defense for the field of NAFLD. While discussing weight loss targets for patients with different degrees of Fatty Liver disease, it’s identified that ≥7% weight reduction is a “golden number” for patient resolution. In terms of how weight reduction is achieved and maintained, it is noted that long-term adherence to lifestyle modification poses significant challenges. Choosing the right diet for a diverse population of patients can be daunting. Before disclosing her own ideas, Shira asks for the group’s approach to the topic. Jörn suggests hepatologists are not particularly effective at assessing diets or prescribing specific solutions. As such, he adheres to simple protocols like intermittent fasting. Jörn also asks a question to the group that he receives often: Why is there a need for drugs in this disease if patients just need to lose weight? Ken notes that in the US, excess caloric intake can be treated with the prescription of weight-loss medications, like a GLP-1, or more NASH-specific agents, like pioglitazone. He also suggests endocrinologists are better equipped to provide education on nutrition to patients. The group agrees that partnering with a nutritionist is invaluable for developing strategies around long-term self-management. Finally, Louise shares her belief that successful solutions begin with small, achievable goals.

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In a timely debut during the American Thanksgiving holiday, Surfing the NASH Tsunami hosts its first episode dedicated to nutrition and NASH with distinguished guest, Prof. Shira Zelber-Sagi. Surfing alongside in this rich discussion are Ken Cusi, Jörn Schattenberg, Louise Campbell and Roger Green. 

After sharing how she came to the intersection of nutrition and NASH, Shira leaps into the topic of weight reduction as a first line defense for the field of NAFLD. While identifying ≥7% weight reduction as a “golden number” for patient resolution, it’s noted that long-term adherence to lifestyle modification poses a significant challenge. Choosing the right diet in a diverse population of patients also poses a significant challenge. Jörn suggests hepatologists are not particularly effective at assessing diets or prescribing specific solutions. As such, he adheres to simple protocols like intermittent fasting. Ken comments that endocrinologists are better equipped to provide education on nutrition to patients. He notes that in the US, excess caloric intake can be treated with the prescription of weight-loss medications, like a GLP-1, or more NASH-specific agents, like pioglitazone. Louise adds that successful solutions begin with small, achievable goals.

Shira goes on to describe her own approach, termed weight-inclusive, which focuses on holistic coaching measures that extend to all facets of a healthy lifestyle. By including exercise with all other reachable means of positive feedback, patients are relieved from becoming too fixated on weight-loss. This approach also integrates setting and driving realistic goals, and dietician visits as a life-long therapy. Shira relates visits to the dietician to be as simple as returning for a haircut every month or two. She also suggests any healthy diet that works for the patient is permissible. Jörn comments on the value of biofeedback and highlights the ability to drive better health through digital tools. Shira is excited by the potential, but cautions negative feedback can be detrimental to progress.

Roger states that the reality of failure is unavoidable: everyone eventually makes poor dietary choices. The group agrees the key is to not let a fleeting shortcoming deter progress. From here they consider the psychology of decision making around diet in similar terms to that of addiction treatment. Louise notes that while the field of NAFLD deals with areas requiring immense psychological support, those resources are lacking for patients. Ken adds that working interprofessionally with dieticians is not well supported by insurance companies in the US. He states that in his dealings with insurance companies, obesity management has generally been regarded as an expense, not an investment. 

Roger revisits the theme of finding value in apps and digital interventions. Shira believes that while they can be a helpful tool for many, they cannot replace human interaction. Ken elaborates that while an app can catalyze momentum, motivation often wanes after several months. Those trying moments are exactly when he envisions human intervention to be critical. Recalling Shira’s statement that “diet is everyday,” Jörn emphasizes that behavior and diet can play a key role in improving patient self-care and overall health. Roger highlights that a combination of medications and self-management can be a powerful, reinforced and effective treatment solution.

Shira provides a step-by-step vision of how to work with patients in improving bad habits. She notes clinicians and leaders need to appreciate the importance of policy in supporting clinical goals. For the final question, Roger asks the panelists for a piece of advice for providers seeking to push behavioral change in their patients. This is a fun, applicable and endlessly important topic to be explored. Surf on to learn more!

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Thursday, June 9, marked #NASHDay 2022, the 5th annual celebration of International NASH Day by the world’s largest liver patient advocacy organization, the Global Liver Institute. For the #NASHDay Wrap-up Panel, Global Liver Institute invited NASH Tsunami co-hosts Jörn Schattenberg, Louise Campbell and Roger Green to join NASH Programs Director Jeff McIntyre to discuss themes of the day and major issues in the Fatty Liver community.

This conversation includes the last fifteen minutes of the GLI NASH Day wrap-up panel. Jeff McIntyre asks two questions to the group. First, he asks each panelist to respond to the slogan #StopNASHNow and its implication that for patients, it might be enough simply to arrest the progression of fibrosis. Therefore we should devote efforts in research and regulatory energy to stopping the progression instead of focusing entirely on regression. For his last substantive question, he asks each of us to discuss something that puts a twinkle in our eyes as we consider the next 3-5 years of progress in the fight against Fatty Liver disease. Surf on for great questions that yield interesting and diverse answers.