Surfing the MASH Tsunami

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In a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. This conversation starts with Jörn Schattenberg investigating the impact that the use of a broad set of NITs in this study will have on NIT adoption and use in clinical patient treatment. Mazen Noureddin comments on how the use of NITs in clinical trials can reduce recruitment time and costs associated with the trials. Scott Friedman points out that as we strive to learn how to identify drug failures faster, FDA might require broad NIT use as part of that effort. 

As the conversation continues, Rachel Zayas and Scott jump into more basic scientific issues. Rachel asks whether there is synergistic effect between LDL lowering and the primary endpoints and what that means for the disease. Scott asks what the results tell us on two fronts: first, what does it tell us about the ability of fat lowering to regress fibrosis if THR beta has no direct antifibrotic effect. Second, what about this drug converts fat lowering into fibrosis regression when other drugs that can lower fat and maintain lower fat levels do not demonstrate antifibrotic effects? After more comments about the science of the trial, Michael Betel asks how quickly focus will shift from monotherapy to combination therapy given how many patients did not succeed with resmetirom monotherapy. Mazen notes that other therapies were administered to patients in this trial. As the session ends, Louise Campbell asks questions about semaglutide design and Mazen discusses benefits and trial opportunities for this drug.

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In a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. This conversation starts with Louise Campbell commenting on two specific benefits. First to mention is the fact that the multiple metabolic measurements "check a lot of boxes," as she puts it, in terms of liver disease. Second, she notes there is great benefit for patients now that caregivers can tell them “if diet and exercise does not work, there is something else we can do.” Mazen Noureddin agrees, but notes that for F3 patients, drug therapy should start on the first or second visit. He also discusses the value of Hispanic patients and ways to discuss efficacy. Jörn Schattenberg asks whether the relatively similar results at two dose levels build or defeat the case for two dose levels. Kris Kowdley states confidently that having two dose levels is a benefit that these results demonstrate.

Louise asks how we can drill down into the patients that did not succeed, and Scott Friedman raises issues around payer response and precision therapy. He notes that it may also redefine use of placebo in clinical trials. Michael Betel asks what role bariatric therapies – notably surgery – might play in liver therapy and how we evaluate it. Through the rest of this session, Kris, Mazen and Roger discuss ways that the scope of data in this study and the rest of the Madrigal program will enrich scientific knowledge for years to come.

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In a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. This conversation is the first in a series which navigates the reactions of eight panelists, including Michael Betel, Scott Friedman, Kris Kowdley, Mazen Noureddin, Rachel Zayas and co-surfers Jörn Schattenberg, Louise Campbell and Roger Green. As each recalls their various reactions to the news, the group addresses several points. Mazen describes his relief that we now have a Phase 3 trial that achieves efficacy and safety goals. Scott follows up with his anticipation of increased enthusiasm and energy for the entire set of stakeholders. Michael, the patient advocate representative among the group, reacts with a question: are we ready? Comments from Kris and Jörn drive one interesting outlook: this is the second positive Phase 3 trial in terms of efficacy. Such results might clear the field for a simpler approval process. Additionally, Jörn notes an approval would be in consideration in the EU where EMA requires both NAS improvement and regression of fibrosis.

From the entrepreneur’s perspective, Rachel recalls her decision a couple of years ago to pivot her company from hepatocellular carcinoma to NASH as what she calls a “bet on science.” This statement aligns with Roger’s persistent belief that this study will open the doors for more investment. Jörn and Mazen discuss some of the specific elements of patient screening and population that demonstrate the power of this study. As the session winds down, Roger shares an interesting observation: while the researchers have begun by talking about patients, in an earlier, separate conversation Donna Cryer began by talking about investors. 

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In a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. This first conversation from the series incorporates highlights of our exclusive discussion with Donna Cryer, Founder and CEO of the Global Liver Institute. Donna focuses her initial comments around the MAESTRO-NASH data and the ways it benefits the overall field and demonstrates sustainability for NASH therapy as a whole. She extends her notes to consider the breadth of the Madrigal program and its implications for the full range of patients. Another consideration explores the program’s impact on practical use of NITs in demonstrating value in patient management and to the various stakeholders interested in building integrated systems. As Roger describes, this conversation is “pulling on all threads” of what these results and this energetic moment mean for sustainability in the field. This is a rich dialogue with many more notes and insights on how this story develops our understanding of where the liver fits in both the biological system and what efforts are required to integrate healthcare systems with timely, seamless adoption. 

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NASH-TAG 2023 co-course director Stephen Harrison and scientific advisory board committee member Jörn Schattenberg join Louise Campbell and Roger Green to preview what is shaping to be a highly anticipated conference leading the field into a promising New Year. In light of Madrigal’s announcement of positive topline results from the MAESTRO-NASH trial of resmetirom, the first half of this conversation focuses on Stephen’s assessment of the emerging story. He then provides an overarching walk through of the format and schedule for the event held in Park City, Utah on January 5-7. The group notes there to be a full stack of “wow” presentations embedded in the program in addition to the developing takeaways from Madrigal’s announcement. Jörn looks forward to discourse on what he calls the “next generation of NITs” and Louise highlights an interest in updates on moving pathways forward. Surf on for the full preview and visit the NASH-TAG 2023 website to review this riveting agenda. 

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Yesterday, in a monumental moment in the never-ending pursuit of putting a major dent in Fatty Liver disease, Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH clinical trial of resmetirom for the treatment of NASH and liver fibrosis. Madrigal’s leadership intends to file for resmetirom’s accelerated approval with the FDA in the first half of 2023. If approved, the drug may become the first NASH medication introduced to market, depending on the outcome and timing of Intercept Pharmaceuticals’ refiling of obeticholic acid.

To recognize this special occasion, Surfing the NASH Tsunami hosts its largest ever suite of panelists who react to the enthusiasm, synergy and implications surrounding the news. Alongside regular Surfers Jörn Schattenberg, Louise Campbell and Roger Green are friends of the podcast, Michael Betel, Donna Cryer, Scott Friedman, Kris Kowdley, Mazen Noureddin and Rachel Zayas. This is an unmissable, full house discussion which surveys what is primed to be a momentous breakthrough for the field. Read the Madrigal press release and surf on to hear what is to be a memorable episode.

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In another exciting installment of the Surfing NASH year-end interview series, Jörn Schattenberg, Louise Campbell and Roger Green are joined by Donna Cryer, founder, president and CEO of the Global Liver Institute (GLI). This conversation embodies the progressive and collaborative energy of GLI from the outset, beginning with Donna’s explanation that they now have NASH materials available in sixteen different languages. And while acknowledging the momentous nature of 2022, she points positively and determinedly toward what could be an even more remarkable 2023. The diversity of efforts extending across the GLI network have never been so far-reaching. This array of engagement is exactly why GLI is now making its preparations to capitalize on a flood of opportunities that may arrive with any drug approvals. Looking back at an eventful year, what stands out to Donna are things like being involved in co-authoring a paper for the National Committee for Quality Assurance. Quality measures are especially important as the field develops and implements guidelines and pathways so that patients have meaningful access to treatments.

The conversation continues on the track of what is required in terms of preparedness as Donna also describes de-risking the environment with GLI presence and readiness for investments in liver health to ensure sound, equitable pricing is placed on any approvals. There is the need to adequately characterize and profile patients’ different risk stratification and comorbidity profiles and match the right combination of treatments to them. This idea segues to the importance of screening and the challenge of identifying all those who need treatment that remain undiagnosed. From here, Jörn prompts Donna to discuss illuminating perspectives on quantifying quality of life considerations and how much focus should be allotted to these measures. She suggests both more expanded holistic benefit design and a more diversified workforce will positively contribute to the varying needs of patients at different stages of disease. Roger next leads discussion to consider the dynamism of investment energies that can play a pivotal role in education and driving action toward more preventative liver health solutions. Donna agrees this line of defense continues to develop and impart a positive influence on the space, be it through emerging technology, community-based resources or a combination of both.

There are many more takeaways to be gleaned from this exceptional interview which champions the patient perspective. Donna provides tremendous and directed optimism to this conversation, presaging another impactful year to come for GLI. Surf on to learn more. 

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In this exclusive interview, Hannes Hagström joins Jörn Schattenberg, Louise Campbell and Roger Green to explore papers emerging from Scandinavia which offer fascinating insights to the field at large.

Hannes opens the conversation with his idea that 2022 was an encouraging year for research, specifically in that the mechanisms of drugs in development “feel more realistic.” When asked what he means by realistic, Hannes explains his interpretation of NAFLD to be a public health problem by which the metabolic system is overloaded with nutrients. He suggests a general pathway would aim to reduce this burden, citing examples like GLP-1s and possibilities surrounding an imminent announcement on resmetirom. From here Hannes describes developing a population-based cohort of liver disease patients using relatively accurate registers in Sweden. He highlights that this system enables studies to navigate issues around selection bias and capture the whole of a population with any diagnosed liver disease dating back to the sixties - roughly 350,000 unique patients in Sweden. The data available in this cohort can be linked back to the general population and used to examine several important research considerations. Long-term outcomes of chronic liver diseases, risk factors for disease progression, impact of dispensed drugs, disease panorama and time trends are among examples.

Segueing to several studies utilizing this cohort, Hannes first introduces a paper which examines cardiovascular disease (CVD) risk and life expectancy in patients with NAFLD compared with the general population. While NAFLD was associated with a higher risk of nonfatal CVD, it notably did not affect post-CVD mortality risk. Another conclusion: patients diagnosed with NAFLD have a lower life expectancy than the general population. Strikingly, this loss in life expectancy was accentuated depending on the age of patient at time of diagnosis. The younger in age one has a diagnosis of NAFLD, the more one can expect to have a drop in life expectancy. Hannes suggests this may summon an urgency in screening younger populations. A caveat of this cohort is noted to be the reality of true incidence rates could be higher than what has been captured in diagnosis in specialty care. At this point, Jörn and Louise ask a series of thought-provoking questions which spur Hannnes to describe additional compelling facets of working with this rich data set. Studies can link research cohorts examining biopsies of patients with NAFLD to these registers, allowing for long-term follow-up. Hannes also mentions collaboration with the Swedish Diabetes Register which captures at least 90% of patients with type 2 diabetes. Such granularity enables investigation into the influence of comorbidities on the risk of liver disease. Roger notes a theme of recent guidelines is to assume that diabetic patients have NAFLD, therefore the recommendation is to immediately search for NASH in the evidence of fibrosis. As these databases are pooled, NAFLD can be examined through a diabetes lens or vice versa. The group goes on to briefly discuss elements of screening, guidelines and the influence of NITs on interpreting prevalence. Hannes bridges this discussion to a just-accepted paper whereby his team looked at developing FIB-4 in a more meaningful way through stratifying subgroups within the overarching risk categories. Simply, the three parameters used are age, presence of diabetes and a gamma-glutamyl transferase test. The latter is noted to be useful in linking cardiac outcomes and an imperfect marker for alcohol use. 

As the session winds down, the panelists explore speculative questions around genetics and the microbiome, and any foresight into how these factors could be filtered through the aforementioned registers and databases. In closing, Hannes provides a glimpse at what awaits for his research in 2023. Surf on to find out. 

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In the Season 3 NAFLD Year-in-Review  conversations series, Surfers Jörn Schattenberg, Louise Campbell and Roger Green embark on a string of interviews with a handful of Key Opinion Leaders who made headlines and advances in Fatty Liver disease in 2022. In this exclusive segment, Scott Friedman joins to discuss his perspective on what has been an eye-opening year for liver science.

Scott prefaces this session with the idea that in the absence of an approved drug, the field has responded with an urgency to develop improved pathways and targets. This urgency is coupled with progressive efforts to modify and improve clinical trials and endpoints, and noninvasive markers to make those trials more streamlined and accessible. From here he introduces illuminating findings on genetic variants associated with protection from Fatty Liver disease. An attention-grabbing conclusion: rare germline mutations in the CIDEB gene conferred substantial protection from liver disease. Scott states the implications are twofold. This summons recognition of the power of genetics in uncovering new pathways. This also highlights the complexities of a disease featuring genetic variants that may variably contribute to the likelihood that a patient with obesity develops NASH. He suggests that broadly, the challenge in NASH is sifting through an enormous palette of drivers - be it genetic, derived from the microbiome, or attributable to diabetes and the consequences of metabolic syndrome. All of which influence how we decide to establish and prioritize strategies for the discovery of new therapeutic targets. Reinforcing his recent comment on the podcast that gene therapy has effectively arrived, he notes the speed by which genetic information can translate into real therapies.

Continuing on the theme of scientific advancements, Scott points to papers emerging from the Columbia University lab of Robert Schwabe. The aim of the Schwabe lab is to understand the regulation of wound healing responses to chronic liver injury with a specific focus on how the activation of hepatic stellate cells (HSCs) promotes liver fibrosis and liver carcinogenesis. Scott raises a spate of compelling questions in response to Schwabe’s interrogation and subsequent findings on functions of HSCs, the main source of liver fibroblasts, during hepatocarcinogenesis. He accredits the feasibility of these studies back to the emerging availability of single cell sequencing technologies. Once again, Scott reveals his acceptance that the “devil is in the details,” alluding to the back-and-forth switching capacity of particular cellular functions. By identifying the transcription factor that drives this switching to a protective role, Scott suggests there is potential to enhance the expression of that transcription factor using gene therapy. Whether we can realistically expect to change the behavior of cells in the setting of an injured liver through the manipulation of gene expression is something to look forward to. “The best is yet to come.”

The group breaks into a brief discussion around the stepwise commercial progression and eventual success of Hepatitis C treatment. As the interview winds down, Scott returns to one last paper of interest stemming from his own laboratory and set to be published in the imminent future. The focus of the paper postulates stage-specific therapies as NASH develops. While admittedly “a long way off” from a clinical setting, this project framework injects Scott with invigoration to address possibly the largest unmet need of patients who have or are approaching cirrhosis. Surf on to his upcoming NASH-TAG talk for a more explicit demonstration of this unfolding story. 

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The latter half of December marks the Surfing the NASH Tsunami annual NAFLD Year-in-Review. In Part 1 of this Season 3 finale, Surfers Jörn Schattenberg, Louise Campbell and Roger Green interview Scott Friedman, Hannes Hagström and Donna Cryer to discuss putting a dent in Fatty Liver disease in 2022 and beyond. This episode features compiled excerpts from our respective guest interviews. Each interview in its entirety will debut as this week’s conversations, releasing Friday through Sunday.

Surf on to hear the diverse and powerful perspectives provided by a handful of the field’s Key Opinion Leaders who made headlines and advances in Fatty Liver disease in 2022.