Surfing the MASH Tsunami

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Roger Green starts this interview with Jeff Lazarus by asking what Jeff has been focusing on since the Barcelona conference in May.

Jeff describes his extensive daily efforts to develop and garner support for a global consensus strategy on COVID-19, similar to his work on a global consensus statement on Fatty Liver disease. (This was the topic of Season 2, Episode 59.) Like the Fatty Liver work, his COVID-19 consensus work included representatives from over 200 countries with an array of public, academic and not-for-profit portfolios. However, he suggests that the high levels of agreement and, sometimes, virtually unanimity evident in the Fatty Liver work was impossible to match on an issue as immediate and terrifying as COVID-19.

Roger then asks about the NAFLD Nomenclature Conference. Jeff describes the conference as a midway point for a Delphi process to explore the prospect of assigning a new name(s) in the description of fatty liver diseases. Jeff describes the six principles any name change must achieve:

• Affirmative
• Accurate 
• Adaptable 
• Adoptable 
• Applicable 
• Able.

The rest of this conversation covers prospects for success of the Nomenclature effort and the nature of the challenges ahead.

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The group concludes the preview of the upcoming Paris NASH conference after taking a thorough look at the diversity of topics in Session 5. Roger Green poses the closing question: What insights or energy would you like to see come out of this event? What is the immediate response, and what’s going to stick after 3 to 5 years?

Jörn Schattenberg indicates his interest in the future of drug development and what implications this meeting will have on it. In a more immediate sense, he notes an interest in the more recent learnings of disease biology covered in Scott Friedman’s basic science sessions.

Louise Campbell anticipates an immediate integrated response as a result from this meeting. She suggests a joint meeting between specialists to tease out the implications of liver health in a holistic outcome. “We don't try and repair a car without opening the bonnet to look at the engine - but we're trying to solve diabetes, cardiovascular disease and all of the other linked metabolic diseases without taking the lid off the liver.”

Rachel Zayas looks for a joint response across specialities to activate steps to break down thinking in terms of “organ silos.”

Roger provides his final thoughts by way of a double entendre on the word “global.”. Global refers to how widely NAFLD-associated challenges vary in different parts of the world, but it also refers to the liver as part of a holistic web of non-communicable metabolic diseases. He concludes, “We need to understand how we're going to address this in different parts of the world, but as the challenges vary, we also need to understand how we're going to address the whole body in the context of the liver.”

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This conversation picks up focusing on the program’s opening session: Epidemiology and Public Health. Roger, Louise and Jörn begin to unpack the field of NASH in terms of adopting a holistic, metabolic approach. Roger asks, “How much of NASH are we thinking about in a holistic metabolic sense versus how much do we pay lip service to that, but really focus on the liver?”

In response, Rachel poses a strong question for the surfers. “What do you hope to get out of this session with an integrated approach between specialties? And how is that going to move the field forward?” Jörn takes the first shot. He suggests that data and insights might point the field toward pathway refinement and help identify where patients are lost on this journey. Louise agrees, noting one specific point of challenge: liver patients frequently present too late in the journey.

Next, Roger offers his take. “One of the problems the liver has always had is that nobody knows how to measure fatty liver disease.” How will the field move forward? He suggests the way to appreciate the importance of fatty liver disease is to demonstrate how many metabolic diseases and deaths it contributes to, using direct links. “If anybody can provide data that says, if you see this in the heart, the kidney, wherever, that's likely to be a liver issue or more likely to be a liver issue.” From here, the field can start to broaden the context of liver health in a more holistic sense.

Rachel then provides her answer. She is looking for strategies to link fatty liver with cardiovascular disease. Suggesting the establishment of if, then statements, Rachel looks to elucidate what actionable results can be taken with those links.

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In this conversation, Roger Green, Louise Campbell, Jörn Schattenberg and Rachel Zayas share their particular interests in what’s to come from the 6 sessions hosted at this year’s Paris NASH Meeting.

Rachel identifies a presentation in Session 2: Clinical Aspects, titled Controversy: are HIV infected patients more at risk of NASH? She notes the specific challenges faced by HIV patients and shares her hope the prompt leads to speculation on how to improve patient stratification. Rachel also brings forth a concept of moving beyond ideas of personalized medicine to what she describes as a more “intentional approach.”
Staying in Session 2, Jörn draws anticipation toward a talk by Cyrielle Caussy titled, Type 2 diabetes sub-populations with varying outcome profiles. He is curious to learn something about which type two diabetes patients are more severely liver diseased. Jörn also mentions an interest in the last remaining presentation in Session 2, with Kris Kowdley discussing the natural history and clinical outcomes in adults with NAFLD - lessons from cohort studies and placebo arms of trials.

Next, Louise calls attention to the opening session and her interest in the integration of the liver under cardiometabolic health. This topic will be presented by Faiez Zannad. Additionally, Louise mentions NASH PASS. In Session 5, Marcus Hompesch discusses three years of data & experiences on a metabolic disease focused patient registry and biobank supporting biomarker and drug development research.
Also in Session 5, Frank Anania of the FDA presents on a subject recently explored in last week’s episode 43: How to approach combination therapies for NASH. Following, Roy Sabo discusses response adaptive trial design to pick the best dose. This piques Roger’s interest.

The tone of this conversation conveys a sense of excitement about what this meeting will bring.

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The 8th Paris NASH Meeting takes place on September 8th & 9th, where key opinion leaders from both sides of the Atlantic come together to present pivotal learnings and host exciting discussions on fatty liver diseases. Surfers Roger Green, Louise Campbell, and Jörn Schattenberg are joined by Rachel Zayas to discuss this year’s program and provide preview commentary on talks and sessions of interest.

Roger opens the floor by asking everyone to highlight what specifically stands out to them on the program to look forward to. “Brave one go first.”

Rachel notes a presentation in Session 2: Clinical Aspects, titled Controversy: are HIV infected patients more at risk of NASH? Emerging data and insights will be discussed as to why the prevalence of NAFLD, NASH and subsequently fibrosis present higher in HIV-infected patients in comparison to the general population. Rachel hopes the prompt leads to speculation on how to improve patient stratification. She suggests the field is moving beyond ideas of personalized medicine to what is described as a more intentional approach. Jörn echoes Rachel’s interest in this topic. There is the need to address not only individuals, but also a group of overlooked patients that call for an intentional and stratified investigation into potentially shared biomarkers. Session 2 also features a discussion on type 2 diabetes sub-populations with varying outcome profiles, solidifying the Clinical Aspects leg as a ‘can’t miss’ for the whole group.

Next, Louise calls attention to the opening session and her interest in the integration of the liver under cardiometabolic health. “That's where we're going to find the breadth and depth of patients for future NASH studies.” She asserts that a larger recruitment to clinical trials will be required in the next 3 to 5 years to move the field forward.

Roger relates the relevance of last week’s episode on finding the right combinations for NASH therapy. Friday afternoon features a look into the current status and future directions in NIT-based drug development and clinical management of NASH.

The conversation shifts to comparative outcomes of the Barcelona meeting and its focus on pathways before transitioning into part 2 of this episode: a one on one interview with Prof. Jeff Lazarus. Much of Jeff’s summer was spent working in preparation for the impact COVID will have on the northern hemisphere this autumn. However, he also managed to attend the NAFLD Nomenclature Conference in Chicago. The conference is described as a midway point for a Delphi process that explores the prospect of assigning a new name(s) in the description of fatty liver diseases. What was determined is that should a name change occur, it needs to be organized through global consensus and consistent with the following 6 principles:

• Affirmative
• Accurate
• Adaptable
• Adoptable
• Applicable
• Able

Roger believes that the meeting was successful at strengthening consensus on this topic. He then asks Jeff to describe his role in the NAFLD Summit and to mention any other presentations of interest outside of his own. Jeff shares that he will be talking about evolving models of care and future implications. Specifically, he is also interested in attending discussions and panels around the impact of NITs in addition to the topic of personalized medicine. Likewise, Roger expresses an interest in emerging technologies before offering a final question - or, rather, a request for commitment. Will Jeff return to the podcast to disclose what occurred at the Wilton Park meeting this October? It seems he might, after a few weeks digestion. Stay tuned, stay safe and surf on.

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This conversation from The Vault - Season 3, Episode 25.3 is part of a broader overview of NASH drug development in 2022, led by Stephen Harrison and Jörn Schattenberg. It starts with Louise Campbell asking whether design and management of the ongoing trials will provide sufficient granularity on matching patient types to medications or drug classes. Stephen Harrison notes that we have not paid sufficient attention to this issue historically. In fact, he notes a range of key variables we do not explore at baseline: genotype disease markers like PNPLA3, microbiome and non-Caucasian population segments, to name three. He also notes that some promising drugs have been killed because of trial design issues. In the end, he returns to core positive concepts: combination therapies, looking for agents with multiple positive metabolic effects and safety.

At this point in the conversation, Stephen’s transmission starts to fail. Eventually, he leaves the conversation and focus shifts to cirrhosis.

This episode from the Vault is sponsored by Madrigal Pharmaceuticals. 

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The group investigates potential for different combination packages, beginning with Roger’s suggestion for an oral semaglutide. Naim notes that there are other combination trials in the works that may provide more insight.

The episode then wraps up with Roger’s final question: in seven years, what percentage of patients being treated for NASH fibrosis, non-cirrhotic then cirrhotic, will be treated using combination therapies? Naim thinks the majority of patients with NASH cirrhosis will be on combination therapy, and the majority of patients with F2 or F1 fibrosis will be on monotherapy. He also thinks F3 will see a trend of adding more agents over time to prevent progression to cirrhosis. Mazen suggests in seven years we will not get to combo for NASH patients because of regulation, partnership, and logistics. Louise settles for a position between Naim and Mazen. Jörn highlights that many hurdles remain, especially in identifying these patients. Roger agrees that these diagnostics will be hard to scale over the next seven years. He also imagines there to be less combination packages and more step therapy.

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This conversation begins with a broader look at the strategies behind developing combination agents and the role these combination therapies will play in what Mazen Noureddin describes as the coming “combo-combo” world.

The group agrees that 2 or 3 agents are the most they can see in a combination therapy at this time. They all agree that some patients will require combination therapies while others will succeed with monotherapies. This will be linked with disease severity. Naim Alkhouri  shares another long term study he is working on.

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The discussion shifts to the challenges behind collaborating in a field that, as Naim puts it, “no one has figured out what to do with.” Mazen calls on the “larger companies” to work with the smaller ones to make these studies more common, noting that the economics and risk profiles of smaller companies require them to focus on getting a single drug to market as quickly as possible. Naim notes that precedent has taken form in Hepatitis C. It was very difficult to treat and different companies’ drugs were combined for a while until each company figured out their own combination and that collaboration stopped.

A debate next emerges when Naim describes LEGEND, a trial combining the promising PPAR agonist with the SGLT-2 agent, empagliflozin. Naim describes empa as an excellent agent to counteract potential weight gain with lani. Mazen shares his belief that the trial should have combined lani with a drug that provides greater weight loss, possibly a GLP-1 agonist or dual agonist. Roger suggests it depends on the target: liver and metabolic disease targeting might lead to a PPAR/GLP-1 combination, while a more holistic look at metabolic outcomes might prefer SGLT-2s for their proven beneficial effects on kidney and cardiovascular diseases.

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Naim opens this conversation with his hope for finding eventual combination therapies that begin to realize a cure for NASH in some patients. In particular, he is encouraged to see so many patients achieve greater than 30% relative fat reduction in such a short study. Louise notes that the ability to show patients “real-world results” quickly will motivate them to maintain therapy and lifestyle modification.

The discussion shifts to the inclusion of NITs in these combination therapies, and the need for sound pricing strategies. Naim proposes a 6-month “futility” standard: if the drug does not provide results in 6 months, discontinue. Roger notes the importance of combination therapy in a disease that has so many theoretical target points and pathways within the liver.