Surfing the MASH Tsunami SurfingNASH.com

In this conversation, Sven Francque and William Alazawi join Jörn Schattenberg, Louise Campbell, and Roger Green to review papers co-authored by Sven in 2023 and Jörn in 2020 to discuss what failure has taught us about future MASH drug development.

00:00:00 - Surf's Up: Season 5 Episode 12
Roger comments briefly on Stephen Harrison's passing and explains why this episode will be more sedate than usual.

00:01:45 - Introduction
Opening comments from panelists.

00:02:28 - Groundbreakers
Each panelist shares one piece of good news from the previous week (NOTE: This was recorded before Stephen's death.)

00:05:10 - Sven Francque on the State of the Graveyard in 2023
Sven starts by noting how different the world is now than when he co-authored this paper in 2023. He goes on to describe three key issues in successful trials that are as relevant now as when the episode was written.

00:10:59 - Efficacy endpoint challenges
The group discusses an array of challenges: that fibrosis regressions is a high bar, that patient heterogeneity presents a dilemma for trial recruitment, and that NAS score presents its own challenges.

00:18:29 - Thinking more broadly about metabolic values
Louise suggests that in addition to stabilizing MASH, endpoints might look at related metabolic diseases that poor liver health can affect. The group considers whether placebo rates can provide guidance and reconsiders the regression and response rate issues, noting the differences between RCT patients and those in usual clinical practice. 

00:28:05 - Lessons from 2020 Graveyard article
Roger asks what we have learned since 2020. Jörn points to improved consistency in reading biopsy results and greater diligence in analyzing pre-clinical data before rushing into larger late-stage trials.

00:31:49 - Implications for metabolic agents on MASH therapies
Roger returns to the issue of complex drug effects, noting a recent tirzepatide Phase 3 trial on dual agonist's effect on obstructive sleep apnea. Louise notes that apnea correlates highly with SLD. Louise and Will discuss the importance of educating more physician specialties about liver health. Will discusses a presentation he made to an academic session on MASH at the Diabetes UK conference the previous week and noted that it was well-attended.

00:36:05 - Looking ahead
Roger asks what insights investors and others might take from this discussion. To Jörn,  (i) we now know how to get a drug approved, and (ii) drugs in development today may be potent enough to overcome issues that challenged earlier agents. Sven adds that in future years, the use of incretin double-agonists and triple-agonists will change the nature of therapy.

00:42:23 - Wrap-up and closing question
Louise asks whether we are thinking broadly enough about older agents in MASH, using a recent study on low-dose aspirin (S5 - E11.) . Jörn and Roger each raise a practical challenge for such a trial. 

After a brief digression, Roger asks his closing question: how will having a drug approved affect the conduct of trials going forward. Answers vary and present a complex picture. you'll have to listen to learn

00:51:45 - Question of the Week
The question asks for the greatest hurdle left to overcome that will improve the percent of MASH agents achieving approval and, separately, speed approval times.

00:52:14 - Back-end report
This report includes Roger's usual weekly comment on Ukraine and Israel, followed by a tribute to Stephen Harrison.

This episode was recorded the day before Stephen Harrison's untimely passing. His influence on this entire podcast was massive. Three years after he ended his co-hosting stint, there are at least two references to his research, insights, or what we called "Stephenisms" during our first anniversary episode.

Earlier in this episode, the panel discusses different prescribing models for MASH drugs, triggered by Roger Green's question about whether MASH prescribing will resemble an oncology model. This conversation, from the EASL Congress 2023 wrap-up episodes, takes a very different view of the relationship between MASH and oncology.

The conversation includes Jörn Schattenberg, Stephen Harrison and Roger Green. The original post has an excellent description:

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.

This final conversation starts by considering prescribing models for other diseases and how they might work here, shifts to discussing the challenges of keeping a patient enrolled in a long-term clinical trial (or even participating in a trial in the first place), and moves on to the final question for the episode. 

The conversation picks up on the FG-21 conversation, particularly how FGF-21 might be prescribed alongside Rezdiffra. Roger Green starts by asking whether and how this prescribing pattern might fit in an "oncology" model, where FGF-21 might be an induction drug and Rezdiffra a maintenance drug. Michael Charlton suggests that benefits from FGF-21s are likely to fade once therapy is discontinued, which would make this model suboptimal.
Jörn Schattenberg raises the issue of keeping patients in the long-term clinical trials necessary to achieve hard outcomes. Jörn advocates keeping his patients in trials but notes that long-term compliance will become increasingly challenging as more therapeutic options become available and the patient may not be improving. Michael suggests we will find similar challenges in recruitment for new trials if patients have to accept the possibility of receiving a placebo. Roger notes that biopsy requirements increase this challenge. 
As the episode winds down, Roger asks participants what they believe are exciting studies likely to come to light over the next three months. Their answers vary. You'll have to listen to learn. 

This conversation sees the end of the "hot topics" discussion, followed by Michael Charlton discussing issues and excitement around the FGF-21 class.

As we begin, Louise Campbell and Jörn Schattenberg speculate on ways to incorporate metrics like the Dietary Inflammation Index into multifactorial care. Michael asks whether alcohol is figured in the index, given its pro-inflammatory nature, and celebrates the fact that we can now evaluate MetALD patients as a group instead of removing them from classical MASH clinical trials. Louise, who raised the issue in the first place, does not know. As she notes, she first found the issue within the last week. One key question for her is how we can use this in 5-10 years when primary care becomes a key player in MASLD and all metabolic diseases. 

Roger Green's hot topic involves "Ask the MD" columns in US newspapers and magazines. He gives "two cheers" for help columns in which MDs recommend that MASH patients  "go to your doctor and ask for an ultrasound."  He asks whether the PCP is the right destination and whether "ultrasound is the test to seek. However, he appreciates that all this brings MASH badly-needed visibility in the public eye. Michael and Louise agree that given how few patients are treated today, any such public acknowledgment is positive.
Michael discusses the emerging excitement around the FGF-21 class. The recent agents from Akero and 89bio are "emerging as highly potent" in terms of PDFF change and transaminase responses. While we need to learn more, he asks how this will fit in with Rezdiffra and, more generally, how long we can give a patient a "potent" growth factor and what will happen if/when the patient needs to discontinue therapy. Jörn and Michael note adherence challenges with this therapy; Roger comments that even with daily oral drugs, adherence can be a challenge.

After Michael Charlton finishes discussing research he finds compelling, Jörn Schattenberg and Louise Campbell each describe one item they have been focusing on recently. 

Michael mentions the recent JAMA publication of a small, randomized controlled trial exploring the use of low-dose aspirin in biopsy-confirmed MASLD patients, which he describes as "a tremendous result." The results suggest benefits in terms of both fat fraction (PDFF) and transaminase levels. Jörn provides more detail about the trial. While the sample size was small, the results were highly promising. There is much to learn here from a larger RCT and also from understanding the biological mechanism better, but the group agrees this is a promising development.

Roger Green asks his fellow Surfers to discuss one item that has attracted their attention in the past week. Jörn Schattenberg goes first and discusses the upcoming Innovations in SLD Think Tank 2024. He expresses excitement that changes in format should yield unique, high-value benefits. Roger notes that Jörn and his co-chair Jeff Lazarus will discuss the think tank's results during the episode posting on May 15. 

Louise mentions her constant pursuit of finding ways to improve prediction with FibroScan.  In doing so, she found a study indicating correlation between the Dietary Inflammation index score and kilopascal level on FibroScan testing. Investigators are exploring the use of this index in an array of non-liver diseases related to metabolic syndrome or chronic kidney disease, but the correlation with kilopascals is fairly clear. Louise would like to see research looking at controlled attenuation parameter, since she can usually "see a fat change faster than a stiffness change." 

Michael Charlton and the Surfers discuss two issues: defining therapeutic futility for Rezdiffra and describing some advances in MASLD translational medicine. 

The conversation starts by continuing the topic of therapeutic futility. Louise Campbell asks Michael how he plans to determine therapeutic futility with Rezdiffra in terms of side effects or efficacy. Michael indicates that he will continue patients on Rezdiffra as long as their disease does not progress. While he would prefer a more robust approach, he describes the scale of challenge in defining futility for a drug where FibroScan and transaminase levels did not provide strong prediction.
Roger Green asks what percentage of patients are taking concomitant GLP-1 therapy. This leads to a brief sideline discussion on levels of therapeutic adherence.
Roger asks Michael what he find exciting in translational medicine these days. Michael cites the LiverRisk score, a developing test he describes as "substantially superior" to other biomarkers. His group is currently working with NHANES data to see whether this is predictive for patients who had transient elastography and met MASH criteria. He particularly wants to determine whether this is a dynamic test. 
Michael goes on to discuss the work his group is doing on the microbiome, where he and others are finding potentially valuable insights. The challenge continues to be how to translate these insights into clinically meaningful interventions.