Surfing the MASH Tsunami SurfingNASH.com

One theme in this week's episode involves different ways to use NITs in drug development and assessing the value of older drugs in MASH. This conversation, from our review of last September's FDA workshop on NITs, considers two additional roles that NITs might play in drug development.

The conversation includes Jörn Schattenberg, Louise Campbell, Roger Green, and guest Laurent Castera. The original post has an excellent description:

This conversation begins with a discussion of a point from a previous episode in 2022 about the difference between NITs to qualify patients for trials versus to evaluate the efficacy of drugs. This point stems from the idea that the way disease regresses may not be the same way it progresses. Laurent notes that NIMBLE and LITMUS have demonstrated important results with large data over the last two years. Jörn comments on the limits of using transaminase as a key NIT and Laurent replies by discussing a study over time that shows faster early declines on liver stiffness and slow declines over time as therapy might shift from reducing inflammation to regressing fibrosis. Louise shifts focus to ask about the relationship between kilopascal drops related to lifestyle change, specifically to ask whether these are false positives or real effects. Laurent notes that BMI is a confounder for liver stiffness and that CAP might help assess this issue. Finally, in response to a question from Louise, Laurent answers that we do not know about some of the key changes in test scores, and need to know more.

Plenty more ideas are explored as this is both a fascinating and pivotal workshop which covers a range of topics on NITs with presentations by the some of the field's most innovative and knowledgable contributors. If you have questions or comments around the workshop, NITs, drug development or any other themes addressed in this episode, we kindly ask that you submit reviews wherever you download the discourse.

This wrap-up conversation about MASH Drug Development covers two issues: combination therapies with old drugs and using NITs to speed and smooth the path to approval.

Louise Campbell starts this final conversation by asking whether we are paying sufficient attention to old drugs that might have value in MASH. She points to a recent study demonstrating that low-dose aspirin significantly affects liver fat and suggests that we are not thinking broadly enough about use of older agents in MASH. Jörn Schattenberg comments that without robust NITs, it will be difficult to prove these effects, particularly, as Roger Green adds, for a drug that will not produce sufficient revenue for BioPharma to conduct a larger trial.

After a brief digression over whether we know how to shorten the time to drug approvals (short answer: not until we have better approaches to using NITs), 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

This conversation starts by focusing on the impact of concomitant metabolic therapies in MASH drug development and patient treatment and then moves on to explore some major implications of the earlier conversations. 

Roger Green begins this conversation by returning to the issue of metabolic drugs. Specifically, he mentions a recent tirzepatide Phase 3 trial that demonstrated efficacy against symptoms of obstructive sleep apnea. Louise Campbell points out that sleep apnea correlates highly with SLD as well as obesity. She suggests this is one more point proving that we need to educate more physician specialties on liver health and educate them more effectively. Will Alazawi agrees with Louise's comment, citing a talk he and a colleague gave at the Diabetes UK conference the previous week that was part of an academic session on liver disease, noting that the session itself was well-attended. Will emphasizes applauding Diabetes UK for arranging and promoting this kind of multidisciplinary academic session of MASLD and MASH.
 
Roger shifts focus by asking what insights investors or other professionals who listen to the episode should take from this discussion. Jörn Schattenberg starts with the most important point: we now know how to get a drug approved. Considering other drugs in development, he adds that the drugs we are studying now may be potent enough to overcome issues that challenged earlier agents. Sven Francque adds that in future years, prior use of incretin double-agonists and triple-agonists will change the nature of the MASH patient population and make drugs like Rezdiffra that have liver-specific modes of action more important and valuable.
   

This conversation includes two sections: one optimizing efficacy endpoints to reflect clinical practice and a second looking back at what has improved in MASH drug development since 2020.

The first part of this discussion explores the idea that MASH drug development should reflect the clinical use of the target drug. Sven Francque starts by discussing how much larger the drug effect for Rezdiffra looks if we add lack of fibrosis progression to regression in creating the efficacy endpoint. Will Alazawi agrees but notes that the level of other metabolic diseases will also have an impact on how to assess a drug’s performance and that we do not adequately control for this in trials today. Jörn Schattenberg and Will discuss the value and meaning of stabilizing Type 2 diabetes in relevant patients.  
Sven points out that the purpose of a clinical trial is different than the goal of clinical practice. Will agrees but wonders whether this might be a reason that some trials fail.
Roger Green shifts the focus of the conversation by asking Jörn Schattenberg what we have learned since the article he co-authored in 2020. Jörn points to two specific areas where the field has improved: greater consistency in reading biopsy results, and a tendency back then to rush agents into clinical trials without sufficient consideration of pre-trial data and even complex Phase 1 or 2a results. Will notes that trials that reported in 2020 were designed in the early or mid-10s, which means they could not take advantage of the innovations described in the 2020 paper. He goes on to point out that the failed trials produced data that provided the foundation for analyses from consortia and other groups. Sven commends the companies that produced this data for "digging deep" into results to find insights.

In this conversation, the panel discusses challenges in MASH Drug Development that are centered around efficacy endpoints and NAS scoring.

This conversation starts with Will Alazawi suggesting that the MASH clinical trial field suffers from the previous experience with Hepatitis C, where medications became capable of eradicating disease in a fairly linear fashion. He suggests that MASH trials undervalue the value of simply preventing progression, which leads Sven Francque to note that preventing progression to cirrhosis is now accepted by regulators as an endpoint. 
Roger Green refers to last week's episode (S5 – E11), in which Michael Charlton said he would continue Rezdiffra therapy for any patient exhibiting a lack of progression, and that a clinically valuable efficacy measure must be applicable to true clinical practice. Roger goes on to recall Sven’s earlier comment that having the NAS score as a co-endpoint complicates the challenge of proving efficacy because the scale is relatively blunt and not well suited to the task at hand. He suggests that an activity score focused on inflammation and ballooning might function better than one including steatosis. Jörn Schattenberg suggests that this depends on the drug's Mode of Action. 
Sven reminds the group that Stephen Harrison presented a paper at AASLD suggesting the approach Sven describes: splitting NAS into separate steatosis and activity scores, with the activity score based on lobular inflammation and ballooning. Roger asks whether the widely reported challenges in coding ballooning will render this method less valuable. Sven says it might, and states the challenge stems from the lack of detail in the scoring system. 
Louise Campbell suggests that in addition to stabilizing MASH, endpoints might look at related metabolic diseases that poor liver health can affect. Will agrees, noting that many patients may be on other metabolic agents at the outset of a trial or, more challenging, the definition of "good practice" might change during the trial, which can add variability to the sample. He wonders whether differences in placebo rates can provide insight on this issue. Roger recalls a comment from Dean Tai of HistoIndex (S4 - E50.4) that some HistoIndex AI-driven analyses produce consistent placebo rates of ~33%, with efficacy rates far higher.
 

In this initial conversation, Sven Francque shares some of the key messages from the MASH Drug Development graveyard paper he co-authored in 2023. Jörn Schattenberg and Will Alazawi comment.

This conversation explores key points from Learnings from the Graveyard of Phase 2 and 3 Nonalcoholic Steatohepatitis Trials, which Sven Francque co-authored in 2023 with Aleksander Krag and Mazen Noureddin on lessons from recent clinical trial failures and the reasons to be more hopeful about the future. Sven starts by noting how different the world is now than when he co-authored this paper in 2023, and the reason why: we now have an approved drug.  He goes on to describe three key issues the paper discussed that are still relevant: regression of fibrosis is a "high bar" for efficacy; researchers and trial sites cannot optimize heterogeneous patient samples to create samples that are more rigorously stratified, and the complexity of physiology leaves some attractive modes of action insufficiently efficacious.

Jörn Schattenberg goes back to the first issue: regressing fibrosis vs. simply stopping progression. He comments that if the challenge is to stop progression, the researcher needs to manage the trial and control groups. If the control group has disease that is too stable, the test group will likely fail to differentiate, but if the test group progresses too rapidly, it might not perform well enough. Sven agrees on the opportunity and the challenge if patients’ disease is too active.

As the conversation ends, Will Alazawi uses the metaphor of the hamburger to describe how finely balanced this kind of patient recruitment and assignment must be. The punchline: you need to hold the hamburger tight enough, but not too tight.