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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.