S5 - E26.2 - Looking Back at #TLM2024 - Patient Genotyping and MASH Clusters

Surfing the MASH Tsunami

In this episode, Naim Alkhouri, Mike Betel, Michelle Long and Jeff McIntyre join Jörn Schattenberg and Roger Green to look back at The Liver Meeting 2024. This conversation considers how the anticipated approval of a second MASH drug without biopsy might affect clinical trials and discusses two recent publications on patient genotyping and patient clusters.
The conversation starts with Roger asking the group whether the presence of two approved MASH medications that do not require biopsy will make recruiting clinical trials that require them more challenging. The group doubts this will not add a significant new challenge to already-challenging trial recruitment. Naim comments that while this is a concern, it is already factored into trial schedules and that, given the number of patients available for trial, this should be highly manageable. Michelle discusses the importance of risk stratification in overall trial enrollment and this issue. Jeff and Mike agree that while this is a concern, it is part of a broader concern about the use of biopsy and should not in itself be a primary focus in terms of trial design at this point in time.
Naim introduces two other topics he considers worthy of consideration: the impact of synergy between resmetirom and GLP-1 agonists and the importance of different genetic polymorphisms in predicting the impact of drugs on specific patients. On synergy, he comments that MAESTRO-NASH data suggests that the presence of a GLP-1 does not affect the impact of resmetirom on fibrosis level. On the second point, he notes that several papers looked at major genotypes like PNPLA3 and HD17N13 and specifically cites a late-breaker from Arun Sanyal indicating that g-allele status may impact MASH independent of weight or insulin. Michelle mentions a recent paper in Nature identifying distinct clusters of patients based on how their SLDs progress over time, with a two-cluster solution indicating patients with concomitant diabetes and obesity vs. those without these two concomitant diseases. Roger shares a key point from each paper on treatment in the US. Data in the PNPLA3 paper might suggest that the course of disease in Hispanics, who have high levels of g-allele abnormalities, might be different from other ethnic groups with far lower abnormality rates. He also notes that the faster disease progression in the non-metabolic cluster highlights the importance of learning more about Lean MASH and how to treat it, since faster progression of disease suggests later diagnosis and higher morbidity, mortality and treatment costs levels.