S5 - E20 - Lessons From EASL Congress 2024: Exciting Advances in Drug Development

Surfing the MASH Tsunami

00:00:00 Surf's Up, Season 5 Episode 20
Naim Alkhouri and Mazen Noureddin join co-hosts Jörn Schattenberg and Roger Green to discuss major drug development stories from the EASL Congress 2024. They pay tribute to Stephen Harrison and proceed to groundbreakers.
00:08:16 - Presentations on Resmetirom
Mazen shares a paper he presented looking at resmetirom dose-response. The 100mg dose performed better than the 80mg dose. Jörn notes that the most important element of the study might be the demonstrated 36-month effect.
00:14:19- Implications of Different Analytical Modes
Naim compares different modes of analysis. Intent to Treat, which treats all non-completers as failures, will produce lower rates of response than a "completer" or "modified Intent to Treat" analysis, which either eliminates non-completers or assigns them placebo-level response.
00:16:12 - The "Twin-Cretins"
Jörn coined the name "Twin-cretins" for agents with GLP-1 agonism plus another incretin effect. Tirzepatide is a GLP/GIP while survodutide, pemvuditide, and efinopegdutide, are GLP/glucagons. Naim reviews the tirzepatide late-breaker presentation, which showed high rates of MASH resolution, but, as a completer analysis, might not have proven whether a GLP/GIP can achieve significant fibrosis regression. Naim notes that Stephen doubted strongly this was possible, but that bariatric surgery's effect creates a paradox. Mazen concurs, and states he is more confident in the GLP/glucagon agents. Jörn agrees.
00:23:09 - Implications of widespread GLP use
Roger asks how widespread prior patient use of incretins will affect prescribing. Naim states that many of his Rezdiffra MASH patients have been on GLP-1 already. He describes a key difference between the three GLP/glucagon agents in development.
00:24:20 - The previous GLP/glucagon studies
Naim expresses his excitement about glucagon agents in general. He mentions that the efinopegdutide study included a semaglutide cell, which showed a further reduction in liver fat compared to the GLP-1 agent.
00:26:44 - Safety of survodutide in cirrhosis
Jörn comments on the high level of tolerability in the survodutide trials. Mazen shares his high hopes for GLP/glucagons and the triple agents. He reviews survodutide data from the NEJM article.
00:29:41 - FGF-21s, starting with efrux data
Focus shifts to FGF-21s. Mazen shares data from the efruxifermin late-breaker, a 96-week, triple biopsy study showing dramatic, sustained one- and two-level fibrosis improvement. Jörn notes the design demonstrates durability, which Roger finds particularly encouraging given the pegbelfermin experience. Naim adds that a sustainable two-stage drop in fibrosis might position FGF-21 as induction therapy before long-term oral maintenance.
00:35:28 - Is a drug-based MASH "cure" possible?
Mazen wonders whether sustained FGF-21 efficacy might return livers to their "normal" state, almost like a "cure." Jörn briefly discusses pegozafermin, and Mazen notes that a third FGF-21 is in development.
00:42:22 - Wrap-up
The panel covers three other agents: the FASN inhibitor, denifenstat, Ionis's DGAT-2 antisense inhibitor, ION224, and Takeda's TAK-227, a TG2 inhibitor, plus the results of SPECIAL, a study evaluating the effect of bariatric surgery on people with cirrhosis. After these, Roger asks Mazen and Jörn what they consider likely to be the biggest story at AASLD in November.
00:53:03 - Question of the Week
Given this discussion, Roger asks what are likely to be the three most prescribed medications for MASH five years from now.
00:53:36 - Business Report
The next EASL Congress review episodes, how to attend recording sessions live, and a vault discussion from last year's EASL Congress wrap-up.