This week, NASH Tsunami responds to listeners who have asked “Where are the episodes on drug development?” by asking Stephen Harrison to lead a review of the NASH pipeline.
Stephen starts by noting that the mechanics of the drug development pathway, which we discussed earlier this year in the context of NASH-TAG and strategies on how to shift away from traditional metrics, remain what they have been: same conditional endpoints (fibrosis improvement without worsening NASH or NASH resolution without worsening fibrosis, or improving both) and the same need for biopsy read as is has been. Stephen explains the difference between dual primary endpoints and co-primary endpoints in the context of a recent announcement from Madrigal.
From there, he goes on to list the various drugs and modes of action in different stages of development, starting with the five agents in Phase 3, then working his way back through the Phase 2b studies to discuss some of the more significant or interesting agents earlier in development.
One interesting point Stephen raises is that clinical development for obeticholic acid, the Intercept drug that FDA failed to approve, continues. By now, he notes we have data on over 2,000 patients and a significant number of patients that have been studied for over four years. Jörn Schattenberg registers his excitement at the size of this population and the wealth of data they offer researchers. Throughout this discussion of ongoing research, including not only Intercept but the length of some of the resmetirom studies, Stephen notes that NASH drug development is very much a work in process.
Led by Stephen, the group goes on to consider what our failures to date have taught us about doing drug development better, a phenomenon that Stephen, Jörn and Louise all note makes them hopeful for the future. Stephen specifically notes that drug developers and researchers alike have broadened their ambitions from simply reducing fibrosis and liver fat to being part of a total metabolic solution that includes diabetes, obesity and cardiovascular health along with liver. Before leaving the conversation, Stephen notes the critical need to improvement diversity of clinical trial populations and notes that while it may take some years, he sees the future of patient treatment as lying in combination therapy.
After Stephen leaves, the discussion shifts slightly, with more focus on cirrhosis, the reasons for drug development and increasing optimism that the drug development community is on the right path. Toward the end, the discussion turns to consider quality of life, which if affected negatively by Fatty Liver disease. Jörn notes that it could serve as the third leg of a stool or tripod to pull NASH drugs over the line. Roger suggests the possibility that a lot of antidepressants are being prescribed for patients who would feel better with less fatty livers. On that optimistic note, the group provides final answers about the most striking part of the episode and departs to live another week.
This episode is sponsored by Madrigal Pharmaceuticals. Today’s extra-sode is a summary of Madrigal’s disease-focused presentation at the recent CLDF LiverConnect meeting.