Maybe we could just start a bit with your practice background, your research split and your clinical involvement, clinical study involvement you have currently.

Can you discuss current NASH clinical treatment paradigm as you see it, what therapies and lifestyle modifications are recommended, in what order, and what remaining unmet needs you primarily see.

Great, maybe, let’s get the elephant out of the room early, what are your thoughts on the data we’ve seen on tirzepatide so far, it does seem like the additional weight loss observed there is impressive. 

What were your thoughts on the failed phase 2 for semaglutide back in the summer? It was shocking how bad the data was, do you think the F4 stage of the patients or 29% placebo rate had anything to do with it?

Has that affected your enthusiasm at all for GIP/GLP dual agonist approach, whether on cirrhotic patients or not?

Moving onto the Madrigal drug, on a high level, what are your thoughts about the mechanism of resmetirom? Clearly it’s defatting the liver, improving liver enzymes, and helping with metabolic syndrome

Discussing the MAESTRO-NASH trial. They’ve split the co-primary between NASH resolution and fibrosis, patients have fibrosis stage 1b, 2 or 3. I guess, just from your perspective, let’s say they hit on resolution but not on fibrosis, how would that affect your enthusiasm for the drug? Assuming it was approved, would you still use it? 

What are your thoughts on the fibrosis endpoint? Do you think 52 weeks is enough time to show a benefit?

Another concern I had is with the ballooning definition, there was a recent paper using HistoIndex (Dr. Brunt), which is an AI histology company. There was a substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, so it might be too subjective to be used unequivocally as an endpoint.  And I guess there is also intrinsic variability in the biopsy sample. What are your thoughts on that? 

Regardless of how the biopsy data reads out, we are still going to be waiting on the 54 month composite clinical outcome endpoint. Obviously this is still very far out, but I’m wondering what degree of confidence you have that there would be a positive outcomes benefit, and over what period of time you think you would need before the curves begin to separate meaningfully. 

Madrigal also initiated the MAESRO-NASH Outcomes study in August, 700 patients with early Nash cirrhosis, monitoring for progression to liver decompensation events. What are your thoughts on the odds of a positive study, given the level of disease in these patients?

If you had to, what % probability would you assign that both primary endpoints are hit for MAESTRO-NASH?

What are your thoughts on FXR agonism? Even if Ocaliva does get the approval in NASH, do you think this is a drug that would be used much, or is the pruritus just too much of an issue?

Are you familiar with the data Akero released on their FGF21 analogue? The data read positive , but there was significant dropouts in the treatment arms. If you used ITT it seems like this would have missed on stat sig, and of course the BMY FGF21 failed their mid stage trial last year. 

Are there any other mechanisms I haven't discussed that you think are interesting for therapies in NASH?

Overall, can you rate your enthusiasm out of 10 for the various mechanisms, including GIP/GLP, THR-Beta, FXR, and FGF21? And can you provide high level comments on potential for combination use?