Aureus posted over on Investor Village:

"The link on brd4 and NASH seems provocative to say the least. Footnote 5 I believe it is ,takes you to a publication regarding more interesting information. There appears to be a very large percentage of incidence of NASH in type 2 diabetics; and Metabolic Syndrome sufferers. I think it is highly likely that a majority of BetonMace patients present with NASH at enrollment. ALP is part of routine liver panel monitoring and I cant imagine the DSMB not using this as part on determining Safety during the entire duration of the Trial. Is the Company seeing in the blinded data significant drops in ALP not only in a good percentage of the CKD population but in a good percentage of the entire population which would include lots of NASH patients ? I have no idea , but to be dismissive seems inappropriate to me, and thats just my opinion. ALP is an approvable surrogate marker and resulted in Intercept gaining approval of Ocaliva back in May 2016."

Aureus makes a good point about the incidence of NASH in patients with type 2 diabetes, insulin resistance and metabolic syndrome. NASH has three primary components: fat build up in the liver, immune cell invasion and inflammation, and scarring. Apabetalone has many anti-inflammatory properties that have been shown to reduce the immune cell invasion and inflammatory cascade. There is evidence from primary human hepatocytes that has shown apabetalone to reduce the expression of genes involved in cholesterol and fatty acid synthesis (lipid synthesis). Bromodomain proteins (i.e. BRD4) and some BET inhibitors have been shown to decrease liver fibrosis, which may ameliorate scarring in NASH. The liver is a primary target of apabetalone.  I agree that if one puts the puzzle pieces together, apabetalone sounds like a promising NASH therapeutic worthy of further investigation.

My comments in this Agoracom thread here and here may be interpreted by some as dismissive. However, my point was that there are still a lot of unknowns. So maybe instead of dismissive one can say cautiosuly optimistic. There have been no NASH-targeted pre-clinical or clinical studies announced by Resverlogix for apabetalone and I don't think BETonMACE did any NASH related screening of patients at baseline or during BETonMACE. Yes, ALP was approved as a surrogate marker for other NASH trials. But ALP can come from many tissues depending on the disease. I think we can all agree that if BETonMACE shows that apabetalone significantly lowers ALP in the pre-specified secondary endpoint, similar to what was observed in Phase 2 post-hoc analyses, then this is tremendously encouraging data warranting further follow up for not just CKD but also NASH.

BearDownAZ