Coming up at EASD 2018 (European Association for the Study of Diabetes) October 1-5, 2018, Resverlogix will present for the 4th time this year an abstract surrounding the topic of "Apabetalone (RVX-208) an epigenetic modifier lowers risk of MACE in diabetes patients with CVD by affecting monocyte adhesion to endothelial cells." 

What catches my eye in these abstracts is the observation that apabetalone treatment of primary human hepatocytes robustly and rapidly suppressed the mRNA and protein expression of farnesoid X receptor (FXR). Why do I bring this up again? Other than these conference abstracts, Resverlogix hasn't discussed the significance of this FXR observation. One must keep in mind that these observations have been made in isolated primary human hepatocytes, and not in an intact animal/human, so we don't know for sure how liver FXR in an intact human treated with apabetalone is responding.

FXR is a key transcription factor whose endogenous ligands are bile acids:

https://www.ncbi.nlm.nih.gov/pubmed/16037564

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063452/

Now changing subjects to liver enzymes. Back at the 2015 AGM (transcript courtesy of imtesty), Michael Sweeney and Ewelina Kulikowski discussed the documented transient increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elicited by apabetalone. Note: alanine/aspartate aminotransferase is same as alanine/aspartate transaminase. For more detail on the elevated ALT/AST data from the ASSURE study, see this document, the 2015 AGM transcript (linked above), or the 2016 R&D day presention (link no longer available). But just to summarize, the incidence of transaminase elevations >3X upper limit of normal (ULN) in apabetalone treated patients is 7-8% and cases <5x ULN resolved without dose interruption. No cases of Hy’s law is observed (elevated bilirubin >2X ULN coincident with ALT/AST >3X ULN), which would indicate serious hepatic injury. The ALT/AST elevations tend to occur early (within four to six weeks). Additionally, as described in the 2015 AGM transcript, levels of osteopontin, whose levels are linked to MACE and is a marker of liver injury and inflammation, are downregulated by apabetalone. The fact that BETonMACE has cleared 7 DSMB reports to date without recommending any changes and that some patients have been on drug for over 33 months attests to the safety of apabetalone. Additionally, in the 2016 R&D day slides, it stated that Dr. Paul Watkins, former head of the FDA liver injury department joined the BETonMACE DSMB and has implemented the DILIsym program. So from a clinical standpoint, these transiently elevated transaminase elevations don't seem like too much to worry about.

Now to connect FXR and the ALT/AST observations, I share this from the 2015 AGM transcript: 

"We think we’re getting to the bottom of this adverse event. We’ve done a lot of work in the laboratory to investigate this. And we seem to see that there is a change in bile acid metabolism in selected patients, because BET inhibition does change the expression of bile transporters and bile enzymes in selected individuals. So there’s an increase in influx of cholesterol, and a change in bile pathway, and a down regulation, transient. But this down-regulation does not persist for long; there is an adaption within the liver cell, which accounts for why the enzyme levels go away with continued therapy. The net effect is an increase in bile acids in a very small number of patients. And we’re working in the lab to confirm this hypothesis. One of the reasons behind our BETonMACE study, apart from outcomes, is to get a very large safety database, to truly document the incidence and the consequences of these hepatic enzyme increases."

So sounds like apabetalone --> lower liver FXR --> altered hepatic bile acid metabolism --> transient elevation in transaminases during adaptation period --> normalized transaminases after adaptation

Anyone seen anything else put out by Resverlogix that fills in any more gaps here?

BearDownAZ