"Bear, it is my understanding that the occurrence of elevated transaminases was relatively rare, and importantly the rare elevated levels were temporary / transient. Yet more importantly there was no detection, at any dose, of bilirubin which would indicate liver injury."

I guess that depends on how you define rare. I've written about the liver transaminase issue before here. There are lots of links in that post to AGM transcripts, the complete ASSURE study document, recent posters showing how apabetalone robustly suppresses FXR in hepatocytes, and some links to papers about FXR. In particular, I recommend folks look at the details on the elevated ALT/AST data from the ASSURE study (see this document).

For the purpose of this discussion, I will copy the following from that prior post:

"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."

Based on the summary above, you are correct that elevated bilirubin, which would be suggestive of liver injury/Hy's law, did not occur along with the elevated transaminases. However, as you can see in the ASSURE study document, 7-8% of patients in ASSURE treated with apabetalone experienced ALT/AST elevations above 3X the upper limit of normals. Among apabetalone patients with any ALT/AST elevation, 7% were above 5X the upper limit of normal. 

From the ASSURE study document:

"Summary of ALT Elevations: In the RVX000222 group, 7.0% (17/243) had ALT elevations >3x ULN; among patients with any ALT elevation, 9.3% (9/97) had elevations >5x ULN and 6.2% (6/97) had elevations >8x ULN. All these liver enzyme elevations began between Weeks 4 and 11."

"Summary of AST Elevations: A smaller proportion of patients in both groups had elevated AST compared to ALT. Approximately 29.2% (71/243) of patients treated with RVX000222 had an AST elevation, compared with 8.8% (7/80) of patients in the placebo group. In the RVX000222 group, 4.1% (10/243) had AST elevations >3x ULN; among patients with any AST elevation, 7.0% (5/71) had elevations >5x ULN and 1.4% (1/71) had elevations >8x ULN. Among patients treated with RVX000222 who had AST elevations >3x ULN but less than 5x ULN, 100.0% (10/10) had AST levels that returned. Study drug discontinuation was not required in any of these cases. AST elevations followed a similar pattern to ALT elevations."

"Per the protocol, study drug was to be interrupted if a patient had ALT or AST >5x ULN at any time. Study drug was to be permanently discontinued if a patient met any of the following criteria: 1) ALT or AST >8x ULN; 2) ALT or AST >5x ULN for more than 2 consecutive weeks; 3) ALT or AST >3x ULN AND bilirubin (total) >2x ULN; 4) ALT or AST >3x ULN with the appearance of worsening fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia (>5%)."

So depending on how you define "rare" this may or may not be an issue. But there were several apabetalone-treated patients in ASSURE that hit the per protocol guidance to discontinue dosing due to the severity of the ALT/AST elevations. Most with ALT/AST elevations either didn't get to the severity that required discontinuation or they returned to normal. However, we should expect some of this to occur in BETonMACE as well.

BearDownAZ