As we all should know, apabetalone is known to cause alanine aminotransferase (ALT) elevation in some patients; mostly mild and transient. Here is a post from last year on this subject. The recent BETonMACE rational and design paper summarized these ALT observations from Phase 2 trials.

"Among 556 patients randomized to apabetalone, alanine aminotransferase (ALT) elevation to more than 3 times upper limit of normal was observed in approximately 8%, compared with none of the 242 patients receiving placebo. ALT elevation usually occurred between 4 and 12 weeks of exposure to apabetalone, with rapid normalization to baseline levels either with ongoing treatment (when maximum transaminase elevation was <5 times upper limit of normal) or upon cessation of treatment (when maximum ALT level was >8 times upper limit of normal), as specified in the study protocols."

The paper also very clearly described how patient ALT and bilirubin elevations will be dealt with in BETonMACE. Figure 3 doesn't really contain anything that the text below doesn't cover. 

"Because of the increased incidence of transaminase elevations with apabetalone in Phase 2 studies, frequent monitoring of liver safety was specified in the BETonMACE protocol. Liver function testing was performed at each follow-up visit, with the safety algorithm shown in Figure 3. If any measurement of ALT was elevated to more than 3 times the upper limit of normal (ULN) or total bilirubin was elevated to more than 2 times ULN, repeat testing was performed every 3-4 days until ALT was less than 1.5 times ULN or bilirubin was within normal limits, respectively. During repeat testing, study medication was continued if ALT was elevated to levels up to 5 times ULN, with suspension for any measurement of ALT more than 5 times ULN or total bilirubin more than 2 times ULN. If a second measurement of ALT was greater than 5 times ULN or a second measurement of bilirubin was greater than 2 times ULN, study medication was permanently discontinued. If study medication had been suspended due to ALT elevation that has a likely cause other than study medication, it could be resumed at 50 mg twice daily once ALT had returned to less than 1.5 times ULN and resumption had been approved by the medical monitors and sponsor. After resumption, additional liver function testing was performed according to the original study schedule. Suspension or continuation of statin therapy following ALT elevation was at the investigators’ discretion according to normal clinical practice."

One last tidbit from the paper regarding BETonMACE: "The overall screen failure rate was 38% and 5% of screened subjects failed due to abnormal liver enzymes or bilirubin."

BearDownAZ