One must keep in mind that the patient population is diabetic, low-HDL, with a recent coronary artery disease event within 90 days of first visit. These are high-risk cardiovascular disease patients, so the occurence of future cardiovascular events is expected! They have a good idea of the expected frequency of 3-point and 5-point MACE events in this population based upon past cardiovascular outcomes trials with similar patient populations. Therefore, cardiovascular events that occur within the expected frequency in this high-risk patient population are not going to trigger a safety concern.

Safety analyses by the DSMB are more concerned with unexpected events. The hypothesis is that apabetalone/RVX-208 is decreasing the time to first occurence of 3-point MACE event. Therefore, one safety criteria is to ensure that the treatement isn't doing the opposite, which would be apabetalone increasing the number of 3-point MACE events relative to placebo. However, based on the Phase 2 studies and other research that has gone into apabetalone, this seems unlikely. Not impossible, but very unlikely.

A more important facet of the continued safety analyses is to ensure that no unexpected, adverse effects are being elicited by long-term treatment with apabetalone. Yes, over 1000 patients have been treated in various clinical trials to date with apabetalone and aside from the transient elevation of liver transaminase enzymes (which seems to occur in only a subset of patients and resolves itself after a few weeks), there haven't been any safety issues to date. However, we are in unchartered territory right now in terms of patients receiving long-term treatment with apabetalone. First patients in BETonMACE were dosed November 2015, so these patients have now been dosed for almost 16 months. Patients in past trials were dosed 6 months max. And most patients in BETonMACE have been dosed for under a year. There is still a concern that adverse effects may pop up with longer term use of apabetalone. So there are still significant safety concerns for chronic apabetalone administration. That being said, with each passing day, each passing month, each DSMB report, the confidence that apabetalone is safe increases. Patients will be dosed for max 2 years. So once we get into Q3/Q4 2017 and those first patients who started dosing in November 2015 complete their 2-year dosing......if we still see no adverse events that concern the DSMB, then we should be able to breath a sigh of relief from a safety standpoint.

But until then, we cannot assume that just because apabetalone was safe for 6 months that it will be safe for 2 years. Take a look at the literature from pan-BET inhibitors in pre-clinical and clinical use. Lots of safety concerns. Apabetalone is not a pan-BET inhibitor, but is a bromodomain-2 selective inhibitor. So we can't assume that the adverse events elicited by pan-BET inhibitors will arise with apabetalone. But from a safety/DSMB standpoint, they are very likely on close watch for these and other potential adverse events. When you are the first bromodomain-selective BET inhibitor in clinical trials and going where no man has gone before, you need to be extra careful and scrutizine for safetey. That is both the burden and the blessing of being a first in class molecule in clinical trials.

As for futility/efficacy........similar to stated above we expect a certain frequency of 3-point MACE events in this population. As long as apabetalone is not increasing the number of events, then the question is: Is apabetalone decreasing the number of MACE events relative to controls, or having no effect. This will be answered by the futility analysis expected to occur in H2 2017.

BearDownAZ