"Let ask you then, and of course this question is based in financial terminology, Is it possible there is a decling rate of return for the drug? In other words it’s possible the longer period of use may have a much lower efficacy?"

Cardiovascular outcome trials typically dose patients for an average length of time between 2 and 5 years. In general, the higher the CVD risk of the patient population, the shorter duration of the trial. Patients in secondary prevention trials have a greater risk of experiencing a subsequent CV event than do patients in primary prevention trials who have not experienced a prior CV event. The initial few month period after experiencing an acute coronary syndrome event is a period of very high risk for a patient experiencing a subsequent MACE. Check out the ELIXA (https://www.nejm.org/doi/full/10.1056/NEJMoa1509225) and EXAMINE (https://www.nejm.org/doi/full/10.1056/NEJMoa1305889) trials, which we've talked about exhaustively on this board, as examples of risk in diabetic patients with recent ACS event. ELIXA and EXAMINE failed to reduce MACE. Any drug (on top of current standard of care) that can lower MACE rate in recent ACS diabetic patients is going to be a huge accomplishment. Don't overlook that. Additionally, diabetics and low-HDL patients are at higher risk of CV events than non-diabetics and normal HDL patients. Put it all together and I hope you appreciate that the low-HDL, diabetic patients with an ACS event within 7-90 days in BETonMACE are a super-high risk population that are at high risk for experiencing not only one MACE event during the BETonMACE trial but 2 or more MACE events during BETonMACE. Declining rate of return? You are missing the point.  Total event (not just first) is becoming very important. Look at this EXAMINE trial total event analysis (https://onlinelibrary.wiley.com/doi/full/10.1002/clc.22960) and the recent REDUCE-IT total event analysis (https://www.ncbi.nlm.nih.gov/pubmed/30898607).

"Was there any animal model testing completed over longer periods of time that has given the company some idea of efficacy long term?"

The longest animal studies for apabetalone (RVX-208) that I know of are:

1) Treatment of apoE mice for 14 weeks (https://www.ncbi.nlm.nih.gov/pubmed/25016363)

2) Treatment of African Green Monkeys for 63 days (https://www.ncbi.nlm.nih.gov/pubmed/20513599)

Human Phase 2 trials (ASSERT, SUSTAIN, ASSURE) have all met or exceeded the duration of these animal studies. Therefore, past animal studies are irrelevant at this point in determining long term efficacy in humans.

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