"Would Apabetalone being a first in class drug be more likely or less likely to be required to have a PH4 study? What would be the determining factors that would provoke the need of a Ph4 study?"

Great questions Tada. Apabetalone is the first and only BET inhibitor being tested outside of oncology. Apabetalone is the only BET inhibitor in a Phase 3 trial. No BET inhibitor has been approved by the FDA. Outside of oncology, I don't think any epigentic drug has been approved yet. Apabetalone is leading the way in the clinical development of BET inhibitors. However, this means apabetalone/Resverlogix is navigating in unchartered territory. With that comes the additional burden of proof.

Prior to BETonMACE, the longest any patient had been on apabetalone was ~6 months in the Phase 2 ASSURE/SUSTAIN trials. In BETonMACE, ~1200 patients will have been on apabetalone for up to ~38 months, with the anticipated average dosing period being about 2 years. That is not a lot of patients and not a lot of time relative to other drugs that undergo clinical evaluation for cardiovascular disease. Look at pretty much any other cardiovascular outcomes trial (CVOT) and you'll see that they involve many more patients and run for a lot longer time. Part of this is because the absolute risk and projected relative risk reduction in these other trial is not large relative the testing of apabetalone in low-HDL, recent ACS diabetics in BETonMACE. 

Most drugs (all?) that I can think of in the cardiovascular space usually go through extensive Phase 2/3 testing for modulating a particular risk factor (LDL, glucose, triglyceride, inflammation) prior to completion of a CVOT. Some recent examples are PCSK9 antibodies for LDL-lowering, Vascepa for triglyceride lowering, SGLT2 inhibitors for glucose lowering, GLR-1R agonists for glucose lowering, DPP4 inhibitors for glucose lowering. These were thoroughly evaluated in Phase 3 trials and FDA approved for modulating their respective endpoints (LDL, glucose, triglyceride) prior to completion of the CVOT. So lots of clinical testing in various patient populations that together accrued a large number of patient years and clinical observations.

This history of apabetalone is far from linear and smooth. It is quite uncommon to jump from a failed Phase 2 to a Phase 3 CVOT trial and to change the endpoints/mechanism of action along the way of clinical development. Resverlogix is entirely reliant upon post-hoc analysis of Phase 2 trials for their Phase 3 CVOT justification. Because of this and the other points above, apabetalone should be the poster child of why a Phase 4 trial should be done, assuming BETonMACE succeeds and FDA/EMA approval goes smoothly. Also, diabetic, low-HDL, recent ACS event is a very narrow population. Follow up trials will be necessary in order to expand the marketing to these other patient populations and prove that apabetalone is beneficial outside of the narrow diabetic, low-HDL, recent ACS criteria.

BearDownAZ