Great posts Sidebar and Paladin. Paladin wrote "To be honest I do still have some concerns whether the positive outcomes of BoM can be replicated on a larger scale in BoM2, however I think the risk of that happening is now significantly less than was the case when we moved from Ph2 to Ph3."

I feel the same Paladin. There is definitely some concern of BoM2 replicating original BoM. However, these concerns are minor compared to the unknowns when moving from Phase 2 to original Phase 3 BETonMACE.

1) Endpoints. The justification for original Phase 3 BETonMACE was based upon post-hoc analyais of 5-point MACE is Phase 2 ASSURE, SUSTAIN, ASSERT trials. As I pointed out in the past (see here), these MACE events were primarily "soft" events: 1) coronary revascularization; or 2) hospitalization for unstable angina or heart failure. There were very few of the "hard" MACE in the Phase 2 post-hoc (cardiovascular death, non-fatal MI, non-fatal stroke), which were the endpoints of BETonMACE. So in BETonMACE they were somewhat flying blind and hoping that the effects seen in Phase 2 "soft" events translated to "hard" events in BETonMACE. BETonMACE2 will be informed by more solid data, based on more relevant actual endpoints in BETonMACE.

2) Heart failure. Fast forward to present and we know that apabetalone had no effect on stroke in BETonMACE (slide deck here), but did have effects on CVD death and non-fatal MI (about 20% RRR for each) in the total BETonMACE population. Furthermore, it turns out that one of those "soft" events that was screaming out as relevant in Phase 2 post-hocs showed incredible (>40% RRR) replication in BETonMACE: hospitalization for heart failure. However, hospitalization for heart failure was not a primary endpoint in BETonMACE. BETonMACE2 will likely incorporate this amazingly responsive outcome as one of its primary endpoints.

3) Patient Population. Going into BETonMACE, Phase 2 post-hocs (5-point MACE) on a relatively small number of patients suggested better response in diabetics. BETonMACE was all diabetics, and this now that this trial is complete there is improved confidence that this diabetic population is the right one to work in. The effect of apabetalone was extremely robutst in BETonMACE subgroup with chronic kidney disease. I am sure that Resverlogix, the FDA and the Clinical Steering Committee will be pouring over this BETonMACE data closely to identify additional factors to consider (i.e. type and duration diabetes, time since recent ACS event, NAFLD status, CKD status, etc) to best inform the patient selection criteria for BETonMACE2.

4) Synergy. There was also some evidence from those Phase 2 post-hocs that apabetalone synergizesdwith rosuvastatin but not atorvastatin (for 5-point MACE). This did not seem to be the case for the 3-point MACE in BETonMACE. It would be interesting to know if the hospitalization for heart failiure endpoint in BETonMACE showed a differential effect with one statin or the other. In BETonMACE, post-hoc analysis shows synergy of apabetalone with the SGLT2 inhibitor and the GLP1 receptor agonist classes of drugs. This is great, because these are 2 of the most effective and promising diabetes drugs on the market that have shown additional MACE reducing effects (not just glucose control). The fact that apabetalone synergizes with these to provide huge additional MACE reduction on top of SGLT2i or GLP1R-agonist monotherapy is amazing and extremely promising. A very large number, if not all, of BETonMACE2 trial patients will likely be on these drugs as required standard of care, which should maximize this drug synergy effect.

It will be very interesting to see the trial design, patient population and endpoints that are proposed for BETonMACE2. And I won't even get into renal function in this post, but that is still unresolved and potentially promising territory.

BDAZ

P.S. Happy late Canada Day to my neighbors to the north, and happy early 4th of July to my fellow USA peeps.