Harland asked "Bear why do you think Rvx did not highlight the Assure result with Crestor ,which I believe was twice what they were trying to show.and persue that instead of the Mace. The Mace trial would seem to me a higher risk."

It sounds like you are asking why did they decide to pursue a MACE/cardiovascular outcomes (CVOT) trial vs. pursue another IVUS plaque reduction trial as done in ASSURE. Long story short, 1) MACE is more meaningful than plaque reduction, and 2) a MACE/CVOT trial will be needed before brining RVX-208 to market. Longer answer follows.

Resverlogix did indeed highlight the rosuvastatin(Crestor) vs. atorvastatin(Lipitor) results in their post-hoc analyses of ASSURE for IVUS plaque reduction, as noted in this news release and referred by you in your message. However, ASSURE was never designed to compare one statin vs. the other, so the primary endpoint of the trial had to be judged on the entire patient population. As we all know, ASSURE did not meet its primary endpoint in the entire patient population that was not separated by statin type. Furthermore, RVX-208 had a greater effect on apoAI and HDL in the Crestor population compared to Lipitor.

Subsequent to the completion of the ASSURE study, they realized that in ASSURE post-hoc analysis and also in the combined SUSTAIN+ASSURE post-hoc analysis that there was a very impressive and statistically significant effect of RVX-208 on reducing 5-point MACE in the entire patient population. MACE was never a pre-defined endpoint of SUSTAIN or ASSURE, so they couldn't claim success just based off of post-hoc. Although Resverlogix, to the best of my knowledge, has never disclosed the MACE data from Crestor vs. Lipitor patients, the company has painted a picture that MACE was reduced in both Lipitor and Crestor patients. Furthermore, they have observed that the MACE reduction was even greater in the diabetic and/or high hsCRP populations (not separated by statin type).

So why MACE and not plaque reduction?

First, because effects on MACE were more impressive than effects on plaque reduction. This is not too surprising based upon the mutliple pathways that have now been shown to be affected by RVX-208. Although plaque accumulation contributes to MACE, MACE incidence is also influence by other pathways beneficially affected by RVX-208. Effects on MACE are clinically much more important than effects on plaque reduction alone. Another IVUS trial would only be looking at one aspect of RVX-208 efficacy. MACE as an endpoint encompasses the multi-modal effects of RVX-208 better than plaque reduction alone.

Second, another plaque reduction trial would likely have been another Phase 2b trial in order to prove their Lipitor vs. Crestor hypothesis before proceeding to Phase 3. Even if another plaque reduction trial could have been a Phase 3, it would have likely needed to be a longer term than ASSURE (6-months), with more patients than ASSURE, and include both statins (based on clinical steering committee/FDA/EMA recommendations in BETonMACE). In terms of trial design, it might have looked to be similar in size/length as BETonMACE. Most importantly, drugs in the cardio world won't be approved based on HDl/apoAI modulation or plaque reduction alone. MACE/cardiovasular outcomes would be necessary for approval based on recent drugs in the space (see trials for CETP inhibitors, SGLT2 inhibitors, GLP-1R agonists, Esperion's ETC-1002). So instead of wasting money on another plaque reduction trial, they went straight for the MACE/CVOT that they would have to do anyway for approval.

The jury is still out as to whether RVX-208 will work with both statins for MACE reduction. I think it will. But doing another IVUS trial just to confirm the Crestor vs. Lipitor effect on plaque reduction would be a waste of time and money, IMO. Post-hoc analyses of SUSTAIN and ASSURE, as well as various microarray gene profiling and plasma protein biomarker analysis have indicated that RVX-208 is bigger than just plaque reduction alone. MACE as an endpoint better encompasses these multiple affected biological pathways than looking at plaque reduction alone.

Hartland also asked, "Do you consider Zenith a lifeboat if Betonmace is a dud.I know very little re science but on stock trading etc am ok"

Yes, I think Zenith has a great chance to be a leading BET inhibitor company perhaps with even greater potential than Resverlogix. However, both companies need to be more clear with thier long-term plans in terms of what other molecules and indications are in line to next enter clinical trials, and the "Star Factory" aspect of things as SanFran has discussed. These topics have been discussed at length on the board recently. In the case that BETonMACE fails, I do think that Zenith can still be very successful. We will know a lot more about Zenith before BETonMACE concludes, so this will be an evolving topic.

BearDownAZ