I have seen a lot of questions appear on this board in the last 24 hours about the origins of the rosuvastatin/apabetalone synergy. Some of these have been answered already, but perhaps lost in long threads wiht a different title. At the end of this message there is a copy of the first paragraph of this post of mine (pay attention to the news release and patent) and here is a link to Imtesty's transcript of the 2013 AGM that George Parros also recently linked to in another thread that details the synergy. Must reads for those who haven't yet and are asking questions about rosuvastatin/apabetalone!

Keep in mind that all we know is that the BETonMACE primary endpoint of 3-point MACE in the combined statin population didn't achieve statistical significance of p-value less than 0.05. It could have just missed and have been p=0.06 for all we know. So there could still be an extremely impressive ~30% RRR for the combined statin group BETonMACE primary endpoint, but it just missed the p-value cut off of 0.05. P-value thresholds suck, don't tell the whole story, and are somewhat arbitrary. But that's how clinical medicine rolls right now. But imagine if this was the case. ~30% RRR for combined statin group, p-value of 0.06. To assume that apabetalone/BETonMACE completely failed is completely premature. 

With the knowledge of the rosuvastatin synergy, it could be that the rosuvastatin/apabetalone group had %RRR MACE benefit much greater than the combined statin group due to a more modest benefit in the atorvastatin/apabetalone group. The rosuvastatin vs. atorvastatin synergy was only reported for plaque reduction (see news release and patent). But importantly, plaque reduction is only one of several cardioprotective mechanisms of apabetalone! So there are many other beneficial pathways/mechanisms of action by which apabetalone works well regardless of statin type. The plaque reduction is likely most relevant to the reverse cholesterol transport mechanism. But recall there's also benefit in vascular inflammation, vascular calcification, coagulation, complement, acute phase response, and glucose metabolism. Just keep in mind there is no evidence that apabetalone depends on rosuvastatin for these other mechanisms....only evidence for the plaque reduction. And if you scroll down towards the end of the patent, you will see a figure that splits the Phase 2 post-hoc MACE reduction by statin type and you can still see MACE benefit in those treated with atorvastatin.

As for discussions with the FDA and other agencies on only using rosuvastatin vs. using both statins.......back in the September 2015 Resverlogix Rodman and Renshaw webcast before BETonMACE begain (transcript courtesy of Imtesty), DM stated: 

"The trial here is going to be called BETonMACE. And as I mentioned all of the packaging and the CMC (chemistry, manufacturing and control), and the organizing the clinics, the PIs (principal investigators), doing the safety reviews, that’s already completed and we are moving forward with this trial quite quickly. The patient population will be patients with low HDL, below 40 (mg/dL), that’s where about 70% of the cardio events take place. And they will have diabetes. All of the patients this time. We will still be testing both Rosuvastatin and Atorvastatin as a request by the agencies. But it’s really designed to show that the one does work better than the other, and that will allow us to move forward in the future with a fixed-dose combination with the superior one, which we do believe is Rosuvastatin."

The synergy of rosuvastatin (Crestor) with apabetalone

From the Sept 3, 2013 news release post-ASSURE "In patients with low HDL receiving RVX-208 and Rosuvastatin (Crestor), plaque regression was twice as pronounced as compared to the pre-specified primary endpoint.....Those patients taking Rosuvastatin and RVX-208 had a highly statistically significant Percent Atheroma Volume (PAV) plaque regression of -1.43% with probability value of p<0.002. This PAV regression exceeded the trial's pre-specified PAV endpoint (-0.6%) by more than two-fold. But those patients taking Atorvastatin (Lipitor ) together with RVX-208 had a PAV plaque progression of +0.19% with a non-significant probability value. The synergistic effect of the Rosuvastatin and RVX-208 combination is the basis for two recent provisional patent applications by Resverlogix......The responder population (i.e. HDL <39 mg/dL taking Rosuvastatin and RVX-208) exceeded the primary endpoint and also surpassed secondary endpoints reflecting regression in coronary atherosclerosis. These measures included total atheroma volume (TAV) and changes in the 10 mm most diseased segment of the coronary arteries, we noted marked regression versus baseline of -12.3 mm3 ( p< 0.0001) and -4.3 mm3 (p<0.0001), respectively." You can see the data for yourself in this patent "COMPOSITIONS AND THERAPEUTIC METHODS FOR ACCELERATED PLAQUE REGRESSION." As discussed previously, Resverlogix wanted to just do BETonMACE with rosuvastatin; however, the story goes that the FDA and other regulatory agencies pushed for both atorvastatin and rosuvastatin to be included. They have pre-specified looking at the primary 3-point MACE endpoint in those treated with atorvastatin vs. rosuvastatin. Today's top-line was just for the combined statin group. So we will have to cross our fingers and wait and see in the rosuvastatin/apabetalone synergy occured for MACE reduction in BETonMACE as it did for plaque reduction in ASSURE. Other pre-specified sub-group comparisons for the primary outcome are mentioned in the appropriate sections below. How will the FDA, EMA, and other regulatory agencies treat pre-specified sub-group comparisons for the primary endpoint in their consideration of drug approval? Great question that I do not have an answer to. 

BearDownAZ