Absolutely,

Thank you very much for your thorough post. What you wrote about slowing/stopping the enrollment at non-US sites to allow for US participation makes sense. If they are still aiming for ~2400 patients and 250 MACE events (as the slides from the other day re-iterated), then they need to make these adjustments at non-US sites to make room for US participation. I recall DM saying previously that BETonMACE wouldn't be stopped early, or at least the company's preference is not to stop early. I agree. With a relatively small number of patients and relatively short duration in the BETonMACE cardiovascular outcomes trial (CVOT) compared to most CVOTs, it doesn't make sense to stop it early. They still need to prove long-term safety. Although 1-2 year dosing is long relative to past apabetalone trials, it is not very long with respect to the chronic dosing that will be desired once approved and marketed. This may be the first BET inhibitor to make it to market, so the burden of proof for long-term safety for this novel class of drugs needs to be shown.

OK. On to the atorvastatin vs. rosuvastatin subject. There have always been 4 study arms (placebo/atorvastatin, placebo/rosuvastatin, apabetalone/atorvastatin, apabetalone/rosuvastatin). The ClinicalTrials.gov page doesn't make this clear, but the comparison of atorvastatin vs. rosuvastatin has always been a pre-specified comparison. The hope all along is that there would be a 1:1:1:1 ratio of the 4 study arms. Very nice to hear that the numbers appear to be close to that. Hopefully the ~600 patients in each arm (600 X 4 = 2400) will be statistically strong enough to show a difference between atorvastatin and rosuvastatin for MACE occurrence, assuming that an effect exists.

Absolutely wrote: "I believe we know (hope) from prior study that the only effiacious arm is Apabetalone + rosuvastatin.  The other 3 arms are then somewhat like placebo, as the results are somewhat already anticipated.  In my mind, that means that 3/4 of the patients are likely to have earlier 3-pt MACE events than the Apabetalone + rosuvastatin arm.  This could mean that the 3-pt MACE events happen more rapidly than we first expected as only say 1/4 are getting our preferred formulation."  

The strongest clinical data we've seen from the Phase 2 apabetalone trials that compared the rosuvastatin patients to the atorvastatin patients is the plaque reduction data. This clearly showed that rosuvatatin+apabetalone performed way superior to atorvastatin+apabetalone for changes in percent atheroma volume (PAV) and total atheroma vlume (TAV) as measured by the intravascular ultrasound (IVUS) in the ASSURE trial. It was night and day, especially in the sub-populations that were low-HDL and at higher doses of rosuvastatin. So clearly for changes in plaque volume, there appears to be a synergy between rosuvastatin and apabetalone that is not seen for atorvastatin and apabetalone.

However, just to remind you......reductions in plaque volume is not the only endpoint that influences the risk for experiencing a major adverse cardiovascular event (MACE). Other things such as plaque composition, plaque stability, systemic inflammation, vascular inflammation, complement pathway activity, coagulation cascade activity, calcium deposition in the vasculature, glucose metabolism can all influence MACE susceptibility. There might even be benefits of increased apoAI/HDL beyond changes in plaque volume. So all of these aforementioned effects, and not just plaque volume reduction, that are beneficially modulated by apabetalone potentially influence the MACE reduction of apabetalone. 

Check out the patent US 20160206617 A1 entitled "COMPOSITIONS AND THERAPEUTIC METHODS FOR ACCELERATED PLAQUE REGRESSION" that was previously discussed here on Agoracom. In that patent are several figures that detail the apabetalone/rosuvastatin synergy on the PAV/TAV plaque volume measures. However, pay close attention to Figure 6. The cumulative MACE rate (%) for the atorvastatin+apabetalone is at or below that of the rosuvastatin+apabetalone group throughout the 180-210 days since randomization. This data supports what I discussed in the previous paragraph. The caveat being that this data includes all patients, regardless of low-HDL, statin dose or diabetes status. It could still be that certain subgroups respond better to one statin or the other.

BearDownAZ