Iconoclast,

There are a few issues imbedded in your post. What is needed for the FDA and EMA? What is needed for successful BETonMACE? How to interpret relative risk reduction (RRR)?

What is needed for the FDA and EMA?

Safety and efficacy. There is no %RRR threshhold required by the FDA/EMA. However, successfully meeting the primary outcome with statistical significance will be required for NDA/MMA marketing approval by the FDA and EMA. In other words, clinical trials need to be successful in meeting their primary outcome for the drug/indication to be approved by the FDA/EMA. Someone please correct me if I am wrong here.

What is needed for successful BETonMACE?

Similar to answer above. The 30% RRR was just a placeholder for trial design and trial statistical powering issues. ANY %RRR that is statistically significant between the placebo and apabetalone groups for the primary outcome will mean that BETonMACE is successful. The chance of a small trial like this achieving a statistically significant difference between the placebo and apabetalone groups will be greater with a more impressive %RRR. However, %RRR values less that 30% are still successful as long as statistically significant. 

How to interpret relative risk reduction (%RRR)?

One must define the patient population and their absolute risk to put %RRR in context. Yes, statins decrease the MACE risk in diabetic, low-HDL patients with recent ACS event (this is the patient population in BETonMACE). However, there is HUGE residual risk. This is why there is such great need for new therapies to FURTHER decrease the risk in these high-risk patients. All patients in BETonMACE are on statins. So all are experiencing that statin-mediated benefit. The point of BETonMACE (with apabetalone), or ODYSSEY/FOURIER (with PCSK9 antibodies), or EMPA-REG OUTCOMES/CANVAS/DECLARE-TIMI (for SGLT2 inhibitors), or REDUCE-IT (for Vascepa) or SUSTAIN-6/LEADER/PIONEER-6/HARMONY/REWIND (for GLP1-R agonists) is to show that another drug ON TOP OF STANARD OF CARE will further reduce MACE risk.

As pointed out on this board before, very few trials have actually focused exclusively on the diabetic, recent ACS event population. Sure, in many trials there are some patients that meet this criteria. But most patients in these past trials are lower risk and have either never had an ACS event (primary prevention) or had an ACS event beyond 180 days or more beyond enrollment (secondary prevention). ELIXA (ACS events w/i 180 days) and EXAMINE (ACS event w/i 90 days) were the only secondary prevention CVOT trials I know of the enrolled diabetic, high risk patients. Both trials failed to show benefit. In other words, NO clinical trial has been successful in showing that a drug can significantly reduce MACE incidence in diabetics with recent ACS event. IF APABETALONE SHOWS THIS IS BETONMACE IT WILL BE HUGE REGARDLESS OF THE %RRR VALUE AS LONG AS STATISTICALLY SIGNIFICANT.

BearDownAZ