This previous post kind of goes hand in hand with this thread.

I agree that BETonMACE is binary for meeting the primary outcome "Time to first occurrence of adjudication-confirmed narrowly defined MACE (single composite endpoint of CV death or non-fatal MI or stroke)" for the total population. It is either going to meet the primary outcome with statistical significance or it is not going to meet the primary outcome with statistical significance. So from a binary perspective on statistical significance, it is either going to meet or miss.

But there are several sub-scenarios that come into play if BETonMACE meets (or misses) the primary outcome. The recent Van Leeuwenhoeck Analyst report by Marcel Wijma on 5/2/2019 covers a few different scenarios on pages 18 to 28. However, there are several other factors to consider that I will brainstorm below. 

1) What is the %RRR for the 3-point MACE primary outcome in the total BETonMACE population? Obviously, the greater the %RRR the better.

2) Was the %RRR for the 3-point MACE primary outcome even greater for any of the other pre-specified sub-group analyses based on statin, days since ACS event, baseline HbA1c, baseline eGFR, etc? For a list of pre-specified sub-groups, see here. Recall that Phase 2 post-hoc analyses identified a hyper responder population of low-HDL treated with apabetalone and rosuvastatin. 

3) For the 3-point MACE composite %RRR, was this driven in part by significant reductions in cardiovascular death or was it primarily driven by reductions in non-fatal MI or non-fatal stroke? Reductions in cardiovascular death are the most important of the 3-point MACE composite. Recall that for the SGLT2 inhibitor empagliflozin in EMPA-REG OUTCOMES, it wasn't its modest 14% RRR in 3-point MACE that caught the most headlines and got a standing ovation, but it was the 38% RRR in cardiovascular death.

4) Did BETonMACE also achieve significant improvement in renal function (eGFR) and/or alkaline phosphatase levels in CKD sub-study? If so, what degree of renal improvement? This result will also factor in to the planned follow up renal/CKD trial. 

5) Did BETonMACE also achieve significant improvement in MoCA scores in cognition sub-study? If so, what degree of cognition improvement? This result will also factor in to the planned follow up vascular cognitive dementia trial.

Based on the above, one can envision several combinatorial scenarios.

1) Did BETonMACE hit a grand slam by not only meeting the primary outcome for 3-point MACE reduction with statistical significance, but also achieving significant reduction in the cardiovascular death component, significant improvement in renal function in CKD sub-study, and significant improvement in MoCA scores in cognition sub-study?

2) Did BETonMACE meet the primary outcome for 3-point MACE reduction with statistical significance, but find no effect in renal or cognition sub-studies?

3) Did BETonMACE fail to meet the primary outcome for 3-point MACE reduction with statistical significance, but find significant improvement in renal function in CKD sub-study, and significant improvement in MoCA scores in cognition sub-study?

4) Did BETonMACE fail to meet the primary outcome for 3-point MACE reduction with statistical significance for the total population, but find significant MACE reduction in one or more of the pre-specified sub-group analyses? For a list of pre-specified sub-groups, see here. In this scenario, will these sub-group findings be valid or likely for NDA and MMA approval?

5) Did BETonMACE meet the primary outcome for 3-point MACE reduction with statistical significance, but find no effect on cardiovascular death (effects mostly due to reduced non-fatal MI or non-fatal stroke)?

I could go on and on. So although achieving statistical significance and meeting the primary outcome is a binary event, there are many ways that BETonMACE could play out to influence the valuation of Resverlogix and the likelihood of apabetalone approval.

BearDownAZ