Great post Buckeyes!

In response to SanFran, I don't think anything has changed in the short term other than the breakthrough therapy designation back in February. However, I think the recent excitement is that it is finally sinking in that the Phase 3 BETonMACE cardiovascular outcomes trial (that first reported top-line data nearly a year ago) wasn't a complete failure after all....far from. Some people may finally be coming to that realization.

Yes, BETonMACE failed to achieve a p<0.05 for its primary endpoint of 3-point MACE (non-fatal MI, non-fatal stroke, cardiovascular death). There is no arguing, BETonMACE failed from that strict perspective. However, if one looks past that in more detail, one sees that BETonMACE achieved a p=0.11 with an 18% relative risk reduction and 2.1% absolute risk reduction for 3-point MACE. As has been broken down in detailed analyses, when one looks at other pre-specified endpoints (i.e. heart failure), other drug synergies (i.e. SGLT2 inhibitors), and other pre-specified patient sub-populations (i.e. CKD patients), one sees that BETonMACE hit one out of the park!

The problem is that BETonMACE was too small of a trial (most CVOTs have MANY more patients), did not recruit as many CKD patients as they wanted to, and most importantly did not meet statistical significance for their primary endpoint. They did indeed achieve statistical significance and impressive RRRs for other pre-specified endpoints as well a sub-group analyses of the primary endpoint. Most of these were pre-specified with the exception of the drug synergy sub-groups with SGLT2 inhibitors, which is post-hoc. However, regardless of pre-specified or post-hoc.....without achieving p<0.05 for the primary endpoint, these other analyses don't count. Again, they missed the primary endpoint by a hair....p=0.11. For an underpowered Phase 3 CVOT, this p-value is nothing to dismiss and far from a failure. You can look at all the details here.

So maybe nothing new to warrant this excitement. Maybe more of a case of folks finally opening their eyes.

BDAZ