Thanks 10BagR for the statistics explanation.

Statistical analysis in clinicals trials is both necessary and arbitrary. Some have argued for more stringent statistical significance cut-offs than p<0.05. Others have recently argued for doing away with statistical significance as the sole measure of difference. Here are some recent articles/opinions on these issues.

Evaluation of Lowering the P Value Threshold for Statistical Significance From .05 to .005 in Previously Published Randomized Clinical Trials in Major Medical Journals

Statisticians' Call To Arms: Reject Significance And Embrace Uncertainty!

Scientists rise up against statistical significance

EMPA-REG OUTCOMES and REDUCE-IT trials exemplify just squeezing by with significance (p=0.04 for 3-point MACE primary outcome) and passing with very strong statistical significance (p=0.00000001 primary 5-point MACE outcome; p=0.0000006 secondary 3-point MACE outcome), respectively. One caveat is that in EMPA-REG OUTCOMES, like many diabetes cardiovascular outcomes trials (CVOT) on already approved glucose lowering drugs, the CVOT was being done to prove both non-inferiority (no increased risk of cardiovascular events) and testing for superiority (significant lowering of cardiovascular events). 

A big difference between apabetalone/BETonMACE and some other recent CVOTs like EMPA-REG OUTCOMES is that many of these other drugs had already passed Phase 3 trials and been FDA approved for glucose lowering (SGLT2 inhibitors, GLP1-R agonists, DPP4 inhibitors), LDL-C lowering (PCSK9 antibodies, soon to include PCSK9 RNAi inclisiran and ATP-citrate lyase inhibitor bempedoic acid), or triglyceride lowering (Vascepa) prior to initiation or completion of a Phase 3 CVOT. Apabetalone has been shown in Phase 2 to increase apo-AI and HDL-C; however, Resverlogix has never pursued an NDA or MMA for raising apo-AI or HDL-C. Apabetalone has never been tested in a Phase 3 trial prior to BETonMACE. Based on a lack of clinical trial data showing that modulating apo-AI, HDL particle number, or HDL-C affect cardiovascular outcomes, it is very likely that a NDA/MMA for increasing apo-AI, HDL particle number or HDL-C for apabetalone would not be approved without CVOT data. 

As discussed in this article "The primary outcome fails: What next?", failing to meet the primary outcome isn't necessarily the end of the road for a drug like apabetalone. However, until the rules of the game change let's all hope that BETonMACE clears the statistical significance cut-off hurdle with room to spare.

BearDownAZ