Bfw, your response was not just a simple response, but an oversimplifying response.

If one only uses MACE data from non-cardiovascular outcome trials (CVOT) as a meter stick for the MACE-reducing therapeutic potential of past, current or future cardio therapies, then most if not all LDL-cholesterol lowering therapies would be deemed failures. If one takes a look back at the large volume of non-CVOT trials with statins, ezetimibe and PCSK9 drugs for LDL-cholesterol lowering, one will find that in most, if not all, cases these non-CVOT trials achieved robust LDL-cholesterol lowering but did not acheive statistical significance for lowering MACE events. Importantly, MACE reduction was not a specificed primary outcome for these non-CVOT LDL-cholesterol lowering trials. These non-CVOT trials serve a purpose to show drug tolerability, safety and efficacy at modulating a risk factor (i.e. LDL-cholesterol, hsCRP) prior to performing a larger, longer, properly designed and properly powered CVOT trial. 

As we know, these LDL-cholesterol lowering agents have gone on to prove themselves very effective at reducing MACE when the subsequent and properly designed/powered CVOT trials were run. CVOTs are usually Phase 3 trials 3-5 years in duration with a large patient population run after previous Phase 2/3 trials have shown success in tolerability, safety and efficacy with shorter duration and smaller patient population. In the case of bempedoic acid, this latest ~2200 patient non-CVOT Phase 3 bempedoic acid trial was 52 weeks long compared to all previous trials that did not exceed 12 weeks. The observations that there were no statistically significant differences in adverse events with 52 week treatment improves the confidence that bempedoic acid will be safe. And if you really want to get into the details, bempedoic acid group in this 52-week trial had a non-significant ~20% reduction in 5-point MACE and a non-significant ~9% reduction in 3-point MACE. The ongoing bempedoic acid CVOT trial will: 1) have average dosing of ~3.75 years; 2) have 12,600 patients with, or at high-risk for, cardiovascular disease; 3) use 5-point MACE as endpoint; 4) aim for ~1400 MACE events; 5) powered to detect a 14% RRR. A 14-20% RRR would be on par with the RRR achieved by other recent LDL-C lowering CVOT trials, as well as the RRR acheived by SGLT2 inhibitors, GLP1-R agonists and anti-IL1B canakinumab therapy. 

We all know, or should know, the history of apabetalone's clinical trials. No completed apabetalone clinical trial has been longer than 6-month treatment period. No Phase 3 trial of apabetalone has been completed. Phase 2 ASSERT and Phase 2 SUSTAIN met their primary endpoints of apo-AI and HDL-cholesterol modulation, respectively. No apo-AI/HDL-cholesterol modulating therapy tested in a Phase 3 CVOT trial has shown statistically significant MACE reduction except for the modest ~9% RRR for the now abandoned CETP inhibitor anacetrapib from Merck. Phase 2 ASSURE trial failed to meet primary endpoint of plaque reduction assessed by IVUS. Apabetalone/Phase 3 BETonMACE, which is following 3-point MACE, is based on promising post-hoc 5-point MACE analyses of 6-month long SUSTAIN/ASSURE trials. Very few 3-point MACE events in those post-hoc analyses of 5-point MACE.

It has been far from a smooth, straight ride on the clinical trial path for apabetalone. But if apabetalone performs as advertised in BETonMACE, the acheived MACE relative risk reduction will be unprecedented and make history.

BearDownAZ