A lot of misconceptions on ESPR and its bempedoic acid trial results announced today. Could bempedoic acid fail to get FDA/EMA approval for LDL-C lowering indication prior to completion of the ongoing CVOT trial? Of course. Could bempedoic acid fail in future trials including its ongoing CVOT trial? Of course. Were today's trial results a bust? I dont' think so. Let me explain. Forgive my rant, but one needs proper perspective for this.

First of all, this was not a cardiovascular outcomes/MACE trial. That one is ongoing and won't read out until 2022. The one that read out today was the longest trial to date (52 week) primarily geared towards safety readout, but also still assessing LDL-C lowering.

Second, today's top-line data of LDL-C lowering after 52 weeks of treatment is consistent with the ~20% LDL-C lowering acheived by bempedoic acid top of max tolerated statin in previous Phase 2 trials (8-12 weeks). Bempedoic acid has been shown to elicit further LDL-C lowering on top of statins, ezetimibe, or PCSK9 drugs in other trials as well.

Third, and the reason that ESPR got crushed, was the perception (misunderstanding? over-reaction) to the portion of the safety data dealing with fatal adverse events. 2/742 placebo had fatal adverse events (0.3%) and 13/1487 (0.9%) had fatal adverse events. On the surface, this looks bad: 0.3% vs. 0.9%. I can't disagree with that. However, patients in this trial are older, high-risk ASCVD and/or HeFH patients with prior cardio event, on max tolerated statin (95% on moderate or high-intensity), and 2/3 past or current smokers. If you compare this trial to a recent safety trial for the PCSK9 alirocumab that was of similar size and length, you see that in the combined treatment and placebo group there were 18 total fatal adverse events in that trial (placebo and treatment groups combined) compared to the 15 total in the bempedoic acid trial (placebo and treatment groups combined). Importantly, the placebo group in the bempedoic acid trial achieved 0.3% and the placebo group in the alirocumab trial achieved 1.3%. The placebo groups of both trials are on the 2 extremes of the range. 

My opinion is that the increased # of fatal adverse events was just bad luck in this trial and the placebo group in this trial had less than the expected # of fatal adverse events. Consistent with this notion, during the Q&A, Esperion stated "There were no fatal adverse events related to study treatment. The KOLs who reviewed these results with us commented that the numbers as shown on this slide were very low for such a high-risk patient population." Also, a bulk of the observed fatal adverse events were either fatal cardiovascular events or lung neoplasms/cancers. Most of these fatal lung came w/i first 3 months of trial. There were no previous fatalities in previous 8-12 wk trials with bempedoic acid. It's hard to believe that this could be due to bempedoic acid, and the independent adjudication concluded that these were likely driven by the high-risk nature and medical history of these patients and not by the drug treatment. As for the fatal cardiovascular events, they made a statement during the Q&A that there was a balance between treatment between BA and placebo for these adjudicated fatal CVD events, with slightly less in BA group. There's your hint at the MACE/CVD outcomes. Trending in the right direction! 

Importantly, keep in mind that an open-label extension (N=1,462) of the study announced today is ongoing. Additional ongoing Phase 3 trials with 12-, 24- and 52- week data to read out in August '18, May '18, Sept '18, respectively. So if there really is something to the fatalities, it should be observable in these other trials that will read out in the next 5 months.

Now, if you want to criticize bempedoic acid for it's degree of LDL-C lowering relative to the PCSK9 drugs, or argue that PCSK9 price will come down and make bempedoic acid irrelevant, that is a fair criticism. However, there is a lot of speculation and uncertainty in those types of statements. The LDL-C hypothesis is alive and well and the PCSK9 studies have proven that the lower the LDL-C goes the better.

Now just to tie this in to apabetalone so I don't get flagged......fortunately apabetalone is not an LDL-C drug, so all these LDL drugs can duke it out for king, and apabetalone can be theoretically used with any of them to hit all of those other risk factors that LDL drugs don't effect.

BearDownAZ