Great questions Buckeyes. I look forward to hearing from Fenix and others experienced in the medical arena to chime in to answer your questions. 

I was following the social media response on Twitter before and after REDUCE-IT results for Amarin's Vascepa. It seemed that there were many doctors that were confused right after REDUCE-IT results were announced because of not understanding how Vascepa was working to reduce MACE. Vascepa was shown in prior Phase 3 trials to lower plasma triglyceride levels, and REDUCE-IT was designed to show that reducing plasma triglycerides in patients with elevated baseline triglycerides (150 to 500 mg/dL) elicits cardiovascular benefit. However, REDUCE-IT found that Vascepa lowered MACE independent of patient baseline triglyceride level and independent of change in patient triglyceride level. It was already known prior to REDUCE-IT that omega-3 fatty acids like the EPA in Vascepa elicit beneficial effects via multiple mechanisms and not only via triglyceride lowering. However, some voices in the medical field fostered confusion because of the REDUCE-IT benefit being disconnected from the triglyeride hypothesis. It was as if being unable to ascribe a single specific mechanism of action by which Vascepa was eliciting cardiovascular benefit frustrated some in the medical field. Perhaps for some doctors, it is too complex to accept that there may be multiple mechanisms of action all contributing to an overall benefit. Although Vascepa was shown to reduce MACE in patients with elevated triglycerides, its benefts are derived from mechanims not limited to triglyceride modulation and likely will benefit patients with normal triglycerides as well. This is a tough pill for some docs to swallow. 

This doesn't mean that the confusion described above was the majority opinion in the medical community; the loudest voices in medicine are not the same as the predominant opinions. Importantly, I saw this criticism early on after REDUCE-IT results were announced and I haven't seen similar statements of confusion in some time. This alleviation of confusion is likely in part to self-education by those in the medical field over time, as well as a strong effort by Amarin and REDUCE-IT clinical investigators to present at recent cardiovascular conferences (i.e. AHA, ACC, etc). So initial skepticism and confusion will naturally wane over time as folks become more familiar and educated about the drug, the trial results, the background research and the implications.  

Places like Twitter are pretty quiet for Resverlogix, Apabetalone and BETonMACE at the moment. And major cardio biomedicine writers are not giving this any attention either. I do expect there to be quite a bit of confusion, mis-information, and FUD once the dam breaks and Resverlogix/Apabetalone/BETonMACE starts getting the attention it deserves. Apabetalone and its mechanims of action are not easily understood at a supericial level. The mechanism of action of apabetalone has evolved dramatically since the early days of apo-AI and HDL-C. BET proteins. Bromodomains. Acetylated lysines. Epigenetics. Bromodomain-2 selectivity. Those are not easy concepts to understand. Nothing against medical doctors, who know a lot more than I do about most medical topics, but most doctors are not educated enough in the molecular aspect of genetics to quickly assimilate these topics.  

It used to be easy, back when apabetalone/RVX-208 was being developed as a simple apo-AI/HDL-C/reverse cholesterol transport drug. But now with effects on vascular calcification, inflammation, glucose metabolism, complement pathway, coagulation/thrombosis, kidney function, cognition, etc.....this story is not a quick read. Some may still have a knee-jerk reaction and incorrectly think of apabetalone as only an apo-AI/HDL drug, and unfairly negatively associate it with the failed CETP trials. However, that is old news. This is a new science, and a new frontier. And it will take time for the medical community to fully embrace and understand it. As described for Vascepa above, the multiple mechanims of action may be a tough pill to swallow for some docs. If BETonMACE does what we all hope it does, then apbetalone will have reduced MACE dramatically in diabetics with low-HDL, and the magnitude of the benefit will be beyond what one would expect based upon the degree of apo-AI and HDL-C modulation. This willl suggest cardio benefits with normal HDL-C as well. It will require time and education and perhaps more clinical trials to truly break free of this constraining mold of apabetalone being just for low HDL-C and just and HDL-C modulating drug.

One last comment on something Buckeyes wrote: "I think about things like the infamous thalidomide example, but it is good that stopping RVX-208 also stops effects without permanent or lingering effects if I understand correctly?" I think Buckeyes is talking about when thalidomide was purposefully prescribed to pregnant women for morning sickness and it was subsequently found to cause birth defects in the offspring. As with a lot of pharmaceutical drugs, women who are pregnant or who are planning to be pregnant should not take apabetalone in my opinion. Contemporary medicine has erred on the side of caution with avoiding prescribing new drugs to pregnant women. It's pretty common sense to avoid taking an epigenetic drug during a time when a fertilized egg is dividing and growing into a baby. Lots of epigenetic processes going on during development. Pregnant women were excluded from BETonMACE for a good reason. Most women who experience a cardiovascular event are going to be past child bearing age anyways, but I am sure that apabetalone, if approved, will indicate that it is not to be used in women who are pregnant or planning to be pregant. There may even be cautions for men too. Unlike women, who go through the menopausal transition and will become infertile with age, men can continue to produce viable sperm capable of fertilization (and with the help of erectile dysfunction drugs to facilitate delivery of aforementioned sperm) long past the age at which most women undergo menopause and become infertile. The unknown and potential effects of apabetalone on sperm may warrant a cautionary statement on the potential product label.

OK. Saturday morning rant off. Time for another cup of joe.

BearDownAZ