Interesting paper, even though the authros don't exactly endorse BET inhibitors as a COVID19  treatment. That said, I think it is import to look at the authors' conclusion in the right context.

The authors state that because BET inhibitors are antiinflammatory, they should not be used against COVID19. Read again: Because it is antiinflammatory, it will not work. This makes great sense, as the inflammatory system is designed to ward off intruders such as vira. On the other hand, Resverlogix - supported by numerous scientists as well as the FDA - claims that antiinflammatory drugs may reduce mortality in many scenarios - not only the heart diseases that Resverlogix initially worked exclusively on, but also in the COVID19 setting. That is, the claim is that: BECAUSE it is antiinflammatory, it will work. This is seemingly contradictory statements - but not necessarily so when inspected facts a bit closer.

Before reading on - keep in mind that an antiinflammatory antibody (tocilizumab), which ironically (I'll come back to the irony part) is an IL6-antibody, has provided statistically significant results in mortality in COVID19 patients who had progressed to point of being admitted to an ICU. Prompting the FDA to issue the following statement (and authorization) on June 24, 2021:

"Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for the drug Actemra (tocilizumab) for the treatment of hospitalized adults and pediatric patients (2 years of age and older) who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Actemra is not authorized for use in outpatients with COVID-19."

(https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-drug-treatment-covid-19)

A JAMA paper on July 6, 2021 reported from a meta-analysis on IL6 antagonists:

"Administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in patients hospitalized for COVID-19."

Exactly why the FDA issued the above statement at that time, is not clear to me, but it could very well be due to the results from the trials that were included in the meta analysis in the JAMA paper. But why is IL6 so important? That is the irony of the paper BDAZ referred to: IL6 is an inflammation master regulator - and the paper describes how IL6 (among a couple of other proteins) is reduced by BET inhibitors (ABBV-744 and JQ1), and claims this to be a problem...  but wait, this was actually the mode of action behind the emergency authorization of Tocilizumab - an anti-IL6 drug! By now, it should be clear that things are more complex that just saying something is 'good' or 'bad'.

Without having studied everything as deeply as I would have liked to do (my time is scarce theses days), the unifying hypothesis I have arrived is that: Very early in the infection course, inflammation is beneficial - and you should not use IL6 antagonists or BET inhibitors, as this reduces the body's ability to fight the virus and potentially eliminate it altogether. However, if the inflammatory system proves unable to eliminate the virus in due time, the inflammatory system may turn into the sword that kills the host (i.e. the patient) - resulting in a cytokine release syndrom or the "cytokine storm" that has been referred to many times in relation to COVID19. At the critical point where patients get admitted to the hospital, chances are that they have begun struggling with over-activated inflammation, and in those cases, IL6 antagonists and BET inhibitors start to have a place. Read the CELL paper again if you still have doubts about the BET inhibition.

Also interestingly, in the paper in the root of this thread, BD2 in particular is pointed out as being essential for the inflammatory response. This is actually a nice endorsement of the antiinflammatory properties of the BD2-specific BET inhibitor, Apabetalone. (I have actually spent hours on end trying to understand if BD2 BET inhibition alone - without affecting BD1 - was enough to quell inflammation - this paper suggests it definitely has an impact on it own, but that is besides the point for COVID19).

I must admit that I got a bit surprised when I first read the paper, but having thought about it and read some more papers, I am not overly worried: RVX just has to make sure that the patient population is the right one, and patients being admitted to the hospital (the current target group) - perhaps particularly if they have a high IL6 or CRP level, would be a promising cohort to study using Apabetalone.

As much as everybody clamours for clear yes/no answers, the frustrating fact of life is that things are rarely clearcut one way or the other - especially not if you care/dare to dive deep into a question - nuances that nobody had considered keep appearing. The IL6 results, to take a relevant example, are not super-well documented. Thus, in the science community, the results are still being debated - and they most certainly will for a long a time. That's why it was an emergency authorization, and not a full authorization.

Apabetalone is not a panacea, but it sure does seem to have extremely interetings and highly promising properties - its antiinflammatory properties in particular are promising - also in a COVID19 setting. 

Best regards,

BKC