BKC, Thanks for confirming that there is not a published apabetalone study in SARS-Cov2 infected mice. And thank you for your insightful posts yesterday in this thread!

Digging into some details between the Cell paper (Mills RJ et al, Cell 2021) and the current Chen IP et al bioRxiv study. Both studies used the same transgenic K18-hACE2 C57BL/6J mice to allow for the mice to be susceptible to SARS-Cov2 infection. However, there are some methodological differences in how the BET inhibitors  are administered in the two studies. In the Mills Cell study, INCB054329 is given on the day of infection, but in the Chen bioRxiv study, JQ1 and ABBV-744 were given starting at 1 day post-infection. Though 1 day seems like a minor difference, it may be very significant to the outcomes of the two studies. The Mills Cell study used only female mice, whereas the Chen bioRxiv study used both male and female mice. So there may be some sex differences. Both studies reported to deliver the same intranasal dose of SARS-Cov2 viral particles. However, there may or may not be viral strain differences; the Mills Cell study didn't report which particular SARS-CoV2 strain was used but the Chen bioRxiv study reported using the SARS-Cov2 WA1 strain.

Interestingly, the new Chen bioRxiv study refers to this Mills Cell study in a negative light "Similar to our observations, Mills et al. found that therapeutic application of K18-hACE2 mice with BET inhibitor, INCB054329, resulted in severe lung pathology and significant viral RNA in the lung." However, in the Mills Cell study, they didn't report any positive or negative effect on the lung pathology or lung infection due to INCB054329. Instead, they focused on the observed beneficial effects in the heart and stated "This response was more specific to the heart, because INCB054329 did not regulate any genes in the lungs (data not shown)." So INCB054329 didn't seem to exacerbate lung related outcomes in the Mills Cell study (or at least it wasn't reported)....it may be more correct to correct to say that INCB054329 did not improve the severe lung pathology or reduced the viral RNA in the lung.

The Chen bioRxiv study really focused on the lungs and not the heart, whereas the Mills Cell focused on the heart and not the lungs. So BET inhibitors in the context of COVID-19 may still be good for the heart but also bad for the lungs. If indeed BET inhibitors exacerbate lung response to SARS-Cov2 infection, it is surprising that the treatment with INCB054329 in the Mills Cell study didn't seem to elicit any lung gene expression profile differences between BET inhibitor treated mice and controls.

One last note.....BET inhibitor delivery method and tissue distribution. In the Mills Cell paper they report delivering INCB054329 to mice via oral gavage. In the Chen bioRxiv study, the deliver the JQ1 or ABBV-744 via intraperitoneal injection. So there could be drastically different tissue distribution profiles between the two delivery methods. Perhaps one method of delivery gets more compound to the lungs than the other delivery method. This should not be overlooked and we should keep this in mind when thinking about potential of apabetalone. As far as I know, nothing has been reported on how much apabetalone gets to the lungs after oral delivery.

BDAZ