Author's response

Richard J Mills and James E Hudson shared

1. Given systemically, BRD4 inhibition will affect all tissues, what do you suspect will be the principal off-target effects of BRD4 inhibition? And would you speculate that the inhibitory effects may outweigh the off-target effects?

Bromodomain inhibitors generally target all the BET (Bromo- and Extra-Terminal domain) family: BRD2, BRD3, BRD4 and BRDT. The drugs generally prevent the protein-protein interactions with acetylated histones and regulate transcriptional responses by binding to the bromodomains. There are 2 bromodomains (BD1 and BD2) on the proteins and the first generation of molecules target both with side effects including shrinking of testis and thrombocytopenia in some clinical trials. Newer generation drugs targeting the BD2 domain more specifically have a reduced side effect profile and have been safe in phase III clinical trials (https://www.globenewswire.com/news-release/2020/03/30/2008314/0/en/Resverlogix-Announces-Publication-of-Key-Apabetalone-Study-BETonMACE-in-the-Journal-of-the-American-Medical-Association.html). Our ambition is to repurpose these newer drugs to the clinic, and we have new data demonstrating that all BET inhibitors that have been in clinical trials (except ABBV-744 with its AR effects) are efficacious in our cytokine storm model. As apabetalone is the most specific for BD2 and has been safe in clinical trials, this is our lead candidate.