Betting on BET inhibitors

Resverlogix publishes work in PNAS detailing how BET inhibition was found to reduce SARS-CoV-2 infection in mice and human cell lines

December23rd,2020
DDN Staff

CALGARY, Canada—Resverlogix Corp. has reported the publication of research findings in Proceedings of the National Academy of Sciences regarding the therapeutic potential of bromodomain and extra-terminal (BET) inhibitors as a treatment for COVID-19. The paper in question, “Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2,” details the role of host cell receptors in viral entry into cells and resulting infection, and demonstrates how BET inhibitors reduce infection by inhibiting the expression of said receptors.

After SARS-CoV-2 enters cells in the lungs via the ACE2 receptor, the virus is activated by the TMPRSS2 protein. Among the highlights of these findings was the discovery that in mice, BET inhibitor treatment reduced the levels of both ACE2 and transmembrane serine protease 2 (TMPRSS2) in the lungs. Decreased expression of ACE2 and TMPRSS2 was also seen when BET inhibitors were tested in human lung and prostate cells, as was decreased SARS-CoV-2 infectivity. As noted in the publication, Resverlogix has shared plans for a Phase 2 clinical trial further exploring this approach by leveraging its advanced BET inhibition technology.

This is the most recent of a number of articles the company has published this year regarding the possible role of BET inhibitors in the fight against COVID-19. Resverlogix shared an article in March detailing the interaction between SARS-CoV-2 protein E and BET proteins, after which it began in-house preclinical research to further characterize apabetalone's efficacy in treating COVID-19 infection. More recently, in October, the company reported news of another publication that discussed apabetalone's potential in reducing cytokine storms.

Resverlogix's in-house studies found that apabetalone inhibits the expression of angiotensin-converting enzyme 2 (ACE2), the receptor SARS-CoV-2's Spike protein uses to enter human cells. Additionally, collaborators have shared preliminary data from multiple cell models that implies that administering apabetalone prior to SARS-CoV-2 exposure can significantly reduce viral infection.

“The PNAS study gives us the clearest evidence to date of the mechanism behind the efficacy of BET inhibitors in the treatment of COVID-19,” Donald McCaffrey, president and CEO of Resverlogix, stated in a press release regarding the publication. “So far, Resverlogix has been collaborating with three separate research groups each studying apabetalone in a live virus setting. We have reviewed the early data from these groups and have made the corporate decision to proceed with a human clinical trial as soon as possible. Our live virus data will be published upon completion of the work. We will be initiating our clinical design and applications prior to publication. As the only BET inhibitor with a well described clinical safety record, apabetalone is uniquely positioned as a potential therapeutic for this and future coronaviruses.”

Apabetalone is an investigational, first-in-class small molecule, and has received Breakthrough Therapy Designation from the FDA for a major cardiovascular indication. BET inhibition can regulate disease-causing causing genes, and apabetalone is a BET inhibitor that is selective for the second bromodomain within the BET proteins.

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