Companies Taking Very Different Approaches to ACE2-Focused COVID-19 Therapies
Viruses don’t just wander into the cells they infect. They have to turn the doorknob, meaning, attach themselves to specific receptors found on certain types of cells. SARS-CoV-2, the novel coronavirus that causes COVID-19, uses a specific receptor called ACE2 to do this.
ACE2, which stands for angiotensin-converting enzyme-2, in healthy people, cuts up two forms of the angiotensin protein in order to stabilize blood pressure, as well as other functions. SARS-CoV-2 attaches to ACE2, letting itself into the cell, where it then replicates itself in the cell. Usually, ACE2 is found on lung, kidney, heart, and gut cells. Recently, researchers discovered ACE2 receptors on the cells in the nose.
At least three different biotech companies are working on two ACE2-related drugs to find a solution to the COVID-19 pandemic. They are Vienna, Austria’s APEIRON Biologics, Cambridge, Massachusetts-based Alnylam Pharmaceuticals, and San Francisco-based Vir Biotechnology.
Apeiron’s approach is to actually flood the body with more ACE2 in order to confuse the virus. On April 2, the company received the go-ahead from regulators in Austria, Germany and Denmark to launch a Phase II trial of APN01 to treat COVID-19. APN01 is the recombinant form of the human angiotensin-converting enzyme 2 (rhACE2), which, the company indicates, has the potential to block the infection of the cells by SARS-CoV-2, decreasing lung injury. The trial plans to treat 200 severely infected COVID-19 patients.
APN01 imitates the human ACE2. The virus binds to soluble ACE2/APN01 instead of ACE2 on the cell surface, so it can no longer infect the cells. APN01 also decreases the inflammatory response seen in the lungs of COVID-19 patients.
“Based on its unique dual mechanism of action, APN01 has the potential to be the first drug approved to treat COVID-19 that specifically targets the new SARS-CoV-2 virus,” said Peter Llewellyn-Davies, Apeiron’s chief executive officer.
Alnylam and Vir are taking a markedly different approach, instead of offering more ACE2, they are attempting to decrease the amount of available ACE2.
On March 4, Vir and Alnylam expanded an existing collaboration to include development and commercialization of RNA interference (RNAi) therapeutics against SARS-CoV-2, which has since been expanded again. They will leverage Alnylam’s advances in lung delivery of novel conjugates of siRNA, the molecules that mediate RNAi, with Vir’s infectious disease expertise and capabilities. They are focused on developing siRNAs Alnylam recently identified that target highly conserved regions of coronavirus RNAs.
Essentially, Vir and Alnylam’s overall approach is to silence a protein that causes a disease that is the result of an overproduction of the protein. In the case of COVID-19, the focus is on silencing the ACE2 receptor, with the rationale that without it, the virus won’t be able to infect cells.
“There are other antivirals that act on host factors,” John Maraganore, chief executive officer of Alnylam, told STAT, pointing to interferon. “In the history of developing antivirals, [targeting] host factors are an established strategy.”
But it is unknown whether silencing ACE2 might have unintended consequences, particularly since angiotensin levels play a role in regulating blood pressure and stop or start inflammatory processes. RNA-based drugs that target the liver have also been a real challenge, and it’s not completely clear if the technology can get the therapies into the deepest parts of the lungs, the site of the worst COVID-19 infections.
The two companies are also working on RNAi approaches that attack the coronavirus directly. The research expansion announced on April 2 indicated the two companies are working on up to three additional targets focused host factors for SARS-CoV-2, including ACE2 and TMPRSS2. It will also utilize Alnylam’s advances in delivering siRNA conjugates into the lungs.