Battling BA.5: How Do Monoclonals and Drug Therapies Stack Up?

Volume 17, Issue 3

The scourge of COVID-19 continues to evolve and inflict significant morbidity and mortality on people around the world. New subvariants continue to emerge, each one slightly more contagious and more effective at evading immunity than the last. Unfortunately, variant evolution has also dwindled our drug therapy armamentarium, as newer mutated strains have unique spike proteins that can evade monoclonal products that were coded against a prior variant’s spike protein.

In this week’s issue of Talking Therapeutics, we explore a new study in the New England Journal of Medicine that tested the efficacy of various COVID-19 therapies against the BA.5 variant in a laboratory setting.

Point 1: Ongoing Loss of Drug Therapies

This new paper evaluated the in vitro neutralizing capacity of several key monoclonal products and antiviral drug therapies against various strains of COVID-19, include the BA.5 strain, which is currently the dominant strain in the United States. The key findings were as follows:

• Casirivimab/imdevimab retained some activity against BA.5; however, the neutralizing strength of this product was greatly reduced.
• Tixagevimab/cilgavimab (branded as Evusheld) retained activity against BA.5, although it was reduced when compared to the ancestral strain of COVID-19. This is important as this product is the only option for pre-exposure prophylaxis for patients with compromised immune systems.
• Sotrovimab, which was highly effective against BA.1, lost all inhibitory capacity against BA.5.
• Only bebtelovimab retained full neutralizing capacity against BA.5 (as well as against other variants like BA.4 and BA2.12.1).
• Remdesivir, molnupiravir, and nirmatrelvir all retained good activity against BA.5.

Point 2: This Is Just a Lab Study

Some of the findings of this study are reassuring, given that all of the antiviral drugs and one of the monoclonal products (bebtelovimab) retain in vitro efficacy against BA.5. However, this study was conducted in vitro, and hence the real-world clinical efficacy of these agents against BA.5 remains undetermined.

Furthermore, sotrovimab was highly effective against BA.1, but lost nearly all efficacy against every Omicron subvariant to follow. This suggests that the ongoing efficacy of bebtelovimab against future strains of COVID-19 is not guaranteed.

Given the spike protein of the SARS-CoV-2 virus is the main site of mutation for this virus, it would make sense for pharmaceutical manufacturers to develop future products that do not depend so heavily on effective binding to the spike protein for viral neutralization.