VITN Blog #1: Baloxavir as an antiviral agent for influenza

While vaccination can be an effective tool in the annual fight against global influenza infections, recent history has shown us that the flu vaccine is at best the result of intelligent guesswork and may not be fully protective against a particularly nasty viral strain that pops up in a given year. Therefore, it is critical to have potent antiviral drugs available to treat influenza patients, especially those who are especially vulnerable (e.g. the young, the old, and the immunocompromised).

This study describes testing of the antiviral agent baloxavir marboxil in phase 2 and phase 3 clinical trials, the former intended to evaluate efficacy and the latter to compare baloxavir to the current standard of care: oseltamivir (you might know it as Tamiflu) is a neuraminidase inhibitor, targeting the N in a viral subtype such as H1N1.

Instead of targeting neuraminidase, which is found on the surface of influenza and whose inhibition prevents new virions from exiting an infected cell, baloxavir directly attacks the virus’s equipment for replication. In class, we briefly discussed the importance of the 5’ cap in initiating translation of mRNA at the eukaryotic ribosome. In the case of influenza, this cap is essential to polymerase basic protein 1 (PB1), which has an RNA-dependent RNA polymerase function. Initially lacking the cap, viruses must find a way to steal it from the host cell. After binding of polymerase basic protein 2 (PB2) to the cap of host mRNA, polymerase acidic protein (PA) cleaves that cap and hands it over to PB1, allowing the production of more viral RNA. What does baloxavir do? Well, it selectively inhibits PA, thus undermining viral replication more aggressively than oseltamivir.

This molecular strategy pays off in the clinic. The authors found that baloxavir is more effective than both placebo and oseltamivir in treating influenza patients (measuring factors such as time to alleviation of symptoms and viral load). These data are encouraging to physicians concerned about the rise of influenza strains resistant to neuraminidase inhibitors like oseltamivir as well as another class of antiviral drugs known as M2 ion-channel inhibitors. However, the trials had a cautionary tale to tell as well, in that the authors observed the emergence of PA mutations reducing influenza’s susceptibility to baloxavir in both the phase 2 and phase 3 trials. While baloxavir is a promising candidate for clinical use, influenza no doubt will remain a menace as long as it retains its capacity for genetic innovation and pharmacologic resistance.

Study: “Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents” (https://www.nejm.org/doi/10.1056/NEJMoa1716197)

Article: “Meagre ranks of anti-flu drugs look set to grow” (https://www.nature.com/articles/d41586-018-06184-9)

- Panos Vandris