Back in 2021, at the height of the pandemic, scientists at Pfizer revealed the development of a novel antiviral molecule, designed to hinder the SARS-CoV-2 virus’s ability to replicate. Clinical trials moved quickly, and by the end of the year we had the very first oral COVID antiviral, called nirmatrelvir.
The pace of the drug’s development was astonishing. Despite using the backbone of a molecule previously produced in the early 2000s to combat the first SARS epidemic, scientists deployed every bit of cutting-edge technology available to create a bespoke drug that could target this newly emerged coronavirus.
The result was a medicine called Paxlovid. But as with many things developed quickly, it was far from perfect. One of the big problems with this novel antiviral molecule was that the human body metabolized it swiftly. So to slow that process down the molecule had to be co-administered with another drug called ritonavir.
Ritonavir was an older drug, originally developed in the 1980s as an antiviral to combat HIV. While it mildly worked to stifle the replication of HIV, scientists quickly learned it was even more effective at blocking the activity of a key enzyme our body uses to metabolize some foreign molecules. So ritonavir ultimately became a useful drug to give alongside some other drugs to help boost their efficacy.
It was an imperfect, but effective solution.
This combination of nirmatrelvir and ritonavir was undeniably valuable, helping vulnerable patients clear the virus from their system and reducing rates of death and hospitalization. However, the side effects from ritonavir were problematic. Anyone who has taken Paxlovid is likely familiar with the awful metallic taste that comes with taking it. This is from ritonavir.
But more dangerous are the effects ritonavir has on other drugs a patient may be taking. The enzyme ritonavir inhibits doesn’t just block the body’s metabolism of the coronavirus antiviral. It also slows the body metabolizing a whole assortment of drugs, from opioids like oxycodene to immunosuppressive medicines and even some sedating drugs like midazolam.
Basically, Paxlovid was unsafe for a whole bunch of patients.
So for the last couple of years scientists at Pfizer have been doing some nifty chemistry, tweaking the nirmatrelvir molecule in the hopes of finding a way to slow how quickly the body metabolizes it without the need for ritonavir. Through a combination of machine learning and AI-driven modeling, the scientists could simulate the effects of scores of different molecules before finally homing in on the most likely effective candidate. The result is a new molecule that has been called ibuzatrelvir.
Preclinical and preliminary human tests in 2024 revealed ibuzatrelvir was safe and potentially at least as effective as its first-generation counterpart. In December 2024 Pfizer initiated the last phase of testing, a large Phase 3 trial.
The trial will enroll over 2,000 participants within 24 hours of a confirmed COVID diagnosis (and within five days of symptom onset). Comprising both adults and adolescents, the cohort will randomly receive either ibuzatrelvir or a placebo for five days. Alongside tracking major outcomes like hospitalization, the trial will also monitor viral load differences between drug and placebo, and evaluate signs of long COVID up to six months following the initial treatment.
In an interview late last year with infectious disease news site Contagion Live, Pfizer’s head of discovery and early development Charlotte Allerton was hopeful this new antiviral iteration could help a significant cohort of vulnerable patients who were previously unable to take Paxlovid. She also noted ibuzatrelvir was resistant to ongoing mutations presenting in SARS-CoV-2, meaning the drug will be valuable regardless of any changes the virus makes.
“Current variants of concern arise due to mutations in the spike protein of the SARS-CoV-2 virus,” Allerton said. “However, like PAXLOVID, ibuzatrelvir works intracellularly by inhibiting the highly conserved Mpro protease of the SARS-CoV-2 virus to block viral replication. This mechanism suggests that ibuzatrelvir, like PAXLOVID, will remain effective against current variants of concern.”
If all goes to plan ibuzatrelvir could be available as soon as 2026.