After more than 118,000 cases across 114 countries and 4,291 deaths, the World Health Organization declared COVID-19 a pandemic on March 11, 2020.
Just two days later, medicinal chemist Dafydd Owen was sent home from his laboratory at Pfizer in Cambridge, Massachusetts. Like millions of others around the world, he found himself closing his office door without knowing when — or if — he would return.
He went home to the same unsettling new reality everyone else was facing. Supermarkets were running low on essentials, shipping lines were disrupted, and daily life retreated into private spaces, with work, school, and family compressed under one roof. But Owen was also facing something most were not.
While the world was told to stay inside and wait, he and a small team of scientists were about to attempt the near impossible — design an oral antiviral treatment for a virus the world had only just begun to understand, and do it in a fraction of the time drug discovery usually requires.
Owen led the pre-clinical discovery team that would go on to invent Paxlovid, the first FDA-authorized oral therapy for COVID-19. DDN attended his talk at the European Laboratory Research & Innovation Group (ELRIG) 2025 conference in Liverpool, where he shared the story of a scientific race against time.
From intravenous to oral therapy
Pfizer’s strategy focused on SARS-CoV-2’s main protease (Mpro), an enzyme essential for viral replication but absent in humans, reducing the risk of side effects. Inhibiting viral proteases has a proven track record. Similar approaches have successfully treated HIV and hepatitis C. While SARS-CoV-2 was a new challenge, the strategy was a well-established and promising route for antiviral development.
This was also made somewhat easier by the fact that the company already had a head start. In 2003, during the SARS outbreak, Pfizer researchers had developed a compound, PF-00835231, that could block the main protease of the original SARS virus. But by the time clinical testing was possible, the outbreak had ended.
When scientists compared SARS to SARS-CoV-2, they discovered that the binding site in the new virus was identical, suggesting that the old molecule might work against COVID-19. Tests showed they were right.
But there was a problem: PF-00835231 could only be administered intravenously. Its peptide-like structure included five hydrogen bond donors, creating a polar surface area that trapped the molecule in the gut if swallowed. In other words, an oral pill was impossible.
The solution lay in chemistry. Owen and his team took a systematic approach: interrogate each hydrogen bond in the molecule. Which ones were essential for binding to the protease? Which could be eliminated without sacrificing potency? “We were looking for hydrogen bonds that we could get rid of without losing antiviral activity,” Owen explained.
Through careful design, the team reduced the number of hydrogen bonds and introduced a trifluoride group, dramatically improving oral absorption to nearly 50 percent. Paired with ritonavir, a pharmacokinetic enhancer that slowed the molecule’s metabolism, the therapy maintained effective drug levels with twice-daily dosing, creating the oral antiviral that would become Paxlovid.
Saving lives beyond the lab
The EPIC-HR trial provided the definitive proof of the drug’s capabilities. Among high-risk, unvaccinated adults, Paxlovid reduced the risk of hospitalization or death by 89 percent when treatment began within three days of symptom onset, and by 88 percent when begun within five days. Follow-up real-world data from over 44,500 nonhospitalized adults aged 50 and older in the US confirmed the therapy’s impact, showing a 44 percent reduction in hospitalization or death compared with untreated patients.
The results were so striking that the study was halted early. As Owen recalled, the figures were staggering: “There was nearly a 90 percent reduction in hospitalization among people taking the new drug, and 100 percent protection against death.”
“I remember where I was and how I felt when I was told the clinical trial results,” Owen said. “It’s an incredible moment when months of lab work, strategy, and sleepless nights translate into something that will save lives.”
The development timeline for Paxlovid was unprecedented — just 21 months from program initiation to FDA approval, a remarkable achievement compared with the typical 10-12 years required for drug development.
A model for rapid drug development
Owen described himself as a “glass three-quarters full” person. While many drug candidates fail in development, Paxlovid’s success was a testament to persistence, collaboration, and scientific ingenuity. “To have achieved this and see it featured on the front cover of Science in December 2021 was an honor,” he said, “but it still comes second to knowing we are helping people suffering from COVID-19.”
The development of Paxlovid represents a historic achievement in drug discovery and pandemic response. By transforming a lab-scale molecule into a globally available oral antiviral in just 21 months, scientists showcased a new model for rapid, collaborative, and technologically driven therapeutic development. Lessons learned from Paxlovid’s development will continue to shape the future of medicine, speeding therapies to patients and improving preparedness for future pandemics.
