FDA greenlights Pfizer’s oral COVID-19 drug | Science

The U.S. Food and Drug Administration (FDA) has granted an emergency use authorization for the potent oral antiviral regimen developed by Pfizer to treat COVID-19, making it just the second such drug to receive a regulatory greenlight by any country. Last month, the United Kingdom authorized the use of a Merck-made pill that appears much less effective than the Pfizer drug.

Today’s authorization of Pfizer’s candidate, dubbed Paxlovid, is “a major step forward in the fight against this global pandemic,” says Patrizia Cavazzoni, director of FDA’s Center for Drug Evaluation and Research.” It’s “outstanding news,” tweeted Leana Wen, a public health policy expert at George Washington University. Paxlovid “can be of great help to reduce the growing strain on hospitals,” she wrote.

In the final analysis of a clinical trial, Pfizer reported its therapy reduced hospitalizations and deaths by 88% in unvaccinated patients with at least one risk factor for severe disease, such as diabetes or obesity. The Merck drug, molnupiravir, cut those numbers by about 30%. It also comes with more safety concerns.

Paxlovid combines two pills designed to be taken over a period of 5 days, starting within 5 days of the onset of COVID-19 symptoms. Following in the footsteps of revolutionary treatments for HIV/AIDS and hepatitis, one oral compound, nirmatrelvir, inhibits the main protease of SARS-CoV-2. When the virus replicates, it initially produces two long “polyproteins,” which are then cut into smaller functional proteins that carry out a host of key viral functions. SARS-CoV-2’s main protease makes 11 of those cuts; by inhibiting the enzyme, nirmatrelvir blocks the virus from replicating.

The second compound is another protease inhibitor called ritonavir. Originally developed to tackle HIV’s protease, it also slows down metabolism of other drugs in the liver, allowing nirmatrelvir to remain in the body for longer periods of time.

Pfizer scientists originally designed a coronavirus protease inhibitor in 2003 to treat severe acute respiratory syndrome (SARS), the deadly viral disease that emerged in China and caused a worldwide outbreak that year. But it was shelved when the SARS epidemic ended. Company scientists resurrected the drug when SARS-CoV-2 broke out, and quickly showed that it blocked the new virus in cell culture and animals. But the drug had to be given by infusion, so company scientists tweaked its structure to make it more soluble, which means it can be packaged as a pill.

FDA has authorized Paxlovid for use by adults and children 12 years of age and older who have tested positive for SARS-CoV-2 and are at high risk of developing severe symptoms. Pfizer is also continuing clinical trials for use of the drug regimen on COVID-19 patients at standard risk of developing severe disease and, prophylactically, for people who had contact with infected individuals.

Two drugs, two targets

As SARS-CoV-2 infects cells, reproduces itself, and spreads, the coronavirus relies on dozens of viral and host proteins to complete its life cycle. Pfizer’s new oral pill inhibits the main viral protease used to create other proteins for the virus. And Merck’s drug inserts a defective RNA building block when the virus uses an enzyme known as a polymerase to copy its genome.

Graphic of how SARS-CoV-2 infects cells


All these uses will likely increase demand for COVID-19 tests. And that has Wen and other public health officials worried this could exacerbate testing shortages that have arisen as Omicron cases have exploded.

Antiviral pills are not expected to have an immediate impact on the spread of COVID-19. But by preventing many hospitalizations and deaths, they could relieve the pressure on health systems and change the course of the pandemic, provided they’re made widely available at reasonable prices. (Science’s news team made oral COVID-19 treatments a runner-up for the magazine’s Breakthrough of the Year.)

In November, President Joe Biden’s administration announced it planned to purchase 10 million courses of Paxlovid for more than $5 billion. Pfizer says it expects to produce up to 80 million treatment courses by the end of 2022, with 30 million courses available in the first half of the year. In a conference call today, Jeffrey Zients, White House COVID-19 response coordinator, said 265,000 courses of Paxlovid will be available in the United States in January 2022. But because manufacturing of the drug can take up to 8 months, the full 10 million treatment courses ordered by the Biden administration won’t be available until late summer of 2022.

The company says it is working to ensure access around the world and will offer the drug to low-income countries at a discount. Pfizer has also signed a voluntary license agreement with the Medicines Patent Pool to facilitate access to the drug in 95 low- and middle-income countries that account for approximately 53% of the world’s population. Some public health advocates have said this deal leaves out many millions of people, however.

FDA authorized Pfizer’s pill regimen without holding an advisory committee meeting, perhaps a reflection of the enormous pressure the Omicron surge is expected to place on the U.S. hospital system. The European Medicines Agency (EMA) is still reviewing Paxlovid, but in an unusual move told countries on 16 December that the drug nevertheless “can be used” in patients at high risk—another indicator of the high hopes that the drug can blunt the impact of the Omicron wave. EMA suggested countries could use Paxlovid “for example in emergency use settings, in the light of rising rates of infection and deaths due to COVID-19 across the EU.”

FDA has not authorized molnupiravir yet, although some outsiders expect it will do so very soon. Merck’s drug had an advisory panel meeting on 30 November, at which members expressed significant reservations about its modest effectiveness and possible dangers. Molnupiravir induces mutations in the virus’ genome during replication, which some panelists think could facilitate the emergence of new virus variants; others feared it could lead to cancer-causing mutations in patients. Both concerns remain theoretical, however, and some scientists suggest the two drugs should be combined in a cocktail to reduce the risk of SARS-CoV-2 developing resistance to either drug.