Pfizer antiviral slashes COVID-19 hospitalizations

Opening a new chapter in the treatment of COVID-19—one borrowed from successfully tackling the AIDS virus—the drug behemoth Pfizer today reported upbeat results for a 5-day pill regimen to treat early infections with SARS-CoV-2. In a trial that an outside monitoring group halted early because the treatment appeared so promising, the company’s experimental compound slashed hospitalizations by 89% among those treated within 3 days of symptom onset, and by nearly that much among people who started on the pills within 5 days. The Pfizer antiviral is a protease inhibitor, a well-studied class of drugs that revolutionized the fight against HIV and have a known safety record.

“All I’d say is, ‘Yahoo!’” says Mark Denison, a virologist at Vanderbilt University who has worked on developing drugs for SARS-CoV-2. “This is wonderful news.”

The Pfizer announcement comes on the heels of other promising COVID-19 treatment news: an antiviral pill from Merck & Co., which works by a different mechanism, was approved in the United Kingdom this week. Denison and other scientists say if Pfizer’s treatment joins the pandemic arsenal, it could quickly become a powerful weapon to forestall severe symptoms of COVID-19 and help patients clear the virus more quickly, which would also reduce transmission. Although the trial reported on today only tested the drug in about 1200 unvaccinated people, it may also help those who are vaccinated and suffer a breakthrough infection.

The early morning announcement from Pfizer came as a surprise. (Only a few days prior, on Tuesday, the company reported to investors that the trial was ongoing.) In a press release, Pfizer reported that just three of 389 peoplewith confirmed COVID-19, or 0.8%, who took its antiviral therapy within 3 days became hospitalized, compared with 27 out of 385, or 7%, in the placebo group. Ten of those patients who got the placebo subsequently died; no one who got the Pfizer pill did.

Getting antivirals to people within 3 days of a diagnosis can be a challenge, and the trial cohorts were part of a larger group who started the therapy within 5 days of symptoms. There, six out of 607 on the antiviral, or 1%, were hospitalized, versus 41 out of 612, or 6.7%, in the placebo group. In addition to being unvaccinated, all the participants had at least one medical condition, such as diabetes or lung disease, that put them at higher risk of severe COVID-19.

As has been typical for companies throughout the pandemic, Pfizer did not make detailed data available—only the topline results—and the work has not yet been peer reviewed or published. It received the results only Wednesday, when the monitoring board alerted company officials, and plans to seek emergency use authorization for the treatment in the United States and elsewhere as soon as possible.

There’s broad agreement among doctors and scientists that drugs that cripple SARS-CoV-2 directly and early in an infection are crucial to helping end the COVID-19 pandemic.(They are quick to emphasize that such treatments shouldn’t replace vaccines as the first line of defense.) For months, treatment for early disease has consisted of basic home care, such as lots of fluids, rest, and over-the-counter pain relievers to ease symptoms. “The real therapeutic approach would be a direct antiviral,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told Science earlier this year.

Monoclonal antibodies blocking surface proteins of the coronavirus can slow the infection of new cells with SARS-CoV-2, but their application has been hamstrung by cost, availability, and the need to infuse or inject them. In contrast, Pfizer’s ingestible candidate operates inside an infected cell; it blocks enzymes, called proteases, that normally act early in a virus’ life cycle to help it replicate (see graphic, below). Many protease inhibitors are approved for HIV treatment, and Pfizer’s compound has a nearly 20-year history. Pfizer scientists designed a version of the compound back in 2003 to block a protease in the coronavirus that causes severe acute respiratory syndrome (SARS), a cousin of SARS-CoV-2.

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.

Coronvirus cycle graphic

Then SARS abated, and Pfizer shelved the product. Last year, the company dusted it off, discovered it could stop SARS-CoV-2 from replicating in human cells, and began to develop it for COVID-19. An early version, tested about a year ago, was given intravenously, and the company subsequently crafted an easier to deliver tablet.

The Pfizer treatment actually consists of two distinct medications: the SARS-CoV-2 protease inhibitor designed by Pfizer, known as PF-07321332, and a decadesold generic HIV drug called ritonavir that boosts the effectiveness of protease inhibitors. The company added ritonavir to the regimen when it switched from an intravenous treatment to a pill. That was because, in tablet form, the protease inhibitor was metabolized too quickly, broken down by the body before it could effectively disable the virus, says a Pfizer spokesperson.

When taken together, ritonavir helps stave off the enzymes that break down the Pfizer antiviral, keeping it intact in the body so it has time to do its job. In the current trial, patients took six pills per day, two of Pfizer’s antiviral and one ritonavir in the morning, and the same regimen at night.

The regimen is also being tested in two additional trials. One is enrolling people who have a standard risk of developing severe COVID-19, including those who are vaccinated; the other offers the pills as a preventive therapy to people who’ve had a member of their household test positive for the virus. Those trials continue and Pfizer hasn’t yet reported their results.

Today’s news marks the second time in about 1 month that a COVID-19 antiviral appears to be successful. On 1 October, Merck and Ridgeback Biotherapeutics announced their antiviral, called molnupiravir, cut hospitalization by half in trial volunteers. (That trial was also halted early because of the drug’s effectiveness.) Yesterday, U.K. regulators approved molnupiravir for people with mild or moderate COVID-19 and at least one risk factor, such as obesity. An advisory committee to the U.S. Food and Drug Administration will consider the therapy later this month.

Molnupiravir works very differently from a protease inhibitor: It tricks SARS-CoV-2 into incorporating the compound into its genetic information, encoded by RNA, and in doing so mutates the virus to a point where it can longer replicate. But some experts worry that in the long term, widespread use of the drug could spur the evolution of additional harmful viral variants. There also remain theoretical concerns about whether the drug could cause mutations in people. So having another COVID-19 drug option like Pfizer’s protease inhibitor is welcome.  

“Protease inhibitors are really powerful antivirals, and that’s been demonstrated with HIV and hepatitis C,” says Celia Schiffer, a structural biologist at the University of Massachusetts Chan Medical School. Other protease inhibitors for SARS-CoV-2 are racing through their own clinical trials. In its press release, Pfizer said there were no notable side effects associated with its drug candidate.

 Ultimately, scientists say, drug combinations may be key to treating early COVID-19; that molnupiravir and protease inhibitors act on the virus in different ways could make stacking them together a potent strategy if resistance to one becomes widespread. HIV and hepatitis C treatments both employ such combinations now, Schiffer says. It’s “incredibly exciting,” she says, to have today’s news from Pfizer in hand—and to consider how combining the oral antivirals now hitting the scene might change the pandemic’s trajectory.

Author: Histidine

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