A pill that will help Covid-19 patients avert life-threatening illness has been something of a holy grail for doctors and drugmakers. The earliest therapeutics shown to help have typically been administered to patients via a transfusion or once they have become sick enough to require hospitalization. Two years after the first Covid cases were reported in China, the pill-based treatment Paxlovid emerged, offering a huge advance. Intended for newly infected patients at risk of developing severe disease, the medicine reduces hospitalizations and death and makes users less likely to spread the coronavirus. Research is ongoing to determine how well Paxlovid and other treatments perform against the omicron variant of the virus identified late last year.
1. What is Paxlovid?
Developed by Pfizer Inc., Paxlovid is a combination of two antiviral pills taken orally. One is designed to block the action of a key enzyme that the coronavirus uses to make copies of itself; the other, the HIV medication ritonavir, helps slow the breakdown of the first, enabling it to remain active in the body for longer and at higher concentrations. The U.S. Food and Drug Administration cleared Paxlovid on Dec. 22 for emergency use. China on Feb. 11 granted emergency approval for Paxlovid, the first foreign pharmaceutical product specifically targeting Covid that it has endorsed.
2. Is there any other pill for treating Covid?
Yes: molnupiravir, from Merck & Co. and Ridgeback Biotherapeutics LP. Originally developed to treat influenza, the pill inhibits replication of the coronavirus by a mechanism known as lethal mutagenesis. In simple terms, it causes the machinery that reproduces the virus’s genetic material to make mistakes, thereby rendering the copies defective. That’s raised concerns about sparking drug-resistant Covid variants. The FDA has authorized molnupiravir in cases where other treatments aren’t accessible or appropriate for patients. Japanese drugmaker Shionogi & Co. said Jan. 31 that an antiviral pill it’s developing was effective in an early clinical study. Shionogi’s experimental therapy employs the same mechanism as Paxlovid but requires fewer pills.
3. How effective are the authorized pills?
Paxlovid was shown to reduce the risk of hospitalization or death by 89% in high-risk Covid patients, according to an interim analysis of a trial reported on Nov. 5 by Pfizer, which supported the research, and published Feb. 16 in the New England Journal of Medicine. The results were the same whether people started treatment within three or five days of developing symptoms. Researchers are puzzled by reports of some patients taking Paxlovid, getting better and testing negative for the coronavirus, then showing symptoms again and testing positive. In its filing to the FDA, Pfizer said that several trial subjects appeared to have a rebound in viral levels around Day 10 or Day 14, but that there was no clear evidence the coronavirus had developed resistance to any of the primary components in Paxlovid. Molnupiravir was found to reduce the likelihood of hospitalization or death by 30% in a study, supported by Merck, of 1,433 unvaccinated adults with an increased risk of severe Covid, Merck and Ridgeback reported on Nov. 26. Results were published Feb. 10, also in the NEJM.
4. How are they meant to be used?
The FDA said both drugs, available in the U.S. only by prescription, should be started as soon as possible after a Covid diagnosis and within five days of the start of symptoms. The agency authorized Paxlovid for adults and children 12 and older who weigh at least 88 pounds (40 kilograms). It limited molnupiravir to those 18 and older because of concerns the drug may affect bone and cartilage growth and said the treatment isn’t recommended for use during pregnancy, as it may also have an impact on dividing cells. Under guidelines from the U.S. National Institutes of Health, molnupiravir should be used only when other options can’t be. Paxlovid is administered as three tablets taken together orally twice daily for five days, for a total of 30 tablets. Molnupiravir is given as four capsules taken orally every 12 hours for five days, for a total of 40 capsules.
5. How do these drugs differ from other treatments?
• Affordable and easy-to-administer antivirals are ideal treatments, assuming they are safe and well-tolerated, because they directly counter the virus, limiting the duration of illness and its damage to the body.
• There are other proven therapeutics that specifically target the coronavirus: Gilead Sciences Inc.’s antiviral remdesivir as well as laboratory-made antibodies that mimic the body’s immune defenses against the virus. But these are all administered via infusion, adding complexity and cost that may put them beyond the reach of poor countries. Infusing patients in hospitals can also raise the risk of transmission to medical staff and other patients.
• Other medications reduce hospitalized Covid patients’ symptoms, but don’t directly fight the virus. These include the cheap steroid dexamethasone and interleukin-6 receptor blockers, which can suppress a harmful overreaction of the immune system. Blood thinners can also prevent Covid-linked clots that destroy patients’ organs.
6. How well do treatments work against the omicron variant?
• The World Health Organization has said that steroids and interleukin-6 receptor blockers should remain effective for managing patients with omicron infections, since the drugs target inflammation rather than the virus itself.
• Treatments that directly combat the virus are being assessed to see how they perform against omicron. Pfizer and Merck have said that lab experiments on their antiviral pills suggest they are active against omicron. Gilead said the same about its infusion remdesivir. The antibody therapies are of greater concern because they target the spike protein that the coronavirus uses to enter cells, and omicron is characterized by 30 or more changes to that region. U.S. health authorities have restricted use of a number of antibody therapies after concluding they were unlikely to be effective against the variant. In February, the FDA authorized use of a new Eli Lilly antibody, bebtelovimab; the company said lab tests demonstrated it neutralizes omicron.
7. What other types of treatments are being investigated?
Studies published in September 2020 focused on the role of an immune substance called interferon that helps orchestrate the body’s defenses. The research found that people with low levels of the substance do poorly in fighting off the coronavirus, suggesting that interferon treatments could help in the early stages of the infection and perhaps prevent life-threatening illness. However, interferon therapy didn’t help hospitalized patients in a study reported in October 2021. A number of Covid treatments have lost favor. The WHO in December advised against treating Covid patients with an infusion of plasma from people who’ve recovered from the virus. It said the treatment, while costly, doesn’t improve survival or reduce the need for mechanical ventilation. U.S. regulators in March 2020 authorized the use of the malaria drugs chloroquine and hydroxychloroquine to treat Covid, and the next June reversed themselves after determining the drugs were unlikely to work against the coronavirus and could have dangerous side effects.
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