May 19, 2022

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The New COVID Drugs Are a Bigger Deal Than People Realize

Although masks, distancing, ventilation, testing, and contact tracing have all helped forestall a collapse of the American health-care system under the weight of COVID-19, the pandemic will come under control in only two ways: Preventives—specifically vaccines—will harness people’s immune system to keep them from becoming infected, getting sick, and spreading the coronavirus, while targeted therapeutics will offer hope to those who have already developed symptoms. The emergence of Omicron, a worrisome new variant of the coronavirus, underscores the need to use multiple tools to fight the disease. In infectious diseases, control of a pathogen means reducing its impact even if it remains endemic in the world. Fortunately, the United States is poised to authorize two oral antivirals: molnupiravir and Paxlovid. The former is the generic name of a drug made by Merck; the latter is the trade name of a drug combination made by Pfizer. Both come in pill form, and a five-day treatment course of each will provide certain patients with significant benefits.

These miraculous drugs arrived with minimal fanfare but represent the biggest advance yet in treating patients already infected with COVID-19. The supply of vaccines in the U.S. has exceeded demand for some time, and authorities recently widened eligibility to include children as young as 5, but uptake is not universal. Millions of Americans have decided, for a variety of reasons, not to get shots, while many more around the globe have yet to be offered a vaccine. And although the vaccines have remained amazingly effective against severe disease, some patients, especially those who are older or immunocompromised, remain at risk of hospitalization if they get a breakthrough infection. The widespread use of oral treatments for influenza hints at the value of COVID drugs that can be provided in an outpatient setting and reduce the severity of symptoms for unvaccinated and vaccinated patients alike.

Molnupiravir and Paxlovid are particularly exciting because antivirals that effectively target viruses at specific points in their life cycle are the “holy grail” of viral therapeutics—as past experience with other viruses has shown. Infection with HIV was fatal for nearly all patients until antivirals were developed against enzymes crucial to viral replication and researchers figured out how to combine those drugs to maximize their effectiveness and limit the emergence of resistant viral strains. These changes revolutionized HIV treatment, massively improving the prognosis for people who had access to  antivirals. Instead of developing severe illness, treated patients could live healthily and expect normal life spans.

The development of these highly active oral antivirals for HIV infection took a decade and a half after the disease first came to light; the incredible progress in COVID-19 therapeutics took 18 months. Intriguingly, the COVID-19-treatment research borrowed many ideas from the HIV field; the two new COVID-19 drugs focus on similar pathways in the viral life cycle that HIV drugs target. In essence, these drugs prevent the target virus from reproducing itself. Because they work differently from the majority of COVID-19 vaccines, which teach the immune system to identify and attack the coronavirus’s characteristic spike protein, the antivirals remain effective against mutant variants whose spike proteins are harder for immune cells to recognize. Designing, manufacturing, and distributing vaccines updated for new variants will take time, so the availability of antivirals will be all the more essential.

The rapid development of vaccines against COVID-19—something that doesn’t yet exist for HIV—has overshadowed the progress on treatments. And yet, the need and public demand for effective medications are evident. Doctors and patients have sought out potential oral COVID-19 treatments, including drugs such as hydroxychloroquine and ivermectin, that did not prove effective in clinical trials. But researchers needed to keep working on the question, because COVID-19 will be with us for the long haul. Although health experts agree that preventing a disease is better than treating its symptoms, not everyone will get vaccinated. People who become infected are worthy of compassion and care, regardless of the circumstances of their infection, and medical treatments that shorten the period of viral transmission and keep unvaccinated COVID-19 patients out of hospital beds will protect everyone.

The COVID-19 treatments that have shown some effectiveness up to this point have significant drawbacks. Remdesivir is an intravenous antiviral used for hospitalized patients with COVID-19. But by the time a patient is admitted, the virus may already have caused considerable damage, and viral replication may have stopped. An intravenous drug has far less power to affect the trajectory of the pandemic than affordable, effective, and short courses of oral pills do. Until now, the only outpatient therapeutic for COVID-19 has been monoclonal antibody treatments, which are effective in preventing severe disease in high-risk patients. But they are expensive and require intravenous infusion or subcutaneous injection, and health-care providers must monitor their administration closely.

Although molnupiravir—which is named after the Norse god Thor’s hammer, Mjölnir—was being tested for the treatment of the Ebola virus, researchers had not settled upon a purpose for the drug before SARS-CoV-2 arrived on the scene. Early studies of molnupiravir showed that its recipients cleared the coronavirus more rapidly than recipients of a placebo did. The drug did not help patients who were already hospitalized, but in outpatients with mild to moderate disease who had a high vulnerability to severe disease, it reduced the risk of hospitalization or death by 30 percent if given within five days of developing symptoms. The drug proved so beneficial that the clinical study was called off early. Merck applied for emergency-use authorization, and the FDA is expected to review the drug this week. Merck has promised to share its technology with the Medicines Patent Pool (MPP), which will allow for more affordable global access to molnupiravir.

Paxlovid, a formula developed largely from scratch for the current pandemic, is actually an RNA-virus protease inhibitor called PF-07321332 “boosted” with another drug called ritonavir. It too was the subject of a clinical trial that was stopped early because the treatment looked so effective. Outpatients who had both COVID-19 and medical conditions that put them at high risk of severe illness were 89 percent less likely to be hospitalized if they received Paxlovid twice daily for five days than if they got a placebo. The FDA will likely review this important therapeutic before the end of the year. The U.S. government has bought millions of courses of molnupiravir and Paxlovid for Americans in anticipation of the authorization of both. Moreover, Pfizer has promised to accelerate worldwide access to Paxlovid through an agreement with MPP.

The importance of these two highly anticipated outpatient antivirals for COVID-19 cannot be overstated. Both medications were studied in unvaccinated individuals, of which the U.S. and other countries around the world have many. For the vaccinated, “breakthrough” infections are generally mild, but they can lead to time out of work and require cutting back contact with others. Not only should rapid treatment with one of these two antivirals shorten symptoms in breakthrough infections (as is the case with influenza), but bringing down the viral load quickly by inhibiting viral replication should limit transmission.

Further study of the new COVID-19 drugs is under way for potential use in lower-risk individuals and as preventive medications. The development of HIV antivirals also led to the development of “post-exposure prophylaxis,” a strategy in which people who have come in contact with that virus take antivirals to avoid becoming HIV-positive. The new COVID drugs have at least the potential to provide a similar benefit. Moreover, the development of these two antivirals is spurring research on other COVID-19-specific antivirals. So despite the arrival of Omicron, we still have grounds for optimism. Last year ended with the authorization of highly effective COVID-19 vaccines, and 2021 should end with the availability of highly effective, targeted COVID-19 treatments that will help the world live with COVID-19.