Here come the oral Covid-19 antivirals
Two new drugs offer are anticipated to offer FDA-approved oral treatments
On December 22nd and December 23rd, 2021, the Food and Drug Administration issued Emergency Use Authorization for two new medications to treat COVID-19.
These are the first two new oral drugs specifically targeting COVID-19 to be reviewed by the FDA.
Other drugs have been investigated outside of the FDA new drug approval process, in clinical trials in the US and abroad. These are considered repurposed drugs—drugs that were originally designed to treat other conditions, but then examined in the context of treatment for Covid-19. Some of these drugs are found to have in vitro (in the glass/test tube) effectiveness, but when studied in vivo (in life or living organism or people) but may not pan out as effective.
These repurposed drugs include:
hydroxychloroquine—used to treat malaria and rheumatoid arthritis, was found to be WORSE than placebo.
ivermectin—an antiparasite agent. In well-designed trials has not been found consistently more effective than placebo, but may not be worse either
fluvoxamine—an antidepressant. Small trials have shown this drug IS more effective than placebo. Larger trials are needed to confirm, but this drug is both cheap and currently plentiful. Some institutions have put fluvoxamine on the “approved” treatment list.
dexamethasone—a steroid that reduces inflammation. This drug has been shown to reduce mortality in hospitalized patients
baricitinib and tocilizumab—these drugs, also anti-inflammatory medications designed for rheumatoid arthritis, have been shown to be helpful in some hospitalized patients who worsen despite treatment with dexamethasone. These two drugs are still very expensive.
Multiple protocols involving various vitamins have NOT been shown to be consistently effective in well-designed studies.
The challenge for repurposed drugs has been that, by and large, they are off-patent. That means they are cheap, but also means that well-designed (ie, expensive) trials need to be funded by some entity other than pharmaceutical companies. Usually these are governments, universities or foundations, which, other than governments, have pretty limited budgets.
The first new drug explicitly researched for COVID-19 was remdesivir. This drug had originally been developed for treatment of Hepatitis C, a viral infection that causes hepatitis. It was then researched for use against Ebola virus and Marburg virus. However, it is an intravenous medication, and there are several very good oral medications for Hepatitis C, and there are competing medications to treat Ebola, so remdesivir sat on the shelf—until the COVID-19 pandemic.
Remdesivir is an intravenous-only preparation. In early studies, it was shown to be superior to placebo when treating COVID-19 in hospitalized patients. However, when steroids are used, remdesivir is shown to be of little benefit. It has fallen out of favor for treatment in most circumstances. There is evidence that for early infection, three daily doses by intravenous treatment will reduce the need for hospitalization by 87%. Bringing COVID-19 patients in for three days for an IV treatment remains a challenge in most healthcare settings.
Enter the oral anti-virals.
Molnupiravir (named after Thor’s hammer, Mjölnir) was developed by Merck for the treatment of SARS-CoV-2 and other RNA viruses. It has a new mechanism of action for an anti-viral—it creates “viral error catastrophe” during viral replication. Bluntly, it causes fatal mutations in the viruses. Because of these mutagenic properties, there is concern this drug should not be used on women who are pregnant, especially in early pregnancy, or in women of child bearing potential. It also appears to be not as effective as the other new oral medication. Molnupiravir reduces hospitalization by a not insignificant 30%.
On December 23, 2021, the FDA approved molnupiravir under Emergency Use Authorization for treatment of COVID-19. It is approved for patients at high risk of proceeding to hospitalization or death. It should be taken within 5 days of symptom onset, and is taken for 5 days.
A more effective oral drug, Paxlovid (nirmatrelvir), was approved under Emergency Use Authorization by FDA on December 22, 2021. Like molnupiravir, it is for early COVID-19 infection in high risk individuals. It is in a family of drugs called protease inhibitors, which have been used for years in patients with HIV and Hepatitis C. If given within 5 days of symptom onset, it reduces progression of COVID-19 progressing to hospitalization or death by 88%. It is given twice a day, along with another medication, ritonavir, that helps boost the levels of Paxlovid. This medication will have a long list of interactions with other medications.
Unfortunately, both will be in short supply for the next several weeks, especially for Paxlovid, and states will be scrambling to decide on an ethical framework for distribution.
These drugs are expected to be effective against the Omicron variant of COVID-19 currently surging in the United States, but must be used early. They are not intended for hospitalized patients.
To match distribution of these medications, there will need to be a surge of reliable tests with rapid turnaround. The earlier treatment starts, the less risk of progression to severe disease.
The best strategy to prevent severe complications of SARS-CoV-2/COVID-19 remains immunization—and not spreading infection inadvertently by wearing a mask when there is a lot of virus circulating.