While vaccines have dominated the landscape in the fight against COVID-19, oral antiviral pills that can be taken as an outpatient, with the goal of forestalling serious illness, are also in the works.
This so-called "Tamiflu approach" to treating COVID-19 offers several advantages over current therapies, such as monoclonal antibodies and convalescent plasma, which require intravenous infusions.
An oral treatment for COVID-19 could be easily produced, transported, and stored, making it easier to obtain and take quickly. As with Tamiflu, the sooner one takes an antiviral, the lower the chances of developing serious illness, according to Joan Butterton, MD, vice president of clinical research in infectious disease at Merck in Boston.
"One of the real things for controlling the pandemic is making sure that drugs can get to the people who need them," Butterton told 乌鸦传媒. "An oral drug for COVID-19 would be something that people could take quickly. You wouldn't have to go to a clinic to get an infusion or have a van drive around and bring the infusion to you. It could be something that you could just order and pick up at a pharmacy."
Another potential advantage: many antivirals work by blocking the genetic machinery that viruses use to replicate themselves. So antivirals could provide broad spectrum coverage against emerging SARS-CoV-2 variants with spike protein mutations.
Promising Early Results: Molnupiravir
Molnupiravir (EIDD-2801/MK-4482), developed by Merck in partnership with Ridgeback Biotherapeutics, is one of the front-runners among investigational oral antivirals for the early, outpatient treatment of COVID-19. is a ribonucleoside analog that inhibits replication in several RNA viruses, including SARS-CoV-2.
Promising for molnupiravir from a phase II trial of 175 patients were presented at this year's Conference on Retroviruses and Opportunistic Infections.
Data showed that among participants with early SARS-CoV-2 infection, no infectious virus could be cultured from nose swabs taken 5 days after taking molnupiravir. In comparison, 24% of participants who received placebo still had infectious virus on nose swabs at day 5 (P=0.001).
The results are noteworthy because many studies measure RNA using PCR, which can pick up RNA fragments that are no longer functional. In contrast, this study actually looked at infectious virus -- by growing it in vero culture in the lab -- that could be transmitted from one person to another, Butterton said.
"This is important because it shows not only are you getting rid of replicating virus, but it also might mean, from a public health perspective, that people could be less likely to transmit the virus to other people," she said.
The double-blind, randomized, placebo-controlled study took place at 11 sites in the U.S. It included patients who were not hospitalized and had symptoms of COVID-19 within the past 7 days and a positive SARS-CoV-2 PCR test within the past 4 days. Patients were randomized to 5 days of molnupiravir (200 mg twice daily) or placebo, followed by 5 additional days of molnupiravir (200 mg, 400 mg, or 800 mg) or placebo. There were 4 serious adverse advents, none of which were considered related to molnupiravir.
Data from the phase II dose-ranging study in outpatients is expected out "very shortly" and will allow for dose selection in a phase III study, Butterton said.
Other Oral Antivirals in the Pipeline
Several other oral antivirals for outpatient use in COVID-19 are also in development. RedHill Biopharma's upamostat (RHB-107) is being investigated for symptomatic COVID-19 in the outpatient setting in a randomized, double-blind, placebo controlled study at 3 sites in the U.S. The was dosed in this study on Feb. 17, and results are expected later this year, the company said in an email to 乌鸦传媒.
is a serine protease inhibitor that has both anti-inflammatory and antiviral activity. It has been granted orphan drug status by the FDA as adjuvant treatment in pancreatic cancer.
A third investigational oral antiviral, AT-527, is being developed by Atea Pharmaceuticals in partnership with Roche. The drug is being studied for mild to moderate COVID-19 in the outpatient setting in a randomized, double-blind, placebo-controlled trial being conducted in the U.K., Ireland, and Bulgaria.
is an oral direct-acting antiviral agent that interferes with viral RNA polymerase, and the was dosed on Feb. 4.
Researchers are also investigating in several countries for the treatment of COVID-19, including mild or asymptomatic infection among outpatients. is a broad spectrum RNA-dependent RNA polymerase inhibitor that is approved for the treatment of new influenza viruses in Japan, and has received emergency use authorization for COVID-19 in a number of countries including Italy, Russia, Japan, and India.
In the U.S., favipiravir is being investigated in a randomized, double-blind, placebo-controlled trial based at Stanford University. In the study, researchers are looking at whether oral favipiravir decreases the duration of viral shedding better then placebo when given within 72 hours of diagnosis in outpatients with mild or asymptomatic COVID-19.
Researchers expect to have data on safety and differences in viral shedding between favipiravir and placebo by early May, principal investigator Yvonne Maldonado, MD, said in an email.
The oral protease inhibitors lopinavir/ritonavir (Kaletra) used in HIV treatment are also under investigation for early, outpatient treatment of COVID-19. These drugs are being studied in the and studies.
Potential for Prophylaxis
When it comes to viral infection, the general rule of thumb is the earlier you treat, the better. Which brings up the question: can oral antivirals be used for prophylaxis?
"Absolutely," said Butterton. "This is a real sweet spot for oral antivirals. It's something that could be easily distributed to members of the family if somebody in the family becomes infected."
She added that Merck is "actively looking at ideas for pursuing a post-exposure prophylaxis study. I think molnupiravir will very much be useful in that setting."
In December 2020, researchers at Georgia State University in Atlanta published a that suggested the potential for molnupiravir in prophylaxis. The study showed that giving molnupiravir to ferrets infected with SARS-CoV-2 prevented transmission to uninfected ferrets housed in the same cage.
Drugmaker Atea also said its AT-527 . And trials with lopinavir/ritonavir in this setting are already underway in and .
The idea of post-exposure prophylaxis for COVID-19 is appealing because it could bridge coverage gaps for people with sub-par response to vaccines, or who live in areas with vaccine shortages, said William Schaffner, MD, professor of infectious diseases at Vanderbilt University. And, if a variant develops that is resistant to current vaccines, prophylactic use of oral drugs could serve as a bridge until replacement vaccines become available.
"This may be important for people who may not benefit from the vaccines, such as the immunocompromised," Schaffner said. "I get all kinds of emails from strangers and their families regarding the response to vaccines in people who are immunocompromised. That gap means a lot to that family."