NEW Drugs for COVID Treatment and Prevention

Could an antiviral medication called Molnupiravir eliminate SARS-CoV2 from an infected person's nose and throat?

This oral medication, taken twice a day for five days, was initially developed to treat influenza. However, Molnupiravir seems to also be effective against SARS-CoV-2.

A phase 2a study has recently been completed. It enrolled 202 non-hospitalized adults with signs and symptoms of COVID and confirmed infection. At baseline, 42% of participants had detectable levels of SARS-CoV-2 virus when cultured.

The study had three treatment groups, arms, taking 200 mg, 400 mg, and 800 mg of Molnupiravir, respectively, and a control group. Participants' noses were swabbed on days 3,5,7,14, and 28.

A reduction in SARS-CoV-2 was noted in all treatment groups but was only significant in the 800 mg group. Therefore, a much larger phase 3 trial is underway with 1300 participants.

Molnupiravir works by introducing copying errors when viral RNA replicates. Like DNA, RNA comprises four different nucleotides: adenine, cytosine, guanine, and uracil.

Molnupirivir exists in two forms. In one form, it mimics cytosine, and in the other form, it mimics uracil. When SARS-CoV2 grows in this drug's presence, its RNA-dependent RNA polymerase (the enzyme that reads RNA) reads cytosine as uracil and puts the wrong nucleoside in the RNA sequence.

This misreading creates a massive number of mutations in the viral genome, rendering the new RNA useless.
Molnupiravir was originally developed at Emory University and was later acquired by Miami-based Ridgeback biotherapeutics, who later partnered with Merck & Co to develop it further. In April 2020, a whistleblower complaint by a former head of BARDA, Rick Bright, expressed concerns that similar drugs could damage DNA.

Bright notes in his complaint that "similar experimental drugs in this class had been shown to cause reproductive toxicity in animals, and offspring from treated animals had been born without teeth and without parts of their skulls."

George Painter, CEO of Drug Innovation Ventures at Emory (DRIVE), replied, "We haven't seen robust evidence for any sort of mutagenicity as had been seen in the past [by Schinazi and others]."

In the phase 2A clinical trial, seven participants discontinued treatment though only four experienced adverse events, none of which were considered related to Molnupiravir. However, the trial is still blinded, so what the exact adverse events were is not known.

Several other antiviral drugs for COVID are developing, like Upamostat (RHB-107), AT-527, and favipiravir.

And what about COVID Prophylactic drugs?
Let's say you are exposed to someone with COVID. Is there a post-exposure prophylactic drug you can take?
In December 2020, researchers at Georgia State University published a study in Nature Microbiology that showed that giving Molnupiravir to ferrets infected with SARS-CoV-2 prevented transmission to uninfected ferrets housed in the same cage. So this is great news for ferrets. Human trials should be coming soon.

What about another treatment option for COVID that must also be given early in the illness, monoclonal antibodies?
SARS-CoV-2 uses a spike protein to attach to the ACE-2 receptor and then enter human cells. Monoclonal antibodies bind to a specific protein surface, meaning antigens. These monoclonal antibodies bind to the spike protein of the virus, preventing it from invading human cells, and at the same time, it tags it to let the immune cells know that it can destroy it.

Monoclonal antibodies can be produced by exposing a mouse or a hamster to an antigen, and the antibodies made are collected.
Today antibodies can be made in the lab and treat nearly 100 conditions, including cancer and autoimmune disorders.
The monoclonal antibodies used to treat COVID include Regeneron's clone of an antibody harvested from a person who recovered from COVID and an antibody harvested from a genetically modified mouse engineered to have a human immune system.

Eli Lilly's monoclonal antibody Bamlanivamab was identified in a blood sample from a patient who recovered from COVID.
Clinical trials show that monoclonal antibodies can prevent deaths and hospitalizations in people with mild to moderate COVID who are at risk of severe disease.
A study of VIR-7831, a product made by VIR and GSK, reduced the chances of hospitalization or death by 85%. In addition, a randomized, double-blind, placebo-controlled phase 3 study showed a cocktail of two antibodies- Bamlanivimab and Etesevimab, both made by Eli Lilly, cut the risk of hospitalization death by 87%.

Doctor Mike Hansen, MD
Internal Medicine | Pulmonary Disease | Critical Care Medicine
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