Although the focus has been largely on vaccines, you may have heard that Pfizer is testing a treatment pill. COVID-19.
It almost sounds too good to be true. In fact, the results are very preliminary – but this is a promising approach.
Where most antiviral agents we have tried to treat COVID-19 target the inflammatory and immune response as a result of infection, the Pfizer pill is targeted directly. SARS-CoV-2 – the virus itself.
Installing our virus protection
Much of the disease associated with COVID-19 is due to the intense inflammatory and immune response that can occur with infection. The most successful treatments so far have focused on this overly zealous immune response.
Taken at the beginning of the disease, the inhaled corticosteroid budesonide reduces the development of more severe disease.
In people hospitalized with COVID-19 in need of oxygen, the oral corticosteroid dexamethasone reduces the likelihood of death.
In the most severe cases – patients with COVID admitted to the intensive care unit – the anti-inflammatory tocilizumab administered intravenously gives the person a better chance of survival.
But these treatments are not aimed at SARS-CoV-2 itself; only the effects of the infection. Direct targeting to the virus proved more difficult.
Targeting to SARS-CoV-2
A virus such as SARS-CoV-2 must enter the host cell in order to multiply. It does this by using its protein (a protein on the surface of the virus) to attach to the cell and then uses the cell’s own proteins to gain access.
Once inside the cell, SARS-CoV-2 removes its outer shell and releases its virus. RNA (ribonucleic acid, type of genetic material). This acts as a template, allowing the virus to replicate and then infect other cells. At any point in this life cycle, the virus can be vulnerable to interference.
SARS-CoV-2 carries an enzyme, 3C-like protease (3CLpro), which plays a crucial role in the replication process. This protease is almost identical to the protease used by the SARS-CoV-1 virus (SARS) and similar to the protease used by the Middle East respiratory virus (MERS).
Thus, a drug that can effectively target 3CLpro and prevent virus replication may be beneficial against many known coronaviruses and possibly those that appear in the future.
Protease inhibitors have been used successfully to treat other viral infections, especially chronic infections such as HIV and hepatitis C.
They were presented at the beginning of the pandemic as a possible treatment for COVID-19. However, two clinical trials have shown that the drug lopinavir-ritonavir is ineffective, with drug levels probably too low to act against SARS-CoV-2. Although a higher dose may be effective, it is also likely to cause more side effects.
The researchers also suggested a re-prescribed antiviral drug, remdesevir, originally developed to treat Ebola. Remdezivir slows the virus’s ability to replicate its RNA.
Initial reports appeared promising and saw that the US Food and Drug Administration approved the drug for emergency use. But the results of randomized controlled trials in hospitalized patients with severe COVID-19 were disappointing.
Although there was a reduction in the duration of the disease for surviving patients, this did not significantly reduce a person’s chance of dying.
Of course, none of these agents are specifically designed to target SARS-CoV-2. But in 2020, Pfizer / BioNtech identified a small molecule – PF-00835231 – that blocks the SARS-CoV-2 3CLpro protease. It was originally designed against SARS-CoV-1, but the enzyme in the two viruses is almost identical.
PF-00835231, both alone and with remdesevir, appears to reduce the replication of a number of coronaviruses, including SARS-CoV-2, in cells in the laboratory. It also reduces viral replication in a number of animal models without adverse safety signals. But it is important to note that this study has not yet been reviewed.
Pfizer / BioNtech is taking two drugs for clinical trials for COVID-19: PF-07304814, an intravenous injection for use in patients hospitalized with severe COVID-19 and PF-07321332, an oral agent or pill that could be used earlier in the disease. Both are formulations of a 3CLpro inhibitor.
These phase 1 studies, launched in March, represent the earliest stage of drug development. These studies select healthy volunteers and use different doses of drugs to determine their safety. They also look at whether the drugs cause enough reactions in the body to show that they can be effective against SARS-CoV-2.
The next step will be phase 2 or 3 tests to see if they improve COVID-19 results. This process usually takes years, but as the pandemic continues to rage worldwide, Pfizer says it will do so in a few months if the Phase 1 trials are successful.
The use of antivirals in acute COVID-19 is difficult and impossible. Although the results are preliminary at this stage, these agents from Pfizer / BioNtech are promising. They can be used at the beginning of the disease, especially in people who are poorly protected from vaccination or in those who have not been vaccinated.
They could also be used as a means of prevention, to control outbreaks in exposed people. They should be effective against all SARS-CoV-2 variants of concern, as well as against other known and potentially emerging coronaviruses.
The recent suggestion by Pfizer’s CEO that the pill could be available by the end of the year is probably a long one. But the pandemic has shown us what is possible in the field of rapid scientific progress, and we will be watching this area with interest.
Written by Peter Work, Associate Professor, School of Medicine and Public Health, University of Newcastle.
Originally published in The Conversation.