Diagnostics
and were effective in treating this phase of Covid-19. These drugs continue to work.
Monoclonals and antivirals Treating the first phase of Covid-19 has involved two types of drugs: monoclonal antibodies, which are given intravenously, and antivirals. The vast majority of patients recover from Covid-19 without medication, so the antiviral and monoclonal antibody drugs are used only with vulnerable patients at high risk of moving to the second phase. These include, among others, patients with down’s syndrome, sickle cell disease, HIV or AIDS, chronic kidney disease and certain types of cancer. In the UK, the three antiviral medications approved for use are remdesivir (brand name Veklury), molnupiravir (brand name Lagevrio) and the combination drugs nirmatrelvir and ritonavir (brand name Paxlovid). Of these, molnupiravir and Paxlovid were developed specifically to treat Covid. Remdesivir, however, is a repurposed drug, originally developed to treat Ebola, at which it proved ineffective. Both Paxlovid and remdesivir reduce hospitalisation by nearly 90%, but molnupiravir by only 30%.
The sole monoclonal antibody to have been approved for use in the UK is sotrovimab. A clinical trial conducted when the Delta variant was dominant showed it reduced hospitalisation and death by 79%.
The antiviral drugs have continued to be effective against all variants. Zania Stamataki, associate professor in viral immunology at the University of Birmingham, says that this is to be expected: “They are working against proteases and polymerases, which are essential enzymes for the virus to replicate inside the cell.” Those enzymes don’t change substantially when a new variant emerges. The monoclonals, in contrast, “are directed against proteins that go on the outer area of the virus, like the spike protein, for example, and because they are accessible to antibodies, any little mutation that the virus makes is going to be selecting for escape variants.” Once the spikes have changed, then the monoclonal antibodies are no longer able to bind to them.
A problem that will recur The Omicron variant has proved challenging. In the US, three formulations of monoclonal antibodies have been approved for use, but two have proved ineffective against Omicron, and the Food and Drug Administration (FDA) withdrew recommendations for their use. Of the remaining one, sotrovimab, there was “not nearly enough to go round”, says Gallagher. “Unless they’re developed in such a way to bind to a part of the virus that changes less, then it’s a problem that’s going to recur for those types of drugs.”
Practical Patient Care /
www.practical-patient-care.com BA.2 avoids sotrovimab in the lab
After proving to be one of the few antibody treatments still effective against the Omicron variant, recent research data now suggests sotrovimab is less effective against the newest subvariant, Omicron BA.2. The scientific journal Nature published a news article in February that presented several pre-print studies yet to undergo peer review that revealed a steep drop in sotrovimab’s ability to neutralise BA.2. The teams, which included sotrovimab producer Vir Biotechnology, emphasised that in-vitro study results could not be extrapolated to the clinic. But acting on the information, the FDA has since limited the drug’s authorisation to patients in the US likely to have been infected with or have been exposed to a susceptible SARS-CoV-2 variant, meaning those in areas without a high prevalence of BA.2. On top of this, the regulator also authorised the use of bebtelovimab, another monoclonal antibody produced by Eli Lilly and Co and shown to work against both Omicron and its subvariant BA.2. This authorisation only extends to mild-to-moderate cases of the disease, however, and cannot be administered to patients hospitalised with it, meaning patients in the US are still likely to be treated with other monoclonal antibodies if their symptoms become more severe.
There are good reasons why some patients need monoclonals rather than antivirals. “What’s becoming a practical reality is that there are several choices of outpatient therapies, and they are being chosen for different patients based upon logistics and the characteristics of the patient,” says Gallagher. “For example, Paxlovid has a lot of drug interactions and there are some patients on medications that you can’t give it with, or that it’s very difficult to give it with, meaning, in my practice, that it shifts us to using one of the intravenous medications for them. So it’s become an interesting boots-on-the-ground decision-making [process].” For researchers developing new monoclonal antibodies, the unusual way the Covid-19 virus has mutated is making it hard to stay ahead of the game. Stamataki points out that in most cases, when a virus evolves naturally within a population, each new variant is slightly adapted from the previous strain. “You can begin to predict mutations that might be affecting your antiviral treatments,” she says. Because Covid-19 is a virus that has affected the population worldwide, it has not worked like that. “The variants that are happening are springing up from nowhere, so for example, Omicron has not emerged from Delta,” she says. It is something that is “foxing” scientists, she adds: “We don’t know where the new variants are going to come from, and they could be very different from the viruses we were dealing with as a population before.” It has meant that monoclonal antibodies that worked with Delta did not work with Omicron, and a monoclonal antibody that works with Omicron might not work with the next variant.
A spanner in the works
The biggest challenge is in treating immunosuppressed patients, such as those receiving cancer treatment, or who have underactive immune responses for other reasons. Antivirals such as protease inhibitors need to undergo safety trials, and after that need to be administered to groups of immunosuppressed
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