Vaccination remains is the most effective therapeutic for preventing COVID-19 or reducing risk of serious disease, but as we enter the third year of the pandemic, a number of treatments have emerged, including monoclonal antibodies and oral antivirals.
UC San Diego Health physicians are at the forefront of both investigating new COVID-19 treatments and delivering them to eligible patients in need. They are available to discuss the state and future of COVID-19 treatments.
Shira Abeles, MD
Infectious disease specialist, UC San Diego HealthMedical program director of Antimicrobial Stewardship, UC San Diego HealthAssociate medical program director of Infection Prevention and Clinical EpidemiologyAssistant clinical professor of medicine, UC San Diego School of Medicine
Lucy Horton, MD, MPH
Infectious disease specialist, UC San Diego healthCo-director of COVID-19 Telemedicine Clinic, UC San Diego HealthAssistant professor of medicine, UC San Diego School Medicine
Michele Ritter, MD
Infectious disease specialistCo-director of COVID-19 Telemedicine Clinic, UC San Diego HealthClinical professor of medicine, UC San Diego School of Medicine
A BACKGROUNDER Q&A ON COVID-19 TREATMENTS
Question: What are monoclonal antibodies?
Answer: Monoclonal antibodies (mAbs) are proteins produced in the laboratory that function like antibodies generated by the human immune system in response to an infection. They circulate in the body, where they bind and inactivate foreign substances or trigger other immune cells to actively eliminate targeted, infected cells. Each antibody recognizes a single specific antigen, a molecule on the infectious or invasive pathogen that triggers the immune response.
Monoclonal antibody therapies have been widely used to treat other viral conditions, such as Ebola and respiratory syncytial virus, and chronic illnesses, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Researchers are looking at their potential to target cancer cells.
The basic idea is to restore, enhance or mimic the immune system’s attack on invasive pathogens and infected cells.
In the case of COVID-19, mABs work by blocking SARS-CoV-2 virus particles from attaching to human cells, making it more difficult for the virus to reproduce and cause harm. They may also neutralize a virus. Monoclonal antibody therapy is not generally considered preventive. The goal is to reduce disease progression and help infected, high-risk patients avoid severe outcomes, including hospitalization or worse.
Q: What monoclonal antibody therapies are available?
A: It is important to note, first and foremost, that mAB treatments specific to COVID-19 are quite new, though the concept is not. The SARS-CoV-2 virus that causes COVID-19 was unknown before late-2019; the disease wasn’t even given an official name until February 2020. The first mAB treatments granted emergency use authorization (EUA) by the U.S. Food and Drug Administration didn’t appear until late-2020.
As a result, mAB therapy is typically reserved for patients who meet strict eligibility criteria and who will most benefit from receiving it, particularly in terms of preventing more severe disease, hospitalization or death.
A number of mAB treatments have debuted over the past year or so.
A combination of monoclonal antibodies (casirivimab and imdevimab) known as REGEN-COV was granted in December 2020, initially as an early treatment for patients at high risk of progressing to severe COVID-19, including hospitalization or death. It has since been used to treat mild-to-moderate COVID-19 in adults and qualifying pediatric patients, but has proven less effective against the Omicron variant.
The first monoclonal antibody therapy to receive EUA by the FDA was bamlanivimab in November 2020. Questions arose about its effectiveness prompted the FDA to revoke the EUA for bamlanivimab alone in April 2021. However, when combined with another mAB called etesevimab, it is more therapeutic and the combination of these mAbs received EUA in February 2021. It was not particularly effective against early Beta and Gamma virus variants, but is more so against the Delta variant, and has been used to treat COVID-19 patients ages of 12 and up for high risk of severe complications. The bamlanivimab-etesevimab combination has not been shown to be as effective against Omicron.
Sotrovimab received EUA from the FDA in May 2021. It is recommended for non-hospitalized patients at high risk of worsening symptoms. Early studies suggest it remains effective against Omicron, and is recommended for treatment of high-risk patients recently diagnosed with COVID-19.
Evusheld combines two monoclonal antibodies, tixagevimab and cilgavimab, which have been chemically modified to persist longer in the human body. The FDA gave EUA to Evusheld in December 2021 for use among immunocompromised patients for whom COVID-19 vaccines were expected to provide decreased benefit; it is used as a prophylaxis to prevent infection. Preliminary studies suggest it may retain some activity against the Omicron variant, but more data is needed to fully understand its effectiveness against Omicron. Like other mAB treatments, supplies are extremely limited.
Current mABs require 30 to 60 minutes of intravenous infusion, depending on the drug. Evusheld, which is used as a preventive, is delivered by intramuscular injections. Numerous pharmaceutical companies, research universities and others continue to explore and test mABs, various combinations and means of delivery.
Q: How are the new antiviral pills different from monoclonal antibody therapies?
A: In December 2022, the FDA issued an EUA for Pfizer’s Paxlovid, an oral tablet that combines two antiviral compounds, nirmatrelvir and ritonavir, to treat mild-to-moderate COVID-19 in adults and qualifying pediatric patients at high risk of progression to severe disease, hospitalization or death. The treatment, which consists of a course of 30 tablets taken over five days, is intended to be prescribed by a physician within five days of symptom onset.
Nirmatrelvir works by inhibiting a SARS-CoV-2 protein that, in turn, stops the virus from replicating. Ritonavir slows down the breakdown of nirmatrelvir, allowing it to persist at higher concentrations in the body for a longer period of time. Clinical trials have shown that Paxlovid dramatically reduces disease severity and is effective against all known virus variants, including Omicron, but safety and effectiveness of the drug continue to be evaluated. Ritonavir is known to have drug interactions with other medications that high-risk patients may take so a physician and pharmacist need to review whether Paxlovid is appropriate for these patients using particular medications. It is not recommended for people with advanced kidney or liver disease.
One day after approving Paxlovid, the FDA granted EUA to molnupiravir by Merck, a second oral antiviral for treatment of certain adults with mild-to-moderate COVID-19 and high risk of disease progression.
Like Paxlovid, molnupiravir should be given as soon as possible after diagnosis and within five days of symptoms appearing. The antiviral works by introducing errors into the SARS-CoV-2 virus’ genetic code, hindering replication. Treatment consists of 40 capsules taken over five days. Molnupiravir does not appear to be as effective as Paxlovid, but it is also intended to treat all current virus variants. Like Paxlovid, it continues to be evaluated in ongoing clinical trials. Due to how the drug works, it is not recommended for pregnant patients with COVID-19, and there are considerations providers should review with patients regarding contraception. In addition, there are considerations health care providers should review concerning immunosuppressed patients.
Paxlovid and molnupiravir are the first two oral antivirals to be available. They are also currently in extremely limited supply as drug makers ramp up production. Consequently, neither antiviral is currently widely available and where available, both are prescribed only for patients who meet strict criteria and need.
Antiviral treatments date back to 1963 and the first human drug called idoxuridine, which was used to treat certain viral infections of the eye, but is no longer used in the United States. Rather than kill a virus directly, antivirals usually suppress the virus’s ability to infect and multiply in cells, typically by inhibiting molecular interactions and functions employed by the virus to produce new copies of itself. They may also boost the immune system or lower the viral load (amount of active virus) in the body.
Antivirals have been developed and used for a number of diseases or infections, including Ebola, influenza, herpes, hepatitis B and C and HIV. In some cases, the drugs rid the body of viruses; in other cases, such as HIV and herpes, they render the virus latent (inactive) so that there are few, if any, symptoms of disease.
Remdesivir is an antiviral compound originally developed to treat Ebola and Hepatitis C. It was the first antiviral approved by the FDA (October 2020) to treat COVID-19. The drug can shorten recovery time in adults hospitalized with COVID-19, and a recent study showed that if given early in disease treatment in high risk patients, it can prevent severe disease. It is administered as an intravenous infusion once daily, and appears to be effective against Omicron.
Q: What are some of the criteria that qualify COVID-19 patients for currently limited mAB or antiviral treatments?
A: A number of underlying medical conditions or co-morbidities increase a COVID-19 patient’s risk of experiencing severe disease, hospitalization or death. These conditions are considered by physicians when determining appropriate treatment. They include immunosuppressive conditions, advanced age, obesity, cancer, cerebrovascular disease, diabetes, mood disorders and schizophrenia, chronic diseases of the kidney, lungs, liver and heart, pregnancy, smoking, tuberculosis, HIV, Down syndrome, sickle cell disease, substance abuse disorders and more.
Q: What other COVID-19 treatments are being used?
A: In early 2020, doctors began treating hospitalized patients with severe COVID-19 with dexamethasone, a powerful corticosteroid that reduces inflammation. Dexamethasone was found to significantly benefit severely ill COVID-19 patients on oxygen. It is prescribed for seriously ill patients, and can do harm if given to someone with COVID who does not have severe disease with an oxygen requirement.
# # #
RSS