Drugs to treat COVID-19: What’s new?

When a drug is authorized by Health Canada, this does not necessarily mean that it can cure COVID-19, but that it can reduce mortality, serious complications (i.e. intensive care), the length or need for hospitalization, as well as the severity or duration of symptoms, with minimal serious side effects.

Vaccines remain the weapon of choice to counter the pandemic. No other medication currently offers such effective protection. By stimulating our immune system, vaccines enable the body to recognize and destroy the virus. So far, two main types of vaccines have been approved by Health Canada: the brand-new messenger RNA vaccines (Pfizer/BioNTec and Moderna) and the viral vector vaccines (Astra-Zeneca, Janssen). Clinical studies are still underway on virus-like particle vaccines, such as the one from Medicago (Quebec).

In some cases, an individual’s immune system is too weak to produce enough antibodies to respond to vaccination. So why not inject these patients directly with antibodies to fight the virus?

This hypothesis has been the basis for many treatments of infectious diseases that are derived directly from the serum of patients who have recovered from an infection (convalescent serum). Although the direct use of convalescent serums is not currently approved for the treatment of COVID-19, the pharmaceutical industry is capable of producing “semi-synthetic” antibodies, called “monoclonal antibodies” from this convalescent serum. These drugs, which target the so-called S (spike) protein of SARS-CoV-2, are intended for immunocompromised individuals who do not respond to the vaccine, or people suffering from a chronic illness who are at high risk of developing a severe form of the disease.

Currently, bamlanivimab (Eli Lilly), sotrovimab (GlaxoSmithKline) and the combination of casirivimab/imbivimab (Hoffman La Roche) are approved in Canada, while AZD7442 (AstraZeneca), a combination of two long-acting monoclonal antibodies (tixagevimab and cilgavimab), is being studied. According to the manufacturer, if approved, AZD7442 would be the first drug to not only treat but also prevent COVID-19. Another advantage is that its duration of action is believed to be three times longer than conventional monoclonal antibodies.[2]

Antiviral agents are used to control viral infections by targeting one or more stages of the virus’ life cycle. In the case of SARS-CoV-2, research is focused primarily on preventing the virus from multiplying by interfering with the action of the proteins required for its replication.

Let’s remember that the coronavirus genome is composed of a single strand of ribonucleic acid (RNA) carrying the information to produce proteins essential for the creation of new infectious viral particles. One of these proteins, called RNA polymerase, makes new RNA molecules by assembling their constituent parts, the nucleotides. The pharmaceutical industry has developed modified nucleotides. When these are used by RNA polymerase, they stop the process of making complete viral RNA, thereby halting the production of new virus particles.

This is the case for Veklury containing remdesivir (Gilead), which has been approved for use, and molnupiravir (Merck), which is currently under study. The advantage of molnupiravir is that it is available in tablet form instead of intravenous injections like other drugs. Patients could therefore take it at home, making it much easier to use.[3]

Among the other proteins produced by the virus’ RNA, some are formed in a line and must be detached from one another to be active. The viral protease is responsible for this process, which is called “protein maturation.” Drugs that can block this enzyme are currently being studied, such as Paxlovid (Pfizer), which would also be available in tablet form, which was approved in January 2022. By blocking production of the virus, this drug would prevent a mild or moderate form of COVID-19 from developing into a severe disease in people at risk.[4]

Chloroquine and hydroxychloroquine, used to treat malaria, and more recently ivermectin, used to treat scabies, have gained widespread interest among the public in the fight against SARS-CoV-2. These drugs are thought to have antiviral properties that prevent the virus from entering a cell’s nucleus, where it is replicated. Specifically, they are thought to impair the functioning of the endosome, a small pocket surrounded by a layer of fat, in which the virus must reside in order to enter the nucleus. However, no study has yet proven their efficacy, and Health Canada is not authorizing their use in the context of the pandemic. In fact, they have issued advisories to discourage people from using these drugs to prevent or treat COVID-19.[5,6]

One of the main problems with COVID-19 is the inflammatory response to the virus, which is thought to be partly responsible for hospitalizations and deaths. This excessive inflammatory response is referred to as a “cytokine storm” when it occurs in adults, usually during the later stages of infection, and a “childhood multisystem inflammatory syndrome” (CMIS) when it occurs in children at some point after infection (two to six weeks). While the rate of respiratory complications and death is high in adults, CMIS is characterized by a severe fever with conjunctivitis and swelling, as well as gastrointestinal or cardiovascular symptoms.[7]

Several drugs such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and interleukin-6 antagonists (IL-6) have long been used to combat inflammation. However, as the pandemic evolved, it became clear which ones were most useful for COVID-19 and at what doses to use them. At the beginning of the pandemic, NSAIDs such as ibuprofen were thought to worsen the symptoms of COVID-19, but health authorities have since changed their minds.[8] As a result, ibuprofen can continue to be used to relieve mild inflammatory conditions.

Dexamethasone, an anti-inflammatory drug in the corticosteroid family, was the first drug to save lives, especially in patients on ventilators.[9] The WHO also recommends the use of IL-6 antagonists for patients with a severe form of COVID-19, especially when combined with corticosteroids.[10] Originally developed to treat rheumatoid arthritis, tocilizumab (Roche) and sarilumab (Sanofi) are monoclonal antibodies that block the IL-6 receptor, a molecule involved in the inflammatory response. These drugs are believed to reduce the risk of death and the need for ventilator support.[11]