Virus World

The Food and Drug Administration has approved Tocilizumab for use against moderate to severe Covid-19 symptoms. The FDA has approved an early gift for those suffering from Covid-19 this holiday season. Tocilizumab, branded Actemra by pharmaceutical company Genentech, is a monoclonal antibody now approved for treating Covid-19 in hospitalized adult patients in moderate to severe conditions. All treatments to this point of the pandemic were only temporarily approved via emergency use authorization, speaking to the value of Tocilizumab. Here we discuss how the antibody was discovered and how it works. Unlike many monoclonal antibody treatments we discuss, Tocilizumab has a long history dating back 25 years. Clinical development of the antibody began in 1997 by Chugai Pharmaceuticals in Japan to treat rheumatoid arthritis. Chugai Pharmaceuticals and Genentech are now under the Roche Group umbrella, a Swiss multinational healthcare company. The researchers at Chugai Pharmaceuticals found that specific mouse antibodies contained anti-human IL-6 receptors. Interleukin-6, or IL-6, is a secreted cytokine protein expressed by white blood cells. In terms of disease, IL-6 stimulates inflammatory processes when the body is exposed to various pathogens and clinical conditions such as diabetes, multiple sclerosis, and rheumatoid arthritis.

Upon identifying the anti-human IL-6 receptors in mice, the researchers grafted the receptor onto a human IgG constant Fc region using recombinant DNA technology, effectively humanizing the receptor. Later research by Kishimoto et al. confirmed that the engineered mouse antibody receptor grafted to the human IgG constant Fc exclusively blocked IL-6 trans-signaling without affecting other significant pathways. IL-6 inhibition sufficiently blocks inflammation without inhibiting other immune defenses against infection. Contrary to popular belief, many of the classic symptoms we experience when we are sick are not directly caused by an invading pathogen but rather consequences of our immune system fighting off the pathogen. Inflammation is one of the most prominent causes of body pain, fatigue, fever, rash, and other significant symptoms most endure during sickness. In severe cases, inflammation may cause severe pain, lack of appetite, and severe headaches and chills. To produce the drug en masse, Chugai Pharmaceutical used genetic manipulation of host cells. They encoded the genes that code for tocilizumab production onto a human host T-cell. The encoded T-cell is then transfected into Chinese hamster ovary cells. These cells are then manipulated to express countless tocilizumab genes, creating a master that can be copied several times.

Two drugs that dampen the body’s immune response can save the lives of people with severe COVID-19. Some people gravely ill with COVID-19 have tissue damage inflicted by their own immune response, and also show increased activity of immune-system molecules and cells regulated by a protein called IL-6. To study the effect of quashing IL-6 activity, Anthony Gordon of Imperial College London and his colleagues tested the drugs tocilizumab and sarilumab, which block the protein that immune cells use to detect IL-6 (A. C. Gordon et al. Preprint at medRxiv https://doi.org/fqgf; 2021).

The team gave the drugs to 803 adults with COVID-19 who were in intensive care and receiving organ support, such as ventilation or high-flow oxygen. Of these participants, 353 received tocilizumab, 48 received sarilumab and 402 received neither. The drug treatment reduced the death rate — from nearly 36% in the control group to 28% among those who received tocilizumab and 22% for sarilumab. The results have not yet been peer reviewed.

Preprint in medRxiv (Jan. 9, 2021):

https://doi.org/10.1101/2021.01.07.21249390 

Many Covid-19 patients may be dying from their immune response to the virus, not from the virus itself. Can science figure out how to save them? Back in April, as the pandemic was cresting over New York, Iris Navarro-Millán, a physician at Weill Cornell Medicine in Manhattan, treated a Covid-19 patient, a Hispanic woman in her 60s, who would prove to be a turning point in how she approached the disease. The woman was just a little short of breath when Navarro-Millán first saw her; a day later, she deteriorated so rapidly that she was rushed to intensive care, put on a ventilator and hooked up to a dialysis machine for her failing kidneys. Navarro-Millán feared that she would die. (She survived after spending two months sedated on the breathing machine.) When Navarro-Millán saw another Covid-19 patient soon after — a white man in his 60s already struggling to breathe — her first thought was, Not again. Believing that the prevailing standard of care — which, lacking drugs to directly fight the virus, consisted primarily of supportive measures like supplemental oxygen — was insufficient, she resolved to try something different, a treatment that was heretical in some circles but that she thought could save his life.

Navarro-Millán had unusual expertise for a hospitalist. Weill Cornell had asked her to move into that role when the pandemic hit, but she was a rheumatologist by training, a doctor whose specialty is autoimmune ailments in which the immune system, tasked with defending the self from invading pathogens, inexplicably turns on the body’s own tissues. Now she drew on her experience to try to help this Covid-19 patient. She suspected that the greatest danger here wasn’t the coronavirus itself but an immune overreaction so severe that it could cause lungs to fill up with fluid and prompt organs to shut down, possibly killing the patient. Rheumatologists often describe this type of immune reaction as a “cytokine storm” or “cytokine release syndrome.” Cytokines are proteins released by cells in order to send messages to other cells — signaling, for instance, that a viral invasion is underway. The number of different cytokines is large, perhaps exceeding 100, and each one calls for a specific response. To save her patient, Navarro-Millán decided that she would have to calm his immune system and prevent that storm from getting started. Early in her career, Navarro-Millán worked at the University of Alabama at Birmingham, where most of her patients had lupus, an autoimmune disease that can affect various parts of the body, including the kidneys, blood and even the brain. Its sufferers are especially prone to cytokine storms, which are often triggered by viral infections. What Navarro-Millán saw now in her Covid-19 patients wasn’t, she thought, all that different from what she encountered in Alabama.

A major lesson learned from her years there was that saving patients from cytokine storms often required doctors to intervene early, preferably long before the patients landed in the I.C.U., when it was frequently too late to bring the immune system to heel. So, the sooner she treated her Covid patient by tamping down his inflammatory response, she figured, the better. At the same time, she was leery of subduing his immune system for too long or too profoundly, because that might hobble his body’s ability to fight the virus that was making him sick in the first place. An array of drugs was available to her, ranging from antibodies that target specific pathways in the immune system to molecules that have a more widespread effect on the body. One, called tocilizumab, blocked the cytokine interleukin-6, but it remained in the body for up to a month — too long, in her view. Steroids, which dampen the entire immune system, might open the door to other infections. (Hydroxychloroquine, an antimalarial drug that has been promoted by President Trump for its supposed coronavirus-fighting potential, also happens to suppress the immune system. But because this effect, which is mild, comes only after months of daily use, it is unlikely to be suitable as a way to quell an immune firestorm started by an infection. The evidence so far suggests that it doesn’t work as an antiviral remedy, either, and that it can cause severe side effects.)..

The FDA has issued an emergency use authorization for tocilizumab to treat hospitalized patients receiving corticosteroids who require supplemental oxygen, mechanical ventilation or extracorporeal membrane oxygenation, according to a press release. The emergency use authorization for tocilizumab (Actemra, Genentech) — now the fourth monoclonal antibody authorized for COVID-19 — is is specifically for hospitalized adults and children aged 2 years and older; it is not intended for outpatients or as a treatment for COVID-19, the FDA noted.  “Today’s action demonstrates the FDA’s commitment to making new therapies available through every stage of the global COVID-19 pandemic,” Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, said in a press release. “Although vaccines have been successful in decreasing the number of patients with COVID-19 who require hospitalization, providing additional therapies for those who do become hospitalized is an important step in combating this pandemic.”

The FDA based its emergency use authorization on results from four randomized, controlled trials — RECOVERY, EMPACTA, COVACTA and REMDACTA — that evaluated the safety and efficacy of tocilizumab in more than 5,500 hospitalized patients with COVID-19. In particular, the RECOVERY and EMPACTA trials provided the “most important scientific evidence on the potential benefit of Actemra for its authorized use,” the FDA noted. In the RECOVERY trial, hospitalized patients with severe COVID-19 pneumonia (n=4,116) were randomized to receive either tocilizumab plus standard care (n=2,022) or standard care alone (n=2,094). The primary endpoint was death through 28 days of follow-up.

According to the FDA, the “results of the primary analysis were statistically significant” with the probability of death by day 28 estimated to be 30.7% for patients receiving tocilizumab and 34.9% for patients receiving standard care alone. Additionally, the median time to hospital discharge was 19 days in the tocilizumab group compared with more than 28 days in the standard care group. Supplemental data from the EMPACTA trial, in which hospitalized patients with COVID-19 pneumonia (n=389) were randomized to receive tocilizumab (n=249) or standard care (n=128), demonstrated a lower risk for progression to mechanical ventilation or death by day 28 in hospitalized patients who received tocilizumab (12% vs. 19.3%). “Even with the availability of vaccines and declines in deaths from COVID-19 in various parts of the world, we continue to see new hospitalizations from severe forms of the disease,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a company press release. “We are pleased that Actemra is now authorized as an option that may help improve outcomes for adults and children hospitalized with COVID-19 in the United States.” The emergency use authorization requires that fact sheets be made available to health care providers and patients, parents and caregivers featuring information on the potential side effects, which include constipation, anxiety, diarrhea, insomnia, hypertension and nausea.

See also FDA information (June 24, 2021):

https://www.fda.gov/media/150345/download 

A study of a drug that mutes the body’s immune response found that it did not prevent the deaths of people with moderate COVID-19, dealing a blow to a once-popular hypothesis about treatments for the disease. In some people with severe COVID-19, the immune system launches an excessive inflammatory response, suggesting a link between grave illness and an overly vigorous immune defence against SARS-CoV-2. The link is bolstered by the association between high levels of a protein called IL-6, which stimulates the immune system, and both death and the need for ventilation in people with COVID-19.

John Stone at the Massachusetts General Hospital in Boston and his colleagues tried to dampen inflammation in people with COVID-19 by treating them with the drug tocilizumab, which interferes with IL-6 activity (J. H. Stone et al. N. Engl. J. Med. https://doi.org/ffjp; 2020). But in a randomized, controlled trial of 243 people with moderate disease, the team found no statistically significant reduction in deaths or the need for ventilation among those who received tocilizumab compared with those who didn’t. The study does not rule out the possibility that a larger trial with more statistical power could uncover a benefit.