COVID-19: Tocilizumab did not significantly improve clinical status or mortality rate


In a study published online February 25, 2021 in The New England Journal of Medicine, a repurposed drug used to treat arthritis did not significantly improve the outcomes of patients with severe COVID-19 pneumonia.

Results of the Phase III clinical trial, conducted by an international team led by senior author Atul Malhotra, MD, research chief of pulmonary, critical care and sleep medicine at UC San Diego Health, found that tocilizumab did not significantly improve clinical status or mortality rate at 28 days for participants who received it compared to a placebo.

“Although our trial was negative based on primary outcomes, we did see some benefits, including an improvement in length of stay of eight days with tocilizumab compared to placebo, as well as fewer days on the mechanical ventilator with our intervention,” said Malhotra.

“Although it is important to be cautious in interpreting secondary outcomes, our trial helped in the design of subsequent studies which do show some improvement in outcomes with tocilizumab, particularly when given in combination with corticosteroids.”

Marketed as Actemra, tocilizumab is an immunosuppressive drug used primarily to treat rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of the disease in children.

The therapy works by using humanized monoclonal antibodies to specifically target and block cellular receptors for interleukin-6 (IL-6), a small protein or cytokine that plays an important role in triggering inflammation as an early immune response to disease.

In some patients with COVID-19, the immune response runs amok, overexpressing IL-6 and generating a “cytokine storm,” which can lead to potentially life-threatening damage to lungs and other organs.

Cytokine storms have been linked to a number of inflammatory diseases, from respiratory conditions caused by coronaviruses such as SARS and MERS to some forms of influenza to non-infectious diseases, such as multiple sclerosis and pancreatitis.

Researchers hoped that the heightened role of IL-6 in respiratory diseases and the fact that many severe cases of COVID-19 involve respiratory failure, hospitalization and death pointed to tocilizumab as a potentially effective therapy. Early case reports and retrospective observational studies buttressed that optimism.

The Phase III clinical trial, which began April 2020 and was conducted in 62 hospitals in nine countries, involved 452 patients with confirmed cases of severe COVID-19 pneumonia, randomized into a group of 294 persons who would receive an intravenous infusion of tocilizumab and 144 persons who received a placebo.

Malhotra expressed his gratitude to his team at UC San Diego as well as the countless individuals around the world who helped in the execution of a carefully done study.

The researchers found no significant difference in how the two groups fared, and no reduced mortality rate associated with tocilizumab, though they noted the trial was not designed to fully assess that outcome.

No safety issues arose regarding the use of tocilizumab, and the authors said study data suggested the treatment may have some therapeutic benefit during hospital stays and in shortening stays in intensive care units. In both cases, though, they said more research was required.

“Since this trial launched, a lot has been learned about the virus and about how COVID-19 manifests in different people, in different ways and stages,” said Malhotra. “These findings need to be understood in that context. We looked at very sick patients. There are very few proven therapies for severe COVID-19. Tocilizumab and some monoclonal antibody treatments may still have utility in specific circumstances, but more work needs to be done.

“In fact, more work must be done. The need for effective treatments for patients with severe COVID-19 pneumonia remains a major challenge of this pandemic. Each new study brings us one step closer to putting that challenge behind us.”

The clinical course of COVID-19 ranges from asymptomatic infection or mild respiratory symptoms to severe or life-threatening pneumonia and death. With no definitive curative treatment insight, and high mortality rate in vulnerable populations, health authorities have sought to re-stratify risks, and focus on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies, targeting the hospitalized and critically ill.

Several antiviral/antimalarial agents such as remdesivir, ritonavir/lopinavir combination, hydroxychloroquine, chloroquine; and immuno-modulating therapies such as tocilizumab, sarilumab, lenzilumab, eculizumab, ravulizumab, convalescent plasma, and interferon are currently being evaluated in randomized controlled trials (RCT) in many countries to evaluate their efficacy and safety in the treatment of COVID-19.

Current therapeutic pipelines for COVID-19 infection

One other investigational drug is also currently being evaluated for its use in COVID-19. Favipiravir is another RNA polymerase inhibitor that hinders viral replication. Its efficacy and safety profile were mostly obtained from preclinical data with influenza and Ebola virus disease [26,27,28,29,30]. Clinical evidence for the use of favipiravir in COVID-19 is limited. A prospective, multicentre RCT of 240 COVID-19 patients was randomized in a 1:1 ratio to receive either favipiravir or arbidol [31].

Favipiravir did not significantly improve the clinical recovery rate at day 7 [31]. No difference was observed in the requirement for supplemental oxygen or non-invasive mechanical ventilation [31]. Duration of febrile illness and cough, however, was significantly shorter in the favipiravir group [31]. To better evaluate the efficacy of favipiravir in the treatment of COVID-19, RCTs with a placebo control group will need to be conducted.

The anti-cytokines and immune-modulatory agents are also being evaluated for their use in severe COVID-19 disease. Pro-inflammatory cytokines, such as interleukin (IL)-2, IL-6, IL-7, IL10, granulocyte colony-stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α have been implicated in the underlying pathophysiology of a dysregulated host hyperinflammatory response in severe COVID-19 disease [32,33,34].

There are ongoing clinical trials evaluating the treatment options for this dysregulated host hyperinflammation targeting the inflammatory cascade. Earlier case studies from China suggest that IL-6 may be the predominant mediator of this dysregulated immune response [35]. Peak IL-6 level is associated with severity of pulmonary complications [36]; hence, monoclonal antibodies against IL-6 could reduce inflammatory response and improve clinical outcomes.

Tocilizumab, an IL-6 receptor antagonist, has been used in a small case series of 21 patients with severe COVID-19 with promising evidence [37]. Clinical improvement in respiratory function was evidenced by the reduction in oxygen requirement, and interval reduction in lung opacity on CT imaging [37].

A significant reduction in the percentage of lymphocytes and C reactive protein levels was also observed after tocilizumab treatment [37]. No SAE or AE was reported in this study [37]. In more recent RCTs, tocilizumab did not show benefit in clinical status [38], or in the prevention of intubation or death in moderately ill-hospitalized patients with Covid-19 [39].

Other immune-modulatory agents that are being investigated for the management of patients with dysregulated host hyperinflammatory response include humanized monoclonal antibody against circulating granulocyte macrophage colony-stimulating factor 40, 41 and humanized monoclonal antibodies that inhibit the late stage of complement cascade (ravulizumab [42], and eculizumab [43]).

Convalescent plasma therapy, though limited in experience and evidence, is regarded as one possible treatment of COVID-19. It is increasingly being used to urgently counter the COVID-19-associated mortality [44]. The hypothesis is that convalescent plasma of SARS-CoV patients carries antibodies against coronavirus, which may lead to phagocytosis or direct neutralization of the virus.

In a study during the SARS pandemic in 2003, 80 SARS patients were given convalescent plasma [45]. 41% of patients who were treated with convalescent plasma in the first 14 days of illness were discharged by day 22 [45]. The mortality rates, however, were no different in the group who received treatment before or after 14 days of illness [45].

It is difficult to make any conclusion from this study due to several limitations. These included a non-randomized study with no placebo group for comparison, variability of antibody dosing, and lack of long-term follow-up for risk of infusion-related infections.

It has been suggested, however, that empiric usage of convalescent plasma may be detrimental in some patients as “antibody-dependent enhancement (ADE)” may lead to a more severe infection later [44]. The risk of ADE is thought to occur in a patient with pre-existing antibodies. These antibodies may cross-react, and enhance infection against another virus, or a subtype of the same virus [44].


More information: Ivan O. Rosas et al, Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2028700


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