Scientists began to investigate Tocilizumab in clinical trials as a possible therapy for COVID-19 because of the drug’s potent anti-inflammatory properties. Tocilizumab, a monoclonal antibody drug manufactured by Hoffman-La Roche, is marketed in the US as Actrema® and is approved for treating arthritis. Tocilizumab effectively treats arthritis by reducing the progression of inflammation in the body. Specifically, Tocilizumab reduces inflammation by blocking the effects of the cytokine interleukin-6 (“IL-6”). Cytokines such as IL-6 are substances produced by the body to regulate normal immune response. In COVID-19, levels of IL-6 and other cytokines increase to much higher than normal levels in attempting to rid the body of the SARS-CoV-2 virus. Clinicians and immunologists refer to this phenomenon as a “cytokine storm.” Exposure of the body’s tissues to sustained high cytokine levels produces sustained tissue inflammation, particularly in the lungs. Sustained inflammation is not a normal response and can severely damage the lungs. Damaged lungs of COVID-19 patients viewed by CT scan are often infiltrated by opaque areas that resemble ground glass, and thus are called “ground glass” opacities. The damaged lungs can no longer expand properly upon inhalation and exhalation. Patients can develop pneumonia, and; in severe cases, respiratory failure leading to death. As the progression of severe inflammation leading to COVID-19 pneumonia may be triggered by a cytokine storm, it seems reasonable to consider that a drug that selectively blocks cytokine activity could effectively treat the disease. Thus, it was hypothesized that Tocilizumab’s ability to block IL-6 activity could help alleviate the cytokine storm of COVID-19 infection and lead to clinical cure. Since Tocilizumab is available in worldwide markets, international investigators began actively investigating its role as a COVID-19 therapy in late winter of 2020.
Several clinical trial designs were used to investigate Tocilizumab safety and effectiveness for treating COVID-19 disease. Patients in these trials were hospitalized males and females, ranging in age from 22 to 99 years. Patient comorbidities included cancer; sickle-cell anemia; hypertension; diabetes; stroke; chronic obstructive pulmonary disease (“COPD”); chronic heart disease; chronic kidney disease; and obesity. Trials were conducted in China, France, Italy, and the U.S. Tocilizumab was given either intravenously at 4- or 8-mg/kg body weight or subcutaneously at 162- or 324-mg doses, as either single doses or 2-3 doses given 12-72 hours apart. Trial designs included observational (8 trials), observational with matched controls (5 trials), or randomized placebo-controlled (2 trials). Two trials were designed to evaluate Tocilizumab as part of a combination regimen, and 3 trials studied Tocilizumab safety.
In observational trials, COVID-19 patients improved when treated with Tocilizumab as adjunct therapy in standard drug treatment regimens, but trials had no control groups for comparison. Patients in these trials had either severe or critical COVID-19 infections. Severe COVID-19 infections are diagnosed by CT scans or X-rays showing infiltrates in more than 50% of the lung field and by lung function measurements – such as pulse oximetry values – below normal ranges. Critical infections are diagnosed in patients who progress to shock, multiple organ failure, or respiratory failure requiring invasive mechanical ventilation. In the observational trials, Tocilizumab was given to patients with severe or critical COVID-19 infections as adjunct therapy added to standard treatment protocols. Standard treatment consisted of regimens of lopinavir/ritonavir, hydroxychloroquine, azithromycin, ribavirin, interferon-α, or methylprednisolone. Clinical improvement occurred shortly after Tocilizumab treatment. Fevers generally resolved within 24-48 hours. Lung ground glass opacities and infiltrates disappeared, respiratory function improved, and many patients who had been ventilated no longer required mechanical ventilation. Patient mortality ranged from 0 to 20%. Many or all of the patients in each trial were discharged by 6 to 40 days after hospitalization. Blood levels of the “immune markers” C-reactive protein, D-dimer, and ferritin, which are high in a cytokine storm, were elevated in patients’ blood at the time of hospitalization and declined to nearly normal levels after Tocilizumab treatment. Although the improvement in Tocilizumab-treated patients in these early trials was rapid and remarkable, it is not known if patients would have recovered as quickly without Tocilizumab, because there were no controls for comparison. Also, it is not known to what extent the concomitant standard drug treatment regimens contributed to disease recovery.
In two small observational trials designed to evaluate Tocilizumab in combination with another drug, COVID-19 patients with severe or critical disease improved rapidly and dramatically. Both trials did not include controls. The first trial used Tocilizumab in combination with the steroid hormone drug Methylprednisolone. In this trial of 21 patients with critical infections who needed invasive mechanical ventilation, 20/21 were disconnected from ventilators within an average of 8 days after receiving Tocilizumab. No patients died. The second trial studied a single pregnant patient with severe disease treated with a combination of Tocilizumab and the antiviral drug Remdesivir. The patient had many co-morbidities and required supplemental oxygen. One day after receiving Tocilizumab, her attending physicians were able to reduce the level of oxygen that she needed. One day after her Remdesivir 5-day treatment ended, she was released from the hospital. At a 14-day follow-up, her blood IL-6, C-reactive protein, ferritin, and D-dimer levels had all returned to normal. Notably, both Methylprednisolone and Remdesivir are known to be effective in treating COVID-19 infections. Thus, the relative contribution of Tocilizumab as adjunct therapy in these trials is not known.
Effectiveness of Tocilizumab as adjunct therapy for COVID-19 disease treatment seemed to vary with disease severity in several trials that used matched control groups. These trials studied from 45 to 239 patients who received lopinavir/ritonavir, hydroxychloroquine, azithromycin, or corticosteroids throughout the trials. Tocilizumab did not reduce mortality in patients with moderate infections. In 3 trials of patients with severe infections, Tocilizumab either did not reduce mortality or slightly reduced mortality. In one trial, mortality was similar in Tocilizumab-treated patients and controls. In the second trial, mortality in Tocilizumab-treated patients was 16% versus 33% in controls; in the third trial, mortality in Tocilizumab-treated patients was 25% versus 48% in controls. These differences were not statistically significant due to the small numbers of patients. In a large trial that studied patients with critical infections on ventilators, Tocilizumab did significantly reduce mortality at 28 days compared to controls; values were 18% versus 36%. Regarding Tocilizumab effects on clinical outcome, results of these trials were mixed. In only 2 trials of patients with severe disease, time in hospital and time to clinical improvement were shorter in Tocilizumab-treated patients. In the other trials of patients with either severe or critical disease, clinical outcomes were similar in Tocilizumab-treated patients and controls. Interpretation of the results of these matched controlled trials is confounded because (1) there is the possibility of bias in selecting the “matched” control group; and (2) the relative contributions of the other therapies to patient outcome is not known.
In two large, randomized, placebo-controlled trials, Tocilizumab as monotherapy did not improve either survival or clinical status of COVID-19 patients. The first of these trials was a late stage trial in 450 patients with severe COVID-19 infections, sponsored by Hoffmann-La Roche, and intended to be submitted to the FDA to support Tocilizumab approval for treating COVID-19 infections. The trial was conducted at multiple centers in the US and patients were randomly assigned to receive either single doses of Tocilizumab as monotherapy or placebo. After 4 weeks of observation, mortality was similar in the Tocilizumab-treated patients and controls. In addition, Tocilizumab did not improve clinical status compared to controls, although it did reduce time to hospital discharge. Limited information is available about the second trial, which was conducted in Italy. The second trial was stopped early with the support of the Italian Medicines Agency, after treating 126 patients, because Tocilizumab did not reduce severe respiratory symptoms, intensive care visits, or mortality, compared to standard treatments.
Three recent trials identified safety issues with Tocilizumab treatment of COVID-19 patients. As Tocilizumab suppresses the immune system, a concern is that its use can induce severe infections that follow the original COVID-19 infection. In one trial, about 50% of patients developed bacterial pneumonia after Tocilizumab treatment. In another trial, about 7% of Tocilizumab-treated patients developed candidaemia, which is the presence of a Candida ablicans – yeast – infection in the bloodstream. Extremely concerning are the results of an observational trial in which blood levels of cytokines and immune markers in two COVID-19 patients increased by 10-40 fold rather than decreasing after Tocilizumab treatment. The two patients died. The authors of this last trial speculated that if Tocilizumab is given at the wrong time during COVID-19 disease progression, this could lead to aggravation rather than alleviation of the cytokine storm. The authors of all three of these safety trial reports cautioned that, since Tocilizumab is not yet approved for treating COVID-19, it should not be used outside of a clinical trial. Notably, the FDA has not issued an Emergency Use Authorization promoting the off-label use of Tocilizumab for treating COVID-19.
Large placebo-controlled trials are needed to determine whether Tocilizumab has a role in treatment of COVID-19 infections and to further characterize its safety. Results of small uncontrolled clinical trials conducted to date suggest that Tocilizumab may be effective as adjunct therapy if given in combination with drugs known to be effective in treating COVID-19 infections, in particular Remdesivir or Methylprednisolone. In controlled trials, Tocilizumab effectiveness varied with disease severity; having no effect in moderate disease, modest effects in severe disease, and the most pronounced effects in critical disease. Tocilizumab as monotherapy was not effective in treating COVID-19 patients in two large, randomized, placebo-controlled clinical trials. Several recent trials identified safety concerns with Tocilizumab treatment, notably onset of new infections and the possibility of aggravating rather than reducing COVID-19-associated cytokine levels. Additional randomized, placebo-controlled trials can be designed to determine how to optimize the role of Tocilizumab in COVID-19 disease management by identifying the appropriate (1) patient population; (2) timing for treatment initiation; (3) drugs for co-administration; and (4) strategies to minimize adverse events.