The emergence and reemergence of tocilizumab for COVID-19
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The economic and societal impacts of emerging infectious diseases remain ever present, with COVID-19 being at the forefront.
Over the past year, we have all experienced how mitigation and prevention strategies contend with more genetically adaptable microbes. Social distancing, wearing masks and vaccines have proven to be effective in flattening the COVID-19 curve. The optimal therapeutic approach for treating COVID-19 is less clear.
COVID-19 treatment challenges lie in the heterogenous clinical syndrome, ranging from asymptomatic infection to acute respiratory disease syndrome, multiorgan failure and death. The mechanism spurring progression to more severe COVID-19 illness is not completely understood. A leading hypothesis points to a hyperimmune response reflected by a flux of circulating proinflammatory cytokines. Suppression of proinflammatory cytokines, such as interleukin-6 (IL-6), is a potential strategy. This notion aligns with the corticosteroid dexamethasone being one of the few therapies demonstrating a mortality benefit in hospitalized patients with COVID-19. Recent evidence has shown more targeted anti-inflammatory agents like tocilizumab could provide further benefit.
Tocilizumab is a recombinant monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors, preventing IL-6 binding and reducing IL-6 signaling. Tocilizumab is approved for use in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen receptor T-cell therapy. In the setting of COVID-19, early observations from China showed patients with COVID-19 and elevated IL-6 levels had a higher risk for death. Case reports and case series revealed tocilizumab having possible benefit. Off-label tocilizumab use emerged for COVID-19 patients with worsening oxygen requirements and evidence of hyperinflammation, although use varied greatly, often resulting in it being a last-line treatment option. The studies that saw a treatment benefit included patients who were receiving higher levels of oxygen support and/or had greater receipt of corticosteroids. However, many of these trials were underpowered and single centered with diverse populations and had a low frequency of concomitant corticosteroid use. Smaller, open-label, randomized controlled trials were published, with many not showing clear evidence of tocilizumab efficacy, resulting in tocilizumab falling out of favor. More recently, tocilizumab has reemerged for COVID-19. This article provides a careful evaluation of the impact trials that caused this shift in practice.
EMPACTA and COVACTA
EMPACTA and COVACTA were double-blind, multicenter, randomized controlled trials funded by Genentech that yielded conflicting results.
Evaluating Minority Patients with Actemra (EMPACTA) met its primary endpoint, showing a lower risk for progression to mechanical ventilation or death by day 28 in hospitalized patients who received tocilizumab (8 mg/kg, maximum 800 mg dose; 12% vs. 19.3%) but found no difference in mortality between the tocilizumab and standard-of-care groups. More than 80% of the patients enrolled in EMPACTA received concomitant systemic corticosteroids and greater than 50% received remdesivir.
In comparison, COVACTA, which enrolled hospitalized patients with severe COVID-19 pneumonia, failed to demonstrate improvement in clinical status among patients who received tocilizumab (8 mg/kg, maximum 800 mg dose) compared with those in the standard-of-care group. However, patients in the tocilizumab arm had a shorter length of hospital stay. Notably in COVACTA, the proportion of patients who received systemic corticosteroids was lower (36.1% in the tocilizumab arm and 54.9% in the control arm), possibly cementing further a greater benefit with tocilizumab when administered in conjunction with corticosteroids.
REMAP-CAP
The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) study included 865 critically ill, hospitalized patients with COVID-19 in several countries who were admitted to an ICU and received respiratory or cardiovascular support. This open-label trial excluded patients who had been in the ICU for longer than 24 hours, those who were immunosuppressed and/or with liver impairment (alanine transaminase [ALT] greater than 5 times upper limit of normal). Patients were randomly assigned to receive either tocilizumab 8 mg/kg of body weight plus a possible second dose within 12 to 24 hours of the first (n = 353), one dose of sarilumab 400 mg (n = 48), or standard of care (n = 402). Those who received tocilizumab had a lower mortality (28% vs 35.8%) and shorter duration of organ support. Roughly 90% of patients were on concomitant corticosteroids. These same results cannot be applied to sarilumab because of a very small proportion of patients in this arm.
RECOVERY
The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial has been the largest tocilizumab randomized, open-label study to date. In all, 2,022 patients in the United Kingdom with either oxygen saturations less than 92% or on supplemental oxygen and with an elevated C-reactive protein levels (75 mg/L or greater) received tocilizumab in comparison to 2,094 patients in the standard of care group. Eighty-two percent of patients were on corticosteroid therapy. The tocilizumab dose was determined by total body weight (greater than 90 kg: 800 mg; 66 to 89 kg: 600 mg; 41 to 65 kg: 400 mg; less than 41 kg: 8 mg/kg tocilizumab). The primary outcome, all-cause mortality within 28 days of randomization, occurred in 31% of patients in the tocilizumab cohort and 35% of patients receiving standard of care. In addition, patients in the tocilizumab group were more likely to be discharged from the hospital within 28 days than the control group. With a better understanding of the hyperimmune syndrome and more firm data supporting an optimal time frame to administer tocilizumab, it has reemerged as a potential treatment option in the setting of COVID-19.
Tociluzumab is not without risks
Tocilizumab has returned, at least for now. Currently, patients with COVID-19 with high and worsening oxygen requirements, along with elevated inflammatory markers, appear to garner the greatest benefit from tocilizumab. Much more needs to be understood about the hyperimmune response associated with severe COVID-19 cases and how best to target it. Studies investigating other immunomodulating therapies, like sarilumab, have not shown similar benefit as is seen with tocilizumab. Preliminary findings from a third Genentech trial, REMDACTA, with tocilizumab plus remdesivir vs. placebo plus remdesivir, did not show improvement in time to hospital discharge up to day 28, according to a press release.
Tocilizumab is not without its own risks and associated costs. The secondary infection and long-term adverse event risks have not been well defined in patients with COVID-19. Lastly, the long-term mortality impact is not known. Tocilizumab is an added agent to our COVID-19 treatment armamentarium that needs to be used with continued caution.
- References:
- Gordon AC, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2100433.
- Khan FA, et al. Thorax. 2021;doi:10.1136/thoraxjnl-2020-215266.
- Morens DM, Fauci AS. Cell. doi:10.1016/j.cell.2020.10.022.
- National Institutes of Health COVID-19 Treatment Guidelines: Interleukin-6 inhibitors. (nih.gov). https://www.covid19treatmentguidelines.nih.gov/immunomodulators/interleukin-6-inhibitors. Accessed May 16, 2021.
- Parr JB. JAMA Intern Med. 2021;doi:10.1001/jamainternmed.2020.6557.
- Recovery Collaborative Group. Lancet. 2021;doi: 10.1016/S0140-6736(21)00676-0.
- Roche. Roche provides update on the phase III REMDACTA trial of Actemra/RoActemra plus Veklury in patients with severe COVID-19 pneumonia. Accessed May 17, 2021. https://www.roche.com/media/releases/med-cor-2021-03-11.htm.
- Rosas IO, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2028700.
- Salama C, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2030340.
- Tocilzimab [package insert]. South San Francisco, CA: Genentech; 2021.
- For more information:
- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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