Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: An observational study

Abstract

Objective The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. Methods The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). Results CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. Conclusion In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

Efficacy and safety of Ixekizumab vs. low-dose IL-2 vs. Colchicine vs. standard of care in the treatment of patients hospitalized with moderate-to-critical COVID-19: A pilot randomized clinical trial (STRUCK: Survival Trial Using Cytokine Inhibitors)

“…Interestingly, anti-IL-17 treatment with netakimab or secukinumab in patients with severe COVID-19 decreased the incidence of pulmonary embolism, suggesting that IL-17 is a key player contributing to this disease complication 40,41 which is in line with the reported pro-coagulant and pro-thrombotic effects of IL-17 42 . The treatment of patients with moderate COVID-19 with netakimab significantly reduced systemic inflammation and improved clinical disease, decreasing the length of stay and mortality 43 . Altogether, these results suggest that anti-IL-17 treatment efficacy is dependent on the severity of the disease, being more effective in COVID-19 cases where the inflammation status is more intense.…”

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters

“…When acting as immune regulator, IL6 is able to work on both the innate and acquired arms of the system: on one side, it can de-regulate natural killer and CD8 + T cell responses, thus reducing antiviral defenses; on the other side, it can interfere with acquired immune responses by promoting B cell differentiation toward antibody-producing plasma cells and by regulating CD4 T cell differentiation toward Th2 and Th17 lymphocytes [ 98 , 100 , 101 , 102 , 103 ].…”

“…Since the beginning of the pandemic, different observational studies and clinical trials have investigated the effectiveness of IL6 signaling inhibitors in preventing ARDS and mortality in SARS-CoV-2-positive patients. In this context, the most studied drug is tocilizumab, a recombinant humanized monoclonal antibody directed to IL6 receptor alpha [ 101 , 107 , 108 ]. Recent meta-analyses, including the most recently published results of randomized clinical trials performed using a random-effects model to pool the results of the clinically heterogeneous trials, found that tocilizumab administered along with the standard of care therapy was able to reduce both 28-day mortality index and the need of mechanical ventilation and ICU admission, as well as to shorten the time to discharge [ 97 , 102 , 109 , 110 ].…”

Severe COVID-19versusmultisystem inflammatory syndrome: comparing two critical outcomes of SARS-CoV-2 infection

“…For later presentations, anti-inflammatory agents (e.g. tocilizumab or baricitinib) are well established [196][197][198] and further stratification may allow selection of patients requiring treatment with various other immunomodulatory agents at later stages of disease. In MIS patients, anti-inflammatory strategies can be used, although with some differences, and intravenous immunoglobulin and thromboprophylaxis with low-dose aspirin is also considered [199][200][201][202][203][204][205].…”