Background: Levilimab (LVL) is a novel anti-IL6Rmonoclonal antibody against IL6Rα. Cytokine release syndrome plays the key role in the pathogenesis of a range of life-threatening conditions including the acute respiratory distress syndrome in severely ill COVID-19 patients. Thus, the use of LVL could be considered as anti-cytokine therapy with a potency to prevent the complications and progression of respiratory failure in COVID-19.

Objectives: We analyzed the changes in the serum concentrations of inflammatory markers (Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and IL-6) in patients treated with LVL or placebo as part of a phase III multicenter randomized double-blind placebo-controlled adaptive-design CORONA clinical study aimed to evaluate the efficacy and safety of LVL in subjects with severe COVID-19 (NCT04397562).

Methods: A total of 217 patients were enrolled in the study, 206 patients were randomized, and 204 patients received the investigational product (IP, LVL or placebo).

Study included men and non-pregnant women aged ≥18 years, hospitalized for severe COVID-19 pneumonia, receiving standard therapy according to the national guidelines. Patients with acute respiratory failure with the need in invasive respiratory support, septic shock, multiple organ failure or life expectancy less than 24 hours could not participate in the study. The use of other monoclonal antibodies and glucocorticoids for the treatment of COVID-19 were not allowed.

Subjects were stratified according to the CRP level (CRP ≤ 7 mg/L; CRP > 7 mg/L) and then randomized (1:1) into 2 groups to receive LVL 324 mg or placebo. LVL/placebo were administered as a single subcutaneous injection, investigator and patients were unaware of the received therapy.

Among secondary endpoints of the study changes from baseline in ESR, CRP and IL-6 concentrations were assessed. CRP level and ESR were measured before the IP administration and on Days 3, 5, 7, 14, 21, 29 and 30. Blood samples for the measurement of IL-6 concentration were obtained before the IP administration and then every day for 2 weeks after administration.

Results: We observed the pronounced decrease of ESR in LVL group compared to Placebo group. The difference was statistically significant on Days 3 and 7: the median ESR change from baseline was -3 mm/h and +3 mm/h on Day 3, -11 mm/h and -3.1 mm/h on Day 7, in LVL and Placebo groups, respectively (p=0.0319 and p=0.0110, Days 3 and 7). The statistically significant difference in the change of CRP level was detected between the groups on Day 3: -26.6±41.9 mg/L and -19.2±58.2 mg/L in LVL and Placebo groups, respectively (p=0.0241). Numerically the same dynamics of ESR and CRP was observed over entire study period.

The dynamics of IL-6 serum concentrations in LVL and Placebo groups was strikingly different. After LVL administration we detected the rapid significant increase in IL-6 concentration due to IL-6 receptors inhibition. Maximum change from baseline was observed on Day 3 (+91.9±117.7 pg/mL), on Day 14 the value was +31.9±62.7 pg/mL.

In the Placebo group, the IL-6 concentration increased slightly until Day 4 (+5,1±76,5 pg/mL), and then decreased significantly (-39.2±55.1 pg/mL on Day 14) due to clinical improvement in this group.

Conclusion: The significant differences in the dynamics of ESR, CRP and IL-6 after LVL administration compared to placebo confirmed the pharmacodynamic effect and its potency to prevent the excessive release of inflammatory substances in severely ill COVID-19 patients.

REFERENCES:

[1]Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020 May 19;117(20):10970-10975. doi: 10.1073/pnas.2005615117. Epub 2020 Apr 29. PMID: 32350134; PMCID: PMC7245089.

Acknowledgements: We thank all contributors to the CORONA study.

Disclosure of Interests: Nikita Lomakin: None declared, Bulat Bakirov: None declared, Gaziiavdibir Musaev: None declared, Denis Protsenko: None declared, Olga Moiseeva: None declared, Elena Pasechnik: None declared, Vladimir Popov: None declared, Elena Smolyarchuk: None declared, Ivan Gordeev: None declared, Michail Gilyarov: None declared, Daria Fomina: None declared, V Mazurov: None declared, Maria Morozova Employee of: JSC BIOCAD, Ekaterina Dokukina Employee of: JSC BIOCAD, Dmitrii Bogdan Employee of: JSC BIOCAD, Anton Lutskii Employee of: JSC BIOCAD, Arina Zinkina-Orihan Employee of: JSC BIOCAD, Iulia Linkova Employee of: JSC BIOCAD, Anton Seleznev Employee of: JSC BIOCAD.