biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2022-22-4-446-459biopreparat-443Research ArticleСтатьиКлиническая эффективность ингибирования рецептора интерлейкина-6 при COVID-19 левилимабом и перспективы его применения при синдроме высвобождения цитокинов другой этиологииLevilimab clinical efficacy for interleukin-6 receptor inhibition in COVID-19 and its potential for treating cytokine release syndrome of other aetiologieshttps://orcid.org/0000-0001-8830-7231ЛомакинН. В.LomakinN. V.

Ломакин Никита Валерьевич,  д-р мед. наук. 

ул. Маршала Тимошенко, д. 15, Москва, 121359

Nikita V. Lomakin, Dr. Sci. (Med.)

15 Marshal Timoshenko St., Moscow, 121359

lomakinnikita@gmail.comhttps://orcid.org/0000-0002-3297-1608БакировБ. А.BakirovB. A.

Бакиров Булат Ахатович,  д-р мед. наук, проф. 

ул. Ленина, д. 3, г. Уфа, Республика Башкортостан, 450008

 

 

Bulat A. Bakirov, Dr. Sci. (Med.), Professor

3 Lenin St., Ufa, Republic of Bashkortostan 450008

bakirovb@gmail.comhttps://orcid.org/0000-0002-6550-7975МусаевГ. Х.MusaevG. H.

Мусаев Газиявдибир Хадисович,  д-р мед. наук, проф. 

ул. Ляхова, д. 47, Махачкала, Республика Дагестан, 367026

Gaziyavdibir H. Musaev, Dr. Sci. (Med.)

47 Lyakhov St., Makhachkala, Republic of Dagestan 367026

gasiyav@mail.ruhttps://orcid.org/0000-0002-1570-2748ПоповВ. В.PopovV. V.

Попов Владимир Васильевич,  д-р мед. наук, проф. 

Волоколамское шоссе, дом 11, Москва, 125080

ул. Ставропольская, д. 23, корп. 1, Москва, 109386

 

Vladimir V. Popov, Dr. Sci. (Med.)

 11, Volokolamskoye Hwy, Moscow 125080

23/1 Stavropolskaya St., Moscow 109386

clinpharmcb6@mail.ruhttps://orcid.org/0000-0002-2615-7167СмолярчукЕ. А.SmolyarchukE. A.

Смолярчук Елена Анатольевна,  канд. мед. наук, доц. 

Трубецкая ул., д. 8, стр. 2, Москва, 119991

Elena A. Smolyarchuk, Cand. Sci. (Med.), Assoc. Prof.

8/2 Trubetskaya St., Moscow 119991

smolyarchuk@mail.ruhttps://orcid.org/0000-0002-5463-1022ЛиньковаЮ. Н.LinkovaYu. N.

Линькова Юлия Николаевна, канд. мед. наук

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

Yulia N. Linkova, Cand. Sci. (Med.).

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

linkova@biocad.ruhttps://orcid.org/0000-0002-3334-3531БогданД. В.BogdanD. V.

Богдан Дмитрий Владимирович

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

 

Dmitrii V. Bogdan

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

bogdan@biocad.ruhttps://orcid.org/0000-0001-5196-6911ЕремееваА. В.EremeevaA. V.

Еремеева Анна Викторовна, канд. мед. наук.

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

Anna V. Eremeeva, Cand. Sci. (Med.)

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

eremeevaav@biocad.ruhttps://orcid.org/0000-0001-9790-8207ПухтинскаяП. С.PukhtinskaiaP. S.

Пухтинская Полина Сергеевна, канд. мед. наук.

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

Polina. S. Pukhtinskaia, Cand. Sci. (Med.)

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

puhtinskaya@biocad.ruhttps://orcid.org/0000-0001-7755-7526МорозоваМ. А.MorozovaM. A.

Морозова Мария Андреевна, канд. мед. наук.

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

Maria A. Morozova, Cand. Sci. (Med.)

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

 

morozovama@biocad.ruhttps://orcid.org/0000-0002-8499-2232Зинкина-ОриханА. В.Zinkina-OrikhanA. V.

Зинкина-Орихан Арина Валерьевна

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Arina V. Zinkina-Orikhan

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zinkina@biocad.ruhttps://orcid.org/0000-0003-2884-1568ЛуцкийА. А.LutckiiA. A.

Луцкий Антон Александрович, канд. мед. наук.

ул. Связи, д. 38, стр. 1, помещ. 89, п. Стрельна, Санкт- Петербург, 198515

Anton A. Lutckii, Cand. Sci. (Med.)

room 89, 38/1 Svyazi St., Strelna, St. Petersburg 198515

 

lutskii@biocad.ruФедеральное государственное бюджетное учреждение «Центральная клиническая больница с поликлиникой» Управления делами Президента Российской ФедерацииРоссияCentral Clinical Hospital of the Administrative Directorate of the President of the Russian FederationRussian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Башкирский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияBashkir State Medical UniversityRussian FederationГосударственное бюджетное учреждение Республики Дагестан «Республиканская клиническая больница им. А.В. Вишневского»РоссияA.V. Vishnevsky Republican Clinical HospitalRussian FederationМедицинский институт непрерывного образования федерального государственного бюджетного образовательного учреждения высшего образования «Российский биотехнологический университет (РОСБИОТЕХ)»; Частное учреждение здравоохранения «Клиническая больница «РЖД-Медицина» им. Н.А. СемашкоРоссияMedical Institute of Continuing Education, Russian Biotechnological University (BIOTECH University); N.A. Semashko Railroad Clinical HospitalRussian FederationФедеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияI.M. Sechenov First Moscow State Medical University (Sechenov University)Russian FederationАкционерное общество «БИОКАД»РоссияBIOCAD JSCRussian Federation202225112022224Разработка биологических лекарственных препаратов для профилактики, диагностики и лечения COVID-19446459Copyright © Ломакин Н.В., Бакиров Б.А., Мусаев Г.Х., Попов В.В., Смолярчук Е.А., Линькова Ю.Н., Богдан Д.В., Еремеева А.В., Пухтинская П.С., Морозова М.А., Зинкина-Орихан А.В., Луцкий А.А., 20222022Ломакин Н.В., Бакиров Б.А., Мусаев Г.Х., Попов В.В., Смолярчук Е.А., Линькова Ю.Н., Богдан Д.В., Еремеева А.В., Пухтинская П.С., Морозова М.А., Зинкина-Орихан А.В., Луцкий А.А.Lomakin N.V., Bakirov B.A., Musaev G.H., Popov V.V., Smolyarchuk E.A., Linkova Y.N., Bogdan D.V., Eremeeva A.V., Pukhtinskaia P.S., Morozova M.A., Zinkina-Orikhan A.V., Lutckii A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/443

Смертность при COVID-19 ассоциирована с повышением уровня интерлейкина-6 (ИЛ-6). Левилимаб – моноклональное антитело к рецептору ИЛ-6 с доказанной клинической эффективностью у пациентов с тяжелым течением COVID-19.

Цель работы

Цель работы: уточнить ассоциацию тяжести клинических проявлений COVID-19 и эффективности левилимаба с уровнем ИЛ-6 и определить возможность применения левилимаба при других состояниях, сопровождающихся синдромом высвобождения цитокинов.

Материалы и методы

Материалы и методы: для подгруппового анализа использованы данные пациентов с COVID-19, участников клинического исследования CORONA, у которых был определен исходный уровень ИЛ-6. Подгруппы были сформированы на основании исходных значений уровня ИЛ-6: ≤5 пг/мл (нормальный уровень) и >5 пг/мл (повышенный уровень). Подгрупповой анализ включал описательную статистику и динамику клинико-лабораторных параметров пациентов изучаемых подгрупп на этапе скрининга, в день введения исследуемого препарата и далее до 14 суток. Сравнение долей пациентов, которым потребовалось назначения терапии спасения, было выполнено точным тестом Фишера.

Результаты

Результаты: в анализ включили 91 пациента (47 из группы пациентов, получивших левилимаб, и 44 из группы пациентов, получивших плацебо). Исходно повышенный уровень ИЛ-6 наблюдался у 31 (66%) из 47 в группе пациентов, получивших левилимаб, и 29 (48,4%) из 44 в группе пациентов, получивших плацебо. У пациентов с высоким уровнем ИЛ-6 наблюдались более выраженные клинические проявления пневмонии и отклонения показателей маркеров воспаления. Высокий уровень ИЛ-6 был ассоциирован с необходимостью назначения терапии спасения (ОШ=3,714; 95% ДИ 1,317–9,747; p=0,0183), в большей степени в группе пациентов, получивших плацебо (ОШ=8,889; 95% ДИ 2,098–33,31; p=0,0036), в которой также наблюдались длительно сохраняющиеся отклонения клинико-лабораторных параметров.

Выводы

Выводы: ИЛ-6 является одним из важнейших элементов патогенеза синдрома высвобождения цитокинов при COVID-19 и других состояниях. Повышенный уровень ИЛ-6 ассоциирован с более тяжелым течением COVID-19. Ингибирование рецепторов ИЛ-6 левилимабом приводит к клиническому улучшению у пациентов с тяжелым течением COVID-19, что позволяет предположить эффективность левилимаба в качестве патогенетической терапии синдрома высвобождения цитокинов различной этиологии.

The COVID-19 mortality is associated with an increase in interleukin-6 (IL-6) levels. Levilimab is an anti–IL-6 receptor antibody with proven clinical efficacy in patients with severe COVID-19.

The aim of the study was to assess the association of COVID-19 severity and levilimab effectiveness with IL-6 levels and to explore the potential for using levilimab in other conditions accompanied by cytokine release syndrome.

Materials and methods

Materials and methods: the subgroup analysis was based on the data of COVID patients with known baseline IL-6 levels from the CORONA clinical study. Subgroups were formed according to baseline IL-6 levels: ≤5 pg/mL (normal) and >5 pg/mL (elevated). The subgroup analysis included descriptive statistics of the patients and time courses of their clinical and laboratory findings (at screening, on the day of investigational product administration, and further until day 14). In order to compare the percentages of patients who had required rescue therapy, the authors used Fisher's exact test.

Results

Results: the subgroup analysis included 91 patients (47 from the levilimab group and 44 from the placebo group). At baseline, the authors observed elevated levels of IL-6 in 31/47 (66%) subjects in the levilimab group and 29/44 (48.4%) subjects in the placebo group. The subjects with elevated IL-6 demonstrated more pronounced clinical signs of pneumonia and abnormalities in inflammatory markers. Elevated baseline IL-6 levels were associated with the need for rescue therapy (OR=3.714; 95% CI: 1.317–9.747; p=0.0183); this association was stronger in the placebo group (OR=8.889; 95% CI: 2.098–33.31; p=0.0036). Also, the placebo group showed long-term abnormalities in the clinical and laboratory findings.

Conclusions

Conclusions: IL-6 is one of the key elements in the pathogenesis of cytokine release syndrome related to COVID-19 and other conditions. Elevated IL-6 levels are associated with the severity of COVID-19. Inhibition of IL-6 receptors by levilimab leads to clinical improvement in patients with severe COVID-19, suggesting the effectiveness of levilimab in pathogenesis-oriented therapy for cytokine release syndrome of other aetiologies.

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The authors declare that there are no conflicts of interest present.