Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation

Musa Khaitov; Alexandra Nikonova; Ilya Kofiadi; Igor Shilovskiy; Valeriy Smirnov; Olga Elisytina; Artem Maerle; Artem Shatilov; Anastasia Shatilova; Sergey Andreev; Ilya Sergeev; Dmitry Trofimov; Tatyana Latysheva; Natalia Ilyna; Alexander Martynov; Sevastyan Rabdano; Ellina Ruzanova; Nikita Savelev; Iuliia Pletiukhina; Ariana Safi; Vyacheslav Ratnikov; Viktor Gorelov; Viktor Kaschenko; Natalya Kucherenko; Irina Umarova; Svetlana Moskaleva; Sergei Fabrichnikov; Oleg Zuev; Nikolai Pavlov; Daria Kruchko; Igor Berzin; Dmitriy Goryachev; Vadim Merkulov; German Shipulin; Sergey Udin; Victor Trukhin; Rudolf Valenta; Veronica Skvortsova

doi:10.1111/all.15663

Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation

Musa Khaitov, Alexandra Nikonova, Ilya Kofiadi, Igor Shilovskiy, Valeriy Smirnov, Olga Elisytina, Artem Maerle, Artem Shatilov, Anastasia Shatilova, Sergey Andreev, Ilya Sergeev, Dmitry Trofimov, Tatyana Latysheva, Natalia Ilyna, Alexander Martynov, Sevastyan Rabdano, Ellina Ruzanova, Nikita Savelev, Iuliia Pletiukhina, Ariana SafiVyacheslav Ratnikov, Viktor Gorelov, Viktor Kaschenko, Natalya Kucherenko, Irina Umarova, Svetlana Moskaleva, Sergei Fabrichnikov, Oleg Zuev, Nikolai Pavlov, Daria Kruchko, Igor Berzin, Dmitriy Goryachev, Vadim Merkulov, German Shipulin, Sergey Udin, Victor Trukhin, Rudolf Valenta, Veronica Skvortsova

Scientific Working Group Allergology and Immunology

Research output: Journal article (peer-reviewed) › Journal article

14 Citations (Scopus)

Abstract

BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 ®) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19.

METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 ® (3.7mg and 11.1 mg/day: low- and high-dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N=52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization.

RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing and oxygen saturation of >95% for 48 hours significantly earlier (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) than patients from the control group (8 days (95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%) and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with MIR 19 ®.

CONCLUSIONS: MIR 19 ®, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.

Original language	English
Pages (from-to)	1639-1653
Number of pages	15
Journal	Allergy: European Journal of Allergy and Clinical Immunology
Volume	78
Issue number	6
Early online date	31 Jan 2023
DOIs	https://doi.org/10.1111/all.15663
Publication status	Published - Jun 2023

Keywords

SARS-CoV-2
clinical trial
efficacy
safety
siRNA

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1111/all.15663

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Khaitov, M., Nikonova, A., Kofiadi, I., Shilovskiy, I., Smirnov, V., Elisytina, O., Maerle, A., Shatilov, A., Shatilova, A., Andreev, S., Sergeev, I., Trofimov, D., Latysheva, T., Ilyna, N., Martynov, A., Rabdano, S., Ruzanova, E., Savelev, N., Pletiukhina, I., ... Skvortsova, V. (2023). Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation. Allergy: European Journal of Allergy and Clinical Immunology, 78(6), 1639-1653. https://doi.org/10.1111/all.15663

@article{a48f4a961a6c4f1eb617f2e9ad725f5a,

title = "Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation",

abstract = "BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 {\textregistered}) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19.METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 {\textregistered} (3.7mg and 11.1 mg/day: low- and high-dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N=52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization.RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing and oxygen saturation of >95% for 48 hours significantly earlier (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) than patients from the control group (8 days (95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%) and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with MIR 19 {\textregistered}.CONCLUSIONS: MIR 19 {\textregistered}, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.",

keywords = "SARS-CoV-2, clinical trial, efficacy, safety, siRNA",

author = "Musa Khaitov and Alexandra Nikonova and Ilya Kofiadi and Igor Shilovskiy and Valeriy Smirnov and Olga Elisytina and Artem Maerle and Artem Shatilov and Anastasia Shatilova and Sergey Andreev and Ilya Sergeev and Dmitry Trofimov and Tatyana Latysheva and Natalia Ilyna and Alexander Martynov and Sevastyan Rabdano and Ellina Ruzanova and Nikita Savelev and Iuliia Pletiukhina and Ariana Safi and Vyacheslav Ratnikov and Viktor Gorelov and Viktor Kaschenko and Natalya Kucherenko and Irina Umarova and Svetlana Moskaleva and Sergei Fabrichnikov and Oleg Zuev and Nikolai Pavlov and Daria Kruchko and Igor Berzin and Dmitriy Goryachev and Vadim Merkulov and German Shipulin and Sergey Udin and Victor Trukhin and Rudolf Valenta and Veronica Skvortsova",

note = "Funding Information: The study was supported by the Federal Medico‐biological Agency of Russia (FMBA Russia). This paper is dedicated to the memory of Professor Rakhim Khaitov—mentor, colleague, friend, and father. Publisher Copyright: {\textcopyright} 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.",

year = "2023",

month = jun,

doi = "10.1111/all.15663",

language = "English",

volume = "78",

pages = "1639--1653",

journal = "Allergy: European Journal of Allergy and Clinical Immunology",

issn = "0105-4538",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "6",

}

Khaitov, M, Nikonova, A, Kofiadi, I, Shilovskiy, I, Smirnov, V, Elisytina, O, Maerle, A, Shatilov, A, Shatilova, A, Andreev, S, Sergeev, I, Trofimov, D, Latysheva, T, Ilyna, N, Martynov, A, Rabdano, S, Ruzanova, E, Savelev, N, Pletiukhina, I, Safi, A, Ratnikov, V, Gorelov, V, Kaschenko, V, Kucherenko, N, Umarova, I, Moskaleva, S, Fabrichnikov, S, Zuev, O, Pavlov, N, Kruchko, D, Berzin, I, Goryachev, D, Merkulov, V, Shipulin, G, Udin, S, Trukhin, V, Valenta, R & Skvortsova, V 2023, 'Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation', Allergy: European Journal of Allergy and Clinical Immunology, vol. 78, no. 6, pp. 1639-1653. https://doi.org/10.1111/all.15663

TY - JOUR

T1 - Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation

AU - Khaitov, Musa

AU - Nikonova, Alexandra

AU - Kofiadi, Ilya

AU - Shilovskiy, Igor

AU - Smirnov, Valeriy

AU - Elisytina, Olga

AU - Maerle, Artem

AU - Shatilov, Artem

AU - Shatilova, Anastasia

AU - Andreev, Sergey

AU - Sergeev, Ilya

AU - Trofimov, Dmitry

AU - Latysheva, Tatyana

AU - Ilyna, Natalia

AU - Martynov, Alexander

AU - Rabdano, Sevastyan

AU - Ruzanova, Ellina

AU - Savelev, Nikita

AU - Pletiukhina, Iuliia

AU - Safi, Ariana

AU - Ratnikov, Vyacheslav

AU - Gorelov, Viktor

AU - Kaschenko, Viktor

AU - Kucherenko, Natalya

AU - Umarova, Irina

AU - Moskaleva, Svetlana

AU - Fabrichnikov, Sergei

AU - Zuev, Oleg

AU - Pavlov, Nikolai

AU - Kruchko, Daria

AU - Berzin, Igor

AU - Goryachev, Dmitriy

AU - Merkulov, Vadim

AU - Shipulin, German

AU - Udin, Sergey

AU - Trukhin, Victor

AU - Valenta, Rudolf

AU - Skvortsova, Veronica

N1 - Funding Information: The study was supported by the Federal Medico‐biological Agency of Russia (FMBA Russia). This paper is dedicated to the memory of Professor Rakhim Khaitov—mentor, colleague, friend, and father. Publisher Copyright: © 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

PY - 2023/6

Y1 - 2023/6

N2 - BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 ®) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19.METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 ® (3.7mg and 11.1 mg/day: low- and high-dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N=52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization.RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing and oxygen saturation of >95% for 48 hours significantly earlier (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) than patients from the control group (8 days (95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%) and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with MIR 19 ®.CONCLUSIONS: MIR 19 ®, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.

AB - BACKGROUND: Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 ®) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19.METHODS: We conducted an open-label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 ® (3.7mg and 11.1 mg/day: low- and high-dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID-19 (N=52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization.RESULTS: Patients from the low-dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing and oxygen saturation of >95% for 48 hours significantly earlier (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) than patients from the control group (8 days (95% CI: 7-10). No significant clinical efficacy was observed for the high-dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%) and 28 (53.85%) patients from the low-, high-dose and control group, respectively. None of them were associated with MIR 19 ®.CONCLUSIONS: MIR 19 ®, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID-19 compared to standard therapy in a randomized controlled trial.

KW - SARS-CoV-2

KW - clinical trial

KW - efficacy

KW - safety

KW - siRNA

UR - http://www.scopus.com/inward/record.url?scp=85148291938&partnerID=8YFLogxK

U2 - 10.1111/all.15663

DO - 10.1111/all.15663

M3 - Journal article

C2 - 36721963

SN - 0105-4538

VL - 78

SP - 1639

EP - 1653

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

IS - 6

ER -

Treatment of COVID-19 patients with a SARS-CoV-2-specific siRNA-peptide dendrimer formulation

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