TY - JOUR

T1 - DFV890

T2 - a new oral NLRP3 inhibitor—tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function

AU - Madurka, Ildiko

AU - Vishnevsky, Alexander

AU - Soriano, Joan B.

AU - Gans, Stephanus J.

AU - Ore, Danilo Joel Salazar

AU - Rendon, Adrian

AU - Ulrik, Charlotte S.

AU - Bhatnagar, Sushma

AU - Krishnamurthy, Srikanth

AU - Mc Harry, Kirsten

AU - Welte, Tobias

AU - Fernandez, Alberto A.

AU - Mehes, Beata

AU - Meiser, Karin

AU - Gatlik, Ewa

AU - Sommer, Ulrike

AU - Junge, Guido

AU - Rezende, Ederlon

AU - Study group

A2 - Tidemandsen, Casper

A2 - Benfield, Thomas

A2 - Pedersen, Karen Brorup Heje

N1 - Funding Information: We thank the patients who participated in this study. We also thank other principal investigators, Konstantin Sementsov, Elena Vishneva, Konstantin Trufanov, Tamara Gaygolnik, Galina Ignatova, Tatiana Martynenko, Diego Carrillo Perez, Akshay Budhraja, Alex Soriano Viladomiu, Elena Smolyarchuk, Thomas Benfield, Boris Orihuela, Amitabha Saha, Anna Frey, Lars Maier, Alejandro Brigante, and Claudio Marcel Stadnik for their contributions in the study. Priyanka Malla and Hemangi Rawal (Novartis) provided medical writing support and editorial guidance. The study was funded by Novartis Pharma in accordance with Good Publication Practice guidelines. Patient consent was not required for the publication. Funding Information: Ildiko Madurka: none to declare. Alexander Vishnevsky: none to declare. Joan B. Soriano: received a grant from Novartis to conduct this trial via the Instituto de Investigación Hospital Universitario de la Princesa. Stephanus J. Gans: none to declare. Danilo Joel Salazar Ore: honorarium from Novartis for conducting this clinical trial at the Hospital Nacional Cayetano Heredia. Adrian Rendon: contract from Novartis as a PI in the Monterrry Investigation Center. Charlotte Suppli Ulrik: received fees for lectures, advisory board meetings, and presentations from AZ, GSK, BI, Chiesi, TEVA, Sanofi Genzyme, Novartis and Orion Pharma outside the submitted work. Sushma Bhatnagar: none to declare. Srikanth Krishnamurthy: received honoraria/research grants from AZ, BI, Sanofi, Novartis, Vicore Pharma, Sun Pharma, Dr. Reddys Lab, and Glenmark outside the submitted work. Kirsten Mc Harry: none declared. Tobias Welte: received research grant from German Ministry of Research and Education, German Ministry of Health; and fees for lectures/advisory board from AZ, Biontech, Roche, GSK, Novartis, Pfizer, Johnson & Johnson, Boehringer Ingelheim, and MSD; and advisory board honorarium from Novartis. Alberto Alfredo Fernandez: received honoraria for dissertations from AZ, Novartis, and BI. Guido Junge: employee and shareholder of Novartis. Beata Mehes: employee and shareholder of Novartis. Karin Meiser: employee of Novartis. Ewa Gatlik: Employee and shareholder of Novartis. Ulrike Sommer: employee and shareholder of Novartis. Ederlon Rezende: received research grants from Novartis and fees for lectures and presentations from Pfizer, Baxter, and MSD. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

PY - 2023

Y1 - 2023

N2 - Background: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. Methods: This randomised, multinational study enrolled hospitalised patients (18–80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. Findings: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. Interpretation: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. Trial registration: ClinicalTrials.gov, NCT04382053.

AB - Background: Coronavirus-associated acute respiratory distress syndrome (CARDS) has limited effective therapy to date. NLRP3 inflammasome activation induced by SARS-CoV-2 in COVID-19 contributes to cytokine storm. Methods: This randomised, multinational study enrolled hospitalised patients (18–80 years) with COVID-19-associated pneumonia and impaired respiratory function. Eligible patients were randomised (1:1) via Interactive Response Technology to DFV890 + standard-of-care (SoC) or SoC alone for 14 days. Primary endpoint was APACHE II score at Day 14 or on day-of-discharge (whichever-came-first) with worst-case imputation for death. Other key assessments included clinical status, CRP levels, SARS-CoV-2 detection, other inflammatory markers, in-hospital outcomes, and safety. Findings: Between May 27, 2020 and December 24, 2020, 143 patients (31 clinical sites, 12 countries) were randomly assigned to DFV890 + SoC (n = 71) or SoC alone (n = 72). Primary endpoint to establish clinical efficacy of DFV890 vs. SoC, based on combined APACHE II score, was not met; LSM (SE), 8·7 (1.06) vs. 8·6 (1.05); p = 0.467. More patients treated with DFV890 vs. SoC showed ≥ 1-level improvement in clinical status (84.3% vs. 73.6% at Day 14), earlier clearance of SARS-CoV-2 (76.4% vs. 57.4% at Day 7), and mechanical ventilation-free survival (85.7% vs. 80.6% through Day 28), and there were fewer fatal events in DFV890 group (8.6% vs. 11.1% through Day 28). DFV890 was well tolerated with no unexpected safety signals. Interpretation: DFV890 did not meet statistical significance for superiority vs. SoC in primary endpoint of combined APACHE II score at Day 14. However, early SARS-CoV-2 clearance, improved clinical status and in-hospital outcomes, and fewer fatal events occurred with DFV890 vs. SoC, and it may be considered as a protective therapy for CARDS. Trial registration: ClinicalTrials.gov, NCT04382053.

KW - Coronavirus-associated acute respiratory distress syndrome

KW - DFV890

KW - NLRP3 inhibitors

KW - Randomised controlled trial

KW - SARS-CoV-2

U2 - 10.1007/s15010-022-01904-w

DO - 10.1007/s15010-022-01904-w

M3 - Journal article

C2 - 36104613

AN - SCOPUS:85138306751

VL - 51

SP - 641

EP - 654

JO - Therapies

JF - Therapies

SN - 0300-8126

IS - 3

ER -