DFV890: a new oral NLRP3 inhibitor—tested in an early phase 2a randomised clinical trial in patients with COVID-19 pneumonia and impaired respiratory function
Ildiko Madurka, Alexander Vishnevsky, Joan B Soriano, Stephanus J Gans, Danilo Joel Salazar Ore, Adrian Rendon, Charlotte S Ulrik, Sushma Bhatnagar, Srikanth Krishnamurthy, Kirsten Mc Harry, Tobias Welte, Alberto A Fernandez, Beata Mehes, Karin Meiser, Ewa Gatlik, Ulrike Sommer, Guido Junge, Ederlon Rezende, Alberto Alfredo Fernandez, Ana Maria Bagu, Florencia Heredia Amido, Maria Belen Costa, Jorge Alejandro Brigante, Gaston Franco, Nadia Johanna Ahmed, Natalia Zerega, Marcelo Rodrigues Bacci, Caio Cesar Fernandes, Henrique Gitti Ragognete, Ederlon Alves De Carvalho Rezende, Caio Vinicius Gouvea Jaoude, Ellen Pierre De Olivera, Vania Quinato Malacize, Claudio Marcel Berdun Stadnik, Eduarda Annoni Ramos, Graziela Regina Kist, Gynara Rezende Barbosa, Henrique Filik, Sabrina Nalin, Charlotte Suppli Ulrik, Casper Tidemandsen, Kjell Hakansson, Thomas Benfield, Karen Brorup Heje Pedersen, Tobias Welte, Marcus Bachman, Mathias Stoll, Ilona Olzik, Natascha Scharf, Nicole Shearman, Isabell Pink, Anna Frey, Petra Schulze, Cyrus Michael Sayehli, Dirk Weismann, Hartwig Klinker, Maria-Elisabeth Goebeler, Lars Maier, Florian Geismann, Frank Hanses, Judith Zeller, Julian Hupf, Matthias Lubnow, Sabine Sag, Sarah Ripfel, Steffen Pabel, Stilla Bauernfeind, Ulf Leisner, Florian Hitzenbichler, Ildiko Madurka, Dora Iharos, Krisztina Kormosoi Toth, Maria Hejja, Tamas Esze, Sushma Bhatnagar, Anant Mohan, Anuja Pandit, Balbir Kumar, Brajesh Kumar Ratre, Pawan Tiwari, Ram Singh, Saurabh Vig, Shweta Bhopale, Swati Bhan, Akshay Budhraja, Ankit Agrawal, Srikanth Krishnamurthy, Ambika Srikanth, Kalaiyamishan Kaneesan, Mauila Raghavan Jaymohan Unnithan, Nagarajan Srinivasan, Nandagopal Velayuthaswamy, Senthil Kumar Mothu Gounder, Venkatraman Vaidyanathan, Amitabha Saha, Abhishek Bhattacharjee, Avijatri Datta, Adrian Rendon, Adrian Camacho Ortiz, Berenice Soto Moncivais, Brenda Nohemi Lozano Rodriguez, Erick Joel Rendon Ramirez, Romulo Omar Flores Perez, Diego Luis Carrillo Perez, Jose Sifuentes Osornio, Maria L Morales Ortega, Miguel Angel Jandete Medina, Stephanus J Gans, Jan Williem Vanden Berg, Lisenka Boom, Esther Panhuis, Gerieke Lancee, Martine Lammens, Nancy Boeve-Epping, Danilo Joel Salazar Ore, Enrique Renzo Morello Bustios, Ernesto Moises Zavala Flores, Milagros Ivette Maguina Farronay, Boris Galin Orihuela, Ramon Mendoza Del Pino, Alexander Yurievich Vishnevsky, Evgeny Morozov, Ilia Repnikov, Maria Kiseleva, Mikhail E Kotov, Mikhail M Terskikh, Vladislav Anatolievich Zykov, Elena Anatolievna Smolyarchuk, Dariya Kurguzova, Dmitriy Andreevich Garkavi, Oleg Messnikov, Svetlana Kharlamova, Yulia Andereevna Bondareva, Konstantin Valerievich Sementsov, Dmitry Nikolaevich Katagarov, George Arkadievich Belekhov, Sergey Petrovich Alferov, Tatiana Ivanovna Martynenko, Elena Vasileva, Ilya Vyacheslavovich Lazarenko, Konstantin Konstantinovich Gatalsky, Oleg Vladimirovich Rudikh, Olga Sergeevna Ganova, Olga Sergeevna Paraeva, Vladimir Vladimirovich Pashkevich, Elena Mikhailovna Vishneva, Aleksey Viktorovich Martynov, Anna Pavlovna Isakova, Ekaterina Aleksandrovna Egorova, Tamara Valerievna Gaygolnik, Valeria Nikolaevna Pinzhina, Vladimir Vladimirovich Hinovker, Vladislav Gennadievich Abramov, Galina Lvovna Ignatova, Elena Vladimirovna Blinova, Irina Viktorovna Grebneva, Olga Vasilievna Rodionova, Vladimir Nikolaevich Antonov, Konstantin Vasilievich Trufanov, Andrey Alexandrovich Krylov, Elena Nikolaevna Radchenko, Kirsten Mcharry, Elizma Snyman, Joan B Soriano, Diego Rodriguez Serrano, Adrian Martinez Vergara, Maria Celeste Marcos, Alex Soriano Viladomiu, Celia Cardozo, Felipe Garcia
Infection, doi:10.1007/s15010-022-01904-w
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.
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1007/ s15010-022-01904-w . Author contributions All authors meet the International Committee of Medical Journal Editors criteria for authorship for this article, take responsibility for the integrity of the work as a whole, were involved in drafting and critical review of the manuscript, and approved the final version for submission. All authors agreed to be accountable for all aspects of the work and attest to the accuracy and integrity of the work. BM, KM, EG, US, and GJ designed and conceived the study. IM, AV, JSO, SJG, DJSO AR, CSU, SB, SK, KMH, TW, AAF, BM, KM, EG, US, GJ, and ER interpreted the data. IM, AV, JSO, SJG, DJSO, AR, CSU, SB, SK, KMH, TW, AAF, and ER acquired the data. IM, BM, KM, EG, US, GJ, and ER analysed the data. Funding Novartis Pharma AG.
Data sharing The datasets generated and analysed during the current study are not publicly available. Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved based on scientific merit. All data provided are anonymised to respect the privacy of patients who have participated in the trial, in line with applicable laws and regulations. The data can be requested from the corresponding author of the manuscript. The protocol can be made available on request by contacting..
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DOI record:
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"value": "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."
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