Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial
Background: Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflamm...
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Elsevier
2025-01-01
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| Series: | Journal of Intensive Medicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667100X24000938 |
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| author | Norberto Chavez-Tapia Muneeba Ahsan Sayeed Shobha Luxmi Douglas J. Kasper Fenchao Xue Yang Shen Weiliang Fan Wei Yuan Bin Du |
| author_facet | Norberto Chavez-Tapia Muneeba Ahsan Sayeed Shobha Luxmi Douglas J. Kasper Fenchao Xue Yang Shen Weiliang Fan Wei Yuan Bin Du |
| author_sort | Norberto Chavez-Tapia |
| collection | DOAJ |
| description | Background: Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Methods: This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical efficacy. Results: Forty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were ≥ grade 3. Fewer SIR1-365-treated vs. placebo-treated patients experienced TEAEs (30.4% vs. 57.9%) and serious TEAEs (13.0% vs. 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. Compare to placebo, SIR1-365 significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] vs. -24.2 [23.6]; P=0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days vs. [8.6±5.6] days; P=0.0145) and respiratory failure incidence (8.3% vs. 38.1%; two-sided P=0.0291) during the study, and numerically shortened the time to clinical improvement in World Health Organization ordinal scale (median: 5.0 days vs. 9.0 days, P=0.0766). Conclusions: SIR1-365 was well tolerated and demonstrated a trend toward quicker recovery than placebo in hospitalized patients with severe COVID-19.Trial Registration ClinicalTrials.gov number: NCT04622332 |
| format | Article |
| id | doaj-art-41a54be75f724e8781db5d23f35f233f |
| institution | Kabale University |
| issn | 2667-100X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Intensive Medicine |
| spelling | doaj-art-41a54be75f724e8781db5d23f35f233f2025-01-05T04:28:47ZengElsevierJournal of Intensive Medicine2667-100X2025-01-01517078Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trialNorberto Chavez-Tapia0Muneeba Ahsan Sayeed1Shobha Luxmi2Douglas J. Kasper3Fenchao Xue4Yang Shen5Weiliang Fan6Wei Yuan7Bin Du8Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Mexico City, MexicoSindh Infectious Diseases Hospital and Research Centre, Dow University of Health Sciences, Karachi, Sindh, PakistanSindh Infectious Diseases Hospital and Research Centre, Dow University of Health Sciences, Karachi, Sindh, PakistanDepartment of Medicine, Division of Infectious Disease, University of Illinois School of Medicine, OSF HealthCare System d/b/a Saint Francis Medical Center, Peoria, IL, USASironax USA, Inc., Edison, NJ, USASironax USA, Inc., Edison, NJ, USASironax USA, Inc., Edison, NJ, USASironax USA, Inc., Edison, NJ, USAMedical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China; Corresponding author: Bin Du, Medical Intensive Care Unit, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Beijing, 100730, China.Background: Receptor-interacting protein kinase 1 (RIPK1), a serine/threonine protein kinase, is mainly activated by pro-inflammatory cytokines and pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its activation could result in apoptosis, necroptosis, or inflammation. This study was conducted to evaluate the safety and efficacy of a potent and selective inhibitor of RIPK1, SIR1-365, in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Methods: This multicenter, randomized, double-blind, phase 1b study screened patients from December 18, 2020 until November 27, 2021. Adults hospitalized with severe COVID-19 (diagnosed ≤2 weeks before screening) were randomized 1:1 to receive oral placebo or SIR1-365 100 mg three times daily for ≤14 consecutive days, with standard-of-care. The primary objective was to evaluate SIR1-365 safety and tolerability. Secondary objectives included an assessment of SIR1-365 efficacy. Descriptive statistics were used to summarize safety. The study was not powered for efficacy testing. Relevant inferential statistical tests were used to aid interpretation of differences in clinical efficacy. Results: Forty-five patients were randomized, 42 were treated. Eighteen patients experienced treatment-emergent adverse events (TEAEs) and 7 patients were ≥ grade 3. Fewer SIR1-365-treated vs. placebo-treated patients experienced TEAEs (30.4% vs. 57.9%) and serious TEAEs (13.0% vs. 26.3%) within 28 days of the first dose. There were no serious treatment-related TEAEs or deaths. Compare to placebo, SIR1-365 significantly increased arterial oxygenation from baseline to day 7 (least-squares mean change [standard error]: 109.4 [26.4] vs. -24.2 [23.6]; P=0.0095), significantly reduced hospitalization duration after treatment (mean±standard deviation: [4.7±3.7] days vs. [8.6±5.6] days; P=0.0145) and respiratory failure incidence (8.3% vs. 38.1%; two-sided P=0.0291) during the study, and numerically shortened the time to clinical improvement in World Health Organization ordinal scale (median: 5.0 days vs. 9.0 days, P=0.0766). Conclusions: SIR1-365 was well tolerated and demonstrated a trend toward quicker recovery than placebo in hospitalized patients with severe COVID-19.Trial Registration ClinicalTrials.gov number: NCT04622332http://www.sciencedirect.com/science/article/pii/S2667100X24000938COVID-19Phase 1b trialReceptor-interacting protein 1RIPK1RIPK1 inhibitorSIR1-365 |
| spellingShingle | Norberto Chavez-Tapia Muneeba Ahsan Sayeed Shobha Luxmi Douglas J. Kasper Fenchao Xue Yang Shen Weiliang Fan Wei Yuan Bin Du Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial Journal of Intensive Medicine COVID-19 Phase 1b trial Receptor-interacting protein 1 RIPK1 RIPK1 inhibitor SIR1-365 |
| title | Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial |
| title_full | Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial |
| title_fullStr | Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial |
| title_full_unstemmed | Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial |
| title_short | Safety and efficacy of selective RIPK1 inhibitor SIR1-365 in hospitalized patients with severe COVID-19: A multicenter, randomized, double-blind, phase 1b trial |
| title_sort | safety and efficacy of selective ripk1 inhibitor sir1 365 in hospitalized patients with severe covid 19 a multicenter randomized double blind phase 1b trial |
| topic | COVID-19 Phase 1b trial Receptor-interacting protein 1 RIPK1 RIPK1 inhibitor SIR1-365 |
| url | http://www.sciencedirect.com/science/article/pii/S2667100X24000938 |
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