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Br J Pharmacol
. 2024 Aug 19.
doi: 10.1111/bph.17322. Online ahead of print. Effects of a pro-resolving drug in COVID-19: preclinical studies to a randomized, placebo-controlled, phase Ib/IIa trial in hospitalized patients
Pedro R J Almeida 1 , Alexandre M Periard 1 , Fernanda L Tana 1 , Renata E Avila 2 , Larissa B Milhorato 1 , Katlen M M Alcantara 1 , Carolina B Resende 1 , Angela V Serufo 1 , Felipe R Santos 1 , Danielle C Teixeira 1 , Celso M Queiroz-Junior 1 , Talita C M Fonseca 1 , Barbara L V Silva 1 , Vivian V Costa 1 , Renan P Souza 3 , Mauro Perretti 4 , Thomas E N Jonassen 5 , Mauro M Teixeira 1 6
Affiliations
Introduction: Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19.
Methods: C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg-1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air.
Results: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1β by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017).
Conclusion: Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.
Keywords: COVID‐19; melanocortin; resolution of inflammation; resolution pharmacology.
. 2024 Aug 19.
doi: 10.1111/bph.17322. Online ahead of print. Effects of a pro-resolving drug in COVID-19: preclinical studies to a randomized, placebo-controlled, phase Ib/IIa trial in hospitalized patients
Pedro R J Almeida 1 , Alexandre M Periard 1 , Fernanda L Tana 1 , Renata E Avila 2 , Larissa B Milhorato 1 , Katlen M M Alcantara 1 , Carolina B Resende 1 , Angela V Serufo 1 , Felipe R Santos 1 , Danielle C Teixeira 1 , Celso M Queiroz-Junior 1 , Talita C M Fonseca 1 , Barbara L V Silva 1 , Vivian V Costa 1 , Renan P Souza 3 , Mauro Perretti 4 , Thomas E N Jonassen 5 , Mauro M Teixeira 1 6
Affiliations
- PMID: 39159951
- DOI: 10.1111/bph.17322
Introduction: Pro-resolving molecules may curb disease caused by viruses without altering the capacity of the host to deal with infection. AP1189 is a melanocortin receptor-biased agonist endowed with pro-resolving and anti-inflammatory activity. We evaluated the preclinical and early clinical effects of treatment with AP1189 in the context of COVID-19.
Methods: C57BL/6j mice were infected intranasally with MHV-A59 or hK18-ACE2 mice with SARS-CoV-2. AP1189 (10 mg·kg-1, BID, s.c.) was given to the animals from day 2 and parameters evaluated at day 5. Human PBMCs from health donors were infected with SARS-CoV-2 in presence or absence of AP1189 and production of cytokines quantified. In the clinical study, 6 patients were initially given AP1189 (100 mg daily for 14 days) and this was followed by a randomized (2:1), placebo-controlled, double-blind trial that enrolled 54 hospitalized COVID-19 patients needing oxygen support. The primary outcome was the time in days until respiratory recovery, defined as a SpO2 ≥ 93% in ambient air.
Results: Treatment with AP1189 attenuated pulmonary inflammation in mice infected with MHV-A59 or SARS-CoV-2 and decreased the release of CXCL10, TNF-α and IL-1β by human PBMCs. Hospitalized COVID-19 patients already taking glucocorticoids took a median time of 6 days until respiratory recovery when given placebo versus 4 days when taking AP1189 (P = 0.017).
Conclusion: Treatment with AP1189 was associated with less disease caused by beta-coronavirus infection both in mice and in humans. This is the first demonstration of the effects of a pro-resolving molecule in the context of severe infection in humans.
Keywords: COVID‐19; melanocortin; resolution of inflammation; resolution pharmacology.