tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Alexandre M Periard[SUP] 1 [/SUP], Fernanda L Tana[SUP] 1 [/SUP], Renata E Avila[SUP] 2 [/SUP], Larissa B Milhorato[SUP] 1 [/SUP], Katlen M M Alcantara[SUP] 1 [/SUP], Carolina B Resende[SUP] 1 [/SUP], Angela V Serufo[SUP] 1 [/SUP], Felipe R Santos[SUP] 1 [/SUP], Danielle C Teixeira[SUP] 1 [/SUP], Celso M Queiroz-Junior[SUP] 1 [/SUP], Talita C M Fonseca[SUP] 1 [/SUP], Barbara L V Silva[SUP] 1 [/SUP], Vivian V Costa[SUP] 1 [/SUP], Renan P Souza[SUP] 3 [/SUP], Mauro Perretti[SUP] 4 [/SUP], Thomas E N Jonassen[SUP] 5 [/SUP], Mauro M Teixeira[SUP] 1 6 [/SUP]
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[SUP]-1[/SUP], 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 SpO[SUB]2[/SUB] ≥ 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[SUP] 1 [/SUP], Alexandre M Periard[SUP] 1 [/SUP], Fernanda L Tana[SUP] 1 [/SUP], Renata E Avila[SUP] 2 [/SUP], Larissa B Milhorato[SUP] 1 [/SUP], Katlen M M Alcantara[SUP] 1 [/SUP], Carolina B Resende[SUP] 1 [/SUP], Angela V Serufo[SUP] 1 [/SUP], Felipe R Santos[SUP] 1 [/SUP], Danielle C Teixeira[SUP] 1 [/SUP], Celso M Queiroz-Junior[SUP] 1 [/SUP], Talita C M Fonseca[SUP] 1 [/SUP], Barbara L V Silva[SUP] 1 [/SUP], Vivian V Costa[SUP] 1 [/SUP], Renan P Souza[SUP] 3 [/SUP], Mauro Perretti[SUP] 4 [/SUP], Thomas E N Jonassen[SUP] 5 [/SUP], Mauro M Teixeira[SUP] 1 6 [/SUP]
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[SUP]-1[/SUP], 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 SpO[SUB]2[/SUB] ≥ 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.