Effects of a pro‐resolving drug in COVID‐19: preclinical studies to a randomized, placebo‐controlled, phase Ib/IIa trial in hospitalized patients

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 effect...

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Published in:	British journal of pharmacology Vol. 181; no. 23; pp. 4750 - 4765
Main Authors:	Almeida, Pedro R. J., Periard, Alexandre M., Tana, Fernanda L., Avila, Renata E., Milhorato, Larissa B., Alcantara, Katlen M. M., Resende, Carolina B., Serufo, Angela V., Santos, Felipe R., Teixeira, Danielle C., Queiroz‐Junior, Celso M., Fonseca, Talita C. M., Silva, Barbara L. V., Costa, Vivian V., Souza, Renan P., Perretti, Mauro, Jonassen, Thomas E. N., Teixeira, Mauro M.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-12-2024
Subjects:	ACE2 Angiotensin-converting enzyme 2 Anti-inflammatory agents Coronaviruses COVID-19 CXCL10 protein Hospitalization Infections Melanocortin Patients Placebos resolution of inflammation resolution pharmacology Severe acute respiratory syndrome coronavirus 2 COVID‐19 resolution pharmacology resolution of inflammation melanocortin
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Summary:	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. AP1189, a biased MC1/MC3 receptor agonist, decreases inflammation in animal models of betacoronavirus infection and shows benefits in patients with COVID‐19 in a randomized, placebo‐controlled early trial.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	0007-1188 1476-5381 1476-5381
DOI:	10.1111/bph.17322