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- Title
Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial.
- Authors
Gusdon, Aaron M.; Faraday, Nauder; Aita, John S.; Kumar, Sunil; Mehta, Ishan; Choi, HuiMahn A.; Cleland, Jeffery L.; Robinson, Keith; McCullough, Louise D.; Ng, Derek K.; Kannan, Rangaramanujam M.; Kannan, Sujatha
- Abstract
Hyperinflammation triggered by SARS-CoV-2 is a major cause of disease severity, with activated macrophages implicated in this response. OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetylcysteine conjugate that specifically targets activated macrophages, improves outcomes in preclinical models of systemic inflammation and neuroinflammation. In this multicenter, randomized, double-blind, placebo-controlled, adaptive phase 2a trial, we evaluated safety and preliminary efficacy of OP-101 in patients with severe COVID-19. Twenty-four patients classified as having severe COVID-19 with a baseline World Health Organization seven-point ordinal scale of ≥5 were randomized to receive a single intravenous dose of placebo (n = 7 patients) or OP-101 at 2 (n = 6), 4 (n = 6), or 8 mg/kg (n = 5 patients). All study participants received standard of care, including corticosteroids. OP-101 at 4 mg/kg was better than placebo at decreasing inflammatory markers; OP-101 at 4 and 8 mg/kg was better than placebo at reducing neurological injury markers, (neurofilament light chain and glial fibrillary acidic protein). Risk for the composite outcome of mechanical ventilation or death at 30 and 60 days after treatment was 71% (95% CI: 29%, 96%) for placebo and 18% (95% CI: 4%, 43%; P = 0.021) for the pooled OP-101 treatment arms. At 60 days, 3 of 7 patients given placebo and 14 of 17 OP-101–treated patients were surviving. No drug-related adverse events were reported. These data show that OP-101 was well tolerated and may have potential to treat systemic inflammation and neuronal injury, reducing morbidity and mortality in hospitalized patients with severe COVID-19. A dendrimer nanotherapy for COVID-19: OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetyl cysteine conjugate, that specifically targets activated macrophages was evaluated in patients with severe COVID-19 in a phase 2a clinical trial. A single intravenous infusion of OP-101 was well tolerated and reduced the risk of death or mechanical ventilation at 30 and 60 days after treatment when compared to placebo. OP-101 treatment was associated with decreased serum concentrations of proinflammatory markers as well as markers of neurological injury (neurofilament light chain and glial fibrillary acidic protein). OP-101 may have potential for treating systemic hyperinflammation in severe COVID-19.
- Subjects
WORLD Health Organization; POLYAMIDOAMINE dendrimers; GLIAL fibrillary acidic protein; COVID-19; CLINICAL trials; TREATMENT effectiveness; MICROGLIA
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 654, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abo2652