Dendrimer nanotherapy for severe COVID-19 attenuates inflammation and neurological injury markers and improves outcomes in a phase2a clinical trial

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.

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice

“…Conjugation of small molecule drugs to dendrimer nanoparticles have been posited as a mechanism to improve PK properties. In fact, hydroxyl PAMAM dendrimer conjugates discovered by our team are currently being tested in phase I (NCT05395624 and NCT03500627) and phase II clinical trials (NCT04458298), with positive Phase 2a results in severe COVID-19 patients in several measures of efficacy including survival, attenuation of neurological injury, and hyper-inflammation [ 53 ]. Several preclinical studies have demonstrated that dendrimer conjugation of small molecules can prolong their half-life in target tissues [ 44 , 45 , 46 , 47 ] and deliver drugs in a targeted manner to areas of neuroinflammation where they are engulfed by activated microglia [ 44 , 48 , 49 , 50 ].…”

“…Previous research by our lab has shown that these dendrimers selectively localize in activated glia in the brain in small and large animal models, and can deliver drugs to the site of injury, thus producing positive therapeutic outcomes [ 33 , 48 , 50 , 51 , 52 ]. In fact, hydroxyl-dendrimer nanotherapy was recently shown to attenuate inflammation and neurological injury markers and improve outcomes in a phase 2a clinical trial in patients with severe COVID-19 [ 53 ]. We therefore aimed to improve the oral bioavailability, half-life, and brain delivery of DPTIP by conjugating it to a hydroxyl-PAMAM dendrimer delivery system (D-DPTIP).…”

Structure‐Activity Relationship of Anionic and Cationic Polyamidoamine (PAMAM) Dendrimers against Staphylococcus aureus

“…In a phase 2a therapeutic trial, patients with severe COVID-19 received OP-101, a hydroxyl-polyamidoamine dendrimer-N-acetyl cysteine combination that targets active macrophages. Op-101 was well tolerated and reduced the probability of death or mechanical ventilation at 30 and 60 days following treatment compared to a control group [16]. Treatment with OP-101 resulted in a decrease in serum levels of proinflammatory and neurological indicators (neurofilament light chain and glial fibrillary acidic protein).…”

Dendrimers, an Emerging Opportunity in Personalized Medicine?

“…OP-101 reduced morbidity and mortality in hospitalized patients with severe COVID-19. Indeed, at day 60, only three of seven patients given placebo were surviving, whereas they were 14 of 17 for OP-101–treated patients [ 51 ].…”