Nanotherapy May Help Reduce Death in Severe COVID-19July 21, 2022
An investigational macrophage-targeting dendrimer nanotherapy was safe, improved outcomes in people with severe COVID-19, and reduced inflammatory and neural injury markers, a small phase IIa study found.
Risk of a composite outcome of mechanical ventilation or death after 30 and 60 days was 71% (95% CI 29-96) in the placebo group and 18% (95% CI 4-43, P=0.021) among hospitalized severe COVID patients treated with a single injection of intravenous OP-101, a hydroxyl-polyamidoamine dendrimer–N-acetyl cysteine conjugate, reported Sujatha Kannan, MBBS, of Johns Hopkins University School of Medicine in Baltimore, and co-authors.
At 60 days after treatment, three of seven patients who received placebo and 14 of 17 patients treated with OP-101 were surviving, Kannan and colleagues wrote in Science Translational Medicine.
OP-101 was better than placebo at decreasing inflammatory markers at a 4 mg/kg dose. At 4 and 8 mg/kg, OP-101 bested placebo at reducing the neurologic injury markers neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). No drug-related adverse events were reported.
“Severe COVID is an extreme representation of macrophage-driven inflammation throughout the body involving many organs including lungs, heart, and even the brain,” Kannan said.
“The fact that a single injection of a very small dose of a broad anti-inflammatory and antioxidant agent — N-acetyl cysteine — when delivered specifically to cells involved in inflammation leads to such remarkable improvements in survival, inflammation, and in neurologic injury markers underscores the importance of targeted therapy and how such therapies can be effective and safe for many disorders where inflammation plays a role,” she told MedPage Today.
Dendrimers are synthetic, radially symmetric, hyperbranched nanoscale molecules that can penetrate the blood-brain barrier. They have an inner core and outer shells; functionalized groups on the periphery give them diverse properties with multiple potential applications. Earlier research showed that dendrimers can selectively target activated macrophages and microglia.
The active agent in OP-101 is N-acetyl cysteine, which usually is used in high doses because of its poor bioavailability. In a rabbit model of cerebral palsy, dendrimer-based N-acetyl cysteine was more efficacious and potent than the free-drug N-acetyl cysteine at much lower doses.
In the current phase IIa study, preliminary efficacy was seen with a single dose of OP-101 at a fraction of the dose of N-acetyl cysteine typically used for other clinical indications (total doses of over 100 mg/kg), Kannan and colleagues observed.
“This indicates that targeted delivery of OP-101 is probably responsible for the promising efficacy seen here,” they wrote.
The researchers evaluated 24 patients classified as having severe COVID-19 who had a baseline score of 5 or more on the World Health Organization 7-point ordinal scale. Participants were randomized to receive a single intravenous dose of placebo (7 patients) or OP-101 at 2 mg/kg (6 patients), 4 mg/kg (6 patients), or 8 mg/kg (5 patients).
Participants were enrolled at five U.S. centers between August 2020 and March 2021. More men than women were enrolled in the study (17 vs 7). All participants received standard of care, including corticosteroids.
The findings may extend beyond severe COVID and have implications for people with long COVID, Kannan noted.
“A proportion of patients with long COVID appear to have persistent inflammation leading to their neuro-psychiatric, cardiac, or respiratory symptoms,” she pointed out. “OP-101 specifically targets reactive macrophages attenuating inflammation and converts the cells to a phenotype that promotes repair and recovery.”
The main limitation of the study was its small sample size. The trial was not powered for efficacy and larger studies are needed to further evaluate the safety and efficacy of OP-101, the researchers acknowledged.
This phase IIa clinical study was funded by Ashvattha Therapeutics.
Kannan and a co-author are inventors on patents about dendrimer-based therapeutic nanodevices and dendrimers for the treatment of severe acute respiratory syndrome. “Under license agreements involving Ashvattha Therapeutics and Johns Hopkins University, several researchers are entitled to royalty distributions and share ownership or equity related to the dendrimer platform and product discussed in this study,” the disclosure information notes.
Kannan and a co-author are founders and have served on the board of directors of Ashvattha Therapeutics; they were were not involved in conducting the clinical trial. Other co-authors reported relationships with Ashvattha Therapeutics, Acasti Pharma, and Medtronic.