Orpheris, a wholly-owned subsidiary of Ashvattha Therapeutics, a biotech company focused on developing novel hydroxyl dendrimer therapeutics (HDTs) to treat unmet medical needs in inflammatory, oncology and ocular diseases, announced enrollment of the first patients in its multicenter Phase 2 PRANA clinical study of the HDT, OP-101, to treat hospitalized adults with severe Covid-19.

The study will be conducted by investigators at leading U.S. academic medical centers, including Johns Hopkins Hospital, Emory University, Loma Linda University Health and The University of Texas Health Science Center at Houston (UTHealth).

Severe COVID-19 is characterized by excessive activation of macrophages, the immune cells responsible for hyperinflammation, which can lead to life-threatening complications. Unlike single agent approaches that address only one pathway such as antibodies, OP-101 is designed to target and shut down all proinflammatory pathways and restore the macrophages to a normal, anti-inflammatory state.

“Patients with severe COVID-19 can deteriorate rapidly because their immune response to the SARS-CoV-2 virus is exaggerated. This results in hyperinflammation, tissue damage and a cytokine storm, which can lead to lung injury,” said Ishan Mehta, M.D., an investigator in the PRANA study at Emory University School of Medicine. “OP-101 is a promising treatment for this patient group due to its ability to selectively target reactive macrophages in the lungs. Patients hospitalized with severe COVID-19 are in desperate need of novel treatments that can accelerate their recovery, reduce length of critical illness and potentially avoid prolonged hospitalization.”

PRANA (OP-101 to ArRest HyperinflAmmatioN in COVID-19 PAtients) is a randomized, double-blind, placebo-controlled Phase 2 clinical study evaluating OP-101 in patients with severe COVID-19 as defined by the World Health Organization’s (WHO) ordinal score. The study will enroll approximately 24 patients who, in addition to standard of care therapy, will be randomized to a single intravenous (IV) infusion of OP-101 (2 mg/kg, 4 mg/kg or 8 mg/kg) or placebo. The primary endpoint is safety and tolerability. Secondary endpoints include efficacy as measured by resolution of fever, improvement in oxygenation, discharge from clinic or hospital, number of days free from a ventilator, number of days in the intensive care unit (ICU), hospitalizations and deaths, among other measures. The study also will evaluate the effect of OP-101 in reducing blood levels of pro-inflammatory biomarkers (e.g., c-reactive protein [CRP], ferritin and interleukin-6 [IL-6]) after a single dose of OP-101.

“With all five clinical trial sites up and running, we are eager to complete enrollment of very sick COVID-19 patients on oxygen and ventilators in our Phase 2 study. As the pandemic continues to spread in the United States and globally, novel approaches that can reduce the devastating effect of hyperinflammation in critically ill hospitalized patients are urgently needed,” said Jeffrey Cleland, Ph.D., chairman, CEO and president of Ashvattha Therapeutics and executive chairman of Orpheris. “We believe there is strong scientific rationale for the clinical development of OP-101 to treat patients with severe COVID-19 due to its unique mechanism of action, which has been shown in animal models to shut down multiple pathways that cause hyperinflammation, potentially reducing or eliminating lung inflammation and multi-organ failure.”

Initial data from the Phase 2 proof-of-concept study is expected to be reported in the fourth quarter of 2020. An expansion into a double-blind, placebo-controlled COVID-19 trial has been discussed with the U.S. Food and Drug Administration (FDA), which is anticipated to include up to 20 sites after the results from the ongoing stage are evaluated.

About OP-101

OP-101, an investigational compound created by the conjugation of N-acetyl cysteine to the hydroxyl dendrimer, is the only clinical-stage therapeutic with the ability to shut down multiple pathways causing hyperinflammation. OP-101 selectively targets reactive macrophages, which are responsible for hyperinflammation, lung injury and multi-organ failure caused by viral or bacterial infections. Through this unique targeting mechanism of action, OP-101 increases the probability of effectiveness in stopping hyperinflammation while potentially avoiding side effects and non-specific immune suppression.

OP-101 has been shown to arrest hyperinflammation by normalizing reactive macrophages, reducing the pro-inflammatory cytokine storm, and reducing oxidative stress after a single dose in multiple animal models of inflammation. Once inside the macrophage, OP-101 inhibits I??β and NF?β, blocking the expression of pro-inflammatory cytokines such as IL-6 and IL-1β, and inhibits the JAK/STAT/MAPK pathway.

Results from a Phase 1 study of a single IV dose of OP-101 (20 or 40 mg/kg) in healthy volunteers demonstrated that it was well tolerated based on an assessment of clinical and laboratory adverse events. A Phase 1 study of a single subcutaneous (SC) dose of OP-101 (4 or 8 mg/kg) in healthy volunteers demonstrated that it was well tolerated, with only mild transient injection site reactions and no other adverse events. Preclinical studies have demonstrated that OP-101 persists for up to one month at the site of inflammation and is systemically cleared within two days, potentially enabling once per month SC dosing.

ovid-19.