Quantum Leap Healthcare Discontinues Razuprotafib I-SPY COVID Trial

Quantum Leap Healthcare Collaborative (QLHC), the sponsor of the I-SPY COVID Trial, will not proceed with further testing of the Aerpio drug, razuprotafib. Razuprotafib was chosen for testing in the I-SPY COVID Trial because it is hypothesized to stabilize and repair the blood vessels in the lung and improve gas exchange.

The I-SPY COVID Trial is a Phase II adaptive platform trial that is testing agents that show promise for reducing the risk of death from and severity of illness for people who become critically ill after contracting COVID-19. The purpose of the trial is to rapidly screen multiple agents to find those with the best chance of effectively improving outcomes for those critically ill. The I-SPY COVID Trial now includes 18 sites as well as leaders in pulmonary and critical care centers from around the country who are working to identify and test new agents to improve patient outcomes.

The sponsor halted testing of Aerpio's razuprotafib in the I-SPY COVID Trial because it was challenging to administer in the setting of COVID-19, with 30% of patients discontinuing the agent due to disease-related hypotension, including protocol-mandated stopping rules. There was no indication that razuprotafib caused the hypotension that led to clinical decline in systolic blood pressure. However, at the conclusion of two safety lead-in cohorts, it was determined there was a small but not clinically significant decline in systolic blood pressure and mean arterial blood pressure by approximately 4–5 mm Hg; there was no significant difference between the 10 mg and 20 mg dose in blood pressure decline. In addition, there was little if any blood pressure reduction in patients with pre-dose blood pressure readings of less than 100 mm Hg, even when on vasopressors, and there was no evidence that razuprotafib reduced the efficacy of vasopressors.

Because blood pressure monitoring with additional scrutiny is challenging in the setting of a surge in ICU admissions from COVID-19, the Data Monitoring Committee recommended that razuprotafib not be advanced after the second safety lead-in. This agent could be revisited in the setting of acute respiratory distress syndrome (ARDS) absent pandemic COVID-19.

"We remain enthusiastic about the potential for razuprotafib in ARDS given its very strong mechanistic rationale. Unfortunately, the monitoring required to safely assess this agent was difficult to execute while sites were strained and short-staffed due to the pandemic; thus, we have not been able to fully evaluate its effectiveness,” Dr. Nuala Meyer, an I-SPY COVID Trial co-investigator and chaperone (PI) of the razuprotafib arm, and an associate professor of medicine at University of Pennsylvania, said.

"While we were disappointed to not to be able to continue with razuprotafib in this trial, we are continuing to press onward in our search for new treatments that may help us treat patients who become severely ill with COVID-19," Dr. Carolyn Calfee, also a professor of medicine at UCSF and principal investigator for the I-SPY COVID Trial, said.

"We were pleased with the overall tolerability of razuprotafib in these patients with critical COVID-19, including those in shock and on vasopressors. The modest reduction in blood pressure noted in this trial is attributed to the production of nitric oxide by endothelial cells downstream of Tie2 activation, which is considered an important component of the vascular stabilizing effects of razuprotafib," said Dr. Kevin Peters, Chief Scientific Officer and Chief Medical Officer, Aerpio Pharmaceuticals. "Ironically, what could have been considered a sign of potentially beneficial effects of razuprotafib actually contributed to the difficulty encountered in monitoring drug administration in the pandemic setting of COVID-19. We are grateful to our I-SPY colleagues for this early indication of the tolerability of razuprotafib in this critically ill population and certainly agree with them regarding the potential of razuprotafib and Tie2 mediated vascular stabilization in patients with non-COVID-19 related ARDS.”