REG1 Novel Anticoagulant Falters in REGULATE PCI Trial

March 15, 2015—The American College of Cardiology (ACC) announced that findings from the REGULATE PCI study, which sought to determine the efficacy and safety of REG1 compared to bivalirudin in patients undergoing percutaneous coronary intervention (PCI), were presented at the ACC’s 64^th annual scientific session in San Diego, California.

The REG1 investigational anticoagulation system is a novel therapy that would allow doctors to turn the body’s blood-clotting ability off and on in a more controlled way than established anticoagulants. REG1 is manufactured by Regado Biosciences, Inc., which sponsored the trial.

The ACC advised that in this analysis of data from the terminated phase III REGULATE PCI trial, REG1 was approximately as effective as established anticoagulants in patients undergoing angioplasty but was associated with higher rates of moderate-to-severe bleeding. The study was officially halted in August 2014 because of excess severe allergic reactions. The investigators cautioned that the data should be considered exploratory given the early termination, noted the ACC.

According to the ACC, the study was designed to compare the safety and efficacy of REG1 and bivalirudin in a total of 13,200 patients. Patients were equally randomized to bivalirudin or REG1 in an open-label fashion and data were collected at 3 and 30 days. Before the trial was stopped, 3,232 patients undergoing angioplasty were enrolled in the study at 225 hospitals in 17 countries, including North America and Europe.

The investigators found no differences between patients receiving REG1 compared to bivalirudin in terms of the study’s primary efficacy endpoint—a composite of all-cause death, heart attack, stroke, or urgent revascularization, which was reported in 6.7% of patients in the REG1 arm and 6.4% of patients receiving bivalirudin 3 days after angioplasty. Efficacy was still comparable at 30 days.

The REG1 system failed to show a benefit in the primary safety endpoint of bleeding compared to bivalirudin. Using a validated bleeding scale, patients receiving REG1 had a 0.4% rate of severe or fatal bleeding compared to 0.1% with patients who were given bivalirudin for anticoagulation. Moderate-to-severe bleeding was significantly higher in the REG1 group compared with bivalirudin.

Serious allergic reactions were seen in 10 out of 1,605 patients in the REG1 arm, one of which was fatal and the others were anaphylactic reactions. Only one patient in the bivalirudin group had a serious allergic event.

“This anticoagulant system is associated with infrequent but an unacceptably high rate of severe allergic reactions,” commented Roxana Mehran, MD, in the ACC press release. Dr. Mehran serves as one of the trials principal investigators and is Director of Interventional Cardiovascular Research and Clinical Trials at Mount Sinai Heart at The Mount Sinai Hospital and Professor of Medicine in Cardiology at Icahn School of Medicine at Mount Sinai in New York, New York.

As noted in the ACC announcement, research is ongoing to determine the exact cause of the allergic reactions. Dr. Mehran said she hopes this does not deter the search for novel anticoagulants for use in this patient population. Physicians must balance preventing blood clots with the risk of potentially dangerous bleeding. She concluded, “It’s the Achilles’ heel in cardiovascular medicine—how do we protect patients against any kind of blood clotting without exposing them to a higher risk of bleeding? We are constantly refining the antithrombotic therapies we use during PCI, and this seemed promising.” Dr. Mehran added that the ideal anticoagulant is one that works fast, has a predictable dose, and can efficiently stop clots from forming on top of catheters, but it can also be quickly reversed.

The REG1 system uses a pegnivacogin molecule that binds to the blood coagulation Factor IXa receptor to deactivate blood clotting, and anivamersen, an active control agent that rapidly reverses the anticoagulant effect to quickly help return blood clotting activity to normal.

“Within seconds of giving the reversal agent anticoagulation is nearly completely reversed because it looks for its friend and grabs it off the receptor immediately,” stated Dr. Mehran. “With a technique like this, we could provide blood thinning as needed and then take it away immediately after finishing angioplasty.” But, she said, further improvements are needed in its safety profile.