RADAR: First Significant Use of Novel Anticoagulation System

Sue Hughes

April 07, 2011

April 7, 2011 (New Orleans, Louisiana) — A phase 2 trial of a novel anticoagulation system that involves first giving a factor IX inhibitor and then administering a reversal agent has shown preliminary encouraging results, albeit with a question about potential allergic reactions.

REG1 (Regado Biosciences) consists of an RNA aptamer of factor IX--pegnivacogin--which binds to and inhibits the factor IX molecule for a 24-hour duration, and the reversal agent--anivamersen, which binds to and inactivates pegnivacogin.

Dr Thomas J Povsic [Source: Duke University]

Presenting results of the trial at the American College of Cardiology 2011 Scientific Sessions, Dr Thomas J Povsic (Duke University, Durham, NC) explained: "The system allows very high levels of anticoagulation for a short period, and then, on administration of the reversal agent, coagulation levels go back to normal quickly, so it is ideal for use in procedures such as PCI, where you just need high levels of anticoagulation during the procedure itself. We found that because we can normalize anticoagulation levels more quickly with the REG1 system, this allows faster removal of the sheath."

He added that the REG1 system would also be suited to other percutaneous procedures such as the new valvular procedures where large sheath sizes are used. And there is also a program looking into its use in open-heart surgery.

Povsic reported results of the first significant clinical use of REG1 system in the phase 2 RADAR trial. A very small phase 2a study has been reported previously. In the trial, 640 ACS patients scheduled for catheterization were randomized to pegnivacogin 1 mg/kg (n=479) or heparin (n=161) in an open-label fashion. Then, after the PCI procedure, anivamersen was given at four different doses (corresponding to 25%, 50%, 75% and 100% reversal) in a blinded fashion to the patients who had been given pegnivacogin.

The data safety and monitoring board stopped the lowest-dose anivamersen arm (25% reversal) early on in the trial because of a high bleeding rate. "So we showed that enough anivamersen to give at least 50% reversal of pegnivacogin is needed," Povsic said.

The three other arms showed good results, with a rate of total ACUITY bleeding similar to heparin, with the suggestion of a stepwise reduction in major bleeding with higher doses of the reversal agent.

RADAR: Major Results

Outcome REG1 25% reversal, n=40 (%) REG1 50% reversal, n=113 (%) REG1 75% reversal,

n=119 (%)

REG1 100% reversal, n=194 (%) Heparin, n=160
Total ACUITY bleeding 65.0 33.6 34.5 30.4 31.3
Major bleeding 20.0 10.6 8.4 7.3 10.1
Ischemic events (death/MI/target vessel revascularization/recurrent ischemia) 7.5 0.9 4.2 2.6 5.7

Povsic noted that overall bleeding rates were hard to compare between the REG1 and heparin groups because of the open nature of pegnivacogin administration. "Less severe bleeding is quite a subjective measure, and operators may be more sensitive to minor bleeding with a new investigational agent," he commented to heartwire .

He reported that in the overall REG1 population there was a suggestion of a reduced rate of ischemic events (3.0% vs 5.7% on heparin), but this was based on a very small number of events (23 in total, mostly MIs), and no definite conclusion on efficacy could be drawn from a trial of this size.

Sheaths were removed an average of 24 minutes after the procedure in the REG1 patients vs three hours in the heparin group.

Allergy Question Mark

However, there were three allergic reactions in the trial. Povsic reported that these all occurred near the end of the trial in Europe shortly after administration of pegnivacogin. They ranged from a mild dermal reaction to one patient who needed hemodynamic support. "These reactions do not appear to be related to drug stability or contamination, and we need to get a better handle on what happened. Investigations are still under way," Povsic told heartwire .

The investigators are now working on the design of a phase 3 trial, which is likely to be a PCI study in both ACS and elective patients.

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