System can attenuate thrombin generation

Thrombus

Credit: Kevin MacKenzie

Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.

The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.

REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.

Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.

The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.

In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.

The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).

The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.

Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.

Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.

Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.

Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.

Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.

Thrombus

Credit: Kevin MacKenzie

Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.

The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.

REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.

Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.

The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.

In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.

The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).

The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.

Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.

Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.

Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.

Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.

Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.

Thrombus

Credit: Kevin MacKenzie

Results of a phase 1 trial suggest the REG2 anticoagulation system can attenuate thrombin generation and then restore thrombin following reversal.

The REG2 system consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen.

REG2 is formulated to provide a controllable level of anticoagulation for up to 2 weeks for sub-acute uses, especially in cases where a patient may be unable to swallow an oral anticoagulant.

Results observed with REG2 were published in the Journal of Thrombosis and Thrombolysis. The study was sponsored by Regado Biosciences, Inc, the company developing the REG2 system.

The study included 32 healthy volunteers who were enrolled sequentially into 4 cohorts. Patients in cohorts 1-3 were randomized (3:1) to ascending doses of pegnivacogin—from 0.5 mg/kg to 3 mg/kg—or placebo, with no anivamersen administered.

In cohort 4, all patients received 2 mg/kg of pegnivacogin and were randomized (1:1) to reversal by 1 dose or multiple doses over time of 1 mg/kg of anivamersen.

The researchers drew blood samples in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. They initiated thrombin generation with tissue factor and measured thrombin generation kinetics using the calibrated automated thrombogram (CAT).

The team found that REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose- and concentration-dependent response to pegnivacogin.

Specifically, there was a decrease in velocity index (VIx) from baseline to 24 hours after pegnivacogin administration. The largest percent change in VIx was in cohort 3 (3 mg/kg). There was a 90% decrease at 24 hours post-dose. This remained stable up to 48 hours in cohort 1 and up to 96 hours in cohorts 2 and 3.

Similarly, mean peak thrombin generation (PTG) values decreased as pegnivacogin dose and plasma concentrations increased. Cohort 3 had an 80% decrease in PTG at 24 hours post-dose. The percent change in mean PTG was consistent and preserved for at least 24 hours for all pegnivacogin doses. In cohorts 2 and 3, it was stable for at least 96 hours.

Endogenous thrombin potential (ETP) levels also decreased after pegnivacogin administration. Again, the largest decrease occurred in cohort 3, which exhibited a 65% decrease at 24 hours. Beyond that, the percent change in ETP was stable within each dose group, up to the last recorded measurement at 96 hours.

Peak time (PTm) was positively correlated with pegnivacogin concentration and relative activated partial thromboplastin time values. The correlation between PTm and quartile of pegnivacogin concentration was statistically significant (P=0.04) but weaker than that of ETP (P=0.001), PTG (P<0.001), or VIx (P<0.001). The changes in PTm persisted for at least 96 hours after pegnivacogin administration.

Finally, the researchers found that anivamersen reversed the effects of pegnivacogin, restoring thrombin generation without rebound effect.