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Rivaroxaban antidote met all endpoints in phase 3 ANNEXA-R study
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ORLANDO, Fla. — Andexanet alfa, a novel agent for reversal of Factor Xa-inhibitor anticoagulation, successfully reversed the effects of rivaroxaban in elderly individuals, according to data presented at the American Heart Association Scientific Sessions.
In a simultaneous published in the New England Journal of Medicine, the ANNEXA-R investigators reported that andexanet alfa (Portola Pharmaceuticals) was also successful for reversal of the effects of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) in elderly individuals.
Mark R. Crowther
Mark R. Crowther, MD, MSc, FRCPC, professor of medicine at McMaster University, Hamilton, Ontario, Canada, said during a press conference that andexanet alfa had previously demonstrated success in phase 2 proof-of-concept studies for reversal of four Factor Xa-inhibitor anticoagulants. He said two phase 3 registration-enabling studies, ANNEXA-R for reversal of rivaroxaban (Xarelto, Janssen Pharmaceuticals) and ANNEXA-A for reversal of apixaban, have now been completed.
In ANNEXA-R, 39 healthy elderly volunteers were randomly assigned on a 2:1 basis to receive andexanet alfa or placebo after taking rivaroxaban for 4 days. All received a bolus followed by an infusion of the study drug after last dose of rivaroxaban.
The primary endpoint was percent change in anti-Factor Xa activity at the end of the infusion. Secondary endpoints included percent change in anti-Factor Xa activity at the end of the bolus and the following parameters at the end of the infusion: occurrence of at least 80% Factor Xa reduction, change in free rivaroxaban concentration, change in thrombin generation and occurrence of thrombin generation above lower limit of derived normal range.
ANNEXA-R results
Crowther reported no safety issues in any of the ANNEXA-R participants, including serious adverse events, reactions to the infusion and thrombotic events.
Mean percent change in anti-Factor Xa activity in those receiving andexanet alfa was 97% after the infusion (P < .0001 vs. placebo), Crowther said.
“When you give the reversal agent, you have an immediate and almost complete correction of the blood-thinning effect, which persists throughout the duration of the infusion,” he said.
He also noted that the secondary endpoints of percent change in anti-Factor Xa activity after the bolus (95%; P < .0001 vs. placebo), occurrence of at least 80% Factor Xa reduction (andexanet alfa group, 100%; placebo group, 0%; P < .0001), mean change in free rivaroxaban concentration (reduced by 23.4 ng/mL in the andexanet alfa arm vs. 4.2 ng/mL in the placebo arm; P < .0001), change in thrombin generation (fully restored in 96% of the andexanet alfa arm vs. 7% of the placebo arm; P < .0001) and occurrence of thrombin generation above lower limit of derived normal range (P < .0001 vs. placebo) were all met.
“Our conclusion is that [andexanet alfa] rapidly reduced the blood-thinning effect in every patient in whom it was administered,” Crowther said.
ANNEXA-A results
According to the NEJM article, in the ANNEXA-A study, Factor Xa activity was reduced 94% in the 21 participants assigned andexanet alfa after apixaban and 21% in the nine participants assigned placebo after apixaban (P < .001).
Unbound apixaban concentration was reduced by 9.3 ng/mL in the andexanet alfa arm vs. 1.9 ng/mL in the placebo arm (P < .001), the researchers wrote. In addition, 100% those assigned andexanet alfa had thrombin fully restored within 2 to 5 minutes vs. 11% of controls (P < .001).
No serious adverse or thrombotic events were reported in the ANNEXA-A study, according to the researchers.
“The results of the studies are all very congruent,” Crowther said.
Portola plans to submit an application for FDA approval by the end of 2015, and has begun a study of andexanet alfa in patients who are actively bleeding, Crowther said. – by Erik Swain
References:
Crowther MR, et al. Late-Breaking Clinical Trials 4. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.
Siegal DL, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1510991.
Disclosures: The studies were funded by Bristol-Myers Squibb, Johnson & Johnson, Pfizer and Portola Pharmaceuticals. Crowther reports financial ties with AKP America, Bayer, Celgene, CSL Behring, Janssen Pharmaceuticals, Leo Pharma, Portola Pharmaceuticals and Shire.