Astrazeneca Regulatory News (AZN)

29 March 2022 07:00 BST 

Ondexxya approved in Japan for reversal of acute major bleeds in patients on Factor Xa inhibitors

Ondexxya is the first approved reversal agent specifically for Factor Xa inhibitors, providing a major advance in the treatment of patients hospitalised with life-threatening bleeding

Ondexxya (andexanet alfa) has been approved in Japan for patients treated with the Factor Xa (FXa) inhibitors apixaban, rivaroxaban or edoxaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The approval by the Japanese Ministry of Health, Labour and Welfare was based on positive results from the  ANNEXA-4 Phase III clinical trial showing Ondexxya rapidly and markedly reversed anti-FXa activity in patients with acute major bleeding.

Ondexxya is the first approved medicine in Japan to specifically reverse the anticoagulant effect of FXa inhibitors apixaban, rivaroxaban or edoxaban in patients experiencing a life-threatening or uncontrolled bleed. Japan is also the first country to provide full regulatory approval of Ondexxya for use with all three of the FXa inhibitors currently available. FXa inhibitors are increasingly used for the prevention and treatment of thrombotic events, including deep vein thrombosis and pulmonary embolism, or in patients at high risk of a stroke due to an irregular heart rate (atrial fibrillation). While they prevent unwanted clots from forming, they can also increase the risk of major bleeding, which can be life-threatening.1,2

Masahiro Yasaka, MD, PhD, National Hospital Organisation Kyushu Medical Centre, Fukuoka, Japan, said: "FXa inhibitors are essential medicines for people prone to developing blood clots, but they can also present a risk of uncontrolled bleeding and related complications, which can be fatal if left untreated. Ondexxya's rapid reversal of the anticoagulating effects of apixaban, rivaroxaban and edoxaban effectively reduces the bleeding and is a major advancement in patient care."

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: "With the approval of Ondexxya in Japan, we are working to make this important medicine available as quickly as possible for the small proportion of patients with life-threatening or uncontrolled bleeding who are on FXa inhibitors and who have not previously had an approved reversal agent treatment option."

Ondexxya received approval by the US Food and Drug Administration under the accelerated approval pathway in May 2018 and conditional approval by the European Commission in April 2019 for adults treated with FXa inhibitors apixaban and rivaroxaban. In the US, Ondexxya is marketed under the trade name Andexxa [coagulation factor Xa (recombinant), inactivated-zhzo].

Notes

Life-threatening bleeding

There is an urgent need for a specific reversal agent for patients treated with FXa inhibitors hospitalised with a major bleed. Millions of patients worldwide depend on FXa inhibitors every day to prevent harmful blood clots from forming;3 however, these agents increase the risk of major bleeding.1,2 Major bleeding can be very serious and life-threatening, and can happen inside the body and may not be visible. As prescriptions for FXa inhibitors increase, the potential for serious bleeding hospital admissions grows.4,5

ANNEXA-4

The approval of Ondexxya is supported by data from the ANNEXA-4 Phase III trial, which evaluated the haemostatic efficacy and safety of Ondexxya in patients receiving a FXa inhibitor who were experiencing an acute major bleed.6 In the trial, Ondexxya markedly reversed anti-FXa activity within minutes, with 80% of patients having excellent or good haemostatic efficacy sustained at 12 hours following administration. During the trial, 10.4% of patients experienced at least one thrombotic event, the majority of which occurred in patients who delayed or did not restart anticoagulation during the follow-up period.6 Consistent with previous trial results in patients who are at increased risk of thrombosis, 15.7% of patients died during the trial.6

Ondexxya 

Ondexxya (andexanet alfa) is a recombinant protein specifically designed to bind to FXa inhibitors and rapidly reverse their anticoagulant effect. Ondexxya is a modified form of the human FXa molecule, an enzyme that helps blood clot. Ondexxya works by acting as a decoy for oral and injectable FXa inhibitors, which target and bind to FXa, allowing them to exert their anticoagulant effect. When Ondexxya is given through an intravenous infusion to a patient with FXa inhibitor-related bleeding, it binds with high affinity to the FXa inhibitor, prevents it from inhibiting the activity of FXa and reverses the anticoagulant effects of the inhibitor. 

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References 

1. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015;36:1264-1272. 

2. Piccini JP et al. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014;35:1873-1880. 

3. Coleman CI, et al. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study. Future Cardiol. 2021;17:127-135.

4. Budnitz DS, et al. US Emergency Department Visits Attributed to Medication Harms, 2017-2019. JAMA. 2021;326:1299-1309.

5. Geller AL, et al. Emergency Visits for Oral Anticoagulant Bleeding. J Gen Intern Med. 2020;35(1):371-373.

6. Presentation: Milling T, Middeldorp S, Xu L, et al. Final Study Report of Andexanet Alfa for Bleeding with Factor XA Inhibitors. Poster presented at 2021 European Stroke Conference; September 2021; Virtual.

Adrian Kemp 

Company Secretary 

AstraZeneca PLC