AstraZeneca to proceed with regulatory filings to convert from conditional to full approval in the US and EU

ANNEXA-I, a post-marketing Phase IV trial to assess the efficacy and safety of ANDEXXA (andexanet alfa) in patients on oral FXa inhibitor treatment including apixaban and rivaroxaban experiencing an intracranial hemorrhage, will be stopped early.¹ The decision is based on achieving pre-specified stopping criteria of superior hemostatic efficacy, the ability to limit the expansion of a potentially life-threatening bleed in the brain, versus usual care.^1,2

The recommendation to stop the trial was made by the independent Data and Safety Monitoring Board (DSMB) following a planned interim assessment of efficacy after 450 patients had been randomized and followed for one month, which showed ANDEXXA’s reversal benefits earlier in the study enrolment than originally anticipated.

Stuart J. Connolly, MD, FRCPC, Senior Scientist at Population Health Research Institute and professor emeritus at McMaster University in Hamilton, Ontario, said: “We are pleased that the study has met its efficacy endpoint at the planned interim analysis, showing improved control of bleeding with targeted anticoagulation reversal, compared to usual care. We look forward to sharing the full efficacy and safety results after further analysis, with the hope that the data will pave the way for further guidance on the treatment of potentially life-threatening bleeds.”

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said:

“Millions of people worldwide depend on FXa inhibitors to prevent harmful blood clots from forming, but these agents also carry a small but significant risk of increasing the likelihood that an acute major bleed could occur. We are proud to offer the first and only approved treatment to specifically reverse FXa inhibitor activity and help achieve hemostasis, providing an effective and reliable treatment when immediate care is required.”

ANDEXXA is specifically designed to rapidly reverse the anticoagulation effects of direct oral FXa inhibitors due to life-threatening or uncontrolled bleeding.³ The treatment has been granted accelerated approval in the US and is conditionally approved in the EU, Switzerland and UK as Ondexxya for adults treated with FXa inhibitors apixaban and rivaroxaban. It is also approved in Japan as Ondexxya for FXa inhibitors apixaban, rivaroxaban, or edoxaban. Use of ANDEXXA is supported by over 15 national and international guidelines across multiple disciplines.^4-19

AstraZeneca will now initiate closure of ANNEXA-I and proceed with regulatory filings in the US and EU to convert to full label approval. The full efficacy and safety results will be submitted for presentation at a forthcoming medical meeting and publication.

IMPORTANT SAFETY INFORMATION FOR ANDEXXA^® (coagulation factor Xa [recombinant], inactivated-zhzo)

WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS

Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including:

• Arterial and venous thromboembolic events
• Ischemic events, including myocardial infarction and ischemic stroke
• Cardiac arrest
• Sudden deaths

Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.

WARNINGS AND PRECAUTIONS

• Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death, have occurred during treatment with ANDEXXA. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA. The safety of ANDEXXA has not been evaluated in subjects who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safety of ANDEXXA also has not been evaluated in subjects who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event.
• Re-elevation or incomplete reversal of anticoagulant activity can occur.
• ANDEXXA may interfere with the anticoagulant effect of heparin. If anticoagulation is needed, use an alternative anticoagulant to heparin.

ADVERSE REACTIONS

The most common adverse reactions (≥ 5%) in bleeding subjects receiving ANDEXXA were urinary tract infections and pneumonia. The most common adverse reactions (≥ 3%) in healthy volunteers treated with ANDEXXA were infusion-related reactions.

Please see full Prescribing Information, including Boxed WARNING.

INDICATION

ANDEXXA^® (coagulation factor Xa [recombinant], inactivated-zhzo) is a recombinant modified human factor Xa (FXa) protein indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies that demonstrate an improvement in hemostasis in patients.

Limitations of Use

ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.

Notes

Life-threatening bleeding

Millions of people worldwide depend on Factor Xa (FXa) inhibitors to manage their risk of blood clots developing.²⁰ These medicines are important to maintaining health and wellbeing, however, carry a small but significant risk of an acute major bleed.^21-26 There are different forms of uncontrolled bleeding that may occur. One that has high risk of being life threatening, if left untreated, is an intracranial hemorrhage (ICH).^27-29 There is an urgent need for access to specific reversal agents for patients treated with FXa inhibitors as major bleeding can be life threatening and can happen inside the body, so may not be visible. As prescriptions for FXa inhibitors increase, the need for efficacious and reliable care for uncontrolled bleeds grows.^30,31

ANNEXA-I

ANNEXA-I is a randomized, multi-center clinical trial designed to determine the efficacy and safety of andexanet alfa versus usual care in adult patients (≥18 years) with an intracranial hemorrhage who have received oral FXa inhibitors, including apixaban and rivaroxaban, and is part of the post-marketing study commitment required to support full US and EU approvals.¹ ANNEXA-I enrolled over 450 adult patients with an intracranial hemorrhage who were also being treated with FXa inhibitors (apixaban and rivaroxaban), a type of direct oral anticoagulant (DOAC), commonly referred to as blood-thinners. The primary endpoint was the rate of effective hemostasis, or stopping the flow of blood, following treatment with ANDEXXA compared with usual care, including four-factor prothrombin complex concentrate (4F-PCC).^1,2 ANNEXA-I was conducted in patients with acute ICH, which are typically assessed by hematoma bleed size and location.¹ There is an established method for measurement of hematoma size and expansion, allowing for definitive assessment of hemostatic efficacy.^32,33

ANDEXXA

ANDEXXA (andexanet alfa) is a recombinant protein specifically designed to bind to FXa inhibitors and rapidly reverse their anticoagulant effect.³⁴ ANDEXXA is a modified form of the human FXa molecule, an enzyme that helps blood clot. ANDEXXA 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 ANDEXXA 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.

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and improving outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.

AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

References

1. ClinicalTrials.gov. Trial of Andexanet Alfa in ICrH Patients Receiving an Oral FXa Inhibitor. ClinicalTrials.gov website. [cited 2023 May 26] Available from: URL: https://clinicaltrials.gov/ct2/show/NCT03661528.
2. Hemostasis [Internet]. Cleveland Clinic. [cited 2023 May 26]. Available from: https://my.clevelandclinic.org/health/symptoms/21999-hemostasis https://my.clevelandclinic.org/health/diseases/23969-hemorrhagic-stroke.
3. Heo YA. Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA. Drugs Ther Perspect. 2018;34(11):507-512. doi: 10.1007/s40267-018-0561-8. Epub 2018 Oct 5. Erratum in: Drugs Ther Perspect. 2018;34(12):593. PMID: 30459509; PMCID: PMC6223707.
4. Greenberg SM et al. 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: A guideline from the american heart association/american stroke association. Stroke. 2022:e282-e361.
5. Steffel J et al. 2021 european heart rhythm association practical guide on the use of non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation. EP Europace. 2021;23:1612-76.
6. Kakkos SK et al. Editor's choice–european society for vascular surgery (esvs) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg. 2021;61:9-82.
7. Tomaselli GF et al. 2020 acc expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: A report of the american college of cardiology solution set oversight committee. J Am Coll Cardiol. 2020;76:594-622.
8. Hindricks G et al. 2020 esc guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the european association for cardio-thoracic surgery (eacts) the task force for the diagnosis and management of atrial fibrillation of the european society of cardiology (esc) developed with the special contribution of the european heart rhythm association (ehra) of the esc. Eur Heart J. 2021;42:373-498.
9. Cuker A et al. Reversal of direct oral anticoagulants: Guidance from the anticoagulation forum. Am J Hematol. 2019;94:697-709.
10. Baugh CW et al. Anticoagulant reversal strategies in the emergency department setting: Recommendations of a multidisciplinary expert panel. Ann Emerg Med. 2020;76:470-85.
11. Gibler WB et al. Management of severe bleeding in patients treated with oral anticoagulants: Proceedings monograph from the emergency medicine cardiac research and education group-international multidisciplinary severe bleeding consensus panel october 20, 2018. Crit Pathw Cardiol. 2019;18:143-66.
12. Christensen H et al. European stroke organisation guideline on reversal of oral anticoagulants in acute intracerebral haemorrhage. European stroke journal. 2019;4:294-306.
13. Ahmed N et al. Consensus statements and recommendations from the eso-karolinska stroke update conference, stockholm 11–13 november 2018. European stroke journal. 2019;4:307-17.
14. Álvarez FC et al. Consensus document of the spanish society of digestives diseases and the spanish society of thrombosis and haemostasis on massive nonvariceal gastrointestinal bleeding and direct-acting oral anticoagulants. Rev Esp Enferm Dig. 2022;114:375-89.
15. Oakland K et al. Diagnosis and management of acute lower gastrointestinal bleeding: Guidelines from the british society of gastroenterology. Gut. 2019;68:776-89.
16. Tibi P et al. Sts/sca/amsect/sabm update to the clinical practice guidelines on patient blood management. The Annals of thoracic surgery. 2021;112:981-1004.
17. Witt DM et al. American society of hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood advances. 2018;2:3257-91.
18. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Hearth Rhythm. 2019;16:e66-e93.
19. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest. 2018;154(5):1121-1201.
20. 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.
21. Milling Jr TJ et al. Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding. The American journal of managed care. 2017;23:S67.
22. Chai-Adisaksopha C et al. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: A systematic review and meta-analysis. Blood, The Journal of the American Society of Hematology. 2014;124:2450-8.
23. Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-91.
24. Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92.
25. Beyer-Westendorf J et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: Results from the dresden noac registry. Blood, The Journal of the American Society of Hematology. 2014;124:955-62.
26. Siegal DM et al. Andexanet alfa for the reversal of factor xa inhibitor activity. N Engl J Med. 2015;373:2413-24.
27. Bower MM et al. Stroke. 2019;50:529-536​
28. Gulati D et al. Front Neurol. 2017;8:80​
29. Mayer SA. Stroke (2002) 34(1):224–9​
30. Portola. Prospective, Open-Label Study Of Andexanet Alfa In Patients Receiving A Factor Xa Inhibitor Who Require Urgent Surgery (Annexa-S), last update July 2020. [cited 2023 May].
31. Kornej J, Börschel CS, Benjamin EJ, Schnabel RB. Epidemiology of Atrial Fibrillation in the 21st Century: Novel Methods and New Insights. Circ Res. 2020 Jun 19;127(1):4-20. doi: 10.1161/CIRCRESAHA.120.316340. Epub 2020 Jun 18. PMID: 32716709; PMCID: PMC7577553.
32. Davis S et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175-81.
33. Purrucker JC et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA neurology. 2016;73:169-77.
34. ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) [prescribing information]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2021. [cited 14 Jan 2022]. Available from: URL: https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/4f256543-46a3-46b3-b835-4cf121aa57d6/4f256543-46a3-46b3-b835-4cf121aa57d6_viewable_rendition__v.pdf.

View source version on businesswire.com: https://www.businesswire.com/news/home/20230605005286/en/