ONDEXXYA▼(ANDEXANET ALFA) PHASE IV TRIAL STOPPED EARLY AFTER ACHIEVING PRE-SPECIFIED CRITERIA ON HAEMOSTATIC EFFICACY VERSUS USUAL CARE

London, UK, Thursday 8 June 2023 – The first randomised control clinical trial to assess the efficacy and safety of Ondexxya (andexanet alfa) – a treatment for life-threatening or uncontrolled bleeds in patients on oral FXa-inhibitor treatment (blood thinning medicines) including apixaban and rivaroxaban – versus usual care, has been stopped early after the medicine demonstrated superior efficacy in treating potentially life-threatening bleeds in the brain, versus usual care.^[1],[2]

The recommendation to stop the trial called ANNEXA-I was made by the independent Data and Safety Monitoring Board (DSMB) following a planned interim assessment of the efficacy of 450 randomised patients who were followed for one month. The decision is based on achieving pre-specified stopping criteria of superior haemostatic efficacy, the ability to limit the expansion of a potentially life-threatening bleed in the brain, versus usual care. The interim assessment showed andexanet alfa’s reversal benefits earlier than anticipated in the trial, which was due to run until July 2024.¹

In the UK, there are almost 1.6 million adults who are taking oral FXa inhibitor medicines and are therefore at risk of an uncontrolled or life-threatening bleed.^[3],[4] Whilst uncontrolled bleeding in patients taking these anticoagulant medicines is uncommon, it can be life-threatening and requires urgent medical care.⁴

Professor Adrian Parry-Jones, Consultant Vascular Neurologist at the Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, said: “Despite FXa inhibitors’ well-recognised clinical benefits in reducing the risk of stroke, they conversely carry a risk of major uncontrolled brain bleeds. This announcement following the trial’s interim assessment indicates improved management of bleeding with targeted anticoagulation reversal, compared to usual care, demonstrating the potential of andexanet alfa for patient care and emergency medicine in the UK.”

Ed Piper, Medical and Scientific Affairs Director, AstraZeneca UK, said: “The early stop of the ANNEXA-I trial demonstrates that the direct reversal effect of andexanet alfa on FXa inhibitors has a significant benefit over usual treatment. We hope that findings from this study open the door to change the way that life-threatening intracranial haemorrhages are treated in patients taking FXa inhibitors in the UK.”

Tom Keith-Roach, President, AstraZeneca UK, said: “The growing adoption of FXa inhibitors has led to a corresponding need to urgently address FXa inhibitor-related intracranial haemorrhage. Today’s announcement demonstrates the potential of andexanet alfa for patient care and emergency medicine in the UK. We look forward to engaging with NICE to ensure there is equitable access to andexanet alfa for patients who are on FXa inhibitors across the UK to manage this significant unmet need in situations of life-threatening or uncontrolled bleeding.”

Andexanet alfa currently has a conditional marketing authorisation by the MHRA – the regulators for medicines in Great Britain – and is currently recommended by the National Institute for Health and Care Excellence (NICE) for eligible patients with life-threatening or uncontrolled bleeds in the gastro-intestinal (GI) tract,^[5] and by the Scottish Medicines Consortium (SMC) for all types of life-threatening or uncontrolled bleeding.^[6]

AstraZeneca will now initiate closure of ANNEXA-I and work with regulatory agencies to convert the conditional marketing authorisation to a full marketing authorisation.

NOTES TO EDITORS

About ANNEXA-I

ANNEXA-I is a randomised, multi-centre clinical trial designed to determine the efficacy and safety of andexanet alfa versus usual care in adult patients (≥18 years) with an intracranial haemorrhage (ICH) 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. ANNEXA-I enrolled over 450 adult patients with an ICH who were being treated with Factor Xa (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 haemostasis, or stopping the flow of blood, following treatment with andexanet alfa compared with usual care. ANNEXA-I was conducted in patients with acute ICH, which are typically assessed by hematoma bleed size and location. There is an established method for measurement of hematoma size and expansion, allowing for definitive assessment of hemostatic efficacy.²

Life-threatening or uncontrolled bleeding linked to Fxa inhibitors (apixaban and rivaroxaban)

Almost 1.6 million people in the UK depend on Fxa inhibitors to manage their risk of blood clots developing.³ These medicines are important to reduce patients’ chances of developing serious conditions such as strokes and heart attacks,^[7] however they carry a small but significant risk of an acute life-threatening major bleed.^[8],[9],[10] There is an urgent need to ensure cost effective options to reduce the clinical and economic burden on the NHS.^[11],[12]

About andexanet alfa

Andexanet alfa is a recombinant protein specifically designed to bind to FXa inhibitors and rapidly reverse their anticoagulant effect. Andexanet alfa is a modified form of the human FXa molecule, an enzyme that helps blood clot. Andexanet alfa works by acting as a decoy for oral FXa inhibitors (apixaban and rivaroxaban), which target and bind to FXa, allowing them to exert their anticoagulant effect. When andexanet alfa 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.⁴

Andexanet alfa currently has a conditional marketing authorisation by the MHRA for adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.^[13]

For complete information on Andexanet Alfa, the summary of product characteristics, including a full list of adverse reactions is available here:

https://www.medicines.org.uk/emc/product/10933/smpc#gref

https://www.emcmedicines.com/en-gb/northernireland/medicine?id=79cb9dc8-d19d-46e2-8dc1-86e22d0bcd56&type=smpc

AstraZeneca in CVRM  

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About AstraZeneca 

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With a proud 100-year heritage in advancing UK science, today AstraZeneca is the UK’s leading biopharmaceutical company. AstraZeneca is based in six separate locations across the UK, with its global headquarters in Cambridge. In the UK, around 8,600 employees work in research and development, manufacturing, supply, sales, and marketing. We supply around 35 different medicines to the NHS. 

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References

[1] AstraZeneca. Andexxa phase IV trial stopped early after achieving pre-specified criteria on haemostatic efficacy versus usual care. Available at: https://www.astrazeneca.com/media-centre/press-releases/2023/andexxa-phase-iv-trial-stopped-early-after-achieving-pre-specified-criteria-on-haemostatic-efficacy-versus-usual-care.html. Last accessed: June 2023

[2] ClinicalTrials.gov. Trial of Andexanet Alfa in ICrH Patients Receiving an Oral FXa Inhibitor. Available at: https://clinicaltrials.gov/ct2/show/NCT03661528. Last Accessed June 2023.

[3] AstraZeneca UK Ltd. Data on File. ID: REF-191470. June 2023

[4] European Medicines Agency (EMA). Committee for Medicinal Products for Human Use (CHMP) assessment report: Ondexxya. Available at: https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_en.pdf. Last accessed June 2023.

[5] National Institute of Health and Care Excellence (NICE). Technology appraisal guidance [TA697]. Available at: https://www.nice.org.uk/guidance/ta697/chapter/2-Information-about-andexanet-alfa. Last accessed June 2023

[6] Scottish Medicines Consortium (SMC). Andexanet alfa (Ondexxya). Available at: https://www.scottishmedicines.org.uk/medicines-advice/andexanet-alfa-ondexxya-full-smc2273/#:~:text=Indication%20under%20review%3A%20For%20adult%20patients%20treated%20with,improved%20haemostatic%20efficacy%20in%20adults%20with%20major%20bleeds. Last accessed June 2023.

[7] NHS. Anticoagulants. Available at: https://www.nhs.uk/conditions/anticoagulants/. Last accessed June 2023

[8] Amaraneni A, Chippa V and Rettew AC. Anticoagulation Safety. StatPearls 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK519025/. Last accessed June 2023.

[9] Marcucci M, et al. Benefits and harms of direct oral anticoagulation and low molecular weight heparin for thromboprophylaxis in patients undergoing non-cardiac surgery: systematic review and network meta-analysis of randomised trials. BMJ. 2022;376:e066785.

[10] Chai-Adisaksopha C, et al. Hemodialysis for the treatment of dabigatran-associated bleeding: a case report and systematic review. J Thrombosis and Haemost. 2015;13(11):2012-2020

[11] Witte KK, et al. Burden of oral anticoagulation in embolic stroke of undetermined source without atrial fibrillation. BMC Cardiovasc Disord. 2021;21:160

[12] Kessler C, Goldstein J. A new strategy for uncontrollable bleeding after treatment with rivaroxaban or apixaban. Clin Adv Hematol Oncol. 2019;17(Suppl 15):1-20

[13] Electronic Medicines Compendium (EMC). Ondexxya 200 mg powder for solution for infusion. Summary of Product Characteristics (SmPC). Available at: https://www.medicines.org.uk/emc/product/10933/smpc/print. Last accessed June 2023