Andexanet alfa (2) – Ondexxya®

• Clinical trials
  • The ANNEXA-I trial included adults with acute intracerebral haemorrhage who were being treated with an oral factor Xa (FXa) inhibitor.

a1) Adults being treated with a direct factor Xa inhibitor (apixaban or rivaroxaban) who require repeal of anticoagulation due to life-threatening or uncontrollable intracerebral haemorrhages

• Overall, the G-BA, in accordance with Section 5(7)(6) of the AM-NutzenV, that, given the statistically significant disadvantage in the overall rates of SUEs, coupled with the absence of positive effects based on the available data, andexanet alfa offers less benefit than individualised therapy for adults being treated with a direct factor Xa inhibitor (apixaban or rivaroxaban) and who require repeal of anticoagulation due to life-threatening or uncontrollable intracerebral haemorrhages, there is less benefit.
• Due to the short study duration of 30 days and an unclear proportion of patients receiving doses of andexanet alfa that deviated from the guidelines in the SmPC, a hint is identified regarding the certainty of the findings.
• mortality
  • For the endpoint of overall survival, the ANNEXA-I study showed no statistically significant difference between the treatment arms.
• Morbidity – Invasive intracranial procedures
  • For the endpoint of invasive intracranial procedures, no statistically significant difference was observed between the treatment arms.
• Morbidity – Functional impairment (mRS)
  • For the endpoint of functional impairment, assessed using the mRS, no statistically significant difference was observed between the treatment arms.
• Morbidity – Health status (EQ-5D-VAS)
  • Overall, there are no suitable data available for health status, as assessed using the EQ-5D VAS.
• Side effects – Serious adverse events (SUEs)
  • For the endpoint of serious adverse events (SUEs), a statistically significant difference was observed to the disadvantage of andexanet alfa compared with standard treatment.
  • In detail, there is also a statistically significant disadvantage for andexanet alfa compared with individualised therapy for the specific adverse events of thrombotic events (SUEs), ischaemic stroke (PT, SUEs) and heart disease (SOC, SUEs).
• Side effects – discontinuation due to adverse events (AEs)
  • For the endpoint of discontinuation due to AEs, there was no statistically significant difference between the treatment arms.
• Overall assessment
  • For the benefit assessment of andexanet alfa for use in adult patients being treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when repeal of anticoagulation is required due to life-threatening or uncontrollable intracerebral haemorrhage, the multicentre, open-label RCT ANNEXA-I, commissioned by the EMA as part of the conditional authorisation, was submitted to compare andexanet alfa with standard treatment.
  • For the endpoint of overall survival, the ANNEXA-I study showed no statistically significant difference between the treatment arms.
  • For the morbidity endpoint category, no statistically significant difference was observed between the treatment arms for the endpoints of invasive intracranial procedures and functional impairment, as assessed using the mRS. No suitable data are available for the health status endpoint (EQ-5D VAS).
  • No relevant endpoints were recorded for the health-related quality of life endpoint category.
  • In the adverse effects endpoint category, the overall rates of serious adverse events (SAEs) showed a statistically significant disadvantage for andexanet alfa compared with individualised therapy; in detail, this comprised, in particular, thrombotic events, ischaemic strokes and cardiac events. For the endpoint ‘discontinuation due to AEs’, there is no statistically significant difference between the treatment arms.
  • Overall, based on the results of the ANNEXA-I study, no additional benefit of andexanet alfa over individualised therapy can be identified for any endpoint category. By contrast, for the endpoint category of side effects, there is a statistically significant disadvantage of andexanet alfa in terms of the overall rates of serious adverse events (SAEs). For the significant, patient-relevant endpoints of thrombotic events, ischaemic stroke and heart disease – all of which, beyond their inherent patient-relevance, can in principle lead not only to death but also to permanent functional impairment – a statistically significant difference was found between the treatment groups, with a disadvantage for andexanet alfa.
  • In the present study, treatment with andexanet did not result in increased mortality.
  • The extent to which increased morbidity occurred in this study cannot be assessed on the basis of the limited data available here: the Modified Rankin Scale (mRS) is only a rough measure and, due to its scaling, does not adequately reflect patient-relevant differences. Furthermore, the mRS is a measure designed to describe limitations in daily life following a stroke, but not to measure symptoms relevant to the patient. However, no usable data, e.g. using the NIHSS, are available.
  • The higher rate of serious adverse events, manifested, amongst other things, in ischaemic strokes, thrombotic events and heart disease, therefore results in exclusively negative effects for andexanet alfa, which are not offset by any positive effects.
  • The G-BA concurs with the IQWiG’s assessment findings from dossier evaluation A25-87 of 24 September 2025 and, in accordance with Section 5(7)(6) of the AM-BenefitV, that, given the relevant disadvantage identified and the simultaneous absence of positive effects based on the available data, andexanet alfa offers less benefit than individualised therapy for adults treated with a direct factor Xa inhibitor (apixaban or rivaroxaban) and who require repeal of anticoagulation due to life-threatening or uncontrollable intracerebral haemorrhages, there is less benefit.

a2) Adults being treated with a direct factor Xa inhibitor (apixaban or rivaroxaban) who require repeal of anticoagulation due to life-threatening or uncontrollable bleeding (excluding intracerebral haemorrhages)

• There is no additional benefit of andexanet alfa for adults being treated with a direct factor Xa inhibitor (apixaban or rivaroxaban) and who require repeal of anticoagulation due to life-threatening or uncontrollable bleeding (excluding intracerebral haemorrhages) is not proven.

Courtesy translation only, please refer to the German original.