Fully published results from Athos Therapeutics’ AZALEA-TIMI 71 trial for its novel Factor XI inhibitor abelacimab, confirming the drug’s lower bleeding risks, but leaving researchers uncertain about its ability to prevent stroke in AFib patients.
- Current guidelines recommend direct-acting oral anticoagulants (DOACs) for AF because they reduce ischemic stroke with a lower risk of brain hemorrhage.
- Unfortunately, DOACs often cause gastrointestinal bleeding, which prompted the development of new stroke-prevention methods like Factor XI inhibition.
- By inhibiting Factor XI (an anticoagulation enzyme), drugs like abelacimab potentially prevent thrombosis without increasing spontaneous bleeding risks.
To see if abelacimab was a safer alternative, researchers randomized 1,287 AFib patients at risk of stroke to receive abelacimab (either 150mg or 90mg) or rivaroxaban (20mg) and found that abelacimab treatment substantially reduced bleeding during a 2.1 year follow-up.
- Abelacimab 150mg led to a 62% reduction in major or clinically relevant bleeding and an 89% reduction in gastrointestinal bleeding compared to rivaroxaban.
- This bleeding reduction was so overwhelming that IDMC stopped the whole trial after only 21 months.
- Monthly 150mg doses of abelacimab also led to 99% inhibition of Factor XI that was sustained over 2 years.
Despite these excellent bleeding results, AZALEA-TIMI 71’s stroke outcomes were not strong enough to sway researchers one way or another due to the study’s early termination and small sample size (28 patients had a stroke or systemic embolism).
- Both abelacimab 150mg and 90mg led to higher incidence rates of stroke than rivaroxaban (1.21 & 1.36 per 100 person-years vs. 0.83).
- Abelacimab’s ischemic stroke incidence rates were similar (1.21 & 1.24), far higher than rivaroxaban’s rate of 0.59 per 100 person-year.
These stroke concerns aren’t unique to abelacimab, with both Bayer and Bristol Myers-Squibb running into similar study issues for their Factor XI inhibitors.
- Bayer terminated its OCEANIC-AF trial for its Factor XI inhibitor, asundexian, due to 3X greater stroke (1.3% vs. 0.4%) and 4X ischemic stroke rates (csHR = 4.06).
- Results from BMS’ AXIOMATIC-SSP study found that its factor XI inhibitor, milvexian, failed to meaningfully reduce ischemic stroke.
The Takeaway
AZALEA-TIMI 71 provides incredibly strong evidence that Athos’ abelacimab reduces bleeding risks, but gives little evidence supporting it as a stroke prevention. Without stronger stroke results in future studies, abelacimab and other factor XI inhibitors may struggle to replace DOACs.
