AHA 2021 – Bristol touts its Eliquis follow-on

Phase 2 data with milvexian look good, but Eliquis will be a hard act to follow.

The strongest patent for the blood thinner Eliquis is set to expire in 2026, leaving its makers, Bristol Myers Squibb and Pfizer, with a $10bn-plus hole to fill. No wonder, then, that Bristol is highlighting the first mid-stage data with its follow-on project, the oral factor XIa inhibitor milvexian, presented at the AHA meeting yesterday. 

The Axiomatic-TKR trial found that the highest doses of milvexian were better than the older anticoagulant enoxaparin at preventing venous thromboembolism in patients undergoing total knee replacement surgery, with a similar bleeding risk. However, a bigger question is how milvexian stacks up against Eliquis, and whether Bristol, along with its partner Johnson & Johnson, will be able to shift patients to its newer project should it gain approval. 

Dose response 

Axiomatic-TKR, also published in the NEJM, evaluated milvexian dosed at 25mg, 50mg and 200mg once daily, and 25mg, 50mg, 100mg and 200mg twice daily, versus once-daily enoxaparin. The primary efficacy endpoint was venous thromboembolism, and the primary safety endpoint was bleeding. 

In terms of preventing VTEs, milvexian showed a dose response, with the 200mg doses performing the best. Taking into account just milvexian doses of at least 100mg, the rates of VTE were significantly lower than with enoxaparin, Bristol said.  

Within and cross-trial comparison of milvexian vs enoxaparin & Eliquis
  Milvexian 200mg Enoxaparin 40mg once daily* Eliquis 2.5mg twice daily**
  Once daily Twice daily
VTE rate 7% 8% 21% 9-15%
Bleeding rate 6% 3% 4% 3-4%
*Enoxaparin arm included in Axiomatic-TKR; **cross-trial comparison with Advance-1 & Advance-2, primary endpoints were all VTE & death from any cause. Source: company release & Bernstein note.

The numbers also look similar to, or perhaps slightly better than, those seen with the factor Xa Eliquis in the Advance-1 and Advance-2 studies in knee replacement patients. However, the usual caveats about cross-trial comparisons apply.

Bleeding rates with milvexian – always a potential worry with anticoagulants – did not raise any eyebrows. Furthermore, there were no major bleeds in the milvexian-treated patients, versus one in the enoxaparin group.

Bristol is not the only group targeting factor XI, the table below shows, but milvexian has the advantage of being oral. Bristol also has an unnamed factor XIa inhibitor in earlier development, according to its website.

Still, perhaps not all FXIa inhibitors are created equal: the Axiomatic-TKR investigators noted that Bayer and Aronora’s antibody osocimab, when given after knee arthroplasty, was non-inferior but not superior to enoxaparin for the prevention of VTEs.

Things might become clearer as more data on these novel agents accumulate. Bristol, for one, is set to report more data on milvexian, from the Axiomatic-SSP study in secondary stroke prevention, in the first half of next year.

Selected novel blood thinners in mid to late-stage development
Project Company Description Trial details
Phase 2/3
Glenzocimab Acticor Biotech Anti-platelet glycoprotein VI MAb fragment Actisave in stroke completes Jun 2025
Phase 2
Fesomersen (IONIS-FXI-LRx) Bayer/Ionis Factor XI antisense Emerald in dialysis pts completed 2019, still listed in pipeline
AB002 Aronora Protein C activator enzyme NCT03963895 in dialysis pts completed 2020, still listed in pipeline
AB023 Aronora Recombinant factor XI antibody NCT03612856 in dialysis pts reported Jul 2021 
Milvexian (BMS-986177) Bristol Myers Squibb Oral factor XIa inhibitor Axiomatic-TKR reported at AHA 2021; Axiomatic-SSP completes Mar 2022
Asundexian (BAY 2433334) Bayer Oral factor XIa inhibitor Pacific-AF completed Oct 2021; Pacific-AMI & Pacific-Stroke complete Feb 2022
Osocimab (BAY1213790) Bayer/Aronora Anti-factor XIa MAb Convert in dialysis pts completes Jan 2022
Temanogrel Arena Pharmaceuticals 5-HT2A receptor inverse agonist NCT04848220 for microvascular obstruction in PCI completes Apr 2022
Abelacimab (MAA868) Anthos Therapeutics Anti-factor XI & XIa MAb Azalea Timi 71 in AF completes Jan 2023
BMS-986141 Bristol Myers Squibb Protease activated receptor-4 antagonist NCT05093790 in volunteers and CAD pts not yet recruiting
AF=atrial fibrillation; AMI=acute myocardial infarction; CAD=coronary artery disease; PCI=percutaneous coronary intervention. Source: Evaluate Pharma & clinicaltrials.gov.

The table in this story has been updated to include Bayer's asundexian.

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