Bristol Myers and Janssen race toward PhIII with a next-gen blood thinner

15 Nov 2021
endpts.com
AHA
Bristol Myers Squibb and J&J joined forces three years ago with a vision: They wanted to create a blood thinner with the efficacy of their current drugs Eliquis and Xarelto, but without the heightened risk of bleeding. On Monday, they announced they’re well on their way with a Factor XIa inhibitor called milvexian. Milvexian, also known as BMS-986177, significantly lowered patients’ rate of venous thromboembolism (VTE) after knee surgery compared to the commonly used anticoagulant enoxaparin in a Phase II study, the partners said at this year’s American Heart Association conference — and without increasing risk of bleeding. “Current DOACs — direct acting oral anticoagulants — either are underutilized or are not indicated because of concerns for bleeding,” James List, global therapeutic head of Janssen’s cardiovascular, metabolism, and retina departments, told Endpoints News. List said blood clots can be broken down into two basic, interrelated categories: hematosis, which is stopping bleeding, and thrombosis, which is forming a clot. There’s a growing body of evidence that suggests the blood protein Factor XI is very important for the propagation and enlargement of thrombin, but not so important to initial hemostasis, he said. There are also data that show people with Factor XI deficiencies have less of a tendency to bleed. Factor Xa inhibitors — like Eliquis and Xarelto — are approved to treat and prevent VTE, a disorder that includes deep vein thrombosis and pulmonary embolism. But they come with a risk of serious or fatal bleeding. “Our scientists were looking to try to advance beyond factor Xa inhibition as a target,” Roland Chen, head of BMS’ cardiovascular department, said. “What has come forward is data, both preclinical and clinically now, including what is being presented here at AHA, to show the promise of Factor XIa inhibition in preventing major thrombotic conditions, without an increase in bleeding.” At daily doses of at least 100 mg, those treated with milvexian in the Phase II AXIOMATIC-TKR study saw significantly lower rates of VTE compared to enoxaparin (p≤0.014). A group of patients receiving the highest once-daily dose (200mg) of milvexian saw a 7% VTE rate, compared to a 21% rate for the group of patients who took 40 mg of enoxaparin, according to BMS. While the study tested both single and twice-daily doses of milvexian, Chen said the companies will wait to see the results from another Phase II trial in secondary stroke before they decide on a regimen. That readout is expected in the first half of 2022. There were no major bleeds in the milvexian arm of the AXIOMATIC-TKR study, compared to one in the enoxaparin arm, the companies reported. The rates of major plus clinically relevant non-major bleeds (CRNM) were 0.8% and 1.4% in the milvexian and enoxaparin arms, respectively. “The consistently low rates of bleeding across a 16-fold range of milvexian doses suggest that it has a wide therapeutic window, which opens the opportunity to explore milvexian across a broad range of patients including those for whom factor Xa inhibitors are underutilized or not indicated,” Thrombosis and Atherosclerosis Research Institute executive director Jeffrey Weitz said in a statement. List said the companies are shooting to enter Phase III sometime next year. Although they’re keeping the financial terms of their collaboration under wraps for now, they’ve agreed to share all development costs and commercial profits.
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