PRINCETON, N.J.– Bristol Myers Squibb (NYSE:BMY) in collaboration with Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson and Johnson (Janssen), today announced results from the Phase 2 AXIOMATIC-TKR study, which showed investigational oral milvexian reduced the risk of postoperative venous thromboembolism (VTE) in a dose dependent manner without increasing the risk of bleeding compared with enoxaparin in patients undergoing total knee replacement (TKR) surgery. These data were presented today at a Late-Breaking Science session at the American Heart Association (AHA) Scientific Sessions 2021 and simultaneously published in The New England Journal of Medicine (NEJM).
“This study establishes proof-of-principle for milvexian as a differentiated antithrombotic agent,” said Jeffrey Weitz, M.D., Professor of Medicine & Biochemistry and Biomedical Sciences at McMaster University and Executive Director of the Thrombosis and Atherosclerosis Research Institute. “Furthermore, 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.”
The trial met both of its pre-specified proof-of-principle requirements: the dose response for efficacy with twice-daily milvexian was significant (p<0.001), and the 12% rate of VTE with combined twice-daily doses of milvexian was significantly lower (p<0.0001) than the prespecified benchmark rate of 30%.
At daily doses of at least 100 mg, the rates of VTE with milvexian were significantly lower than with enoxaparin (p≤0.014).
|
|
Milvexian Twice Daily |
Milvexian Once Daily |
Enoxaparin |
|||||
|
25 mg |
50 mg |
100 mg |
200 mg |
25 mg |
50 mg |
200 mg |
40 mg |
|
|
No. of patients evaluated |
129 |
124 |
134 |
131 |
28 |
127 |
123 |
252 |
|
Venous thromboembolism* |
21% |
11% |
9% |
8% |
25% |
24% |
7% |
21% |
|
No. of patients evaluated†|
148 |
148 |
149 |
148 |
33 |
150 |
147 |
296 |
|
Any bleeding |
1% |
5% |
5% |
3% |
0 |
5% |
6% |
4% |
|
Major or clinically relevant nonmajor bleeding |
0 |
1% |
1% |
1% |
0 |
1% |
1% |
2% |
|
Major bleeding |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0.3% |
|
*Primary efficacy outcome defined as the composite of asymptomatic deep-vein thrombosis (detected by mandatory unilateral venography performed 10 to 14 days after surgery) confirmed symptomatic venous thromboembolism (symptomatic deep-vein thrombosis of the leg or nonfatal pulmonary embolism) or death. |
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†Safety outcomes were assessed in the safety population, which consisted of all patients who received at least one dose of trial medication. |
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There were no major bleeds with milvexian and one with enoxaparin. The rates of major plus clinically relevant non-major bleeds (CRNM) with milvexian and enoxaparin were 0.8% and 1.4%, respectively. Across a 16-fold range of doses, milvexian demonstrated a low risk of major plus CRNM bleeding, with no major bleeds and no dose-response on this composite outcome.
“We are encouraged by the results of the milvexian TKR trial, which are consistent with our scientific understanding of the FXIa mechanism,” said Roland Chen, M.D., senior vice president and head of cardiovascular development, global drug development at Bristol Myers Squibb. “The clear dose efficacy response without increased bleeding provides additional evidence to support our belief in the promise of milvexian. We look forward to results from our second Phase 2 trial of milvexian for secondary stroke prevention, which will add to our body of evidence for milvexian and help inform our Phase 3 development program.”
The TKR study is the first of two studies to read out from the Phase 2 milvexian program. Results from the ongoing Phase 2 study of milvexian for secondary stroke prevention (AXIOMATIC-SSP) are expected in the first half of 2022. Bristol Myers Squibb and Janssen thank the patients and investigators involved in this clinical trial.
