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Late-Breaking Phase 2 Data for Investigational Oral Factor XIa Inhibitor Milvexian Suggest Favorable Antithrombotic Profile Across a Wide Range of Doses

BMY | November 15, 2021

Milvexian demonstrated efficacy and no increase in bleeding across doses, with no major bleeds in the milvexian arms, when compared with enoxaparin, for postoperative venous thromboembolism (VTE) prevention in patients undergoing elective total knee replacement (TKR) surgery

AXIOMATIC-TKR is the first of two studies to read out from the Phase 2 milvexian program, which together will inform the design and dose regimens of the Phase 3 program

Data simultaneously published in The New England Journal of Medicine and presented at the American Heart Association Scientific Sessions 2021

Milvexian is being developed by The Bristol Myers Squibb-Janssen Collaboration

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 Once Daily
	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.
† Safety outcomes were assessed in the safety population, which consisted of all patients who received at least one dose of trial medication.

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.

About AXIOMATIC-TKR

AXIOMATIC-TKR is a Phase 2, randomized, open-label, parallel-group, dose-ranging multicenter study that evaluated the efficacy and safety of milvexian, an oral factor XIa (FXIa) inhibitor, versus subcutaneous enoxaparin in patients undergoing elective TKR surgery. The primary efficacy outcome was the incidence of total VTE up to 14 days. The principal safety outcome was any bleeding, defined as the composite of major, clinically relevant nonmajor and minimal bleeding.

A total of 1,242 patients were randomized to receive one of seven regimens of oral milvexian given twice or once-daily or to receive 40 mg of subcutaneous enoxaparin once-daily. The assignment to milvexian or enoxaparin was open label but the milvexian dose assignment was blinded. Treatment was given for 10-14 days. More information can be found on www.clinicaltrials.gov (NCT03891524).

About Milvexian*

Milvexian is a potential first-in-class oral factor XIa (FXIa) inhibitor (anti-thrombotic) for the prevention and treatment of major thrombotic conditions. Phase 2 TKR data, complementing human genetic, epidemiologic and preclinical evidence, now provide further support for the hypothesis that inhibiting FXIa can reduce the risk of vascular events without increasing the risk of bleeding. The milvexian Phase 2 clinical trial program consists of two Phase 2 studies: AXIOMATIC-TKR (NCT03891524) evaluating milvexian in TKR surgery and AXIOMATIC-SSP (NCT03766581) evaluating milvexian for secondary stroke prevention (SSP).

*Milvexian is an investigational agent and has not been approved for use in any country, for any indication.

About the Bristol Myers Squibb/Janssen Collaboration

Bristol Myers Squibb and Janssen Pharmaceuticals, Inc., two leaders in thrombosis treatment and care, are collaborating to develop and commercialize milvexian, a potentially first-in-class oral factor XIa (FXIa) inhibitor, with the goal of improving upon the benefit/risk profile of existing anticoagulants. With extensive expertise and unparalleled leadership in cardiovascular treatments spanning decades, Bristol Myers Squibb and Janssen share a long-standing commitment to improving treatment options for patients with life-threatening cardiovascular conditions.

About Bristol Myers Squibb

Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results will be consistent with the results to date, that milvexian may not achieve its primary study endpoints or receive regulatory approval for the indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such indication described in this release will become commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2020, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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