Milvexian
(Synonyms: BMS-986177; JNJ-70033093) 目录号 : GC63873
Milvexian (BMS-986177) 是一种口服生物利用度高、可逆、直接的人和兔因子 (FXIa) 抑制剂，其 Ki 值分别为 0.11 nM 和 0.38 nM。
Cas No.:1802425-99-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Milvexian (BMS-986177), an effective antithrombotic agent, is an orally-bioavailable, reversible and direct inhibitor of human and rabbit factor XIa (FXIa) with Ki of 0.11, and 0.38 nM, respectively[1].
[1]. Wong P, et al. Small-Molecule Factor XIa Inhibitor, BMS-986177/JNJ-70033093, Prevents and Treats Arterial Thrombosis in Rabbits at Doses that Preserve Hemostasis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1).
| Cas No. | 1802425-99-5 | SDF | Download SDF |
| 别名 | BMS-986177; JNJ-70033093 | ||
| 分子式 | C28H23Cl2F2N9O2 | 分子量 | 626.44 |
| 溶解度 | DMSO : ≥ 100 mg/mL (159.63 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5963 mL | 7.9816 mL | 15.9632 mL |
| 5 mM | 0.3193 mL | 1.5963 mL | 3.1926 mL |
| 10 mM | 0.1596 mL | 0.7982 mL | 1.5963 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Milvexian for the Prevention of Venous Thromboembolism
N Engl J Med 2021 Dec 2;385(23):2161-2172.PMID:34780683DOI:10.1056/NEJMoa2113194.
Background: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of Milvexian, an oral factor XIa inhibitor. Methods: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of Milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. Results: Among the patients receiving Milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving Milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily Milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily Milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking Milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively. Conclusions: Postoperative factor XIa inhibition with oral Milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).
First-in-human study of Milvexian, an oral, direct, small molecule factor XIa inhibitor
Clin Transl Sci 2022 Feb;15(2):330-342.PMID:34558200DOI:10.1111/cts.13148.
Milvexian (BMS-986177/JNJ-70033093) is a small molecule, active-site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of Milvexian were assessed in a two-part, double-blind, placebo-controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive Milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200- and 500-mg panels investigated the pharmacokinetic impact of a high-fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive Milvexian (once- or twice-daily) or placebo for 14 days. All Milvexian dosing regimens were safe and well-tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum Milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half-life (T1/2 ) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose-proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased Milvexian bioavailability in a dose-dependent fashion. In MAD panels, steady-state Milvexian plasma concentration was reached within 3 and 6 dosing days with once- and twice-daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of Milvexian are suitable for further clinical development.
Safety, pharmacokinetics, and pharmacodynamics of Milvexian in healthy Japanese participants
Sci Rep 2022 Mar 25;12(1):5165.PMID:35338177DOI:10.1038/s41598-022-08768-y.
This randomized, double-blind, placebo-controlled, multiple ascending-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of Milvexian, an oral small-molecule FXIa inhibitor, in healthy Japanese participants. Participants received oral Milvexian daily under fasted (50 mg and 200 mg) or fed conditions (500 mg) or placebo over 14 days; 24 participants (8/cohort: 6 Milvexian; 2 placebo) were planned. Due to an unblinding event, participants in one cohort (200 mg daily) were discontinued, and a second cohort enrolled; 32 participants were included in safety and pharmacodynamic analyses, and 24/32 in pharmacokinetic analyses. Milvexian up to 500 mg daily for 14 days was generally well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Milvexian exposure increased between 50-mg and 200-mg doses. Median Tmax was similar with 50-mg and 200-mg doses (2.5-3.0 h) and delayed under fed conditions (500 mg, 7.0-8.0 h). Median T1/2 was similar across doses (8.9-11.9 h). Multiple oral Milvexian administrations resulted in concentration-related prolongation of aPTT and decreased FXI clotting activity. Milvexian was generally safe and well tolerated. The pharmacokinetic and pharmacodynamic profile of Milvexian demonstrates suitability for further clinical development in Japanese participants.
Milvexian, an orally bioavailable, small-molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits
J Thromb Haemost 2022 Feb;20(2):399-408.PMID:34752670DOI:10.1111/jth.15588.
Background: Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials. Objectives: To evaluate in vitro properties and in vivo characteristics of Milvexian. Methods: In vitro properties of Milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Results: Milvexian is an active-site, reversible inhibitor of human and rabbit FXIa (Ki 0.11 and 0.38 nM, respectively). Milvexian increased activated partial thromboplastin time (APTT) without changing prothrombin time and potently prolonged plasma APTT in humans and rabbits. Milvexian did not alter platelet aggregation to ADP, arachidonic acid, or collagen. Milvexian was evaluated for in vivo prevention and treatment of thrombosis. For prevention, Milvexian 0.063 + 0.04, 0.25 + 0.17, and 1 + 0.67 mg/kg+mg/kg/h preserved 32 ± 6*, 54 ± 10*, and 76 ± 5%* of carotid blood flow (CBF) and reduced thrombus weight by 15 ± 10*, 45 ± 2*, and 70 ± 4%*, respectively (*p < .05; n = 6/dose). For treatment, thrombosis was initiated for 15 min and CBF decreased to 40% of control. Seventy-five minutes after Milvexian administration, CBF averaged 1 ± 0.3, 39 ± 10, and 66 ± 2%* in groups treated with vehicle and Milvexian 0.25 + 0.17 and 1 + 0.67 mg/kg+mg/kg/h, respectively (*p < .05 vs. vehicle; n = 6/group). The combination of Milvexian 1 + 0.67 mg/kg+mg/kg/h and aspirin 4 mg/kg/h intravenous did not increase BT versus aspirin monotherapy. Conclusions: Milvexian is an effective antithrombotic agent with limited impact on hemostasis, even when combined with aspirin in rabbits. This study supports inhibition of FXIa with Milvexian as a promising antithrombotic therapy with a wide therapeutic window.
Single-Dose Pharmacokinetics of Milvexian in Participants with Mild or Moderate Hepatic Impairment Compared with Healthy Participants
Clin Pharmacokinet 2022 Jun;61(6):857-867.PMID:35262846DOI:10.1007/s40262-022-01110-9.
Background: Patients with hepatic impairment receiving antithrombotic agents metabolized primarily through the liver can be at risk for bleeding. Milvexian (BMS-986177/JNJ-70033093) is a small-molecule, active-site inhibitor of activated Factor XI (FXIa). Modulation of FXI may provide systemic anticoagulation without increased risk of clinically significant bleeding. Objective: This open-label study evaluated the effects of mild or moderate hepatic impairment on the pharmacokinetics of Milvexian to assess their impact on safety and dosing. Methods: Single doses of Milvexian 60 mg were administered to participants with mild hepatic impairment (n = 9), moderate hepatic impairment (n = 8), and normal hepatic function (n = 9). Healthy participants were matched to participants with hepatic impairment by body weight, age, and sex. Analysis of variance was performed on natural log-transformed Milvexian exposure parameters, with hepatic function group as a fixed effect. Results: Single doses of Milvexian 60 mg were generally well tolerated, with no serious adverse events (AEs), bleeding AEs, or discontinuations due to AEs. Geometric mean ratios (90% confidence interval) for total Milvexian maximum observed plasma concentration and area under the plasma concentration-time curve from time zero extrapolated to infinite time were 1.180 (0.735-1.895) and 1.168 (0.725-1.882), respectively, for mild hepatic impairment versus normal hepatic function and 1.140 (0.699-1.857) and 0.996 (0.609-1.628), respectively, for moderate hepatic impairment versus normal hepatic function. Across groups, Milvexian exposure-related increases were observed for activated partial thromboplastin time. Conclusion: Milvexian was well tolerated in participants with normal, mildly impaired, and moderately impaired hepatic function. Observed pharmacokinetic changes suggest it is unlikely that dose adjustments will be necessary in patients with mild or moderate hepatic impairment. Clinical Trial RegistrationClinicaltrials.gov identifier: NCT02982707.