Pharmacological Class:
Protein synthesis inhibitor.

Active Ingredient(s):
Omacetaxine mepesuccinate 3.5mg/vial; lyophilized powder for SC injection after reconstitution; contains mannitol; ­preservative-free.

Company
Teva Pharmaceuticals
Indication(s):
Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI).

Pharmacology:
The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaebacteria. In vitro, omacetaxine mepesuccinate ­reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member.

Clinical Trials:
The efficacy of omacetaxine mepesuccinate was eva luated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. ­Patients were treated with omacetaxine mepesuccinate at a dose of 1.25mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months.

In the first trial, a total of 76 patients with chronic phase CML were included in the efficacy analysis. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). At efficacy endpoint, 18% (14/76) achieved a major cytogenetic response (MCyR) with a mean time to MCyR onset of 3.5 months. The median ­duration of MCyR for these patients was 12.5 months (Kaplan-Meier estimate).

In the second trial, a total of 35 patients with accelerated phase CML were included in the efficacy analysis. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). At efficacy endpoint, 14% (5/35) achieved a major hematologic ­response (MaHR) with a mean time to response onset of 2.3 months. The median duration of MaHR for these patients was 4.7 months (Kaplan-Meier estimate).

Legal Classification:
Rx

Adults:
Induction: 1.25mg/m2 by SC injection twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Repeat cycles every 28 days until hematologic response achieved. Maintenance: 1.25mg/m2 by SC injection twice daily for 7 consecutive days every 28 days, over a 28-day cycle. Dose adjustments and modifications: see full labeling.

Children:
Not established.

Warnings/Precautions:
Risk of myelosuppression (thrombocytopenia, neutropenia, anemia), hemorrhage. Monitor CBCs with platelets weekly during induction, initial maintenance cycles, and every 2 weeks during later cycles. Monitor glucose levels (esp. in diabetics). Avoid in poorly controlled diabetes until glycemic control is ­established. Elderly. Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.

Interaction(s)
Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding.

Adverse Reaction(s)
Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia.

How Supplied:
Single-use vial—1

LAST UPDATED:
3/4/2013
Synribo获准治疗某些慢性粒细胞白血病
圣路易斯(MD Consult)——2012年10月26日，美国食品药品管理局(FDA)和梯瓦制药宣布，Synribo(高三尖杉酯碱)已被加速批准，用于对至少2种酪氨酸激酶抑制剂(TKI)耐药和(或)不耐受的成年慢性期(CP)或加速期(AP)慢性粒细胞性白血病(CML)的治疗。Synribo的作用机制尚未被完全阐明，但包含对蛋白质合成的抑制作用。在体外研究中，该药可通过独立地直接结合BCR-ABL而降低BCR-ABL肿瘤蛋白和MCL-1蛋白的水平。

FDA批准该适应证是基于该药的应答率。目前尚无试验证实Synribo可改善疾病相关症状或延长生存。FDA加速批准Synribo的依据是对2项2期、开放性、多中心研究数据的汇总分析。这项汇总分析纳入了已接受至少2种已获准的TKI治疗且至少对达沙替尼和(或)尼罗替尼耐药或不耐受的患者。47%的CP患者和63%的AP患者对伊马替尼、达沙替尼和尼罗替尼无应答。多数患者还接受了其他治疗，包括羟基脲、干扰素和阿糖胞苷。

结果显示，在CP患者组中，18%(14/76)获得了主要细胞学应答(MCyR)，至获得MCyR的平均间隔时间为3.5个月。MCyR的中位持续时间为12.5个月。在AP患者卒中，14%(5/35)获得了主要血液学应答(MaHR)，至获得MaHR的平均间隔时间为2.3个月。MaHR的中位持续时间为4.7个月。

在研究受试者中最常见的不良反应为血小板减少、贫血、中性粒细胞减少、腹泻、恶心、疲乏、无力、注射部位反应、发热、感染和淋巴细胞减少。

Synribo的用法是每日2次皮下注射，连续使用14天，每 28天为1个疗程，直至获得血液学应答。然后改为每日2次皮下注射，连续使用7天，每 28天为1个疗程，只要患者显示出临床获益就继续使用。