2012年10月26日，美国食品和药品管理局（FDA）批准omacetaxine mepesuccinate（Synribo，Teva制药）治疗成人慢性粒细胞性白血病（CML）。该药物的适应症是至少2个酪氨酸激酶抑制剂治疗后仍然发生进展的患者。
FDA的药物评价和研究中心血液学和肿瘤学产品办公室主任，Richard Pazdur博士表示：“今天对该药物的批准，为发生耐药或不耐受已批准的药物的慢性期或加速期的CML患者提供了一个新的治疗选择。”
Omacetaxine mepesuccinate应用方法为：皮下注射，每日两次，d1-14，28天为一周期，直到血液学反应和白细胞计数恢复正常。岁后只要病人继续临床受益，改为每日两次，连续使用7天，28天1个周期。
根据FDA数据，omacetaxine mepesuccinate对慢性期CML的作用是通过降低细胞费城染色体的基因突变，而这项突变在大多数慢性粒细胞白血病患者中被发现。76例中的14例患者（18.4％）在平均3.5个月内产生了突变的减少，持续减少的中位时间为12.5个月。
对于加速期CML的有效性，在于发生重大的血液学缓解（白细胞计数正常或没有证据表明白血病）患者的数量。35例患者中有5例（14.3％）在平均2.3个月里取得了重大的血液学缓解，平均持续时间4.7个月。
在临床研究中最常见的不良反应报告为血小板减少，贫血，中性粒细胞减少和性中性粒细胞减少性发热，腹泻，恶心，全身无力，疲劳，注射部位反应和淋巴细胞减少。
Pazdur博士指出“Omacetaxine mepesuccinate”是第二个批准用于治疗慢性粒细胞白血病，在今年九月，美国食品药品管理局批准的bosutinib（Bosulif，辉瑞公司）治疗发生耐药或不能耐受其他疗法的慢性期、加速期或急变期费城染色体阳性慢性粒细胞白血病患者。
完整说明
http://synribo.com/pdf/synribo_pi.pdf
SYNRIBO
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 evaluated 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