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 Approved for Chronic Myelogenous Leukemia
Synribo (omacetaxmie mepesuccinate) has been approved by the FDA to treat adults with chronic myelogenous leukemia (CML), a disease of the blood and bone marrow. It is intended for use in patients who cancer has progressed after treatment with at least two drugs from a class known as tyrosine kinase inhibitors (TKIs), also used to treat CML.

Synribo blocks certain proteins that promote the development of cancerous cells. It is administered twice daily for 14 consecutive days over a 28-day cycle until white blood cell counts normalize (hematologic response). Synribo is then administered twice daily for seven consecutive days over a 28-day cycle for as long as patients continue to clinically benefit from therapy.

Synribo is now the second drug to gain FDA approval for treatment of CML in the past two months. On Sept. 4, 2012, the FDA approved Bosulif (bosutinib) to treat patients with chronic, accelerated or blast phase Philadelphia chromosome positive CML who are resistant to or who cannot tolerate other therapies.

The effectiveness of Synribo was eva luated using a combined cohort of patients whose cancer progressed after previous treatment with two or more TKIs. All participants were treated with Synribo.

The drug’s effectiveness in chronic phase CML was demonstrated by a reduction in the percentage of cells expressing the Philadelphia chromosome genetic mutation found in most CML patients. Fourteen out of 76 patients (18.4%) achieved a reduction in an average time of 3.5 months. The median length of the reduction was 12.5 months.

In accelerated phase CML, Synribo’s effectiveness was determined by the number of patients who experienced a normalization of white blood cell counts or had no evidence of leukemia (major hematologic response, or MaHR). Results showed five out of 35 patients (14.3%) achieved MaHR in an average time of 2.3 months. The median duration of MaHR in these patients was 4.7 months.

The most common side effects reported during clinical studies include a low level of platelets in the blood (thrombocytopenia), low red blood cell count (anemia), a decrease in infection-fighting white blood cells (neutropenia) which may lead to infection and fever (febrile neutropenia), diarrhea, nausea, weakness and fatigue, injection site reaction, and a decrease in the number of lymphocytes in the blood (lymphopenia).

Synribo is marketed by Frazer, Pa.-based Teva Pharmaceuticals. Bosulif is marketed by New York City-based Pfizer.

References:
FDA.gov