General Information

Synribo (omacetaxine mepesuccinate) is a cephalotaxine ester. It is a protein synthesis inhibitor and is independent of direct Bcr-Abl binding.

Synribo is specifically approved for the treatment of adults with chronic or accelerated phase chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.

Mechanism of Action

Synribo (omacetaxine mepesuccinate) is a cephalotaxine ester. It is a protein synthesis inhibitor 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 archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member.

Side Effects

Adverse events associated with the use of Synribo may include, but are not limited to, the following:

• thrombocytopenia
• anemia
• neutropenia
• diarrhea
• nausea
• fatigue
• asthenia
• injection site reaction
• pyrexia
• infection
• lymphopenia

Dosing/Administration

Synribo is supplied as a solution for subcutaneous administration. The recommended initial dose of the drug is as follows: Induction schedule: 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response. Maintenance dosing: 1.25 mg/m2 administered subcutaneously twice daily for seven consecutive days every 28 days, over a 28-day cycle. Treatment should continue as long as patients are clinically benefiting from therapy.

Clinical Trial Results

The FDA approval of Synribo was based on a combined cohort of adults with CML from two trials. The combined cohort consisted of subjects who had received two or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. The subjects were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days, every 28 days (induction cycle). Responders were then treated with the same dose and twice daily schedule for seven consecutive days every 28 days (maintenance cycle) for up to 24 months.

Chronic Phase CML
A total of 76 subjects were included in the efficacy analysis. The efficacy endpoint was based on major cytogenetic response (MCyR). Fourteen subjects (18.4 percent) achieved MCyR; 7.9 percent achieved confirmed complete cytogenic response and 3.9 percent achieved confirmed partial cytogenic response. The mean time to MCyR onset was 3.5 months and the median duration of MCyR was 12.5 months.

Accelerated Phase CML
A total of 35 subjects were included in the efficacy analysis. The efficacy endpoint was based on major cytogenetic response (MCyR) and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]. Five subjects (14.3 percent) achieved MaHR; four subjects (11.4 percent) CHR and one (2.9 percent) NEL. Zero subjects achieved MCyR. The mean time to response onset in the five subjects was 2.3 months and the median duration of MaHR was 4.7 months.