Omacetaxine mepesuccinate

Omacetaxine mepesuccinate

Systematic (IUPAC) name
1-((1S,3aR,14bS)-2-Methoxy-1,5,6,8,9,14b-hexahydro-4H-cyclopenta(a)(1,3)dioxolo(4,5-h)pyrrolo(2,1-b)(3)benzazepin-1-yl) 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate
Clinical data
Trade names	Synribo
AHFS/Drugs.com	monograph
Licence data	US FDA:link
Pregnancy category	US: D (Evidence of risk)
Legal status	US: ℞-only
Routes of administration	Subcutaneous, intravenous infusion
Pharmacokinetic data
Protein binding	50%
Metabolism	Mostly via plasma esterases
Biological half-life	6 hours
Excretion	Urine (≤15% unchanged)
Identifiers
CAS Number	26833-87-4
ATC code	L01XX40 (WHO)
PubChem	CID: 285033
IUPHAR/BPS	7454
ChemSpider	251215
UNII	6FG8041S5B Y
KEGG	D08956
ChEBI	CHEBI:71019 Y
Chemical data
Formula	C29H39NO9
Molecular mass	545.62 g/mol
SMILES CC(C)(CCC[C@@](CC(=O)OC)(C(=O)O[C@H]1[C@H]2c3cc4c(cc3CCN5[C@@]2(CCC5)C=C1OC)OCO4)O)O
InChI InChI=1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25-,28+,29-/m1/s1 Key:HYFHYPWGAURHIV-JFIAXGOJSA-N

Omacetaxine mepesuccinate (INN, trade names Synribo or Myelostat ), formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML). It is a natural product first discovered in Cephalotaxus harringtonia, now manufactured by hemi-synthesis. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).

Medical uses

Omacetaxine/homoharringtonine is indicated for use as a treatment for patients with chronic myeloid leukaemia who are resistant or intolerant of tyrosine kinase inhibitors.

In June 2009, results of a long-term open label Phase II study were published, which investigated the use of omacetaxine infusions in CML patients. After twelve months of treatment, about one third of patients showed a cytogenetic response. A study in patients who had failed imatinib and who had the drug resistant T315I mutation achieved cytogenetic response in 28% of patients and hematologic response in 80% of patients, according to preliminary data.

Phase I studies including a small number of patients have shown benefit in treating myelodysplastic syndrome (MDS, 25 patients) and acute myelogenous leukaemia (AML, 76 patients). Patients with solid tumors did not benefit from omacetaxine.

Adverse effects

By frequency:
Very common (>10% frequency):

• Diarrhoea
• Myelosuppression^†
• Injection site reactions
• Nausea
• Fatigue
• Fever
• Asthenia
• Joint pain
• Headache
• Cough
• Hair loss
• Constipation
• Nosebleeds
• Upper abdominal pain
• Pain in the extremities
• Oedema
• Vomiting
• Back pain
• Grade 4 hyperglycaemia
• Grade 3/4 Hyperuricaemia
• Rash
• Insomnia

Common (1-10% frequency):

• Seizures
• GI haemorrhages

^† Myelosuppression, including: thrombocytopenia, anaemia, neutropenia and lymphopenia, in descending order of frequency.

Mechanism of action

Omacetaxine is a protein translation inhibitor. It inhibits protein translation by preventing the initial elongation step of protein synthesis. It interacts with the ribosomal A-site and prevents the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs. Omacetaxine acts only on the initial step of protein translation and does not inhibit protein synthesis from mRNAs that have already commenced translation.