Aetna considers omacetaxine mepesuccinate (Synribo) medically necessary for members with chronic myelogenous leukemia (CML) (see Appendix).

Aetna considers omacetaxine mepesuccinate experimental and investigational for all other indications including the following (not an all-inclusive list):

• Acute myelogenous leukemia (AML)
• Myelodysplastic syndrome (MDS)
• Solid tumors including cervical carcinoma

Synribo (omacetaxine) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). This labeling states that this indication is based upon response rate.  The labeling notes that there are no trials verifying an improvement in disease-related symptoms or increased survival with omacetaxine.  Current guidelines from the National Comprehensive Cancer Network (NCCN, 2014) recommend Synribo in CML for patients with resistance and/or intolerance to 2 or more TKIs for chronic phase, disease progression in accelerated phase, and for post-transplant relapse.

Quintas-Cardama and Cortes (2008) stated that homoharringtonine (HHT), a natural alkaloid extracted from various Cephalotaxus species, exerts its anti-tumoral and anti-angiogenic activity through an inhibition of protein synthesis and the promotion of apoptosis.  ChemGenex Pharmaceuticals Ltd, in collaboration with Stragen Group, is developing omacetaxine mepesuccinate, a semi-synthetic formulation of HHT, as a potential treatment for CML, myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).  In pre-clinical studies, omacetaxine mepesuccinate induced apoptosis in leukemia cell lines.  Results from phase II clinical trials revealed omacetaxine mepesuccinate to be active in patients with CML that was resistant to TKI therapy, including those patients who carry the BCR-ABL1T315I mutation, which is highly insensitive to the TKIs imatinib, nilotinib and dasatinib; the therapeutic was also generally well-tolerated.  Phase II and III clinical trials have been underway to assess the activity of omacetaxine mepesuccinate, either alone or in combination with TKIs or other cytotoxic drugs, in patients with CML that is resistant to TKI therapy.  Phase I and II clinical trials for omacetaxine mepesuccinate in the treatment of AML and MDS are also ongoing; intravenous, subcutaneous (SC) and oral formulations of the drug are being developed.  The authors concluded that omacetaxine mepesuccinate appears to hold potential for the treatment of CML and, in particular, imatinib-resistant CML; the development of alternative formulations of the therapeutic further expands the potential for success in drug development.

Daver et al (2013) noted that HHT (omacetaxine mepesuccinateis) is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies.  In a phase II clinical trial, these investigators reported the findings of a pilot study of HHT in MDS.  Induction consisted of HHT at 2.5 mg/m(2) via continuous infusion for 7 days.  Maintenance was given every 4 weeks.  A total of 9 patients were enrolled: 5 with refractory anemia with excess blasts, 2 with refractory anemia with excess blasts in transformation, 1 each with refractory anemia and CML, respectively.  Median age was 70 years (55 to 84) and 6 (66 %) were males.  Per International Prognostic Scoring System (IPSS), 2 patients were intermediate-1, 5 intermediate-2 and 2 high-risk.  Median chemotherapy courses were 1 (1 to 3).  One patient (11 %) responded with complete hematological and cytogenetic remission after 1 course.  Eight patients did not respond (4 had stable disease, 2 progressed to acute leukemia and 2 died during induction -- from aspergillus pneumonia and intra-cerebral hemorrhage, respectively).  Grade 3/4 myelosuppression seen in 56 % (5/9).  Serious non-hematological toxicities included 1 case of grade 4 left bundle branch heart block and 1 grade 3 nephrotoxicity.  Median time between courses was 42 days (35 to 72 days).  The authors concluded that HHT might have clinical activity in some patients with MDS.

Nemunaitis et al (2013) stated that omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in CML.  A SC formulation demonstrated efficacy and safety in phase I/II trials in patients previously treated with greater than or equal to 1 TKI.  These researchers evaluated pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers.  Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1 to 14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity.  Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites.  Adverse events, including QT interval prolongation, were recorded.  Tumor response was assessed at cycle 2 completion.  Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients.  Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 hour, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2).  Plasma concentration versus time data demonstrated bi-exponential decay; mean steady-state terminal half-life was 7 hours.  Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively.  Urinary excretion of unchanged omacetaxine accounted for less than 15 % of the dose.  Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %).  Two grade 2 increases in QTc interval (greater than 470 ms) were observed and were not correlated with omacetaxine plasma concentration.  No objective responses were observed.  The authors concluded that omacetaxine is well-absorbed after SC administration.  Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.

Shim et al (2014) noted that anti-cancer chemotherapy usually involves the administration of several anti-cancer drugs that differ in their action mechanisms.  These researchers examined if the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these 2 drugs could enhance their anti-tumor effects in cervical carcinoma model.  OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers.  OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL).  DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL).  The combination index (CI) values were calculated to evaluate the synergism of the 2 drugs.  In-vitro anti-tumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining.  In-vivo anti-tumor effects of various liposomes were tested using HeLa cell-bearing mice.  Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT).  The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL.  In-vitro, DOL showed higher anti-tumor activity than OL, DL or EL in cervical carcinoma HeLa cells.  In-vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6 % and 97.3 % relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively.  The authors concluded that these results suggested that liposomal co-delivery of DOX and OMT could synergistically potentiate anti-tumor effects.

Appendix

Synribo is considered medically necessary for members who meet the following criteria:

1. Patients diagnosed with chronic myeloid leukemia (CML) in chronic phase, accelerated phase, or posttransplant relapse, and
2. Patients have failed prior therapy with 2 or more tyrosine kinase inhibitors (See table for list of tyrosine kinase inhibitors) or documentation of T315I mutation

Table: Tyrosine Kinase Inhibitors (TKIs)

• Chronic phase
• Accelerated phase
• Post-transplant relapse