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Omacetaxine mepesuccinate

Also known as Homoharringtonine, HHT, Synribo, Tekinex

A semisynthetic form of homoharringtonine, an ester of cephalotaxine from Cephalotaxus plants, that inhibits protein synthesis. Its only approval found is a US one for chronic myeloid leukaemia resistant or intolerant to TKIs; Drugs@FDA lists the US product as discontinued.

From discovery to approval

  1. 1970 · Earliest report found

    The earliest paper found that names homoharringtonine is a 1970 report by Powell and colleagues on the structures of harringtonine, isoharringtonine and homoharringtonine (title only). A 2017 review says cephalotaxine was isolated by Paudler in 1963 and dates harringtonine's activity against mouse leukaemias to 1969.[2][3][4][5][1]

  2. 2012-10-26 · FDA accelerated

    NDA 203585: adult patients with chronic or accelerated phase chronic myeloid leukaemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors; the letter states approval under the accelerated approval regulations (21 CFR 314 Subpart H) and the label says the indication is based upon response rate.[6]

  3. 2014-02-10 · FDA converted

    NDA 203585/S-001, signed 02/10/2014 (signature page; Drugs@FDA lists the same date): the letter reads 'Subpart H fulfilled' and says the supplement fulfils the commitments made under 21 CFR 314.510 (final analysis report with 24 months of follow-up). The word 'converted' is not used by the letter.[7]

How it works

The label says its mechanism is not fully elucidated but includes inhibition of protein synthesis, independent of direct Bcr-Abl binding. It binds the A-site cleft of the large ribosomal subunit (shown with an archaeal ribosome), and in vitro it lowered Bcr-Abl and Mcl-1 protein levels.[1]

Where it came from and why

The 2017 review says Cephalotaxus extracts showed significant activity against leukaemia in mice, and that homoharringtonine, being the easiest to purify and most abundant, was selected by the US National Cancer Institute for clinical development. It adds that homoharringtonine and harringtonine, or a mixture, have been used in traditional Chinese medicine since the 1970s.

Cancers

  • Chronic myeloid leukaemia

    The 2012 US label lists chronic or accelerated phase chronic myeloid leukaemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.[1]

Worth knowing

  • The 2012 US label says the indication was based upon response rate and that there were no trials verifying an improvement in disease-related symptoms or increased survival.[1]
  • In the final analysis with 24 months of follow-up, 18% of chronic-phase patients achieved a major cytogenetic response (median duration 12.5 months) and median overall survival was 40.3 months; in accelerated phase, 14% achieved or maintained a major haematologic response.[8]
  • In January 2011 the company withdrew its EU application (Tekinex, for Ph+ chronic myeloid leukaemia with the T315I mutation after imatinib failure) at day 120; the EMA committee's provisional view was that the medicine could not have been approved because benefits were uncertain and follow-up was insufficient.[9]
  • A 2017 review suggests homoharringtonine may hold the record for the longest time to reach the market after its first use in traditional Chinese medicine.[4]

References

  1. U.S. Food and Drug Administration. Synribo (omacetaxine mepesuccinate) for injection, prescribing information, NDA 203585, original approval October 2012. Source
  2. Powell RG, Weisleder D, Smith CR Jr, Rohwedder WK. Structures of harringtonine, isoharringtonine, and homoharringtonine. Tetrahedron Lett. 1970;(11):815-8. PubMedDOI
  3. Powell RG, Weisleder D, Smith CR. Antitumor alkaloids from Cephalotaxus harringtonia: structure and activity. Journal of Pharmaceutical Sciences. 1972;61(8):1227-30. DOI
  4. Pérard-Viret J, Quteishat L, Alsalim R, Royer J, Dumas F. Cephalotaxus Alkaloids. Alkaloids Chem Biol. 2017;78:205-352. PubMedDOI
  5. Smith CR Jr, Powell RG, Mikolajczak KL. The genus Cephalotaxus: source of homoharringtonine and related anticancer alkaloids. Cancer Treat Rep. 1976;60(8):1157-70. PubMed
  6. U.S. Food and Drug Administration. Accelerated approval letter, NDA 203585 (Synribo, omacetaxine mepesuccinate), IVAX International GmbH / Teva, 2012. Source
  7. U.S. Food and Drug Administration. Supplement approval letter, NDA 203585/S-001 (Synribo, omacetaxine mepesuccinate): fulfilment of Subpart H postmarketing requirement, Teva Branded Pharmaceutical Products R&D; Drugs@FDA lists the action as 02/10/2014. Source
  8. Cortes JE, Kantarjian HM, Rea D, Wetzler M, Lipton JH, Akard L, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer. 2015;121(10):1637-44. PubMedDOI
  9. European Medicines Agency. Questions and answers: withdrawal of the marketing authorisation application for Tekinex (omacetaxine mepesuccinate), EMA/13310/2011, 20 January 2011. Source
  10. U.S. Food and Drug Administration. Drugs@FDA: approval date(s) and history, letters, labels for NDA 203585 (Synribo, omacetaxine mepesuccinate). Page read 2026-10-29. Source