Eribulin

Eribulin
Names
Trade namesHalaven
Other namesE7389, ER-086526, NSC-707389, eribulin mesilate (JAN JP), eribulin mesylate (USAN US)
IUPAC name
  • 2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2',3'-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
Clinical data
Drug classMicrotubule inhibitor[1]
Main usesBreast cancer, liposarcoma[2]
Side effectsTiredness, hair loss, peripheral nerve damage, abdominal pain, fever, low white blood cells, low red blood cells[2]
Pregnancy
category
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    US NLMEribulin
    MedlinePlusa611007
    Legal
    License data
    Legal status
    Chemical and physical data
    FormulaC40H59NO11
    Molar mass729.908 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1CC2CCC3C(=C)CC(O3)CCC45CC6C(O4)C7C(O6)C(O5)C8C(O7)CCC(O8)CC(=O)CC9C(CC(C1=C)O2)OC(C9OC)CC(CN)O
    InChI
    • InChI=1S/C40H59NO11/c1-19-11-24-5-7-28-20(2)12-26(45-28)9-10-40-17-33-36(51-40)37-38(50-33)39(52-40)35-29(49-37)8-6-25(47-35)13-22(42)14-27-31(16-30(46-24)21(19)3)48-32(34(27)44-4)15-23(43)18-41/h19,23-39,43H,2-3,5-18,41H2,1,4H3/t19-,23+,24+,25-,26+,27+,28+,29+,30-,31+,32-,33-,34-,35+,36+,37+,38-,39+,40+/m1/s1 checkY
    • Key:UFNVPOGXISZXJD-JBQZKEIOSA-N checkY

    Eribulin, sold under the brand name Halaven, is a medication used to treat breast cancer and liposarcoma.[2][7] It is used when other treatments have failed.[7] It is given by injection into a vein.[2]

    Common side effects include tiredness, hair loss, peripheral nerve damage, abdominal pain, fever, low white blood cells, and low red blood cells.[2] Other side effects may include low potassium, low calcium, and QT prolongation.[2] Use in pregnancy may harm the baby.[2] It is a microtubule inhibitor.[1]

    Eribulin was approved for medical use in the United States in 2010 and Europe in 2011.[1][7] In the United Kingdom 0.88 mg cost the NHS about £360 as of 2021.[8] This amount in the United States costs about 580 USD.[9]

    Medical uses

    It is used for the treatment of:

    • people with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and a taxane unless the people were not suitable for these treatments.[4]
    • adults with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease.[4]

    Breast cancer

    The mesylate salt was approved by the U.S. Food and Drug Administration (FDA) on November 15, 2010, with an indication to treat people with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies.[10][11] It was approved by Health Canada on December 14, 2011, with an indication for the treatment of people with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease.[12][13][14] Metastatic breast cancer impacts about 150,000 people in the U.S. and due to the small patient population, Eisai was able to file a New Drug Application (NDA) under the orphan and rare disease designation.[15][16]

    Liposarcoma

    On January 28, 2016, the U.S. Food and Drug Administration (FDA) approved eribulin for the treatment of inoperable liposarcoma in people who received prior chemotherapy that contained an anthracycline drug.[17] A Phase III trial reported: With eribulin the median overall survival for participants with liposarcoma was 15.6 months, compared to 8.4 months for participants treated with dacarbazine.[17]

    Dosage

    It is generally given at a dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle.[2]

    Side effects

    Serious side effects may include a decrease in white blood cell count, which can increase the risk of serious infections that could lead to death; numbness, tingling or burning in the hands and feet (neuropathy); harm to a developing fetus; as well as changes in heartbeat (QTc prolongation), that may also lead to death.[17]

    Mechanism of action

    Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B,[18][19] the parent molecule being a naturally occurring, potent mitotic inhibitor with a unique mechanism of action. The parent molecule was orginally found in the sponge Halichondria okadai.[20][21]

    Eribulin is a mechanistically unique inhibitor of microtubule dynamics,[22][23] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[24][25] Eribulin has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade.[26][27] In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. These non-mitotic mechanisms include vascular remodeling that leads to increased tumor perfusion and mitigation of tumor hypoxia, phenotypic changes consistent with reversal of epithelial-mesenchymal transition (EMT), and decreased capacity for migration and invasion leading to reduced metastatic capacity as measured in a preclinical experimental metastasis model.[28][29] In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively.[30] Taxane-resistant cancers are often unresponsive to eribulin. A recent study found that this resistance is due to expression of multidrug resistance protein 1 (MDR1).[31] Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.[31]

    The synthesis of eribulin was first published[32] in 2001; a new synthetic route to the drug was published in 2009.[33]

    Society and culture

    Intellectual property

    Currently there are five active patents in the United States that are associated with the Halaven drug application, N201532. The first one expired on June 16, 2019, the last one (USRE46965) expires on January 8, 2027.[34]

    Research

    Two eribulin based products are in the research and development phase; a liposomal formulation and antibody drug combination therapy, both are for the treatment of solid tumors. The liposomal formulation of eribulin, E7389 liposomal, is currently in Phase I clinical trials.[35] Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation.[36] The drug antibody eribulin combination therapy is a joint venture between Eisai and Merck. The clinical trials combine eribulin and pembrolizumab, a PD-1 inhibitor, for the treatment of breast cancer and other advanced cancers.[37]

    Eribulin is being investigated for use in a variety of other solid tumors, including breast cancer, non-small cell lung cancer, prostate cancer, brain cancer, cervical cancer, urothelial cancer, melanoma, solitary fibrous tumors, and various sarcomas.[38]

    References

    1. 1 2 3 "EriBULin Monograph for Professionals". Drugs.com. Archived from the original on 28 January 2021. Retrieved 15 December 2021.
    2. 1 2 3 4 5 6 7 8 9 "Halaven- eribulin mesylate injection". DailyMed. 22 December 2017. Archived from the original on 9 July 2020. Retrieved 9 July 2020.
    3. ↑ "Eribulin (Halaven) Use During Pregnancy". Drugs.com. 22 October 2019. Archived from the original on 11 July 2020. Retrieved 9 July 2020.
    4. 1 2 3 "Eribulin EPAR". European Medicines Agency (EMA). Archived from the original on 9 July 2020. Retrieved 9 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
    5. ↑ "Eisai Announces Japan Launch Of Anticancer Agent Halaven" (Press release). Eisai Co., Ltd. 19 July 2011. Archived from the original on 4 June 2021. Retrieved 15 February 2021.
    6. ↑ "Anticancer Agent Halaven Approved For Treatment Of Locally Advanced Or Metastatic Breast Cancer In China" (Press release). Eisai Co., Ltd. 17 July 2019. Archived from the original on 4 June 2021. Retrieved 15 February 2021.
    7. 1 2 3 "Halaven". Archived from the original on 9 July 2020. Retrieved 16 December 2021.
    8. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 977. ISBN 978-0857114105.
    9. ↑ "Halaven Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 April 2021. Retrieved 16 December 2021.
    10. ↑ "Drug Approval Package: Halaven (erbulin mesylate) NDA 201532". U.S. Food and Drug Administration (FDA). Archived from the original on 9 July 2020. Retrieved 9 July 2020.
    11. ↑ "FDA approves new treatment option for late-stage breast cancer" (Press release). U.S. Food and Drug Administration (FDA). 2010-11-15. Archived from the original on November 17, 2010. Retrieved November 15, 2010.
    12. ↑ Notice of Decision for Halaven
    13. ↑ "Halaven for Metastatic Breast Cancer". Canadian Agency for Drugs and Technologies in Health. 9 March 2015. Archived from the original on 9 July 2020. Retrieved 9 July 2020.
    14. ↑ "Eisai Announces Canadian Approval of its Anticancer Agent Halaven". Eisai Co., Ltd. (Press release). Archived from the original on 9 July 2020. Retrieved 9 July 2020.
    15. ↑ "CDER Rare Disease And Orphan Drug Designated Approvals" (PDF). U.S. Food and Drug Administration. Archived (PDF) from the original on 2017-05-06. Retrieved 2021-08-09.
    16. ↑ "Patents and Exclusivity" (PDF). CDER SBIA Chronicles. 19 May 2015. Archived (PDF) from the original on 1 March 2019. Retrieved 9 August 2021.
    17. 1 2 3 "FDA approves first drug to show survival benefit in liposarcoma". U.S. Food and Drug Administration (FDA) (Press release). 28 January 2016. Archived from the original on 9 July 2020. Retrieved 9 July 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    18. ↑ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, et al. (February 2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research. 61 (3): 1013–21. PMID 11221827.
    19. ↑ Yu MJ, Kishi Y, Littlefield BA (2005). "Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B". In Newman DJ, Kingston DG, Cragg GM (eds.). Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN 978-0-8493-1863-4.
    20. ↑ Hirata Y, Uemura D (1986-01-01). "Halichondrins - antitumor polyether macrolides from a marine sponge". Pure and Applied Chemistry. 58 (5): 701–710. doi:10.1351/pac198658050701. ISSN 1365-3075. Archived from the original on 2021-08-09. Retrieved 2021-08-09.
    21. ↑ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). "Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data". The Journal of Biological Chemistry. 266 (24): 15882–9. PMID 1874739.
    22. ↑ Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, et al. (July 2005). "The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth". Molecular Cancer Therapeutics. 4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID 16020666.
    23. ↑ Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). "Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase". Molecular Cancer Therapeutics. 7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC 2562299. PMID 18645010.
    24. ↑ Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 2010). "Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability". Biochemistry. 49 (6): 1331–7. doi:10.1021/bi901810u. PMC 2846717. PMID 20030375.
    25. ↑ Wilson L, Lopus M, Miller HP, Azarenko O, Riffle S, Smith JA, Jordan MA (October 2015). "Effects of eribulin on microtubule binding and dynamic instability are strengthened in the absence of the βIII tubulin isotype". Biochemistry. 54 (42): 6482–9. doi:10.1021/acs.biochem.5b00745. PMID 26435331.
    26. ↑ Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, et al. (August 2004). "Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389". Cancer Research. 64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID 15313917.
    27. ↑ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, et al. (January 2011). "Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions". Cancer Research. 71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID 21127197.
    28. ↑ Funahashi Y, Okamoto K, Adachi Y, Semba T, Uesugi M, Ozawa Y, et al. (October 2014). "Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models". Cancer Science. 105 (10): 1334–42. doi:10.1111/cas.12488. PMC 4462349. PMID 25060424.
    29. ↑ Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. (March 2014). "Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states". British Journal of Cancer. 110 (6): 1497–505. doi:10.1038/bjc.2014.80. PMC 3960630. PMID 24569463.
    30. ↑ Kawano S, Asano M, Adachi Y, Matsui J (April 2016). "Antimitotic and Non-mitotic Effects of Eribulin Mesilate in Soft Tissue Sarcoma". Anticancer Research. 36 (4): 1553–61. PMID 27069131.
    31. 1 2 Laughney AM, Kim E, Sprachman MM, Miller MA, Kohler RH, Yang KS, et al. (November 2014). "Single-cell pharmacokinetic imaging reveals a therapeutic strategy to overcome drug resistance to the microtubule inhibitor eribulin". Science Translational Medicine. 6 (261): 261ra152. doi:10.1126/scitranslmed.3009318. PMC 4330962. PMID 25378644.
    32. ↑ Seletsky BM, Wang Y, Hawkins LD, Palme MH, Habgood GJ, DiPietro LV, et al. (November 2004). "Structurally simplified macrolactone analogues of halichondrin B". Bioorganic & Medicinal Chemistry Letters. 14 (22): 5547–50. doi:10.1016/j.bmcl.2004.08.068. PMID 15482921.
    33. ↑ Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". Journal of the American Chemical Society. 131 (43): 15636–41. doi:10.1021/ja9058475. PMID 19807076.
    34. ↑ "Patent and Exclusivity for: N201532". Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. U.S. Food and Drug Administration. Archived from the original on 2020-09-24. Retrieved 2021-08-09.
    35. ↑ Clinical trial number NCT03207672 for "Study of E7389 Liposomal Formulation in Subjects With Solid Tumor" at ClinicalTrials.gov
    36. ↑ Yu Y, Desjardins C, Saxton P, Lai G, Schuck E, Wong YN (February 2013). "Characterization of the pharmacokinetics of a liposomal formulation of eribulin mesylate (E7389) in mice". International Journal of Pharmaceutics. 443 (1–2): 9–16. doi:10.1016/j.ijpharm.2013.01.010. PMID 23313921.
    37. ↑ Clinical trial number NCT03222856 for "Ph II Study of Pembrolizumab & Eribulin in Patients With HR+/HER2- MBC Previously Treated With Anthracyclines & Taxanes (KELLY)" at ClinicalTrials.gov
    38. ↑ "184 Studies found for: eribulin OR E7389". ClinicalTrials.gov. U.S. National Library of Medicine. Archived from the original on 2020-09-27. Retrieved 2021-08-09.
    External sites:
    Identifiers:
    • "Eribulin mesylate". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-06-04. Retrieved 2021-08-09.
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