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|Chemical and physical data|
|Molar mass||729.90 g/mol|
|3D model (JSmol)|
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Eribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin is also known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389. It is used to treat certain patients with breast cancer and liposarcoma.
Currently there are 4 active patents in the United States that are associated with the Halaven drug application, N201532. The first one expires on June 16, 2019, the last one to expire, expires on July 2023.
Approvals and indications
The mesylate salt was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane-based chemotherapies. It was approved by Health Canada on December 14, 2011, for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Metastatic breast cancer impacts about 150,000 people in the USA, due to the patient population, Eisai was able to file and New Drug Application (NDA) under the orphan and rare disease designation.
On January 28, 2016 the US FDA approved Halaven for the treatment of inoperable liposarcoma in patients who received prior chemotherapy that contained an anthracycline drug. A phase III trial reported: With Halaven the median overall survival for patients with liposarcoma was 15.6 months, compared to 8.4 months for patients treated with dacarbazine.
Research and Development
Two new 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 1 clinical trials. Preliminary in vivo experiments show a decrease in C(max) and a longer half-life with the liposomal formulation. 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.
Structure and mechanism
Eribulin is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, the parent molecule being a potent naturally occurring mitotic inhibitor with a unique mechanism of action found in the sponge genus Halichondria.
Eribulin is a mechanistically unique inhibitor of microtubule dynamics, binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules. 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. 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. In other studies, eribulin treatment of leiomyosarcoma and liposarcoma cells leads to increased expression of smooth muscle and adipocyte differentiation antigens, respectively. 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). Fluorescently labeled eribulin has been used to study the pharmacokinetics and pharmacodynamics at single cell level in vivo.
A new synthetic route to the drug was published in 2009.
- https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=201532&Appl_type=N[full citation needed]
- "FDA approves new treatment option for late-stage breast cancer" (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
- Notice of Decision for HALAVEN[permanent dead link]
- https://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/drugandbiologicapprovalreports/ndaandblaapprovalreports/ucm544019.pdf[full citation needed]
- https://www.fda.gov/downloads/drugs/developmentapprovalprocess/smallbusinessassistance/ucm447307.pdf[full citation needed]
- FDA approves first drug to show survival benefit in liposarcoma. Jan 2016
- http://www.clinicaltrials.gov/ct2/results?term=eribulin+OR+E7389[full citation needed]
- https://clinicaltrials.gov/ct2/show/NCT03207672?cond=E7389+Liposomal&rank=1[full citation needed]
- Yu, Yanke; Desjardins, Christopher; Saxton, Phil; Lai, George; Schuck, Edgar; Wong, Y. Nancy (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.
- https://clinicaltrials.gov/ct2/show/NCT03222856?term=eribulin+and+pembrolizumab&rank=1[full citation needed]
- Towle, M. J; Salvato, K. A; Budrow, J; Wels, B. F; Kuznetsov, G; Aalfs, K. K; Welsh, S; Zheng, W; Seletsky, B. M; Palme, M. H; Habgood, G. J; Singer, L. A; Dipietro, L. V; Wang, Y; Chen, J. J; Quincy, D. A; Davis, A; Yoshimatsu, K; Kishi, Y; Yu, M. J; Littlefield, B. A (2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B". Cancer Research. 61 (3): 1013–21. PMID 11221827.
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- Smith, Jennifer A; Wilson, Leslie; Azarenko, Olga; Zhu, Xiaojie; Lewis, Bryan M; Littlefield, Bruce A; Jordan, Mary Ann (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 . PMID 20030375.
- Wilson, Leslie; Lopus, Manu; Miller, Herbert P; Azarenko, Olga; Riffle, Stephen; Smith, Jennifer A; Jordan, Mary Ann (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.
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- Kim, Dae-Shik; Dong, Cheng-Guo; Kim, Joseph T; Guo, Haibing; Huang, Jian; Tiseni, Paolo S; Kishi, Yoshito (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.