Eribulin

Structural formula
General
Non-proprietary name	Eribulin
other names	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-9 H , 15 H -furo [3,2- i ] furo [2 ′, 3′-5,6] pyrano [4,3- b ] (1,4) dioxacyclopentacosine-5- ( 4 H ) -one
Molecular formula	C 40 H 59 NO 11
External identifiers / databases
CAS number 253128-41-5 (eribulin) 441045-17-6 (eribulin mesylate ) EC number 803-583-7 ECHA InfoCard 100.230.372 PubChem 11354606 DrugBank DB08871 Wikidata Q408717
Drug information
ATC code	L01 XX41
Drug class	Cytostatic
properties
Molar mass	729.90 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 301 + 311 + 331-341-351-361 P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Eribulin (trade name Halaven ; manufacturer Eisai ) is a non- taxane- based cytostatic that is used in monotherapy for the treatment of patients with locally advanced or metastatic breast cancer . By inhibiting the microtubule dynamics, eribulin prevents the replication of tumor cells, but without causing any depolymerization of existing tubules. Eribulin is a structurally simplified synthetic analogue of the naturally present in the marine sponge Halichondria okadai occurring halichondrin B .

History and Development

The development of eribulin took place in several steps. It began with the isolation of halichondrin B from the Pacific sea sponge Halichondria okadai in 1986 and its chemical synthesis by Harvard scientists six years later. Halichondrin B has clear anti-tumor activity, but is structurally very complex. With Eribulin, Eisai developed a synthetic analogue of this natural product in 1997, which has a simpler but still relatively complex molecular structure.

Therapeutic use

Eribulin monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have progressed (worsened) after previous chemotherapy for the treatment of advanced breast cancer. The previous therapies should have included an anthracycline and a taxane , unless these treatments were unsuitable for the patient. Eribulin is the first monotherapy treatment for which a significant benefit in terms of overall survival has been demonstrated in patients with advanced breast cancer after taxane and anthracycline treatment.

Admission status

Eribulin was approved by the Food and Drug Administration (FDA) as monotherapy in the United States in November 2010 for the treatment of patients with locally advanced or metastatic breast cancer.

In March 2011, the European Commission approved eribulin in all 27 EU member states for the above indication. The Canadian regulatory authority Health Canada approved eribulin for Canada in December 2011 in the above indication.

Early benefit assessment

Since 2011, newly approved drugs with new active ingredients have to undergo an " early benefit assessment " by the Federal Joint Committee (G-BA) based on Section 35a SGB ​​V ( AMNOG ) if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. This also applied to eribulin. First of all, the Institute for Quality and Efficiency in Health Care (IQWiG) submitted an assessment. The G-BA passed a positive resolution ("hint for a minor additional benefit") in April 2012.

Mechanism of action of eribulin

Eribulin is an inhibitor of microtubule dynamics. The substance inhibits the polymerization of tubulin molecules to form microtubules and encapsulates tubulin in non-productive aggregates. The lack of development of the spindle apparatus causes a blockage of mitosis and induces apoptosis. Eribulin differs from the well-known microtubule inhibitors (taxanes, vinca alkaloids) in that it binds to the microtubules and has no effect on microtubule shortening. These properties are discussed on the one hand as the reason for the lower toxicity of eribulin compared to taxanes and vinca alkaloids. On the other hand, this also explains the effectiveness of eribulin in taxane-resistant tumor cell lines with ss-tubulin mutations.

effectiveness

In patients with locally advanced or metastatic breast cancer who had been pretreated with anthracycline and taxane, eribulin showed a significant survival advantage as monotherapy compared to the treatment of physician's choice (TPC). This advantage was achieved without increasing the number of discontinuations due to adverse events. The observed toxicities and adverse effects correspond to those of a chemotherapeutic agent, with which a calculable and manageable tolerance profile could be established in the studies. The short infusion over 2–5 minutes contributes to the satisfaction of the patients with the therapy. The present results of the EMBRACE study and the improved overall survival suggest that eribulin is a substance that could establish itself as the standard option in heavily pre-treated patients with locally advanced or metastatic breast cancer.

Survival benefit in metastatic breast cancer

Eribulin has shown promising results in intensively pre-treated women with advanced breast cancer.

Eribulin was compared in a phase III EMBRACE study (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice vs. Eribulin) with various monotherapies (Treatment of Physician's Choice = TPC) determined by the study centers. The updated analysis of 589 events required by the European and US regulatory authorities resulted in median overall survival of 13.2 and 10.5 months respectively (HR 0.81; nominal p = 0.014). This corresponds to an increase in overall survival of 2.7 months. This was the first time that a significant survival advantage for a single substance could be proven in patients who had been heavily pre-treated.

Trade names

• Monopreparation : Halaven

Web links

• Public Assessment Report (EPAR) of the European Medicines Agency (EMA) on: Eribulin

Individual evidence

1. ↑ There is not yet a harmonized classification for this substance . A label of [No public or meaningful name is available] in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 5, 2020, is reproduced from a self-classification by the distributor .
2. ↑ Ledford H .: Complex synthesis yields breast cancer therapy . In: Nature 2010; 468: 608-609, doi: 10.1038 / 468608a .
3. ^ Specialist information Halaven , as of March 2011.
4. ↑ European Public Assessment Report (EPAR) (PDF; 65 kB) of the European Medicines Agency (EMA) (German).
5. ↑ FDA press release
6. ↑ Eribulin (Halaven) receives approval from the European Commission for Advanced Breast Cancer Journal Onkologie 2011.
7. ↑ Summary of the European public assessment report (EPAR) for Halaven European Medicines Agency (EMA).
8. ^ Eisai announces Canadian approval of its anticancer agent HALAVEN ^™ , Eisai press release of December 15, 2011.
9. ↑ Information archive | Early benefit assessment (Section 35a SGB V) , accessed on the website of the Federal Joint Committee (G-BA) on November 30, 2012.
10. ↑ Resolutions on the benefit assessment of eribulin (PDF; 392 kB), G-BA resolution text on an amendment to the Drugs Directive (AM-RL): Annex XII, published under BAnz AT June 15, 2012 B3 .
11. ↑ Jordan et al .: How Do Microtubule-Targeted Drugs Work? An Overview , Current Cancer Drug Targets 2007 (7): 730-742 doi: 10.2174 / 156800907783220417 .
12. ↑ ^{a b} Javier Cortes, Joyce O'Shaughnessy and a .: Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. In: The Lancet. 377, 2011, p. 914, doi : 10.1016 / S0140-6736 (11) 60070-6 .
13. ↑ Twelves et al., Updated Survival Analysis of a Phase III Study (EMBRACE) of Eribulin Mesylate vs Treatment of Physician's Choice in Subjects with Locally Recurrent or Metastatic Breast Cancer Previously Treated with an Anthracycline and a Taxane. 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010, P6-14-08.
14. ↑ Schreiberhuber A., Intensive pretreated breast cancer: Eribulin - confirmed significant survival benefit , Hematologie & Onkologie 2011.

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