Date: 2015-04-24
Type of information: Product launch
Product name: Halaven®
Compound: eribulin
Therapeutic area: Cancer - Oncology
Action mechanism: mitotic inhibitor/tubulin binder. Eribulin is a non-taxane, microtubule dynamics inhibitor indicated for the treatment of patients with breast cancer who have previously received at least two chemotherapeutic regimens for metastatic disease and whose prior therapy should have included an anthracycline and a taxane. Eribulin belongs to a class of antineoplastic agents, the halichondrins, which are natural products, isolated from the marine sponge Halichondria okadai. It is believed to work by inhibiting the growth phase of microtubule dynamics without affecting the shortening phase and sequesters tubulin into non-productive aggregates.
Company: Eisai (Japan)
Disease: locally advanced or metastatic breast cancer
Latest news: * On April 24, 2015, Eisai announced that its pharmaceutical sales subsidiary in Mexico, Eisai Laboratorios S. de R.L. de C.V. (Location: Mexico City, “Eisai Mexico”) has launched the anticancer agents Halaven® (eribulin mesylate) and Gliadel® (carmustine implant) in Mexico. These are the first products to be exclusively marketed by the Eisai Group in Mexico. Halaven® was approved in Mexico in August 2014 for third-line treatment for locally advanced or metastatic breast cancer, subsequent to treatment with at least two chemotherapy regimens including an anthracycline and a taxane, and since then Eisai has been working on preparations for the launch of the product. Gliadel® is a sustained-release formulation approved for intracranial implantation. Each wafer contains carmustine, a nitrosourea alkylating agent, distributed in a biodegradable copolymer matrix. Gliadel was approved in Mexico in November 2014 as an orphan drug for the treatment of patients with newly diagnosed high-grade malignant glioma (brain cancer) as an adjunct to surgery and radiation, as well as for the treatment of patients with recurrent glioblastoma multiforme as an adjunct to surgery. Eisai Mexico was established in August 2011, and has since been working to complete product registration procedures. In addition to these newly launched anticancer products, Eisai Mexico has submitted the antiepileptic agents Inovelon® and Fycompa® , the anticancer agent Targretin® as well as the antiobesity agent Belviq® for regulatory review. Meanwhile, Eisai established its first pharmaceutical sales subsidiary in Latin America in Brazil in April 2011, and commenced sales of Halaven in the country in November 2014. * On April 22, 2015, Eisai announced that Halaven® (eribulin) has been launched in the United Arab Emirates (UAE) for the treatment of women with locally advanced or metastatic breast cancer (MBC). The treatment will be marketed and commercialised in the UAE by Eisai's regional partner NewBridge Pharmaceuticals. The approval of eribulin in the UAE is based on the pivotal Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) study. EMBRACE showed eribulin prolongs median overall survival in women with MBC compared to women receiving an alternative treatment of physician's choice by 2.7 months (13.2 vs 10.5 HR 0.81 (95% CI 0.67, 0.96) nominal p=0.014). The most commonly reported adverse reactions in the eribulin study arm are fatigue, neutropenia, alopecia, peripheral neuropathy, nausea and constipation. * On December 18, 2014, Eisai announced that women with locally advanced or metastatic breast cancer (MBC) in Russia will have earlier access to Halaven® (eribulin). Eribulin is now indicated for patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. The decision is based on clinical evidence from two global Phase III trials; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice Versus Eribulin) and study 301.These studies involved more than 1,800 women. * On November 25, 2014, Eisai announced that its Brazil subsidiary Eisai Laboratórios Ltda. has launched Halaven® (eribulin mesylate) in the country. This marks the Eisai Group's first product to be marketed by Eisai in Latin America. In Brazil, Halaven® was approved for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapy regimens for advanced disease. Eisai Brazil has been preparing for the launch of Halaven since receiving approval in May 2013. Eisai established Eisai Brazil in April 2011 as its first pharmaceutical sales company in Latin America and has since been working on submitting products for marketing authorization. In addition to Halaven being launched, the company currently has submitted the anticancer agent Gliadel®, the antiepileptic agents Fycompa® and Inovelon® as well as the antiobesity agent Belviq® for review. * On November 3, 2014, Eisai announced that the German Institute for Quality and Efficiency in Health Care (IQWiG) has published a report which concludes that an additional benefit of Halaven® (eribulin) versus certain comparator therapies as defined by the Federal Joint Committee (G-BA) for the treatment of women with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease has been proven. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. IQWiG has limited this positive assessment to patients who can no longer be treated with taxanes or anthracyclines. In the report published by the IQWiG, the Institute subsequently defined sub-populations and assessed the extent and probability of an additional benefit. Eisai is critical of some aspects of this approach and will address them in its written statement to the GB-A. The G-BA is expected to publish its final decision after due consideration of the IQWiG report, written statements and an oral hearing at the end of January 2015. The reassessment for eribulin is based on clinical evidence derived from two global Phase III trials; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice Versus E7389) (Study 305) and Study 301.These studies involved more than 1,800 women. In line with the G-BA requirements, additional pooled analyses of data have been specifically performed for the benefit assessment procedure in Germany and reviewed by IQWiG. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether the drug offers an added benefit over the appropriate comparator therapy in these patient groups. According to the findings,IQWIG said there are both positive and negative effects. There is proof of minor added benefit for one group of patients. For other groups, there are hints or indications of lesser benefit. IQWiG already presented a dossier assessment of eribulin in February 2012. The subsequent decision on the added benefit made by the Federal Joint Committee (G-BA) was limited until April 2014. In addition, the drug manufacturer meanwhile obtained approval for an expanded therapeutic indication: In March 2011 eribulin was only available for patients who have progressed further after at least two chemotherapeutic regimens. Since June 2014, however, the drug can already be used after one unsuccessful treatment attempt. Hence there were two reasons ? independent from each other ? for the reassessment of eribulin. G-BA specified appropriate comparator therapies: When the G-BA specified the appropriate comparator therapy, it distinguished between several treatment situations: The first one refers to patients who are not eligible for further chemotherapy with a taxane or an anthracycline. In this situation, eribulin was to be compared with individual chemotherapy containing the drugs capecitabine or vinorelbine. In patients for whom taxanes or anthracyclines are principally still an option, eribulin was to be compared with an individual chemotherapy containing a taxane or an anthracycline. The decision for the adequate treatment should take into account whether the patients’ cancer cells have highly increased levels of certain human epidermal growth factor receptors (HER) (“HER2/neu status positive”). If treatments targeting these growth receptors (anti-HER2/neu treatments) are an option for these patients, eribulin was to be compared with an anti-HER2/neu treatment. If this was not the case, the comparator therapies mentioned above applied to these patients. Only data for patients with negative HER2/neu status evaluable. Two studies were available for the assessment, study 301 and EMBRACE. EMBRACE was already the basis of the first dossier assessment of eribulin. Both studies were open-label, randomized, controlled, multinational approval studies. However, IQWiG could only include the data of the participants with HER2/neu status negative in the dossier assessment because it was unclear whether it was assessed if the patients with positive status were suitable for anti-HER2/neu treatment. And it was unknown how many of the patients with an unclear status were to be rated as positive and how many as negative. It has been the standard approach in Germany for several years, however, to determine the HER2/neu status of the primary tumour as a basis for decision for further treatment. Advantage in survival, but disadvantage in severe side effects: Overall, IQWiG sees proof of an added benefit of eribulin with an extent that is to be rated as minor for patients who can no longer be treated with taxanes or anthracyclines and whose HER2/neu status is negative. These patients survived longer under eribulin treatment. But at the same time, severe side effects (CTCAE grade 3 and 4) were more common under eribulin. Number of affected organs influences the result: There were both positive and negative effects of eribulin in patients who can still be treated with a taxane or an anthracycline and whose HER2/neu status is negative. However, the treatment result also depended on the number of organs where the tumour had already formed metastases. On the one hand, patients in the eribulin group discontinued treatment less frequently due to adverse events, which resulted in a hint of lesser harm. On the other hand, severe adverse events (CTCAE grade 3 and 4) were more common, i.e. eribulin caused greater harm. The dossier contained no data on the outcomes of symptoms (morbidity) and quality of life for women who can still be treated with a taxane or an anthracycline and whose HER2/neu status is negative. Overall, IQWiG considers there to be a hint or an indication of lesser benefit in these patients. * On October 1, 2014, Eisai announced that its Australian pharmaceutical sales subsidiary Eisai Australia Pty. Ltd. (Eisai Australia) has launched Halaven® (eribulin mesylate) in the country. The product is the first to be marketed exclusively by Eisai in Australia. * On September 30, 2014, Eisai announced that Halaven® (eribulin) has received reimbursement in Australia for the treatment of patients with locally advanced or metastatic breast cancer. The approval and reimbursement of eribulin in Australia is based on the results of the pivotal Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) study. In the EMBRACE study population (n=762), eribulin is shown to prolong overall survival in heavily pre-treated patients with metastatic breast cancer by 2.5 months compared to patients receiving Treatment of Physicians Choice (TPC), which represents a mix of real-life treatment choices (eribulin 13.1 months vs. TPC 10.6 months, HR 0.81 (95% CI 0.66, 0.99), p=0.041). Updated data confirms that patients treated with eribulin survived a median of 2.7 months longer than patients who received TPC (overall survival of 13.2 months versus 10.5 months, respectively, HR 0.81 (95% CI 0.067, 0.96), nominal p=0.014). * On July 3, 2014, the European Commission (EC) has issued Marketing Authorisation Approval (MAA) for Halaven® (eribulin) in the treatment of patients with locally advanced or metastatic breast cancer (MBC) who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. The MAA for eribulin is based on clinical evidence from two global Phase III trials; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice Versus Eribulin) and study 301.These studies involved more than 1,800 women. EMBRACE showed eribulin can prolong median overall survival in heavily pre-treated women with MBC compared to women receiving an alternative treatment of physician's choice by 2.7 months (13.2 vs 10.5 HR 0.81 (95% CI 0.67, 0.96) nominal p=0.014). The most commonly reported adverse reactions in the eribulin study arm were fatigue (asthenia), a decrease in infection-fighting white blood cells (neutropenia), hair loss (alopecia), numbness and tingling in arms and legs (peripheral neuropathy), nausea and constipation. Study 301, a head-to-head trial of eribulin vs capecitabine, had a co-primary endpoint of overall survival and progression-free survival. The study demonstrated a trend favouring improved overall survival with eribulin compared to capecitabine in the intention-to-treat population, although the improvement was not statistically significant. [3] Women treated with eribulin had a median overall survival of 15.9 months versus 14.5 months with capecitabine (HR 0.879; 95% CI: 0.770-1.003; p=0.056).[3] For women with human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer, overall survival was 15.9 months for eribulin vs 13.5 months for capecitabine (HR 0.838; 95% CI: 0.715-0.983).[3] The most common adverse events reported for eribulin and capecitabine (?20% all grades) were neutropenia (54% vs 16%), hand-foot syndrome (<1% vs 45%) alopecia (35% vs 4%), leukopenia (31% vs 10%), diarrhoea (14 vs 29%) and nausea (22% vs 24%), respectively. * On 22 May 2014, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for Halaven®. The CHMP adopted a change to an indication as follows: "Halaven® is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments." * On January 6, 2014, Halaven® (eribulin) has received reimbursement approval in the Czech Republic as a highly innovative drug for patients with metastatic breast cancer, effective from the 1 January 2014. Eribulin received European Commission approval on 17 March 2011 based on the results of the pivotal Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) study. Eribulin is now available in 50 countries worldwide. * On October 1, 2013, Eisai has announced that Halaven® (eribulin) has received reimbursement approval in Belgium as a novel treatment for patients with metastatic breast cancer. Eribulin received European Commission approval on 17 March 2011 based on the results of the pivotal Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) study. Eribulin is now available in 50 countries worldwide. * On September 4, 2013, Halaven® (eribulin), has received reimbursement approval from the Spanish Directorate General of Pharmacy and Health Products, belonging to the Spanish Ministry of Health as a novel treatment for patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapeutic regimens for advanced disease. Prior therapy should have included two common types of chemotherapy, an anthracycline and a taxane, unless patients were not suitable for these treatments. In the Phase III EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Treatment of Physician's Choice (TPC) Versus Eribulin E7389) study population (n=762), eribulin was shown to prolong overall survival in heavily pre-treated patients with metastatic breast cancer by 2.5 months compared to patients receiving Treatment of Physicians Choice (TPC), representing a mix of real-life treatment choices (eribulin 13.1 months vs. TPC 10.6 months, HR 0.81 (95% CI 0.66, 0.99) p=0.041).Updated data from the pivotal Phase III EMBRACE trial confirmed these results, showing that patients treated with eribulin survived a median of 2.7 months longer than patients who received treatment of physician's choice (overall survival of 13.2 months versus 10.5 months, respectively, HR 0.81 (95% CI 0.067, 0.96), nominal p=0.014). A pre-planned analysis of patients from Region 1 of the study (North America/Western Europe/Australia) showed a significant overall survival benefit of eribulin over TPC of 3.0 months (p=0.009). The most commonly reported adverse reactions among patients treated with eribulin were asthenia (fatigue), neutropenia, alopecia (hair loss), peripheral neuropathy (numbness and tingling in arms and legs), nausea and constipation. Eribulin received European Commission approval on 17 March 2011 based on the results of the Phase III EMBRACE study. Eribulin is approved in 50 countries across the world including the European Union, USA, Russia, Switzerland, South Korea Japan, and Singapore. Halaven has received pricing authorisation and has launched in Canada, Denmark, Finland, France, Iceland, Italy, Norway, Sweden, Switzerland, Slovenia, and the UK. In addition, Halaven is available in Austria and Germany. * On July 10, 2012, Eisai has announced that Halaven® (eribulin) has received reimbursement approval from the French health authorities. Prior therapy should have included two common types of chemotherapy, an anthracycline and a taxane, unless patients were not suitable for these treatments. In addition to the French authorities granting reimbursement for the use of eribulin in heavily pretreated women with metastatic breast cancer, Eisai announces it is expanding its footing in the Israeli market with the registration grant of eribulin. Following marketing authorisation, Eisai and Neopharm group, its partner in Israel, plan to launch the product by the end of Eisai's financial year 2012 (31 March 2013).
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UE authorization: 2011-03-17/2014-07-03
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Pediatric exclusivit _USA:
Pediatric exclusivity UE: OTC status: Other news:
