Halaven TM FDA Approval Press Conference Statement

Transcription

1 Halaven TM FDA Approval Press Conference Statement Haruo Naito President Eisai Co., Ltd. at Tokyo Headquarters Auditorium November 16, 2010

2 It is with great pleasure that I inform you all here today that Halaven TM (eribulin mesylate) Injection, for which Eisai submitted an NDA in March this year, was approved by the the United States Food and Drug Administration (FDA) on November 15, U.S. local time. I would like to start by explaining briefly about this background. Materials extracted from the marine sponge Halichondria okadai collected from the coast along the Miura Peninsula in Kanagawa Prefecture, Japan were known to exhibit potent antitumor activity. In order to isolate, purify and identify these biologically active substances known as the halichondrins, Professor Yoshimasa Hirata and Dr. Daisuke Uemura of the Nagoya University Faculty of Science collected some 600 kg of Halichondria okadai. After grinding the marine sponge up in a mixer, the scientists obtained a crude extract by treating it with an organic solvent. By repeatedly purifying the extracted material using chromatography, they were able to extract a total of eight halichondrin homologues, including 12.5 mg of halichondrin B, the substance they had in fact been targeting. That is just 12.5 mg of halichondrin B from 600 kg of Halichondria okadai. In other words, from marine sponge weighing the equivalent of 10 adults, Professor Hirata and Dr. Uemura were able to extract halichondrin B the size of a single grain of rice. When it comes to substances that naturally occur in trace amounts, such as the halichondrins, it is not easy to identify their structure even after isolation and purification. A material s putative structure is normally determined using cutting-edge measuring instruments. However, in order to determine whether or not the proposed structure of halichondrin B was in fact accurate, we needed to confirm through multi-step synthesis that the structure of the totally synthesized synthetic compound was identical to that of the natural product. Achieving total synthesis in the contextual framework of synthetic organic chemistry is considered an important milestone not only to pave the way for the supply of rare natural substances, but also to create related substances in the form of valuable drug products. In 1985, Professor Hirata, Dr. Uemura and their team of scientists were able to determine the full structure of halichondrin B using just 12.5 mg of the substance isolated from 600 kg of Halichondria okadai. In 1992, a team of scientists led by Professor Yoshito Kishi from Harvard University went on to succeed in the first total synthesis of halichondrin B using convergent methodology that utilized Nozaki-Hiyama-Kishi (NHK) coupling as the key reaction. In doing so, the team was able to demonstrate that the structure proposed by Professor Hirata, Dr. Uemura and their team was in fact correct. With this information in hand, the Eisai Research Institute of Boston embarked on full-scale synthetic studies in 1992 with the aim of developing a halichondrin B analog initially under an agreement with Harvard University. While conducting structure-activity relationship studies using a synthetic intermediate, scientists achieved a major breakthrough when they discovered that a certain lactone ring compound found only in the right portion of the complete halichondrin B molecule exhibited antitumor activity as potent as the parent halichondrin B. Having ascertained that the right portion of the molecule was a pharmacophore, scientists went on to -2 -

3 synthesize a large number of novel derivatives in order to optimize it, and in 1997, succeeded in discovering Halaven TM (eribulin mesylate), which exhibited activity in both in vitro and in vivo tumor models. The mode of action of Halaven TM was first elucidated by Eisai scientists using fluorescent protein imaging experiments. The fluorescent proteins made it possible to visualize the vibrations of microtubules. As the result, Eisai scientists were able to carefully observe tubulin dynamics and concluded that while taxane-based anticancer agents inhibit cell division by stabilizing microtubules, Halaven TM is a microtubule dynamics inhibitor with a new mechanism of action that arrests the cell cycle through inhibition of the growth of microtubules without interfering with microtubule shortening. The U.S. National Cancer Institute (NCI) also selected halichondrin B as a candidate for clinical development as a chemotherapeutic agent with the expectation that it would exhibit characteristic cancer specificity and offer favorable clinical benefits compared to existing tubulin-targeting agents due to its highly potent cytostatic activity and unique chemical and biological profile. Synthesizing Halaven TM is an extremely difficult and complex process, involving some 62 steps to achieve total synthesis. Halaven TM has a molecular weight of 826, including 19 chiral carbons, which means the theoretical number of stereoisomers is 2 19, or a possible 524,000, making stereocontrol potentially extremely difficult. However, due to the advanced technological capabilities and strategies of the Eisai discovery and process research teams, it was possible to stereoselectively control all synthetic reactions and commercially synthesize Halaven TM. In this sense, Halaven TM can be considered to be a masterpiece of modern synthetic organic chemistry. After the discovery of Halaven TM, the Eisai clinical development team went on to carry out independent clinical development of the agent, which resulted in the submission of marketing authorization applications in Switzerland and Singapore last year. The company also filed simultaneous regulatory applications in Japan, the United States and the European Union in March this year. Both the United States and Japan have established priority review systems in place and Halaven TM was granted priority review status in both countries and approved by the United States Food and Drug Administration (FDA), Eisai s in-house sales force will now commence independent marketing of the drug in the United States followed by other countries subject to receiving approval. Next, I would like to give you a brief overview of the results of clinical studies with Halaven TM. Halaven TM was evaluated in a pivotal Phase III study, known as the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) study, which compared it with Treatment of Physician s Choice, rather than placebo, reflecting a common clinical practice at the time of the study. The study randomized 762 women with metastatic breast cancer previously treated with at least two prior chemotherapy regimens, including an anthracycline and a taxane, at a 2-to-1 ratio to receive either Halaven TM or Treatment of Physician s Choice. Treatment of Physician's Choice was defined as any single agent -3 -

4 chemotherapy, hormonal treatment or biological therapy approved for the treatment of cancer or palliative or radiotherapy administered according to local practice. Results demonstrated that the EMBRACE study met its primary endpoint of overall survival, showing that patients treated with Halaven TM survival a median of months compared to months for patients who received Treatment of Physician's Choice, a difference of 2.5 months. With a p-value of 0.041, the study confirmed that the difference in overall survival between the two treatment arms was statistically significant. Based on these study results, we were able to confirm that Halaven TM is the first and only single chemotherapeutic agent in the world to provide a statistically significant improvement in overall survival in patients with late-line breast cancer. Overall survival is regarded as the preferred endpoint by the U.S. FDA in oncology clinical trials. Achieving this endpoint with statistical significance is by no means an easy thing to do. I believe that the fact that the study showed that patients who received Halaven TM survived a median of 2.5 months longer than patients who received Treatment of Physician s Choice, as opposed to placebo, is a significant achievement for Eisai. It demonstrates that the agent is effective, as backed up by concrete evidence, in extending the lives of breast cancer patients, which provides hope for both patients and their families. Halaven TM was approved by the FDA for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens, for the treatment of metastatic disease. Prior therapy should have included two common chemotherapy treatments, an anthracycline and a taxane, for the treatment of metastatic disease. Breast cancer is one of the most common types of cancer among women worldwide, and has especially high incidence rates in developed nations in North America and Europe. In recent years, both incidence and mortality rates of breast cancer have been growing in Japan. As the incidence rate starts to rise when women are in their thirties, with a peak incidence among women in their late forties or early fifties, breast cancer poses a more compelling problem than other types of cancer. Nowadays, the number of patients diagnosed with breast cancer is increasing in accordance with advancements in the healthcare system and screening technology to promote early detection and diagnosis. It is estimated that approximately one million women worldwide are newly diagnosed with breast cancer each year, approximately 40% of which will go on to develop locally advanced or metastatic disease. Studies show that only one in five metastatic breast cancer patients is expected to live more than five years. In the United States, where Halaven TM has received approval, approximately 200,000 women are newly diagnosed with advanced breast cancer each year, and over 40,000 pass away from the disease. In Europe, breast cancer strikes 110 out of every 100,000 people, with 38 out of every 100,000 losing their lives to the disease. In Japan, these numbers are 33 and 8, respectively. With the number of patients increasing steadily year on year, breast cancer is considered to constitute an area of high unmet medical need. -4 -

5 It is also important to note that, while there are currently a number of anticancer agents commonly used to treat advanced or refractory breast cancer patients who have been heavily pre-treated with chemotherapeutic agents, including an anthracycline and a taxane, oncologists are still in calling for new breast cancer treatment guidelines that include a standard state-of-the-art therapy that has been scientifically proven to be the most highly effective drug available. With outpatient-based chemotherapy becoming the norm in recent years, it is necessary for us to consider ways to shorten dosing times and improve patients quality of life, in line with the medical community s call for products that are effective in treating metastatic breast cancer and suitable for use in an outpatient setting. A key feature of Halaven TM is its administration method. It is administered simply and quickly by intravenous infusion over 2 to 5 minutes. As the drug is highly water soluble, there is no need to add solubilizing agents, and as a result it is not necessary to administer a cumbersome premedication to prevent solubilizing agent-induced oversensitivity reactions. The most common adverse reactions (incidence 25 percent) reported among patients treated with Halaven in the EMBRACE study were asthenia(fatigue), neutropenia, anemia, alopecia (hair loss), peripheral neuropathy(numbness in the arms, legs and other parts of the body), nausea and constipation. However, after analyzing data for all adverse reactions grade 1 and above, we determined that Halaven has a manageable and predictable safety profile if used in accordance with prescribing instructions. As only 10% of patients in the EMBRACE study experienced grade 3 or 4 neuropathy, Halaven TM is a drug that is expected to make a significant contribution to patients. As for future development plans, Eisai hopes to expand the indications for Halaven TM to include other types of cancer to help make contributions to a wider group of patients. We aim to submit applications seeking approval to market the drug for the treatment of patients with refractory breast cancer with fewer prior treatments some time in fiscal Late stage clinical trials (Phase II) investigating Halaven TM s potential as a monotherapy in the treatment of other types of cancer such as non-small cell lung cancer, sarcoma, and prostate cancer are already underway. Thank you November