Creating an Oncology Powerhouse

Millennium Pharmaceuticals CEO Deborah Dunsire talks about the company’s innovative pipeline, the hopes for its market-leading cancer product VELCADE, and its position as a global oncology leader after joining forces with Japanese-based Takeda Pharmaceuticals.

Founded on the principles of the human genome, Millennium Pharmaceuticals is a company where innovation is inherent – and its recent acquisition by Japanese pharma giant Takeda Pharmaceutical Company Limited will only help to further exploit its innovative pipeline and stretch its oncology arsenal.

The $8.8 billion dollar deal that closed in May sets both companies on an accelerated growth trajectory – pairing the complementary strengths of Millennium’s oncology expertise with Takeda’s broad commercialization capabilities and development resources.

“The acquisition is about growth for both companies,” says President and Chief Executive Officer Deboarah Dunsire. “Takeda has laid out their vision to become an oncology leader of the coming decade. They thought that they needed a jump-start and a center of excellence for oncology, and they saw that in Millennium.”

The purchase of Millennium marks the biggest overseas acquisition by a Japanese drug maker, and is further evidence of the recent trend of biotech acquisitions by pharma companies who have been increasingly turning to biotechs to juice up their pipeline.

As Millennium will serve as the global oncology strategy hub for Takeda, Dunsire anticipates the size and scope of Millennium’s preclinical and clinical development operations will double with the ability to commercialize through Takeda’s European and Asian subsidiaries.

Through the new relationship, Millennium’s inflammation compounds will be able to find a home in Takeda’s experienced gastrointestinal sales force; but most importantly, the expanded commercialization capabilities will enable the company to capitalize on the efficacy and potential applicability of their market-leading blood cancer drug, VELCADE.

The VELCADE opportunity
The acquisition will only open the doors to greater market potential for Millennium’s standout cancer drug. Jointly marketed in the US and other countries with Johnson & Johnson, VELCADE has been approved in more than 85 countries, and last year alone the drug brought in global sales of over $800 million.

Its huge success stems from its tremendous efficacy against multiple myeloma, which managed to gain the drug rapid approval from the FDA in roughly four months.

In fact, Dunsire reveals that the phase III VISTA trial for VELCADE was stopped early in light of the fact that adding VELCADE to the existing regimen of melphalan and prednisone was far superior to using melphalan and prednisone alone; and the drug safety monitoring board of phase III trials deemed it unethical to treat patients without offering Velcade as a treatment option.

“The efficacy of VELCADE is quite remarkable as a single-agent and in combination with novel and existing therapies,” Dunsire says. “In combination, it seems to transform the efficacy of some of the common therapies that are currently used in the frontline myeloma setting.”

Today the blood cancer drug is approved as a second-line treatment for multiple myeloma and in the US, the drug is also approved as second-line treatment for mantle cell lymphoma. Currently the drug is under approval for newly diagnosed multiple myeloma, a breakthrough approval that would nearly double the number of individuals who could benefit from the drug.

“The front-line multiple myeloma opportunity has a PDUFA date of June 20, 2008 and the file is actively under review at the FDA,” Dunsire says. “The approval potentially doubles the number of multiple myeloma patients who can benefit from VELCADE. So once we have approval, we’ll be able to educate physicians around the use of VELCADE in the newly diagnosed multiple myeloma setting.”

Trials and approvals
VELCADE’s remarkable efficacy presents significant opportunities for further application, which today are being pursued through various research studies and clinical trials.

Currently Millennium is conducting a number of trials in the frontline myeloma setting and related to non-Hodgkin’s lymphoma. With approximately 55,000 multiple myeloma patients in the US and approximately 65,000 non-Hodgkin’s lymphoma patients, data from the trials has the potential to show even greater promise for VELCADE.

Already Millennium has received approval for VELCADE in relapsed mantle cell lymphoma, a more rare but aggressive form of lymphoma that affects approximately 5,000 patients in the US, so further opportunity in non-Hodgkin’s lymphoma is very plausible.

“VELCADE was approved for relapsed mantle cell lymphoma in December of 2006 based on a phase II trial, so we know that VELCADE is already demonstrating strong efficacy in a sub-set of non-Hodgkin’s lymphoma patients,” Dunsire remarks. “We have a much broader trial in progress with and a large number of patients with follicular and marginal zone lymphomas. The trial is over 80 percent-accrued right now. We expect final data from that in 2010.”

Just as exciting is recent findings that suggest potential applicability of VELCADE against lupus, which would represent a huge breakthrough since a new drug hasn’t been approved for the chronic autoimmune disease in over 30 years.

As Millennium attempts to push the drug into various new and extended approvals, it’s backed by an array of experienced teams who helped to move VELCADE rapidly through the approval process and who will be able to apply their know-how and experience to further applications of the drug.

“We’ve established a very strong group in toxicology, drug metabolism, drug formulation, and then clinical development that was honed in the VELCADE development,” Dunsire points out. “It took about four and a half years from the first time VELCADE was dosed in patients to the time that it was submitted for FDA approval. So we have experience in working with both a highly effective compound, but also in a very streamlined way to bring oncology products forward.”

Forward-looking ambitions
Although it’s just the onset of the new relationship, Dunsire foresees countless opportunities as a result of the acquisition by Takeda and has high hopes for what the companies can accomplish in tandem.

“The opportunities include the ability to accelerate the development of oncology therapeutics, both our own and coming in from Takeda, because we have the skill base to do it,” Dunsire says. “We now have the global ability to have a very strong commercialization for the inflammatory bowel disease product coming out of our portfolio. There are tremendous opportunities to make more of what both the companies have because we’re together.”

In addition to the magnified opportunities, Dunsire is also attentive to the need for Millennium to retain its entrepreneurial culture, and the challenge of dealing with the large cultural differences between a young Cambridge-based biotech and a 227-year-old Japanese pharma giant. “The challenges are going to be both a big company and a small company working together, and how to ensure that we continue to be as nimble and entrepreneurial as we always have been,” Dunsire explains. “It’s understanding, respecting and benefiting from that culture, while they understand, respect and benefit from us. I know we’ll get there, but I also know that we’re going to have to work hard to understand those cultures and understand how we can benefit from them.”

A key part of the formula for sustaining Millennium’s innovative culture is the new reporting structure designed to help the company retain its traditional mode of operation – with Millennium’s management team still reporting to Dunsire and then Dunsire reporting to the presidents of Takeda. The structure is also geared to improve talent retention. “People have chosen to work in this nimble, entrepreneurial environment so we believe we need to keep the talented people here and that is an absolutely critical component of being successful,” Dunsire remarks.

Beyond Millennium’s own contributions and its new partnership, Dunsire also has grander hopes for the field of oncology overall as it evolves in the direction of personalized medicine .

“Today we know much more about the biology of cancer, and with that, we can be more specific in the design of drugs to address that,” she acknowledges. “We also are beginning to understand more about how cancers differ between people – why some people respond to a therapy where others will not. If we can better understand the differences in what’s actually driving the tumor in specific groups and types of patients, it will allow us the opportunity to be more selective in which therapies we utilize.”

With a vision of greater personalized therapy in the near future and with the added capabilities from the recent acquisition, it’s an exciting time to be at Millennium, a company based on the understanding of the genetics of cancer. “Millennium was founded on the principle of understanding the human genome and how genes would influence disease,” Dunsire says. “We’re still in that process as an industry of understanding the genetics of disease, but oncology is a place where that science is advancing faster.”

From the CEO

NGP asks Chief Executive Officer Deborah Dunsire what she’s excited about coming down Millennium’s pipeline:

NGP.In addition to VELCADE, Millennium is advancing at least seven molecules in the areas of oncology and inflammation, and will also leverage its expertise over Takeda compounds coming into Millennium for development. What’s the next product to enter phase III?
DD. The next product to enter phase III clinical trials in our pipeline is MLN0002, a novel monoclonal antibody that binds to the T-cell integrin, alpha 4 beta 7. It inhibits the migration of T-cells to the GI tracts. This drug has the potential to address gastrointestinal disorders, specifically inflammatory bowel disease, including ulcerative colitis and Crohn’s disease.

Both diseases are now treated with general immunosuppression: patients are given azathioprine or steroids or TNF inhibitors, all of which suppress lymphocytes, or the T-cells, the white blood cells, around the body.

With MLN0002, the drug targets the T-cells that are specific to the GI tract, so you can suppress the immune response in the GI tract without affecting it in the rest of the body. This is the first time, to my knowledge, that we’ve been able to target immune modulation to the specific organs where we need it.

We’re also bringing another molecule into the clinic, MLN3126, for Crohn’s disease.

Initially, when we were thinking about continuing Millennium as a standalone entity, we would have had to secure partners to move both compounds forward. Now with Takeda, who has a gastrointestinal franchise, we have the resources and the experienced people we need to move these products forward.

NGP. Do you have any new indications in the area of hematological cancers?
DD. We have a number of different compounds for hematologic and solid tumors. One that’s about to start a phase II trial and is an oral kinase inhibitor is MLN518. We’ve seen some efficacy in acute myelogenous leukemia.

A group at the National Cancer Institute is going to be doing a study combining 518 with Avastin in brain cancer because 518 suppresses platelet-derived growth factors, which is a growth factor involved in blood vessels supporting tumors.

Avastin suppresses vascular endothelial growth factor, or VEGF, and that also affects the blood supply to tumors. In model systems, it looks like these two are synergistic. So we’re excited to see the clinical trials for that again, which should begin before the end of this quarter.

NGP. You have another molecule, an Aurora A kinase inhibitor, MLN8237, which is in phase I trials now. What is special about this molecule?
DD. At the National Cancer Institute, there’s a group who focuses on pediatric tumors. They very specifically go out looking for new therapies for pediatric tumors where there’s really no adequate therapy.

We sent a sample of 8237 to the National Cancer Institute and they tested it in their cell line and found that it has exquisite activity in a tumor called “pediatric neuroblastoma,” which is a rare, fatal tumor of very young children. These children will often get it before they’re two-years-old and they really don’t have adequate therapy at the moment.

In these cancer cell lines that represent the tumor, they haven’t seen a drug as active as MLN8237. We’re now very quickly working on a pediatric formulation, a form that can be given to babies and toddlers. We’re working with a children’s oncology group to see if we can start a trial addressing these neuroblastomas. That data on the neuroblastoma cell line was presented at the American Academy of Cancer Research.

In addition, MLN4924 inhibits a novel Millennium-discovered target in the protein homeostasis pathway called NAE. NAE specifically controls a subset of proteins, which regulates survival of cancer cells. MLN4924 has shown substantial activity in a broad range of preclinical solid and hematological tumor models. It’s always exciting to do something totally new because it can open up new ways of therapy.

About Dr. Deborah Dunsire
Dr. Deborah Dunsire joined Millennium in July 2005 with nearly 20 years of experience in commercial, operational, clinical and scientific aspects of a world-leading pharmaceutical business. Her vision for Millennium is to establish a vibrant, growing biotechnology company, which discovers and develops new medicines that change standards of care in cancer and inflammation. Previously, Dunsire led the Novartis US Oncology business, managing12 product launches and building the business from approximately $50 million to $2.1 billion in revenues over 10 years.

Takeda Meets Millennium
The key strategic benefits that Takeda expects the acquisition of Millennium will bring:
*Provide access to a fully-integrated oncology discovery, development and commercial platform with a seasoned management team and talented employee base
*Add VELCADE, a growing and market-leading oncology product with near-term worldwide blockbuster potential
*Supply access to Millennium world-class drug discovery organization, including expertise in the novel research area of protein homeostasis
*Capitalize on Millennium’s proven drug development capabilities and regulatory expertise, which allowed the company to bring VELCADE to market rapidly
*Leverage the Millennium’s experienced sales force, established relationships with oncology thought leaders and highly-regarded marketing capabilities to launch future products
*Expand Takeda’s global pipeline in GI, adding a novel anti-a487 antibody and an oral CCR9 inhibitor for the treatment of IBD

About Takeda
Founded in 1781 and located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products.

On May 14 th, Takeda Pharmaceutical Company Limited and Millennium Pharmaceuticals, Inc. announced the completion of Takeda ’ s tender offer by its wholly-owned subsidiary, Mahogany Acquisition Corp., to acquire all outstanding shares of Millennium common stock for US$25 per share. Following the merger, Millennium is now an indirect wholly-owned subsidiary of Takeda.

Fast Facts:
Company name: Takeda Pharmaceutical Company Limited
Founded: June 12, 1781
Incorporated: January 29, 1925
President: Yasuchika Hasegawa
Number of employees: 6115 (parent), 15,717 (consolidated)
Number of shareholders: 149,478
Scope of business: Manufacturing, marketing and import/export of pharmaceutical drugs
R&D facilities: Osaka, Tsukuba (Japan); Palo Alto, San Diego, San Francisco, Deerfield ( U S); London, Cambridge (UK); Singapore
Production Facilities: Osaka, Hikari; Italy; Ireland; China; Indonesia
Overseas subsidiaries and affiliates: US, UK, France, Italy, Germany, Austria, Switzerland, Ireland, Netherlands, China, Taiwan, Philippines, Thailand, Indonesia, Singapore