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EXCLUSIVE LIFE SCIENCE FEATURE leaders LIFESCIENCELEADER.COM JULY 2014 24 Takeda's Oncology Therapeutic Area Unit (OTAU) has 15 clinical development projects under way. The global head of OTAU, Michael Vasconcelles, M.D., sheds some special light on several outstanding candidates in the pipeline. IXAZOMIB is a novel molecule that targets the proteasome, the "waste remover," in cancer cells. But Vasconcelles says the drug has fea- tures that differentiate it from other protea- some inhibitors, including Velcade. Ixazomib is in several late-stage programs in multiple myeloma and earlier-stage programs in other hematologic malignancies. "The profile of this agent clinically suggests it has real potential to make additional step changes in the care of patients with myeloma. It is orally bioavail- able and has an emerging safety profile that would allow for protracted administration. The incidence of peripheral neuropathy and cumulative toxicities typically seen with other agents is much lower with ixazomib. Velcade- based regimens are the only ones that have demonstrated overall survival advantages in myeloma, and administering such a drug for a protracted period of time could allow for exposure of the underlying malignancy to pro- duce more inhibition, making it a compelling candidate for us." ADCETRIS (brentuximab vedotin), the focus of the company's development and commercial- ization partnership with Seattle Genetics, is an antibody drug conjugate targeting the cellular protein CD30, which is expressed on Hodgkin lymphoma and T-cell non-Hodgkin lymphomas, including anaplastic large cell lymphoma. Adcetris is already approved in the relapsed and refractory setting in both Hodgkin lymphoma and anaplastic large cell lymphoma. OTAU has a substantial development program to study the drug in combination with earlier lines of therapy in those diseases, which represent significant unmet needs in Western countries but have an especially high prevalence in Asian populations compared with Western countries. It is also studying Adcetris in a more uncommon but severe disease, cutaneous T-cell lymphoma. "Adcetris is a transformative therapy, and it has the opportunity to change the standard of care for those diseases," says Vasconcelles. MLN4924 targets a specific enzyme called the NEDD8 Activating Enzyme, the first step in a sub- set of proteins that go through "ubiquitination" (attachment of the regulatory ubiquitin mol- ecule) on their way to entering the protea- some. It is in a combination Phase 1b study with 5-azacytidine in acute myeloid leukemia as well as with standard-of-care agents in solid tumors. "Both areas of interest are based on nonclinical data showing very nice synergy between 4924 and agents already used in those diseases. We are quite intrigued with the signals emerging there, and I look forward to later-stage development with 4924. We also have another molecule, MLN7243, that is earlier in development but is even further upstream in the same pathway, targeting the ubiquitin-activating enzyme. The compound recently began testing in a Phase 1 program." MLN0264 is an antibody drug conjugate that targets the cell surface protein, guanylate cyclase-C (GC-C), which is expressed in the luminal surface of the GI tract. It is entering Phase 2 studies in gastric cancer, pancreatic cancer, and gastro-esophageal cancer in the United States, Europe, and Asia this year. "GC-C expression is restricted to GI malignancies, and because the target expression is restricted to the luminal surface of normal epithelial cells (essentially an immuno-restricted site), we thought it would be a good target." NEW STARS RISING and come to imbed it in myself. It is audacious, but if you're not audacious, you'll never succeed. I see the same pas- sion throughout the organization and I'm doing everything I can not only to maintain it, but deepen it. We have all the ingredients here to take Takeda Oncology to even broader and deeper places than it's ever been before." Returning to the Millennium legacy, As OTAU integrates the company's oncology programs, it is also increasing its outreach to external discovery. "We have a great internal discovery team, and their work will continue unabated, but Takeda and Millennium have long been leaders in working with external part- ners," says Vasconcelles. Takeda most recently established important new col- laborations with major academic cen- ters in New York and a "novel incubator effort" in Israel. Even though neither of those is cancer-specific, he says, "One of the nice benefits of being part of our integrated R&D; is having a connection into those initiatives. For example, the three institutions involved in the New York effort are Rockefeller University, Memorial Sloan Kettering, and Weill Cornell Medical College, so clearly there is a potential focus on cancer or relat- ed biology. We also have some specific oncology collaborations, and we exam- ine them on an ongoing basis to make sure they remain consistent with our own internal strategy." ONE STEP AT A TIME Vasconcelles expresses some concern that external forces of a different sort (e.g., unrealistic outsider expectations) will cause unwanted difficulties for cancer-drug R&D; — not by impeding it, but by pushing it too hard. "In oncology, in my lifetime, we have made real head- way, but the usual and customary way we make headway is in a methodical, incremental fashion, and eventually we might get all the way from A to Z. And that process will more often than not continue to be the path to success. What I hope is that those who set high expectations for innovators do not dis- parage the incremental path, because it has worked well for us for many years. The widespread expectation is that we can just go from A to Z or close to it every single time." He recalls walking into Millennium's Cambridge headquarters for the first time and seeing a large sign proclaiming the company's vision of curing cancer. "I literally stopped short. I'm an oncolo- gist, I know how hard that is to do, and I've reflected on the vision repeatedly Vasconcelles emphasizes the con- tinued importance of the company and its operations in Cambridge. In the globalization of Takeda Oncology, Millennium's headquarters remains "the center of our universe." For all of its global commercial infrastructure, he says the company is committed to maintaining that center — and its original vision. L MILLENNIUM CARRIES ON WITH THE TAKEDA ONCOLOGY EXPANSION By W. Koberstein 0 7 1 4 _ F e a t u r e _ T a k e d a . i n d d 5 0714_Feature_Takeda.indd 5 6 / 2 0 / 2 0 1 4 1 1 : 2 0 : 0 6 A M 6/20/2014 11:20:06 AM