Millennium Carries On With The Takeda Oncology Expansion

By Wayne Koberstein, Executive Editor, Life Science Leader
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Since I’ve been writing about the pharma industry for many years, I often find it impossible to walk in any direction without bumping into a connection from the past. It seems like a thousand years ago that I interviewed Millennium’s founder, Mark Levin, soon after the launch of its hallmark cancer drug. Certainly enough has transpired since then.

Millennium itself found success — and some frustration — with championing a new class of cancer drugs inspired by release of the first human genome maps. The prize, the company’s proteasome inhibitor Velcade (bortezomib), won its initial FDA approval in 2003 for treatment of refractory multiple myeloma (MM) and was later approved elsewhere for MM and for mantle cell lymphoma. Velcade remains Millennium’s sole original oncology franchise product, though it shares commercial rights with Seattle Genetics for Adcetris (brentuximab vedotin) for Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL).

In 2008, Millennium became “Millennium: The Takeda Oncology Company,” when it was acquired by the Japan-based corporation as the keystone of an ambitious global expansion in the cancer area. Now in charge of all of oncology R&D at Millennium and Takeda is Michael Vasconcelles, M.D., as global head, the Oncology Therapeutic Area Unit (OTAU). Vasconcelles helps put the company’s past, present, and future into the context of Takeda’s oncology expansion.

STRUCTURAL CLUES — TAKEDA & OTAU
A continuum of integration seems to be developing among the many industry mergers, acquisitions, and business-unit swaps now transpiring. Typically, on one end, a large company will absorb the smaller one, harvesting the “synergies” and erasing all vestiges of the acquired entity. On the other end, the acquired organization becomes the dominant force in the merged company. Millennium’s acquisition falls nearer the latter, continuing its former identity and contributing most of the operational support for the OTAU, which is the umbrella that covers all of Takeda’s oncology R&D. Hence, Vasconcelles’ remarks apply to the parent company’s entire oncology program, including R&D partnerships, yet they also draw from Millennium’s achievement.

“Millennium built a legacy that led to a transformation in treatment of a disease that not long ago had a very poor outcome,” he says. “Velcade is a large reason the lives of patients with myeloma are looked at substantially different today. It is a foundation that still drives the way we think.”

Vasconcelles could be naturally skeptical of mergers, considering he joined his current company only two years ago, in March 2012, after coming from Genzyme following its purchase by Sanofi. The Takeda/ Millennium union had a four-year track record by then, however, and it offered continuity, especially in his area. “The company’s commitment to the oncology space was unchanged, and that was actually one of the challenges. We were in the midst of many late-stage programs and an early pipeline that has real potential. First and foremost, we needed to continue to prosecute those efforts as flawlessly as we could. But we also made a shift in strategic direction, which was to integrate the R&D structure of legacy Millennium into the Takeda R&D organization."

In addition to realizing efficiencies from the integration, Vasconcelles says the company had the strategic goal of “a truly global footprint” for its R&D beyond what a wholly owned subsidiary such as Millennium could achieve. “Operating reasonably independently, even at the scale of Millennium, would potentially present growing challenges as our portfolio matures and our footprint in oncology strengthens and deepens.”

According to Vasconcelles, another action that strengthened Takeda’s global R&D footprint was its acquisition of Nycomed in September 2011. A longtime licensor and developer, Nycomed immediately increased the number of products in Takeda’s product portfolio and pipeline, and it bolstered Takeda’s presence in Europe and “high growth emerging markets.”

“Now we have all the key organizational ingredients for delivering medicines to patients truly in a global sense. But we also need to make sure we think about our opportunities in the context of variations in disease patterns that occur in cancer globally, and our thinking was strengthened by the global integration."

Have the downside effects of large-scale corporate change intruded into this global harmony? “I’ve seen many similarities to the changes I went through at other times in my professional life. It is critical that leaders within the organization do everything possible to be clear in their communication and transparent in their actions — to paint a clear picture of the underlying reasons for the changes and their intended results. Because, I believe, we have done a good job in that respect, we now have a settled organization with a clear set of objectives, and we are as passionate and excited about our mission as ever.”

FROM FRONTIER TO FRONTIER
Besides globalization, another challenge for Millenium and the OTAU has been moving beyond the legacy of Velcade in ways that reflect the scientific progress since the product entered the scene. The initial enthusiasm over genetic and molecular targeting has been tempered by experience — tumors quickly develop resistance to targeted drugs, and their remarkable heterogeneity defies application to broad patient populations. Though Vasconcelles might be expected to mount a rigorous defense of the targeting strategy, his response is quite nuanced.

“There are certain malignancies with identifiable disease-driving mutations that have allowed us to sufficiently understand the biology and target our discovery efforts accordingly,” he says. “But there are also large areas of human cancers where the genomic complexity obligates us, not necessarily to shift from the targeting paradigm, but to increase our biological understanding with even more sophisticated tools and methodologies so we can refine the paradigm.”

He cites the collective need of targeted drug developers to use and interpret whole genome sequencing for a higher-resolution understanding of the biologics in cancer. “Understanding and targeting cancer is a struggle that all cancer-drug developers are facing right now, and we recognize we may not be able to build some of our development programs around a highly specific, genetically designed approach.”

Because scientists’ ability to interrogate tumors is at an “inflection point,” Vasconcelles says his unit must also rely on other ways to define appropriate patient populations for its medicines. “But because of these incredible successes that we have demonstrated, whatever set of criteria we use — biomarker-driven, a constellation of biomarker and clinical factors, or simply understanding the target sufficiently — I believe we will duplicate those clinical successes more often than not. The bar has been raised by past successes, and our job has just become more challenging.”

Vasconcelles also acknowledges the need to find new strategies against tumors. He likens the current battle with cancer to the historical fight against communicable diseases, with tumors quickly developing resistance to drugs the way microbes evade antibiotics or antivirals. He is particularly interested in immunotherapeutic approaches.

“My former company, Genzyme, had an early commitment to cancer immunotherapy, so I was steeped in the complex effort at the time. Now we may have the opportunity with the checkpoint inhibitors to see a real transformation in the care of patients, at least with certain cancers. So we are looking at immuno-oncology very carefully.”

He explains that the company’s oncology R&D now incorporates three primary areas: protein quality control, cellular infrastructure targets such as cancer metabolism, and antibody-drug conjugates, with the last two still at the discovery stage. Its immunology expertise resides mainly in the last area, antibody-drug conjugates, a focus of Takeda scientists in Cambridge and San Diego. As with targeted therapy, he believes further progress in immuno-oncology will require continued study and greater understanding of the biology involved. Combinations of immunotherapies will likely be necessary in widespread practice to obtain a sufficient immune response to arrest and kill tumors, he believes, at least initially and in clinical development.

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 partners,” says Vasconcelles. Takeda most recently established important new collaborations with major academic centers 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 related biology. We also have some specific oncology collaborations, and we examine 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 headway, 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 disparage 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 oncologist, I know how hard that is to do, and I’ve reflected on the vision repeatedly and come to imbed it in myself. It is audacious, but if you’re not audacious, you’ll never succeed. I see the same passion 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, Vasconcelles emphasizes the continued 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.

NEW STARS RISING

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 features that differentiate it from other proteasome 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 bioavailable 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 produce more inhibition, making it a compelling candidate for us.”

ADCETRIS (brentuximab vedotin), the focus of the company’s development and commercialization 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 subset of proteins that go through “ubiquitination” (attachment of the regulatory ubiquitin molecule) on their way to entering the proteasome. 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.”