Anna Protopapas: Takeda's Oncology Taskmaster

Millennium Takeda’s new president, Anna Protopapas, explains the life choices that brought her from Cyprus to Cambridge—and a lead position in the hotly contested search to make cancer a treatable disease. By William Looney, Editor-In-Chief, Pharmaceutical Executive.

With a freshly minted brand identity bound tightly to its formidable Japanese parent, Millennium: The Takeda Oncology Company is shedding its reputation as a “one drug wonder.” That drug, Velcade [bortezomib] is the first FDA-approved proteasome inhibitor and the first approved 21st century treatment for multiple myeloma; with its multiple expanded indications, the blockbuster has, for many patients, turned what was once seen as a death sentence on diagnosis into something resembling a chronic disease. There are a few more spins on the cycle to come from Velcade, and Millennium now has its second marketed product, Adcetris, for relapsed Hodgkin lymphoma. The capstone is what looks like a new drug pipeline of steady, solid performers, all centered on oncologic applications, and with roughly half of the candidates now being tested at an advanced Phase III level. A globalized organizational model, the positive R&D buzz, the scale and deeper pockets afforded by the combination with Takeda – all this suggests Millennium may finally be moving up the ranks in the cancer league play. It’s a view expressed with sunny, Greek-style confidence by Millennium’s new President, Anna Protopapas, in an interview last month with Pharm Exec.

PE: Millennium Takeda’s singular focus on oncology avoids the frequent strategic R&D repositioning that characterizes the more diversified big Pharma players. But there are risks, too, in depending on what is now seen as a crowded, highly competitive sector, where the science is challenging and pricing pressures are intense. How does Millennium maintain its therapeutic advantage in this environment? Is the overriding commitment to oncology products a hard fact for investors going forward?

Protopapas: Contributing to the fight against cancer has always been Millennium’s mark of distinction. This was reaffirmed and accentuated by our merger with Takeda in 2008, where we now serve as the company’s global “center of excellence” in oncology research, product development and commercialization. This commitment remains firm. In fact, we do not believe that oncology products bind us too narrowly in serving patients. Cancer is a complex condition; it affects patients in different ways. It is now accepted that cancer is a highly heterogeneous collection of diseases. Understanding these at the genetic and molecular level helps us discover new medicines.

PE: Oncology is not only at the frontier of science, it is the focal point for change in the practice of medicine as well as in the way new therapies are promoted to the provider and payer communities. The business model for oncology specialists is under significant financial pressure, while proactive patient education has become essential to a successful launch strategy. What is Millennium Takeda doing to address these structural transformations in the marketplace?

Protopapas: Our response to transition in the marketplace is very simple. It is to generate the right data and evidence to support our products’ value proposition to clinicians, payers and patients. The starting point is the clinical trial, which we design and position not as an end in itself but as part of a research continuum that will extend well into the Phase IV post-marketing work that oncology stakeholders are coming to regard as even more important than the data submitted to secure initial FDA authorization. In fact, the differentiating factor in success is how well this evidence relates to the real-world clinical setting after registration. We build a strong data trail designed to support additional indications, to guide physicians in deciding among choice of therapy, to demonstrate compliance with relevant treatment protocols, to establish cost-effectiveness against the current standard of care, and to set proper expectations for the patient in terms of outcomes. Our data is increasingly targeted to this latter objective, because, as more cancer therapies are introduced, the patient experience is now the dominant thread driving treatment eligibility decisions.

With greater choice, we face an equally important obligation to help patients and their provider decide what is best for their condition. This is precisely what we did with Velcade, where strong trial data put us in the fortunate position as the only approved FDA treatment for myeloma with a demonstrated survival benefit in its label. We were able to leverage this evidence very quickly to ensure physicians took it into account in prescribing decisions.

Another example is the truly compelling evidence compiled on Adcetris, the treatment recently approved for patients with relapsed-refactory Hodgkin lymphoma. This cancer strikes young adults disproportionately and the drug is indicated for those who have exhausted other drug options – so the stakes for the eligible patient are very high. Trial data we presented with our partner, Seattle Genetics, at the December 2013 American Society of Hematology conference, yielded a median survival curve of 40.5 months – more than three years – for trial patients, most of whom, based on historical controls, typically would not be expected to do very well.

In our view, the strength of this data leads immediately to a conversation about value – no convincing is needed. We want products that advance the discussion beyond incremental benefit; our ultimate aim is to produce a cure. I think that attitude filters back to positively influence our relationship with providers and – obviously – patients.

PE: Can you quantify whether good evidence increases access, particularly as the price point for new cancer treatments leads to payer “sticker shock?”

Protopapas: Access in oncology today is a complex proposition. Though it is critical, evidence alone will not move market share. There is an additional premium required in interpreting and explaining the evidence. Millennium has put significant resources into recasting our sales force to make it an informative source of case-relevant information and expertise; physicians see our reps because they need to or want to, not because they happen to have a free moment. As the accompanying table shows, every year since the launch of Velcade in 2003 we have had important new data to share around the drug’s indications and clinical performance. We see this as an educational investment in market uptake. What good is a great medicine if the community lacks any awareness of its merits?

And we have metrics to prove a return on that investment. Independent third party surveys put our reps at the top of the league in obtaining access to practicing prescribers; that access is secured through the informative, accessible data we generate around our products. Millennium actually scores better in building relationships with cancer specialists than rival pharma players with more medicines to sell and a bigger name recognition in oncology.

PE: Who is behind the trend toward raising the bar on data and evidence as a condition for approval – and reimbursement – of oncology medicines? Is government driving the process or is your main concern what is happening on the private payer side?

Protopapas: The pressure to quantify value is coming from multiple fronts. Private and non-profit insurers, PBMs and managed care providers are no longer complacent, third party participants in a system where costs are simply passed on to others. Patients are bearing more of the direct cost of care, so they too expect an explicit connection between investment and outcome. As for government, its influence around the value debate is variable; in Europe, public authorities play a dominant role as the basic underwriter of health care services, while here in the US it is still an evolving player in a mixed public-private system. But we are clearly heading in the European direction.

Millennium is prepared to work closely with any regulator or government that seeks to better understand the ways our medicines create value for the health system. This commitment extends to cooperation at the very earliest stages of the drug approval process, where we deliberately seek out the FDA and EMA, as well other agencies, for advice in the design of our trials. The biology around cancer is novel and unprecedented, so quite often our scientists are designing protocols that have not been done before. It’s a matter of self-interest to do so, but nonetheless we are finding these interactions are very collaborative and constructive. The contacts were instrumental in obtaining, in October 2012, European registration and subsequently local reimbursement for Adcetris as indicated for one type of Hodgkin’s lymphoma and refractory/relapsed anaplastic large-cell lymphoma [ALCL]. It’s another example where our investment in generating the right kinds of evidence really pays off.

PE: What professional attributes do you look for in recruiting sales staff? Does science trump marketing?

Protopapas: Experience in the oncology area is what distinguishes our sales team. A very high percentage of them have been with the company since the launch of Velcade 10 years ago. We want to avoid a culture that looks at selling as something driven by quarterly results, where sales staff come and go too quickly to develop roots with the customer. In oncology, a strong ongoing relationship with physicians is a competitive differentiator. Consistency in these relationships is the best way to deploy our human capital. We want to retain people whose careers develop in tandem with our products.

PE: How is the recent decision to globally integrate R&D activities at Takeda headquarters in Tokyo impacting the work at Millennium? How does this new reporting structure ensure liaison between the science and commercial functions?

Protopapas: In a practical sense, the changes had very modest effects on us, except that Millennium is now more tightly associated with the Takeda name and brand. On the commercial side, we are now known as Millennium: the Takeda Oncology Company, while our formerly autonomous R&D operation now reports to Takeda’s global organization headed by Dr. Tachi Yamada. Nevertheless, all of the company’s oncology work is consolidated in a new Therapeutic Area Unit [TAU] still based here in Cambridge. The TAU proposes the strategy, sets investment priorities and manages R&D projects for its designated area according to budgets approved in Tokyo. It was felt that with such a critical mass of expertise here, Cambridge would be the best place to execute while benefiting from the scale and efficiencies derived from managing globally.

With reference to the relationship between my commercial responsibilities and our science and clinical development colleagues, our work served as precedent for what Dr. Yamada is trying to do for other therapies, through the new TAUs. Millennium always depended on a team-based approach; we paid little attention to reporting lines. I meet every two weeks with colleagues in the R&D operation to address all the key strategic decisions, from business development, to stepping up the pace in a clinical program, to brand planning for Velcade. I just spent two days with them going through our budget submission; Takeda, like all Japanese companies, operates on the basis of an April 1 fiscal year. The key point is we do it all as a team. In oncology, you really get to know the people you work with, because product development does not cease when the product is approved. That’s actually just the start of a necessary relationship between clinical and commercial that endures right to the end of the product cycle.

PE: The ascent to the “c suite” is not exclusively the result of hard work. Culture, personality – and, yes, luck – are often more important determinants. Can you describe how you handled some of the transition points that led you to the position you hold today?

Protopapas: I was born and spent my childhood in Cyprus, in the midst of a civil war. It was my earliest formative experience, teaching me that nothing should ever be taken for granted. My parents lost everything and the cold reality was such that I had no choice but to take risks. The experience shaped both my personal and professional life, expressed in a mindset that makes me very open to change and to trying new things.

Luck was also an element. After deciding to leave Cyprus, I applied for a US government scholarship to attend university here, but found I was disqualified for having a working mother. What happened next is an example of that random act of good will that you think only happens in the cinema: a staffer at the US Embassy in Nicosia glanced at my application, invited me in to meet him, and then at his own behest helped me file applications independently to a number of US universities, adding in his own – and entirely unsolicited – letter of recommendation. This led to my admission to Princeton as a scholarship student. I never saw that man again, but I would not be here today had he not seen something in my application that induced him to make this extraordinary effort to help me when I needed it most.

The immigrant experience has prodded me to embrace change at crucial stages of my career. After graduate work in engineering at MIT and Stanford, I worked for many years in the engineering business. But I wanted more exposure to smaller start-ups in growth industries. I became interested in pharmaceuticals after meeting the founder of Millennium, Dr. Mark Levin, who sold me on his vision of a future in which the mapping of the human genome would transform biology and create an entirely new class of medicines to treat incurable diseases. Science in the pursuit of a social mission appealed to me, so when he offered me a job I took it, even though a small voice in my head cautioned that Millennium was not yet a sustainable business; my job, as is the case in many start-ups, would require me to make it up as I went along. That was 1997, and I have been here ever since.

PE: You made your mark at Millennium by building the business development function, which led ultimately to the assignment from Takeda President and CEO Yasuchika Hasegawa to manage this function globally and to oversee the acquisition of Swiss-based Nycomed. What learnings can you share from your many years on the front lines of pharma licensing and M&A?

Protopapas: Business development has been critical to the growth of Millennium and is also a high priority for Takeda as it seeks to become more global, so throughout my career in both companies I have never been far from the center of decision-making. Prior to the merger with Takeda, I led numerous discussions on partnerships, which were pivotal to Millennium’s pipeline strategy. This resulted in Takeda CEO Hasegawa asking me to run business development for the entire company, a position I accepted because achieving the vision of globalization depended on a well executed acquisition strategy. Again, it was not without risks, as I was aware of being the first non-Japanese executive to supervise this important activity. Since then, in addition to purchasing Nycomed, we have acquired five other companies.

These acquisitions have literally changed the face of the company. While Takeda was clearly innovative, it lacked the global commercial infrastructure necessary to bring these innovations forward to more patients. Plugging this gap became our priority objective. Subsequently, we identified Nycomed as an acquisition target because it had strong commercial roots in Europe and the emerging country markets, areas where Takeda was weak, without duplicating our strength in the US and Japan.

Nycomed proved to be a more complicated transaction than we had anticipated. It took six months of very intense negotiations requiring extensive due diligence because Nycomed was a private equity operation. We had to move step by step to compile the evidence to secure internal – and external – support for the transaction. I knew we had to build a story that allowed others in both organizations to reach the same conclusion about going forward, on their own, especially in light of Takeda’s consensus based decision-making. This was different than the top down stance of simply saying “we’re doing this, so get on board.”

The inclusive approach strengthened my conviction that the acquisition would create two productive synergies. The first was the cost and efficiency gains. These have been completed and the savings have far exceeded our expectations. The second is “top line” enhancements from the expansion and redesign of commercial infrastructure, moving Takeda products through the Nycomed distribution channels, and vice versa. This is still a work in progress, but as more new products come on stream, the value of a bigger development, sales and manufacturing network is going to become apparent.

PE: How has culture influenced the combination between Millennium and Takeda? Japanese companies are notoriously insular, which some experts cite to explain why its pharma sector has failed to seize the market potential that exists beyond the domestic base.

Protopapas: Awareness of company culture is vital in making any combination a good fit. I think the addition of Millennium to the Takeda family is proof that culture can be a dynamic, flexible and adaptive tool – one that actually makes it easier for large organizations to cope with disruptive change. Takeda has a history that goes back 230 years, where it began selling Chinese herbal products, followed by its move to Western-style medicines early in the 20th century. The point is that age is not a barrier to change, especially when management has the confidence to rely on that strong culture to acknowledge the need for a different way forward. Hasegawa is himself the symbol of a confident company culture, having been chosen by the Takeda family as the first outsider to head the business. His mandate has been to refresh the corporate brand —and to make Takeda a young company once again. Over the past five years, he has put the company on a clear path to global player status by acquiring Millennium and Nycomed; realigning sales strategy in the US, dissolving the TAP venture; and recruiting and empowering dozens of non-Japanese executives like me. The result is that diversity is now an ingrained part of Takeda’s culture. In fact, Takeda is positioned to be led by a French citizen and former GSK executive, Christophe Weber, who is our new COO as of April 1 and is expected to be named President when Hasegawa relinquishes that position in June 2015.

PE: Can you outline your key management goals for Millennium over the next three years. What will the organization look like then, as a consequence of your leadership?

Protopapas: I am very optimistic about growing the business by delivering on our pipeline of new products, where we have 15 candidates, nine of which are at the final Phase-III stage of testing. Millennium Takeda is emphatically no longer a one product company. MLN 9708 [ixazomib], the first all oral combination treatment for treatment of relapsed and previously untreated multiple myeloma, is performing extremely well in three Phase III trials, in relapsed/refractory multiple myeloma, relapsed/refractory amyloidosis; and previously untreated multiple myeloma. It stands out as a worthy complement to Velcade and promises to extend our myeloma franchise well into the next decade. Hence I see a successful launch here in the US and other key international markets as a critical milestone for us. Overall, taking the success of Adcetris for Hodgkins lymphoma into account, Millennium will continue to have a dominant market position in treating hematological malignancies. And I expect that Adcetris will deliver additional indications as it is taken up in the market, just like Velcade.

A second priority for me is to motivate and energize our commercial teams through ever closer engagement with Millennium’s R&D operation. One of our key assets is the clarity and focus that we place on our science, where we seek leadership in medicines aimed at the biological pathways cancerous tumor cells rely on to survive and multiply. It’s a commitment easily understood. And that commitment will not change.

Finally, partnerships remain a central element in our growth plan. Takeda as more than 20 such tie-ins underwahy, ranging from the formal licensing of products and technologies to providing seed money to academic enterprises. There are fewer surprises in store when you work with us; this is an important factor for the smaller biotechs and academia. Last year, we initiated a very innovative collaboration called the Tri-Institutional Therapeutics Discovery Institute with three academic institutions in New York – Memorial Sloan-Kettering Cancer Center, Rockefeller University, and the Weill Cornell Medical College. The focus is to investigate early stage compounds to produce useful “proof of concept” studies that will identify specific biologic pathways and favorably alter the course of a disease, not just for cancer but other conditions as well. Takeda is sending some of our best chemists in Japan to work with the biologists around this very open-ended agenda, one that minimizes all the legal pre-conditions, paperwork and reporting that usually permeates these arrangements.

PE: Are there potential “disruptive innovations” that pose a threat to the business plan and might require a change of course?

Protopapas: The science behind cancer is progressing rapidly. The more we know, the more complex are the challenges facing our researchers. Keeping pace will demand a significant augmentation of resources, both human and financial. That is something that keeps me up at night. Nevertheless, it is a truly exciting time to be in this business. There are byproducts from the expanding knowledge of biologic pathways to cancer, such as protein homeostasis, where controlling protein replication in the cell can inhibit malignancies. Immunotherapy is another promising field, with progress occurring after many years of dead ends. Our studies on Adcetris have sparked interest in toxin-conjugated antibodies and other highly targeted therapies linked to individual mutations. Whether any of these initiatives will yield that “silver bullet” is unclear right now, but with commitment and a lot of luck the scenario could change dramatically.

PE: Millennium is driven by the search for innovative new treatments. What message do you have for governments and regulators in helping you to better deliver on this mission?

Protopapas: Two messages stand out. First, innovation begins with the basic research conducted at the major academic teaching institutions. Academic research is vital to oncology because so little is understood on how cancer cells grow and mutate to where they become resistant to current therapeutic interventions. The goal post in cancer is always moving. Research has to keep pace. Second, patient access to new treatments depends heavily on the commercialization of basic research. Society must be sensitive to the incentives that compensate for the cost of moving compounds forward to the point where they can be certified as safe and effective for human use. Appropriate reimbursement prices facilitate access to patients, which in turn generates evidence that can demonstrate a positive health outcome. If it is not economically feasible for companies to invest in this process, innovation will dry up.

PE: There is a difference of opinion on what is “economically feasible.” How do you overcome the views of some stakeholders that pharma companies are profiteering at the expense of payers and patients?

Protopapas: My response is to return to the fundamental premise of our business mission – to evidence better outcomes for patients. Our robust development program that generated Velcades’s approved label has a tangible, justifiable impact on the patient: who could say Velcade is not worth paying for? Conversely, if a company brings to market a fifth in class medicine that carries no evidence of a differentiated value proposition, then I think it appropriate to ask why it deserves a premium price.

William Looney is Pharmaceutical Executive’s editor. He can be reached at mailto:wlooney@advanstar.com