By Wayne Koberstein, Executive Editor, Life Science Leader magazine
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Astellas has placed a big emphasis on oncology this year, pointing to its many assets, particularly in targeted therapies that are later stage, but also focusing through partnerships on immuno-oncology (IO). A conversation with Drs. Steven Benner, head of oncology, and Peter Sandor, head of oncology marketing strategy, follows.
WHY THE PRIMARY EMPHASIS ON ONCOLOGY? WHAT IS THE THINKING BEHIND THAT STRATEGY, BOTH NEAR-TERM AND FAR-TERM?
BENNER: Oncology is our largest therapeutic area and it’s the area of our greatest investment right now. That’s really because of the emerging clients and the opportunities to create important medicines for patients. Astellas has been in a number of other therapeutic areas based on its legacy companies, but for its future growth and the opportunity to create value for patients, oncology will be critical.
What we’ve done as a company is to try to build a broad portfolio of therapeutics for both hematology and solid tumors. We’re looking for innovative science, and we’re willing to do a variety of different kinds of deals or collaborations to obtain it, trying to find areas of excellence that we can bring into the company.
WHICH PRODUCTS AMONG YOUR ONCOLOGY ASSETS DO YOU NOW CONSIDER MOST IMPORTANT IN LEADING YOUR AREA STRATEGY?
BENNER: We have a combination in our pipeline of internal and external assets. Gilteritinib is in Phase 3 for AML that targets the tyrosine kinases FLT3 [FMS (McDonough feline sarcoma)-Like Tyrosine Kinase 3] mutation and AXL [from the Greek “anexelekto,” uncontrolled]. That’s an example of a drug that came out of our internal research at Tsukuba, Japan. We also have an antibody-drug conjugate (ADC) called enfortumab vedotin, which came from our fully owned subsidiary, Agensys, which was brought on as part of Astellas in order to allow us to be in the antibody space and to focus on antibody-drug conjugates. That’s just reached proof-of- concept, showing single-agent responses in patients with liver metastases, previously exposed to checkpoint inhibitors. That’s a partnership codevelopment with Seattle Genetics, who had the original technology for the ADC. We completed an acquisition of Ganymed Pharmaceuticals [Note: German company] in December last year, giving us access to the biology around the claudin molecules and a lead antibody called IMAB362, which appeared to be very active against gastro-esophageal cancer in a presented Phase 2 study called FAST, which triggered our interest at Astellas.
WERE YOU ATTRACTED BY THE RESULTS IN GENERAL OR IN THE PARTICULAR INDICATION?
BENNER: Gastro-esophageal cancer is very difficult to treat — the outcomes are poor. To have a new therapy that, combined with chemotherapy, could significantly improve survival would be a very important advance. Based on expression of the target, IMAB362 is also a therapy being developed in pancreatic cancer. Ganymed also brought to us another earlier stage antibody, IMAB027, in development for ovarian cancer with a completed Phase 1 study. There are also research programs in earlier preclinical stages.
YOU SAID YOU WERE LOOKING AT ALL SORTS OF COLLABORATIONS TO BRING INNOVATIVE SCIENCE INTO THE COMPANY.
BENNER: We have a collaboration with MD Anderson around an antibody for treating AML and ongoing collaboration with Potenza Therapeutics in Cambridge focused on immuno-oncology. Through the Potenza collaboration, we’ll be putting two IO drugs into the clinic this year. The second IND (investigational new drug) will be for a novel antibody that regulates T cells to change the response of the tumor microenvironment. With that program, we’ve already identified a lead for the third antibody, but that won’t come into the clinic until after that.
YOUR CURRENT ONCOLOGY ASSETS ARE MAINLY MOLECULAR TARGETED DRUGS OR ANTIGEN-TARGETING ANTIBODIES. DO YOUR NEWER IMMUNO-ONCOLOGY ACQUISTIONS SIGNAL A RECOGNITION OF IO AS THE NEW LEADER IN CANCER THERAPY?
SANDOR: During the current period, while IO is still developing, we are still in a good position with technologies and assets that can deliver a very significant increment of benefit for patients and the healthcare system. Our product XTANDI (enzalutamide), introduced in 2012, is now used worldwide in treating prostate cancer. It has become the most frequently prescribed drug in the urology segment. Meanwhile, immuno-oncology has struggled to find an effective application in prostate cancer.
DESPITE THE PROBLEMS OF TARGETED THERAPY SUCH AS DRUG RESISTANCE AND TUMOR HETEROGENEITY, TARGETED DRUGS WILL BE ON THE FRONT LINES AT LEAST UNTIL IO CATCHES UP. BUT DO YOU SEE IO EVENTUALLY BEING THE STANDARD AND OTHER TYPES OF THERAPY SUPPORTING IT?
SANDOR: Not in prostate cancer, not in the near term. The T cell mechanism is definitely one that needs to be solved, but the long-term outlook is probably the same standard of care with some modifications and combinations within the same class. As we’re thinking about our development for the agents that don’t specifically work through an IO mechanism, there is a place, such as bladder cancer, where we know that enfortumab vedotin produces responses in patients who have been exposed to a checkpoint inhibitor — including patients with liver metastases, which is a very poor prognostic group. At the same time, especially as our own pipeline continues to mature, we’re also thinking of combining our IO agents with other novel IO approaches.
CO-STIMULATION IS ONE OF THE PATHWAYS THAT YOU WANT TO EXPLOIT.
BENNER: Right. We have a variety of approaches at the basic research level, looking at emerging technologies. As we see how the field evolves, and our own internal capabilities and our collaborations evolve, we’ll continue to pick areas that we want to focus on for a more in-depth kind of concentration.
The concept of the disease is very interesting right now because, typically for decades, really since cancer started being diagnosed and treated, we focused on the tumor, the organ of origin. Now we’re increasingly characterizing these tumors, so we know our AML drug will be really important for patients with a FLT3 mutation. It is only a minority of those AML patients, but for them targeted therapy may be more effective.
Ultimately, to characterize the individual patient’s tumor from a genetic standpoint and then pick the most effective treatment combinations would make the most sense, and it will be a powerful way to use these therapies going forward. We’ll increasingly see a trend toward more personalized medicine in cancer.
IS THAT THE DIRECTION YOU ARE TAKING WITH YOUR PARTNER PFIZER IN THE CONTINUED DEVELOPMENT OF XTANDI?
BENNER: Yes. Just in the past year, additional studies in prostate cancer were added to the label to better inform physicians about patients and about the characteristics of XTANDI. We have other studies going on in prostate cancer eventually to bring into earlier patient populations. We’re also studying XTANDI with Pfizer in early stage and other prostate cancer subsets. We are looking every place where it makes sense scientifically to see whether there could be a benefit from the drug.
A BIG PHARMA PARTNER LIKE PFIZER PROBABLY ALSO HELPS YOU ANTICIPATE MARKET NEEDS AND DEMANDS AND ADJUST THE DRUG’S DEVELOPMENT ACCORDINGLY.
SANDER: We are equal partners in the United States, and there is a continuous cooperation and exchange of experience between the two companies. We are producing the strongest strategies possible out of our combined teams.
WHAT ARE SOME OF THE KEY CHALLENGES IN PERSONALIZING CANCER TREATMENT, OUT IN THE REAL WORLD?
SANDER: It makes our job more complicated, in development and everything that follows. For a long time and until recently, oncology development and commercialization were relatively straightforward based on scientific knowledge of the drug candidates. Now there are many more products coming to the market. They are more complex. They may require physicians to select patients for particular treatments, often sequential regimens, based on disease biomarkers. Educational challenges are much higher, not only with physicians and providers, but even on the payers’ side.
HOW DOES PERSONALIZED MEDICINE AFFECT THE CUSTOMARY PRACTICE OF OFF-LABEL PRESCRIBING IN ONCOLOGY?
BENNER: In the United States, oncologists have always prescribed off-label. We’ve also seen rapid uptake in the United States without promotion based on quality scientific publications or presentations. Regulatory agencies also have worked with us to bring new therapies forward with accelerated approval standards, surrogate endpoints, and many other mechanisms. It’s important to remember, however, that Astellas only promotes its product for approved indications. Pricing and reimbursement issues will have an impact for some of these therapies.
PFIZER AND OTHER BIG PHARMAS HAVE TAKEN A LOT OF HEAT FOR POOR R&D PRODUCTIVITY IN THE PAST COUPLE OF DECADES; ARE SMALLER COMPANIES JUST BETTER SUITED FOR NEW-DRUG INNOVATION?
BENNER: What we’ve seen is that larger companies cannot sustain themselves and grow based solely on internal research. Our internal research is productive — it has produced gilteritinib, it has produced enfortumab vedotin along with Seattle Genetics — and we believe it’s important to have core capabilities internally in research. But the science is emerging pretty rapidly, and we’re interested in a variety of different things, and it’s just not feasible for a company to be in all the areas that require such expertise. We have used a variety of strategies to work with the best people, to gain access to the best science and most innovative approaches. Similar to our collaboration with MD Anderson, we have an earlier program at Dana Farber around the KRAS [Kirsten ras] oncogene. We’re also working with other universities around the world, including Japan, to harness some of this great science that’s coming out of academics. We’re also working with startups like Potenza that are focused on producing antibodies in immuno-oncology — carefully defining what they want to do and focusing on that. Companies of that kind are often very productive, and by picking the most productive ones, we can develop an entire pipeline supplemented by our internal research. It will be necessary for us to be innovative in how we structure partnering deals, to continue to be competitive. Obviously, in the oncology space, there is now a tremendous amount of interest from basically every company with significant science.
SANDOR: This also goes beyond oncology; at Astellas, this is the corporate strategy. Putting these external innovation networks in place to supplement what we have internally was a conscious decision. It extends to partnerships with startups, academia, and other players in the field. It is part of the company’s long-term innovation strategy.
IS ASTELLAS STILL A JAPANESE COMPANY?
BENNER: It’s a global company based in Japan. They really did something pretty remarkable in the first place by creating Astellas through the merger of two legacy Japanese companies, one of which was over a century old. They did a successful integration and then decided to set up headquarters in Northbrook, outside of Chicago, to do global development. Many of our shareholders are outside of Japan now, and we also have aspirations to do global sales.
THAT IS QUITE A CHANGE — FROM THE TRADITIONAL TO THE GLOBAL STAGE — AND NOW PUTTING A RELATIVELY NEW ONCOLOGY FRANCHISE IN THE POSITION OF GROWTH LEADER.
BENNER: Neither of the legacy companies was focused on oncology, though they were tremendously strong in transplant and infectious disease. Medicinal chemistry was a great strength for both companies. After the merger, the company looked forward to the future, and two observations really catapulted oncology into the center: the explosion in the science itself and, more importantly for a developer, the ability to start translating some of those scientific observations into meaningful therapeutic approaches.
WOULD YOU SAY THE DIALOGUE BETWEEN COMPANIES AND ACADEMIA IS IMPROVING? IT HAS ALWAYS BEEN A BIT OF A CHALLENGE.
BENNER: I would say yes. Academic centers have become more focused and sophisticated in how they interact with industry. Industry has hopefully become more sensitive to where the development opportunities and needs are. It is hard for an academic researcher with great science and maybe preclinical models to take the next steps into human investigation and clinical trials, not the conduct but the regulation of them. That is where we can help. By identifying those synergies, where the academic science and our industry skills match precisely, we can do a better job of working together.
HOW CRITICAL IS MANUFACTURING FOR CLINICAL TRIALS AS A DEVELOPMENT SKILL?
BENNER: It is surely critical. With a small molecule, typically our chemists and our technology folks can produce as much as we need, and it’s pretty cheap for them to do the manufacturing once the synthesis is well understood. But when we start moving into antibody therapies, the timelines obviously go way out, and the costs for the antibody are probably as great as total costs for all of the early clinical trials in first part of Phase 1. Now, with patient-specific therapies or cell-drug therapies, quality and manufacturing for clinical trials will become critical for companies to be successful.
Reshaping Astellas R&D
Sef Kurstjens, M.D., Ph.D., chief medical officer, heads pharma global development at Astellas. Here, Kurstjens gives a brief summary of the changes the company has made to the R&D organization and its current strategy.
KURSTJENS: About 2005 onwards, there was an express intention in Astellas to define our legacy. What do we want to be going forward? But we realized the research organization needed to continue evolving, so we embarked on a process of reshaping research, starting with the organizational structure. It had been a very line-driven organization, and we made it more therapeutic-area focused, thereby empowering the people deeper in the organization. The therapeutic-area focus actually provides a much better continuity of connection between research, development, and commercial through strategic teams.
Our second insight was, we were a great performer in immunology and urology, but we needed to continue to expand our focus. We subsequently decided to move into muscle disease, ophthalmology, vaccines, and regenerative medicine. We embraced the changes happening right now in new technologies, and we embraced open innovation. We put together the Astellas Innovation Management Group, which now has offices in Boston and San Francisco, because we want to partner with academia as well as biotechs. Our scientists in Japan have coined the phrase: “Best science, best place, best time.”
Our therapeutic areas can be synergistic. Our deal with Cytokinetics gives us access to its fast skeletal muscle troponin activators, which have broad potential applicability in conditions such as COPD, general wasting, and cachexia in cancer. We look to apply technologies across different areas as appropriate.
Overall, we have focused on therapeutic areas, new modalities, and external innovation. We also know we need to maximize the value of the products we currently have — meaning, maximize their value for patients. We have our drug enzalutamide for prostate cancer, and as we expand its use to as many prostate cancer patients as is appropriate, we are driving it further, looking at other antigen-driven cancers. We also focus on productivity, and in the majority of cases, we will invest to determine whether we have value as quickly as possible because, sadly, this is a business of failure more than a business of success. At the same time, we’re going to place some bets where we see the need is high, and the rationale is really good.