EXECUTIVE INTERVIEW – SDP Oncology: Uncovering New Biology
In recent years, the oncology community has seen a shift in understanding how the immune system interacts with cancer cells. Researchers have learned that people’s immune systems may help fight cancer, as evidenced by the approval of multiple immune checkpoint inhibitors. While these drugs have revolutionized the treatment of cancer for some people, they don’t work for everyone. As one of its many areas of focus, Sumitomo Dainippon Pharma Oncology, Inc., a wholly-owned subsidiary of Sumitomo Dainippon Pharma Co. Ltd. based in Japan, has been committed to learning why some people benefit from immune-targeted agents and others do not. Through this research, the company has discovered that the tumor microenvironment plays a crucial role in the immune response to a tumor. David J. Bearss, PhD, Chief Scientific Officer and Global Head of Research* at SDP Oncology recently spoke with Drug Development & Delivery about the company’s unique structure that has supported its robust research in the tumor immune microenvironment as well as its investigational assets being studied in this space.
Q: What is SDP Oncology’s business model and what are the benefits of being a wholly-owned subsidiary of Sumitomo Dainippon Pharma?
A: We are a global oncology-focused company that is dedicated to developing novel cancer therapeutics that will make a meaningful difference in the lives of patients with cancer. Our efforts encompass moving programs from very early drug discovery through clinical development and commercialization. Often, big companies acquire smaller companies and then integrate them into the parent company. Recently, there’s been a movement towards keeping the smaller companies more independent, which allows the smaller company to maintain its culture, environment and nimbleness while having the infrastructure, financial support and value that comes from a large organization. You have the best of both worlds.
In addition, we have the power that comes from being in multiple geographic locations. We have research and development teams in Japan that are part of this new oncology focus. From the research side, it’s exciting for us to think that all day, every day, there’s someone working on these programs. Cancer doesn’t sleep and neither should we. SDP Oncology is always working on our programs and there is constantly somebody actively pushing forward the research behind them.
Q: SDP Oncology is a company with multiple platforms. What does this mean for your portfolio and the types of novel drugs you are discovering?
A: Because we have a multitude of drug modalities – the technologies that serve as the platform – we are not limited to the types of targets that we can pursue. I’ve always been a believer that we will follow the best biology that’s available to us. Having multiple drug modality platforms gives us access to technology that allows us to pursue any target that we think is novel and has potential. We have access to a number of drug delivery technologies as well as several approaches for target engagement. We are not constrained to just small molecules, for example. We have nanomedicine technology that allows us to change the pharmacokinetics and distribution of a drug. We have peptide conjugation technology, aptamer technology, antibody-drug conjugate technology, biomolecule conjugates and polymer conjugates, just to name a few. The proprietary technology that exists within SDP Oncology doesn’t put any limits on us with respect to pursuing biology that we find interesting.
Q: Can you describe SDP Oncology’s focus on the tumor immune microenvironment and why it is important in creating novel oncology drugs?
A: Over the past several years, there has been a shift in understanding how the immune system interacts with cancer cells. The immune checkpoint inhibitors that have been approved are among the most successful oncology drugs that we have in our arsenal today. The oncology community has discovered that our own immune system is probably the best medicine we have in fighting cancer. These drugs have been revolutionary and provided benefit for a lot of people, but they don’t work for everybody. As we’ve tried to understand why it is that some people benefit from immune-targeted agents and others do not, we’ve discovered that the microenvironment of the tumor is important.
Most tumor cells interact with the surrounding normal cells, what is called the “tumor microenvironment,” and these interactions are critical to the survival of the tumor. The cancer cells influence the cells they interact with, and that microenvironment determines if a patient will respond to an immune-targeted agent. We’ve been trying to understand what targets exist, both on cancer cells and non-cancer cells, that create an immune microenvironment that competes for resources in the tumor. We want to target the right biology that will change that microenvironment and the behavior of both the cancer cells and the immune cells within the tumor to activate an immune response.
Q: What strides has SDP Oncology made in studying the tumor immune microenvironment?
A: We’ve identified a number of new targets that we think are crucial in modulating interactions that immune cells have with cancer cells. It’s been such a dramatic change in the way that we develop drugs. In the old days, therapeutics were focused on just killing cancer cells or putting those cells into a more sensitive state so that they can be either targeted with a single agent or in combination with different types of therapy. The new biology that we are trying to uncover might not necessarily have a direct effect on the cancer cells. In fact, they may not kill cancer cells at all, but they change that microenvironment. It is challenging as a drug discovery research group to develop the right systems, the right assays, and the right models to test these types of agents. Most of the models that we use preclinically are focused on killing cancer cells and shrinking tumors that are grown in animal models. We’ve had to change those model systems to assess mechanistically what new agents are doing.
Q: Can you describe dubermatinib and its role as an AXL kinase inhibitor and the role of TP-1454 as a PKM2 activator, within the context of the microenvironment?
A: Dubermatinib is a compound we discovered in a model system that involved the zebrafish. We used the fish as a screening tool to look for a very specific biology to target the AXL protein. AXL is a receptor expressed in many cells in our body and it is responsible for sensing cell damage and cell death. When it gets activated in tumor cells, it changes the behavior of these cells, making them less differentiated, more aggressive and resistant to therapy. We refer to this state as the “mesenchymal phenotype.” We screened thousands of compounds and found that dubermatinib was the only one – in this particular model – that can reverse this mesenchymal change. AXL kinase is a tumor immune microenvironment target because not only does the cancer cell express the protein, but so do the surrounding immune cells. When activated in immune cells, it changes their behavior and makes it harder for the body to mount an immune response against the cancer. Dubermatinib has a specific effect on the cancer cells, changing this aggressive behavior, and targets the immune cells at the same time by pushing them into a more responsive state to mount an appropriate immune response against the cancer.
TP-1454 is another compound unique in its biology. Almost every drug inhibits protein activity. In this case, our drug is an activator of the PKM2 protein. PKM2 is a metabolic enzymatic “switch” that gets turned on in cancer cells. As cancer cells become more aggressive and the tumor starts to grow, the tumor changes its metabolism and its ability to utilize different types of nutrients to adapt to the changing environment in which cancer cells find themselves. PKM2 is expressed but it’s not a very active enzyme, which is of metabolic benefit to the tumor cells. TP-1454 makes this enzyme become highly active, shifting the metabolism of the cancer and starving it of certain essential building blocks necessary for growth. For years, we thought a characteristic distinguishing cancer cells from normal cells was the metabolic requirements and changes that occur during tumor formation. If you could exploit these differences, it could serve as an Achilles heel for those cancer cells. Unfortunately, as industry tried targeting these metabolic pathways, the cancer cells were quick to adapt to the changing environment. PKM2 looked like an attractive target. As we started to think about this target in the tumor immune microenvironment, we questioned whether other cells inside the tumor express the enzyme and what happens to those cells. While we know cancer cells can adapt, normal cells are restricted in what they can do. It turns out the normal immune cells inside the tumor are competing with the cancer cells for resources. To mount a reaction against the cancer, you have to take off the ”brake,” which is the immune checkpoint. But there also needs to be fuel for immune cells to proliferate quickly, in terms of energy production. It turns out that access to fuel is suppressed in the tumor immune microenvironment, in part through PKM2.
Q: Are you saying the AXL inhibitor and the PKM2 activator work together in the tumor immune microenvironment?
A: We developed them separately to target very different pathways. It’s possible these compounds may work in combination with existing agents, which we are evaluating. It’s challenging to develop two novel drugs at the same time. If we are looking at combination activity, we will take an already approved therapeutic and combine it with the new compound. It’s easier to study that because the approved drug has been validated in terms of efficacy and safety. There may be opportunities in the future to develop two novel drugs for combination at the same time.
Q: What is the status of these assets in clinical development and what can you share about the results of preclinical studies?
A: TP-1454 has an active IND and will move forward with the first-in-human study, which is just getting started. It’s a first-in-class compound that we hypothesize will change the metabolic microenvironment of the tumor and make it more permissive to an immune response. We’ve shown in animal models that treatment with TP-1454, which activates PKM2, in combination with an immune checkpoint inhibitor, produced a dramatic response. We are excited to see what happens in the clinical studies.
Dubermatinib just completed a Phase 1 study where we treated over 150 patients. Half of the patients were part of the dose escalation evaluation where we determined the safety and the maximum tolerated dose of the drug. We did an expansion from the dose escalation study to explore specific tumor types. We examined biopsies from some of the patients in this expansion study before they received treatment with dubermatinib and then took another biopsy after. We can use these to determine changes not only in the tumor, but also in the tumor microenvironment. We have analyzed these data and they were presented at ESMO 2020 Virtual Annual Congress. This data showed that dubermatinib produced changes consistent with AXL inhibition and will help us design the next clinical study as we move this program forward.
Q: Are you targeting specific cancers?
A: Every cancer is unique from a genetic and mechanistic standpoint. We are interested in identifying the characteristics of an individual patient’s cancer that make it susceptible to a specific therapy. Most cancer types, like breast cancer, share some common characteristics, so we do a lot of drug development around specific tumor types. We are also trying to group cancer types that are similar to one another at the molecular or mechanistic level. We have some ideas on why certain kinds of cancers may be more susceptible to treatment than others and we are trying to validate those quickly in early clinical development to set a clinical development path that will be most effective. We want to deliver therapy that will be as effective as possible for the individual. We also want to develop tools to identify those patients who will respond to particular therapies.
Q: What are your feelings about licensing these drug assets or working with partners?
A: Partnerships can be opportunistic if it makes sense from a development and commercialization standpoint. Part of our strategy in the short term, as programs mature, if appropriate, may involve looking for partners to address different parts of the world where we don’t yet have a presence. Part of my goal leading the research team is to develop our programs internally and to look for partners on specific programs that may not fit our clinical development strategy.
*Note: This interview was conducted before Dr. Bearss made the decision to leave his role as Chief Scientific Officer and Global Head of Research at Sumitomo Dainippon Pharma Oncology and return to academia at the University of Utah. Dr. Bearss will remain at the company as a member of its Scientific Advisory Board.
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