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2019/11/08

The Prostate Cancer Foundation: A Tireless Worker and Voice in the Development for Better Treatments

Prostate cancer is the second most common cancer in men.It is a cancer that occurs in the prostate — a small walnut-shaped gland in men that produces the seminal fluid that nourishes and transports sperm. While some types of prostate cancer grow slowly and may need minimal or even no treatment, others are aggressive and can spread quickly. Prostate cancer that’s detected early, when it’s still confined to the prostate gland, has a better chance of successful treatment. But malignant growths can be a threat to life as they can spread to nearby organs and tissues, such as the bladder or rectum, and can also metastasize to other parts of the body like lymph nodes or bone. Although it can be removed, sometimes it grows back. Treatment side effects can lead to incontinence, erectile dysfunction, depression, fatigue, and infertility. WuXi AppTec Communications has been highlighting companies conducting novel research into different diseases, but another key to finding treatments for unmet medical needs are active disease research organizations and patient advocacy groups, which help provide financial support for research, provide useful patient information on how to get help, and represent the patients in an advocacy role. To coincide with a new WuXi AppTec series about prostate research, we spoke with Jonathan W. Simons, MD, President and CEO of the Prostate Cancer Foundation (PCF), for an overview about the current state of prostate research and the pathways to future treatments and cures. Dr. Simons is an internationally recognized physician-scientist, oncologist and acclaimed investigator in translational prostate cancer research. Prior to joining the PCF in 2007, he was Distinguished Service Professor of Hematology and Oncology at the Emory University School of Medicine and Professor of Biomedical Engineering and Materials Sciences at the Georgia Institute of Technology. Dr. Simons is the Founding Director of the Winship Cancer Institute at Emory University in Atlanta and Co-Director of the National Cancer Institute Center for Cancer Nanotechnology Excellence at Emory and Georgia Tech. WuXi AppTec: What progress has been made in diagnosing and treating prostate cancer since the founding of the Prostate Cancer Foundation (PCF) 25 years ago? Dr. Simons: The PCF has supported the research leading to every major practice-changing advance against prostate cancer since its founding in 1993. This includes early research and development for nearly every life-extending drug approved by the U.S. Food and Drug Administration (FDA) for prostate cancer since 2004. Without a doubt, the prognosis for men diagnosed with prostate cancer at any stage has never been more encouraging. Recent advances enable men with prostate cancer to live longer, more productive lives – and when detected early through routine physical exams and minimally invasive blood tests, prostate cancer is nearly 100 percent treatable. Nearly 100 percent of men diagnosed with prostate cancer in the local or regional stages will be disease free after five years. Equally important is the fact that discoveries in prostate cancer now extend to saving lives in more than 18 other forms of cancer, including breast, myeloma, colon, lung, ovarian, melanoma, pediatric neuroblastoma, bladder, and thyroid cancers. Because the PCF is focused on precision medicine, we are funding research that targets cancers based on their genomic alterations and not the organs from which they came, and therapies that help men with metastatic prostate cancer have been shown to be effective in more than 73 other forms of human cancer. Over the last two decades, the PCF has worked tirelessly and effectively to promote public awareness about the disease to the reduction in the U.S. death rate from prostate cancer by more than 50 percent. WuXi AppTec: And as a follow up, there seems to be a lot of confusing advice coming from the community about what type of prostate testing is most effective. Can you comment?  Dr. Simons: The PCF has always stressed that the question of screening is a personal and complex one, and we believe in strategic and personalized screening. The decision to undergo routine prostate specific antigen (PSA)-based screening in men with a normal risk aged 55 to 69 should be an individual one that includes a discussion about the potential benefits and harms of screening. The PCF believes that every man should be able to talk with his doctor about whether prostate cancer screening is right for him. Additionally, it is the PCF’s position that for men with a family history of lethal breast cancer, ovarian cancer, or pancreatic prostate cancer in a first-degree relative, 40 is the age at which a conversation with a health provider to discuss the potential benefits and harms of prostate cancer screening should begin. In the African-American community, we encourage men at 45 to pay attention to their prostate health and prostate cancer risk and take the opportunity to talk with their doctors about the pros and cons of prostate cancer screening. Above all, the PCF believes there is no ‘one-size-fits-all’ approach to screening. We generally support the recommendation made by the United States Preventive Services Task Force against prostate cancer screening in men over the age of 70, although we acknowledge that this age-based recommendation may not be appropriate for all men over the age of 70 and advocate for a personalized approach that takes into account health, values, and preferences. WuXi AppTec: What are the hot targets today in the field of drug development for prostate cancer? Dr. Simons: Poly-ADP ribose polymerase (PARP) and prostate-specific membrane antigen (PSMA) are two of the “hottest targets” in the field of drug development for prostate cancer today. A study presented recently at the 2019 European Society for Medical Oncology (ESMO) Congress reported positive results from a Phase 3 clinical trial testing the PARP inhibitor olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) who have alterations in certain DNA damage repair (DDR) genes, a result which will likely lead to a new FDA approval. Roughly 20 to 30 percent of mCRPC patients harbor these DDR gene mutations in their tumors and thus may benefit from PARP-inhibition. This trial of olaparib is the first positive Phase 3 “precision medicine” clinical trial testing a targeted therapy in men with advanced prostate cancer with defined mutations. PARP inhibitors were first approved by the FDA as treatments for BRCA1/2-deficient breast and ovarian cancer in 2014. However, PCF-funded studies demonstrated that BRCA1/2 and PARP are also important in prostate cancer. Prostate-specific membrane antigen is a protein on the surface of prostate cancer cells, and is a compelling cell surface drug target. The PCF is supporting research into many new treatments for prostate cancer that target PSMA, including radionuclide therapy, a treatment that brings radiation directly to tumors, and chimeric androgen receptor (CAR) T cells, a form of personalized immunotherapy. Prostate-specific membrane antigen is also a very good target for PET imaging tracers, and PSMA-PET imaging has been demonstrated to be significantly more sensitive than current imaging methods for detecting sites of prostate cancer throughout the body. The PCF anticipates that PSMA-PET imaging will likely be FDA approved by 2020. WuXi AppTec: What are the prospects for treating the disease in its early stages? Will drugs ever be a substitute for surgery and radiation? Dr. Simons: Early potentially lethal prostate cancer if untreated can be cured by not one but two different modalities: radiation therapy or surgery. Eventually, the PCF believes most advanced prostate cancer can be intercepted when it is micro-metastatic and the total burden of cancer in a patient’s body is at its lowest number. If caught early, prostate cancer is 100 percent treatable. Early, strategic detection is thus so important. Early prostate cancer can be treated by not one but two modalities: radiation and surgery. Surgery and radiation therapy remain the standard treatment for localized prostate cancer. But other experimental treatment options have recently become available. As time goes on and the benefits of these treatment options are better understood, it’s possible that they may be reasonable alternatives for certain patients. For now, none of these are seen as standard treatment for localized prostate cancer because they lack support from large randomized clinical investigations in comparison with successful radiation or surgery. WuXi AppTec:  What are the regulatory challenges in evaluating early stage prostate cancer treatments? Dr. Simons: The process of discovering, developing, and delivering new therapies has myriad challenges. In order for the FDA to approve a new therapy, an improvement in length or quality of life due to the therapy must first be demonstrated in clinical trials. The “overall survival” (OS) endpoint, which measures the length of time from randomization to death from any cause, is the gold standard for measuring the impact of a treatment on length of life and the goal line for calling a new treatment curative. However, in localized prostate cancer, reaching an OS endpoint can require 10 to 15 years – a prohibitive timeframe for pharmaceutical companies. This fact has translated into only limited improvements being made in the treatment of early, aggressive prostate cancer in the last decade. For patients urgently awaiting treatments and cures, addressing these regulatory challenges is vital. For this reason, the PCF identified this issue as a critical unmet need, and in 2012, supported the establishment of a working group called ICECaP (Intermediate Clinical Endpoints of Cancer of the Prostate). Led by Dr. Christopher Sweeney of the Dana-Farber Cancer Institute, this is an international collaborative initiative to undertake the arduous task of identifying an intermediate clinical trial endpoint that can accurately predict OS but can be obtained much earlier in the course of the disease. WuXi AppTec: Is clinical trial participation by patients a challenge? If so, how does the PCF encourage participation? Dr. Simons: The first 1,000 men cured of incurable advanced prostate cancer will be in a clinical trial. The road to cures runs through clinical trials. The PCF is the go-to source for information about the latest investigational clinical trials driven by PCF-funded science. In addition to publishing the Prostate Cancer Patient Guide, a comprehensive health guide for prostate cancer patients compiled with the contributions of top-tier doctors and researchers in prostate cancer, PCF.org is the center for must-have resources for prostate cancer patients. It focuses all of the information available about contemporary prostate cancer research, treatment, lifestyle factors, and precision clinical trials. To further improve access to information that can improve outcomes by getting patients on “the right track” as soon as possible, the PCF has also launched a prostate cancer clinical trial finder in collaboration with Smart Patients. Because finding a trial can be confusing for patients, the PCF has custom-curated trials that may be specifically relevant to men with prostate cancer. The tool allows men to search based on their disease state, stage, and their geographical location. WuXi AppTec: What are researchers learning about the causes of prostate cancer? How is it different from other cancers? Dr. Simons: Over the past 25 years, more than 50 hereditary DNA mutations (genetic mutations that run in families) have been discovered that may increase the risk of developing certain cancers. The most famous that you may have heard of are the BRCA1 and BRCA2 mutations that increase risk for breast and ovarian cancer. Prostate cancer has long been recognized to have a familial component. In fact, of all human cancers, prostate cancer is the most common running by hereditary 57 percent among family members, with 40 percent of prostate cancer attributable to genes that run in families. If you have received a prostate cancer diagnosis, it’s important to speak with your family about risk, prevention, and screening. Having a father or brother with prostate cancer increases a man’s risk of developing prostate cancer. The genes that cause this risk have been extensively studied and are complex and need more research. WuXi AppTec: How does the PCF support research and drug development? Dr. Simons: The PCF is unique in its innovative approach to medical research funding. The PCF identifies the most promising “first-in-field” early research ideas and attracts brilliant individuals and teams of scientists early in their careers to the PCF’s Global Research Enterprise. By channeling resources directly to the world’s top scientific minds, the PCF is able to cut through red tape, speed scientific breakthroughs, and deliver new treatments to patients. The PCF funds a variety of different kinds of projects that vary in focus, scope, and duration: PCF Challenge Awards fund teams of scientists working on critical unmet needs for advanced prostate cancer; PCF Young Investigator Awards jumpstart research programs for early-career scientists and researchers; and, PCF researchers connect globally to exchange information and share scientific data in real time. Since its inception the PCF has been a pioneer in new drug development, providing key funding for FDA-approved treatments that improve survivorship. Having recruited more than 5,000 of the best physician-scientists in more than 21 countries, many of the most important discoveries in the fight against prostate cancer since 1993 have resulted from PCF funding or coordination. Thanks in large part to the work of PCF-funded researchers, the number of drugs approved to treat prostate cancer doubled – from just six drugs approved in nearly 30 years to another nine drugs approved in just nine years. Of those nine medicines, eight were FDA-approved because they actually prolong patients’ lives, rather than simply ease their symptoms. As of early 2019, there are now a total of 21 drugs approved by the FDA for treatment of prostate cancer, with even more in the pipeline. WuXi AppTec:  What are some of your most recent research funding efforts? Dr. Simons: Prostate cancer is the most frequently diagnosed cancer among veterans. In 2016, the PCF committed $50 million over five years to create Veterans Affairs (VA) Centers of Excellence that deliver innovative, best-in-class prostate cancer care to veterans. More than half of the PCF’s Precision Oncology funds have already been used to stand up ten Centers of Excellence and fund the research of numerous VA physician-scientists. The platform created by the PCF will be used to build Centers of Excellence for other cancers as well. WuXi AppTec: What is the best strategy for developing new prostate cancer drugs? Dr. Simons: Collaborative teams comprised of young scientists is the fastest route for research and development to end death and suffering from a disease. The contribution, or loss, of even the single greatest researcher, isn’t likely to make or break the attainment of a cancer cure. That achievement will come from the global community of a great team of researchers. These repositories of accumulated intellectual, physical, and financial resources represent the “social capital” of medical progress. The PCF has laid the cornerstone for at least four major social capital initiatives involving this community. The PCF has changed how research is funded to harness the power of teams. Our research awards are designed to attack major problems in prostate cancer biology and treatment by creating synergistic teams of individuals with diverse intellectual capabilities who otherwise might simply conduct isolated research in their own silos they require constant unpublished data sharing. The PCF began seeding this field with individual research awards in 1993. As traditional funding sources have picked up these programs, we’ve adopted a strategy of directing current and future PCF funding to more effective team science. This strategy has resulted in the formation of collaborative teams who are able to take research from bench to bedside rapidly.    WuXi AppTec: What are the top three impediments to delivery of better medicines, faster and cheaper to patients? Dr. Simons: Our greatest challenge of all of the many challenges is less than five percent of men with advanced prostate cancer participate in clinical trials. Our second challenge for advanced disease is that we still need to better understand how to stop prostate cancer cells from evolving in real time to become resistant to our new promising therapies. Cancer cell “evolutionary” resistance is the killing mechanism of fatal cancers. WuXi AppTec: What are your thoughts relating to focal therapy and prostate cancer? Dr. Simons: “Focal” therapies are treatments that target just a region of the prostate thought to have the tumor, instead of treating the entire prostate gland. None of these therapies have yet been proven in large randomized clinical trials to have the same long-term success as surgery or radiation therapy in clinical trials. Claims about them must be viewed with caution. They are still considered experimental treatments. The likelihood of recurrence is high with focal therapy due to the fact that in more than 60 percent of cases prostate cancer is actually “multi-focal,” meaning even if the biopsy and/or MRI showed the cancer to be in only one area, there is likely tumor in many areas of the prostate. WuXi Apptec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure in prostate cancer drug development? Dr. Simons: One of the most promising areas that has the potential to lead a paradigm shift from treatment to cure is the field of immunotherapy. Historically, the problem with curing cancer has been the uncanny ability of cancer cells to reprogram themselves after treatment and hide from the immune system. The promise behind immunotherapy is that when properly activated, the immune system has the potential to evolve as quickly as the tumor and seek out and kill tumor cells anywhere they are hiding in the body. In many types of cancer, immunotherapy has resulted in long-term remissions and even cures in patients with advanced metastatic disease who would otherwise have died from their disease. Numerous ongoing research studies and clinical trials are being conducted around the world trying to discover newer immune cell activations and optimize immunotherapy to treat the many forms of advanced prostate cancer.  

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2019/11/05

OncoSenX Developing New Gene Therapy Approach that Kills Cancer Cells by “Suicide”

Gene therapy faced many challenges in its early days, but scientific advances, drug approvals and millions in investment have accelerated research in the gene therapy field. WuXi AppTec Communications has begun a new series profiling some of the companies developing novel and unique approaches to making gene therapy even more effective in treating intractable diseases. One such company is OncoSenX, based in Seattle. OncoSenX believes “The next generation in cancer therapies will be more targeted with fewer side effects….and should be fought with genetic information.” The company is using brand new technology to develop transient gene therapies for solid tumors in cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal. WuXi discussed OncoSenX’s new gene therapy technology, and what this technology could offer in the future, with company CEO, Chairman and co-founder Matthew Scholz. A serial entrepreneur with a background in computer security and immunology, Matt is also the founder and CEO of Oisín Biotechnologies and former CEO of Immusoft, a biotech firm developing a breakthrough technology that will turn a patient’s B cells into miniature drug factories. He’s a graduate of the University of Washington and a frequent speaker at the UW School of Business. WuXi: The promise of gene therapy has been around for decades. How has gene therapy research progressed over the past 20 years? Do you anticipate a wave of new approvals coming over the next 5 to 10 years? Matthew Scholz: People have wanted to manipulate DNA ever since they knew what DNA was, of course – but as with any new technology, it took a long time for the field to develop. The last 20 years in particular have borne witness to extraordinary progress. They weren’t without challenging circumstances, of course: the 2000s began with the field reeling from the death of Jesse Gelsinger, a sobering event that would chill research and funding for some time, but most recently, we’ve seen the approval of several gene therapies, billions of dollars of investment and renewed excitement about what is possible. There are currently hundreds of gene therapies in clinical trials and I fully expect a commensurate wave of approvals in the future. WuXi: What kinds of diseases are targeted with gene therapies? Matthew Scholz: The first wave of treatments mostly targeted rare monogenic diseases, but now the field is largely dominated by oncology therapeutics. There aren’t many limits on what diseases could be treated with gene therapies, but given their expense and risk, today they are primarily focused on life-threatening or severely debilitating diseases. The gene therapies we’re developing have compelling advantages in these respects. They should be far less expensive to produce at scale. This is largely due to the fact that we don’t need to grow viruses and that it’s an off-the-shelf product with no ex vivo cell culture. Our therapies should be far less toxic than chemotherapies and more broadly applicable & scalable than CAR-T cell therapies. In many respects what we’re building can really be thought of as the next generation of I-O therapeutics. WuXi: What scientific advances are needed to make gene therapies more effective? Is delivery still one of the major challenges? Matthew Scholz: Despite therapeutic developers’ best efforts, delivery remains the Achilles heel of gene therapy. It is less of a challenge for ex vivo gene-modified cell therapies, but there are many tissues one cannot take out of the body to modify. Viruses – adeno-associated viruses specifically – are the primary way of delivering DNA in vivo, and they are fraught with problems. They are exceedingly expensive to manufacture at scales needed for systemic delivery in adults. They have a very limited DNA cargo capacity and they’re also immunogenic, so repeat dosing isn’t feasible. The emergence of a delivery vector that addresses these limitations would be a transformative development for the field. WuXi: Will gene therapies ever be commonplace? If so, how soon? Matthew Scholz: Maybe not commonplace in the near future, but certainly more common. I think we’ll continue to see people preferring pills containing small molecule drugs that can be taken easily and mass produced cheaply. With that said, I think we are approaching the limit of what small molecule drugs can do. The more we learn about human biology, the more personalized and targeted our treatments become. At the root of biology is the code of life – DNA – so one way or another, I think we’ll end up increasingly building treatments that manipulate genes and their expression. If we look further into the future, say 20-50 years, I think it’s possible that gene therapies will start to be used prophylactically and therefore become quite commonplace. WuXi: What are the risks and limitations of gene therapies? Matthew Scholz: The primary risk of gene therapies in general is an unintended integration event that leads to uncontrolled cell proliferation (cancer), though every treatment will have its own set of attendant risks. Some of the more significant limitations of today’s technologies are: the small payload capacity of the delivery vectors, inefficient transduction of the target cells (especially in vivo), immunogenicity of the delivery vectors and manufacturing constraints. WuXi: What gene therapies are you developing and how do they work? Matthew Scholz: We’re developing transient gene therapies for solid tumors – cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal. Our first therapeutics will directly kill cancerous cells with a suicide gene, whereas our second-generation treatments will also actively engage the patient’s immune system. This is a radically different approach than traditional cancer therapeutics or even other gene therapies for cancer. The data we’ve generated so far is really astounding! We can reduce the size of solid tumors in rodents by 90 percent with a single systemic IV injection without any detectable off-target toxicity. It’s also well-tolerated in non-human primates even at massive doses and, unlike viruses, our therapeutic can be administered repeatedly. WuXi:  How does your approach differ from other gene therapy companies? Matthew Scholz: We are killing cells based on their genetics, specifically their transcriptional activity. We deliver the DNA in vivo systemically with a unique lipid nanoparticle (LNP). The LNP is neutrally charged so it doesn’t have the toxicity associated with other LNPs on the market today. It gains entry into cells with a fusogenic peptide on its surface that mixes the lipids of the LNP with the lipids in a cell’s membrane. This results in the DNA being deposited directly in the cytoplasm, bypassing the endocytotic pathway entirely. Since the peptide fuses with cellular membranes, its delivery is indiscriminate – it dumps the DNA payload into any cell in comes in contact with. The DNA payload itself determines which cells are killed. For example, our first therapeutic targets cells have elevated levels of p53 transcription factors. P53 is a tumor suppressor; a cell will typically activate p53 when it detects something, like DNA damage, that needs to be addressed before the cell should be allowed to divide. Since p53 prevents cells from dividing and cancerous cells divide uncontrollably, many cancers have mutated or otherwise broken the p53 gene in the process of becoming cancer. What’s important about this from our perspective is that when p53 is mutated or ablated, the cell often tries to rescue it by making more p53 transcription factors – this is analogous to a person smashing a button harder or repeatedly when it doesn’t work. Our DNA payload encodes a suicide gene that is controlled by a synthetic p53 promoter. That means that damaged cells with elevated levels of p53 transcription factors will read our DNA payload (the suicide gene) and die, whereas healthy cells with normal levels of p53 transcription factors will not read the DNA payload and remain unharmed. We’ve effectively taken targeting out of the realm of chemistry and into the realm of information. This approach allows us to even go a step further and implement Boolean logic in DNA. We can build logic gates in DNA (such as IF /AND/NOT) and make the targeting very specific based on the transcriptional activity of the cells – it’s a radically different approach than others are taking. Our LNP is also far less expensive to produce than viral vectors: the most expensive part is the DNA itself. It can also be made very rapidly at enormous scales, and it can carry relatively large payloads. So far, we’ve administered it to animals for over a year without any detectable immunogenicity, and it is well tolerated at doses that are two orders of magnitude higher than traditional LNPs. WuXi: What are your major regulatory and commercial challenges? What lessons have you learned? Matthew Scholz: We’re pioneering a new class of treatment, and with that, we need to go above and beyond when it comes to demonstrating safety and specificity. It’s early days in the regulatory process of course, but we’re putting a lot of emphasis on those two points. On the commercial side, we’ve needed to educate our audiences on the fact that this is a unique approach to targeting and delivery with an LNP, and that we’re distinct from past LNP approaches that have had their setbacks. In this respect we’ve already started to see progress with a compelling set of data and taking the time to walk people through the merits of the approach. WuXi: As with other new medicines, the prices for some gene therapies generate “sticker-shock” among patients. Will gene therapies be widely accessible for patients? What changes are needed to ensure universal accessibility to these potential disease cures? Matthew Scholz: I’m optimistic that as the industry works through the manufacturing and delivery issues, the costs will come down. In just the last decade we’ve actually seen a tremendous increase in the scale at which these treatments can be produced. As these therapies continue to target diseases with ever-larger patient populations, economies of scale will help drive down costs. Some of the technologies in use today might also simply need to be replaced with next generation versions before gene therapies can be widely accessible, much like vacuum tubes had to be replaced with transistors before computational technologies could be made widely available. Gene therapies won’t ever be as cheap as aspirin, but I do think they will become widely accessible. WuXi: In general, what are the top 3 impediments to delivery of better medicines, faster and cheaper to patients? Matthew Scholz: I’d say first of all is the science itself – there is a lot we don’t know about biology, and it takes a lot of time and resources to create a better medicine in the first place. Second, in gene therapy specifically, we’re also quite limited by the technology: culturing patient cells and growing viruses involves processes and equipment that are clumsy, mostly manual, and nowhere near as mature as say the semiconductor industry. And finally, the entire medical system seems optimized to do the exact opposite of “better, cheaper, faster.” From a regulatory perspective we prioritize safety of medicines over speed to market or cost – especially with new classes of treatments. People may argue over this balance that the regulators have struck in mitigating the dangers of drugs versus the affliction of disease, and I do think the system is delivering progressively better medicines, but I think everyone would agree that the current process is slow and exceedingly expensive. Furthermore, patients, the ones who care most about these goals, have little to no influence over the system, and have to navigate layers and layers of bureaucracy, from the payors and benefit managers to the provider institutions themselves. The science and technology will continue to improve, but other key components of the healthcare system will need to evolve as well to truly make good on those advancements.

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2019/11/05

Divide & Conquer Seeks to Disrupt Cell Communication in New Therapeutic Approach to Glioblastoma

WuXi AppTec Communications strives to find the latest cutting-edge technologies that can potentially offer new treatments for unmet medical diseases. Glioblastoma, a cancer of the brain, ranks high on the intractable disease list. A brand new biotech company, Divide & Conquer has a new approach to fight this deadly condition. Leveraging Co-founder and Chief Scientific Officer Dr. Frank Winkler’s groundbreaking research published in Nature in November 2015 and again in September 2019, Divide & Conquer aims to open a new front in the war on cancer by disrupting the cell-to-cell communication mechanisms of solid tumor cells. The new research shows that the ability of cancer cells to form “social networks” makes them almost invincible, which is why current drugs fail to cure many patients. The company’s initial focus is on glioblastoma, a lethal form of brain cancer, where cancer cells have been shown to communicate with each other via structures called tumor microtubes. These structures allow the trafficking of materials and communication between cells, which appears to be essential for tumor growth and survival as well as resistance to chemotherapy and radiotherapy. Co-Founder David Grainger, PhD commented, “There is mounting evidence, accumulated over decades, and now taken to the next level in Dr. Winkler’s papers in Nature, that solid tumors can leverage this network effect to evade all attempts to kill them. We now have compelling evidence that it can be disrupted, with the potential to render the most lethal tumor types curable.” In this new article on novel glioblastoma research, WuXi AppTec Communications speaks with Dr. Winkler to discuss what makes glioblastoma so difficult to treat and why the UK-based company’s new approach may find an effective therapy for this therapy-resistant disease.  Frank Winkler is a professor of experimental neuro-oncology and managing senior physician in the Department of Neurology at the University of Heidelberg, as well as the German Cancer Research Center (DKFZ) in Heidelberg, Germany. Dr. Winkler earned his medical degree at Freiburg University. He completed a research fellowship at the Steele Lab at Harvard University in Boston, Massachusetts. Later, he received his assistant professor degree from Ludwig-Maximilian University, and became full professor (W3) in Heidelberg in 2012. A member of the German Association of Neurologists, German Association for Clinical Neurophysiology, and the European Organization for Research and Treatment of Cancer, Dr. Winkler also serves as a reviewer for numerous journals, including Nature, Nature Medicine, Cancer Research,the Journal of the National Cancer Institute, Lancet Neurology, and Journal of Neurology. His work has been published in Nature, Nature Medicine, Science, Neuro-Oncology, Clinical Cancer Research, and Neurology, among others. Dr. Winkler is involved in several Phase 2 and 3 studies, and he is the recipient of several research grants. His lab in the German Cancer Research Center (DKFZ) has pioneered novel methods for intravital imaging of brain tumor progression, which was instrumental to discover the membrane tube-connected functional networks of malignant brain tumors (glioblastomas), and their crucial role for tumor progression and therapy resistance. WuXi AppTec:What are the challenges involved in diagnosing and treating brain cancers? How important is early detection? Frank Winkler: The greatest challenge in treating these cancers, particularly astrocytomas and glioblastomas, is their highly diffuse growth in our most delicate organ: the brain itself. These are basically whole-brain diseases from the time of diagnosis on. MRI examinations often show that, but even brain regions that appear disease-free are already colonized by tumor cells on the microscopic level. To make things worse, cancer cells interconnect to normal brain cells, which even includes the formation of functional synaptic contacts with them. It is easy to see that effective killing of cancer cells in this situation, without damaging neurons and other brain cells, is a formidable task. It also explains why early detection is not actually important with these particular types of cancer: unfortunately, by the time the tumor is visible on MRI, diffuse brain colonization has already happened. WuXi AppTec: Why has it been so difficult to find druggable targets for glioblastoma? Frank Winkler: From my point of view, there are four key reasons: First, we have to face a disease with a very high molecular and cellular heterogeneity, both on an intra- and intertumoral level. That means, when you look for druggable targets by studying specific molecular alterations in glioblastoma cells, it is very unlikely that you end up with one single drug that will benefit all glioblastoma patients. The ongoing umbrella trials like the N2M2 trial in Heidelberg address this very problem by searching for druggable molecular alterations that are present in a few percent of glioblastoma patients, and only these patients will receive the drug. Second, the blood-brain barrier is preventing sufficient concentrations of many drugs and, even more so, therapeutic antibodies at the tumor cell site. Third, a subset of tumor cells is displaying high levels of resistance to all available therapeutics, and we are just at the beginning of starting to understand their features. We believe that the tumor cell networks we are targeting at Divide & Conquer are a key factor in this respect. Last but not least, we might be most successful in the end when we focus on basic cellular mechanisms of progression and resistance, and the microenvironmental interactions of glioblastoma. Again, that’s exactly what we do at Divide & Conquer. WuXi AppTec: Has genomic analysis of glioblastoma improved drug discovery? If so how? Frank Winkler: There are different examples of genomic analysis of incurable glioma types that have led to drug discovery. The most notable is the IDH1/2 mutation in astrocytic gliomas, where inhibitors have been developed and are being clinically tested. Additionally, there is the K27M mutation, which makes up a new class of malignant incurable brain tumors in which histone deacetylase (HDAC) inhibitors and other strategies are also being tested. However, for the large proportion of glioblastomas, no such driver mutations have been identified so far. Thus, drugs developed for other tumors entities have been tried with glioblastomas too without any success thus far in controlled clinical trials, which includes immunotherapies. That brings us to the point that we need to do now, from my point of view: understand the crucial cellular and molecular factors of tumor progression and resistance, without looking too much into what is already known from other cancers, and develop completely new treatment strategies. WuXi AppTec: How did you choose to focus on glioblastoma at Divide & Conquer? Frank Winkler: The “why” is very clear: because of exactly the reasons stated above. To be more specific about the “how,” we discovered that glioblastoma cells extend ultra-long, tubular cell membrane protrusions that are used to invade the brain in a scanning mode to colonize it and to interconnect to a highly functional, communicating multicellular network that protects tumor cells from dying after radiotherapy and chemotherapy. This is apparently achieved by an improved homeostasis in these networks that supports cellular resilience. To make things worse, the network is able to detect damage to itself, and to ultimately repair itself in a highly coordinated fashion, which is apparently also responsible for rapid local recurrences after surgical resection. By studying all this, the scales fell from our eyes. If you want to make a real difference in this disease, you need to disconnect the tumor cells. Isolate them from each other, and thereby transform an incurable disease into a potentially curable one. There is actually an example from man: there is a closely related brain tumor type, called oligodendroglioma, in which cells lack the ability to form resistant networks because of a particular genetic alteration (1p/19q codeletion). Happily, this glioma type is not incurable: most patients experience relapse-free survival over decades when treated with radiochemotherapy. WuXi AppTec: How did you develop your drug candidate? Frank Winkler: We have developed an in vitro assay for tumor cell connectivity that nicely reflects the anatomical and functional networks we see in patients and in vivo in mice. We are using this system to screen for drugs that inhibit the membrane tube extensions that connect tumor cells. By doing this, we verified some “typical suspects” interfering with actin and microtubule dynamics that, however, are not druggable. Most importantly, we discovered that the PKC pathway is a master regulator of tumor cell network connectivity, and we have identified lead compounds that target this pathway, and–importantly–can be given to mice with acceptable toxicity too. At Divide & Conquer we are testing all lead compounds in refined mouse models that allow us to study both tumor cell disconnection on a microscopic level, and anti-tumor effects at the same time, using long-term in vivo microscopy combined with MRI and survival studies. That ensures that we really hit the target we want. WuXi AppTec: What is the mechanism of action? Frank Winkler: Next to the PKC pathway, we are looking into other drug classes that target master regulators of cellular connectivity. Among them are ones that are used during (neuro) development to connect cells with each other to form functional syncytia, but are later downregulated and should no longer be critically relevant for the adult organism. In general, we know that tumors recapitulate many molecular and cellular processes of normal development. Thus, at Divide & Conquer, we believe that the establishment of a functional multicellular network can be targeted in a tumor cell-specific way, at least in adults, without unacceptable toxicity to normal tissues. Whether this works out in the end, we will see. It remains a completely new therapeutic concept, and thus therapeutic ratios and windows need to be explored. WuXi AppTec: What regulatory challenges do you face in clinical development? Frank Winkler: Since no working therapies other than surgery, radiation and chemotherapy with alkylating agents exist for the treatment of glioblastoma, there is a great need for novel approaches. In other words: the standard of care is not great. For the large (about 70%) subgroup of patients without MGMT promotor hypermethylation, chemotherapy is basically ineffective, too. That really fosters clinical development, which should ideally be in the primary setting, with the new drug combined with radiotherapy, with or without chemotherapy, depending on the MGMT promotor methylation status. The trial concepts are clear and have worked out very nicely so far in large Phase 3 trials. Only the effective drug is missing. WuXi AppTec: Have you worked with patients in developing your drug development strategy? If so how? Frank Winkler: I work with patients every day and know that the vast majority of them share our view that we need to make true progress in this disease, and that we need to take our thinking in really new directions. As a matter of fact, many of them actively ask for all kind of unproven and often even harmful additional therapies, which from my point of view mostly reflects the lack of therapies with satisfying effectiveness today. The novel concept of disconnecting tumor cell networks is very plausible to many, and I do not foresee any general acceptance problems. WuXi AppTec: What lessons have you learned during the drug development process? Frank Winkler:  As a scientist and clinician, you need to pair with strong partners to get things going. We tried to work on drug screenings ourselves for years, without great success. With Divide & Conquer, we have founded a company with an environment where all the expertise and experience are there to make fast progress. WuXi Apptec: How soon will we have an effective treatment for glioblastoma? Will effective treatments require combinations of drugs? Frank Winkler: If everything goes as planned, we can easily have a drug candidate that can be put forward to a clinical trial in one year from now. Combinations are possible, but not necessarily. More drugs generally mean more toxicity, and often complex interactions. Particularly for early preclinical and clinical development of a completely novel antitumor strategy that can be tricky. However drug screenings continue, and if we discover a truly synergistic mechanism of action of drug candidates, this might be a way to go. WuXi Apptec: Can you comment on the specific progress or lack of progress in treating this disease in the last ten or 20 years? Frank Winkler: The only true progress in the last 20 years was the addition of the alkylating chemotherapy temozolomide to the standard of care – even though it is relevantly active only in a smaller subgroup of patients. Moreover, a physical therapy with alternating electric fields (TTF) has been introduced as well, but is only available in some countries, and costs and compliance are issues. As I mentioned before, the lack of progress is due to disease-inherent and brain-inherent factors. WuXi AppTec: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure for cancer patients? Frank Winkler: Target general principles of tumor cell resistance, which are most likely of a basic cellular nature, and/or target tumor growth modulation by the nonmalignant organ microenvironment which is less heterogeneous and can less effectively escape drug actions compared to cancer cells. One example for this strategy is the disconnection of glioblastoma cells we are currently working on at Divide & Conquer. Outside glioblastoma, the success story of immunotherapies is another. The current “mainstream” drug development strategy is different: target singular molecular alterations of cancer cells. This will only prove effective over the long-term when a) those are present in every cancer cell (which frequently is not the case), b) the tumor has no opportunity for escaping the drug action (which is also rare), and c) a targetable molecular alteration exists at all. Here, the hurdles appear higher.

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2019/10/30

Foghorn® Therapeutics’ Gene Traffic Control Product™ Platform: Regulating Gene Expression to Fight Intractable Disease

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team One of the wonders of nature is how our DNA is compressed over a million times to fit into the nucleus of each of our cells. This compressed form of DNA is called chromatin. Tightly packed chromatin is inaccessible and thus prevents gene expression. An important biological system is needed to unpack chromatin to make our DNA and our genes accessible for transcription. The chromatin regulatory system provides an important mechanism in regulating gene expression. This system is comprised of three components: chromatin remodeling machines, transcription factors and other converging pathways. It orchestrates the movement of molecules that turn genes on and off by enabling the unraveling of chromatin and allowing gene expression to occur. Chromatin dysregulation – when this system goes awry – is implicated across a wide range of diseases and has historically not been accessible for study, understanding or drugging. Recent work has highlighted that more than 25 percent of cancers have a mutation in a key component of this system – the chromatin remodeling machines. Furthermore, transcription factors, another important element of this system are mutated or over-expressed in roughly one third of cancers according to a recent cancer genome atlas study. Foghorn® Therapeutics Inc. is discovering and developing an unprecedented class of medicines targeting diseases with genetically determined dependencies on the chromatin regulatory system via its Gene Traffic Control™ Product Platform. Foghorn was launched in 2017 with a $50 million funding commitment from Flagship Pioneering®. Leading Foghorn’s team is President and CEO Adrian Gottschalk. Prior to joining the company, Gottschalk was at Biogen for 13 years, where he most recently served as Senior Vice President and the Neurodegeneration Therapeutic Area Head. When asked why he jumped from big biotech to a startup, Gottschalk stated that it was the vision and potential broad impact of the science. “The breadth and impact on disease of targeting the chromatin regulatory system is profound. The science struck me as leading to an entirely new wave of medicines that could change the lives of people with cancer and other serious diseases. It was unlike anything I had seen before,” he said. Gottschalk holds a BS in biochemistry from Texas A&M University and an MBA and MS from the Sloan School of Management at MIT and Harvard/MIT Health Sciences and Technology Center. The crux of what makes Foghorn different is the ability to study the interworking of the chromatin regulatory system in context. The basis for targeting the system came from the company’s scientific founders, Cigall Kadoch of Dana-Farber Cancer Institute, Harvard Medical School and the Broad Institute and Gerald Crabtree of the Howard Hughes Medical Institute (HHMI) and Stanford University. Over the past three years, the Foghorn team has built on the learnings from Kadoch and Crabtree to develop an integrated and scalable platform that enables high-throughput drug discovery and development efforts. “It really starts with the context of genetics,” Gottschalk shared. “Once you can take a granular view of the genetics influencing disease, then you’re a step closer towards identifying where the breakdown is taking place and solving the problem. There are an incredible number of mutations in and around this important regulatory system. We have a deep understanding of the chromatin regulatory system and have a platform that allows us to determine how mutations and genetics cause dependencies on this system.  This is the basis for how we target various aspects of this system.” Foghorn’s Gene Traffic Control Product Platform can be described using the following analogy: similar to how airports need air traffic control to direct the movement of aircraft, our cells need a system to direct the movement of molecules that turn genes on and off. The cell’s gene traffic control is the chromatin regulatory system. The Gene Traffic Control Product Platform allows the company to target the system in ways that have not yet been possible. “Previous attempts to drug parts of the chromatin regulatory system suffered from a lack of insights into how the whole system functions. In contrast, our Gene Traffic Control Product Platform allows us to interrogate the biology in the right context and actually identify viable targets and potential drug candidates,” Gottschalk said. Gottschalk was careful to distinguish this work from gene editing. “We’re not changing anyone’s genes,” he emphasized. “We’re drugging the system that’s regulating genes.” Gottschalk believes that Foghorn’s approach will have a huge impact on the overall industry. “We target a fundamental system that controls gene expression, enabling a specific approach with the potential to impact patients with a high unmet need. Disease dependencies associated with chromatin dysregulation are estimated to impact approximately 2.5 million cancer patients in G7 countries and chromatin dysregulation is further implicated in neurological, autoimmune, and other serious diseases.” Technology is an important part of driving this novel approach, with much of it being proprietary trade secrets. “What I will say is we have industrialized a whole suite of biophysical, biochemical and cellular-related assays, allowing us to discover chemical matter for small molecule drug development,” Gottschalk shared. “No other company in the world can study and drug the chromatin regulatory system in such a systematic way.” “The reason why we’re unique is not just our proprietary technology, but also because at this time, no medicines exist for the specific breakdowns with the machinery we are pursuing,” Gottschalk shared. “I’m not saying there’s no treatments for those cancers, but they’re not targeting the specific disease dependencies in the chromatin regulatory system that Foghorn is able to address.” Moving to the pipeline, Gottschalk cited that the chromatin regulatory system is “target rich” and thus there’s no shortage of options. “We are currently in pre-clinical stages of development and moving to the clinic next year. We are rapidly advancing over 10 programs across a wide range of cancers – both rare and more common.” Gottschalk was also enthusiastic about the hire of Carl P. Decicco as CSO late last year. Across his 30+ year career, Decicco has put approximately 200 drugs into the clinic and has already and will continue to add value to Foghorn as the company moves towards the clinic. More recently, Foghorn appointed Sam Agresta as CMO and Allan Reine as CFO and their oncology and financial expertise will be beneficial to the company as it continues to expand. Another key to accelerating drug development at Foghorn is partnerships; this has been true since the company’s inception. “It’s essential for startups like ours to be able to dial up and dial down certain parts of what we do very quickly,” Gottschalk said. “WuXi AppTec is actually a very important partner. Working with WuXi AppTec has been critical to managing the growth of the company as we’ve been able to get the right team in quickly.”   Looking ahead, Foghorn’s aim is to become an integrated biotech company. “Going from discovery to the clinic and from the clinic to commercialization, each of these steps is a cultural evolution,” Gottschalk said. “We have to constantly be asking ourselves questions, we need to be willing to challenge the ‘sacred cows’ of how we do things so that, at the end of the day, we can achieve our goals while staying true to our core values.” He indicated that in the end, “if you get the right people, you’ll give yourself the best chances to get the science right.” Gottschalk offered his commentary on the industry and key challenges Foghorn has overcome as it looks towards the clinic. “The first and biggest hurdle was industrializing our proprietary drug discovery platform, simply because it had never been done before,” he said. “Another barrier was finding chemical matter that can be advanced to become a drug. We are now ready to advance some of our programs to the clinic, which is a great milestone.” Looking forward to how things might look in 2030, Gottschalk is optimistic. “If you look at the past decade, the therapies that the industry is now bringing to patients are really transformative.” He suggested that the low conversion rate across the drug development process will improve for certain types of treatment, and that this combined with further investment will result in more FDA approvals, on average. As for Foghorn, Gottschalk is similarly optimistic. “It’s our plan to reach commercial stage sometime in the next 5 years.” He smiled as he stated, “the beauty of working in biotech now is that we have massive opportunities to make a huge difference for people. I really believe that Foghorn is in a position of leadership in the area of chromatin regulation, which makes me personally grateful that I have this opportunity. You can do many things in life and I show up to work every day really excited about what we’re doing.” “I personally believe that Foghorn is blazing the trail for the fourth wave of cancer therapies and may even have the potential to deliver cures,” he predicted. “My hope is for Foghorn to make a lasting impact in oncology and other serious diseases, and I am confident that our unique approach will help us get there.”

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2019/10/25

Oncoceutics Hopes to Develop the First Effective Drug for High-Grade Glioma by Blocking Dopamine from Feeding the Deadly Cancer’s Growth

High-grade glioma is a deadly brain cancer with no effective long-term treatments, typically leaving children and adults with less than two years to live following diagnosis. Oncoceutics Inc. is tackling this challenge with a new investigational drug, ONC201, which is a small molecule that binds to a specific dopamine receptor in the brain. Dopamine, a neurotransmitter, affects cell behavior and has been implicated in the cancer’s growth. Lee Schalop, M.D., the company’s chief operating officer and co-founder, said there has been little progress in treating high-grade glioma due to its heterogeneity and lack of biomarkers that could select patients who have a better chance of responding to certain therapies. High-grade glioma cells are quite varied, which means a drug that is effective on some of the cells doesn’t work on others. Surgery and radiation are the front-line treatments, but in most cases the cancer recurs – leaving no additional viable treatment options for patients. “There is a long list of drugs that have not succeeded in treating high-grade glioma,” Schalop observed. ONC201 is in clinical trials in the US for treatment of patients with high grade gliomas that harbor a genetic mutation called H3 K27M, which defines a subtype within the family of high-grade gliomas and is associated with a particularly poor prognosis. The mutation allows a targeted therapeutic approach with ONC201 against this subtype, which is more sensitive than other gliomas to the drug. This tumor type occurs in 10 percent of all glioma patients, mostly children and young adults. As part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Schalop about his company’s technology and the challenges of developing new therapies for high-grade glioma patients. Before earning his medical degree at Albert Einstein College of Medicine, Schalop spent more than 19 years in the financial industry with major Wall Street firms, including Morgan Stanley, J.P. Morgan, Credit Suisse and Banc of America Securities. He joined Oncoceutics soon after receiving his medical degree in 2008 and was promoted to chief operating officer in 2016. Schalop earned dual undergraduate degrees from University of Pennsylvania’s Wharton School and College of Arts and Sciences. WuXi: What are the challenges involved in diagnosing and treating high-grade glioma? How important is early detection? Lee Schalop: High-grade glioma is the deadliest type of brain cancer. However, unlike some other cancers, the challenges are not about making the diagnosis. The diagnosis is relatively straightforward using magnetic resonance imaging (MRI). Patients usually have symptoms like seizures or headache and fatigue, and an MRI is taken. If it’s suggestive of a brain cancer, a biopsy is done, and the diagnosis is confirmed by looking at the tumor tissue under a microscope. Unfortunately, early detection does not really change the outcome even if the tumor can be fully surgically resected because high-grade glioma almost always comes back. So the big challenge and unmet medical need is not diagnosis; the challenge is the lack of efficient treatments. High-grade glioma has proven to be an extraordinarily difficult cancer. The overall survival for patients after they’re newly diagnosed is between 12 and 18 months. That outcome really hasn’t changed meaningfully in as long as people have been measuring the success of various treatments for high-grade glioma. WuXi: How would you describe the evolution of drug research in high-grade glioma over the past 20 years? How much progress has been made? Lee Schalop: Almost none. The only drug that’s been approved in the past 20 years is Avastin (bevacizumab). It received Accelerated Approval from the US Food and Drug Administration (FDA) for recurrent/refractory disease, and then when the data were analyzed for full approval it did not increase survival, which is the typical threshold for full FDA approval. So there is no expectation that bevacizumab may prolong survival in these patients despite continued use. There is a long list of drugs that have not succeeded in showing improved overall outcome in high-grade glioma patients, causing a lot of frustration for patients and physicians as well as setbacks for companies interested in this space. WuXi: Why has it been so difficult to find druggable targets for high-grade glioma? Lee Schalop: This is a wonderful question since it addresses one of the major reasons for failure in this disease. Let me answer with a multipronged reply. First, it is hard to find a target that offers pathways and mechanisms to achieve a therapeutic effect. Second, even when a pathway or mechanism is identified, it is difficult to find a compound that engages these pathways or mechanisms. And third, compounds that engage these pathways or mechanisms are frequently too toxic or cannot be given in a way to reach high enough concentrations in a patient for a long enough time. One of the most critical questions for developing therapies for brain cancers is: Can a drug make it into the brain and into the tumor that resides in the brain? This is a hurdle that the vast majority of drug candidates, which show good effects in the test tube, cannot overcome simply because they don’t pass the blood brain barrier. This barrier exists to protect the brain, the body’s most critical organ, from invasion by substances that can be harmful, such as infectious agents, toxins and other compounds that circulate in the blood. As a result, there have been many drugs that have been hypothesized to work against high-grade glioma, and they have generated very nice data in models, both in test tubes and animals. However, when these drugs were tested in clinical trials, they ultimately failed. In addition, high-grade glioma is a very difficult cancer to target because it is so heterogeneous. By heterogeneous, I mean the cells in the tumor are different. So even if the cancer treatment works on some of the cancer cells, it doesn’t work on all of the cancer cells. WuXi: Why did you choose to focus on high-grade glioma? Lee Schalop: All of our early work showed that high-grade glioma was very sensitive to ONC201. Moreover, collaborations with a host of very experienced researchers confirmed that high-grade glioma was very sensitive to ONC201. Early research showed that the drug passes the blood brain barrier and makes it into the tumor that we target. It still was a tough decision to make given the history of drug failures in high-grade glioma, but we decided that we would take this risk. All of us at Oncoceutics cannot thank those individuals enough who gave us encouragement in the early days to embark on this path, in particular, Patrick Wen, the Direct of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute. WuXi: What progress have you made so far? Lee Schalop: We have determined that ONC201 works best against a subset of high grade gliomas. About 20,000 individuals get diagnosed each year with high-grade glioma in the US, with a subset possessing a H3 K27M mutation. We found that ONC201 works quite well for patients that have this mutation. In particular, we’ve seen a number of patients benefit from significant tumor shrinkage. WuXi: How is the drug being tested? Is it a single agent? Lee Schalop: It’s a single agent. Available options for patients are surgery, temozolomide and radiation, depending on their specific disease characteristics. Unfortunately, the tumor always comes back. So when the tumor comes back the patients start on ONC201. Our intention is to move ONC201 towards a frontline therapy for high grade gliomas. In this case it would be given in combination with radiation. WuXi: What is the mechanism of action for ONC201? Lee Schalop: ONC201 works by antagonizing dopamine receptor D2 (DRD2). Dopamine effectively feeds the cancer, and by blocking the dopamine receptor, you are blocking the growth of the cancer. WuXi: What are the risks of blocking dopamine? Lee Schalop: The way this drug works is incredibly specific, so it only binds to DRD2. Moreover, it binds to the receptor in a unique way which allows it to act much more potently at killing cancer cells than other dopamine receptors. It’s not blocking all of the dopamine receptors; that would dilute the antitumor effect of ONC201. The drug also is given infrequently – only once a week. We have seen no side effects that are typical with excess dopamine blockage, such as Parkinson-like symptoms, in the nearly 400 patients who have been treated with ONC201. WuXi: What regulatory challenges have you faced in clinical development? Lee Schalop: The challenges are typical for developing a drug for a rare disease that is immediately life threatening. There are not that many patients. In addition, many patients do not have the energy or ability to enroll in a clinical trial. Nevertheless, we have been successful in mobilizing the neuro-oncology community to send patients to our clinical trials, which are now open at multiple sites across the US. Nonetheless, progress is slow because it’s hard to find patients that have this specific genetic mutation. WuXi: You are developing ONC201 for adults and children. What are some of the differences in developing drugs for adults and children? What are the challenges you face, particularly with respect to children? Lee Schalop: The challenges with children are two-fold. One is that you have to be very careful with your dosing. We have worked with the Children’s Oncology Group to develop an algorithm to find the appropriate dose for children, based on the adult dose, which involves the weight of the children and their body surface area. We’ve developed a relatively sophisticated way to convert the dosing to the children. Secondly, while we are working with the FDA for approval of ONC201 for adults based on tumor shrinkage, this will be difficult for approval with children because of the way their tumors grow. Instead, for children, we will need to seek approval based on survival.  And traditionally the FDA requires that survival studies have a comparative arm, or a control arm. This means that half the patients get the drug and half the patients don’t. For children, this will prove to be completely impossible because no parent will allow their child to go into a trial where there’s a 50 percent chance they will get a placebo. WuXi: What lessons have you learned during the drug development process? Lee Schalop: We have certainly learned that there is a larger unmet need than we thought. We have also learned that the community is very closely connected and highly motivated to work with us. The medical centers, the experts, the patient advocacy groups, foundations that support patients with brain cancer, the National Cancer Institute, the FDA and everyone involved in the field have given us encouragement and support. This support from the outside is best exemplified by a quote from Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence (OCE), who said in a recent interview in The ASCO Post, “We have taken a very active approach to really rapid approvals of our drugs without sacrificing quality by having a smarter approach to how we review these drugs. At the end of the day, I ask: will the American public be better off with this drug than without it?” WuXi: What other drugs do you have in development? Are they based on the same platform? Lee Schalop: Yes they are. Our next two compounds are ONC206 and ONC212. They share in common with ONC201 a core structure of three rings. These three rings are relatively unusual from a medicinal chemistry perspective, and they have proven to be very important in terms of binding to GPCRs (G-protein-coupled receptors). ONC201 binds to the GPCR DRD2; ONC206 also binds to the GCPR DRD2, although differently. ONC212 binds to a different GPCR, called GPR132. GPR132 has been implicated in leukemia, and our intention is to do a clinical trial for patients with leukemia. WuXi: What would be the one thing that has the most potential to lead a paradigm shift from treatment to cure for cancer patients?      Lee Schalop: It’s molecular targeting. It’s moving away from the idea that if one person has breast cancer and another person has breast cancer that they should get the same treatment. Or even if someone seems to have a certain type of breast cancer from a histological review (the old way of looking at cancer based on what it looked like under the microscope) that they should get the same treatment. Instead, today what’s important is which genes are activated and what can be molecularly targeted in that cancer.

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