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2019/10/08

Halozyme Utilizing Unique Tumor Microenvironment Pathway to Fight Pancreatic Cancer

In WuXi AppTec’s latest series on novel drug development for pancreatic cancer, most of the companies featured have concentrated on ways to directly stimulate the patient’s own immune system to fight this stubborn disease. Halozyme, a clinical stage oncology company based in San Diego, has adopted a different, unique strategy based on the tumor’s microenvironment. The company is testing its lead drug candidate, investigational drug pegvorhyaluronidase (PEGPH20), in a Phase 3 trial in patients with HA-high metastatic pancreatic cancer. PEGPH20 targets the area around the tumor rather than the tumor itself, increasing the delivery of oxygen and chemotherapy to the immune cells of the tumor. The tumor microenvironment (TME) includes the malignant cancer cells as well as the many non-malignant cells within a tumor (for example fibroblasts and immune cells), blood vessels, and extracellular matrix components, such as collagen and the polymeric carbohydrate hyaluronan (HA). The cancer cells within the tumor can recruit other cell types into the TME and then stimulate them to generate growth factors, signaling molecules and other matrix components that can further optimize the TME for malignant cell growth and result in an immunosuppressive microenvironment. Decades of investigation have led to the current mechanism-based hypothesis for the role of HA in the TME. Accumulation of HA and associated water within some solid tumors can lead to increased pressure within the tumor microenvironment. The increased pressure can lead to blood vessel compression, restricting blood flow, leading to increased areas of hypoxia, and impeding access of therapeutic intervention into the tumor.   WuXi AppTec communications asked Halozyme’s Senior VP of Research and Development, Dr. Alison Armour, to explain why the company decided to take this unique approach and how PEGPH20 works. Dr. Armour has over 15 years of practice as a clinical oncologist and a strong record of overseeing successful regulatory submissions. Dr. Armour joined Halozyme in May 2019 and she is responsible for Halozyme’s research, clinical development, regulatory, safety and pharmacovigilance efforts. Prior to Halozyme, Dr. Armour served as the Chief Medical Officer at Endocyte, where she was responsible for the company’s clinical division, including all medical operations, clinical operations, regulatory, data management and pharmacovigilance activities. Prior to this role, she served as Vice President of Development and team lead for TYKERB® at GSK and then at Novartis. Earlier in her career Dr. Armour also served as global medical science director at AstraZeneca. Dr. Armour received her B.Sc. in Biochemistry, her M.B., Ch.B. MSc, and Doctorate of Medicine from the University of Glasgow; her FRCR at the Royal College of Radiologists London, UK and her FRCP at the Royal College of Physicians in London, UK, for contributions to the field of oncology. WuXi: Dr. Armour, what is your opinion about the challenges in pancreatic cancer early screening and diagnosis? Are there any specific biomarkers? Alison Armour: It is incredibly challenging to screen for pancreatic cancer at its early stages. A robust biomarker for example hasn’t been developed yet. The pancreas is deep within the abdomen. It’s not easy to detect on routine clinical examination and the symptoms can be non-specific. For example nausea, vomiting, weight loss or pain, which can often be misdiagnosed as other conditions. The current blood biomarker tests are not specific, but CA19 or CEA may sometimes be elevated. Standard tests include CT, MRI and tissue via ERCP, which is an invasive procedure. Panels of potential diagnostic biomarkers are currently being explored. WuXi: What are the hot targets in the field of drug development for pancreatic cancer? Alison Armour: Pancreatic cancer is an extremely resistant cancer in the world of drug development, but so was melanoma until we found the right target. There are multiple targets being explored for pancreatic cancer, including KRAS and CTHRC1. At Halozyme, we believe there’s great promise in targeting hyaluronan (HA)—let me explain why. Pancreatic cancer is known to be surrounded by very dense fibrous tissue. In fact, only around 10 percent of the cells are tumor. We also know that pancreatic tumor cells surround themselves with HA. That’s what we are targeting at Halozyme. HA is a large, complex carbohydrate molecule. It accumulates on the surface of tumor cells and the space around them. It provides a barrier to immune cells from infiltrating the tumor and compresses the blood vessels, which impedes the delivery of chemotherapy to the tumor. PEGPH20 breaks down the large molecule and has been shown in preclinical models to increase the perfusion of oxygen and chemotherapy to the tumor. The breakdown products may also have a role in recruiting immune cells into the tumor. That’s an area that we are actively researching now. WuXi: In recent years, what breakthroughs have been made in drug development for pancreatic cancer? Alison Armour: Sadly, not many. The first real breakthrough came with chemotherapy in the 1970s, then along came gemcitabine in the ‘90s. Since then, people have just combined drugs. There really haven’t been any significant breakthroughs in pancreatic cancer, and that’s why we must keep trying and explore the tumor microenvironment in its entirety. We are starting to target the molecular defects in all cancers though and PARP inhibitors showed some interesting data in the small numbers of patients whose tumors had a DNA repair defect. WuXi: How is your drug (PEGPH20) different from existing pancreatic cancer treatments? Is it a new approach? What are the results of your research so far? Alison Armour: Our lead therapeutic candidate, PEGPH20, utilizes a unique mechanism of action compared to standard anti-cancer therapies. Our preclinical research shows that it doesn’t target the cancer cells, but instead it targets a component of the microenvironment. It breaks down HA in the tumor itself and makes it easier for the blood vessels to deliver oxygen and chemotherapy as well as immune cells in the tumor area. In our Phase 2 study, PEGPH20 plus standard chemotherapy of ABRAXANE and gemcitabine suggested meaningful clinical trends in OS and PFS in patients whose tumors expressed high levels of HA. We are waiting for the results of a confirmatory Phase 3 study later this year. WuXi: What is the specific mechanism of action? Alison Armour: PEGPH20 targets the accumulation of HA in the tumor microenvironment. When HA accumulates, it creates a significant barrier to drug delivery. Enzymatically degrading this accumulated HA has been shown in animal models to reduce tumor pressure, improve vascular perfusion and decrease hypoxia, enabling increased access of anti-cancer therapeutics and immune cells. WuXi: How did you choose to focus on pancreatic cancer? It has been a very difficult disease to treat. Alison Armour: Pancreatic tumors have very high levels of HA, the prime target for PEGPH20. This makes pancreatic cancer an ideal indication for Halozyme to pursue. WuXi: Are you planning to develop the drug through regulatory approval and market it? Alison Armour: Absolutely. We fully intend to commercialize PEGPH20 for the treatment of pancreatic cancer pending the results of our Phase 3 data readout. WuXi: Have patients been involved in the development of your drug, other than participating in clinical trials of course? Alison Armour: Our work with patients predominantly surrounds advocacy and support groups including the Pancreatic Cancer Action Network (PanCAN). WuXi: What major challenges have you faced in trying to bring a new drug for pancreatic cancer to patients? Alison Armour: The biggest challenge in drug development for pancreatic cancer is that we haven’t been able to target the pathways that really drive the development and growth of pancreatic cancer, but as drug developers we will keep trying. Patients are often very ill by the time they present and they succumb quickly to their disease, so we need to find agents that are effective and work rapidly. WuXi: What other drug candidates do you have in the pipeline? Alison Armour: Right now, we are concentrating on developing PEGPH20. Beyond pancreatic cancer, we are conducting studies across multiple solid tumor types to examine if PEGPH20’s demonstrated ability to degrade accumulated HA may help increase the effectiveness of anti-cancer and immuno-oncology therapeutics. WuXi: What are the top impediments in our delivery of “better” medicines “faster” and “cheaper” to patients? Alison Armour: We work tirelessly to create the best treatment options we can, as quickly as possible, because patients are waiting. People often rush through the early stages of development to see if the molecule works, but when a drug gets into trouble, the signs are usually there in the data and the science. We must not underestimate the value of really understanding the target and the drug. WuXi: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure?” Alison Armour: It’s the biology of the disease. There are many mutations in pancreatic cancer, but if we could define one or two pathways that really drive the growth of the disease, we could unlock it.

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2019/09/19

Finch Therapeutics Taps into the Human Microbiome to Find Disease Causes and Cures

Finch Therapeutics is developing microbial therapies designed to alter the microbiome for treatment of patients suffering from diseases as varied as bacterial infections and autism. In 2019, the company received a Breakthrough Therapy designation from the US Food and Drug Administration (FDA) for its microbial therapy CP101, a treatment for recurrent Clostridium difficile (C. difficile) infections (CDI), which can cause extreme diarrhea and life-threating inflammation of the colon. CP101 is the lead drug candidate derived from a technology platform designed to explore the microbiome, the community of micro-organisms that exists throughout the human body, particularly in the gastrointestinal tract. Imbalances and disruptions of the microbiome are linked to a wide variety of diseases. Finch CEO Mark Smith, Ph.D., said C. difficile infections are usually treated with antibiotics, “which often disrupt the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes.” A 2017 clinical trial showed CP101 prevented recurrence of CDI in 88 percent of the 49 patients enrolled, earning the drug its breakthrough designation. A Phase 2 trial of CP101 is underway and, if successful, could serve as a pivotal study expediting FDA approval. As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Smith about the company’s new CDI therapy, the impact of the FDA’s Breakthrough Therapy designation and the role of the human microbiome in diseases. Smith co-founded Finch to develop the next generation of microbiome-based therapies. He earned his Ph.D. in microbiology from Massachusetts Institute of Technology and his B.A. in biology from Princeton University.   WuXi: How did CP101 qualify for Breakthrough Therapy designation? Mark Smith: CP101, our microbiome-based investigational drug for recurrent C. difficile infections (CDI), received the FDA’s Breakthrough Therapy designation because it is intended to treat a serious or life-threatening condition, and the preliminary clinical evidence indicates that CP101 may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. CDI is certainly a serious and sometimes life-threating condition. CDI is the most common hospital-acquired infection in the US, but it also affects individuals with limited or no contact with a hospital setting. In the US alone, an estimated 500,000 individuals suffer from CDI each year, and sadly, CDI is associated with close to 30,000 deaths per year. The US Centers for Disease Control and Prevention (CDC) categorizes CDI as an “urgent threat” to public health, the highest possible threat categorization. CP101 is intended to prevent recurrent CDI; in other words, it is designed to prevent patients from experiencing additional CDI episodes. After an initial CDI episode and treatment with antibiotics, up to 20 percent of patients will experience a second episode. After a patient has experienced two or more CDI episodes, 40-65 percent experience yet another episode. With antibiotics alone it can be extremely difficult to break the cycles of CDI, and the negative impact on patients, their families and the health care system is enormous. The preliminary evidence for CP101 is very exciting — in a preliminary clinical study, 88 percent of patients battling recurrent CDI that received CP101 did not experience a CDI recurrence over a two-month period. Beyond this study, other clinical studies have also shown that transferring a diverse microbial community into the gut of patients suffering from recurrent CDI may be significantly more effective than utilizing antibiotics alone to treat recurrent CDI.   WuXi: How does your drug candidate differ from existing therapies for clostridium difficile infection? What is the mechanism of action? Mark Smith: CDI has traditionally been treated with antibiotics alone, which often disrupts the balance of the gut microbiome, leaving patients susceptible to additional CDI episodes. To combat this, many clinicians are now using fecal microbiota transplants (FMT), an investigational treatment derived from the stool of human donors, to treat patients with recurrent CDI that have failed antibiotic therapy. While many of the FMT treatments used in the US come from OpenBiome, a nonprofit stool bank that rigorously screens its donors, there is wide variation in the donor screening protocols and processes used by other organizations preparing FMT treatments. FMT treatments are often delivered using clinically invasive methods, such as naso-enteric tubes, enemas, or most commonly in the US, via colonoscopy, which requires bowel preparation beforehand, a process that can be quite uncomfortable and difficult for patients.  We consider CP101 the next generation of microbiome-based therapies because it addresses the limitations of currently available options. Specifically, CP101 is an oral capsule, produced under applicable GMP (Good Manufacturing Practices) controls, which contains a diverse community of lyophilized microbiota from human donors that have undergone rigorous screening and testing. The oral delivery method has the potential to significantly improve the patient experience. And, unlike FMT treatments that must generally be kept frozen, the lyophilization of the microbiota avoids the need for CP101 to be kept frozen, simplifying the supply chain and making it much easier for hospitals to store CP101. WuXi: How did you demonstrate the potential clinical benefit beyond existing treatments to secure the breakthrough designation? Mark Smith: We submitted data from a clinical study conducted at the University of Minnesota, which describes the clinical experience with CP101 used to treat patients with recurrent CDI. In the study 88 percent of patients achieved clinical success, defined as no recurrence of CDI over a two-month period. Compared to the published recurrence rates seen after antibiotic therapy, this is a large, and very clinically relevant, decrease in the rate of recurrence. This data allowed us to meet the FDA’s requirement that breakthrough therapies must have preliminary clinical evidence that indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. WuXi: What impact does the breakthrough designation have for your company? Mark Smith: The increased communication and support that the FDA offers to companies with Breakthrough Therapy designation is incredibly valuable and will enable us to accelerate our efforts to make CP101 available to patients fighting recurrent CDI. Just recently, we had a very productive conversation with the FDA in which we learned that it may be possible for PRISM3, our currently enrolling Phase 2 clinical trial, to be considered a single pivotal trial if the statistical results meet the FDA’s highest bar. If we meet this very high, but achievable bar we would be able to submit for FDA approval without needing to conduct a Phase 3 clinical trial. Having a therapy with Breakthrough Therapy designation was also helpful during our last fundraising round, where we raised $53 million dollars to advance our portfolio of therapies. WuXi: What role, if any, have patients played in your drug development and clinical trials, aside from participating in clinical trials, of course? Mark Smith: Patients are always at the center of our work. They inspire us and motivate us to work with tenacity and urgency. We’ve worked closely with many individuals that have battled C. difficile as well as C. difficile patient advocacy groups to understand the needs of those we seek to serve. Their input has helped inform the design of our product and clinical trials. WuXi: What other drugs are you developing based on your technology platform? Mark Smith: We use our Human-First Discovery™ platform to develop therapies for a wide range of diseases and conditions linked to a disrupted gut microbiome. Rather than following the traditional drug discovery process, we begin with proof-of-concept data from human interventional studies to identify meaningful microbial signatures. We have a Full-Spectrum Microbiota® (FSM®) product platform that allows for the development of therapies that contain a diverse community of microbiota from healthy human donors, as well as a Rationally-Selected Microbiota® (RSM™) product platform that allows for the development of therapies containing select microbes, grown in pure culture, that we believe are driving successful clinical outcomes.     In addition to recurrent CDI, we also have a pediatric Autism Spectrum Disorder program that recently received Fast Track designation from the FDA, and a partnership with Takeda Pharmaceutical Company to develop a Rationally-Selected Microbiota therapy for ulcerative colitis. Beyond that we continue to evaluate and advance microbiome research to identify additional areas where our platform can address unmet patient needs. WuXi: What role does the microbiome play in diseases and what kinds of diseases are linked to it? Mark Smith: Scientists are discovering that the microbes inside us are having a much bigger impact on our health than previously thought. In addition to the areas we are currently focused on, researchers have found that the microbiome is linked to the response patients have to cancer therapies, as well as the development of autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, central nervous system disorders such as Parkinson’s disease, and even the development of food allergies and obesity, just to name a few areas of promising research. To further our understanding of the microbiome’s therapeutic potential, we are currently supporting a number of investigator-initiated clinical studies that span a wide variety of neurological, hepatic, infectious disease, and gastrointestinal conditions.     WuXi: What lessons can other companies learn from your drug development experience? Mark Smith: We believe that focusing on bringing clinical data into the development process as early as possible is critical to retire risk and inform product strategy. Because of the favorable safety profile of our microbial therapies we have been able to rapidly generate proof-of-principle clinical data. This approach enabled us to quickly move into the clinic with CP101 and obtain data that allowed us to secure Breakthrough Therapy designation and initiate a potentially pivotal trial. While other companies may not share the unique features of our discovery platform, the principle of tying decisions to clinical data early in development is an important one. WuXi: Have FDA initiatives such as Breakthrough Therapy and Fast Track designations, changed the paradigm of clinical drug development? If so, how? Mark Smith: The FDA plays a pivotal role in the development of effective therapies. Fast Track and Breakthrough Therapy designations increase our ability to interact with the FDA’s multidisciplinary team of experts. These designations allow sponsors to design better trials and more smoothly navigate the necessary regulatory processes that exist to ensure that safe, effective drugs reach patients. WuXi: What are the top three major impediments in our delivery of better medicines, faster and cheaper to patients? Mark Smith: If you consider the biopharma industry as a whole, there are a few main challenges. As we all know, it’s very costly and time consuming to identify a promising drug candidate. And, many drug candidates that show promise in a pre-clinical setting are found to be ineffective once clinical trials start. These factors drive up the cost of drugs and increase the time it takes for new therapies to enter the market. With our product platform and strong partnerships with clinicians studying the gut microbiome in a clinical setting, we are uniquely positioned to overcome many of the traditional challenges. By starting with microbial data sets from human interventional studies, we can reverse engineer successful clinical outcomes to identify the microbial community driving patient outcomes, significantly decreasing the time, cost, and risk associated with our drug discovery process.     

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2019/09/19

Blaze Bioscience Shines a Light on Tumor Cells to Guide Pediatric Brain Cancer Surgeons

Blaze Bioscience is literally lighting the way for cancer surgeons to remove children’s brain tumors without harming their healthy neural tissues. The company is developing drugs that use optimized CDPs, also called cystine-dense miniproteins, derived from natural organisms such as scorpions, violets and sunflowers. The CDP in Blaze’s lead product, tozuleristide, binds to cancer cells and, when combined with a dye, makes the diseased cells glow to help surgeons avoid removing healthy tissue and resect all of the tumor. Tozuleristide was designed using Blaze’s Tumor Paint technology, invented by researchers at the Fred Hutchison Cancer Center, Seattle Children’s Hospital and the University of Washington. The diagnostic drug, which combines a CDP from scorpion venom with a fluorescent dye, is being evaluated in the US in a pivotal clinical trial of pediatric patients undergoing surgery to remove brain tumors. Current techniques rely on “pre-operative scans entered into a neuro-navigation system and the surgeon’s skill,” said Blaze President and CEO Heather Franklin. “There is nothing like tozuleristide in development or on the market for children undergoing brain cancer surgery.” Franklin said the company expects to file a New Drug Application (NDA) in 2021 for approval of tozuleristide by the US Food and Drug Administration (FDA). She said clinical studies have also been conducted in skin and breast cancers, and the technology may be applicable for other solid tumor cancers. Franklin added that Blaze also hopes to introduce its technology to other countries, such as China, “where surgery is a mainstay of cancer therapy and we believe we could help millions more patients and surgeons.” As part of an exclusive series spotlighting the insider perspectives of thought leaders on topics shaping the future of new medicines, WuXi AppTec Communications spoke with Franklin about her company’s technology and the challenges of developing new therapies for pediatric cancer patients. Before joining Blaze, Franklin was senior vice president of business development and alliance management at ZymoGenetics and also held positions at Amgen and Targeted Genetics. She earned a Bachelor of Science from the University of North Carolina-Chapel Hill, a Master of Science from the University of Washington and an MBA from the Wharton School of the University of Pennsylvania. WuXi: Why are there so few pediatric drugs in development? Heather Franklin: The good news is that this is changing through a number of US government efforts to provide incentives and obligations, including the Creating Hope Act and Race for Children Act. Historically, patient organizations such as the Cystic Fibrosis Foundation and the Muscular Dystrophy Association, which have taken venture philanthropy approaches to partner with companies to advance drug development, were the ones making major strides in pediatric therapies possible.  Often there also are perceived additional risks in developing pediatric drugs beyond these being smaller markets. The advent of successful products for rare diseases demonstrated that even these markets can generate good returns for investment in drug development.  When the benefits of your therapy can last decades, as in the case of pediatrics, versus months or years in the case of many other therapeutics, then it shifts the value proposition in favor of developing pediatric drugs. But the safety bar is much higher for a drug developed for children for the same reasons; they may be negatively impacted for decades. And the negative impacts may be greater for pediatric patients who are still developing. A negative safety event in a pediatric patient during a clinical trial, whether eventually attributed to a drug or not, can derail a whole product category, as was seen in gene therapy two decades ago. Thankfully the technology recovered and we are seeing wonderful advancements in that area. WuXi: How does developing drugs for children differ from adults? Aren’t children just small adults? Heather Franklin: Children are not just small adults. This is clear in one of the areas of focus of our drug development, where many pediatric brain tumors are quite distinct from adult brain tumors in terms of underlying cause and location. Additionally, kids are still growing and developing, which poses a number of challenges from simple things like what is the right dose given that children vary widely in size to potential differences in side effect profiles. WuXi: What are the major regulatory challenges in developing drugs for pediatric cancer patients? Heather Franklin: First off is the extra emphasis on safety. Phase 1 studies focused strictly on safety, such as those that are done in normal volunteers in adult drug development, aren’t allowed in pediatric clinical trials. Even studies on pediatric patients, which might have some benefit, can be difficult to enroll as you are asking a parent to consent to treating their precious child with an unproven drug. So enrollment rates in pediatric studies can be slow based on the need to take less risk with children on top of the smaller number of children with a particular disease as compared to adults.  There are also additional challenges early in clinical trials such as sometimes needing to develop a separate dosage form for children. On the other end of the spectrum, I do believe the regulatory agencies are very willing to work with companies developing drugs that can help children provided this safety concern is adequately addressed. So a safe and effective medication can see a rapid approval once that data is collected. WuXi: What clinical development challenges do you face? Heather Franklin: In designing our clinical development program for a diagnostic drug in children with brain cancer, one of the toughest issues to address is how to show there is a low rate of false negatives as opposed to true negatives. This is because it isn’t feasible to sample brain tissue the surgeon believes is truly negative, particularly in a child. But we worked with FDA to address that challenge as we designed our pivotal clinical trial. The trial is now up and running at seven centers – soon to be nine centers – across the US. We anticipate completing enrollment in 2020 and filing an NDA in 2021. WuXi: Why did you select central nervous system tumors as a pediatric cancer indication? Heather Franklin: Pediatric brain cancer is the number one cancer killer of children. Even if a tumor is resected there can be many negative impacts if normal tissue is accidentally removed from a child’s developing brain. And if they do not get all of the tumor, it may mean increased radiation and/or chemotherapy for that patient, which can have life-long negative side effects. So this is the application of our Tumor Paint technology where the potential benefits of complete resection and the avoidance of negative effects of taking too much tissue are most pronounced. WuXi: What kind of diagnostic drug are you developing and what is the mechanism of action? Heather Franklin: Tozuleristide is a diagnostic drug which can be injected intravenously as soon as one hour prior to surgery and appears to still provide meaningful contrast between tumors and normal tissue if surgery takes place even 36 hours later. This is a useful feature in a hospital setting where surgeries in some cases may be emergencies or in other cases may be delayed. It is being investigated for its potential to accurately detect tumors during surgical procedures. While the mechanism of action hasn’t been fully elucidated, laboratory tests have demonstrated it binding both to several different proteins found on cancer cells and binding to many different cancer cell types themselves. These findings were confirmed in our veterinary clinical trial and now we have seen many different tumor types light up in our clinical trials. It appears to be a general mechanism that is at work in most cancer types. WuXi: How does your diagnostic drug differ from what’s already available to children for this disease? Heather Franklin: While there is an imaging agent recently approved for detection of high grade gliomas in adult brain cancer patients, there is nothing available for children undergoing brain cancer surgery. Current techniques include use of pre-operative scans entered into a neuro-navigation system and the surgeon’s skill. Some major hospitals have intra-operative MRI (magnetic resonance imaging) units where the surgeons stop surgery to take a scan mid-surgery, but there is nothing like tozuleristide in development or on the market for children undergoing brain cancer surgery. WuXi: What other cancer indications are you targeting? Heather Franklin: Our Phase 1 program studied adult brain, breast and skin cancers, all of which are areas of interest. We see head and neck cancer and sarcomas as indications similar to brain cancer where successful surgery is critical to downstream outcomes and preservation of function. Beyond that we believe this product may be applicable to most cancer surgeries such as cancers of the gastrointestinal tract as well as prostate and lung cancer surgeries. And beyond addressing many different types of cancer surgery we would also like to bring the technology to countries such as China where surgery is a mainstay of cancer therapy and we believe we could help millions more patients and surgeons. WuXi: What are the top three impediments to delivery of better medicines, faster and cheaper to patients? Heather Franklin: Oddly, access to patients is a key impediment as new approaches and combination approaches to cancer therapy explode. So, it becomes even more critical to be thoughtful about how we approach clinical trials and come up with new algorithms that can detect signals of efficacy – or futility – with fewer patients. I believe the FDA is receptive to this idea, and I’m looking forward to seeing elegant implementations of this approach. I think restoring trust to the pharmaceutical industry is a key as well. Trust needs to be earned and with trust we can re-explore the risk-benefit equation which underlies drug development and approvals possibly resulting in accelerated pathways to patients. You see a desire to shift this equation in movements like the Right to Try Act (The US law enables patients with life-threatening diseases to try unapproved drugs if they failed all approved treatments and cannot enter a clinical trial). I don’t necessarily believe that is the right approach since we do want patients enrolling in clinical studies generating hard data on risks and benefits of a product, but perhaps that movement is indicative that we could continue our shift towards more accelerated approvals and shared risk. WuXi: What would be the one thing that has the most potential to lead to a paradigm shift from treatment to cure in cancer?  Heather Franklin: I think we are mistaken when we try to think of there being a “magic bullet” for cancer. Cancer is many different diseases and ever changing and mutating. The ways to tackle each of these is often multi-factorial. Immunotherapy, including T-cell therapy, holds great promise. We believe that reducing tumor burden with a more successful surgery is a factor that will help out these new therapies as well.  Artificial intelligence and machine learning efforts looking at early diagnosis and other markers of cancer are intriguing. All of these technologies will come together to profoundly change how we treat cancer. As I sometimes tell my investors, I would be happy to someday be put out of the cancer surgery business. Unfortunately, I don’t think that day is on the horizon quite yet.

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2019/09/18

Oncternal Therapeutics Pursuing Novel Treatment for Ewing Sarcoma in Challenging Field of Pediatric Cancer

The WuXi AppTec Communications team is excited to kick-off a new series on pediatric cancer that highlights companies seeking novel therapies for children, long a challenging space. Drug development advances in the last decade have produced new treatments for many diseases. However, since most of those new medicines were discovered and developed for adults, children have often been excluded from this progress. Research has shown that children do not respond to medications in the same way as adults. Even if pediatricians prescribed drugs to children “off-label” children could respond differently than adults in terms of safety and efficacy. “Children are not small adults,” said Dr. James Breitmeyer, President and CEO of Oncternal. Oncternal, the first company profiled in this new series, is a San Diego based oncology company developing TK 216 for Ewing sarcoma, a rare pediatric cancer. TK216 is a small molecule therapeutic candidate that inhibits the biological activity of ets-family transcription factor oncoproteins, which are the main disease drivers in Ewing tumors. “Ewing sarcoma is a very serious bone cancer affecting children and young adults, and the effects can be devastating,” said Dr. Breitmeyer. “These patients have an urgent need for additional treatment options and TK216 represents a potential new therapy for this unmet medical need.” Ewing sarcoma is a cancer that occurs primarily in the bone or soft tissue. While it can develop in any bone, it is most often found in the hip bones, ribs or long bones. It can involve the muscle and the soft tissues around the tumor and can also metastasize to other areas of the body, including the bone marrow, lungs, kidneys, heart, adrenal glands and other soft tissues. The disease can occur at any time during childhood, but most commonly develops during puberty, when bones are growing rapidly – typically between the ages of 10 and 20. WuXi AppTec asked Dr. Breitmeyer to share his thoughts with our readers on why pediatric drug development has been slow in the past and how he sees Oncternal’s TK 216 becoming an effective, novel treatment for Ewing. Dr. Breitmeyer has served as President, CEO and Director of Oncternal since 2015. Previously Dr. Breitmeyer was President of Bavarian Nordic, Inc. and Executive Vice President of Bavarian A/S, a multinational corporation headquartered in Denmark, from 2013 to 2015.  He has been a director of Zogenix, Inc. since 2014 and a director of Otonomy, Inc. since 2018, and was their acting CMO from 2012 to 2013. He also served as the EVP of Development and CMO of Cadence Pharmaceuticals Inc., from 2006 to 2012, and the CMO of Applied Molecular Evolution Inc., from 2001 to 2006. Dr. Breitmeyer was also the founder, President and CEO of the Harvard Clinical Research Institute, and CMO and Head of Research & Development for North America at Serono Laboratories Inc. He earned his B.A. in Chemistry from the University of California, Santa Cruz and his M.D. and Ph.D. from Washington University School of Medicine. WuXi: Why are so few pediatric drugs, in general, in development? James Breitmeyer: Developing pediatric drugs can be challenging due to the small numbers of patients and the variability in pediatric subpopulations, such as between newborns and adolescents. It’s been a priority for the FDA to overcome these disincentives by offering incentives for pediatric drug development. Oncternal is strongly in favor of the FDA’s incentives for pediatric drug development—thoughtful drug development is critical to public health. We believe Oncternal could be eligible for a Rare Pediatric Disease Priority Review Voucher if the program is still active upon approval of one of our drugs, and that incentive is real. WuXi: How does developing drugs for children differ from adults? Aren’t children just small adults? James Breitmeyer: Children are not just small adults—The FDA considers pediatric development to extend to age 16 because there are significant differences and changes, especially with regards to drug metabolism and physiology that vary between age groups. There are even more dramatic changes when you consider infants and newborns. Due to these biologic differences in pediatric development, it is very important to understand drug effect and drug metabolism between subpopulations of pediatric patients. WuXi: Are there ethical issues different from adult drug development? James Breitmeyer: The ability of children to understand their disease and understand the risk and benefits of an experimental therapy varies substantially by age. Therefore, it is essential to make every effort to communicate about the clinical trial and the risks involved in terms the child can understand. It is also essential to make sure you have fully informed consent from parents or guardians. WuXi: What are the major regulatory challenges in developing drugs for pediatric cancer patients? James Breitmeyer: There are no major regulatory challenges. We have found regulatory agencies to be cooperative and helpful, especially when we seek advice about pediatric drug development. From our experience we’ve found that pediatric experts in the FDA are eager to offer assistance and advice in pediatric development programs. WuXi: What clinical development challenges do you face? James Breitmeyer: The major challenge we’ve faced working in a rare pediatric cancer has been recruiting enough participants for clinical trials. To address this issue, we have worked with patient advocacy groups and social media outreach to target patient populations and educate the public on rare disorders and alternative treatment options. WuXi: What disease are you targeting and why did you select it? James Breitmeyer: Ewing sarcoma is the second most common pediatric bone tumor. Patients with recurrent or metastatic Ewing sarcoma have a less than 40 percent overall survival rate after five years. In the last 30 years, no new therapies have been approved by the FDA specifically for Ewing sarcoma. WuXi: What kind of drug are you developing? James Breitmeyer: We set out to create a drug that targeted the Achilles’ heel of Ewing sarcoma. This target is EWS-FLI1, an oncogenic fusion protein which is one of the primary causes of Ewing sarcoma, and had been called ‘undruggable.’ TK216 demonstrates that not only is EWS-FLI1 druggable, but that the potential of TK216 inhibiting a broader range of tumors driven by similar oncogenes is an unexpected benefit. WuXi: How does your drug differ from what’s already available to children for this disease? James Breitmeyer: Standard of care for Ewing sarcoma, which is usually initially diagnosed as a bone tumor, consists of radical surgery, radiation therapy and combination chemotherapy. Unfortunately, in too many cases the frontline standard therapy is not effective and disease either reoccurs or metastasizes. If disease reoccurs or metastasizes, there is no standard second line therapy available. Therefore, alternative treatment options are critical to address this unmet medical need. WuXi: What is the mechanism of action of your drug? James Breitmeyer: TK216 is an investigational, small molecule inhibitor that affects Ewing sarcoma cells by a different mechanism of action than any available therapy, and is in fact the first potential treatment to directly inhibit a key cause of Ewing Sarcoma. TK216 targets the ETS family of oncoproteins. ETS transcription factors are important in embryonic development; however, when mutations in cancer cells such as fusion with other proteins or overexpression occur, ETS family oncoproteins have been associated with tumor initiation, progression and metastasis. Approximately 85 percent of Ewing sarcomas contain a genomic rearrangement that results in the fusion of the FLI1 gene, an ETS family member, and the EWSR1 gene, an unrelated transcription factor. Agents that block the EWS-FLI1 fusion protein were initially identified by Dr. Jeff Toretsky at Georgetown University. In collaboration, Oncternal was then able to develop more potent molecules with anti-cancer activity in preclinical models. The mechanism of action includes inhibiting transcriptome function and the activation of RNA Helicase A by EWS-FLI1. WuXi: Do you engage patients, their parents and patient advocacy groups in your clinical development programs? If so, how are they involved? James Breitmeyer: Engaging with patients, their parents and patient advocacy groups is a great way to get feedback and learn about real world impacts of disease, and issues around risk and benefit of potential therapies. All three stakeholder populations are essential to involve in clinical development and Oncternal regularly works with several Ewing sarcoma advocacy groups.   WuXi: Are there creative trends or policies that have facilitated delivery of better medicines to patients? James Breitmeyer: The FDA has launched a number of initiatives in the last few years that have had significant impacts on the process of developing novel therapies for the treatment of cancers. For example, breakthrough designation appears to be very successful at creating an acceleration of development timelines that include an enhanced level of communication between the developing companies and the FDA. These initiatives are very welcome to both patient communities and the biotech industry, and appear to be improving the efficiency of oncology drug development and potentially shortening development time. TK216 has received orphan drug designation and Fast Track status and we are very happy with our working relationship with the FDA. WuXi: For the disease area you are working on, what would be the one thing that would have the most potential to lead a paradigm shift “from treatment to cure”? James Breitmeyer: Ewing sarcoma is caused by two genes combining through genetic translocation, an event that creates a fusion protein with half of the characteristics of each gene products. By directly targeting the cause of Ewing Sarcoma and inhibiting the oncogenic process we hope one day to be able to shift the paradigm from short-term control to long-term remission and even a cure.

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2019/09/11

Redefining Therapeutics Through Control of Gene Expression, a Conversation with Nancy Simonian, M.D., President and CEO, Syros Pharmaceuticals

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and the WuXi AppTec Content Team Drug development is a very risky business. For more than 20 years, Nancy Simonian, an accomplished veteran drug developer (having served as Chief Medical Officer at Millennium Pharmaceuticals and as Vice President of Clinical Development at Biogen) with a passion for patients, struggled with the realization that most of what we do in drug development does not work and that as an industry, there is a tendency to pursue the same types of targets leading towards a redundancy of programs and drugs. Simonian was very interested in finding new ways to understand disease and to pursue new avenues of drug discovery, which brought her to the labs of Rick Young, Member at the Whitehead Institute and co-founder of Syros. His research on the control of gene expression was leading to new insights in the biology of cancer and other serious diseases. Syros was launched in 2013 with Simonian as President and CEO to pursue a new wave of first-in-class medicines based on this theme, with $30M in Series A financing from ARCH Venture Partners and Flagship Ventures and participation by WuXi PharmaTech Healthcare Fund I and other undisclosed private investors. In 2014, the company closed $53M in Series B financing led by a large, Boston-based public investment firm, which included new investors Polaris Partners, Aisling Capital and Redmile Group. Previous investors Flagship Ventures, ARCH Venture Partners, WuXi PharmaTech Healthcare Fund I and Alexandria Venture Investments also participated in this round. A $40M Series C round added Deerfield Management and Casdin Capital as well as others. The company raised $50M in its IPO in 2016. Rich Soll and the WuXi AppTec Content Team recently spoke with Simonian about Syros. “A major impediment to delivering better medicines faster and cheaper to our patients has been our lack of understanding the fundamentals of human disease biology,” Simonian noted. “Once we understand those things, we do a pretty good job of making drugs.” “Only 2 percent of the genome encodes for proteins, and most genomic work has been focused on this 2 percent. The 98 percent of the genome that does not encode proteins has been a black box,” asserted Simonian. “In fact, one of the most critical components of the non-coding region of the genome is the regulatory region, which coordinates the expression of genes. If you can understand the coordinated expression of genes and how they are regulated, you can get at the core of the function of the cell.” Syros has been a leader in understanding the regulatory genome, specifically the enhancers and the super enhancers that control the expression of critical genes for cell state and fate. They hope to get insight into the function of the cell where other technologies have failed. The super enhancers are like a dimmer switch, on, off, up or down, and control the most critical genes in cells. Syros believes that it is through these genes that we can get good insight into human disease. Syros has developed genomic biology technologies, both wet and computational, that give them a competitive edge. The company has the ability to rigorously generate, analyze and interpret genomic data and apply those capabilities to all phases of drug discovery and development from target discovery to driving the chemistry to selecting patients for clinical trials. “By understanding transcription, we get insights into disease, which is really critical,” Simonian stated. “And we’ve developed a variety of assays and technologies that really allow us to do that in an optimal way. We use our regulatory genomics approach to understand the best targets in a given disease.” Syros has been examining transcription factors and transcriptional kinases; Syros has insight regarding their control of oncogenes in cancer.   “We can ask the question: are genes changing the way we want,” declared Simonian. “What’s occurring in the normal cell vs. disease cell? We can then profile those genes. Using the Syros platform has already yielded 2 compounds in the clinic, SY-1425 (an RAR-α agonist) and SY-1365 (a selective CDK7 inhibitor). For us, it is an exciting time.” The SY-1425 program came from an analysis of the regulatory regions of primary tumor cells. Syros identified a novel biomarker by looking at super enhancers that, when present in the cancers, showed high sensitivity to the drug. Syros is in a Phase II biomarker-driven clinical trial with SY-1425, studying the drug in combination with the hypomethylating agent azacitidine, in AML patients. “Initial data were presented in December 2018 showing high overall response and complete remission rates in biomarker-positive patients and these rates were higher in biomarker-positive than biomarker-negative patients,” Simonian said. “Importantly, the drug was well tolerated without any increased signs of neutropenia, an effect which is seen often during combination therapy in AML.” For Simonian, the results support the importance of selecting patients in this trial based on this regulatory biomarker discovered by Syros’ platform. The company plans to present further data from a cohort of newly diagnosed, unfit AML patients in 4Q 2019 and hopes to have proof-of-concept (POC) data in 2020 in relapsed or refractory (R/R) AML with the same combination with azacitidine. Patients with R/R AML have a very high unmet need as overall survival is less than 6 months. SY-1365 is a highly selective CDK7 inhibitor. “We have been working on selective inhibition of CDK7 since the inception of the company because we knew CDK7 was an important component of enhancers and controlled the expression of many oncogenic transcription factors,” stated Simonian. In November 2018, the first clinical data with a selective CDK7 inhibitor was reported from the dose escalation portion of an ongoing Phase I study in advanced solid tumor patients.   “The company demonstrated proof of mechanism by showing target occupancy that correlated with efficacy in preclinical models, dose dependent and gene expression changes at doses that were generally well tolerated,” Simonian added. “We had a patient with a durable partial response and several other patients had stable disease, which is encouraging in this advanced patient population.” The company is in the expansion phase of that trial in ovarian and breast cancers. The company expects to report initial data in 4Q 2019 with potential POC data in 2020. Simonian noted that Syros also has an oral CDK7 inhibitor, SY-5609, which should be in clinical development by early 2020. Finally, Syros has a program in sickle cell disease, tackling monogenic diseases by altering the expression of disease causing or modifying genes. Last year, the company formed a partnership with Incyte in the area of myeloproliferative neoplasms to uncover disease biology and validate new targets. Simonian also acknowledged the value of WuXi’s enabling platforms. “Syros is reliant on others’ capabilities, including WuXi. Our general approach allows internal scientists to focus on activities needing our people’s expertise, particularly in the area of genomic-based computational and wet lab work,” Simonian stated. “With WuXi, we rely on your medicinal chemistry capabilities for all of our programs, process chemistry and scale up of intermediates and starting materials for API as well as for in vivo studies.” Over the next 3-5 years, Simonian hopes to have a fully integrated company with an eye towards building an enduring company that brings its products to the market. To realize its full potential, Simonian feels that new, different technologies and tools will be needed that focus on human disease to provide target validation. She hopes that by 2030 the industry sees beyond a one-size-fits-all approach and that we will likely see empowerment of patients. “Syros has built a platform that enables a better understanding of human disease and human biology, and what’s the right population and the right drug. Ultimately, in the future we’re going to be much better at understanding disease in the individual patient and being able to tailor our therapies for those patients,” Simonian said. “I would love to have therapies that cure cancer, yet at the same time there are really important medicines out there that have turned some cancers into a chronic disease, allowing patients to live a relatively normal life.” Simonian summed it up in a very optimistic manner: “I’m bullish about the future and I do think the present is the golden era of biology that will bear fruit for patients in need.”

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