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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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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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Salarius Believes Children Should Not Be Left Behind in the Fight Against Cancer

Many pharmaceutical and biotech companies shy away from pediatric drug development. While the genomic revolution has resulted in scores of new cancer treatments for adults, children suffering from cancer have been left behind. It takes a spirit of determined commitment to real innovation to overcome the obstacles to developing new pediatric therapies. That is what Salarius Pharmaceuticals CEO David Arthur feels his company and team are all about. At a recent opening session of NASDAQ, Salarius became a public company. Arthur used this as an opportunity to summarize the company’s mission: “Every day we get to come into the office, go to work and take the fight to cancer.” Salarius, based in Houston, is a clinical-stage oncology company targeting the epigenetic causes of cancers. The company’s lead candidate, Seclidemstat, is currently in clinical development for treating Ewing sarcoma, for which it has Orphan Drug designation and Pediatric Rare Disease Designation by the U.S. Food and Drug Administration (FDA). Ewing sarcoma is a devastating pediatric bone cancer and represents a major unmet clinical need. Currently, chemotherapy, radiation and tumor resection surgery are the only options for patients, and in many cases the tumors recur or develop in a location too sensitive to risk surgery. There is a 70 percent five-year mortality rate for patients whose tumors recur after treatment or who are initially diagnosed with metastatic disease. Salarius began enrollment for a Phase 1/2 trial in Ewing sarcoma in 2018.   The need for a new therapy for this disease is critical, as Arthur points out. “There are 400 to 500 children diagnosed with Ewing sarcoma every year in the U.S. and the average age of diagnosis is about 15. These are children and young adults with their whole lives ahead of them. But figures show that roughly 40 percent to 45 percent either do not respond or relapse from the standard of care. With those patients, there is an approximately 70 percent five-year mortality rate.” WuXi AppTec Communications asked Mr. Arthur to share his thoughts on why pediatric drug development has lagged behind development of adult treatments and how Salarius’ drug can make a difference in children’s lives. Mr. Arthur is an industry veteran with 25 years of experience building and leading medical and marketing organizations in product development as well as launching and managing pharmaceutical and device brands. Prior to Salarius, Mr. Arthur was Managing Director of Dacon Pharma, LLC. Additionally, he spent 20 years with Eli Lilly and Boehringer-Ingelheim in executive roles managing product development, business development, US business, global commercialization, European regional marketing and financial planning/analysis. Mr. Arthur earned a BS in Chemical Engineering from North Carolina State University, an MBA from the Duke University Fuqua School of Business, and is a licensed Professional Engineer and Six Sigma Green Belt. WuXi AppTec: Generally speaking, why are there so few pediatric drugs in development? David Arthur: This is an amazing time for drug discovery and development. With the advances in genetic and diagnostic testing, we are entering a new era of medicine that is capable of developing novel treatments for rare diseases and different cancers every day. However, many drug companies remain disinclined to develop medications for pediatric uses due to small market size and the complexity involved in developing drugs for infants and children. Salarius Pharmaceuticals has stepped up to the challenge by focusing on the development of therapies for pediatric and rare cancers with high unmet needs or for which no targeted therapies are available. In the past 40 years, fewer than 10 drugs have been developed for use in children with cancer, a number that pales in comparison to the hundreds of therapies developed for adult cancers. Our understanding of the various childhood cancers has grown, yet roughly one out of every five pediatric cancer patients will die from their disease. Research into many rare pediatric illnesses often lacks the funding necessary to develop therapies and treat patients in clinical trials. So, with many forms of pediatric cancer, medical advances have been slow and mortality rates remain high. WuXi AppTec: How does developing drugs for children differ from adults? Aren’t children just small adults? David Arthur: No, this is a misconception. Children respond to medications in a very different way than adults. Drugs that are generally safe and effective for adults may be unsafe or ineffective — or both— for some or all pediatric age groups. It is truly unfortunate when the only available treatments are harsh and potentially debilitating, such as the standard chemotherapeutic agents. Besides the severe short-term side effects, chemotherapeutic agents are often associated with long-term consequences, and that can be especially troubling when the patients could still have 60 or more years of life expectancy. That is why Salarius is working to develop safer, less toxic treatments for this critical population. WuXi AppTec: What are the barriers to developing drugs for pediatric cancer patients? David Arthur: Childhood cancers represent a relatively small portion of the U.S. oncology market. Of the estimated 1.7 million new cancer diagnoses expected to be made in the U.S. in 2019, 11,060 could involve children age 15 and younger, according to the American Cancer Society. Add the political backlash over high prices for new medications, and some drug industry players see little incentive to invest in pediatric oncology drug development. But the barriers to developing new cancer drugs for children go beyond market size and potential sales. There are also scientific challenges, such as the smaller number of genetic mutations in children that can serve as therapeutic targets. The biological differences between infants, adolescents and young adults make drug development even more complex. And because experimental drug candidates sometime have toxic side effects, researchers and drug companies are reluctant to include children in clinical trials until safety has first been established in adults, a process that can take years. WuXi AppTec: Is this landscape changing? David Arthur: It is, though slowly. President Trump placed pediatric cancer in the national spotlight this year when he promised during his State off the Union address to add $500 million to research funding during the next decade. Also, several pieces of legislation have been passed that not only expand funding and incentives for drug makers to develop therapies for pediatric cancer patients, but also compels the inclusion of children, as well as adults in cancer drug studies starting in 2020. For example, members of the congressional Childhood Cancer Caucus introduced legislation in September 2019 that would reauthorize the Creating Hope Act, making permanent the FDA’s rare pediatric disease Priority Review voucher program. This is a fantastic program, effectively self-funded by the pharmaceutical industry, which incentivizes drug development expressly for children with cancer and other life-threatening illnesses. Yet the rare pediatric disease Priority Review voucher program is the only voucher program created by the Creating Hope Act that is not permanent. Certainly, the majority of Big Pharma remains attracted to adult cancer’s larger market size. But there is support available from other sources, such as not-for-profit organizations and foundations. Salarius has received more than $20 million in non-dilutive capital and in-kind support from The Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation (NPCF). Also, we are fortunate to have the support of shareholders who want to do good by putting their money to work to advance the development of cancer therapies for children. WuXi AppTec: What form of pediatric cancer is Salarius targeting and why was it selected? David Arthur: Our lead drug candidate Seclidemstat is being studied in a Phase 1/2 clinical trial for Ewing sarcoma, a rare, devastating and deadly pediatric and adolescent bone and soft-tissue cancer. In the U.S. this year, roughly 500 cases will be diagnosed in patients with an average age of 15 years. And 70 percent of patients who relapse or are initially diagnosed with metastatic Ewing will die within five years. We are talking about adolescents who should have their whole lives ahead of them. Is there any better motivation to support the development of pediatric medicines? At Salarius, we are studying epigenetic-based strategies for the treatment of cancer. Based on that research and the lack of targeted treatments available for patients, we feel that we have a real shot at having a meaningful impact in Ewing sarcoma that could benefit the lives of these children and their families. WuXi AppTec: Can you describe Seclidemstat? What type of drug is it and what is its mechanism of action? David Arthur: Seclidemstat is a reversible inhibitor of lysine specific demethylase 1 or LSD1, which is an extensively-studied epigenetic enzyme that is often highly expressed in cancers. Epigenetics is the study of the regulatory system that controls how gene expression is turned on and off. If the epigenetic enzymes that regulate gene expression become dysregulated, it leads to inappropriate activation and silencing of genes, which can lead to the development and progression of cancer. Drugs that are able to safely modify the activity of these epigenetic regulators may correct the gene changes that are driving disease and provide a new treatment for these cancers. In the case of Ewing sarcoma, a chromosomal translocation produces a fusion oncoprotein. The fusion oncoprotein recruits other proteins to alter gene expression to a cancer promoting state. Unfortunately, the oncoprotein itself is difficult to directly target because it is a highly disordered protein. An alternative strategy is to target proteins that interact with the oncoprotein. This is the approach Salarius is taking. Salarius’ lead compound, Seclidemstat, targets the LSD1 enzyme, which is known to interact with the Ewing sarcoma oncoprotein. Salarius licensed the technology from the University of Utah’s Huntsman Cancer Institute, where it was developed by Dr. Sunil Sharma, Salarius’ scientific founder. By inhibiting LSD1 from associating with the oncoprotein, we have shown the ability to reverse the aberrant gene expression. In animal models, Seclidemstat has been shown to slow down, or stop the growth of Ewing sarcoma tumors, and we hope to have a similar therapeutic impact in our ongoing clinical trials. WuXi AppTec:  What do you mean by a reversible LSD1 inhibitor? David Arthur: There are a number of companies researching LSD1 inhibitors. We believe Seclidemstat is one of only two reversible LSD1 inhibitors now in the clinic, and that is an important distinction. An irreversible inhibitor permanently binds to the FAD cofactor within the LSD1 enzyme. Since LSD1 is required for cell homeostasis, irreversibly inhibiting the protein leads to adverse effects which are considered “on-target” as they are related to the biology of LSD1, such as hematological toxicity. In contrast, Seclidemstat reversibly binds to LSD1 allowing it to maintain some degree of functionality; we have not observed any hematological toxicity to date. This gives us the opportunity to explore more flexible dosing schedules which can potentially allow for a higher chance of therapeutic activity.   WuXi AppTec: How does Seclidemstat differ from the treatments already available to children with Ewing sarcoma? David Arthur: Right now, children and young adults diagnosed with Ewing sarcoma have few treatment options, and to be honest, none of them are good. There are no targeted therapies approved for the disease. The standard of care is surgery to remove the primary tumor, radiation and often multi-regimen chemotherapy. In roughly 40 percent to 45 percent of cases, patients don’t respond to the standard treatment or suffer a relapse. Among these patients, there is around a 70 percent mortality rate within five years. WuXi AppTec: So, Salarius hopes to provide a less toxic, more effective therapy. Am I right? David Arthur: You’re absolutely right. In fact, that is the exact mission of the National Pediatric Cancer Foundation, and it is one of the reasons Salarius has received, and continues to receive, such tremendous support from the organization. WuXi AppTec: What is the clinical path forward for Seclidemstat?  Can it be accelerated? David Arthur: Seclidemstat is now in a Phase 1/2 clinical trial involving patients who have failed to respond to previous treatment or who have suffered a recurrence of their tumors. Right now, we are establishing a maximum tolerated dose and developing a safety profile. Patients will be treated with that maximum tolerated dose in a dose expansion phase of the trial. Early safety and efficacy data should be available in 2020, and once we have compiled full results, Salarius will meet with the FDA and talk about the most efficient and expeditious path forward. Is there an opportunity for accelerated approval? We hope so given the unmet need in Ewing sarcoma. Seclidemstat already has Orphan Drug Designation and Rare Pediatric Disease Designation from the FDA. If proven safe and efficacious in early clinical studies, Seclidemstat could qualify for Breakthrough Status, which provides access to programs that accelerate drug development and FDA approval. Also, Seclidemstat could be eligible for priority review and upon approval, receive a Pediatric Priority Review Voucher. WuXi AppTec: Does Salarius engage patients, their parents and patient advocacy groups in your clinical development programs? If so, how are they involved? David Arthur: As I mentioned earlier, Salarius has been fortunate to receive tremendous financial support from both the Cancer Prevention and Research Institute of Texas (CPRIT) and the National Pediatric Cancer Foundation. In fact, the NPCF is funding a significant portion of our ongoing Phase 1/2 study of Ewing sarcoma. The NPCF has also assisted with the initiation of our clinical studies. Salarius is using the foundation’s network of research hospitals, called Sunshine Project Hospitals. This is a great example of industry and not-for-profit foundations working together to address an unmet need. WuXi AppTec: 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?” David Arthur: Developing a therapy targeting the root cause of the disease that is safe and effective would be a giant step forward.

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DelMar Developing Drug to Cross the Blood Brain Barrier to Treat Deadly Glioblastoma Disease

Glioblastoma Multiforme (GBM) is the most common and most lethal form of brain cancer. GBM affects an estimated 12,000 new patients each year in the US alone. The median survival in newly diagnosed patients with the best available treatments is 20.5 months. After diagnosis, today’s standard treatment includes surgical resection of the tumor followed by radiotherapy and chemotherapy with temozolomide (TMZ). Nearly all GBM patients relapse following first-line treatment, and those patients have a one-year survival rate of approximately 25 percent. The average five-year survival rate is less than 3 percent. Treating glioblastoma is very difficult due to several complicating factors: the tumor cells are very resistant to current approved treatments, the brain is susceptible to damage from conventional therapy, the brain has a very limited capacity to repair itself and, perhaps most important, many drugs cannot cross the blood–brain barrier to act on the tumor. The brain is the only organ known to have its own defense system, a network of blood vessels that allows the entry of essential nutrients while blocking others. Ironically, this barrier effectively prevents life-saving drugs from being able to repair the injured or diseased brain. DelMar Pharmaceuticals President and CEO Saiid Zarrabian believes its lead drug, VAL-083 can penetrate this barrier and deliver an effective treatment. “VAL-083 has the potential to treat newly diagnosed patients as a ‘front-line’ treatment in conjunction with radiotherapy, as a ‘maintenance’ treatment after patients complete radiotherapy, and as ‘salvage’ therapy after treatment with temozolomide,” said Zarrabian. “VAL-083 is a small molecule DNA targeting therapeutic that has been proven to cross the blood brain barrier, and to have tumor effecting properties in multiple PH1 and PH2 clinical studies. The biological and tumor effecting activity has been demonstrated in numerous clinical trials and in a prior glioma study has shown extension of median survival rates nearly double that of radiation alone,” he added. WuXi AppTec Communications has begun a new series looking at novel and potentially breakthrough drugs which can make a difference in people lives, especially treating a disease as deadly as glioblastoma. We discussed with Zarrabian the challenges drug developers have had finding an effective therapy for this disease and why he believes the drug will become a successful treatment. Zarrabian is an industry veteran who has served as San Diego based DelMar’s Chief Executive Officer since November 3, 2017, and President since January 1, 2018. Since October 2016, Zarrabian has served as an advisor to Redline Capital Partners, S.A., a Luxembourg based investment firm. From 2012 to 2014 he was Chairman and member of the Board of La Jolla Pharmaceutical Company. From 2012 to 2013 he was President of the Protein Production Division of Intrexon Corporation, a synthetic biology company. He has also been CEO and member of the Board of Cyntellect, Inc., President and COO of Senomyx, Inc., a company focused on discovery and commercialization of new flavor ingredients, and COO of Pharmacopeia, Inc. WuXi AppTec: What are the challenges involved in diagnosing and treating brain cancers? How important is early detection? Saiid Zarrabian: Diagnosis is not the major issue. This disease is hard to treat due to its rapid growth rate of 1.5 percent per day at peak growth, challenges with removing the tumor surgically, as well as the possibility of random cancer cells elsewhere in the brain. Unlike many other solid tumors where the tumor body and sufficient margin tissue can be removed without life threatening or debilitating results, it is not possible to remove the whole tumor mass in GBM both because it infiltrates micro capillaries in the brain and because of our inability to remove tissue surrounding the tumor given its location in the brain. All of this requires a systemic approach to GBM vs. a local solution, which creates the critical necessity of the drug’s ability to cross the blood brain barrier. WuXi AppTec: Why has it been so difficult to find druggable targets for glioblastoma? Saiid Zarrabian: Despite decades of effort to identify and develop novel drug candidates for GBM, most if not all have failed in clinical trials. There are many reasons for this including the impact of the blood brain barrier which limits the exposure of chemicals to protect the brain against toxicities. In addition, many potential biological targets and pathways identified for GBM are vulnerable to mutations that cause the tumors to become resistant to the potential anticancer effects of the therapy. Recently, it has been confirmed that GBM is an immunologically “cold tumor” due to the lack of T cells infiltrating the tumor and as such is a challenging target for novel immunotherapy (I-O) treatments. This creates a much tougher challenge for many existing and new I-O treatment options as the human body’s immune defense mechanisms cannot be effectively exploited for successful brain tumor therapies. WuXi AppTec: Has genomic analysis of glioblastoma improved drug discovery? If so, how? Saiid Zarrabian: Yes, modern genomic analytical techniques have identified various gene expression patterns and mutations in GBM which have been the subject of drug development efforts. These include EGFR viii, IDH wild type versus mutations, and the identification of the expression of MGMT (methyl guanine methyl transferase) a critical DNA repair protein which limits the efficacy of temozolomide first-line therapy for GBM. VAL-083 is active for patients who have been identified through genomic diagnostics to have an unmethylated promoter for MGMT. WuXi AppTec: How did you choose to focus on glioblastoma? Saiid Zarrabian: Although VAL-083 has been studied by the National Cancer Institute (NCI) in approximately 40 Phase 1 and Phase 2 studies in multiple indications the GBM program was the most advanced and the most likely to reach early success vs. other indications like ovarian cancer and non-small cell lung cancer. WuXi AppTec: How did you develop your drug candidate? Saiid Zarrabian: VAL-083 was originally developed at NCI, where close to 40 PH 1 and PH 2 trials in multiple indications were completed. DelMar’s founder and current CSO obtained the right to reference the IND for the drug, including all the preclinical and clinical study information that was developed prior to DelMar’s IND submission. DelMar has been advancing the drug since that time. WuXi AppTec: What is the mechanism of action? Saiid Zarrabian: VAL-083 is a DNA targeting agent that readily crosses the blood-brain barrier and has been shown to preferentially accumulate in brain tumor tissue. VAL-083 exhibits a unique bi-functional DNA crosslinking cytotoxic mechanism creating cross-links at the N7 guanine position. This mechanism is different from existing chemotherapeutic agents used in the treatment of GBM, such as temozolomide, and is not susceptible to the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair pathway. This results in the potential for VAL-083 to be more effective, initially in treating the approximately 60 percent of GBM patients whose tumors are MGMT unmethylated, and for whom the current treatment of temozolomide has limited clinical benefit. In the future, we hope to also include the remaining GBM patients without the MGMT unmethylated status as the drug is agnostic to this biomarker. The choice to go after this biomarker identified population is purely to help accelerate the process and get to the goal line of providing a better treatment option for this grossly underserved GBM patients first, before we extend the study for the remaining patients. WuXi AppTec: What regulatory challenges do you face in clinical development? Saiid Zarrabian: The typical challenges of making sure you have the right study design, the right efficacy endpoints, and are treating the right patient population. Fortunately, DelMar has fast track status with the FDA for VAL-083, so we can benefit from ongoing discussions with the agency on these types of issues. WuXi AppTec: Have you worked with patients in developing your drug development strategy? If so, how? Saiid Zarrabian: Our clinical studies involve extensive pharmacokinetics (PK) analysis. This is important to determine optimized patient dosing and scheduling. In addition, measurement of VAL-083 in the CSF (cerebrospinal fluid) which some patients have consented to, has helped determine the sufficient extent of drug penetration in the brain. WuXi AppTec: What lessons have you learned during the drug development process? Saiid Zarrabian: The importance of working with the right partners. From the manufacturing process where we work with STA Pharmaceutical Co., Ltd. (a WuXi AppTech company) and Italfarmaco, to conducting clinical trials with M.D. Anderson Cancer Center and Sun Yat-sen University Cancer Center, we have seen how important it is to work with the best possible collaborators. WuXi AppTec: How soon will we have an effective treatment for glioblastoma? Will effective treatments require combinations of drugs? Saiid Zarrabian: We expect the completion of both our current Phase 2 trials in approximately a year. The current trials are single agent trials with VAL-083. The Phase 3 registration study timeframe somewhat depends on the results from our current trials, but we are optimistic that we can initiate a trial in 2021, with a drug reaching the market as early as 2023. WuXi AppTec: Can you comment on the specific progress or lack of progress in treating this disease in the last ten or 20 years? Saiid Zarrabian: The development of new therapies for GBM has been extremely disappointing. Many promising approaches have not realized survival benefits for patients due to challenges in developing drugs that effectively cross the blood-brain-barrier, and the inherent aggressiveness of the tumor. There have been extensive clinical trials for drugs affecting unique cellular targets and biologics for immunotherapy that have not met the appropriate clinical trial efficacy outcomes for FDA approvals. In addition, interest and investment by large pharmaceutical companies has been very limited. The creation of novel therapeutics with those unique attributes for brain tumors has not been a high priority. WuXi AppTec: What are the top three impediments to delivery of better medicines faster and cheaper to patients? Saiid Zarrabian: Access to capital, ability to enroll an adequate number of patients quickly into clinical trials, and necessary regulatory hurdles. 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? Saiid Zarrabian: Cancer prevention and early detection will probably provide the greatest impact to solve the cancer problem. The modern genomic screening tools and other diagnostics will continue to provide valuable support to identify patients at risk and potentially more effective therapeutics. Being able to target specific populations of patients, such as DelMar’s approach for MGMT unmethylated GBM patients, can lead to better outcomes.

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Paving the Way to a New Generation of CNS Drugs: Karuna CEO Steve Paul, Neuroscience’s Renaissance Physician, Psychiatrist, Neuroscientist and Executive

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team There are few who have Steve Paul’s perspective, experience and track-record in the neurosciences. A former scientific director at the NIMH/NIH, Paul was formerly President of Lilly Research Laboratories and an accomplished entrepreneur at Third Rock Ventures. Additionally, he co-founded two CNS-focused companies, Sage Therapeutics and Voyager Therapeutics (a gene therapy company). Now, Paul is CEO and Chairman of Karuna Therapeutics. Throughout his multi-decade career, Paul’s interest in the neurosciences and drug discovery, particularly for psychiatric and neurological disorders, never diminished – despite a shrinking emphasis on neuroscience worldwide.          His latest entrepreneurial endeavor is with Karuna, a neuroscience startup developing first-in-class therapeutics to improve quality of life for people living with schizophrenia, Alzheimer’s disease and pain. Rich Soll and the WuXi content team recently caught up with Paul to discuss Karuna and the revitalization of the neuroscience field in general. “In the neurosciences, antipsychotics and Selective Serotonin Reuptake Inhibitors (SSRIs) once dominated the commercial pharmaceutical market; they dwarfed oncology and most other therapeutic areas,” explained Paul. “However, the collapse of the CNS market was attributable to several factors, including limited efficacy, tough clinical trials due to large placebo effects, and nothing better in the pipeline—a dearth of innovation.” That has been changing in recent years. There’s an incredible amount of basic genetic and biological understanding of the etiology of many neurological disorders, especially diseases such as Parkinson’s disease, Alzheimer’s disease, MS, ALS, and Huntington’s. For psychiatric disorders, there’s little that is well understood with respect to genetics, and even those that are clearly inherited are highly polygenic disorders, which makes it very difficult to identify and validate drug targets based on genetics alone. “Our knowledge about the intricacies and complexity of chemical neurotransmission, on the other hand, has advanced considerably over the last decade,” exclaimed Paul. “And we have capitalized on this knowledge with my first company, Sage Therapeutics, where we have developed a rich pipeline of drugs targeting GABA and glutamate receptors, including a recently launched drug for treating postpartum depression, and now with Karuna. These developments are happening primarily in small companies who work in the neurosciences.” Karuna’s lead compound, xanomeline, was originally developed at Lilly in the 1990s for improving cognition in advanced Alzheimer’s patients. Although cognition was only modestly improved in this Phase 2 study, other neuropsychiatric symptoms, for example agitation and psychotic symptoms such as hallucinations and delusions (observed in 40-50 percent of advanced Alzheimer’s disease patients) were substantially improved, and this was accomplished without many of the troublesome side effects of traditional antipsychotic drugs, such as sedation and weight gain. However the elderly population did not tolerate the drug well due to peripheral cholinergic side effects. In another Phase 2 study in another form of psychosis that occurs in patients with schizophrenia, the drug once again appeared to be active. “The drug stimulates preferentially two of the five G-protein coupled muscarinic receptors, M1 and M4 receptors, which led to both the beneficial and side effects. Although xanomeline was not developed further by Lilly, the drug nevertheless had a remarkable antipsychotic profile,” said Paul. “A simple, but elegant solution to this dilemma unfolded: Formulate xanomeline with a generic, non-brain penetrating, peripherally-acting muscarinic antagonist, specifically trospium.” Trospium had other favorable features, including a long elimination half-life enabling it to cover the presence of xanomeline around the clock. Moreover, it’s not metabolized by the same liver enzymes as xanomeline, which meant likely fewer drug-to-drug interactions. The combination product is tagged KarXT. Two Phase 1 studies have been conducted with KarXT and the combo has shown good tolerability. Currently, a large Phase 2 schizophrenia study is ongoing and by year’s end we will know if we see the same antipsychotic effects of xanomeline while attenuating its side effects. “Based on feedback from three independent safety monitoring reviews of our unblinded Phase 2 data, we are cautiously optimistic that we have improved the tolerability of xanomeline through this reformulation,” proclaimed Paul. “We are very focused on M1 and M4 receptors and hope to eventually have other exciting drugs that stimulate these and other GPCRs and in different ways.” Paul was a senior author on the initial Lilly paper describing xanomeline’s antipsychotic effect in Alzheimer’s disease. “People ask me all the time ‘Why didn’t you think of this or do this when you were back at Lilly?’” Paul shared. “It’s interesting. I think we, in our zest to get the purest and cleanest kind of molecules, sometimes ignore data that’s sort of sitting right in front of us. Even if we had thought of this combination strategy, I don’t think we would have pursued it. It was just too inelegant for a large company. What we did was to go back to the labs to try to come up with a single molecule that had fewer of these peripheral cholinergic side effects and still retained the therapeutic benefits. We worked on that for 20 years, and we couldn’t do it.” Paul believes Karuna’s approach has the potential to produce a differentiated therapy relative to current D2 dopamine receptor-based antipsychotic drugs, whose roots date back to the 1950s, and to beneficially impact the lives of millions of patients with schizophrenia and other psychotic and cognitive disorders. Antipsychotics are often used by physicians to address a wide range of neuropsychiatric disorders but are associated with modest efficacy and significant side effects. Karuna believes the preferential stimulation of M1 and M4 muscarinic receptors in the CNS may also address the negative symptoms of schizophrenia, such as apathy, reduced social drive and loss of motivation, as well as cognitive deficits in working memory and attention, all of which currently lack any approved treatments. Other beneficial properties of xanomeline have also been uncovered. It has been known for years that nonselective muscarinic agonists have analgesic properties. Scientists at AstraZeneca published a paper a few years ago showing that xanomeline has very potent analgesic effects across a broad range of animal pain models. “We know that the pathway that mediates the analgesic effects are mediated via muscarinic receptors, instead of opiate receptors,” said Paul. “The drug reduces pain in various animal models distinct from the opiate receptor, so this could be a non-opioid pain medicine. To me, that’s remarkable that you can take an old drug that has been ignored, but you need to ask the right questions at the right time. If it works, we’ll also have good IP protection on the co-formulated product.” Karuna, initially a PureTech-incubated biotech, completed its IPO in early July, raising approximately $102.6 million. So far, it has built its pipeline on the broad therapeutic potential of its lead product candidate KarXT as an oral modulator of muscarinic receptors. However, its intent is to commercialize in the U.S. and partner for all other regions. In five years, Paul’s plan is to have launched its first medicine, KarXT for acute psychosis in schizophrenia and Alzheimer’s disease, to have something in pain, and to have a very full mid-stage and early stage pipeline. All of these plans are being conducted from a virtual organization, no labs. “In today’s ecosystem, this is possible because of organizations like WuXi AppTec, where many parts of the value chain can be accessed with high quality and with people every bit as good as we had in the glory days of big pharma,” stated Paul. “Currently, there are literally hundreds of smaller companies discovering and developing medicines in a very different way than we had traditionally done at big pharma. Gaining access to these critical components was not possible 20 years ago but now they are available, and they are cost-effective solutions.” Paul also discussed two potentially game-changing technologies. The first relates to the availability of reliable, high throughput, in-silico chemistry approaches where biological targets with structural information, including crystal or Cryo-EM structures, are used to find chemical hits and leads much quicker; in many cases the compounds have already also have been prescreened for drug-like properties. The second relates to screening behaviorally complex disorders such as depression or schizophrenia, essentially using phenotypic screening in mice, coupled with artificial intelligence and machine learning analytics, which allow for the design molecules that can modulate complex behavioral biology in a predictable way. Paul concluded with this thoughtful insight: “Looking to the industry’s future there will definitely be more effective CNS drugs approved and more affordable drugs to boot. In the case of Karuna, we’re focusing on psychotic disorders and hope to introduce the next generation of antipsychotic drugs, arguably the first new generation in half a century. That makes me feel good.”

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