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2019/11/05

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

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

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2019/11/05

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

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

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2019/10/30

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

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

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2019/10/25

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

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

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2019/10/23

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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