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2019/09/19

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

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

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2019/09/18

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

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

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2019/09/11

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

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

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2019/09/10

Kymera’s Next Generation Therapeutics: Protein Degraders. New Way and New Rules for a New Modality.

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team Proteins are essential to proper cellular function. Protein dysfunction, arising from any number of causes, can lead to serious diseases. It is often a struggle to pursue disease-causing proteins using existing modalities such as small molecule inhibitors, therapeutic antibodies, and oligo-based therapeutics, which highlights the need for new therapeutic approaches. Kymera Therapeutics has been pioneering a novel approach: targeted protein degradation (TPD). This exciting new modality leverages the body’s natural protein recycling system – the Ubiquitin Proteasome System – whose normal function is to degrade proteins when they are no longer needed. Kymera is seeking to harness this system to redirect the cellular process and degrade specific proteins that contribute to a large variety of diseases. This affinity-based technology was pioneered in the early 2000s, but limitations confined it to academia. Recent advances in the understanding of protein degradation, like the concept of ligandability to E3 ligases, in particular the discovery of small molecules that bind specifically to this class of proteins, have created a surge of interest. This game-changing development led to the founding of Kymera in 2016. Kymera’s heterobifunctional molecules are designed to catalytically recruit a protein to an E3 ligase and tag it for ubiquitination followed by subsequent degradation. The company uses their innovative Pegasus platform to develop the necessary components to efficiently identify and degrade disease-causing proteins with their proprietary E3 ligase toolbox, state of the art degradation assays, and predictive modeling capabilities. Kymera emerged from stealth mode in 2017 with a $30M Series A launch backed by Atlas Venture—which co-founded, seeded and incubated the company—along with Lilly Ventures and Amgen Ventures. Kymera raised $65M in Series B financing in November 2018 with investments from a stellar group of big name VCs and corporate venture fund. The company has established pharma partnerships with GSK and Vertex Pharmaceuticals. Rich Soll and the WuXi AppTec Content Team recently spoke with Mainolfi about Kymera. Kymera’s target selection strategy is based on unmet medical needs, a high degree of target validation, clear patient stratification hypothesis and the prospect for overcoming the limitations of currently available therapies.  “Let’s take STAT3 as an example,” said Mainolfi when describing how the company makes its targeting decisions. “The JAK-STAT pathway is one of the most well validated pathways in human biology but the key node (STAT3) hadn’t previously been drugged well. We identified small molecules that could bind to STAT3 and the E3 ligase of interest. We were able to degrade STAT3 fully in cells as well as in vivo, and we now have degraders that are able to degrade STAT3 and fully regress tumor types sensitive to this mechanism in xenograft models.” In Mainolfi’s view this represents complete success in dissociating binding and function from binding and degradation. “The beauty of the technology is you can go after proteins that are traditionally not inhibitable by small molecules, but you can still do it with a small molecule based technology,” Mainolfi said. “The end compound can be delivered orally or parenterally.” The body’s UPS system uses ligases in a very specific, targeted way to ensure that only the desired proteins are degraded. When asked about how Kymera’s Pegasus platform dealt with this difficulty, Mainolfi indicated that there were three key components to the solution. First, Kymera invested very heavily in building a comprehensive model to understand the fundamental principles of protein degradation to enable the team to predict how changes in molecules would affect various steps of this cascade. Second was Kymera’s use of novel E3 ligases. This technology in fact allows Kymera to almost completely decouple the natural specificity of E3 ligases to substrate. This process enables them to expand their drug discovery “toolbox” well beyond what is possible with traditional methods. Third is Kymera’s sharp focus on the properties of their molecules. “Discovering and developing drugs has always been our priority,” Mainolfi emphasized. “We were able to develop orally active compounds for our drug programs very early on in the process. The Kymera team has vast discovery experience and collectively we developed several drugs now on the market.” Mainolfi affirmed the effect of protein degradation is different from the traditional protein inhibition approach. He reiterated his company’s commitment to pursuing targets that provide unique or additional value beyond what current methods offer. “One example in our pipeline is IRAK4. IRAK4 is a protein that can be inhibited in its kinase domain by small molecule kinase inhibitor,” Mainolfi said. “But we have demonstrated that removing the whole protein has a unique and superior phenotype in blocking downstream biology compared to traditional small molecules.” This is only one of the examples in Kymera’s pipeline showing degradation can redesign treatment paradigms. Mainolfi indicated that Kymera’s rapid progress is a combination of internal effort and external partnership. He described Kymera’s partnership with GSK as a technology collaboration centered around two key areas. First, Kymera utilizes GSK’s DNA-encoded library to identify small molecule binders to targets of interest to Kymera. The second area of the collaboration is jointly identifying new E3 ligases and together finding ligands to these novel E3 ligases. He also praised Kymera’s collaboration with Vertex; their strategic partnership deal was signed in May 2019. In the agreement the two companies have promised to work together on six targets that Vertex is interested in, with an option for Vertex to license and develop the targets should they prove viable and with Kymera receiving royalties and payments for specific milestones. “The great thing about the Vertex deal is that it allows us to maintain ownership of our pipeline while expanding our platform impact,” Mainolfi shared. “This helps us further the mission to make Kymera a target and disease agnostic protein degradation company. And Vertex is a great partner, they’re pursuing some really interesting areas of biology and clinical investigation.” Mainolfi also spoke highly of WuXi’s role as a supporting platform. This allowed Kymera to focus on what it does best while maintaining a small footprint. “We’ve had a long-standing collaboration with WuXi. Our long-term partnerships with many functions of the WuXi team around chemistry, biology, preclinical safety, etc. have enabled us to make really great progress across several programs.” Mainolfi indicated that Kymera is aiming to be a fully integrated drug discovery and development company, successfully taking programs from target ID all the way to commercialization. “We probably cannot achieve this on our own for every program,” Mainolfi admitted. “But we will continue to build our pipeline and work with the appropriate partner when it makes sense. It is important that in 2020 we start clinical investigation of some of our more advanced programs and continue to reach clinical stages with new products each year. We will need to continuously enhance our platform and to be the partner of choice for investors, collaborators, and partners.” “To further a paradigm shift, we also need to have better target validation and translational models that help reduce risk in the early phases of drug discovery. In addition, I would like to better understand protein folding to better predict small molecule ligandability,” Mainolfi stated.  Casting his eyes forward into the future, Mainolfi expects that by 2030 many of Kymera’s current early stage technology platforms will be an integral part of the industry. He expects to see targeted protein degradation applied far beyond its current applications in oncology, utilized in the areas of rare disease, immunology, and neuroscience. And he strongly believes that Kymera will have a huge role to play in the future of medicine.

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2019/09/10

Pioneering Gut Science, Kintai Therapeutics Is Bringing a New Small Molecule Modality to Fruition

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team What if the gut, widely regarded as the body’s second brain, could offer a much more impactful means to effect broad systemic pharmacological actions of orally administered drugs based on the confluence of the enteric nervous system, immune system, and microbiome within it? Scientists at Kintai Therapeutics, based in Cambridge, Massachusetts, have been investigating the nuanced interconnections of a wide variety of systems in the gut. Their explorations have led to fruitful insights and data that have inspired a transformational view that the gut could serve as a way to effectively promote health and to treat disease. Kintai was founded in 2016 by Flagship Pioneering and operated in stealth mode until its CEO, Paul-Peter Tak, was appointed to the organization in October 2018. Tak, who has deep experiences in experimental medicine and specializes in immunology, recognized that leveraging the natural environment of the gut could pave the way for a new class of transformative medicines – and create a new modality of drug treatment. With an eye towards commercialization, Kintai is building a lean workforce, using the flexibility of its partners instead of building vertically with fixed costs. Tak’s vast experiences include being the founding chair of what became one of the world’s largest experimental medicine centers in immunology at the Academic Medical Center of the University of Amsterdam, starting a gene therapy company, and leading GSK’s immuno-inflammatory, oncology and infectious disease R&D as Senior Vice President and later as Chief Immunology Officer. His pioneering work on the role of the vagus nerve in chronic inflammation set the foundation for bioelectronics as a therapeutic approach in autoimmune disease and served, in many ways, as partial validation of Kintai’s platform. In a recent interview with Rich Soll and the WuXi AppTec Content Team, Tak shared the company’s deep gut-related expertise and how it is searching for innovative therapies by exploring the enteric signaling network. Tak believes their approach can drive revolutions in the field of oncology and neuroscience, as well as areas like longevity and healthy aging. “The gut is a very interesting and unique part of the body that forms what is known as the enteric signaling network,” Tak noted. “First, it contains 70-80 percent of our immune cells which then circulate throughout the whole body. Second, there are five hundred million neurons in the gut serving as a second brain and sending signals throughout the body, and third, 95 percent of the microbiome, weighing about three pounds, is found in the gut, producing metabolites and mediators that serve as signaling molecules,” he continued. “Collectively, this constellation serves as a hub of communication to the rest of the body to maintain health. Its dysfunction is implicated in a host of diseases and it can have a profound impact on a drug’s efficacy and toxicity profile.” Kintai has assimilated this knowledge to use as an opportunity for targeting potent therapeutics, exploiting the properties of the gut to activate specific pathways exactly where they need to be activated. For example, in the colon for cases of ulcerative colitis or the liver for cases of non-alcoholic steatohepatitis (NASH). Kintai has utilized this knowledge of the gut to make pioneering discoveries, including the identification of over 44,000 new genes, 19,000 protein families, and hundreds of new metabolites that were not previously known. The knowledge gained from this system has formed Kintai’s proprietary Precision Enteric Medicine™ (PEM™) discovery platform to seek out new druggable targets implicated in disease and has allowed a mapping of the entire enteric system for which Kintai has assembled multi-omics data.  Through technology development, Kintai has actually doubled its knowledge of biodiversity of the gut.  When integrated alongside next generation sequencing, metabolomics, and machine learning, a powerful and deep understanding of the relationship of these cells to health and disease can then be achieved. Leveraging these insights, Kintai has rapidly built a highly actionable pipeline, which now has 10+ programs across multiple therapeutic areas, including oncology, neurology, and immunology.  The company is “in the race to the clinic” and at the time of the interview just got its first IND number for its first program which is in ulcerative colitis. According to Tak, this program is expected to enter the clinic in the first half of next year, taking less than three years from idea to clinic, which he called “remarkable by any standard.” Tak expects the ulcerative colitis product to be a major drug and is confident that it can validate different aspects of their platform. This new chemical entity is inspired by the effects of natural metabolites in the colon, and has the potential to improve the efficacy of clinical treatment by at least 50 percent for patients with abdominal pain, bloody diarrhea, fatigue and other important signs and symptoms. The second program, driven by unmet needs in metabolic syndrome, which is characterized by obesity and other symptoms, is expected to move into the clinic at the end of next year. Two additional programs will go into the clinic in two years from now, and in the short to medium term, Kintai is building a pipeline in neurology and cancer, while increasingly exploring longevity and healthy aging. Projecting into next few years, Tak expects the company to feed its pipeline with at least two candidates per year. While all of the company’s programs were developed in-house, Tak stressed the importance of peer review, partnership, and collaboration, including working with external partners like WuXi AppTec. One form of peer review comes from the company’s esteemed scientific advisory board and another from specific program advisory boards. The company has also established strong ties to academia. It recently established new collaborations with a few leading academic institutions, such as Moffitt Cancer Center, Rhode Island Hospital and the University of Cambridge, to identify novel molecules that play a fundamental role in microbiome to human signaling in different forms of cancer. “A lot of our work is supported by external collaborations. If you imagine what we are doing, you’ll realize it’s a very big effort with many disease programs – and we have only 70 people,” Tak said. “I think working with partners like WuXi is key because it gives much more flexibility and capability at high quality without having to build everything ourselves,” he said. Kintai uses WuXi in two ways. “For flexibility, we use FTE-based chemistry to complement our internal abilities and to expand our footprint without having to invest in fixed cost and capital assets. This has been critical to the success of our programs. We also use the fee for service chemistry for scale-up to support in vivo animal work,” Tak explained. “We also use WuXi to access capabilities we do not have in-house, for example in vivo proof-of-principle studies. We have used WuXi AppTec’s New Jersey group for pharmacology models which entailed compound dosing, formulation animal husbandry, and bioanalytics. The project saw acceleration through WuXi’s contributions,” he said. “For me it’s a natural thing to be part of larger ecosystems and to create real synergy and to be open to partnerships,” said Tak, citing his own experiences of successful collaborations during his previous work at GSK (GlaxoSmithKline), where he founded its Immunology Network. Looking into the future of the industry, Tak suggests that there needs to be a new classification of diseases, a molecular classification rather than the current one. “I’m an immunologist and a rheumatologist. I found that most of the immune-mediated inflammatory diseases as we call them are not real diseases, but syndromes based on a collection of clinical signs and symptoms. They may actually represent completely different pathogenic entities,” Tak said. “A deeper understanding of the disease mechanisms will open up the opportunity of precision medicine. Collaboration is key to accelerate this,” he added. Tak closed by adding that patients should be more involved in driving the research agenda. “Very often in my experience, patients are more open to innovation than prescribers, regulators or companies, because patients know what it means to suffer from a disease, and they know which benefit/risk profile might be acceptable,” he said. “They also may help us understand relevant signs and symptoms that scientists and physicians may not have thought of. The patients’ voice will change the way we do clinical trials.”                                                                                 

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