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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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2019/09/05

Leading the Charge in the Fight Against Cancer: Laurie Glimcher, M.D., President and CEO, Dana Farber Cancer Institute

By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team Cancer is one of the world’s leading causes of death and is a persistent challenge for the global healthcare industry. It comes in many forms, defying an easy “one size fits all” solution. Progress has been uneven, with some cancers completely curable and others resisting our best attempts at treatment. One key locus in the battle against cancer is the Dana Farber Cancer Institute. With more than 5,000 staff, faculty, and clinicians Dana Farber blends patient-centric treatment, teaching, training, and cutting-edge research. It is the number one pediatric oncology center in the US. The institute’s research budget is about $480M and only 40 percent is government funded – the remainder comes from the private sector and philanthropy. Yet the Institute receives more money from the National Cancer Institute than any other cancer center and its publications are cited two to three times more than its peers. Heading up Dana Farber is CEO Laurie Glimcher, MD., a distinguished immuno-oncology (IO) researcher, with present or past chaired-appointments at Harvard Medical School and Harvard School of Public Health and scientific and executive positions at Weill Cornell Medicine. She was also one of the founders of Quentis Therapeutics, which specializes in IO. She currently serves on the boards of GlaxoSmithKline and the Waters Corporation and on several scientific advisory boards. Glimcher is widely recognized as a staunch advocate for increasing both basic and translational cancer research, reducing the complexity of the U.S. healthcare system, and promoting women in science. Rich Soll and the WuXi AppTec Content Team recently discussed the battle against cancer, the complexity and scale of funding cancer research, and the future of cancer diagnosis and treatment with Glimcher. She identified two key barriers to delivering better medicines faster and cheaper to cancer patients. “First is research; it’s at the core of innovation yet government funding is insufficient,” Glimcher stated. “The whole cancer field has broken open over the last couple of decades. It’s logarithmically better. And I think the next 10 years could be even more impressive, but that won’t happen if we don’t have the money.” “The other barrier is the complexity of the U.S. healthcare system,” Glimcher stressed. “Any solution needs to preserve incentives for innovation. If you’re a teaching hospital you’re not just seeing patients, you are the source of the discoveries — research and the training of the next generation of scientists and physicians. So, our costs are just going to be higher, because we are responsible for all the teaching and all the research as well.” She views the challenge as more than just a question of system design. The social determinants of health are, in her view, the key. “It’s hard to compare us to Scandinavian countries or Japan because these countries are extremely homogenous. Immigration is one of America’s strengths. But it also has created a lot of inequality,” Glimcher said. Social inequalities are, in her view, a huge contributor to difference in healthcare outcomes, and any reform needs to address this reality. Turning to cancer specifically, Glimcher views the current situation positively and is very optimistic about the future for two reasons. “We are at the tip of the iceberg,” she exclaimed. The first reason she cited is precision medicine. Being able to identify the majority of cancer-causing mutations is a huge step forward. This is because mutation identification is a critical part of developing drugs that disrupt cancers. Specific examples she cited were EGFR receptor blockers, drugs, which target the ALK kinase, Herceptin and the first targeted cancer drugs that are cancer agnostic. But she made it clear there are still challenges. “The tumor is smarter than we are. It will eventually mutate again to circumvent the therapy,” Glimcher said. This observation led to combination therapy, the use of multiple drugs to treat a condition. Glimcher cited its success in moving HIV from a death sentence to a manageable condition. However, testing is the main challenge here. “We need to be able to test combinations of drugs in people very quickly— but how many clinical trials can you do? We do over 1000 clinical trials at Dana Farber,” Glimcher said. “The whole world can’t do enough clinical trials, and patients don’t have time to wait either.” The second major recent development in cancer treatment is immuno-oncology therapies (IO). Currently, IO therapy is effective in about 10 tumors. “The problem is only about 30 or 40 percent of patients with these tumor types will respond. And then there are a lot of tumors that so far have been totally unresponsive to IO therapy,” Glimcher said. “We want to be able to treat 100% of patients with IO therapies, not just 20% of patients. I have confidence we’re going to come up with many more IO therapies.” She shared a vision for what the future could look like. “For a patient who walks in the door, we need to quickly analyze their cancer— immunoprofiles, genomics, radiology, pathology that had been digitized by machine learning, metabolomics and structuring the medical records, and then be able to take their tumors and the surrounding tumor microenvironment, quickly make organoids out of it (human tissue, complete with micro-environment, an all-human tissue testing approach), and test a wide variety of drug combinations,” she said. She contrasted this with the state of things now, where patients may be able to join only a handful of clinical trials and deciding which are best is seldom easy. To solve this requires diligent data collection. “We need to get to where we can say, ‘Oh, we’ve seen this in 1000 other patients with lung cancer, and given your genomics, immunoprofile, and pathology, drug A is highly likely to work for you while drug B, while also likely to give you strong results, is highly likely to cause you to develop very serious toxicity from it.’ That’s something we just can’t do now,” Glimcher said. Getting there, however, is one of Dana Farber’s highest strategic priorities, alongside developing the next generation of targeted medicines, combination therapy, and discovering new targets for IO therapy. To accomplish this goal, Glimcher views improving cancer testing and evaluation as an important priority. Testing and evaluation helps reduce risk, whether it’s in vivo or in animal models. But in her view, we’ve reached an impasse regarding animal models. “We can cure cancer in mice, but it doesn’t always translate to cancers in humans,” Glimcher said. “Animal models are improving, but they’re still not great. If we could generate all human ex-vivo assays that were predictive for patients, it would be a huge leap forward.” Glimcher also contrasted the progress made in adult cancers vs. children. “Pediatric CNS tumors and sarcomas are different from adults. Children don’t get a lot of single mutations that drive their tumors, rather their cancers often arise from fusion proteins or epigenetic alterations that drive the cancers. It’s our responsibility to focus on them too,” Glimcher explained. Cancer detection is an important component in achieving this data-driven vision. This includes early diagnosis, early detection of minimal residual disease, and detection of early relapse. Early detection requires being able to identify a very small number of cells in a liquid biopsy. She acknowledged it’s a challenge, although some companies like GRAIL are, in her view, making good progress. Missing residual disease continues to be a challenge; she cited several instances where a patient’s cancer was supposedly cured, but then many years later it is discovered that this is not the case, and instead the cancer had widely metastasized. Preventing this requires an ability to detect trace cancer cells that may get missed. Finally, early relapse is also an issue. Glimcher stated that 15-20% of women who are supposedly cured of breast cancer will eventually present with metastatic disease – monitoring is thus key. “Those are some of our strategic priorities,” she said. “And we’re actively trying to harness AI and machine learning to collect the data we need. We’re structuring our medical charts, pathology and radiology, digitizing and then analyzing them.” One of Dana Farber’s most recent partnerships is with Deerfield Management. Announced in November 2018, the $80 million deal created a Center for Protein Degradation at Dana Farber. Protein degradation is a promising but relatively new approach to treatment. “Out of all the 20,000 or so proteins we have, only about 750 or 1000 have been actually targeted by drugs,” Glimcher shared. “So there’s huge room for growth.” She went on to say that innovative partnerships like this are key to advancing science and in speeding up the development of successful treatments. Cancer is one of the disease areas that receives the most attention and funding, but historically the success rate has been low. Glimcher addressed some of the key factors needed to improve outcomes:  better pathway and target validation and more predictable models both in-vitro and in-vivo. Glimcher acknowledged that the nature of cancer itself is also responsible for the difficulties in developing a treatment. “Most cancers are silent until they’ve metastasized. Cancers are all different from each other. Seventy percent of the time they don’t present until they’ve already spread,” she said. This is why she views early detection as vitally important. Her view is that if we can reliably detect cancers at Stage 1, we can almost always cure them. Even at Stage 2, cures are sometimes possible. But, citing pancreatic cancer as a typical example, most cancers don’t get detected until they have spread everywhere – contributing to the difficulties treating cancer. While a cure is desirable, it continues to prove elusive. “Of course, it would be great to cure all cancers,” Glimcher stated. “And for some cancers we’ve gotten there. But I’d honestly be extremely happy if we could make them chronic diseases like we’ve done for HIV.” “We may not get rid of every single cancer cell, but they’re quiescent, and maybe they’ll pop up in a little bit and then we detect them really early and treat again, and people can live for years and years,” she said. Glimcher concluded with a personal perspective on leading Dana Farber. “The future is incredibly bright here. Our staff is 50% clinicians, 50% researchers; this split is unique among cancer centers. 90% of our clinicians have scholarly interests,” Glimcher said. “I get hundreds of letters from patients and they’re almost uniformly positive, which is amazing since people usually write to CEOs to complain. It’s like a family here, we couldn’t have asked for better care. Being a CEO of a hospital can be tough; the amazing people here and the work we do, that’s what keeps me motivated to do my best every day.”

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2019/09/02

The Quest for Anti-Fibrotic Therapies Leads to Blade Therapeutics

By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and the WuXi Content Team Like many start-ups, the story behind the formation of Blade Therapeutics has a personal angle. In this case the research conducted by Dr. Harry Dietz, professor of genetics and medicine at Johns Hopkins University, was followed and supported by Luke Evnin, a founder of MPM Capital and chairman of the Scleroderma Research Foundation. For a patient suffering from scleroderma, a chronic connective tissue disease characterized by hardening and thickening of the skin, the Foundation’s support of the Dietz lab in the area of fibrosis was particularly relevant since there were few therapeutic options available to treat scleroderma and more broadly, fibrotic conditions. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. It is the final, common pathological outcome of many chronic inflammatory diseases. Fibrogenesis is increasingly recognized as a major cause of morbidity and mortality in most chronic inflammatory diseases. Many factors can trigger and contribute to the development of progressive fibrotic disease. Fibrosis triggers include genetic disorders such as Marfan syndrome, persistent infections, recurrent exposure to toxins, irritants or smoke, and chronic autoimmune inflammation. Fibrosis of the liver, lung, and heart as well as other organs has dire consequences. In the case of idiopathic pulmonary fibrosis (IPF), once diagnosed, the average life expectancy is about 4 years. One of the research themes from the Dietz lab focused on causative factors of fibrosis. Myofibroblasts play a key role in the replacement of normal tissue parenchyma with collagen-rich extracellular matrix. Dietz had recently shown that the transforming growth factor-β-induced myofibroblast differentiation of cultured epithelial cells, endothelial cells or quiescent fibroblasts is dependent upon a class of non-lysosomal cysteine proteases called calpains. Sufficient progress had been made to consider forming a company. It was around this theme that Blade Therapeutics was born in late 2015 with $6.5M in Series A funding from MPM Capital and $45M in Series B financing in June 2016 led by Deerfield Management along with new investors Pfizer Venture Investments and equity investments by Norvartis Institute for Biomedical Research. Bristol-Myers Squibb, MPM Capital, and Osage University Partners also participated. Based in South San Francisco, the biopharmaceutical company has assembled a critical mass of anti-fibrotic drug development expertise within its top-tier leadership team and a world-class network of advisors. Blade Therapeutics’ lead compound, BLD-2660, is a highly selective calpain inhibitor targeted for the treatment of chronic fibrotic diseases. BLD-2660 is in a Phase I, healthy volunteer, dose escalation study in Australia, and the company plans to submit an Investigational New Drug (IND) application to the U.S. FDA and initiate a Phase II trial in patients with liver fibrosis by the end of 2019. Recently WuXi’s Rich Soll and the WuXi content team sat down for an interview with the company’s CEO Wendye Robbins M.D. and Ravi Rajagopalan Ph.D., Executive Director, Drug Discovery, who shared the company’s strategy and goals, as well as the challenges on the path to finally find cures for fibrosis. The company was initially started around a target that had never previously been drugged successfully. “It is an intracellular enzyme, and we set about trying to figure out how to create molecules that might covalently bind to it,” Robbins shared. “We knew this was a very tough target, with ill-defined biochemistry at the time and we knew that people had not previously been successful. We did have tool compounds to screen against it. Further, we also looked at protein expression in post mortem human specimens that justified pursuit of this target. So this was a focused effort against a tough target,” she said. “The thought of using covalency as a mechanism to inhibit their target came from past experience in the covalent, reversible viral protease inhibitor field which had yielded approved drugs to treat hepatitis C,” stated Rajagopalan. “So the chemotype was validated by that approach; there was a certain level of comfort in pursuing this theme.” Robbins reiterated the company’s confidence in the target and its plan to continue playing an important role in fibrosis biology research. Blade was originally founded as a virtual company. “We engaged WuXi’s platforms not only for chemistry but also for basic in-vitro screening,” said Rajagopalan. Robbins and Rajagopalan said the collaboration between Blade and WuXi has been very successful. The senior scientists at Blade had very positive experiences with WuXi chemistry from their past InterMune days and so turned to the WuXi chemistry platform for the synthesis of compounds gleaned from structural insights by the Blade scientists.   When it comes to drug development for fibrotic diseases, given the nature of this target and its indications, Robbins identified several bottlenecks that made this campaign inefficient. “Compounds were synthesized, tested in the in vitro screens and then moved into phenotypic screens of limited value; large number of animals essentially to get single data points,” Robbins stated. “It was frustrating that we could not move faster in the biology realm in contrast to other past experiences I had.” Both Robbins and Rajagopalan candidly noted that the WuXi platform enabled Blade since there were lots of compounds being made at WuXi; however testing was limited by the biology throughput to a large extent because of endpoint analysis and lack of qualified biomarkers, so the iterative process of synthesis/test/analyze/synthesis was slow and inefficient. The compounds were prosecuted along 2 pathways, target level (biochemical and cellular for compound optimization along with PK) and fibrosis level (with its current limitations such as histopath) ultimately yielding BLD-2660. BLD-2660 will be ready to start a Phase II before the end of the year, and a second CNS-penetrating molecule is expected to go into Phase I early next year, with a third molecule staged as a fibrosis backup, and we will opportunistically bring in another asset that is mechanistically distinct. “One of the key points for us is the fact that fibrosis therapy will likely be polypharmacy, which means our drug will be used in combination with something else. Given that, we want to be ahead of the curve and test our molecules with other things to figure out where there’s synergy,” Robbins stated. Long term, Blade’s goal is to have a profound impact on fibrosis patients with multiple successful molecules. Fibrosis has been an evolving story. Looking ahead, Robbins concluded, “The more we understand about the metabolome and the transcriptome, the better we will be able to target effective therapies to diseases.” “As a physician, I am looking at the whole patient, what happened here, what are the early signs, and where we could make a difference. By the time you get a patient with full-blown IPF, it is not clear that anything may make a difference. So, it is really figuring out early warning signs, when to intervene and what are the right targets.”

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2019/08/26

OSE Immunotherapeutics Developing Tedopi® to Jump-Start Cytotoxic T-cell Response in Lung Cancer Fight

Tumor cells are usually recognized and destroyed through a complex mechanism of immune surveillance involving different immune cells (antigen presenting cells, macrophages, lymphocytes, proteins and mediators such as interleukins). Tumor cells can escape this surveillance mechanism by blocking immune cells’ activation. They can, for example, express specific antigens that are also expressed by normal cells, thus avoiding being recognized, or block immune cell activation checkpoints neutralizing the immune response. OSE Immunotherapeutics, based in Nantes, France is conducting clinical trials in lung cancer indications using its novel drug Tedopi®, which the company believes can reactivate a cancer patient’s immune system and overcome tumor cells’ “camouflage.”  The drug is a proprietary combination of 10 neo-epitopes aimed at stimulating T-lymphocytes and overcoming tumor cell resistance. OSE, whose corporate investor deck starts with, “We are armed to fight,” is led by CEO Alexis Peyroles. As part of WuXi AppTec’s Communications program to highlight innovative solutions to develop novel drugs and tests that can make a difference in patients’ lives, WuXi spoke with Peyroles about new treatment paradigms for lung cancer and how his company’s new technology might give doctors and patients new tools in fighting the second most deadly cancer. Alexis Peyroles has more than 20 years of international management and financial control experience. He joined Sanofi-Aventis in 1996 as Financial Controller in Japan before becoming Head of Financial Control for the Baltic States. He was subsequently named Head of Activities for Business Development in Eastern Europe. In 2005, he joined the Guerbet Group (a leader in the field of contrast products, especially in medical imaging) as Financial Control Manager and in 2009 became Chief Executive Officer for Latin America, based in Brazil. Since 2013, Peyroles has been involved in OSE Pharma, both as Chief Financial Officer and in charge of Business Development. From May 2016 (the date of the merger of OSE Pharma with Effimune) to April 2018 he served as Chief Operating Officer of OSE Immunotherapeutics, in charge of Finance, Business Development and Operations. Peyroles graduated from EDHEC Business School and holds an Executive MBA from Imperial College in London. WuXi: What are the challenges in lung cancer early diagnosis? Are there any specific biomarkers? Alexis Peyroles: Lung cancer, like many other types of cancer, is significantly easier to treat when caught in its early stages rather than when the disease is advanced. Unfortunately, because symptoms arrive late, most lung cancers are diagnosed when they have already metastasized and are at an advanced stage, making these cancers hard to cure.  Early detection remains a real challenge. Traditional detection methods using CT scans and chest X-rays will soon be combined with circulating biomarker analysis to help improve early detection. Some of these biomarkers can be detected in blood samples, and there are a number of active developmental programs looking at the potential for liquid biopsies with the objective to make possible early diagnosis via blood-based analysis.   In addition, many top cancer research centers are building large tissue banks with specimens donated by patients containing samples of different tumor types. As these tumor banks grow, researchers will be able to use new bioinformatics techniques to analyze diverse arrays of tumor samples that can help identify new biomarkers that could accurately predict lung and other cancers at an early stage. These new biomarkers will complement the already identified panels of biomarkers associated with lung cancer and will hopefully be used to develop accurate tests for early detection. WuXi: What are the hot targets in the field of drug development for lung cancer? Alexis Peyroles: Lung cancer is an indication that is generating a lot of positive attention and great new innovation in the field. Potential new targets for drug development in lung cancer are identified on a regular basis, but many must be validated beyond the early stages of bench research before they can truly be considered new targets. As biomarker analysis becomes more prevalent for targeted therapies (therapies which are developed to specifically combat cancer subtypes identified by expression of known biomarkers) the identification of new targeted therapies will also become more prevalent. While targeted therapies have the potential to make a difference for subsets of patients with a particular cancer, they often don’t have the ability to be effective against larger patient populations. Our efforts to develop novel immuno-oncology treatments are based on our belief that stimulating the immune system to generate active and sustained immune response against cancer cells is the best way to have a lasting anti-cancer effect. We are developing a number of immuno-oncology therapies; some applied to lung cancer that we hope will have a continuing beneficial therapeutic effect. WuXi: What treatment modalities show the most potential? Are there any with the potential to treat early stage disease? Alexis Peyroles: There are a number of promising treatment modalities that are being explored in lung cancer. However, almost all therapies in development tend to target late-stage lung cancer (Stage III/IV) since surgery or occasionally one round of chemotherapy ahead of surgery has historically proven to be effective for patients with lung cancer detected at Stage II or earlier. Modern immunotherapies, particularly checkpoint inhibitors targeting the PD-1/PD-L1 axis, have proven to be effective in select patients with advanced lung cancer. However response rates with modern immunotherapies can range from 20% to 65%, depending on the particular circumstances, which leaves a significant number of patients for which these therapies are ineffective, creating a great unmet need. While first-generation cancer vaccine strategies initially didn’t have much success in this space, more recently the next-generation of this type of approach is gaining traction in the research community. At OSE we’re advancing a cancer vaccine-like approach to combatting lung cancer in patients who have failed on checkpoint inhibitor therapies, which we discuss in greater detail below. Additionally, researchers have begun to focus on identifying effective combination therapies to help increase the effectiveness of modern immunotherapies and to help overcome the tumor drug resistance that sometimes develops. By pairing two different cancer therapies there is increased potential to have a longer-lasting and more effective anti-tumor effect. Effective combinations are a major focus of clinical cancer research, and we are sure to hear more about these types of treatments in the future. Bi-specific antibodies, which are antibodies that have two protein targets rather than one, are a new combination therapy modality that has generated recent attention. By packaging two drug targets into a single molecule, bispecific antibodies have the potential to act like combination therapies. As researchers refine this technology and create clinically test bispecific antibodies we will learn more about their potential to treat different cancers. WuXi: How is your drug different from existing lung cancer treatments? Is it a new approach? What have been results of your research so far? Alexis Peyroles: Our lead asset, Tedopi, is a proprietary combination of 10 neo-epitopes selected and optimized from five tumor-associated antigens aimed at stimulating T lymphocytes to recognize and attack cancer cells. While vaccine-like approaches were used in the past to promote immune response against cancer, Tedopi is differentiated from previous attempts by its innovative design. A rational design approach was used to select neo-epitopes for inclusion in Tedopi based on tumor antigen epidemiology. We used a targeted approach to combat tumor heterogeneity by selecting well-expressed epitopes found in a variety of tumor types. In early testing Tedopi was shown to generate a specific response of cytotoxic T cells versus cancer cells expressing at least one of these tumor-associated antigens and an associated T-helper cell response. Phase 2 clinical studies in patients with advanced (Stage IIIB & IV) non-small cell lung cancer (NSCLC) who were treated with Tedopi showed clinical benefit and increased median overall survival compared to the expected survival in this population. Tedopi is currently being assessed in a Phase 3 trial called Atalante 1. Atalante 1 tests HLA-A2 positive patients with NSCLC at invasive stage IIIB or metastatic stage IV, in 2nd or 3rd line treatment, following failure of a checkpoint inhibitor, compared to docetaxel or pemetrexed chemotherapy treatments in this patient population. Patients who have otherwise failed on checkpoint inhibitor therapies have no other approved treatment options, making this an area of great need. WuXi: What is the specific mechanism of action? Alexis Peyroles: As mentioned in the previous answer, Tedopi is intended to work by stimulating a specific cytotoxic T lymphocyte response targeted at cancer cells. The approach is based on our selection of a variety of cancer associated antigen neoepitopes widely expressed by a variety of tumor types. By packaging 10 neoepitopes together in one vial, we have a strong chance of priming the immune system to recognize cancers that would otherwise avoid immune surveillance. Tedopi is designed to stimulate an immune response as a single agent, as in the Atalante 1 trial, but is also being explored as a combination therapy in an ongoing Phase 2 trial in patients with advanced pancreatic cancer. In this study, Tedopi is administered both as a single agent and in combination with Nivolumab (Opdivo) to see if there is a potential anti-cancer effect by combining these two immuno-oncology agents. WuXi: Why did you choose to focus on lung cancer? It has been a very difficult disease to treat. Alexis Peyroles: We chose to explore the effectiveness of Tedopi in lung cancer for a number of reasons. As you mentioned lung cancer is a devastating disease that has traditionally been very difficult to treat. In the United States, lung cancer is the second most common form of cancer, causing more than 150,000 deaths each year. NSCLC, the target for Tedopi in the Atalante 1 Phase 3 trial, makes up 80-85% of all lung cancer cases. This means we’re targeting one of the largest patient populations with more than 230,000 new cases per year in the U.S. alone. In addition to the great unmet medical need for this large patient population, lung cancer, and NSCLC in particular, has been a field with a lot of recent innovation and newly approved next generation treatment options. These include PD-1 inhibitors such as blockbuster drugs Nivolumab (Opdivo) and Pembrolizumab (Keytruda) as well as targeted treatments including Erlotinib (Tarceva), Afatinib (Gilotrif) and Gefitinib (Iressa), which are targeted therapies for patients harboring a specific and common mutation to the EGFR gene. These new agents, as well as others not directly referenced here, can be combined with chemotherapy in first line and also radiation in advanced settings to provide lung cancer patients with different options. By testing Tedopi in NSCLC, we have not only chosen a cancer with great need but also one where immuno-oncology approaches have been successful in the recent past. The third reason why we chose NSCLC for Tedopi is directly related to my previous point. Even with all the recent advances in approved therapies, there are still many patients who do not respond to chemotherapy, radiation, targeted- and immuno-therapies. Our ongoing Phase 3 study is in a patient population that has no other available treatment options as checkpoint inhibitor therapies are not working anymore for these patients. Our goal is to provide a safe and effective new treatment option for this patient population. WuXi: Have patients been involved in the development of your drug other than participating in clinical trials, of course? Alexis Peyroles: Patients have been integral in the development of Tedopi. Tedopi was designed using a rational design strategy that identified cancer antigens found on a variety of different tumors. In order to identify these commonly expressed tumor antigens, our research team analyzed samples from numerous tumor biopsy samples. Without the contributions made by patients themselves, agreeing to share their tumor tissue with researchers around the globe, we would not have been able to identify the best antigens with the highest chance of instigating an immune response. WuXi: What major challenges have you faced in trying to bring a new drug for lung cancer to patients? Alexis Peyroles: Developing a potential new treatment for patients with lung cancer presents a number of challenges. However, an important challenge that may have overlooked presents itself as both a positive and downside. Lung cancer is a field with a lot of recent innovation and multiple new approved therapies that have come to the market in the past 5-10 years. While these therapies are beneficial for patients, they present an interesting challenge to those developing the next generation of therapeutic options. In order to properly assess if a new drug is effective, extensive clinical testing must be performed and assessments need to be made between comparable populations of patients, some of whom receive the developmental therapy and some who don’t receive the therapy. With so many new treatments, it is increasingly difficult to find a large consistent group of patients for clinical testing. Many patients entering the clinical testing program have significant treatment histories, all of which create a different backdrop on which to try and assess drug efficacy. With our ongoing Phase 3 clinical trial, we have had to reassess enrollment criteria to ensure that we are testing Tedopi in a representative population as well as in a consistent enough population to be able to draw significant conclusions about the potential anti-cancer effects of the treatment. WuXi: What lessons have you learned during the development process? Alexis Peyroles: As with any research endeavor lessons are learned with every clinical trial. An important lesson learned from our studies in lung cancer patients is that proactivity is crucial when researching new therapies within a rapidly changing treatment landscape. Designs for a clinical trial should not only take into account the current standard of care, but should also be conscious of the fact that throughout a trial the standard of care may continue to change. Adaptive clinical trial designs, particularly ones that are able to account for shifts in patient populations, have a better chance of completion without any logistical issues. Every effort to consider this challenge before finalizing a clinical study protocol will pay off in the end. WuXi: Have you benefitted from FDA initiatives, such as Breakthrough Therapy and Fast Track designations? If so how? Alexis Peyroles: To date we have not submitted the Tedopi program to the FDA for consideration for any initiatives such as Fast Track or Breakthrough Therapy designations. We may consider submitting Tedopi to the FDA for one of these initiatives to help streamline the regulatory process in the future. WuXi: What other drug candidates do you have in the pipeline? Alexis Peyroles: OSE has a number of additional drug candidates in both immuno-oncology and autoimmune disease spaces in the pipeline to complement our development of Tedopi in both NSCLC and pancreatic cancer. We have already developed several first-in-class products that activate or regulate the immune system and cover a wide range of clinical indications. In the immuno-oncology space we are advancing BI 765063, formerly OSE-172, a selective SIRPa antagonist targeting the CD47 “don’t eat me” pathway with a differentiated mechanism of action. The CD47 axis has been very active for drug development, but based on preclinical findings we believe that we have a first-in-class product with great potential for success. In June 2019 a Phase 1 first-in-human clinical trial was initiated with our partners in development, Boehringer Ingelheim, evaluating BI 765063 in patients with solid tumors, and we look forward to announcing trial results as soon as they are available. In addition, in March 2019 we announced a new immuno-oncology platform technology called BiCKI. Based on an engineered anti-PD-1 antibody backbone, these bispecific antibodies have the potential to modify the tumor microenvironment by delivering costimulatory signals that both increase anti-tumor T cell activities while also reinstating macrophage responsiveness to tumor tissue. We look forward to announcing the first clinical development products from this new platform in the coming months. Our immuno-oncology pipeline is also complemented by preclinical asset OSE-703, a humanized monoclonal antibody directed against the extracellular domain of the alpha-chain of the receptor for interleukin-7 (IL7). IL7 is an immune mediator known for its key role in the hematopoietic growth of T- and B-lymphocytes. IL7 is produced by various types of cells including keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells. It has recently been demonstrated that IL7 and the presence of IL7R can have a pro-tumor effect in various cancers by decreasing cancer cell apoptosis or accelerating cell proliferation and lympho-vascular formation. We are also advancing a number of assets targeting autoimmune diseases. OSE-127, a humanized monoclonal antibody, is an antagonist of the IL7 receptor (IL7R) present on T effector cells, the CD127 receptor, thus down regulating the immune activity. Recent peer-reviewed publications of preclinical data on OSE-127 has demonstrated its unique mechanism of action, suggesting great potential in mediating antigen-specific blockade of memory T cells. OSE and its development partner Servier Laboratories believe this will have applications in a number of autoimmune conditions, including ulcerative colitis and Sjörgren’s syndrome, a rare autoimmune disease that attacks the glands that make tears and saliva. We also have Phase 2-ready FR-104, a monoclonal antibody fragment and CD28 antagonist that selectively blunts CD28 co-stimulation while sparing the CTLA-4 co-inhibitory signal. The net effect of CD28 antagonism is down regulating effector T-cells while promoting T-Reg activity. Following positive Phase 1 clinical trial results demonstrating that FR104 is generally safe and tolerable, we are looking to advance this asset in the treatment of autoimmune diseases once we have found a suitable partner to work with. WuXi: What are the top three major impediments in our delivery of “better” medicines “faster” and “better” to patients? Alexis Peyroles: One important advancement that can greatly expedite the delivery of better medicines to patients is for researchers to think out of the box to identify novel targets that could be efficacious in treating hard-to-treat cancers that currently lack effective treatments. A major part of our research and development efforts at OSE is strong partnerships we have with premier academic institutions around the world. Academic research institutions are where much of the innovation actually occurs and we work with them to help translate academic findings into clinically relevant drug development products. As a source of innovation, we not only partner with premier oncology research centers, but also partner with centers of excellence that specialize in other fields such as transplant science. Since immunology is a major component of transplants we have gained extremely valuable insight into novel targets that may impact oncology and autoimmune disease spaces from our collaborations with transplant scientists. This innovation is a key to identifying the next potentially better new targets for drug development. WuXi: And finally, for lung cancer what would be the one thing that has the most potential to lead a paradigm shift “from treatment to cure.” Alexis Peyroles: Using the word ‘cure’ when discussing cancer is always tricky because by nature, cancers are a diverse set of diseases and each person’s cancer different from the next person’s, making a broad cure for cancer a challenging target. Some cancers such as advanced lung cancer are definitely not defined as “curable”. Our focus in immuno-oncology research is based on our strong belief that reactivating the cancer patient’s immune system to rehabilitate the active immune surveillance will prevent the growth, the expansion and the metastasis spreading to increase a patient’s survival and be considered as “functionally cured in some way”. There is potential for an effective immuno-oncology treatment to have a lasting protective effect that would actively work to prevent the development of new or secondary cancers. Whether or not this ends up being a true ‘cure’ per se rather than a very long-lasting treatment effect is yet to be seen. One thing I’m sure of is that we’re not alone in working on this endeavor. There is a huge community of researchers, scientists and drug developers actively working together to find new treatments that can potentially be effective cures for devastating cancers. This shared purpose from such a large and engaged community, aided by active patient advocates and the support of everyone that has been affected by cancer directly or indirectly, is the basis for the types of breakthrough discoveries that can turn treatments to cures. We’re excited to be a part of the future work to make this a reality.

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