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Delivering on the Promise of New Modalities: An Interview with David Main, President & CEO, Notch Therapeutics

As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. Our next installment of this interview series features David Main, President & CEO of Notch Therapeutics based in Vancouver, Canada. Notch has unlocked the ability for large-quantity production of T cells and other cells from any source of stem cells to bring best-in-class cell therapies for cancer and other immune disorders. In February of 2021, Notch Therapeutics closed $85 million Series A financing to develop their pipeline of renewable stem-cell derived cancer immunotherapies. Thank you for joining us today David. Looks like Notch’s pipeline will cover a number of therapeutic areas such as cancer and autoimmune diseases. What are your considerations behind those?  David: Notch is primarily interested in treating cancer. Current cancer therapy challenges, which have remained unchanged for decades, include trying to improve treatment specificity and reduce toxicity. But now, significant cancer research and therapy development is focused on the immune system’s response, with cell therapies offering transformational benefits over existing standards of care. Where chemotherapies act on the cancerous tumours themselves, immunotherapies focus on harnessing immune cells to identify and destroy cancer cells directly. Cell therapy does bring its own set of challenges. Access to a uniform and unlimited supply of cells is a critical limiting factor. Further, administering cells that are not produced by a particular patient, could introduce new toxicities such as potential rejection or triggering other immune issues. What is your approach helping to address these challenges? How is it different from existing approaches? David: The principles of cell therapy treatment for cancer are well established. We can take immune cells from a patient, do some engineering, and then give these cells back to the patient, to attack the cancer. However, this approach is limited to very few patients. Not all patients are well enough to donate their own immune cells. Due to a long manufacturing process, by the time we are ready to give the patient back their cells, their disease could have progressed. Even the variability in the manufacturing process means the cells may not work as expected. Thus, Notch’s approach is to create immune cells from renewable cell sources. Our proprietary technology platform enables the development of uniform, T cells from any source of pluripotent stem cells. These cells are now not dependant on an individual patient and can be “sitting on the shelf”, ready to treat the patient. Any potential risks or challenges associated with this approach? David: The benefits of cell therapy have been demonstrated scientifically but our approach is in progress and not yet proven.  We must move forward to demonstrate in clinical trials the cells we produce work to kill cancer and have an acceptable safety profile. To advance our technology, we have already attracted significant interest from companies and investors who view Notch’s technology platform as a means to maximize the benefit for future generations of cell therapies. In 2019, we partnered with Allogene Therapeutics to apply Notch’s T cell production platform to develop CAR-targeted, iPSC-derived or natural killer (NK) therapies for hematologic cancer indications. And in 2020, we closed an oversubscribed Series A financing. This year, we are focused on delivering a clinically representative process—including equipment, procedures, materials, and cell lines—to produce batches of T cells for in vivo testing. This is a critical step in Notch’s move towards IND (Investigational New Drug) studies and ultimately clinical trials. Look forward to your development David. Entering clinic will be an exciting milestone. Looking at the cell and gene therapy field at large, what do you see as a critical challenge to overcome?      David: We will need to work on reducing costs. Applying new technology will help. Also because costs arise not only from how we do research, but from the amount of research required for a drug to be approved, reducing costs requires not only excellent technology, but a strong commitment from and collaboration with Regulators. We are supportive of a strong regulatory progress. We all want to know the drugs going into our body, or that of a loved one, are safe and effective. However, with the current regulatory process, we typically see an annual increase in the body of knowledge and the addition of more regulations. It takes a strong-willed person to say it’s time to streamline the process by reviewing everything at once and then reforming the approvals process.  Dr. Richard Pazdur, Head of Oncology Center of Excellence at the FDA, is one such person. He demonstrated the commitment to revisiting potential cancer drug development and approval process and looked for ways to expedite paths to approval. What’s your outlook for the future of cell and gene therapies? Say 2030? David: I expect cell therapy and gene therapy will be two prominent treatment modalities. Cell and gene therapies are allowing us to harness a natural process to treat disease and to treat diseases at the gene level.  This means we can think cures, and not just treating symptoms. It means eradicating chronic diseases. So, in 2030, I think we will have several cell therapies and a number of gene therapies approved, and these will be the mainstay approach to treating disease. And I also believe that 100 new drugs are achievable by 2030. There is a proliferation of innovation within the industry and the progressive way we tackle treatments is accelerating every year. Thank you David for sharing Notch’s approaches in help advancing the potential of cell and gene therapies. Best of luck in your endeavor. David: Thank you.     David Main President & CEO of Notch Therapeutics David Main is President and Chief Executive Officer of Notch Therapeutics. Previously, as Chairman and CEO of Aquinox Pharmaceuticals, a company he co-founded in 2006, Mr. Main oversaw the advancement of the company’s lead product from target validation through Phase 3 clinical trials. He also led the transition of Aquinox from a private company to a NASDAQ-listed public company with approximately $300 million raised in equity capital and then completed the successful merger of Aquinox with Neoleukin Therapeutics. Prior to his leadership of Aquinox, Mr. Main served as President and CEO of INEX Pharmaceuticals and as a Vice President of QLT. He formerly served as the Chair of LifeSciences BC (formerly BC Biotech), BIOTECanada, and Accel-Rx as well as a Director of Mr. Main began his career as a licensed pharmacist at the Royal Columbian Hospital in New Westminster, B.C. He holds a BSc (Pharmacy) and an MBA from the University of British Columbia (UBC).

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Delivering on the Promise of New Modalities: An Interview with Sue Dillon, CEO of Aro Biotherapeutics

New modalities offer unprecedented therapeutic potential for patients, yet they also pose unique challenges. As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs. Our first episode of this interview series features Sue Dillon, an industry veteran and co-founder & CEO of Aro Biotherapeutics based in Philadelphia. Aro’s proprietary Centyrin technology platform enables precise receptor-mediated delivery of RNA drugs to address intracellular gene targets. In Jan 2021, Aro announced $88 million Series A financing to advance development of Centyrin-Targeted genetic medicines to clinical development. Congratulations Sue on Aro’s series A. What gaps is Aro trying to address in the field? Sue: We are focused on developing tissue – targeted genetic medicines for patients with rare genetic muscle diseases and immune diseases with high unmet medical need. Our approach achieves selective and efficient targeting of RNA medicines, such as small interfering RNA and antisense oligonucleotides, to specific tissues thus enabling first-in-class medicines that precisely modify disease related genes. As a drug class, oligonucleotides have demonstrated dramatic clinical proof of concept for modulating disease related genes in the liver, or when locally delivered to the CNS or to the eye directly. Although this approach offers the possibility of addressing previously “undruggable” disease targets, the gap facing the field has been lack of efficient targeting and delivery of this exciting class of drugs to the many extra – hepatic tissues that cannot be addressed with local administration. Our initial work is focused on targeting siRNA drugs to skeletal muscle, heart, immune cells, and tumors. Tell us a bit more about Aro’s Centryn platform and how is it different from others out there? Sue: We are pioneering a new class of drugs called Centyrin – siRNA conjugates. Centyrins, Aro’s proprietary antigen-binding platform, are small, simple, and highly stable proteins.  Centyrins have been shown to bind target antigens with high specificity and high affinity, and Aro has identified Centyrins that bind to cell surface receptors which internalize post binding, thus carrying the Centyrin inside the cell. By chemically linking Centyrins with siRNAs or other oligonucleotides, we can target these gene modifying RNAs to particular tissues in vivo.  Centyrins have a number of unique properties – small size, low immunogenicity and relative simplicity of chemical conjugation and manufacturing among others – that makes them uniquely suited for targeted delivery of oligonucleotides. Using Centyrin oligonucleotide conjugates, we have shown robust gene modulation in target tissues with little to no effect in non-target tissues and have recently achieved disease relevant pharmacology in animal models. Any challenges or risks that you foresee with Aro’s novel approaches? Sue: We are pioneering a new class of drugs that is comprised of a protein component produced by recombinant technology in bacteria (Centyrin) covalently linked to a chemically synthesized oligonucleotide. There are no drugs of this type that have achieved FDA approval and as such, we are engaging with the FDA early to de-risk the preclinical and manufacturing IND enabling studies that will support our First-in-Human trial. Furthermore, given the nature of our molecules, there are complexities associated with species cross-reactivity for the oligonucleotide and Centyrin that complicates development.  We rely upon certain precedents (ADCs, oligonucleotides) that are not perfect analogues but can still provide valuable information. Additionally, we have recruited an excellent team of experienced scientists and developers and identified external consultants to create development plans for our first product candidate. Importantly, our learnings from our first programs will be deployed against future programs, which will reduce the risks associated with development of new pipeline assets. Look forward to hearing more on Aro’s exciting developments as you advance programs to clinic. It is exciting to see now patients may have more and better treatment options as we gain more insights into new modalities and understand better how to overcome the challenges. How do you see the field will continue to evolve? Sue: While small molecules and antibodies dominate the approval landscape of 2021, there are major shifts in R&D investment given new scientific breakthroughs. In recent years, the first siRNA medicine, cell therapy, and gene therapy have all achieved FDA approval. Just as it took several years for antibody drugs to become a mainstay in the pharmaceutical industry, we are at the very early stages of these new modalities. Across many of these new modalities, targeted delivery of genetic medicines to diseased tissues, while sparing normal tissues, is recognized as a barrier to achieving maximum efficacy and ideal safety profiles. We are very excited to potentially play a meaningful role in solving this issue, as Centyrins have the potential to achieve specific targeting to various tissues for a variety of drug payloads including oligonucleotides, and also more complex drug moieties including mRNA, gene editing technologies and cell therapies. As new modalities continue to broaden and brighten new horizons of therapeutic intervention, do you see our industry collectively may be able to achieve 100+ new drug approvals at 50% of today’s cost? Sue: I am optimistic about the industry’s ability to deliver 100+ approvals by 2030. The application of artificial intelligence and machine learning toward analyzing complex data sets and making associations across data will advance understanding about the root causes of disease and enable new classifications of disease and identification of new drug targets. At the same time, advances in precision medicine will improve success rates by identifying patients who are most likely to respond to a given therapeutic based on linking therapeutic MOA with the patient’s genetic profile. Additionally, accelerated clinical trials and the potential for singular (n=1) trials of highly customized therapeutics should shorten development timelines and reduce costs. Manufacturing costs and capacity of GMP approved sites for genetic and cell therapies are currently a significant challenge and must be addressed to make these medicines more cost effective and widely available. Thank you Sue for your sharing Aro’s approaches in advancing breakthroughs for patients. Sue: My pleasure.     Sue Dillon Co-Founder, President & CEO, Aro Biotherapeutics Sue Dillon, PhD, brings 30 years of experience in executive leadership roles at pharmaceutical and biotech companies to Aro Biotherapeutics. During her more than 16-year career at Johnson & Johnson, Sue led global Immunology R&D, and achieved numerous regulatory approvals for innovative antibody products for autoimmune diseases including REMICADE®, SIMPONI®, STELARA® and TREMFYA®. She also built a robust Immunology development portfolio through internal discovery and external licensing, and championed research into the emerging areas of the microbiome and immune repertoire profiling. Multi-disciplinary teams under Sue’s leadership were twice recognized with the Prix Galien Award for PROMACTA® and STELARA®, each first-in-class medicines. Sue received her PhD in Immunology from Thomas Jefferson University in Philadelphia and completed a postdoctoral fellowship in Immunology at Duke University. She was named by FierceBiotech as one of the “Top Women in Biotech” in 2013.

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Cydan Sets the Pace for Rare Disease R&D

As part of our ongoing interest in rare disease R&D, we interviewed Niels Svenstrup, the Senior Vice President of Development at Cydan, a virtual rare disease accelerator focused on the development of treatments for rare genetic disorders. Tune in to hear discussion on Cydan’s unique disease –agnostic model and their prosperous child orphan drug companies, Imara and Tiburio. Gain insight into the future of rare disease R&D, Cydan’s essential collaborations, and more. We invite you to watch now.

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Galera Therapeutics, Reducing Toxicity & Increasing Anti-Cancer Efficacy for Patients

Dr. Robert Beardsley, Founder and Chief Operating Officer at Galera Therapeutics, shares his company’s R&D vision and pipeline, aimed at improving treatments and outcomes for cancer patients. Recently, Galera’s lead product candidate, avasopasem manganese (GC4419) received Fast Track and Breakthrough Therapy Designations for the reduced incidence and severity of severe oral mucositis (SOM) – a common painful side effect experienced by 70% of head and neck cancer patients undergoing radiotherapy. Tune in to hear more on Galera’s pipeline, the science behind small molecule dismutase mimetics, Robert’s insights for the future, and the partnerships enhancing Galera’s success. Watch now.

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One-Stop Cell and Gene Therapy Solutions for Global Innovators: A Conversation with David Chang, CEO of WuXi ATU

In the past few years, the field of cell and gene therapy has witnessed major breakthroughs. It has become one of the hottest fields in the biotech industry, with the hope that it will eventually revolutionize the way we treat diseases and, ultimately, become a mainstream treatment option. Cell therapy refers to the transfer of healthy or modified human cells to heal or replace damaged tissue or cells, while gene therapy refers to the modifying of genes or replacing of defect genes with healthy ones to treat, cure or prevent a disease or medical condition. Though distinct, the two are closely associated with each other and often considered one field. Though still in their infancy, cell and gene therapies are developing at an explosive rate. There are currently hundreds of related programs in the clinic. This means that, over the next several years, many cell and gene therapies are likely to enter the market. There are clearly good prospects for the future of cell and gene therapy, but the road ahead contains obstacles as well. These include a prolonged and dynamic R&D cycle, safety issues, and manufacturing cost and limitations. Only by addressing and overcoming these challenges can we unleash the full potential of cell and gene therapy to help patients in need. Dr. David Chang, CEO of WuXi ATU, WuXi AppTec’s cell and gene therapy Contract Development and Manufacturing Organization (CDMO), recently sat down with the WuXi AppTec Content Team to share his observations on cell and gene therapy’s current development and insights into the field’s path forward. Prior to joining WuXi AppTec, Dr. Chang held senior positions at several leading companies, such as Celgene (acquired by Bristol-Myers Squibb in 2019) and Genentech. He also has extensive experience in the biotech and cell and gene therapy industries. What’s the current state of cell and gene therapy globally? Dr. Chang: Although the earliest research occurred decades ago, it is only in recent years that we have been able to bring effective therapies to the market. The biggest and by far most famous breakthrough in cell therapy is of course CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy). In 2017, Novartis’ Kymriah, developed for the treatment of certain types of ALL (acute lymphoblastic leukemia) patients, and Yescarta, developed by Gilead’s Kite Pharma for large B-cell lymphoma, were successively approved by FDA. These approvals demonstrated the potential of such therapies for cancer treatment. Gene therapy has also been gaining momentum for a long time, and over the past five years several drugs have been approved by regulators in Europe and the U.S. to treat severe inherent genetic diseases caused by specific genetic mutations, such as spinal muscular atrophy (SMA) and β-Mediterranean anemia. These recent developments are a great encouragement to the industry— to drug developers, to investors, and of course they are tremendously encouraging to patients as well. Keep in mind that, for any new therapy, a breakthrough from zero to one is the hardest. Given these successes, it’s no surprise that enthusiasm for cell and gene therapy has grown significantly lately, with many innovative companies being involved. The current pace of development is explosive. Hundreds of drugs are in the pipelines around the world, and many of them are already in the late clinical stage. To what extent will these types of therapies change the future of medicine?  Dr. Chang:  Cell and gene therapies have enabled people to effectively treat and even cure hitherto very difficult-to-treat cancers and rare genetic diseases, thus rewriting the life stories of many patients. I believe that they will become one of the mainstream treatments in the future. Cell therapy has the potential to be one of the most important treatments in our fight against cancer. For example, current CAR-T therapies have proven effective in treating relapsed/refractory ALL. These specific CAR-T therapies can, in theory, be applied to treat a lot of other cancers, and there’s a lot of relevant research going on right now. As for gene therapy, it has been applied to treat a wide range of diseases, such as cardiovascular disease, eye diseases, nervous system diseases, metabolic diseases and solid tumors, in addition to long-standing efforts in genetic blood diseases such as sickle cell disease and hemophilia. For cell and gene therapy to really take off, what challenges and problems need to be tackled? Dr. Chang: The potential is huge, but the challenges should not be underestimated. To keep our forward momentum there are still a series of bottlenecks to overcome. The industry needs to continuously improve R&D pipeline and lifecycle management, optimize the relevant manufacturing and logistics processes, and reduce costs. I personally believe the major bottleneck is not in R&D, but rather in manufacturing as well as in test and release. One of the major issues to consider in cell and gene therapy is how to scale out or up the manufacturing while reducing the cost at the same time. So, what exactly are the manufacturing challenges for cell and gene therapy? Dr. Chang: In gene therapy, there is a big gap in the production of non-replicable lentiviral vectors and AAV vectors. Depending on the genes of interest, production sometimes requires large-scale fermentations to meet a single patient’s treatment needs, making it commercially challenging or even infeasible. Therefore, yields and efficiency of virus vectors manufacturing are a major challenge for the whole industry. Cell therapy also faces the limitations in commercial manufacturing. Autogenous cell therapy is an individualized treatment that activate, modify and expand the patient’s own immune cells, so a single batch is made for one patient only. This means that the manufacturing scale will never be as large as that of traditional small-molecule or biologics products, and thus is much more costly. At the same time, cell therapy, especially allogeneic cell therapy, which utilizes donor cells, faces the challenge of graft-vs-host disease. It’s necessary to ensure that the modified cells transmitted back to the patient do not generate an immune response (similar to what happens with organ transplant rejection). Finally, cell therapy faces strict requirements for timely and reliable transport of labile raw material and cell products, as well as complexity in product testing and release. As an enabling platform for gene and cell therapy, what solutions and advantages does WuXi ATU have to address these challenges? Dr. Chang:  Through the establishment of an advanced therapies CDMO platform, we offer real one-stop service to our partners to help with their research, manufacturing, and test and release. Most existing CAR-T manufacturing processes are not closed and thus require substantial open, manual manipulation under a biosafety hood, which may lead to errors, high costs, and risk of contamination. To specifically address these problems, WuXi ATU has recently introduced an advanced closed automated CAR-T platform in its base in Philadelphia to meet the manufacturing needs of our partners. Relying on our two bases respectively in the US and China, we can not only meet the diverse manufacturing needs of customers from different regions, but also ensure the timeliness of transportation that CAR-T requires. In gene therapy manufacturing, currently, we have established high-yield, highly scalable AAV and lentiviral platforms which can supply cost-effective and commercially feasible viral vectors in a timely manner. WuXi ATU also has the capability to provide international standard oncolytic virus product development and manufacturing services to customers worldwide. In November, we signed a strategic partnership agreement with Gene Medicine, a Korean gene therapy biotech, to provide services covering oncolytic virus product development, manufacturing and clinical trials for its key programs. In addition to the mainstream approaches of introducing genes into cells, we are also establishing more efficient and promising non-viral technologies such as electroporation, which utilizes electric fields to allow genes to pass through the cell membrane. Most importantly, WuXi ATU also provides the integrated analytical method development and testing services to our manufacturing clients.  With the complexity of testing and releasing advanced therapies products in a timely and reliable manner, this integrated testing and releasing service will greatly support our clients to supply their products to meet either clinical or commercial needs. Through improving efficiency and reducing costs, we’ll support our clients to enhance the accessibility of cell and gene therapy – and help more of our partners’ innovative therapies to reach patients as broadly as possible as soon as possible. The rapid development of cell and gene therapy has attracted a lot of outside attention. People have high expectations. From the perspective of someone on the inside, what do you see when you look at the near future?  Dr. Chang: There is no denying that cell and gene therapy still face challenges. Actually, every new therapy faces or faced a similar situation. Even regulators need to learn alongside industry. This process is both normal and necessary. I believe that in another five to ten years, with the accumulation of relevant knowledge and experience, the whole industry will become more mature, efficient and standardized. I firmly believe that the future for cell and gene therapy is very bright, and WuXi ATU stands ready to join hands with global innovators to move it to the next stage.

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