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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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Powerhouse Collaborator, MassBio’s President & CEO, Bob Coughlin Optimistically Embraces Industry Changes

MassBio is a 35-year standing life sciences trade association consisting of over 1,300 member companies. Today, their programs, services, and industry-critical mass influence, allows them to be truly patient-driven. By utilizing their unparalleled network of innovative companies and industry thought leaders, MassBio is able to advance policy, promote education, and push for innovative cross-industry collaborations. Leading MassBio is President and CEO, Bob Coughlin. Bob focuses on promoting industry growth through the advancement of Massachusetts’ leadership in the life sciences, adding value to the healthcare system, and improving patient lives. Another vital focus for Bob and MassBio is on ensuring collaboration and innovation between the government, industry, and academic sectors. Before joining MassBio, Bob served as the Undersecretary of Economic Development within Governor Deval Patrick’s administration, where he prioritized both healthcare, economic development issues, and advocated for the Massachusetts life sciences industry. Prior to that, he was elected as State Representative to the 11th Norfolk district for three terms. He has also held senior executive positions in the environmental services, capital management and venture capital industries. Currently, Bob serves on the board of directors for The Schwartz Center for Compassionate Healthcare. He is also a member of the Scientific Advisory Board at Boston Children’s Hospital. Recently, Bob sat down with Rich Soll and the WuXi AppTec Content Team to discuss MassBio, their role in the COVID-19 response, industry response takeaways, future preparations, and Bob’s insights into our path forward. WuXi AppTec: What makes Massachusetts unique in the life sciences? Bob Coughlin: We have a critical mass of companies, we have a critical mass of highly educated people, and we have 122 colleges and universities in this state, which is one-sixth the size of California. The high talent pool is a key resource for the life sciences here. We not only educate our own here, we educate the best and brightest from all over the country and around the world. WuXi AppTec: Where does MassBio fit in? Bob Coughlin: Our mission at MassBio is to leverage Massachusetts’ leadership role in the life sciences. We ensure that academia, industry and government are working collaboratively, so together, we can continue to drive innovation. We do that through many different programs and services we offer. Many folks think of us as a lobby entity, but in fact, government affairs amounts to only 15-20% of what we do. Our Innovation Services group works with the amazing tech transfer offices, including five of the top six NIH-funded academic medical centers in the country. They manage our MassCONNECT mentoring program where we funnel those companies, along with other under-the-radar startups, into our Pharma / Partnering days for engagement in business development activities. We help companies grow and raise much-needed capital through traditional fundraising forms or partnerships with large Pharma companies. We help recruit Pharma companies to this area to the extent that today, 18 of the top 20 Pharma companies have a significant physical presence here. We worked closely with the state government on economic development, in a life sciences initiative, which started in 2008 and resulted in a $1 billion investment over 10 years. This really put us in a position to succeed. We offer professional development forums and business services to member companies. For example, MassBio Edge enables our members to procure services and goods at bulk rates, thus offering significant savings, so our membership can work more effectively and collaboratively to address the unmet needs of patients. WuXi AppTec: MassBio has been very involved in taking action during the COVID-19 crisis. Bob Coughlin: Yes, when COVID-19 was coming, we realized early on that this was a particularly tricky virus that could perhaps turn into a pandemic, which it did. Our partners in the health care system were saying, “We are unable to keep our supply chain flowing as it relates to PPE, ventilators, lab supplies, etc. We’re not going to be able to order a lot of the things that come from supply chain partners overseas, because those folks overseas were shut down.” It then became revealing to me — we live in a world of “just in time” inventory. As a consequence, our health care providers were not going to have the proper protection required to care for patients infected with COVID-19. This became our call to action. WuXi AppTec: What action did you take? Bob Coughlin: We have 1300 members in MassBio and there are 500 members in Mass Medic, our counterpart in the medical device space. We thought that if we could inventory in short order what was existing in our member company supply rooms, we may be in a position to help fill some of those voids during the crisis. That led to the creation of the Massachusetts Life Sciences Emergency SupplyHub, known as the SupplyHub, where we could inventory everything our members were able to donate to health care workers. Then, on the needs side, we were able to relay requests from frontline health care providers to the state’s Command Center. First, within 24 hours of initiation, we had close to 200 member companies donate what they had in inventory. Second, more than 500 people volunteered their time to help with supply chain procurement opportunities while also procuring supplies for the hospitals. Third, and most spectacularly, was the giving of commitment by member company volunteers. They would go to the battlefield when frontline health care workers needed relief due to fatigue or sickness. This included doctors, nurses, pharmacists, lab technicians and others. Information was then provided daily to the State and to the Command Center, which then triaged the supply inventory based on needs. Through partnership with the National Guard and Massachusetts Emergency Management Agency (MEMA), the supplies (PPE) were distributed to the sites. The state took over all the operations a few weeks ago, which allowed us to set our energies on getting people back to work. WuXi AppTec: What did you do there especially to be compliant with social distancing? Bob Coughlin: We are working on a program called RESET. Phase 1, which is now completed, was ensuring the buildout of the SupplyHub with sufficient PPE; you can find that information on our website. The next phase focuses on returning more non-essential employees to work. WuXi AppTec: What area do you consider to be of strength of Massachusetts? Bob Coughlin: Our strength is true innovation. Diagnostics, therapeutics, and vaccines go hand in hand, yet who would have thought that in our lifetime the most important thing to the world economy would be a vaccine? In Massachusetts, we have a critical mass in all three areas; there is no better place than here to solve this problem. WuXi AppText: What do you think is the most important lessons learned so far? Bob Coughlin: We have serious supply chain issues in the US that hamper our progress. Despite significant growth in large molecule manufacturing in Massachusetts, certain materials are not readily available so that hinders progress. Yet, this serves as a stark reminder to how essential the life sciences are to the economy in Massachusetts. WuXi AppTec: Yes, health of the life science industry is critically important in Massachusetts. Bob Coughlin: I’ve lived it every day for the last 18 years. My son has cystic fibrosis, but he now has a therapy that works – but it took 18 years to get there. That is why this industry means so much to me—it’s personal. People who once took health for granted think much differently now if they are living through the COVID-19 pandemic, especially if a loved one has suffered from infection. WuXi AppTec: What are two critical areas MassBio has been addressing? First, collaboration is more important than ever because we are in this together; everyone needs to contribute if we are to succeed. The one thing that I’ve noticed, and was inspired by, is the level of collaboration not only between various sectors in the life sciences, but also between the private sector and government. Second, the COVID-19 situation today is unprecedented and we need to better prepare for the future. People are very scared and worried; there is so much misinformation. To help elected officials better communicate with their constituencies, MassBio has established various kinds of briefings, some daily, for elected officials and government officials, especially ones where the complex science needs to be distilled down. WuXi AppTec: Looking to the future– will things be different? Bob Coughlin: Yes, a new norm will result: one that depends on virtual connections and measurable social distancing. I would imagine, until an effective vaccine is in place, we will incentivize infectious disease R&D. We will see more cross-state collaborations and more transparency between elected officials, their constituencies, and supporting industries like ours. I’m going to continue to be an optimist, because I know that this time period is going to change the way we work long-term. I think companies are going to realize that people can work remotely and increase productivity. And really, I think we’re going to be more flexible and nimble as an industry. I think that’s a great thing.   WuXi AppTec: What should be our priority? Bob Coughlin: The most important thing in the world right now is a vaccine; I don’t think you can put a price on it. Our industry has really been showing compassion and willingness to solve problems, and not prioritizing returns. They’re doing the right thing. Closing out, I think we’re going to continue to see more collaborations between companies and private-public partnerships. At this time, many people would say drugs are too expensive. I would say that drugs are too expensive to invent. If this is forcing us all collectively to get better at how we do what we do, it will be less expensive at the end of the day; we’ll be able to bring even more value to the health care system.      

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