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Delivering on the Promise of New Modalities: An Interview with Amber Van Laar, VP Clinical Development of AskBio

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. For our next interview in this series, Amber Van Laar joins us as VP Clinical Development, CNS Gene Therapy of Asklepios Biopharmaceutical (AskBio) to shed light on neurodegenerative disease drug development. AskBio is a company dedicated to develop AAV (adeno-associated virus) based gene therapies for neuromuscular, central nervous system, cardiovascular, metabolic and other disorders. Last year, the company received FDA fast track designation for a novel investigational gene therapy for the treatment of a rare muscular dystrophy with no approved therapies. AskBio is also most notably working on a gene therapy for Parkinson’s Disease, and a gene therapy treating late-onset Pompe disease. One of the leading candidates of AskBio is focusing on Parkinson’s disease. From your perspective, why the treatment for Parkinson’s disease remains challenging? Amber: That’s a good question. To me, non-motor symptoms of Parkinson’s disease such as cognitive impairment, constipation, and depression can be more troublesome to patients than the classical motor symptoms, like tremors or slowness of movement. However, effective symptom management is not adequately addressed by currently available therapies. Further development is needed, particularly for preventative therapies, to evade these complicating and troublesome disease features. The lack of disease-modifying therapies remains a key challenge for patients and researchers, though many promising studies are underway. Close collaboration with regulatory agencies will be critical in order to establish a clear path to agreement on what measures are needed to define disease modification which are meaningful for both regulators and the Parkinson’s community. What are the opportunities for novel technologies to solve these challenges? What’s AskBio’s unique approach? Amber: The safe and accurate neurosurgical drug delivery directly to specific brain regions or neuronal networks has been rapidly evolving to overcome the pre-existing challenges of unmonitored “black box” administration of drugs intracranially. Direct visualization via MRI-monitored drug delivery to the brain was a significant technological leap that now allows neurosurgeons to dose drugs directly, accurately and consistently in brain regions impacted by a particular disease. At AskBio, our Parkinson’s program utilizes direct, MRI-guided delivery of AAV2-GDNF (glial cell-line derived neurotrophic factor) to evaluate the potential of this technology to overcome the challenges of variable delivery which may have contributed to the lack of significant responses observed in prior studies investigating either recombinant GDNF protein delivery or gene therapy approaches for Parkinson’s Disease. We believe that these improvements in delivery are crucial to accurately dose gene therapy to demonstrate a clinical effect, particularly for a neurotrophic growth factor like GDNF. Great. As your platform evolves, how to realize its full potential? What are the key elements for success? Amber: Delivering a new therapeutic platform at scale, particularly for the central nervous system and other disorders requiring specialized delivery, is a challenge on the horizon for cell and gene therapies.  The incorporation of robotic-assisted procedures, portable MRI scanners, and improved delivery devices will be needed to expedite procedures and reduce the resource intensiveness of the current procedure. Alongside the evolution of the surgical procedure, the development of cell and gene therapy centers of excellence will be needed to adequately train and disseminate this new technology beyond a limited number of highly trained neurosurgeons at major academic centers. Additionally, an early dialogue with payers and health agencies is needed for these advanced therapies to facilitate the post-approval path for one-time delivery of potential disease-modifying drugs. Aspects of neurosurgical delivery and the combined use of drug and novel devices further complicate this process, necessitating preemptive discussions with stakeholders to efficiently bring these novel therapies to patients. How do you see the field of gene therapy evolve in the next 10 years? Will gene therapy become the mainstream of new drugs approved? Amber: The approval path in the field of gene therapy has been embarked on by a few sponsors since 2015. The approval process of gene therapies is fraught with hurdles given the manufacturing requirements and the high bar these treatments are expected to achieve. The potential for one-time delivery of gene therapy and unknown long-term effects are additional factors that have prudently been raised as factors needed for the rigorous evaluation of gene therapies. The number of new INDs for gene therapies has sharply risen over the past five years, attesting to the promise that this technology holds. Given lengthy drug development timelines, and challenges with diseases like neurodegenerative disorders, I believe many of these studies may not achieve approval by 2030. This field is in its advent, and with only a few approval successes to provide guidance to subsequent studies. Learnings from future approvals will provide clarity on the rigorous gene therapy approval process for sponsors and regulators. As the regulatory path becomes more trodden, and with further refinement of this powerful technology, gene therapy is on course to open the door to a new modality of treating previously untreatable diseases. Anything else that may evolve over time in your view as we look towards 2030? Amber: The ability to reduce the cost of approvals in half by 2030 may be achievable in select drug development spaces. I believe these savings would not be anticipated for areas like cell and gene therapy. The novelty of cell and gene therapy and the potential of these therapies hold to change the direction of medicine are factors limiting cost and time savings in the early days of cell and gene therapy development. But I believe the utilization of decentralized trial designs, streamlined clinical development strategies, and the implementation of remote monitoring of participants in a real-world setting will hold the potential to reduce the overall costs of bringing drugs to approval. Thank you so much for your time, really appreciate your insights. Amber: My pleasure.     Amber D. Van Laar, MD VP Clinical Development, CNS Gene Therapy, Asklepios Biopharmaceutical Inc. (AskBio) Dr. Amber Van Laar obtained her MD from the University of Pittsburgh School of Medicine, followed by residency training in Neurology and a clinical-research fellowship in Movement Disorders at the University of Pittsburgh Medical Center. She later joined the department as an Assistant Professor in the Movement Disorders Division. As a physician-scientist, Dr. Van Laar continued her academic research in the Pittsburgh Institute for Neurodegenerative Diseases and received formal clinical research training through the Institute of Clinical Research Education at the University of Pittsburgh. Since 2002, Dr. Van Laar has researched gene therapy approaches for Parkinson’s disease and received the Clinician-Scientist Development Award from the Parkinson’s Foundation and the American Academy of Neurology to investigate the therapeutic potential of parkin gene therapy in parkinsonian rodent models. Dr. Van Laar has also been an investigator in clinical trials for neurodegenerative diseases, including multiple gene therapy studies for Parkinson’s disease.  Through volunteer work with local PD support groups and service on the Board of Directors for the Parkinson’s Foundation of Western Pennsylvania, she continues to contribute to the Parkinson’s disease community. Dr. Van Laar continues her work with gene therapy and now serves as the VP of Clinical Development for CNS Gene Therapy at Asklepios BioPharmacetuical Inc. (AskBio). She brings a unique blend of preclinical, clinical, and clinical-trial development experience to the advancement of gene therapy as a new platform to address the underlying causes of Parkinson’s disease and similar brain diseases.

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Delivering on the Promise of New Modalities: An Interview with Kunwoo Lee, Ph.D., CEO of GenEdit

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. Up next in this interview series, Kunwoo Lee shares his insight as CEO of GenEdit. His company is focusing on developing targeted in vivo delivery platform technologies for genetic medicines, and recently secured $26 million in Series A financing. GenEdit is currently developing innovative therapeutics targeting the nervous system, treating a range of diseases with high unmet medical need. Earlier this year, GenEdit announced its collaboration with Sarepta Therapeutics to develop gene editing therapeutics for the treatment of neuromuscular diseases. Congratulations on your recent progress, Kunwoo! What do you see as the major hurdles for genetic medicines? Kunwoo: From our point of view, the top three challenges for genetic medicines are delivery, delivery and delivery. The potential to treat the underlying causes of genetic and sporadic diseases with genetic medicines is unprecedented – gene therapy, gene silencing, gene editing and others – but these technologies are only useful as therapeutics if they can reach the affected tissues and cells. Current delivery options are limited. We categorize the main challenges as tissue selectivity, payload flexibility, ability to re-dose and ease of manufacturing. In addition, safety has become a significant concern. A better delivery system would be truly enabling for genetic medicine to reach its potential. How GenEdit plans to solve these challenges? What’s your technology and how it is differentiated? Kunwoo: We believe that solving the delivery challenge requires new materials and a systematic approach. At GenEdit, we are overcoming this challenge with our proprietary technology, NanoGalaxy. This platform is composed of hydrophilic polymers, which can have diverse interactions compared to hydrophobic systems. By systematically screening a diverse library, we are able to analyze structure-activity relationships (SAR) which identifies structures and properties contributing to tissue selective delivery. Computational SAR and iterative screening accelerate the development of tissue-selective polymers. NanoGalaxy is differentiated as it can deliver various genetic medicine payloads to tissues outside the liver from siRNA to mRNA beyond the size which adeno-associated virus (AAV) packing capacity has demonstrated. On top of that, the hydrophilic polymer can encapsulate various CRISPRs in ribonucleoprotein form, which is a unique feature. Do you see any potential risks and challenges associated with your approach? Kunwoo: Of course. We are developing a novel technology that has never been tested in humans and we understand that we have many challenges. One of our more interesting challenges is really an opportunity: our platform has the potential to be used to develop therapeutics for an enormous range of diseases. But we can’t do everything as a small company. Our solution is to focus on indications where the risk falls as much as possible onto our delivery technology and there is as little risk as possible for the target and payload. As our hydrophilic polymer nanoparticles are novel materials, we plan to engage with the FDA early in order to de-risk. Each validating milestone will enable new applications of the NanoGalaxy platform. Gazing into our crystal ball, what’s the future for genetic medicines? Say 2030? Kunwoo: We are focused on the future of genetic medicines and believe that they will be the mainstream of therapeutics in 2030. We are seeing an emergence of various genetic medicine candidates, including antisense oligonucleotide, siRNA, mRNA, new RNA systems, and CRISPRs. Eventually, in vivo genetic medicine will be generated from the combination of payload and delivery technology. Industry wide, how genetic medicines would transform the current R&D landscape? Kunwoo: The FDA had predicted 10-20 new approvals of gene therapies per year by 2025. The success will be dependent on platforms that are widely applicable and manufacturable. This is a goal which is not easy to achieve based on the current challenges that this industry is facing. Still, there is huge room for improvement in delivery technology regarding tissue selectivity, toxicity, immunogenicity, and manufacturing cost. At the same time, these new platforms are trying to address those challenges. In the end, a safer, cost-effective, and targeted delivery technology would overcome these limitations and could support 100+ approvals per year at half of today’s costs. Thank you Kunwoo for sharing your insights! We with you great success in future endeavors. Kunwoo: Thanks for inviting me. Enjoyed the discussion.     Kunwoo Lee, Ph.D. CEO, GenEdit Kunwoo has been CEO of GenEdit since he founded the company in 2016. He saw that the potential of genetic medicine was held back by the limitations of delivery technology, and the company’s NanoGalaxy platform enables the systematic and iterative screening of polymer-based vectors. He published several high-profile papers in Nature journals that demonstrated delivery of mRNA, protein therapeutics, and CRISPR-Cas9 and CRISPR-Cas12a; and he has 10 patent filings, including the company’s core polymer nanoparticle technology. Prior to GenEdit, he completed graduate research at UC Berkeley and UCSF in the Department of Bioengineering, where he focused on novel delivery systems for macromolecular therapeutics. He was named as a Forbes 30 under 30 in 2017 and was a Siebel Scholar in 2016.

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Delivering on the Promise of New Modalities: An Interview with Ray Tabibiazar, M.D., CEO & Chairman of SalioGen 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. Up next in our interview series, Ray Tabibiazar, M.D., a seasoned executive in the healthcare and biopharma industries, imparts his perspective as CEO & Chairman of SalioGen Therapeutics. SalioGen is advancing a new category of genetic medicine through its unique Gene Coding approach, a genome engineering technology that leverages proprietary mammal-derived enzymes. Earlier this year, SalioGen closed a $115 million Series B financing to advance the company’s goals of transforming the treatment paradigm for patients with inherited diseases and beyond. Thank you for taking the time to sit down with us, Ray. What major bottlenecks or barriers is SalioGen aiming to address? Ray: At SalioGen, we aim to address inherited disorders by addressing some of the limitations of currently available approaches. Current therapeutic approaches include gene editing and viral vector-based gene therapies. These modalities, however, often have limited clinical applicability. Many of the inherited disorders are caused by many different mutations and oftentimes involve a large gene (>5 kb sequence). Gene editing is designed to fix only a few point mutations at a time, and viral gene therapies can only accommodate gene sequences of a few thousand base pairs at most. Additionally, viral gene therapies carry the risk of causing potentially severe immune responses in patients and gene editing carries the risk of causing damage to the DNA that it changes. Altogether, the field of genetic medicine is limited in the number of inherited disorders it can address effectively and safely. How is SalioGen’s approach differentiated and what might be advantages of the approach? Ray: SalioGen is developing a new category of genetic medicine called Gene Coding, which is designed to turn on, turn off or modify the function of any gene in the genome. The cornerstone of Gene Coding is SalioGen’s portfolio of mammal-derived enzymes collectively called Saliogase, which can take a DNA sequence of any length and integrates it into the genome at a precise, pre-defined location. To our knowledge, SalioGen is the only company developing a mammalian genome engineering enzyme. Gene Coding machinery is delivered using a cell specific lipid nanoparticle; therefore, we don’t anticipate any risk of causing the virus-related immune responses that some gene therapies can cause. Furthermore, Saliogase works without causing double-stranded breaks when it inserts new DNA to the genome. It therefore doesn’t trigger any of the error-prone DNA repair pathways that may cause DNA damage and other unwanted downstream effects. Saliogase can also insert DNA sequences of any length, unlocking the potential to address most inherited disorders regardless of the size of the gene or genes involved in the disease. All these features are designed to make Gene Coding applicable to a broad range of inherited disorders. The physical components of the technology are also easily reproducible and scalable, ensuring they can be manufactured to reach large patient populations with prevalent inherited disorders. What challenges are you facing currently and how are you addressing these?  Ray: With the recent explosion of new biotech companies, there has been a shortage across the sector including limited capacity at partner CDMOs and a shortage of non-human primates for GLP toxicology studies. We are working to develop in-house CMC capabilities to maintain control over our manufacturing process. Pipelines of genetic medicines are on the rapid rise. What trends do you see coming in the next few years?  Ray: There has been a clear trend toward the accelerated development timeline for the new fields in genetic medicine. RNA-based therapeutics were largely developed over the course of roughly the past twenty years, with siRNA therapeutics and recently with mRNA therapeutics. On the other hand, the more recent newcomer of gene editing has taken hold in about half the time, in the past 11 years since the first papers on the CRISPR-Cas9 system as we know it were first published. We anticipate that by 2030, we’ll see increased availability of different modalities of genetic medicine for inherited disorders. In addition to currently available products like viral vector-based gene therapies, RNAi and antisense oligonucleotides, perhaps modalities like Gene Coding and other non-viral genome modification platforms, mRNA-based gene therapies and epigenetic therapies will be further advanced and available for patients. Definitely a great outlook and great opportunities for patients.  Any closing thoughts you like to share with our audience? Ray: Looking forward, we expect to see a shift in drug approvals away from single-purpose compounds and toward therapies based on platform technologies. Successful platform technologies will each be capable of yielding multiple successful therapies, each of which can be developed in parallel. Platform technology-based development is becoming more common and is significantly more streamlined than the historically more common trial-and-error, one-molecule-at-a-time path of drug development, and that may push us toward a greater volume of drug approvals by 2030. Thank you Ray, it’s been an insightful discussion into the new breakthroughs SalioGen is bringing to the field of genetic medicine. We wish you luck in your future endeavors. Ray: Thanks for having me.   Ray Tabibiazar CEO & Chairman, SalioGen Therapeutics Ray is a seasoned executive with leadership experience in the healthcare and biopharma industries, including venture capital, pharmaceuticals and diagnostics. As a clinician-entrepreneur and as managing director of 526 Ventures, he has focused on creating new ventures in the form of new companies or spinouts to translate innovative science into commercially viable products. Previously, Ray led Aravive Biologics as President and CEO, served as Senior Vice President, Corporate Development and Business Strategy at Twist Bioscience, a venture partner at Bay City Capital, and other senior executive roles. Prior to moving to industry, Ray was a practicing cardiologist and an adjunct faculty member at Stanford University, having trained as a physician scientist at Harvard Medical School and a cardiologist at Stanford Medical Center. Ray graduated with his medical degree from Harvard Medical School.

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Delivering on the Promise of New Modalities: WuXi AppTec Interview Series

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. Maria Luisa Pineda CEO and Co-founder, Envisagenics; Secretary, The Alliance for Artificial Intelligence in Healthcare SJ Lee CEO, Orum Therapeutics Christopher Thanos President, CEO & Co-Founder, Actym Therapeutics Zachary Hornby President & CEO, Boundless Bio Nikole Kimes CEO & Co-Founder, Siolta Therapeutics Reagan Jarvis Co-Founder & CEO, Anocca AB Geoff Hamilton Co-Founder & CEO, Stemson Therapeutics Yann Chong Tan Founder & CEO, Nuevocor George Wu Co-Founder & CEO, Amberstone Biosciences Andrea van Elsas CSO, Abata Therapeutics Elvire Gouze CEO & Founder, Innoskel SAS, France Mark Frohlich CEO, Indapta Therapeutics Karen Kozarsky Co-Founder & Chief Scientific Officer, SwanBio Therapeutics James McArthur President & CEO, PepGen Daniel Getts CEO, Co-Founder & Board Director, Myeloid Therapeutics Amber Van Laar VP Clinical Development, AskBio Kunwoo Lee CEO, GenEdit Ray Tabibiazar CEO & Chairman, SalioGen Therapeutics David Main President & CEO, Notch Therapeutics Susan Dillon CEO, Aro Biotherapeutics

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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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