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2022/08/09

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Ralph Laufer, CSO of Lysogene

Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.” Thank you for taking the time to join us, Ralph! Before we start, could you please introduce yourself for our audience? Ralph: My name is Ralph Laufer. I’m the Chief Scientific Officer of Lysogene, which is a gene therapy company located in Paris, France, and we are developing gene therapies for neurological diseases. At Lysogene, we have two clinical stage programs for the treatment of rare neurodegenerative lysosomal storage diseases, namely MPS IIIA, also known as Sanfilippo disease and GM1 gangliosidosis, as well as several discovery and preclinical stage programs that are focusing on Fragile X syndrome, Gaucher disease and related diseases, as well as neurodegenerative diseases. What inspired your work in the Fragile X field and what issues are you trying to address? Ralph: Lysogene’s mission is to develop novel gene therapy treatments for neurological diseases, and in particular rare genetic diseases, such as Fragile X. In 2018, we initiated a collaboration with the lab of Dr. Herve Moine from the IGBMC in Strasbourg, France, based on his discovery of a novel downstream target of FMR1 in neurons – the messenger RNA of an enzyme called diacylglycerol kinase kappa. We also call it DGKk in short. And the goal of this collaboration was to evaluate the therapeutic effect of DGKk delivered into the brain using an AAV vector in a mouse model of Fragile X. What approaches are you taking to gene therapies? Ralph: So Lysogene’s approach is gene therapy; and the most widely used gene therapy approach, also known as gene transfer or gene addition, involves delivery of a functional gene to substitute a missing or dysfunctional endogenous gene. Predominantly, this approach relies on the use of an innocuous and replication-deficient viral vector to transduce human cells, such as the adeno-associated virus or AAV vector. However, in the case of Fragile X syndrome, a gene transfer approach using the FMR1 gene presents several important challenges. First of all, FMR1 expression dosage is critical for normal cell condition and neuronal function, and duplications of the FMR1 gene are identified causes of intellectual deficiency. Therefore it would be very difficult to administer a gene therapy treatment which would require such a tight regulation of gene dosage. Secondly, the blood brain barrier, which is constituted by a barrier of cells that surround blood vessels in the central nervous system, impedes crossing of AAV vectors from the bloodstream into the brain parenchyma which is the site where pathology occurs. And therefore, Lysogene’s approach is to target a downstream effector of FMR1, the DGKk gene that I mentioned earlier, as well as to deliver the AAV vector carrying the therapeutic transgene directly into the CNS, bypassing the blood brain barrier. What is the greatest and differentiated value of your modality or technical approach to the treatment of Fragile X syndrome? Ralph: The current treatment for Fragile X remains largely insufficient and the care is primarily symptomatic, focusing on disease management without addressing the primary underlying mechanisms of disease. Importantly, current treatments do not constitute a solution for intellectual disability, which is one of the main features of Fragile X. We believe that focusing on DGKk, which is an immediate downstream target of FMR1 and neurons, offers the opportunity to correct one of the major disease mechanisms, and therefore has the potential of being disease modifying. Could you share with us your progress on this program so far, and what is the next milestone? Ralph: The approach we have taken is based on the identification by Dr. Herve Moine, our collaborator from the IGBMC, of DGKk, as the most proximal messenger RNA target of FMRP neurons. The absence of FMRP leads to the absence of DGKk, and the latter mimics the effect of FMR1-knockdown, both in vitro and in vivo. So to tackle this problem, we constructed an AAV that carries an FMRP-independent variant of DGKk, and we administered this vector directly into the brain of FMR1 knockout mice, which is a well-known animal model of Fragile X syndrome. And when we did this, it led to the correction of all behavioral abnormalities observed in the knockout mice relative to healthy wild-type mice. Also, treatment with this AAV was not associated with any overt toxicity in the mice. These findings were recently published in EMBO Molecular Medicine. We believe on the basis of these findings that gene therapy with DGKk holds considerable promise as a treatment option for Fragile X, and we are currently performing additional non-clinical studies to advance this candidate therapy into the clinic. In your opinion, are there any innovative collaborations or partnership models that the Fragile X community can pursue in order to advance the field faster? Ralph: I would say our collaboration with the lab of Dr. Moine at the IGBMC, as well as with Conectus, which is the technology transfer organization of the Alsace region here in France, were crucially important for the success of this program. The program relies on the combined know-how and expertise of one of the leading academic labs with expertise in Fragile X, molecular biology, and a gene therapy company such as Lysogene, which has expertise in AAV vector design, as well as nonclinical and clinical development of gene therapies, and regulatory affairs in the field. This type of academy-industry partnership, with very close collaboration between the scientists, joint project teams, regular meetings, and joint design of experiments, is in my opinion, a very efficient way to advance basic research into the clinic. Finally, what does patient-centric drug development mean for the Fragile X field? Ralph: For Fragile X, patient-centric drug development really means focusing on clinical outcomes that matter to patients. In drug development, there is an increasing focus on assessing patient and caregiver experiences and preferences. This is important for designing clinical trials that will have clinically meaningful outcome measures, but it is also important during nonclinical development, where we try to identify suitable animal models with phenotypes that can either reproduce or be related to a clinical relevant symptom or biomarker. Thank you very much for your participation and sharing your valuable insights with us. Ralph: Thank you.     Ralph Laufer CSO, LYSOGENE Dr. Ralph Laufer is the Chief Scientific Officer at Lysogene, a gene therapy company based in Paris, focusing on the development of innovative treatments for neurological diseases. Before joining Lysogene in 2018, Dr. Laufer was Senior Vice President and Head of Discovery and Product Development at Teva Pharmaceutical Industries. Prior to that, he held the positions of Scientific Director of IRBM Science Park, a drug discovery partnering organization in Rome, Italy, and Head of Pharmacology at IRBM-Merck Research Laboratories Rome. He is the recipient of the American Chemical Society 2013 Heroes of Chemistry Award for his role in the discovery and development of Isentress (raltegravir), the first integrase inhibitor approved for use in HIV infected patients. Dr. Laufer’s scientific achievements include the discovery of the tachykinin NK-3 receptor and the anti-obesity activity of ciliary neurotrophic factor. He is the author of over 90 peer-reviewed articles and inventor of more than 20 patents. Dr. Laufer obtained his PhD in Biochemistry (summa cum laude) and M.Sc. in Chemistry from the Hebrew University of Jerusalem. He conducted postdoctoral training at the Institut Pasteur in Paris.

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2022/08/09

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with Adrian Newman-Tancredi, CEO of Neurolixis

Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.” Thanks for taking the time to join us, Adrian! Could you please first introduce yourself for our readers? Adrian: My name is Adrian Newman-Tancredi. I’m the CEO and co-founder of a bioscience company called Neurolixis. Neurolixis is a small privately held company, which is developing novel treatments for CNS disorders, particularly neurological disorders. My background is in pharmacology. I have a PhD from the University of Kent at Canterbury in the UK and, after a postdoc, I moved into the pharmaceutical industry. I now have over 25 years of pharmaceutical industry experience, essentially in drug discovery and early development of novel neuropsychiatric and neurobiological drug candidates. Could you tell us what inspired you to work on Fragile X, and what issues are you trying to address? Adrian: We had previously done a lot of work on drug treatments for different disorders, particularly targeting mood deficits, such as anxiety, depression, and cognitive dysfunction disorders. More recently we became interested in autism spectrum disorders because cognitive deficits, mood deficits, agitation, are also prominent in autism spectrum disorders. We started by doing a lot of work on another autism spectrum disorder, which is Rett syndrome, and we gradually broadened our work to Fragile X syndrome too. In fact, we started a collaboration with UCR, University of California at Riverside. We entered discussions with Dr. Khaleel Abdul Razak and his postdoctoral researcher Dr. Xin Tao, who have mice modeling Fragile X syndrome, and we were able to collaborate with that team to test our drug candidate. We think that this drug candidate should be able to address several important aspects of Fragile X, notably mood disturbance, but also cognitive deficits and also importantly, the stimulatory hypersensitivity seen in Fragile X. And this was the object of work that we carried out with Dr. Abdul Razak and Dr. Tao. What unique approaches are you taking? Gene therapy, targeted therapy, drug repurposing or others? Adrian: Our approach is development of a small molecule novel chemical entity. We call it NLX-101 and it’s a compound which has already undergone extensive investigation for antidepressant properties and procognitive activity and we are repositioning it as a treatment for autism spectrum disorders and notably Fragile X syndrome. NLX-101 is a compound which targets the serotonin system. Serotonin is a neurotransmitter in the brain which is known to be involved in a multiplicity of different brain functions and including autism disorders and is involved in regulation of early development, which is relevant to autism and to Fragile X syndrome, However, targeting the serotonin system has been a complex challenge for many years, because there are many serotonin receptors and because it’s a very extensive system. The novelty that we are bringing is that our drug candidate, NLX-101, is different because it is exceptionally selective for one particular receptor of the serotonin system, and we think that brings important advantages in its activity. What is the greatest and differentiated value of your modality or technical approach to Fragile X patients? Adrian: The major aspect of NLX-101 is that it is very specific in targeting a serotonin receptor, known as the 5-HT1A receptor. 5-HT1A receptors are located in specific brain regions, which mediate control of cognition, mood, and also of sensitivity to stimuli. What we’ve found is that this drug candidate can address, we think, several different dimensions of Fragile X syndrome and notably the stimulatory hypersensitivity, the anxiety symptoms and also the cognitive deficits. We’ve shown that NLX-101 influences neurotrophic factors, increasing levels of BDNF, it favors neuronal plasticity and promotes neurogenesis. So NLX-101 elicits a neuronal remodeling effect, at least in animal models. So to sum this up, the really distinguishing feature about an NLX-101, we think, is that it can address a number of different aspects of Fragile X syndrome because of its specific targeting of serotonergic mechanisms, which control neuronal development. Could you share with us your progress and your upcoming milestone? Adrian: Indeed, we’ve made a lot of progress in characterizing NLX101 in a large number of different experimental models, at the laboratory level. We’ve looked at in vitro cellular tests of drug signaling and also at ex vivo measures in different brain regions. We’ve also characterized NLX-101 using brain imaging by microPET imaging and fMRI; we’ve investigated the electrophysiological activity of NLX-101 as well as its neurochemical effects on neurotransmitter release in different brain regions. Most importantly, we’ve shown that these different parameters are influenced in those brain regions which are relevant to autism disorders, such as cortex, hippocampus, and brain stem which are all brain regions involved in different aspects of autism disorders. And just recently we’ve presented some quite striking data at the Gordon Conference on Fragile X syndrome, which took place in June 2022 in Tuscany, Italy. These data were generated by the collaboration with the University of California at Riverside, and show that NLX-101 almost completely abolishes seizures in transgenic, Fragile X mice, when they are subjected to audiogenic stimuli. In these mice, intense audio stimulation triggers lethal seizures and NLX-101 has a striking protective effect against that. So, this really confirms and extends the extensive preclinical validation of NLX-101’s potential as a treatment for Fragile X syndrome. Now, the next milestone is to progress into human trials, NLX-101 is clinical trial ready. We have a little human data already, but we need to advance the phase I safety trials in humans. We have an open IND from the FDA in the US and we’ve also got intellectual property filed; we’ve submitted a patent application to the US Patent Office. So we are really ready to move forward rapidly in development of this drug candidate, and we’re looking for partners to take the drug forward as we move into the human trials. What do you hope the field to do differently in order to advance better medicine faster for Fragile X patients? And what do you hope to see in Fragile X, R&D in the next 10 years? Adrian: This is an interesting question. The research community has probably been focusing a lot on individual symptoms in Fragile X syndrome, maybe also in other autism disorders. For example, there has been a focus on specific aspects such as agitation, and some antipsychotic drugs have been approved for treatment of agitation in autism spectrum disorders. I think what needs to happen is to take at a more holistic approach in the field. It’s interesting to see, for example, how psychedelics are now being tested more widely; they have quite extensive effects on different aspects of mood and cognition, and they’re being tested also for autism spectrum disorders. Now, one of the things that interests me about that is that psychedelics are serotonergic activators. They stimulate the serotonin system, including serotonin 5-HT1A receptors. So I think there’s an emerging story around serotonin and autism disorders, and I expect that over the next few years we are going to see a lot more discussion about that. Are there innovative collaboration and partnership models we may pursue to advance the field faster? Adrian: We are very strong advocates of collaborative models. I mentioned that we’re collaborating with the team of Dr. Abdul Razak at UCR. We are also collaborating with the FRAXA Research Foundation, in discussions with Dr. Michael Tranfaglia. We are now collaborating with a laboratory in Chile led by Dr. Patricia Cogram, who also has a colony of transgenic Fragile X mice, and we will be testing NLX-101 on animals in that colony in order to derive a more extensive profile of NLX-101 in a variety of tests, to complement the data from the audiogenic seizure model and get a broader picture of NLX-101’s activity on Fragile X. So we are very much into collaborations with patient organizations and academic laboratories. At Neurolixis, we bring drug pharmacology and development expertise, but we really rely on these academic teams to bring their neurobiology expertise and on patient organizations to bring really deep knowledge of the patient experience and what medical needs are directly relevant for the patients and for their carers and families. What does patient-centric drug development mean for you in the Fragile X field? Adrian: For Fragile X, patient-centric drug development means that there needs to be a variety of different treatments available, to be used either in different patient cohorts, different subgroups of patients, or maybe concurrently, to improve efficacy, maybe as combination treatments. The reason I think that is because, it’s clear that some patients have more accentuated symptoms in one area, others in other areas. So, clearly there are differences in the symptoms and these most likely reflect differences in the underlying neurobiology. So if the underlying neurobiology is different, that means we need to have appropriate treatments targeting different central nervous system mechanisms to deal with that. So I think that patient-centric drug development means having a battery of different treatments available which target different mechanisms, and making those available ultimately to the patients and the clinicians to see what actually suits the different patients best. Thank you so much for your time. We really appreciate your insights. Adrian: My pleasure.     Adrian Newman-Tancredi CEO, NEUROLIXIS Dr. Newman-Tancredi has over 30 years’ experience of neuroscience research. He is co-founder and Chief Executive Officer of Neurolixis, a biopharmaceutical company that develops innovative treatments for neurological disorders including autism spectrum disorders (ASD) and Parkinson’s disease (PD). Previously, he was Director of Neurobiology at Pierre Fabre Laboratories, a French pharmaceutical company, and responsible for identifying novel antipsychotic, antidepressant and analgesic drug candidates. Prior to his position at Pierre Fabre, Dr. Newman-Tancredi investigated signal transduction mechanisms of monoamine receptors at the Servier Laboratories (another French pharmaceutical company). He has published over 190 articles in peer-reviewed international scientific journals, is co-inventor on a dozen patents and serves as European Councilor for the International Society for Serotonin Research. His principal current focus of interest is the development of first-in-class direct-acting serotonergic “biased agonists” (also known as “functional selectivity”), notably the Phase 1-ready drug candidate, NLX-101, for the treatment of Fragile X syndrome and other ASDs. Other compounds in the Neurolixis pipeline are befiradol (NLX-112) which is undergoing a Phase 2 proof-of-concept study for treatment of dyskinesia in PD patients, and NLX-204, a preclinical stage antidepressant candidate. Dr. Newman-Tancredi previously characterized several approved drugs, including milnacipran (Savella), piribedil (Trivastal), agomelatine (Valdoxan) and levomilnacipran (Fetzima) for various CNS indications.

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2022/08/09

Delivering on the Promise of New Modalities: An Interview with Mark Frohlich, CEO, Indapta 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, we’ll hear from Mark Frohlich, CEO of Indapta Therapeutics. Earlier this year, Indapta received over $50 million in Series A financing for their new approach to allogeneic natural killer cell (NK cell) therapy, a next-generation cell therapy for cancer. Indapta focuses on a naturally occurring and highly potent type of NK cell, known as G-NK cells, and it aims to use them in combination with antibody drugs to improve the cytotoxicity of antibody therapy in multiple cancers. It’s been a big year for Indapta. Congrats on your Series A financing! For the next generation of immuno-oncology therapies, what are the challenges in current therapeutic intervention, or current new modality solutions? Mark: I have focused my professional career on the development of cell therapies for cancer patients, first at Xcyte Therapies, then at Dendreon and Juno, and now at Indapta. The approvals of Provenge for prostate cancer and CD19 CAR-T therapies for leukemia and lymphoma have been exciting developments that have validated the promise of cell therapy. But important challenges remain. First, autologous therapies are too resource intensive and costly to produce. Second, their autologous nature limits their use to patients who cannot wait for the therapy to be produced. Third, the toxicities of autologous CAR therapy have led to patient morbidity and mortality, limiting those who can be eligible for the therapy. Finally, the approved therapies to date have focused on targeting a single cancer antigen. The inherent heterogeneity of the expression of cancer antigens, particularly under selection pressure, has contributed to tumor refractoriness or relapse. What is Indapta’s new approach to address these challenges? How is it different from existing approaches? Mark: Indapta’s NK cell platform is based on the discovery of a highly potent subset of NK cells, G-NK (G minus NK) cells. These cells are present in a subset of individuals exposed to CMV. G-NK cells have undergone epigenetic modification, such that several genes are persistently up or down modulated. As a result of these changes, the cells secrete more cytokines and cytolytic enzymes than conventional NK cells and are extremely potent at mediating ADCC (antibody-dependent cellular cytotoxicity). Based on preclinical benchmarking against conventional NK cells, Indapta believes that G-NK cells have the potential to be a “best-in-class” NK cell therapy, particularly when combined with targeting molecules like monoclonal antibodies or innate immune bispecific engagers. Given the highly encouraging clinical data of other NK cell therapies, we anticipate that G-NK cells will be a highly safe, efficacious, and cost-effective “off-the-shelf” therapy for cancer. Furthermore, by engineering G-NK cells with targeting molecules like CARs and then combining with monoclonal antibodies to achieve ADCC, we can target multiple cancer antigens and address the issue of tumor heterogeneity. How would Indapta develop these G-NK cell therapies in the future, say key milestones? Do you anticipate any critical challenges in realizing the full potential of your new therapies? Mark: We anticipate initiating our first clinical trial in the first half of 2023. The trial will involve single agent dose escalation and include both patients with lymphoma and multiple myeloma. This will be followed by disease-specific cohorts in combination with rituximab and daratumumab. Based on the promising clinical data from other NK cell products in hematologic malignancies, we are encouraged for our prospects for demonstrating clinical activity in this setting. Once we have demonstrated clinical proof of concept, we look forward to combining G-NK cells with the multitude of approved IgG1 antibodies, including ADCs, and to addressing the challenge of solid tumors. We anticipate that solid tumors may require engineering of the cells to target additional antigens, as well as expressing payloads to modulate the tumor microenvironment. With many new modalities advancing into the clinic and getting closer to patients, will the 2030 class of FDA new approvals look similar or different from those today? Mark: I anticipate that approvals in the next decade will increasingly involve multiplexing of targets as well as mechanisms to address multiple cancer pathways in order to overcome the immunosuppressive tumor microenvironment. This could be achieved by delivering a combination of therapeutic agents to a patient. However, one of the beauties of using cells as a therapeutic is that multiple payloads can be engineered into the cells. This will enable a single therapeutic modality to deliver the level of multiplexing that will likely be required to address the challenges of solid tumors and provide curative efficacy. You have more than 25 years of experience developing cellular immunotherapies to treat cancer. What upcoming breakthroughs are you most excited about? Mark: One of the most exciting and gratifying trends in the development of oncology drugs since I started my career has been the acceleration of the rate of innovation. When I trained in oncology, we lacked the sequencing and big data tools to tackle the complexity of cancer, and clinical research involved mixing and matching toxic chemotherapeutic agents in the hope of extending life by a few weeks or months. The bar has risen dramatically, and I am encouraged that the rate of innovation will continue to lead to a greater rate of drug approvals, and ultimately at a lower cost. Much of the current cost of oncology care involves managing the progression of disease and the toxicities associated with our therapies. As we develop safer drugs, and hopefully begin curing a higher percentage of patients, the cost of cancer care should begin to decline. Thank you for your insights Mark!     Mark W. Frohlich, MD CEO, Indapta Therapeutics Dr. Mark Frohlich currently serves as the Chief Executive Officer of Indapta Therapeutics, a biotechnology company developing a natural killer cell platform for the treatment of cancer. Dr. Frohlich has been involved in the development of cellular immunotherapies for cancer for more than two decades. Trained as a medical oncologist, Dr. Frohlich engaged in immunotherapy laboratory research and was involved in early studies of cellular therapy for cancer at UCSF in the 1990s. He subsequently worked at Xcyte Therapies, one of the early biotechnology companies pioneering the use of adoptive T cell therapy. He later served as EVP of R&D and Chief Medical Officer of Dendreon Corporation, where he led the clinical team responsible for development of Provenge, the first cellular immunotherapy approved in the US and Europe. He served as EVP of Portfolio Strategy at Juno Therapeutics, one of the first CAR-T companies. For the past several years, Dr. Frohlich has served as an advisor to several immuno-oncology companies. Dr. Frohlich is a graduate of Harvard Medical School and Yale College.

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2022/07/27

Delivering on the Promise of New Modalities: An Interview with Karen Kozarsky, Co-Founder, Chief Scientific Officer, SwanBio 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 “Delivering on the Promise of New Modalities” interview series installment features Karen Kozarsky, Co-Founder & Chief Scientific Officer of SwanBio Therapeutics. As a gene therapy company advancing AAV-based therapies for the treatment of devastating, inherited neurological conditions, SwanBio Therapeutics recently announced their completion of $56 Million Series B Financing to advance novel gene therapies for neurological conditions. Earlier this year in July, they entered into a partnership with Purespring Therapeutics to license their proprietary in-vivo ‘gene therapy search engine’ to advance AAV-based gene therapies for use in neurological diseases. We’re excited to have you with us, Karen! Congratulations on all of SwanBio’s success this past year. For drug discovery & development related to inherited neurological conditions, what are the challenges in developing therapeutic interventions and potential new modality solutions? Karen: SwanBio Therapeutics is a gene therapy company aiming to bring life-changing treatments to people with devastating neurological conditions. We’re focused on these individuals and their families because of the historic challenges that have hampered advances in neurology. One of the main barriers to progress in neurological R&D has been a lack of understanding about the mechanisms of diseases. Thanks to advancements in genetics, we are now better positioned than ever to identify, target and treat the root cause of disease. In many cases, gene therapy is technically capable of addressing the genetic cause of disease, rather than just the symptoms, which holds great potential for patients who have been waiting for meaningful treatments. This is the case for adrenomyeloneuropathy (AMN), the disease SwanBio is initially targeting. Once that root cause of disease is identified, the next challenge facing drug developers is delivering therapies in a targeted, efficient, and effective way. What is your new modality or technological approach helping to address these challenges? How is it different from existing approaches? Karen: In many cases, gene therapy is technically capable of addressing the root cause of disease. This is what SwanBio is focused on in AMN – a condition with no therapeutic options besides symptom management. In developing a gene therapy that addresses the ABCD1 gene deficiency that causes AMN, we are aiming to address the downstream effects patients experience due to the gene deficiency, which affects the cells of the spinal cord and other tissues, manifesting as spastic paraparesis, and sensory ataxia. These effects lead to loss of mobility in adulthood, incontinence, debilitating pain, and sexual dysfunction, impairing quality of life. To further address the challenges facing experimental gene therapies, we have curated a specific expertise in intrathecal delivery. Our method aims to achieve targeted biodistribution throughout the spinal cord, rather than relying on higher, systemic doses (and higher systemic exposure) others have explored for delivery to the CNS. What are critical challenges in realizing the full potential of gene therapies? What could be the solutions in your opinion? Karen: The success of gene therapies relies on solid manufacturing strategies. The critical importance of this function led us at SwanBio to take an incredibly intentional approach to manufacturing, establishing scalable, commercial-ready processes from the outset. We made a significant upfront investment in process development and optimization to eliminate the need for bridging during clinical development and to ideally minimize regulatory delays. Another challenge facing drug development in any category is translating the success of preclinical research to the clinical setting. Naturally, we’ve seen this challenge in gene therapy as well. Our approach to overcoming this barrier has been to build the connections between efficacy and biodistribution to develop a strong patient dosing strategy. We look forward to executing this careful planning when we officially begin our Phase 1/2 clinical study and start dosing patients later this year. What does global collaboration mean to your company? Karen: At SwanBio, our initial focus is on rare, neurological diseases. A natural consequence of working in rare disease is that the number of clinicians who have true expertise and deep experience working with affected patients is limited, and widespread knowledge of diseases can also be rare. Rare expertise in rare disease means that true, global collaboration is critical to success. As a result, we started making connections and building relationships with centers and expert physicians around the world from the very beginning – even before SwanBio was technically founded. We have made a point to work with them closely from the onset, to understand the science and learn from their experiences spending a lot of time with patients. This approach means that we look for expertise, without worrying about borders. If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of the landscape of gene therapy R&D? Karen: My hope is that in 10-15 years, we will see a faster pace of gene therapy approvals – ultimately getting treatments to people in need much more quickly. This may require new partnership models or strategies to help gene therapy companies translate their early clinical successes into pivotal trials and eventually commercialized products. I also hope that we’ll see greater manufacturing efficiencies and quality across the board. This evolution will require more knowledge sharing – the convergence of methods from groups who have become experts in gene therapy manufacturing, and who are willing to share their best practices for the greater good.     Karen Kozarsky, PhD Co-Founder & Chief Scientific Officer Karen Kozarsky is the co-founder and CSO of SwanBio Therapeutics, a Philadelphia-based gene therapy company focused on bringing life-changing treatments to people with devastating neurological conditions. She leads the development of the company’s pipeline – therapies designed for intrathecal delivery to address targets in both the central and peripheral nervous systems. Karen has 25+ years of experience in gene therapy, with a primary focus on adeno-associated virus (AAV) vectors. Her expertise includes evaluating potential therapeutic opportunities, identifying new areas, and developing products from the earliest preclinical stages through IND. She has been involved in the development of multiple gene therapy products that are in clinical trials. Karen’s roles have included President of Vector BioPartners, Vice President of R&D at REGENXBIO Inc., and Head, Gene Therapy in the GlaxoSmithKline Biopharmaceutical Center of Excellence for Drug Discovery. Previously, she was a Research Assistant Professor at the University of Pennsylvania’s Institute for Human Gene Therapy, and completed postdoctoral fellowships at the University of Michigan in gene therapy and in immunology. She received a PhD in biology from the Massachusetts Institute of Technology and a BA in biology from Amherst College. In 2021, Karen was recognized by the Philadelphia Business Journal as one of the year’s ‘Women of Distinction’ for her leadership and vision. Karen was named by the Alliance for Regenerative Medicine as the first co-Chair of the Gene Therapy Section to support policies to advance novel gene therapies, and has been a committee member for the American Society of Gene & Cell Therapy.

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2022/07/25

Delivering on the Promise of New Modalities: An Interview with James McArthur, President & CEO of PepGen

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 the next installment of our interview series, James McArthur, Ph.D. joins us as the President and CEO of PepGen Inc. (PepGen), a clinical-stage biotechnology company advancing the next generation of oligonucleotide therapeutics with the goal of transforming the treatment of severe neuromuscular and neurologic diseases. Last year, PepGen raised $112.5 million to develop therapies for neuromuscular and neurologic diseases, including a focus on Duchenne muscular dystrophy (DMD). Earlier this year, PepGen dosed their first participant in a Phase I clinical trial of PGN-EDO51 for the treatment of DMD and in May became a Nasdaq listed public company. Thank you for joining us today, James! Congratulations on your clinical trial of PGN-EDO51. For the development of therapies for neuromuscular and neurologic diseases, what are the industry-wide challenges in current therapeutic interventions that your company wants to solve? James: Research and development of therapeutics for rare neuromuscular diseases has advanced significantly, but transformative therapies for diseases like Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) are still lacking. Oligonucleotide drugs have shown considerable potential as a therapeutic class, but challenges associated with their delivery have limited their effectiveness in certain indications. On their own, oligonucleotides are not readily distributed to heart and skeletal muscle, the key affected tissues in neuromuscular diseases, and are not efficiently taken up into these cells. At PepGen, we are developing our EDO platform to address these critical challenges by optimizing the tissue penetration, cellular uptake and nuclear delivery of oligonucleotides. We anticipate that this approach will enhance the therapeutic activity of these therapies, thus delivering on the promise that oligonucleotides have shown in rare neuromuscular indications. Could you further introduce the EDO platform for our readers? How is it different from existing approaches? James: Our Enhanced Delivery Oligonucleotide (EDO) platform is founded on over a decade of research and development, and leverages cell-penetrating peptides to improve the uptake and activity of oligonucleotide therapies. Our EDO peptides are engineered to effectively deliver their oligonucleotide cargos to the hard-to-treat tissues affected in neuromuscular and neurologic disorders, such as the heart, skeletal muscle and the central nervous system (CNS), thereby addressing some of the primary challenges that have impeded treatment of these diseases. Our preclinical data, including in non-human primates, suggests that our EDO therapies achieve greater levels of exon skipping and dystrophin production (in DMD) and correction of mis-splicing and myotonia (in DM1) compared to other therapeutic approaches. As such, we believe that our candidates have the potential to enable new, best-in-class treatments for people living with a broad range of severe neuromuscular and neurologic diseases. What remain to be the critical challenges in realizing the full potential of your new modality? And what are your next key milestones anticipated? James: The efficacy of oligonucleotide therapeutics in neuromuscular disorders requires balancing the effectiveness of delivery to muscle with the safety and tolerability profile of the therapy. PepGen’s preclinical data indicates the potential of our EDO technology to balance these requirements. We recently initiated a Phase 1 clinical trial in healthy volunteers for our lead DMD candidate, PGN-EDO51, and expect to report initial safety, pharmacokinetic (oligonucleotide delivery to muscle) and target engagement (exon 51 skipping in muscle) data by the end of 2022. We also plan to submit an Investigational New Drug (IND) application for our DM1 candidate, PGN-EDODM1, in the first half of 2023 and initiate trials shortly thereafter. In parallel, we are conducting additional studies to assess the safety and exon skipping activity for our other DMD candidates in development. Our hope is that we can overcome the challenges faced by current therapeutics in this space to bring truly transformative treatments to patients. If we were to gather here again in 10 or 15 years’ time, what do you think we’re going to be talking about in terms of what we have already achieved in the industry, and what do you think are going to be some of the solutions going forward? James: Our hope is that in the next 10 to 15 years we will have seen several important advancements in the treatment of complex, rare diseases that require a tailored treatment approach. Our team at PepGen, and many of our colleagues in the industry, are working daily to improve the delivery of biologic drugs, including oligonucleotide therapeutics, to tissues that are currently not accessible or poorly accessible by existing therapies and modalities. The work that we and others in the field are doing to improve delivery and thus address these key challenges will hopefully enable additional innovations, and we anticipate that this will ultimately lead to a broader range of available therapies for patients who remain underserved by current treatment options. Our hope is that the translation of tailored, personalized medicines will become commonplace, and will eventually facilitate a paradigm shift in the way we study and treat rare diseases. Do you foresee any big breakthroughs in life science industry in the next decade? James: As mentioned above, we expect the next decade will bring an increase in both the number and range of precision therapy modalities. As new advancements lower the cost of genetic sequencing, clinical trials have expanded to include more diverse populations and healthcare regulation has begun to adopt better coverage for personalized treatments, leading to a shift in patient care. The hope is that these advancements lead to earlier diagnoses for patients, a factor which will in turn accelerate their treatment journey. At PepGen, we are advancing our EDO therapies to treat a range of patients with neuromuscular diseases, a population often fraught with difficult diagnostic journeys and a lack of effective treatment options. The combination of a more rapid path to diagnosis and more tailored treatments will hopefully lead to meaningful breakthroughs in treatment, and in turn allow more patients to access these transformative treatment modalities. Thank you James for sharing PepGen’s approaches and your insights! James: My pleasure.   James McArthur, Ph.D. President and CEO, PepGen James McArthur currently serves as President and Chief Executive Officer of PepGen and serves on the company’s Board of Directors. James has more than 25 years of industry experience, has cofounded 5 biotechnology companies, 3 of which were acquired, and has served as a Director of two companies through successful initial public offerings. He was founding CEO of Imara, a public company developing therapies for sickle cell disease and beta-thalassemia, co-founder and President of R&D of Cydan, a rare disease accelerator, and founding CSO of Synovex/Adheron, a rheumatology therapy company acquired by Roche. Prior to serving at these companies, James held senior research leadership roles in several pioneering gene and stem cell therapy companies. He was a venture partner at RA Capital and an entrepreneur in residence at HealthCare Ventures. James was previously a post-doctoral fellow at MIT and UC Berkeley working with Drs. David Raulet and Nobel Laureate James Allison, before which he received his PhD in molecular oncology and BSc in biochemistry from McGill University in Montreal. Forward-Looking Statements of PepGen Inc. This interview transcript contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, relating to PepGen Inc. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will,” and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this interview that are not statements of historical fact may be deemed to be forward-looking statements. These forward-looking statements include, without limitation, statements regarding the expected timing of the presentation of data from the ongoing Phase 1 study of PGN-EDO51, the filing of an IND application for PGN-EDODM1 and the nomination of development candidates; and statements about our clinical and pre-clinical programs, product candidates, achievement of milestones, and corporate and clinical/pre-clinical strategies. Any forward-looking statements in this interview are based on current expectations, estimates and projections only as of the date of this interview and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, that we may fail to successfully complete our Phase 1 trial for EDO51 and pre-clinical studies of other product candidates and obtain required approval before commercialization; our product candidates may not be effective; there may be delays in regulatory approval or changes in regulatory framework that are out of our control; our estimation of addressable markets of our product candidates may be inaccurate; we may fail to timely raise additional required funding; more efficient competitors or more effective competing treatment may emerge; we may be involved in disputes surrounding the use of our intellectual property crucial to our success; we may not be able to attract and retain key employees and qualified personnel; earlier study results may not be predictive of later stage study outcomes; and we are dependent on third-parties for some or all aspects of our product manufacturing, research and preclinical and clinical testing. Additional risks concerning PepGen’s programs and operations are described in its registration statement on Form S-1, which is on file with the SEC, and in its most recent quarterly report on Form 10-Q to be filed with the SEC. PepGen explicitly disclaims any obligation to update any forward-looking statements except to the extent required by law.

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