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2022/08/11

Delivering on the Promise of New Therapies for Rare Diseases: An Interview with David Walker, Director of Chemistry, Sentinel Oncology

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 this exciting journey to bring transformative 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.” Hi David! Thank you for joining our interview. To kick off, could you please introduce yourself? David: Hello, my name’s David Walker and I’m the Director of Chemistry at Sentinel Oncology. Sentinel is a Cambridge, UK-based drug discovery company focused on treating diseases with high levels of unmet medical need. I’m also the technical lead on Sentinel’s program to develop a therapeutic for Fragile X syndrome. As a company which is mostly focused on cancer treatments, what inspired Sentinel to work on Fragile X and what issues are you trying to address? David: I’m often asked why an oncology company is working on Fragile X syndrome! Well, we were driven by the science. Sentinel originally set out with a focus on developing selective inhibitors of the kinase S6K1 to treat triple-negative breast cancer. Triple-negative breast cancer is a particularly invasive subtype of breast cancer accounting for 10 to 20% of all breast cancers. Prognosis is generally poor and treatment options remain limited. One of the reasons for such a poor prognosis is the common formation of brain metastases which evade treatment. It has been published that S6K1 is responsible for driving the metastasis. To address this huge unmet medical need, we set about developing a series of brain penetrant S6K1 inhibitors. Then, in 2012, Professor Eric Klann and Dr. Aditi Bhattacharya at New York University published in the journal Neuron, showing that S6K1 plays a key driving role in the pathology of Fragile X syndrome. In short, Fragile X Syndrome is caused by a mutation of the gene Fmr1, leading to the absence of the protein product FMRP. FMRP acts as a repressor of protein synthesis so that in its absence, protein synthesis is always on and elevated. Klann and others have shown that in Fragile X patients and model mice, S6K1 is over-activated in the brain compared to healthy counterparts, and this drives excessive protein synthesis leading to pathology. S6K1 is a master regulator of protein synthesis and Klann and Bhattacharya showed that genetic deletion of S6K1 in a Fragile X model mouse restores healthy protein synthesis in the brain, as well as correcting associated pathologies. This led us to hypothesize that if a small molecule inhibitor of S6K1 could achieve the same effect, it could potentially be a viable treatment option for Fragile X patients. Indeed, we went on to collaborate with Klann and Bhattacharya to test our S6K1 inhibitor in their Fragile X model mice. This work was published in Neuropsychopharmacology in 2016. In short, our S6K1 inhibitor was able to correct a wide range of deficits in the Fragile X mouse. This included dampening down the activity of S6K1 in brain to healthy levels, decreasing protein synthesis in the brain and correcting neuronal spine morphology. Furthermore, we showed efficacy in behavioral models, including the social novelty test, Y-maze, and audiogenic seizure model. Overall, this strong scientific rationale underpinned our choice to invest in the Fragile X space. We are also driven by the high level of unmet medical need with Fragile X. All the existing therapies of Fragile X treat the symptoms only, whereas with our S6K1 inhibitor, we have the opportunity to treat the underlying disorder itself. What is the greatest value of your modality or technical approach to Fragile X syndrome, compared with existing treatments to these patients? David: Today, the drugs available to Fragile X patients treat symptoms only. Probably, the greatest value of our approach is that we have the potential to treat the underlying root cause of the disease. This in turn has a potential to improve profound aspects, such as cognition. To date, there has never been an S6K1 inhibitor in the clinic for Fragile X syndrome, so our approach is differentiated over what has come before. Could you share with us the current progress of your Fragile X program and its upcoming milestone? David: So, our candidate drug SOL784 has shown promising preclinical effects in several models of Fragile X Syndrome, giving us good confidence in taking this molecule forward. We have plans to put SOL784 into a Phase I clinical trial. Right now, SOL784 is in late stage development, undergoing a number of preclinical tests necessary for it to enter clinical trials. Let’s talk about the future. In your opinion, where might the next breakthrough in the field come from? David: In my view, the next paradigm shift looks to be the implementation of new measurable outcomes for drugs in Fragile X clinical trials. Some of this is happening already. Clinical development clearly is not easy in this field and there are challenges such as the placebo effect to contend with; however, outcome measures such as the EEG and eye gaze tracking are now finding their place in Fragile X clinical trial design. We are hopeful that an S6K1 inhibitor which treats the underlying pathology of the disease will show meaningful effect under these measures. From your point of view, how will AI transform the field of Fragile X research? David: I think it probably still remains to be seen. There are groups already using AI to predict rational combination therapy for Fragile X syndrome. These combinations are already in the clinic, so we should see results in due course. Could you highlight how collaborations and partnerships affect your Fragile X program and the field? David: Collaborations and partnerships are very important to this field. Ever since Sentinel got into this field, FRAXA has provided tremendous support to us in terms of advice and practical drug testing. This was not our original field of expertise and it’s fair to say that without that relationship, we wouldn’t have taken this program forward. So, huge thanks to Michael Tranfaglia and Patricia Cogram of FRAXA. Our research collaboration with Professor Eric Klann and Dr. Aditi Bhattacharya at New York University was also instrumental in generating proof-of-concept data on our S6K1 inhibitor in Fragile X model mice. We are very grateful to all our collaborators for their support. Finally, we are excited to be in alliance with MSRD to take our Fragile X program forward. In your opinion, what does patient-centric drug development mean for the Fragile X field? David: This is an important question. Patient-centric drug development means understanding the Fragile X patient population and the makeup of patients in any clinical trial. This will have a bearing on the outcome of said trial. There are important factors to consider such as age, sex, and genetic disposition amongst others. For example, in our case, there’s an argument to start treatment with an S6K1 inhibitor in young patients to target the pathology during development. Furthermore, genetic disposition affects severity of disease. For example, males with full mutation are generally considered the most severely affected group. We know from the world of oncology that patient populations tend to be divided into certain subgroups that respond differently to a drug. We’d like to explore that parallel in Fragile X Syndrome. In 2021, the FDA approved 50 new drugs. If we imagine 2030 and think beyond Fragile X, would we collectively be able to achieve 100+ new drug approvals at half of today’s cost? And in achieving so, do you foresee any major gaps to bridge or any upcoming breakthroughs which you are most excited about? David: Well, the drug discovery landscape has changed a lot in the last five years with biologics and gene therapies and others being added to the portfolio. In other words, the landscape is no longer small molecules. So, probably these additional therapies will supplement numbers, but I don’t think that net cost is necessarily the key question – rather, it’s where is the innovation coming from? In my view, nothing will replace the development cost of a drug, and experiments will get more costly as they get more complicated. In terms of major gaps to bridge; well, innovation starts early. It remains difficult to raise early stage finance, and innovators must have access to good finance to get the work done. Breakthroughs rely on high quality new science. There will be new ways to treat disease besides small molecule. AI may help with areas such as repurposing, but we still need to find those new drugs. Thank you very much for your time, and for sharing your valuable insights with us . David: Thank you.     David Walker DIRECTOR OF CHEMISTRY, SENTINEL ONCOLOGY David is a medicinal chemist with over 20 years’ experience in Biotech & Pharma. David has held positions at Pfizer, Cambridge Discovery Chemistry, Millennium Pharmaceuticals & Astex Therapeutics. Whilst at Sentinel Oncology, David has spent over 14 years managing small molecule drug discovery and development projects via an outsourcing model. David is technical lead on Sentinel’s program to develop a therapeutic for Fragile X Syndrome. David is a named inventor on multiple patents and co-author on several scientific publications.

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2022/08/11

Delivering on the Promise of New Modalities: An Interview with Yann Chong Tan, Founder & CEO, Nuevocor

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. We continue our interview series with Yann Chong Tan, Founder & CEO of Nuevocor, a preclinical-stage biotech company specializing in gene therapy for cardiomyopathies. Recently, Nuevocor closed on $24 million Series A Financing to advance their novel gene therapies. The company believes they are well-positioned to treatLMNA (lamin A/C gene) and other genetic cardiomyopathies, amongst other cardiac diseases. Nuevocor focuses on developing gene therapy-based treatments that have the potential to restore cardiac function in diseased hearts. In your opinion, what are the top challenges in current therapeutic intervention for this disease? Yann Chong: At Nuevocor, we focus on using gene therapy to treat genetic cardiomyopathies. Cardiomyopathy is estimated to affect more than 1 in 250 people and is a disease where the heart gradually loses its ability to pump blood efficiently. Treatment options are limited and the only cure is a heart transplant. With the advent of precision medicine over the past decades, we now know that a large fraction of cardiomyopathies has genetic causes. As each of these genetic cardiomyopathies has a different mechanistic driver, a challenge is understanding the underlying root causes to design targeted treatments. How is your gene therapy approach helping to address these challenges? How is it different from existing approaches? Yann Chong: The majority of genetic cardiomyopathies are inherited in an autosomal dominant manner where one copy of the mutated gene drives the disease even though the patient has a second, normal copy of the gene. This makes a gene replacement approach unworkable. There are also no mutation hotspots for gene editing to be attractive. Our approach is to identify genetic modifiers of cardiomyopathies and deliver them to patients via AAV-mediated gene therapy. To identify such genetic modifiers as therapeutic targets for genetic cardiomyopathies, we utilize our PrOSIA mechanobiology platform to understand the molecular and biomechanical basis of genetic cardiac disease. To illustrate the power of our approach, our lead programme targets LMNA dilated cardiomyopathy. This is the second most common genetic dilated cardiomyopathy and has the worst prognosis, with 70% of patients having cardiac death, a heart transplant or a major cardiac event by the age of 45. Our treatment reduces biomechanical stress on the nucleus of LMNA mutant heart cells, thereby reducing nuclear damage in LMNA dilated cardiomyopathy. In animal models, we have extended lifespan by more than 4-fold with our approach, which is unprecedented for this rare disease. What are critical challenges in realizing the full potential of your gene threapy? What are Nuevocor’s solutions? Yann Chong: The benefits of AAV-mediated gene therapy have been demonstrated with drug approvals and have made a significant difference in patients’ lives. Recent clinical trials, however, have highlighted that there are still quite some ways to go in ensuring that the therapy is safe for patients especially at high doses. The field is coming together to solve these issues and there has been incredible progress in understanding the cause of the safety challenges and in designing solutions. We are actively working on addressing these safety challenges by examining how we can lower the AAV dose and ensuring that our therapeutic protein is not immunogenic. We have made significant progress in the past year and we are confident that we will be able to have a solution in the coming year. To make a prediction, what could be the next big scientific breakthrough in the life science industry? Yann Chong: It is difficult to predict the next big invention, but what is clear is that techniques regularly used in research to perturb systems and answer biological questions, such as anti-sense oligos, or mRNA and DNA vectors for expressing and regulating genes, have formed the basis for new drugs in recent years. There is no turning back from these new nucleic acid therapeutic modalities, which promise to address the root cause of diseases so as to provide cures for patients. Enabling wider use of these technologies is in the interest of patients and their families. A challenge for these modalities is delivering the therapeutic molecule to the intended cell types, ideally with good specificity and importantly, also in a way that is safe. We expect current delivery methods to mature, and at the same time, a proliferation of different delivery methods, both viral and non-viral. It is likely that each delivery method will have its own advantage in being able to deliver well to different organs and cell types. We anticipate the next breakthrough to be the ability of the field to deliver to different cell types achieved through the coexistence of multiple viral and non-viral delivery technologies. Thank you for your insights! Any closing remarks to our readers? Yann Chong: We believe in moving our therapies as quickly as possible into the clinic, and collaborations between different groups with complementary capabilities can accelerate the process. Capabilities do not respect borders and ideally collaborations should be cross-border too. Nuevocor is headquartered in Singapore, a cosmopolitan global city with English as the main communication and is in many ways a bridge between Asia and the West. It should come as no surprise that we already have global collaborations with our strong ties to North America, Europe and Asia. We are always actively seeking more collaborations to move the science forward.     Yann Chong Tan Founder & CEO, Nuevocor Yann Chong Tan, PhD, brings a decade of experience in biotech and commercialisation leadership roles to Nuevocor. He is an inventor on multiple patents and an entrepreneur who has founded multiple biotech companies. Dr. Tan was previously the Chief Innovation Officer at the Genome Institute of Singapore, where he initiated and led strategic programmes resulting in multiple healthcare and biotech spin-offs, one of which is Nuevocor. Previously, as Chief Technologist at Atreca, Inc., a company he co-founded in 2012 from his academic work, Dr. Tan led and built up Atreca’s core foundational antibody discovery technology and discovered the antibody now in clinical trials. Atreca is listed on NASDAQ.

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2022/08/11

Delivering on the Promise of New Modalities: An Interview with George Wu, Co-Founder & CEO, Amberstone Biosciences

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 as part of our featured series highlighting innovation in our ecosystem, we sat down with George Wu, Co-Founder & CEO of Amberstone Biosciences, an emerging biotech company with expertise in developing a new generation of ‘conditionally active’ cancer therapies. Earlier this year, Amberstone Biosciences secured $12 million in Series A Financing to advance the immuno-oncology pipeline of tumor microenvironment activated therapeutics. The company also recently announced the formation of a scientific advisory board comprised of industry leaders in the top fields of drug delivery, oncology, immunology, and pharmaceutical sciences. Greetings George. Amberstone focuses on developing novel immuno-oncology therapeutics. In your opinion, what are the top challenges in current therapeutic intervention for cancer?? George: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, showing great clinical and commercial successes. But the majority of cancer patients don’t respond well to this class of treatments. There are still significant unmet medical needs for cancer patients. In search of novel cancer immune therapies, the field has encountered a major hurdle. Many potentially transformative new immunotherapeutics exhibit a very narrow therapeutic window, making them intractable for further development. Reducing the dose-limiting toxicities while maintaining efficacy of those promising agents is one of the biggest industrial-wide challenges. Inadequate tumor selectivity, poor adaptability to the heterogeneous patient immune systems, and suboptimal preclinical translational efficiency are some of key underlying gaps that the field endeavors to address in order to increase the chance of success. Another major challenge is the alarmingly high cost that has been limiting the upside potential of some innovative treatments such as cell-based therapeutics. It also limits patient access to those novel and effective treatments. What is your unique technological approach helping to address these challenges? How is it different from existing approaches? George: Amberstone Biosciences has a singular focus on developing tumor microenvironment activated immunotherapeutics (T-MATEs). Our molecules are selectively activated in acidic tumor microenvironment but not in physiological normal tissues, thus offering a favorable expanded therapeutic window. Our rationale is based on the well-known tumor acidity, in part due to glycolytic metabolism, a near-universal cancer hallmark that has been established for about 100 years with the solid support of over 10,000 scientific research articles. Our two lead programs are T cell engagers that are uniquely designed to address large and diverse solid tumor patient populations. For the current stage, we only adopt clinically established modalities (e.g. antibodies and cytokines) that provide a clear path of development. We expect that our approach can be integrated with a variety of modalities to target many promising regulatory pathways around the tumor immunity cycle. We are excited with the potential of our approach and are firmly committed to our mission of delivering a next generation of safe and effective treatments to benefit those with devastating cancer. What are critical challenges in realizing the full potential of your new technologies? Could you share with us your solutions and your upcoming milestone? George: While the overall path of development is fairly clear for our T-MATE programs, there is a shortage of highly-relevant preclinical models that can allow us to efficiently characterize our molecules’ efficacy, safety, and pharmacokinetics, thereby translating effectively to clinical benefits. We are working with several academic and industrial partners to address these challenges. For the time being, we are taking rigorous and somewhat redundant approaches to improve the chance of successful translation. Despite these challenges, we are optimistic with our next milestone goals in IND-enabling studies starting later this year. With many new modalities advancing into the clinic and getting closer to patients, do you think the 2030 class of FDA new approvals may look similar or different from those today? George: I think there will be increasingly more new modalities being approved — multispecific antibodies, off-the-shelf cell therapies, cancer vaccines, TLR agonists, and innovative personalized medicines, just to name a few. I also expect to see the approval of many nuanced combination strategies that can innovatively leverage existing treatments and therapeutics of various modalities. One example is to combine two or three immune-modulating molecules to achieve a balanced yet durable tumor-selective immunity to annihilate all cancer cells in a safe and effective manner; another example is to combine a “right” regimen of chemotherapy with a “right” kind of immunotherapy in a synergistic manner to improve the clinical outcome. Do you think we as industry will be able to achieve 100+ new drug approvals at 50% of today’s cost by 2030? And in achieving so, do you foresee any major gaps to bridge? Or any upcoming breakthroughs that you are most excited about? George: I expect there will be significant improvement of productivity for at least some modalities, particularly cell therapy. I am generally optimistic about technological innovations which are arising regularly. On the other hand, the production cost reduction may or may not adequately translate to favorable pricing on the healthcare systems or the improved affordability to patients. This is intricately related to individual countries’ respective situations. Do you see novel data technologies, AI, or machine learning being used in the next couple of years? George: Absolutely. I am a big fan of information/data technologies which have started and will only accelerate to create direct impact. Take a look at the quick evolution of the AlphaFold, as an example. There is no doubt that these enabling data technologies and tools will shape how we discover and develop new medicines in the future. This is not to say these new technologies will overtake or fully replace the established practices. We will have a clearer picture once we start to see more clinical stage assets that are significantly enabled or expedited by these technologies.   George Wu Co-Founder & CEO, Amberstone Biosciences George Wu is a life sciences technology innovator with great passion in developing innovative cross-field technologies to address unmet market needs. He has published over 40 manuscripts and abstracts in cancer biology, immunology, high-throughput drug discovery, single cell technologies, medicinal chemistry, and molecular diagnostics. With numerous patents relevant to anti-tumor molecules or single cell technologies, Wu is a recognized inventor committed to making a difference for the healthcare of patients. Before founding Amberstone, he was President/COO of GeneTex International, where he was closely involved in antibody and research product development, business scaling, and cross-border merger and acquisition. He received a BS in biology from the University of Science & Technology of China, and a PhD in molecular medicine from the University of Texas Health Science Center, San Antonio. As a Susan Komen Research Fellow at the University of California, Irvine, his primary focus was small molecule anti-tumor drug discovery and translational research.

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2022/08/11

Delivering on the Promise of New Modalities: An Interview with Andrea van Elsas, CSO, Abata Therapeutics, Venture Partner, Third Rock Ventures

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. In our latest interview, we’re joined by Andrea van Elsas, Venture Partner at Third Rock Ventures and CSO of Abata Therapeutics, a company focused on translating the biology of regulatory T cells (Tregs) into transformational medicines for patients living with severe autoimmune and inflammatory diseases. The company launched last year with $95 million in Series A Financing to engineer T cells to tackle autoimmune diseases like multiple sclerosis (MS). Most recently, Abata announced the formation of an advisory board comprised of leading industry experts in Treg Biology, Cell Therapy and Corporate Development. Hi Andrea, thanks for taking the time to join us today. Abata is developing targeted, autologous Treg cell therapies for serious autoimmune diseases. Could you please introduce your new modality approach to our audience? Andrea: Regulatory T cells (Tregs) have been well characterized during the past 25 years, demonstrating a wide palette of functions evolved to suppress or limit inflammation and support tissue repair. One of Abata’s founders, Diane Mathis, has led the field publishing a wealth of high impact studies unraveling a critical role for Tregs in limiting overactive immune responses and promoting repair in various organs and tissues. Tregs use several mechanisms to inhibit inflammation by cell-cell interaction as well as by secretion of soluble immunosuppressive factors into the inflamed milieu. These highly potent Treg functions dominate the activity of, for instance, effector T cells such as those found in the aforementioned meningeal lymphoid aggregates, and they can be triggered once the T cell receptor detects myelin-associated antigens produced locally upon tissue destruction. Importantly, by studying lymphocyte trafficking into the brain another Abata founder and CMO Richard Ransohoff showed that T cells require TCR activation by cognate antigen presented on meningeal macrophages to stay in the brain. Treg cell therapy has been clinically tested by a handful of teams during the past few years albeit not in progressive MS patients. Although Tregs were demonstrated to be safe, efficacy has not been optimal. We believe this is due to the fact that Tregs with the proper T cell receptors to direct them to the inflamed tissue are quite rare. By engineering a disease specific T cell receptor into Tregs we dramatically change the number of Tregs capable of trafficking into affected organs and treat ongoing disease using their polypharmacy capacity. It is a numbers game. Moreover, Treg cells are thought to stay around for a long time and differentiate into tissue-resident Tregs, potentially delivering highly durable clinical benefit even following a single dose of Tregs since durability matters in autoimmune disease. Also, in preclinical models Tregs are known to secrete factors that stimulate myelin repair adding to their potential durable benefit. In addition to progressive MS, the Abata team is currently working on specific TCR engineered Tregs for two other diseases, type 1 diabetes and inclusion body myositis. How your Treg approaches might make a difference to MS patients? Andrea: With our first product candidate ABA-101, Abata is aiming to treat patients with progressive MS. ABA-101 is an autologous Treg product that we engineer to express a specific T cell receptor to guide Tregs to the disease site, a discovery project run in close collaboration with Abata founder Roland Martin. Several approved drugs are currently available to treat patients with relapsing remitting MS with considerable success. However, after the flaring phase of the disease passes there are no effective options to treat progressive MS. At least in part this can be explained by the finding that 1) relapsing remitting disease is driven by immune cells that enter the meningeal compartment from the periphery (blood), 2) drugs effectively used to treat RRMS target leukocytes in the periphery, 3) in contrast, progressive MS is driven by lymphoid aggregates that have formed in the meninges secreting factors that activate myeloid and other cells destroying the myelin sheet locally, and 4) the currently approved drugs for MS do not appear to affect inflammatory activity originating from these meningeal lymphoid infiltrates. Learning from oncology, with TCR-engineered Tregs Abata is taking a first step to use the incredible potential of cell therapy in autoimmune diseases with highly unmet medical need. What are critical challenges in realizing the full potential of your new modality? What are Abata’s solutions? Andrea: First, TCRs represent a key element of this therapeutic approach, however self-antigen specific TCRs are very rare and the rules and tools for HLA class II-restricted TCRs are being developed. Second, as a therapeutic modality, autologous cell therapy requires robust investment in well-controlled manufacturing processes, facilities and teams. Third, endpoints demonstrating clinical activity of any product in progressive MS patients have been highly variable from patient to patient. Building from the TCR expertise of Abata founder Michael Birnbaum, Abata has recruited an exceptional team of scientist to set up and run an effective TCR discovery platform that includes optimizing the data science and tools for Treg functional studies and engineering. To maximize learning from the first few ABA-101 patient cohorts, Abata will exploit imaging technology that was developed by a Danny Reich, a key Abata advisor at the NIH, to allow quantitative determination of MS lesions before and after treatment. In addition to a variety of clinical biomarkers to determine Treg cell numbers and their activity in the meningeal compartment, we aim to show proof-of-principle for Abata’s TCR-engineered Treg platform. Following ABA-101, Abata aims to have three Treg products in clinical development by 2026. How would Abata harness the potential of novel data technologies, AI, or machine learning? Andrea: Abata recognized the potential high impact of AI and machine learning by working with existing experts at Third Rock Ventures as the company was being incubated. After its launch in 2021, Abata recruited a very strong data science team that now brings world class machine learning expertise to a variety of aspects that are critical to discover, manufacture and develop our Treg therapy. I believe we are only scratching the surface of possibilities for AI/machine learning in drug development and Abata is exploring novel applications as we speak. Thanks Andrea for your insights! Any closing thoughts? Andrea: In relation to Abata’s autologous engineered cell therapy product candidates, we aim to explore cutting edge science and technical solutions that might enable the production and application of Treg therapy at scale, to a much larger patient population than what the industry has dealt with thus far. A simple problem statement could be, how do we make Treg therapy available, not for 100 or 1000 patients, but for 100,000 patients per year.     Andrea van Elsas PhD Abata CSO and Venture Partner at Third Rock Ventures Andrea van Elsas is a venture partner with Third Rock Ventures (since 2020). He most recently served as Chief Scientific Officer at Aduro Biotech following the acquisition of BioNovion, a company he co-founded 2011. From 1999 to 2011, he held various positions at Organon (acquired by Schering-Plough and later by Merck) in Oss, The Netherlands, and Cambridge, Massachusetts. As Director of Tumor Immunology, he oversaw the immuno-oncology portfolio and led the anti-PD1 program that later became known as pembrolizumab. As a postdoctoral researcher, Andrea worked in the lab of Nobel Laureate Jim Allison at the University of California, Berkeley and is a co-inventor on the original anti-CTLA-4 patents that formed the basis for the development of ipilimumab, the first checkpoint inhibitor approved in 2011 by the FDA for the treatment of melanoma. He currently serves as CSO at Abata Therapeutics, on the Scientific Advisory Board of Lava Therapeutics (chair) and on the Supervisory Board of Immunicum and InteRNA Technologies.

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2022/08/11

Delivering on the Promise of New Modalities: An interview with Elvire Gouze, CEO & Founder, Innoskel SAS, France

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. The next installment of our interview series features Elvire Gouze, CEO & Founder of Innoskel SAS, France, a bioscience platform company developing transformative gene therapies for the unmet needs of individuals with rare bone disorders. When Innoskel launched at the end of 2020, they achieved Series A Financing to the tune of €20 million to advance the company’s lead program clinical stage operations. Innoskel is developing treatment options for a group of rare skeletal disorders collectively known as type 2 collagenopathies that affect the structure of the body’s connective tissues (collagen). Earlier this year, the company announced the enrollment of the first patient in a study, which will evaluate the course of type II collagen disorders in children with short stature. Thank you for taking the time to join us today, Elvire! We were excited to see early progress announced for your clinical trials earlier this year. For rare bone disorders, what are challenges in current therapeutic interventions, or current new modality solutions? Elvire: Innoskel is developing innovative treatments for rare bone disorders. These diseases affect the mechanisms of bone growth, mainly endochondral bone growth, and the challenge is to effectively target the growth plates of the bones of affected children while limiting off target distribution. There is no current modality for the diseases requiring gene therapy that have been shown to be effective at restoring bone growth. Indeed, common modalities, such as AAV or lipid nano particles, are known to be ineffective in targeting growth plates. Our approach is unique and a combination of the gene therapy modality, route of administration and proprietary promoter sequences allows us to have safety advantages combined with a directed biodistribution to the target tissues. How is your gene therapy approach helping to address this challenge? Is your technology differentiated from existing approaches? Elvire: Innoskel develops a lentiviral vector because of the ability of lentivirus to transduce non-dividing cells brings a significant advantage allowing genetic modification of the targeted proliferating cells and transmission to the daughter cells after cellular division. We have to pave the way with regulatory agencies and payers to address these diseases with a lentiviral vector administered systemically. The durability of the effect on bone growth is expected to be permanent – nevertheless, it is anticipated that due to bone growth and chondrocyte turnover, the duration of the LVV activity may be limited to 2-3 years requiring repeat administration. Innoskel is considering an immunomodulation regimen that should allow tempering down the immune reaction to the lentiviral vector and would allow for later redosing. In your opinion, what’s the biggest barrier to realizing the full potential of your LVV based gene therapies? Elvire: Manufacturing is a critical aspect of therapeutic intervention, and one must anticipate the technical challenges to accelerate treatment access for the patients. Indeed, current lentiviral vector production standards need to be optimized to reach a yield and product quality compatible with in vivo systemic administration. To solve these challenges and bring the therapies to global patients, how important is global collaboration to your company? Elvire: Global collaboration is critical for Innoskel. Indeed, when developing an innovative treatment for rare pediatric disorders, collaboration between companies, big pharmas and patient organizations is the only way to develop treatments and achieve patient access successfully and rapidly. Global collaboration is especially important in the rare disease area, where the best experts of these diseases are scarce and where the deep understanding of these diseases and their impacts on the life of patients is limited. It is essential to bring experts and patient representatives together to accelerate the development of therapies that are truly life-transforming and meaningful to patients. Worldwide databases and international collaboration are also critical to identify the few patients that could benefit from the treatment as quickly as possible, as we know that the therapeutic window before irreversible damages are done is tight in most cases. Looking for the best experts, wherever they are, allows us to be agile, creative, relevant and efficient. For Innoskel, the global collaboration approach is the best and only way to truly commit to patients to do the best we can to answer their high unmet needs. Thanks Elvire, really enjoy the discussion. 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? What do you think are going to be some of the solutions going forward? Elvire: The real challenge for the next 10-15 years is to keep alive the interest of the pharmaceutical sector for rare diseases. Altogether rare diseases affect more than 400 million people worldwide. However, 95% of rare diseases have no approved treatment. The disinterest from the rare disease sector would be catastrophic and as a company, we need to be innovative to build a significant market case by regrouping diseases when possible. There are some solutions going forward such as the implementation of basket trials, allowing for the investigation of multiple rare diseases simultaneously with a single treatment intervention. Adaptive trial design is another solution that can be envisioned to accelerate the development of drug candidates for rare disease with high unmet needs.   Elvire Gouze, PhD CEO & Founder, Innoskel SAS, France Elvire Gouze is CEO and Founder of Innoskel. She is a distinguished researcher whose career represents a rare combination of scientific excellence, drug developmentand support for the patient community. Dr. Gouze has a proven track record of progressing the development of an innovative therapeutic pipeline, as seen with her first venture TherAchon, a biotech company focusing on achondroplasia, a rare bone disease, which was acquired at Phase 1 stage for $810M by Pfizer in May 2019. She holds a PhD in molecular pharmacology. She performed her post-doctoral training at Harvard Medical School, where she later became an Instructor in Orthopedic surgery in the Center for Molecular Orthopedics. Elvire Gouze was later appointed Assistant Professor at the University of Florida and in 2009 became Team Leader at Inserm Nice, France. Dr Gouze won twice the prestigious EY Entrepreneur of the year in the Startup category, PACA area, France.

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