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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 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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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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2022/07/27

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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