Well, good day to everyone joining us, and welcome to today's Xtalks webinar. Today's talk is entitled, Successful Approaches from Rare Disease in Cellular and Gene Therapy Product Approvals. My name is Ryan Muse, and I'll be your Xtalks host for today. Today's webinar will run for approximately 60 minutes, and this presentation will not include a Q&A session with our speakers, but I still invite you to submit questions and comments throughout the presentation using the questions chat box, and MedPace will follow up with you after the webinar. This chat box is located in the control panel, which is on the right-hand side of your screen. And if you require any assistance along the way, you can contact me at any time by sending a message using this same chat panel. At this time, know that all participants are in listen-only mode, and please note that the event will be recorded and made available for streaming on xtalks.com. At this point, I'd like to thank MedPace who developed the content for this presentation. MedPace is a scientifically driven global full-service clinical contract research organization providing phase one to four clinical development services to the biotechnology, pharmaceutical, and medical device industries. MedPace's mission is to accelerate the global development of safe and effective medical therapeutics through its high science and disciplined operating approach that leverages regulatory and therapeutic expertise across all major areas. Now I'd like to introduce our speakers for today's event. Joining us today are Dr. Terrence Eagleton, who is a UK-based physician who qualified from the University College London Medical School, after which he trained as a general surgeon with a focus on trauma and critical patient care. He has subsequently worked as a senior pharmaceutical physician in the biopharma and CRO industries for over 20 years in global clinical research and medical affairs in a wide variety of therapeutic areas. And Dr. Marco Tengelder is a clinical epidemiologist with 25 years of academic, pharmaceutical, and biotech industry experience. His clinical and R&D experience includes vascular surgery and medicine, thrombosis and hemostasis, development of antithrombotic therapies for a broad range of indications, and development of gene therapy products. We also have Laura Omobani, who holds a Master of Science in Chemistry and Pharmaceutical Technologies. She has worked within the CRO industry for 22 plus years. Laura started her career as a CRA, progressed through the management levels, and is currently an executive director. She has covered a wide variety of indications with more recent focus on neuroscience and rare diseases. And Dr. Trevor Walker has over 16 years experience in the pharmaceutical industry, gaining extensive global regulatory affairs experience with a number of CROs. Within these global roles he has been involved in a range of investigational medicinal product types including cell and gene therapies and biologics at various stages of clinical development and across several therapeutic indications and with sponsors ranging from emerging biopharma companies to multinational pharmaceutical companies. But now without further ado I'd like to hand the mic over to our speakers from MedPace today. You may begin when you're ready.

Thank you and welcome to our webinar today which is entitled successful approaches from rare diseases and cellular and gene therapy product approvals uh today uh our webinar will be uh structured uh in the following manner so there will be a brief introduction to rare diseases and cellular and gene therapies followed by the medical perspective on the development of these products and then subsequently followed by the operational and regulatory perspectives, and then a few closing comments on key takeaway topics. So I think that everybody who has dialed in has had some interest and exposure to orphan drug development, development, but we thought it would be helpful to provide some context and to illustrate the extent and burden of rare diseases. There is no single widely accepted definition of what constitutes a rare disease. Current definitions are prevalence based and vary by geography and local governing regulatory bodies that are often country-specific and reflect rare disease legislation. For example, the FDA in the U.S. defines a rare disease as one that affects less than 200,000 people, defined by the Orphan Drug Act of 1983. However, in the EU, this number is a disease with a prevalence of no greater than 1 in 2,000 people. The number of patients within each rare indication are by definition small however collectively rare diseases are common there are over 6 000 identified rare diseases with over 200 newly described rare diseases each year principally through genetic analysis there is an estimated world total of over 300 million people living with rare diseases and to get a sense of the magnitude of the numbers if all of these people were to live in a single country, it would be the third most populous country in the world. It is also important to bear in mind that 72% of these rare diseases have a genetic origin, and over 50% of these rare diseases will present in childhood. To get a sense of the impact of rare diseases, a third of these children with rare diseases will sadly die before their first birthday and another 30 percent of children with rare diseases will not live to see their fifth birthday one more additional rather sad fact about rare diseases is that the approved effective treatment options for the great majority of these orphan diseases are relatively few in number making up just about five percent however there is good reason for hope Over the past few decades, there's been a much greater awareness of rare diseases, and very importantly, a much better understanding of their underlying genetic causes and pathophysiology. And, combined with a revolution in bioengineering, which now offers the prospect of new and innovative treatments that can positively impact the natural course of the disease, and in some cases, offer a definitive cure. Many of these new therapeutic modalities being developed for rare diseases are gene and cellular therapies, which is the topic of today's seminar. One of the principal drivers of the development of new therapeutic products and rare diseases has doubtless been the emergence of country-specific orphan drug legislation across the globe, about which we'll speak in more detail later. Though the specifics of orphan drug legislation differs from one country to the next, generally speaking, they offer a unique regulatory pathway to the biotech and biopharma industry with other perks, such as the potential for contracted developmental timelines. extended patent protection, tax incentives, and fee waivers, and in some cases, so-called premium pricing for these products, all of which have resulted in a greater interest by biotech and biopharma companies, and a boon in new medicines being developed and marketed for rare and neglected diseases in many countries across the globe. This slide illustrates this trend. In the period from From 1973 to 1983, prior to the Orphan Drug Act in the U.S., there were only less than 10 products developed by industry and approved for orphan diseases. Following the 1983 Orphan Drug Act in the U.S., there's been a steady growth in submission and approvals of orphan drug designations by the FDA from an average of 63 designations per year in the 1990s to twice that number, with an average of 126 designations per year between 2001 and 2010 which in the last decade has seen an even steeper trajectory of applications for orphan drug designation reflecting increased biopharmaceutical industry in interest in developing drugs to treat rare diseases this trend has been broadly reflected in the growing proportion of new drug approvals attributed to orphan drugs which has risen from 17 percent in the 1990s to greater than 35% between 2008 and 2010, and as you can see on this slide, well over 50% most recently. Indeed, this upward trend in orphan drug development submission and approvals has led Dr. Timothy Coate, the former director of the Office of Orphan Products development at the fda to state as early as 2014 that quote orphan appears to be taking over the agency the age of the blockbuster appears to be over unquote of these a growing number of investigational and approved products are gene and cellular therapies so what are these gene and cellular therapies the principle of a gene therapy is really quite simple gene therapy aims to insert a certain gene, a healthy one if you like, into the cytoplasm or nucleic or nucleus of patients' targeted cells. In general terms, gene therapy medicinal products are recombinant or synthetic nucleic acid molecules to regulate, repair, add or delete a genetic sequence that underlies the disease, thereby preventing or correcting disease progression. There are several approaches to gene therapy is outlined on this slide one you can replace a mutated gene that causes the disease with a healthy copy of the gene secondly you can introduce a new gene into the body to help fight a disease thirdly you can inactivate or knock out a mutated gene that is functioning improperly and is underlying the disease gene therapy is delivered into cell cytoplasm or nuclei via a small a so-called vector or by gene editing also known as crispr cas in order to achieve these effects delivery of a gene can be done via a non-viral vector such as plasmids liposomes or other particles which is called transfection this method is currently mainly used in bench research the other and most common methodology is via a viral vector which is called transduction the most you the most used types are via adeno-associated viruses or aev viruses and this method is most mostly applied clinically in patients this figure shows how transduction with a viral vector works the viral vector containing the appropriate gene sequence also known as the gene cassette infects the target cells packaged in a vesicle and subsequently releases the gene into the cell nucleus. Once delivered, the gene starts to produce the protein needed to treat the specific disease. This slide highlights a number of recent examples of approved gene therapies in the rare disease space. Adenoviral vectors are the most commonly used viral vectors in gene therapy, as mentioned. They are capable of treating a number of genetic rare diseases, many of which are caused by mutations in a single gene, which can be inherited from from parents or can be or can occur spontaneously in germ cells many more gene therapies have been approved in a number of indications many of which are in rare indications transforming the lives of patients across many therapeutic areas outlined on this slide and as we speak many new many newly developed and approved advanced therapy products like these are transforming the lives of patients and other families. Nonetheless, for those companies seeking to develop such products, there are a series of unique challenges and hurdles to overcome that are required for the successful development and cellular and gene therapies in rare disease indications. With that, I'd like to hand it over to my regulatory colleague, Trevor Walker.

Thanks, Terence. It's been recognised that drug development for rare diseases can be more complex and challenging than for other indications which are more prevalent. And development was often limited by high costs combined with a low probability of recovering those costs in a rare disease patient population. So this has been addressed by the implementation of legislation that provides both financial and regulatory incentives to promote research and development for orphaned diseases. And this legislation was introduced as the 1983 Orphan Drug Act in the US and the European orphan regulation that was brought in in the year 2000. In order to qualify for orphan designation the drug or the biological product have to meet the criteria that are listed on the slide. In the US the product should be for diagnosis, prevention or treatment of a rare disease and in the EU the product should be for treatment of a life-threatening, seriously debilitating or a serious and chronic condition. As you can see both regions have set limits for disease prevalence that need to be met or if it's unlikely that there would be sufficient return through sales of the drug for a rare disease that would justify that that would justify the development costs then this would also qualify interestingly the eu also requires that in the case of there being existing methods to treat a rare disease the new treatment should provide significant benefit over existing therapies and this is something important that needs to be considered at the time of requesting orphan designation in the EU. So this slide shows incentives that are provided when orphan designation is granted for a medicinal product under development. Both US and EU regions offer financial incentives such as market exclusivity, there are tax incentives in the US and fee reductions in both regions and importantly Finally, there's also a promotion of regulatory interactions or assistance that can be gained so that sponsors are fully supported throughout the development programme. These frequent interactions with regulators will help to ensure that development programmes are designed to meet regulatory expectations, which is of particular importance as clinical trial plans for drugs with orphan designations can differ significantly from those outlined in a more standard development programme. program. In the US, there's also the benefit of a rare paediatric disease priority review voucher, which can be used to expedite review at the NDA or BLA stage for qualifying products, an exemption from PREA requirements, which means that a paediatric study plan is not required to be submitted. In the EU, products with orphan designation are able to use the centralized procedure for review at the time of their marketing authorization application, which is also the same review procedure that cell and gene therapies would go through. And then in the EU, there's also the opportunity to use expedited approval routes, such as conditional marketing authorisation, which is based on early clinical data and which ultimately leads to patients having earlier access to treatment. So regulators recognise the need to support development of medicines that target unmet medical needs or provide a significant improvement over existing therapies and that of course includes those being developed to treat rare diseases. In addition to the incentives and features of orphan designation drug developers can also use other designations or pathways that provide enhanced regulatory support and can accelerate development. To qualify for these the medicinal product needs to show potential to treat an unmet medical need or be a significant improvement over existing therapy and these programs and pathways are already being used in development of gene therapies to treat rare diseases. So the diagram on the slide provides an overview of these expedited programs in the US and the EU and the central rule of the diagram highlights the key advantages that are provided in terms of expediting the development pathway. In the US, fast track and breakthrough designation provide early and frequent interactions with the FDA and the option for rolling review as a sponsor moves towards NDA or BLA stage. We've also noted RMAT designation, which is specific for cell and gene therapies, and that provides similar incentives to that provided by breakthrough designation. Prime designation in the EU can be granted to new medicines that have the potential to provide a major therapeutic advantage for a non-medical need that provides enhanced interactions with the EMA to discuss development and also the opportunity to be eligible for accelerated assessment. Early approval can be granted using accelerated approval or conditional approval and this is typically on the basis of limited clinical data but it does require a commitment for confirmatory clinical data to be provided at a later time point. And then there are options for reducing timelines at the review stage through priority review and accelerated assessment. So overall, the ability to have early and frequent regulatory advice, the possibility for early marketing approval, and the option to accelerate the review process are all aimed at supporting development to provide patients with faster access to effective treatments. And as we're aware, there are already examples of how these pathways and designations are being used by companies in the successful development of gene therapies to treat rare diseases. I'll now hand over to Marco Tangelder to discuss some of the medical perspectives in gene therapy development for rare diseases.

Thank you, Trevor. I've been a trialist for 30 years and nearly a decade ago, I started to work in the space of gene therapy. And it's a pleasure to share some experience with you today about how to successfully do often complex gene therapy studies and finish the road to BLA and MAA approvals. As Terence already mentioned, gene therapy has been growing rapidly over the last decade. And when we take a closer look to last year, we've seen a growth of 7% compared to the year before in the global gene, cell and RNA therapy pipeline. And that is relatively quite a lot because the total biotech funding has decreased with a steep 44% over the last year. And the success of gene therapies has become obvious with five approvals last year, two for haemophilia, two for oncology, and one for a rare neurometabolic disease. And we have contributed to two of these approvals. Adeno-associated virus remains the most common use factor to deliver gene therapy. And today I will talk about this type of gene therapy specifically. Delivering a successful gene therapy study is actually easier said than done, as these studies are multi-complex, but there are definitely some key factors contributing to success, and I have divided these in study-related, data-related, and patient-related factors. Now, it all starts with the protocol, that is E. It should be scientifically robust with with a carefully designed study, yet feasible, and provide clear unequivocal guidance to your investigators. To achieve this, we work with teams consisting of multidisciplinary experts jointly developing protocols. And bear in mind, particularly for phase 3 pivotal studies, that what you study is what you get in your label. So, your target product profile is leading for protocol development, and your protocol basically sets the scene for your label and future use of your product in clinical practice. Include the right patients. That means those who can benefit most from gene therapy, and that is very disease-specific. For example, in hemophilia trials, the severe patients with clotting factor activities below 2% of normal, requiring prophylactic clotting factors to prevent bleeding, are typically included, aiming to relieve them from weakly intravenous prophylaxis use. Whereas in neurologic and retinal diseases, you want to treat patients who have sufficient function preserved, as the goal is mostly to slow or halt progression of disease. And finally, define, if possible, validated and relevant outcome measures or endpoints. In rare diseases where little or even no trial experience exists, this is not always possible and endpoints may have to be validated within a clinical development plan. An excellent example of this is the development of Luxturna for a retinal dystrophy due to RPE65 mutations, which is a very rare, an ultra-rare disease. Natural history data and prior interventional studies were lacking at that time, and that mandated the need for the development of a novel primary endpoint for the pivotal phase 3 study. Therefore, a multi-luminance mobility test, that is a kind of ultimate functional test for vision, where patients have to navigate through a maze of obstacles with varying luminance levels, was developed and validated. Great for a clinical trial setting, but useless in clinical practice because clinics do not have such a large visual mobility testing lab. So therefore, the correlation with visual field testing, which is a surrogate endpoint for vision, was demonstrated within the study, which now allows for easy monitoring of treatment efficacy in daily practice as this test is available everywhere. The next key factors to success are study data related. First, the choice of comparison, where you have several possibilities. You may compare the investigational treatment effect to an external group, such as a population from a national history study. This is tricky, however, as outcome assessments may be slightly different defined or measured differently, populations and concomitant treatments may be different, and so on. A better choice is an intrapatient comparison, whereby you measure the outcomes of interest in a lead-in phase of the study and compare that with the outcomes after administration of gene therapy, or in ophthalmology, compare the treated eyes with the fellow eyes. These are, in my view, the most valid comparisons, particularly in inherited diseases where the genotype is obviously the same in each individual patient and where, as a consequence, the difference in phenotype after gene therapy is a true difference. The third option is a randomized control group, often the preference of regulatory agencies. This may be considered as the cold standard for clinical trials, but is not always an option as sufficient sample sizes to generate comparable groups and significant statistical analysis may not be feasible within rare disease populations. Also, patients may not be willing to take the chance to be allocated to a control group, but this can be mitigated by offering the gene therapy after a certain follow-up period. You want to avoid missing data because sample sizes are usually already limited and avoid protocol deviations. To put it simple, do everything right. Last but not least, some patient-related factors leading to success. It all starts with including the right patients. But who are those? Well, first of all, make sure that patients are utterly well informed. Patients should be motivated, motivated and motivated. They really have to commit upfront to all study visits and assessments to long-term follow-up and be able to accept risks and disappointment in case of lack of efficacy. In terms of exclusion criteria, they should have no or limited comorbidities, particularly in the target organ for delivery. So, for example, for liver-directed gene therapy, I recommend to exclude patients with liver fibrosis or high liver enzymes at screening. Then the day of treatment. This is an exciting and thrilling day for patients. It is a one-off treatment and the patient knows that very well. And it might be a life-changing therapy. Therefore, it is so important to make patients feel comfortable and at ease. and make sure everything is well planned and prepared for, the treatment and short-term daycare safety monitoring after treatment. And finally, patient retention is, of course, of utmost importance to avoid missing data and for long-term safety and efficacy documentation. So maintain regular contact with patients and facilitate per-protocol study visit by good planning and support as much as needed. Let's take a closer look now at some of the practicalities of a common gene therapy route directed to the liver as target organ for many indications such as hemophilia and inherited metabolic diseases. This is a relatively easy route of administration by peripheral intravenous infusion. Pretty high doses in the range of E11 to E13, hepatic selective infectivity of the viral factor, a liver-specific promoter and codon optimizations maximize efficacy yet at an acceptable safe dose and reduce potential of target effects. Immune responses against the viral capsid, transduced hepatocytes or expressed protein may occur. And these immune responses can be cellular, particularly T-cell responses have been described, humoral or innate. Transient transaminase increases may be an indicator of these, and you should be prepared for monitoring and managing that. The infusion day starts with meticulous preparation in the pharmacy, usually in a biosafety cabinet fulfilling all GMO requirements. Use of a clear pharmacy manual is recommended. I mentioned already, help the patient to relax and infuse carefully at the appropriate method and rate as detailed in the protocol and or in an infusion manual. Allergy-like infusion reactions can occur. In such cases, slow down the infusion rate and treat with antihistamines, glucosteroids and antipyretics as indicated. And finally, keep the patient a few hours in daycare for safety monitoring. For the month following gene transfer, patients should be monitored closely for immune responses and potential inhibition or loss of transgene effect to ensure rapid treatment with immune-modulating drugs if needed. I mentioned already, transaminase increases occur commonly and are usually asymptomatic and transient. The cause is mostly not elucidated, but maybe due to an immune response as mentioned, but also due to cell stress, protein production and excretion, or simply due to the viral overload. This should be monitored very closely as it may coincide with loss of transgene expression which should be treated immediately with immune modulating drugs. We use powerful visualization software for monitoring and clear guidance for immune suppressive therapy is recommended for the study protocol. Here you see such a visualization as an example of an ALT increase as you can see by the black line and concurrent decrease in transgene expression as can be measured by an effect of a produced protein shown by the green line. We also plot immune modulating therapies in this example a tapering course of prednisone so we follow exactly and in almost real time what happens with our patients and this is very helpful in tailoring treatment and preserving efficacy of gene therapy. And again, experience is key here. You must realize that investigators only see their few patients that they enroll in a study, whereas we see far more patients enrolled in multiple studies in the same rare disease. So we use that expertise to guide our investigators throughout the study. Finally, a few words about outcome assessments. First, ensure meticulous recording by investigators and patients, standardize diagnostics, and have the same examiners during the whole course of the study. For patient-reported outcomes, we develop user-friendly apps. Clinical endpoints should be assessed or adjudicated by investigators or by central adjudicators depending on the type of disease and study protocol and endpoints. And And finally, imaging, blood, and other biomarkers should ideally be read and measured by central labs as methods and assays and so on varied between sites. To summarize, many factors related to study, data, and patients contribute to successful gene therapy studies. Careful gene therapy delivery is adamant. It is a one-off as well as close follow-up for safety and efficacy. Trials are complex, and therefore gene therapy experience is extremely important, as well as treatment experience with the disease and the study. As mentioned, we have that experience due to the multiple studies we conduct and seeing the totality of patient data resulting in everyday accumulating expertise. And finally, because of the complexities and all the needs, a motivated, knowledgeable team and great team spirit is a huge key to success. And with that said, I would like to close my part and hand over to Laura Omoboni to provide us the operational perspective for a successful study delivery.

Thanks so much, Marco. Happy to take this on. And in the next slide, so just go through a bit more the operational sites, how this study can be operationalized and what are the successful steps that you can take to make them work. The first time I've been asked to handle or to oversight a gene therapy study in a rare disease, I thought I had to handle something that was really kind of near to what I was used to do in rare disease. But you will see here gene therapy studies are real different, are complex, as we are saying so far, and they have to be handled carefully and specifically to ensure you can really go with a specific and successful execution. And I will go through this in the next slides to help understanding what are the main points that can help to make this happen. First of all, of course, when you are asked to start at the period of the startup and you have to think about the study and strategize, first thing is really to go through a very thoughtful feasibility activities. The uniqueness of the gene therapy is mainly, of course, linked to the complexity of the, sometimes of the administration, but mostly linked to the handling and the preparation of this drug. There are, of course, specific requirements. There are the specific biosafety level that the pharmacy has to handle in terms of receiving drug handling and preparing, which are not making all sites eligible for the participation and the administration of the drug. So this is the first thing that has to be identified and handled at the phase of the feasibility, try really to link and integrate, let's say, the need of identified sites for a rare disease that is mostly, as we know, linked to the disease prevalence with the specific of the gene therapy that will require you to have sites with a well-skilled pharmacy able to run that. So MedPace has been really focused at the very beginning to work on this, understanding what the pharmacy can really deliver and inside an in-depth assessment of the pharmacy skills being at site as well to be sure that you can select the right sites. On the top, of course, the fact that the GMO samples has to be handled, and these are all requirements that also the regulatory authorities will require you to confirm and provide details, as we will see later on. So, in the next slides, it's just a visual thing that what could mostly happen at the time you start strategizing, think how you can set up a gene therapy, a rare disease or ultra rare disease study. You are, of course, as I said, driven by the rare disease population and the type of patients you will have to treat, meaning that you have to go through the incidence prevalence, understanding the right country and the right size and the right QL, of course, that can provide you the type of population that is needed. But as I said, all these sites might be skilled and ready to perform the infusion of a gene therapy. So, most of the time you come up with what is now called up-and-spoke model. We saw this more and more coming out. Visually here, it can be easy to understand. You might have to select some dosing sites. There will be central dosing sites where some of the other clinical sites following patients with that specific disease will have to refer patients for the infusion. And of course, this will be more extreme or less extreme in terms of number of dosing sites, depending on the type of administration you have to perform and the complexity and the phase of the study. In a phase one study, for example, in a neuroscience indication with a very complicated infusion treatment, you might need to limit the number of the dosing sites with a lot of clinical sites that are just referring patients there, while in a phase, in a wider phase, you can have a more balanced frequency. So, what is the operational side of this? Of course, when you are set it up in this way, you have to ensure that patients are able to travel, to move within sites with two main operational aspects that has to be handled carefully. First of all, of course, the travel of the patient, which we know nowadays we can easily handle with travel support, travel vendors that can really make this easy for the patients to move. But there might be the need, depending again on the type of disease you are treating, also for patients to travel cross-border. They might need to travel from country to country, from region to region, even if it happens in some of our med-based study. And again, And we have now possibility to support the patients with this. There are different things that operationally needs to be addressed. First of all, of course, there should be approval for the patient to cross board and move around the countries. There are some issues needed. There are coverage, of course, that are needed in terms of insurance and indemnity. And once all this is set up, the patient will be able to cover. The experience we had is that, yeah, it can happen that in some specific situation, above all for the earliest phase of the study, some competent authority or ethics in some countries will not be as willing to allow patients to be treated outside the country. But for most of them and for most of the study we run, this is something that can be done and can be supported, ensuring that you can use whatever is available to support the patient in this journey, meaning, of course, organising the travel, organising the translation as needed and, of course, having all the approvals in place. So, this is from one aspect of the operational success in terms of making this ABINSPOK model working. The second part, of course, is the collaboration among sites. There should be a clear communication path set up among dosing and clinical sites that there is a strong collaboration among them, of course. And above all, of course, as you know, and as you can image, there is a need of sharing patient's source documents or sharing patient's information from the time the patient, of course, is first identified and randomize or enroll at the clinical sites and then send for dosing and return back for the follow-up. The sharing of all this information, of course, is under the needs of being checked for data protection requirement, which can be different in different countries and has to be handled carefully to ensure that things are working because sites have to speak and information have to be shared with respecting, of course, what is the specific requirement there. The next slide is going next, so we set up our study, we mostly kind of understand which sites we need and how we want to set this up. And then we go next, the usual next questions we have when we are asked to operationalize study in rare disease is like how you can ensure enrollment, of course, because patient population can be limited and you have to be efficient in the way you enroll a study. So, again, I can see this when you have to run a gene therapy rare disease study, having, again, two important perspectives that has to be integrated. Of course, this will remain a rare disease study, so you will have to implement and we implement all the best practices for the rare disease study enrollment execution. Not going too much in details there. I think we, most of us knows, you know, what has to be done sometimes when you have a rare disease study. understanding, of course, the important of identifying the right side, the right patient countries and patient population, enrolling and engaging the sites, of course, to ensure that they can be able to provide what we need. And above all, I think it has been a huge topic for the last years, and I'm happy to see that now it's really integrated in the rare disease study execution, ensuring that patients' advocacy and the patients are also involved in the development of the study at the very beginning. The advocacy groups and the patients' voice are really heard at this time. They are really imbebbed at the beginning of the study by the sponsor, by HUS. Not just because, of course, this can give the study more visibility and patient access, but also having from patient back some feedback, some understanding of the disease and how really then what is written there from a theoretical perspective is becoming feasible in clinical when we go there and execute. So, of course, as I said, when we speak about enrollment, it's about enrollment of rare disease, but the uniqueness of the gene therapy has to be taken into consideration. And Marco, I think, explained this very well when he went through how sites has really to be engaged and how they have to understand the right patients or the patient that has to be involved here. Gene therapy, again, Marco said it very well, but it's a life-changing therapy. One-off treatment is quite an important change in the life of the patients. So, they need to understand. They need to be engaged. They need to understand, of course, all the concerns, be addressed with their concern, and understand the importance of the compliance. And you can get this if you are really able to engage the sites, to engage the PIs and align them to that. The next slide is going one step more. So, we do that. We have the patient and we start infusion day. Again, gene therapy studies are quite unique. It's just one day infusion. They're not the usual study where you have routine administrations of drug weekly or daily with a tablet. It's just one of administration. And as I said before, this administration day is certainly an important day. It's an emotional day for everyone at Sight. I can confirm and that was the perception we had. patient is coming with a lot of emotions, sites is even having emotion on that because they usually follow these patients for a long time. And so patient thinks has to be well prepared. And one thing that I really want to highlight here in terms of successful execution is be sure that there has been a mock run on how the preparation of the drug is working, starting at the pharmacy up to when the drug is coming ready for the infusion at the sites and is returned back after the use. This is, of course, the most important aspect. The sites should be ready, pharmacies should be ready or procedures should be clear. But there should be also a full availability of the team, meaning the zero team, the sponsor team on that day, to support not just operationally with questions that might come up, but just to support also medically as things might happen, and there is a need of immediate support that has to be returned back. So we infused the drug, and again, this study, the gene therapy study, are unique. And I think this is really what is making the difference with all the other studies that you can run over them being, of course, complex and in the process up so far to set them up and to ensure that they can be prepared for the infusion. After the infusion is done, actually the patients are entering a sort of follow-up phase where that can be quite frequent at the very beginning, but then it's becoming more and more infrequent. It can be a six-month frequency and it can be very long. We know that the FDA is coming up. We started with five years follow-up, but there has been requests recently by FDA to stand this much more than that, to double, even adding more years of follow-up. So the uniqueness of this study from an operational perspective are coming here. The big things is about ensuring that you can, first of all, of course, ensure compliance of patient. And second, you can have control of data you are collecting to be sure that data set is coming out as strong. And as Marco said, with no mistakes, with no room for a lot of deviations and no room for missing data. So two things operationally that as a med base we have been able to implement that have been really successful to ensure a robust data set coming out of what we were collecting during the fallout period of this patient. First of all, implementing centralized data review, as again Marco was showing, reviewing aggregate data is allowing us to perform safety review and identify safety alert, implementing monitoring from a statistical perspective, but also a remote monitoring activities are all activities that has to be done in a study like this, where maybe visits at site are not as in terms of monitoring as frequent during the follow-up because patient visits are just happening every six months. This is really the strong way you can control data, you can identify and address safety signal, and you can address and mitigate risk. But the other big things, and I think this is really the big point about this gene therapy study, is the next slide. And it's really the retention of the patients. Patients are treated. They usually tend to feel well. They might have their disease addressed at some point. And so how you can really engage a patient to stay on a study having followed visits every six months for five years, 10 years, that's really the big challenge of a gene therapy study. And again, Again, you can do this, what has been the med-based experience is that you can do this from a mainly two perspective. Of course, there is always the need of engaging patients and sites, understanding the aiming of this protocol, letting them be part of something that is changing the treatment of this disease and can be life changes for many, many patients, sharing data with them, engaging them and not just let them be patients followed for something that is a normal disease. But I think the other big things is just as an operational team, ensure that you can really control what is going to happen with the patients as the life is happening. Of course, in five years and having mostly even young people enroll in this kind of study, things can happen. People can just move city or countries, even countries just having a standard vacation period for a few months in different regions or different countries. And we cannot really afford to lose all these data as data set will not come as strong to show maybe what you need in terms of data and point protection. So luckily, we are in a era where the decentralized thing, activities can help you a lot. And we did a smart pace. We did really experience that you can be creative, you can be flexible, you can really follow these patients during their change and avoiding that the study is going to be impacted by the loss of data. Meaning that, yeah, of course, if someone is moving in another city, you can try to find another site that is nearest to where the patient is moving, opening a new site, that's really important. But if the patient is moving, even in a country where the study is not run, there are ways you can handle that. You can use, for example, on vendor, you can still let the patient be reached by them and collect samples for a central lab assessment as well. So that really data protected and you are not losing and you can handle or what is happened outside of the patient's willingness and compliance that, of course, has to be addressed. And I'm happy to handle back to you, Trevor, so that you can go for a bit more on the regulatory perspective.

OK, thank you, Laura. OK, so just a few slides here from the regulatory perspective. So initially at the development level, clinical trial programmes for rare diseases often, even in the early stages, need to run trials that are both multi-centre and also global, so run in multiple countries. And that's obviously a consideration due to low prevalence and to meet recruitment targets. So one of the critical things is that for those global strategies for clinical trials, sponsors should be considering the regulatory environment for all of the participating countries. The other aspect is that conducting global studies, especially an early phase, provides global clinical data, and that can potentially be used to support approvals across multiple regions. The key thing being of course that the data package meets the regulatory requirements in those target markets and so developers really need to be thinking proactively about a global approval strategy even in the early stages of their development. Also around their overall development, regulatory interactions and gaining regulatory agreement alignment is really critical. rare disease development programs often rely on single pivotal trials and small data size. So early and ongoing engagement with regulators is really essential and that's where the use of designations such as orphan designation and also expedited programs can really help to streamline development. And then talking to the regulators through whether it's scientific advice meetings or more formal regulatory interactions is going to help with sponsors in their development plans, especially aspects such as trial design and manufacturing quality requirements to ensure that they're going to meet regulatory expectations. These aspects are really critical. If we move to the next slide and focus a little bit more on some of the considerations for clinical trials themselves. So, as you would expect, clinical trials for gene therapies in rare diseases, as well as meeting ICHGCP relevant guidelines and national regulations, also have some additional regulatory challenges that need to be addressed. Firstly, regulatory readiness. It's really vital that there's understanding of country requirements or regulations on how the process works in the participating countries and to be sure that documentation for the trial application is going to meet those requirements. Clinical trial strategies in terms of startup should also assess the risks and mitigations and be as proactive as possible to ensure that rapid timelines can be achieved for startup of these studies. It's important to note that gene therapies through their nature are reviewed for an extended period of time when clinical applications are submitted, and they should be factored into trial planning. We're also aware that these types of therapies have extensive manufacturing information. It's highly technical in nature, and it needs to be really clearly documented and with as much information included as possible. In terms of reviews from the Regulator Authorities and Ethics Committees or IRBs, it's expected and certainly it's been our experience that extensive numbers of questions are likely to be received and we've recently taken an experience-based analysis of previous previous queries for gene therapy studies and this is an internal med-based database and it helps us with anticipating mitigating risks and we use this with sponsors when they're going through the startup phase with gene therapy studies so that we can anticipate as much as possible what is likely to come back from the authorities. Just at the bottom of this slide, based on the recent analysis of gene therapy trials, we have seen that typically CMC or quality related questions are the most common questions that come back from regulatory authorities. That's followed by protocol related questions. And then following that, questions around supporting data, both clinical and non-clinical are the most common. If we move on to the next slide, one of the other aspects that's considered for gene therapy trials are the fact that gene therapies are often classified and regulated as genetically modified organisms. This is due to viral or bacterial vector methods being used for in vivo or ex vivo gene transfer. Because these products are GMOs, they need to comply with additional regulations that are in place within the participating countries and quite often there's a lack of harmonisation in regulations and requirements certainly across Europe that's a prime example where this exists and in some cases we've come across examples where there's been limited country-specific regulation and experience and that's provided some additional challenges that needed to be addressed. As a consequence of this additional regulation approvals need to begin from biosafety committees or perhaps environmental competent authorities and that has the ability to potentially extend timelines for start-up of clinical trials that can be offset by in some cases pre-submission consultation to address any issues early on and make sure that the requirements are achieved and as i noted on the on the previous slide documentation is a critical aspect so in addition to the information for gene therapies information around environmental risk assessments also needs to be submitted to these biosafety or environmental committees they've got a focus particularly on on viral shedding and any risk to the environment or healthcare providers there's also an aspect to be considered is that public notifications may be required to be to be provided in national media in participating countries and then the last the last point here and Laura had mentioned this previously is that clinical site requirements are critical and need to be considered so the the clinical trial site needs to be licensed for use of gene therapy products where it's a GMO and ideally appropriate facilities equipment and experienced staff are really critical and similarly storage is an important aspect it may require specialist equipment where ultra low temperatures for storage of gene therapies are required and these are key aspects that need to be considered at the feasibility stage so that clinical sites are able to to be part of the clinical trial Just a couple of other aspects around the GMO aspect. Labelling for investigational products is really critical. Countries have specific labelling requirements and typically for GMO products there's a requirement that there's an additional precaution statement. It's essential to make sure that's included. Often gene therapies are provided in small containers or vials and so there's there's limited information on the primary packaging and again proactive planning if there's likely to be shelf life extensions during the course of the study should be implemented as there can be additional additional complications and these need to be these need to be planned well ahead and then finally just in terms of logistics granting of import licenses is required before product can be brought into countries and for gene therapies that can require additional documentation. Storage and shipping, as I mentioned, if a gene therapy requires either a very low or ultra low temperature then storage and shipping needs to be considered and use of specialist couriers may be required. In cases where products have a very short half-life, sorry shelf life, um expedited shipping may be needed considerations around direct to site shipments or use of like local depots should be required and again if a local depot is handling a GMO containing product it needs to be licensed as well plans for return and destruction of product is also a key consideration and Laura had also mentioned previously shipment of biological samples because these have the potential to contain GMO components. They need to be considered and make sure that any shipping is in line with local and international regulations. So with that, I'd like to now hand over to Terence, who's going to provide a few summary comments.

Thank you, Trevor. Well, we know that orphan drug development presents several unique and major challenges and obstacles. largely due to the complexities of these studies often conducted in vulnerable patient populations, as discussed. But these rare disease studies are made even more complex by the additional scientific, medical, operational, and regulatory requirements of these newly emergent advanced therapies, such as gene therapies, stem cell therapies, and small nucleic acid therapies. However, success means that delivery of these new transformative treatments in rare diseases, meant that we can now provide important treatments where there were previously none or only inadequate treatments that existed before. Thankfully, we can anticipate that many more of these new treatments are expected in the future. As a general approach, success in this space requires proactive planning and meticulous attention to detail from beginning to end of the clinical development program, as we've seen. However, as this slide indicates, there are four key considerations necessary for success in orphan drug development with gene and cell therapies. First, and very importantly, is partnership. A collaborative effort by all stakeholders concerned with these rare indications, including the highly skilled and motivated investigators and their teams, the expertise and resources of the sponsor and the supporting CROs, patient advocacy groups, and the regulatory agencies, and many others, all of whom are laser-like focused on identifying and proactively developing strategies to overcome these challenges through the optimization of clinical trial designs and the tools needed to collect relevant data to the highest standard, combined with a robust regulatory strategy to support the timely submission and approval of these innovative new treatments for rare and ultra rare diseases patient centricity is also key to success central to these programs are of course the patients and their families through engagement of patients and patient advocacy groups early on in rare disease programs patients are rightly having a greater say in advising companies as to the clinical outcomes that matter most to them advising on clinical trial design and outcomes with tailored assessments to meet these objectives to minimize discomfort as well as to plan for a positive patient experience to minimize patient family and caretakers study burden furthermore given the paucity of patients combined with a greater competitive landscape for study subjects in many of these rare diseases now it is of critical importance to provide the utmost practical and logistical support to facilitate travel accommodation and special needs of these vulnerable patient populations all of these measures are especially important in making any trial attractive to patients and their families to support robust recruitment and retention and to drive these clinical trials to success so as to achieve their targets and outcomes. The integration of scientific, medical, operational, and regulatory expertise is critical for the design, the execution, approval, and ultimately delivery of these innovative new gene therapy products in patients with rare disease. And this is why partnership and indeed experience is so important. We know from industry research that the only predictor of future success in orphan drug development, and this is arguably more so with complex gene therapy studies, is a past track record of success in orphan drug development. For sponsors and CROs alike, we know the more rare disease studies we do, the more we learn, and the greater our expertise with experience. Hence, the more likely we are to succeed in delivering these transformative of gene therapies to patients with serious unmet medical needs and rare diseases. In choosing your CRO, we believe that it is very important that you choose one with the right experience. Experience really does count. We hope you've found this webinar of interest, and we look forward to hearing from you. In addition, we welcome the opportunity to continue to support our partners in the development of these exciting and important new gene and cellular therapies in patient rare diseases. Thank you for your kind attention.

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