Good morning, welcome to the AVROBIO Virtual Gaucher Disease Program update. You may ask a question at any time during the presentation by typing it into the Q&A box to the right of your screen and clicking Submit. If we are unable to get to your question, we will follow up directly. Now, I would like to turn the presentation over to Geoff MacKay, President and CEO of AVROBIO. Good morning. We're excited to share today a comprehensive update on our Gaucher disease program, including clinical and regulatory progress. You'll also meet Arianna, shown here, a nine-year-old living with Gaucher disease type 3 alongside her mom, a full-time caregiver, Veronica. Arianna is confined to a wheelchair on a ventilator and fed through a feeding tube and continues to progress despite treatment. The question that we asked ourselves when we first founded AVROBIO is: What if one gene could change your entire world? Our company is determined to develop a better solution, a single-infusion gene therapy with the goal of altering the downward trajectory of debilitating genetic disease. Before we begin today's update, I need to review our Safe Harbor statement. Today's discussion contains statements that are forward-looking under the Private Securities Litigation Reform Act of 1995, including statements based on our current plans, expectations, and beliefs. A description of these risks is contained in our SEC filings, which are available on the investor relations section of our website, which we refer you to for further information. AVROBIO is a hematopoietic stem cell or HSC gene therapy company. This is our engine, we apply it to a leading pipeline of lysosomal disorders. We've carefully selected indications with multi-billion-dollar revenue potential and where we are well-positioned relative to other genetic medicine alternatives. Our 2 lead programs are Gaucher disease and cystinosis. We shared our strong cystinosis clinical data at ASGCT this May. We recently completed dosing in the collaborator-sponsored phase I/II trial and are planning on initiating our cystinosis phase I/II registration enabling trial in 2023. The news today is that AVROBIO is advancing to a late-stage registration trial in Gaucher disease. We'll share progress across our Gaucher program, including strong and durable results to date in Gaucher disease type 1 and 3, which we'll refer to as GD 1 and GD 3. In terms of regulatory progress, following positive MHRA scientific advice and FDA type C meetings, we have a clear path to initiate a registration trial for GD 3 in 2023. I'd like to remind you of our approach. Across our portfolio, AVROBIO leverages the power of genetically modified HSCs. These gene-modified stem cells differentiate into different hematological subtypes, the various blood lineages. Billions of cells which continuously manufacture and distribute therapeutic protein 24/7, including to many hard-to-reach tissues and organs like the brain, which are critical for the indications we target. Although we've developed first-in-class HSC gene therapies in our select indications, remember that HSC gene therapy has already been used to treat hundreds of patients with well over a decade of experience in a dozen monogenic indications being pursued. In fact, the last few quarters have witnessed a de-risking of the regulatory path of HSC gene therapy via marketing authorizations from both FDA and EMA. Equally importantly, payers, health technology assessors in multiple countries, have agreed to establish value-based pricing for HSC gene therapy. What this means is that in terms of probability of success, there's a proven track record of durable efficacy and well understood safety. Of course, we apply this approach to lysosomal disorders, large established indications with well understood pathology. The dotted lines denote our anticipated progress in 2023. Our two lead programs are expected to progress into late-stage clinical development in 2023, and our Hunter syndrome program recently obtained CTA and first patient dose is anticipated in early 2023. On the far right, among multiple regulatory designations, we're pleased to have recently announced 3 rare pediatric disease designations. AVROBIO has built the leading lysosomal disorder gene therapy pipeline. We're here today to talk about Gaucher disease, which is the largest, most common lysosomal disorder in the world by quite a margin, impacting an estimated 23,000 patients. It's caused by a biallelic mutation in the GBA1 gene, which leads to deficient glucocerebrosidase or GCase enzyme activity, resulting in substrate accumulation within macrophage, referred to as Gaucher cells. This triggers a vicious inflammatory cascade throughout the body, causing damage. You can see here how many organs and tissues may be impacted from enlarged liver and spleen, lymphadenopathy, interstitial lung disease, and neurological degeneration. We delineate between GD1 and GD3 based on clinical phenotypes, including severity and neurological manifestations. Gaucher is one disease, and the subtypes have the same underlying pathophysiology. The take-home message is that Gaucher disease is a heterogeneous and systemic disease with broad and debilitating impact. An important question is how well does today's standard of care, ERT, control these serious disease manifestations? The answer for all GD3 patients is clear. Many serious disease manifestations remain refractory to standard of care. However, we recognize that for Gaucher disease type 1, ERT does a pretty good job in some, but not all patients. To provide a data-driven response, here we show a prospective registry of 757 GD1 patients followed for 10 years on ERT. Published by Dr. Weinreb, this is the Genzyme Registry. What we see is an incomplete therapeutic response on one or more of these serious clinical parameters in 60% of GD1 patients on ERT by year 4. We therefore conclude that HSC gene therapy has the potential to play an essential role for the thousands of patients not well controlled on ERT. Central to the pathology of Gaucher disease is the macrophage. Our HSC gene therapy is well-suited for Gaucher disease since the genetically modified stem cells will differentiate down various hematopoietic lineages, with the myeloid lineage being the key to treating the disease. Genetically modified monocyte distribute through the body, including tissue-resident macrophage. This maintenance of continuous physiological cellular enzyme production allows access to sanctuary sites such as lungs, lymph nodes, and brain. This is why we believe HSC gene therapy is particularly well-suited to combat this disease of macrophage. Beyond the strong scientific rationale, I highlight the commercial opportunity. A simple sensitivity analysis illustrates the potential. As mentioned, Gaucher disease is the largest and most common lysosomal disorder. In the dark blue circles, we limit the targeted patient population first, only to our priority markets of North America, Europe, Japan. Second, we allocate all GD3 patients and only the subset of GD1 patients not well controlled on ERT. This limits the minimum initial target population to just over 10,000 individuals. We apply 3 potential penetration rates of 10%, 25%, 33% to get a range of potential patient populations. In terms of pricing, we know payers have recently agreed to value certain gene therapies at 15 years the cost of today's standard of care. For illustrative purposes, we've modeled potential prices calculated based on adding up only the three year, five year, and sever year cost of today's standard of care ERT. Our conclusion is that if we hit our Target Product Profile of a safe, effective, single infusion gene therapy, a very substantial commercial opportunity follows. Today, we'll be providing updates that we believe take us several steps forward in de-risking our Gaucher disease development program. Specifically, we will, one, update on our ongoing GD1 Guard1, phase I/II clinical trial. All patients dosed to date outperform baseline ERT across multiple measures with important clinical reductions in liver and spleen volume. 2. We're excited to share for the first time data from the first pediatric GD3 patient who 15 months post gene therapy has biochemically normalized and shows stabilization and reversal of multiple clinically significant measures. Three. Following meetings with FDA and MHRA, we have alignment on our clinical development strategy and a clear path to pursue one global GD3 trial. While not on this slide, we'll also outline our overall clinical development strategy for our Gaucher program, including GD1. We have a lot to get through, which will include presentations from our Chief Medical Officer, Dr. Essra Ridha, on our new data and plan development pathways, and our Chief Technology Officer, Dr. Azadeh Golipour, on how our plato gene therapy platform stands ready to support our late-stage trials. We're also honored to have with us today three world-renowned key opinion leaders in the area of Gaucher disease research and treatment. Tim Cox, professor emeritus of medicine of the University of Cambridge, will provide an overview of the disease. Robert Wynn, professor of pediatric hematology, Royal Manchester Children's Hospital, and Simon Jones, professor of pediatric inherited metabolic diseases, Manchester Center for Genomic Medicine at St. Mary's Hospital, who will present data from the first trial with GD3, who received our HSC gene therapy 15 months ago. All three will also be available for Q&A. First, I'd like to introduce you to Arianna and her mother, Veronica, who live with Gaucher disease type 3. Within weeks of becoming a first-time mom, Veronica noticed something different about her beautiful baby daughter, Arianna. She made choking sounds when she hadn't eaten. She would sweat excessively and become agitated and inconsolable and lose consciousness when trying to empty her bowels. After being diagnosed with Gaucher disease type three at nine months old, Arianna began a treatment regimen that's improved some of her symptoms but has not stopped the disease's progression. At 20 months old, she started having seizures, now controlled by medication that must be continually adjusted for growth. She has cognitive delays and has never spoken. Arianna also has interstitial lung disease because Gaucher cells have infiltrated her lungs, causing her to be short of breath and prone to chest infections. Now 9 years old, Arianna has a tracheostomy and is ventilator dependent, which also makes her more prone to bacterial infections. Nutrition comes through a tube connected to her stomach, as do the eight medications she has to take every day beyond biweekly infusions. To make room for medical equipment, Veronica has made the living room Arianna's bedroom. Colorful toys and art make it a wonderland for her. Arianna can't move on her own. Her mom uses a mechanical lift to help. Veronica's life centers on her daughter's needs all day, every day. Although she's eligible for more than 100 hours of nursing care a week, it's been difficult to find nursing support since the pandemic started. Veronica keeps Arianna comfortable and happy and shuttles her daughter to many medical appointments each week. In a quiet moment at home, Arianna enjoys laying in her hammock and feeling the sunshine streaming through the windows. While she's never spoken, her smile reveals her love for her mom and the strength of spirit she holds inside. Thank you for asking me to give an introduction on Gaucher disease. You've had a very moving introduction from Arianna and her mother, Veronica, and I will try to provide some of the background to the condition which you appreciated from their presentation. Dr. Gaucher gave his name to the disease. He was a young man who did an autopsy on a patient he looked after for two years. She was only 34 when she died, she had an enlarged spleen and a massive abdomen when she died, she was very wasted with the untreated condition. He thought it was a cancer, his technology, the microscope, set up what we've been able to know and understand about the condition since. Her liver and spleen were enormous, respectively four and nearly five kilos. You can imagine the effects of the illness on her. Here is a man, a patient of ours, who I looked after many years ago when all we could do was to remove the spleen. That was nearly 4 kg there. It should have been only about 80 or 90 g. You can see that vast spleen, a little splenomegaly, and the liver also. In that spleen underneath, you can see the appearance very much like the drawings of the splenic sections by Gaucher. You can see sinusoids stuffed with large cells. We call them Gaucher cells. You can see that they stain positively in brown there for CD68, indicating they're macrophages. Blue ones stained in a bone marrow sample there. When you look under the electron microscope at a single cell, a single Gaucher cell, you can see that the space in the cell is distorted and distended. This is the lysosomal compartment stuffed with a lipid. If you look at these cells, they're all sort of conformations, and extract them, you can find out what they contain because they contain a storage material. It's now known to be glucosylceramide, this woman from the same university but 52 years after Gaucher did record this in her thesis. She identified for the first time correctly beta glucosylceramide or glucocerebroside, that cerebroside. Of course, that enabled people later to work out the enzyme defect, a failure to remove the sugar residue there at that particular bond by glucocerebrosidase or glucosylceramide. The deficiency of that enzyme leads to this condition, a failure to cycle the material derived from cell membranes. Macrophages are scavengers, part of our immune defense. They're recyclers and immune activators too. You can see that they're distributed right throughout the body and the viscera and also found in the brain and the skin. When they're coping with an excess of those bioactive sphingolipids, things go wrong. Their pattern recognition systems activate, and the disease enters a cycle of inflammation and recruitment of more cells, and hence the enlarging state with increased destruction of the formed elements of the blood in the spleen. Gaucher disease is a recessive enzyme abnormality deficiency. It maps to chromosome one and has an autosomal recessive inheritance so that children of either sex of perfectly happy parents can be affected, but in that, on average, only one in four of the pedigree. It's the most frequent or one of most frequent of the lysosomal diseases with a birth frequency around 1 in 60,000 to perhaps 1 in 100,000 live births. It is a progressive lysosomal disease and a multisystem disease, as I'll show you, it is too. Here's the birth incidence in the general population at the top in green. It varies according to the population and is particularly overrepresented in the Ashkenazi Jews, which are, of course, a very small population globally of the 8 billion people on the planet. You can see right across every nation, every ethnic group that have been studied, the disease occurs at various frequencies. It occurs in northern Sweden too. The prevalence is higher because, of course, it's not lethal at birth. You can see in Israel and the U.S., it is many, many times more frequent than it is, for example, in Spain or Portugal. Well, it's a multi-system disorder, the symptoms as shown here were not all recognized. The ones in black represented those documented by Gaucher himself. You can see otherwise that there are features, for example, neurological features, as well as skeletal features, which give rise to the abnormalities that you've heard about already. These reflect, perhaps in part, the organs involved and indeed the macrophages that infiltrate them. We have radiological findings that Gaucher also missed of the skeleton and of course, the lungs and the neurological system that you've heard about. Here we have the late sequelae, the late manifestations of Gaucher disease in the skeleton, which affects all types of the disease. The osteonecrosis, the thin bones with fragility fractures, the collapse of the skeleton, the destruction of joints, indeed, the crush fractures that occur because the bones are thin in the spine. In the viscera, here's the liver replaced really by cirrhotic fibrosis and regeneration in these two livers. One of these patients required a liver transplant, and the calcification occurred in the damaged liver in the bottom left. Also in the lung there, you can see infiltration, a cloudiness in the right lung particularly, and that gave just manifestations of the Gaucher cells, macrophages infiltrating the air spaces. The genetics of the disease is informative and enables us to some extent predict the abnormalities. It is a disease that maps to chromosome 1, the longest arm of the longest chromosome. Mutations, perhaps 300 or more, have been found. Some are widespread and are of diagnostic significance and easily tested for, not always. Here we can find N370S. If you have one copy of that, it guarantees you won't have the neurological manifestations I've been talking about. If you have L44P, it's more a severe disease or more severe disabling mutation of the function, and in fact, of course, as homozygous, that condition is a risk for developing neurological manifestations. That's a recurrent mutation found in all populations across the world. These are patients with neurological disease. We give it various types: Type one, type two, type three. The types two and type three are the neurological variants of varying levels of severity, and these are in the U.K., are patients that seen are in our center in Cambridge. The acute form, type two, is associated with death. It really only at the age of one or two years of age. It's very severe indeed, and the child is very crippled. Subacute or type two to three, there the massive viscera in that child, with also eye movement abnormalities. In the two patients on the right, these are disease, type 3 disease, and you can see indeed a happy young woman who is now a mother of a child, an old lady who worked in the NHS as a geneticist until her mid-50s, just with the eye movement abnormalities. The distribution of the mutations is worldwide, as I mentioned, and the disease is distributed worldwide. The non-neuropathic form is particularly found in the Occident, in Europe, the Americas, and of course, Australasia, to some extent in the Middle East, as referred to Israel. The type 3 disease, the chronic neuropathic disease, which is really the subject of today's talks, that occurs principally in the non-European, the non-America form, and is frequent in those countries that where much of the world's population exists. Africa, Oceania, right through Asia and elsewhere. Indeed, we have 20% of patients of our U.K. patients have neuropathic features. Here we have the diversity. It's no respecter of nations, of populations. These little boys here are shown in Pakistan. They are L44P homozygotes with massive visceral and indeed lung disease. This is an horrific condition demanding treatment. Then you have on the right, patients much older with disease affecting the skeleton and the viscera to some extent, but able to survive much longer. The origin of tissue macrophages is principally the bone marrow and the hematopoietic stem cells that originate from the bone marrow and circulate. They circulate where they can be harvested, but they circulate to find themselves in the tissues of the body where they can form populations in the lungs and the tissues and reconstitute the blood. This lady on the bottom left and in the top right, the bottom right and the top right there, received the first successful bone marrow transplant in infancy. There she is at the age of 45, who she has had some diminution in her abilities and so on, but is able to look after her young niece. Bone marrow transplantation is done for severe aspects of the disease, refractory to treatment, and you can see here the effects on the pulmonary disease. This is a child age 5 from Taiwan, recently reported and presented to me, I remember, quite recently when I presented there. You can see that this child had severe infiltration, both of the right and the left lungs and the peribronchial tissues with distension of the air spaces by the pathological macrophages as shown on the histology. one month after the bone marrow transplantation from a matched, unrelated donor, it's quite a rare thing to get today, this child had restoration of his breathlessness to normal breathing and was less blue and cyanosed. In fact, at three months, the lungs cleared. A great improvement. When we look at the ways to treat this disease, there are existing therapies, they're not satisfactory as yet for the neurological manifestations and the very severe visceral manifestations within me. We have an enzyme therapy targeted to the macrophages. We have a substrate reduction therapy, works on the systemic features, which acts like a statin for the sphingolipids, matching overproduction with the failure to degrade them. The neurological trials which are underway to describe whether or not that will work, discover it, are not there through. Stem cell therapy, of course, is narrows at the moment, but an ex vivo transfer of stem cells from the recipient and the donor all in one offers the chance of a more universal way of attacking this disease and restoring a competent macrophage population, which of course, at a high level of expression of the enzyme, may indeed complement the abnormalities that we hope very much in the central nervous system too. Thank you very much for listening. The other presentations will build very much on this very rudimentary introduction. Thank you very much. Thank you for that overview of Gaucher disease, Professor Cox. AVROBIO's Gaucher disease program includes the evaluation of our hematopoietic stem cell gene therapy approach in both Gaucher disease type 1 and type 3. I will present the most recent clinical data from the Guard1 study of phase I/II clinical trial for GD 1. We will hear from Professors Wynn and Jones from the Manchester University NHS Foundation Trust, where they have treated the very first pediatric Gaucher disease type 3 patient with our investigational gene therapy. We're thrilled to share these data with you today. Our primary focus is to highlight evidence of improvement in the Gaucher disease patients who were treated with our gene therapy to date. Throughout the next two presentations, we will elaborate on three key points. First, all GD1 patients are showing normalization of enzyme activity and substrate reductions, which is translating into some clinically significant reductions in organomegaly. Second, our pediatric GD3 patient shows complete biochemical correction, which means both enzyme activity and substrate levels are normal post gene therapy. This pharmacodynamic efficacy equates with improvements in major refractory elements of disease for this patient, something the child has never experienced before, and we are delighted to have his treating physicians present these data. Finally, none of the five treated patients have experienced adverse events in relation to the drug product, indicative of a favorable and consistent safety profile for AVR-RD-02. I'm now pleased to present the data from the Guard1 study. The Guard1 trial is a phase I/II clinical trial for adult patients diagnosed with Gaucher disease type 1. It's a trial that is actively recruiting in the U.S. and Canada. Within this trial, we are evaluating the safety and efficacy of AVR-RD-02 in an ERT stable population who have received a minimum of 24 months of continuous treatment with clinical stability or a treatment-naive population. The trial has currently enrolled six patients and dosed four, for whom I will be presenting data. Firstly, let's cover the baseline characteristics. Of the four patients treated, 50% are female, all diagnosed with Gaucher disease type 1 in infancy or childhood and treated with an HSC gene therapy between 24 and 44 years of age. All patients harbor biallelic mutations in the GBA1 gene consistent with diagnosis of Gaucher disease as well as deficient GCase enzyme activity. The past medical histories of these patients as it relates to Gaucher disease includes organomegaly, symptoms of fatigue and bone pain, and worsening biochemical markers of disease on treatment, as all four patients were ERT stable at baseline. Additionally, patient one was splenectomized as a treatment for Gaucher disease in childhood. The patients received a CD34 positive cell dose ranging between three and seven million cells per kg. With that, let's start by looking at the engraftment of our genetically modified cells. The vector copy number is an important marker of the engraftment of our genetically modified cells, which are those cells that have been transduced and harbor a healthy copy of the GBA1 transgene. Post-infusion with the gene therapy, we see a sharp rise in vector copy number, indicative of the engraftment of the short-term progenitors, followed by the plateaus which signal the long-term HSC engraftment with vector copy numbers that are ranging between 0.54 and 0.86 at the latest follow-up time point. With this engraftment, we would expect to see enzyme activity rising, a reduction in markers of substrate accumulation and inflammation, which would ultimately translate into clinical efficacy with organ volume reduction. Let's start with enzyme activity. We see the reconstitution of GCase enzyme activity both in the plasma in the top panel and the peripheral blood leukocytes in the bottom panel. Post gene therapy and off of ERT. All four patients now have normalized enzyme activity on a background of enzymatic activity deficiency before gene therapy. With this in mind, we expect to see substrate reduced. That's what we see. These data demonstrate that after HSC gene therapy, lyso-Gb1, the sensitive and specific marker of substrate accumulation, has decreased by 21%-70% below ERT baseline levels. With this substrate reduced, we expect to see a reduction in inflammatory activity as measured by chitotriosidase. Patient one's chitotriosidase has almost completely normalized at 2 years post gene therapy. This is important because the mechanism of action of the gene therapy is to increasingly replace Gaucher cells in macrophage-rich tissues throughout the body with healthy, genetically modified macrophages over time, which are capable of reducing substrate accumulation and inflammation. You can also see that patient two's peripheral blood biochemical markers have been reasonably well controlled on enzyme replacement therapy, and these have been nicely maintained on gene therapy out nearly 1 year. Additionally, patients 3 and 4 will be re-reported in future updates. Let's see how these data translate into clinical efficacy. Keep in mind, all of these patients were ERT stable prior to gene therapy. For context, ERTs are considered biosimilars. We expect similar clinical efficacy on measures of organomegaly between ERTs. When you switch a patient from one ERT to another, you don't see further clinically meaningful reductions in organ volume. I'm excited to share what happens when an ERT-stable patient is switched to treatment with an HSC gene therapy. All three patients have a reduction in liver volume post gene therapy. The enlargement of the liver or hepatomegaly is a primary and independent contributor to disease burden in Gaucher disease. It is reflective of the persistent infiltration of pathological macrophages into the liver, which result in the development of inflammatory liver disease with fibrosis, and if severe enough, cirrhosis in the more severe clinical phenotypes of the disease. For patients one and two who have the longest follow-up time, there is a clinically meaningful reduction of more than 10% in liver volume below their baseline on ERT. Patient three is already showing reduction in liver volume within the first six months post-treatment. Finally, patient four's first MRI is expected before the end of this year after they reach the 6-month time point post gene therapy. Spleen volume measures are following a similar reduction pattern. Reductions in spleen volume are clinically important because the spleen reflects the systemic severity and storage burden of the disease. The spleen volume is also an accepted proxy marker of systemic disease. Both patients two and three, who are non-splenectomized and out 6 months or more post gene therapy, have considerable reductions in spleen volume. What you can see is a 23% reduction and a 19% reduction in patients two and three. Clinically meaningful reductions are greater than or equal to 20%. Remember that patient one underwent splenectomy in childhood for Gaucher disease. As I mentioned, patient four's first scan is expected this year. Please take note, these patients who were at the ceiling of treatment effect with enzyme replacement therapy are now showing additional reductions in spleen volume with gene therapy, further reflecting better overall control of their Gaucher disease. Additionally, we monitor the hemoglobin and platelet levels, a core feature of successful Gaucher disease treatment. You can see that these parameters are well controlled on enzyme replacement therapy and following myeloablative conditioning and gene therapy infusion, we see the expected transient decline in these parameters with a rapid increase indicative of hematological reconstitution early post gene therapy. Thereafter, hemoglobin and platelet levels are maintained in the normal range within 3 -6 months following therapy. As expected, we have not observed any adverse events in relation to the AVR-RD-02 drug product in the four patients treated. Instead, the adverse events and serious adverse events reported are predictable and related to the myeloablative conditioning, the study procedures, and of course, the underlying disease itself and pre-existing conditions. Together, these data demonstrate that the first four patients dosed with an HSC gene therapy have experienced improvements over baseline ERT measures, with some clinically significant reductions in organomegaly, thus having an impact on their disease. We look forward to sharing data on more patients dosed in this trial in the near future. Professors Wynn and Jones will share data from the first GD3 pediatric patient dosed with AVR-RD-02. Thank you, Essra, for that kind introduction. I'd like to introduce the audience to the first pediatric patient with GD3 that has been dosed. This was done in Manchester, well, Manchester Children's Hospital. We are a large transplant center with over 30 years of experience in transplanting children with metabolic disease, and as such, we're one of Europe's largest transplant centers for metabolic diseases. Predominantly using allogeneic transplant, of course, but more recently, we have stem cell gene therapy programs, investigational in MPS IIIA and MPS II, also with AVRO, and commissioned as a UK treatment center for MLD. On the left panel, this is our patient. He's at dosing, at transplant. He was a 12-year-old lad with GD3. He was diagnosed during infancy because of lymphadenopathy and hepatosplenomegaly, and commenced enzyme replacement therapy at 17 months of age, but developed seizures from 10 years of age. His biomarkers and these clinical signs with neurology and lymphadenopathy, of Gaucher disease have never normalized despite maximal multimodal therapies, and this would be typical for a patient with GD3 on such therapies. His primary disease complications then as he came to transplant were twofold. First of all, he had mesenteric lymphadenopathy with a protein-losing enteropathy and additionally, a substrate reduction therapy that had been started at 4.5 years of age to go with his ERT. He had neurology, the typical saccadic eye movements, intellectual impairment, so that his IQ was around 66 at transplantation. He had seizures despite anti-epileptic medications. This Modified Severity Scoring Tool, the MSST, is a bedside, disease-specific scoring tool, and his had been rising through childhood from 1.5 to 12.5. All new therapies start with unmet need, and that unmet need is particularly relevant, of course, to the patient and their family, but also to patients and clinicians. It is also important to regulators as they are looking to license and develop new medications for different illnesses. It's important to purchasers as they're looking to commission licensed treatment. In this disease, in GD3, the unmet need cannot be better stated by anyone more than the mother who says here, "Having a child with GD3 can at times feel hopeless and helpless. Our son was on ERT and developed seizures and protein-losing enteropathy, which requires additional steroids and medications. I was always worried about the long-term use of steroids specifically, as he's still growing, and the process to receive his medications was overwhelming and time-consuming. He was declining cognitively, and he developed seizures that kept getting worse despite anti-epileptic medications. Our son's cognitive decline and seizures were scary and devastating to all of us, and I was looking for new treatment options online when I found gene therapy. We finally had a glimpse of hope." This is the HSC gene therapy. He underwent mobilization, so hematopoietic stem cells mobilized from the bone marrow into the blood, and apheresis using a central venous catheter during leukapheresis. We got plenty of hematopoietic stem cells, which were then transduced ex vivo with a lentivirus vector containing the GBA gene to produce the ATMP medicinal drug product. We used myeloablative, so high-dose busulfan, typical in our allotransplant center, which was uncomplicated. He achieved engraftment very quickly. We do quite a lot of stem cell gene therapy, as I mentioned before, this is very quick engraftment, so at day nine, neutrophils and platelets more than 50. He actually never had any blood transfusions through this process. There were no AEs related to the drug product, he had minimal AS, AEs of low-grade severity and a single episode of febrile neutropenia. In the big scheme of stem cell gene therapy and stem cell therapy for metabolic disease, this was a very straightforward procedure. Despite it being straightforward, we see the hematopoiesis blood manufacture is established from genetically modified stem cells. We see three things in this graph. First of all, the vector copy number with time after transplant approaches the vector copy number of the infused stem cells, which means that the blood cells are all coming from genetically modified stem cells. Not only that, you can see that there are many different lineages of cells that have the gene modified, the marker, the VCN, indicating that this is multi-lineage engraftment, and not only is it multi-lineage, it is sustained. We don't worry that the T cells are low down here. That's because we have not used any T-depleting chemotherapy. busulfan does not get rid of T cells, so most of the cells in his blood are actually non-gene modified because they will not have been depleted by the procedure, unlike all other. The third thing it shows is that the monocytes are gene modified. Of course, GD3, Gaucher disease in general, is predominantly a disorder of monocytes. So it's particularly monocytes, macrophages, and so it's particularly important that they also are genetically modified, and harbor competent enzyme gene. I'd now like to hand over to my metabolic genetic colleague, Professor Simon Jones, to talk about the effect of the treatment on the young man. Thank you. Thank you, Rob. Just to take on really the metabolic outcomes following this transplantation. As you heard, it was a boy on very standard dose therapy and was progressing despite that. We increased his therapy, adding the substrate reduction therapy and the steroids. These disease modifying therapies were stopped during transplant. As you can see from the top graph here in his circulating blood leukocytes, the enzyme activity and the GCase enzyme that's deficient in Gaucher disease gradually rises from transplant from the baseline of 0, increased into the normal range. The chitotriosidase is a marker of macrophage activation, and it's the longest-standing marker of disease activity in Gaucher that's been used. Despite his standard dose ERT, the substrate reduction therapy and everything else he'd undergone in his life, he had never normalized his chitotriosidase. It was very comforting and reassuring to see this normalize over the next few months following transplantation. This would lead us to think that the organ-specific outcomes, which of course are much longer, to read out, are likely to be positive also. We talked about this young man also having mesenteric lymphadenopathy, a very well-described complication of Gaucher disease type 3. Type 1 patients don't tend to have this complication, but type three patients do. It's unmistakably linked to residual storage. If you take out these massive lymph nodes that sit around the gut, they are full of substrate filled macrophages, even on patients on enzyme replacement therapy. This young man had been stabilized with his previous disease modifying therapies, but his albumin was never anywhere near normal. You see that despite us being able to withdraw his enzyme replacement therapy and the substrate reduction therapy, we're able to see a gradual climbing of the albumin, the plasma albumin level, implying an improvement in his enteropathy, his protein-losing enteropathy. He a patient now, eating a much more normal diet, a patient not receiving albumin infusions and generally doing much better on no other therapy than the underlying stem cell gene therapy. As well as the plasma biomarkers and the enzyme activity improving as we would have expected, we see a general reduction in the lymphadenopathy on MRI scans. There are multiple lymph nodes, it's impossible to easily translate that to numbers. In general, the lymph nodes were much smaller. When we looked at serial MRI scans of his brain, he was rapidly developing new lesions on his MRI scans in keeping with the fall in his IQ and the onset of his epilepsy. The most recent scan from following his gene therapy suggested that there were no new lesions. There was no new detectable change or deterioration in his neurological status. As I said, he's now off all other disease-modifying drugs. As Professor Wynn said, there's been no further adverse events related to the transplant. Most importantly, I think as Rob has said, we do this for the patients and this is a very educated family, as you could tell from the previous quote from this mother. Her verdict following gene therapy has been of unmitigated positivity really. Following the gene therapy, they've seen real changes in their life and their son's life. Whilst of course, the first few weeks were a bit rough in terms of mucosal inflammation, hair loss and skin changes. Overall, he appeared to respond to the treatment well. He's off enzyme replacement therapy, steroids and substrate reduction therapy completely, with no return of his protein-losing enteropathy symptoms such as his peripheral edema and his gastroenterological pain and distension symptoms. He still has seizures, but has had no further change in his cognitive abilities. She also notes that her son is now sleeping through the night. A real sense of pediatric wellness if you like, while he used to wake up often. Our family has gained freedom as we're no longer tied to a challenging medication schedule and many home visits. Overall, a very positive experience from the family, but also from ourselves as clinicians. Thank you Professors Wynn and Jones for that update. It is great to hear how well the patient is doing, and we look forward to longer-term data. I will now switch to the clinical development plan for GD3 with a trial we expect to initiate in the second half of 2023. Our immediate plans include pursuing a single global registrational phase II/III clinical trial for GD3, which has received very positive feedback from the FDA and NIH, and moving forward with a clinical development approach that utilizes a combined data set for GD1 and GD3. We expect to begin the first ever randomized control trial for an HSC gene therapy in the second half of next year. This is an open label, parallel arm, randomized control phase II/III trial to evaluate the efficacy and safety of AVR-RD-02 in a pediatric GD3 population. Regulators have been very supportive of our trial design. Approximately 40 patients will be randomized 1-to-1 to receive the HSC gene therapy or continue to receive standard of care enzyme replacement therapy. We will follow these patients for approximately 1 year, following which we will allow patients who received enzyme replacement therapy to cross over into the active arm and receive gene therapy. Thus, our analyses will include a comparison of the active arm versus control arm, as well as a patient of own control comparison. What will we be looking for? The primary efficacy endpoint is a multi-domain endpoint, which reflects the systemic and heterogeneous nature of Gaucher disease type 3. It includes ratings of ataxia, a neurological feature of disease, as well as measures of interstitial lung disease with the diffusing capacity of the lung. Additionally, we have the liver and the spleen volume. Keep in mind, to meet the primary efficacy endpoint, improvements across all primary endpoint domains is not required, and this is due to the variable nature of the clinical manifestations of GD3. There is also a key secondary efficacy endpoint looking at Lyso-Gb1 levels in the CSF, a secondary and confirmatory evidence of the gene therapy treatment effect in the central nervous system. We expect to finalize the details around statistical analyses and confirm the final duration of the follow-up during our next round of regulator feedback. Based on the mechanism of action of gene therapy, our deep understanding of this disease, the clinical data generated to date and positive meetings with the regulators, we believe that this trial design will have a high probability of success. Furthermore, we expect robust recruitment to the GD3 clinical trial and for several reasons. First, there remains a high unmet medical need with systemic and central nervous system disease manifestations of GD3 not completely addressed by the current treatment options. Additionally, the clinical data for GD1 and GD3 patients treated with our HSC gene therapy are expected to generate a high level of interest. Finally, we have long-standing relationships with experts in the field and global patient advocacy groups and can easily direct interested parties to the clinical trial coordinators to determine eligibility. This phase II/III clinical trial is planned for eight to 12 clinical sites, including the highly specialized treatment centers, satellite centers, and referral centers across the U.S., U.K., and EU. Overall, our plans for the clinical development of AVR-RD-02 for GD3 and beyond are substantially de-risked. Now, why do we feel confident in saying this? Well, we have evidence of the gene therapy treatment effect translating into strong clinical efficacy outcomes relative to the standard of care. The regulatory agencies like the MHRA and FDA are supportive of our rigorous randomized controlled trial design. Additionally, with the regulatory designations we hold for AVR-RD-02, we can further streamline the clinical development of our HSC gene therapy for Gaucher disease. Finally, we have early scientific advice scheduled for later this month with NICE, the reimbursement body in the U.K. This will ensure regulatory approvals translate into optimal access and reimbursement. We are very much poised to execute on our plans. Zooming out to our broader Gaucher disease program strategy, we believe two clinical trials, one for GD3 and one for GD1, will create a rich combined data set, enabling us to streamline the development of this investigational gene therapy for Gaucher disease overall. This is possible because Gaucher disease represents a continuum or spectrum of disease severity with the same underlying pathophysiology at a cellular level. As we move forward with the GD3 phase II/III trial, we will continue to recruit subjects in key segments of the population into the GD1 phase I/II clinical trial. Over time, we expect to accumulate data into a combined data set of more than 50 patients, where we will evaluate efficacy, safety, and the durability of treatment effect, which we expect to be consistent across all patients as evidence of the potential for our gene therapy to address significant unmet medical needs across Gaucher disease. We are very excited to continue implementing this plan. To recap, our next steps are to initiate the global registrational clinical trial in GD3 in 2023, while we continue enrolling our Guard1 phase I/II clinical trial. The Gaucher disease clinical trials will not only use the same drug product, but the same end-to-end CMC platform called plato, which has received regulatory clearance for clinical use and can easily scale in the future to meet commercial need. My colleague, Azadeh Golipour, our Chief Technology Officer, will now tell you how our plato gene therapy platform is ready to support our activities in this late-stage clinical trial for Gaucher disease type 3 and beyond. Thank you, Essra. To complete today's update, let's look at Plato innovation and how it supports AVROBIO's vision to bring personalized gene therapy to the world. Plato, our industry-leading gene therapy platform, is an end-to-end solution covering vector design and vector production, drug product manufacturing, as well as analytics. This platform enables us to roll out new indications with little additional investment as only the vector cargo changes across indications. There are three key points I want you to remember about Plato today. Plato is late-stage ready, with no major CMC changes anticipated as we enter late-stage clinical trials. Plato can scale and support commercialization globally. Finally, Plato is designed to substantially reduce the cost of goods at every step. Over the years, our CMC plans have been reviewed by multiple regulatory agencies, through these interactions, we have de-risked our CMC package. We have discussed topics like our approach to potency, release and characterization testing for both vector and drug products, comparability, traceability, and the stability with the FDA and other international regulatory agencies. All their feedback is now incorporated. We anticipate no major changes to our CMC plans before BLA. We believe our CMC package is registration trial ready. One of AVROBIO's differentiators is our automated and closed drug product manufacturing platform, which we believe is the gold standard for HSC gene therapy. The starting material for drug product manufacturing is mobilized peripheral blood. Through automation, CD34 positive cells are selected and transduced with lentiviral vector. Drug product is harvested and cryopreserved. This is a very short two-and-a-half day process with no expansion step. Finally, the drug product is tested and released prior to infusion. The automated nature of our platform is a key advantage. It can promote scalability and reduce cost of goods. Additionally, automation improves manufacturing consistency and in turn, product quality. The fully closed system means we can operate in less stringent clean rooms, translating to less cost and more flexibility with manufacturing facilities and locations globally. Our platform is built to enhance efficiency and consistency as well as product quality and safety while reducing cost. Let's look at a few examples of product consistency. We can assess the performance of our drug product manufacturing platform by reviewing drug products' key quality attributes such as purity,% transduction, and VCN. The collection of data from these three attributes confirms we can make high-quality drug product. The gray box plots are data from drug products manufactured using healthy donor cells as a starting material. These healthy donor runs were used to establish our manufacturing process and capabilities. The blue box plots share for the first time publicly our Gaucher patient drug product data for the same patients whose clinical data were reported earlier. Considering purity on the left, using healthy donors and Gaucher patient cells, we can consistently manufacture drug product with over 90% purity. Achieving this purity led to the FDA agreeing that we can retire the impurity testing for our drug product. Moving to the middle, the median percent transduction of drug product manufactured with healthy donors and Gaucher patient cells is high, between 60% and 70%, which means most cells harbor the correct gene after transduction, further increasing the likelihood of corrected cells in grafting post-drug product infusion. Finally, on the right, the median vector number for drug products manufactured with healthy donors and Gaucher patient cells is between 1 and 2. VCN represents the number of integrated transgenes in transduced cells and is a surrogate for engraftment in patients. Historically, companies have tried to use VCN as a way of evaluating the drug product potency. However, we know that FDA requires the potency assay to be an assay that closely mimics the MOA of the drug, which is not the VCN assay. What should be used to measure drug product potency? We evaluated multiple measures and found GCase enzyme activity most closely mimics the MOA of the drug. These are data we have never shown publicly before, and they confirm that Gaucher drug product potency assay is established. Transducing either healthy donor cells, gray, and Gaucher patient cells, blue, leads to a dramatic upregulation of GCase enzyme activity, and this shows the integrated corrected gene functions as we expected, and the transduced cells are expressing active GCase enzyme. Look at box plots labeled A and C showing GCase enzyme activity before transduction. A shows healthy donor cells GCase enzyme activity. C shows Gaucher patient cells GCase enzyme activity, which is essentially zero, no activity at all. What is remarkable is that as a result of transduction during drug product manufacturing, transduced Gaucher patient cells achieve comparable levels of GCase enzyme activity to transduced healthy donor cells despite it starting at zero, as seen in overlapping box plots D and B respectively. It is well known in the field of cell and gene therapy that drug product potency assays have delayed multiple BLA submissions. For AVROBIO, our drug product potency assay is in place, and our platform is able to manufacture high-quality drug products consistently. The production process and analytics I shared today are what we plan to use during the registration trial. Another piece of plato platform is the vector manufacturing. We are one of the few groups that can manufacture lentiviral vector at commercial scale, which means producing lentiviral vector at the 200 liter scale in a bioreactor using serum-free suspension cell culture system. Each 200 liter production generates enough vector for approximately 50 patients in a single run. Frozen vector can be stored for at least five years, which allows us to meet the demand of thousands of patients per year by making the vector in advance and storing it. Our vector titers are consistently above the industry standard. Let's take a look at the data. The left box plot is the titer data from multiple batches of Gaucher vector. The box plot on the right is the cystinosis vector titer. We optimized the vector production platform over time, learning from each run. The optimization work is now complete, with the most recent Gaucher vector productions yielding the highest titer shown in magenta. This is now an established vector production platform and can reliably make vectors at high titers across our portfolio, as shown on the right with the data from cystinosis vector productions. This vector production process has been reviewed by regulators. In total, with drug product production and analytics, plato is late-stage ready. Every step of plato has been designed with platform synergies and scalabilities in mind. We have completed the scale-up for vector production and we can scale-out drug product manufacturing. We anticipate no major changes in support of global commercialization. Let's see how we can support drug product and vector supply for thousands of patients. Patient demand is accommodated by two key variables, number of suites and production runs per suite. More suites with more runs yields exponentially more vectors and drug products. AVROBIO can quickly and easily accommodate more suites and more runs to meet patient demand because of the innovations we've implemented, which also translates to reduced cost of goods. Some of our innovations include an automated and closed system that allows us to place multiple production units in one clean room in order to manufacture for multiple patients simultaneously. This brings down both suite and labor costs dramatically. Another key innovation is large-scale high-titer vector, which reduces cost of goods by lowering the amount of vector needed per patient and in turn, reducing the number of productions required. Based on today's cost, we estimate further efficiencies as we move to commercialization. We expect our gross margins will exceed 90%. The investments we've made in plato lays the groundwork for AVROBIO's success. Our robust production platform and analytics are ready to support registrational trials. We are fully prepared to scale and serve global patient population. As we look ahead to the future of gene therapy, AVROBIO is well-placed to define technology leadership for years to come. In the next section, I'll introduce our state-of-the-art vector design, as well as the advanced preclinical assays we use to assess vector safety in advance of clinical development. It's important to note there have been no AEs or SAEs related to drug product in AVROBIO's clinical trials. We have not seen any cases of insertional oncogenesis, nor any evidence of persistent dominant clonal expansion in our clinical trials. Let's start with vector safety data from the field of lentivector-mediated HSC gene therapy. Out of the 381 patients treated with lentivector-mediated HSC gene therapy, the vast majority of patients have not exhibited a genotoxic event. While there have been three insertional oncogenic events to date, they have been isolated in a single CLD program and come from one construct, an early generation vector developed more than 10 years ago, using one strong viral promoter used in one indication. In fact, the FDA advisory committee, when considering safety data from lovo-cel and LE cell, concluded that safety should not be extrapolated from one product to another. Outside this CLD program, there have not been any identified insertional oncogenesis event when patients were treated with lentivector-mediated HSC gene therapies. That includes at least 314 patients across 16 disease indications and more than 700 patient years followed. From the beginning at AVROBIO, we've designed our vectors using best-in-class technologies for both safety and efficacy. Working with world's leading gene therapy vector expert, Dr. Axel Schambach from the Hannover Medical School in Germany. Some of the vector design features are listed here. In all our clinical programs, we use the EFS promoter, which is a non-viral promoter used extensively with no known safety concerns. Let's see how we thoroughly test the vectors using 2 advanced vector safety assays during preclinical development. The in vitro immortalization, or IVIM assay, is designed to assess the risk of vector-induced cellular transformation. On the Y-axis here, we see the frequency of transformed cell phenotype, a proxy for vector-induced genotoxicity. I want to draw your attention to the 3 highlighted columns: gray, red, and blue. Gray and red are controls. Gray shows untransduced cells, and red shows cells transduced with an unsafe genotoxic vector, a gamma-retroviral vector with a viral promoter. Blue shows cells transduced with AVROBIO's Gaucher vector. When comparing cells transduced with Gaucher vector, blue column, and the untransduced, the gray column, there were no statistical differences in vector-induced cellular transformation. These data translate to a favorable safety profile for the Gaucher vector and suggests that AVROBIO's Gaucher vector does not show risk of insertional oncogenesis based on the IVIM assay. The novel surrogate assay for genotoxicity assessment, or SAGA assay, detects dysregulation of a specific gene expression signature linked to HSC transformation. Based on the discovery that vectors with propensity to transform HSCs induce an oncogenic gene expression signature that distinguishes them from the non-transforming vectors. This principal component analysis graph illustrates the gene expression signature for cells transduced with genotoxic vectors, red circles, untransduced cells, black circles, and cells transduced with AVROBIO's Gaucher vector, large blue circles. As you see here, Gaucher vector samples, large blue circles, are clearly separated from the genotoxic vector samples, red circles, which is exactly what we want to see. AVROBIO's Gaucher vector data from this advanced vector safety test is congruent with the IVIM data and further supports the favorable safety profile of our vectors. We believe commitment to vector safety is paramount. We use state-of-the-art vectors which are rigorously tested during preclinical development to assess the risk of insertional oncogenesis before entering clinic. Importantly, to date, we have seen no AEs or SAEs related to drug products, no evidence of dominant clonal expansion, and no reported cases of insertional oncogenesis in AVROBIO's clinical trials. Now let me hand it back to our CEO, Geoff MacKay, to close our update. Thank you, Azadeh. Before we get to your questions, I highlight key takeaways. AVROBIO is transitioning to a late-stage company. We have strong positive data from our Guard1 trial showing benefit beyond ERT baseline measures now out more than two years. The first pediatric patient with Gaucher disease type 3 dosed with a gene therapy has biochemical correction, improvement in enteropathy and neurological stabilization 15 months out. We have a clear regulatory path to initiate a phase II/III clinical trial for GD3 and a broad comprehensive Gaucher disease clinical development plan. Finally, PLATO is late-stage ready. Although the focus today has been Gaucher disease, I wanna remind you our overall portfolio is advancing. Most importantly, we also expect our cystinosis program to be in late-stage clinical development in 2023. A key factor when building this portfolio has been to select indications which satisfy 4 important criteria for potential commercial success: high unmet need, being first to market, strong pricing rationale and significant patient populations. We've made sure that our indications check these 4 boxes. The implication is that if we hit our TPP, a safe, effective single infusion gene therapy, we believe this translates into a business model that works and sets up a very attractive commercial opportunity. 2023 is setting up to be a big year with important catalysts across the pipeline. Already, data to date in our 2 lead programs meets or exceeds expectations, and our clinical path forward is clear. Throughout 2023, we anticipate a steady cadence of regulatory milestones and planned data updates across 3 clinical stage programs. We're proud of recent accomplishments and are heads down focused on advancing our programs in 2023. We appreciate you being here. I wanna thank Professors Cox, Wynn, and Jones for joining us, and to Arianna and Veronica for sharing their story. We now have time to answer your questions. As a reminder, you may ask a question by typing it into the Q&A box to the right of your screen and clicking Send. If we're unable to get to your question, we will follow up directly. I'll now turn it over to Q&A. Spleen volume data you shared, can you elaborate on what the clinical meaningfulness is of these further reductions of liver and spleen volume? We'd also like to hear the point of view of the professors as well on this. Okay, thank you. I'll begin. I'll pass it to Essra to discuss the clinical regulatory implications, and then perhaps I'll also call on Professor Cox to talk about the clinical meaningfulness of organomegaly. Thank you, Geoff. First of all, just to maybe recap around some of the GD1 data. We have seen the patients showing a normalization in terms of enzyme activity. We're seeing substrate reductions, and we are seeing that translating to some clinically significant reductions in the liver and spleen volumes. I would start off by saying that the liver, first of all, and its enlargement is a primary and independent contributor to disease burden in Gaucher disease, and it's really reflective of persistent infiltration of the Gaucher cells, the pathological macrophages into that organ. That really typically results in the development of an inflammatory liver disease. The spleen, on the other hand, reflects the systemic severity and storage burden of the disease and is an accepted proxy marker of systemic disease. What you're seeing are the additional clinically significant reductions, and by definition, from a regulatory standpoint as well, the accepted thresholds of 10% and 20% reduction when switching patients from ERT onto a gene therapy. This is very important because the mechanism of action of the gene therapy is increasingly to replace Gaucher cells in these macrophage-rich tissues like the liver and spleen and throughout the body, with healthy macrophages that are derived from our genetically modified stem cells over time, which are capable of ultimately reducing substrate accumulation as well as the inflammatory processes as a whole. That's indicative of what you're seeing there with the reduction in liver and spleen volume. Professor Cox? Thank you. Yes. Well, absolutely. They are remarkable changes, particularly in patients on long-standing approved therapies. They are remarkable. They are manifestations of the pathological Kupffer cells in the case of the liver and of the sinusoids and the spleen. The spleen itself is a clinical target, of course, for therapy because, of course, if you can't remove that, then you're never gonna have normal turnover, normal pools of your circulating blood cells. Those are very important things to do. It's unusual that they escape the other therapies, but in very severe Gaucher disease, they do, and they contribute to the ill health, the fatigue, and as we've been stated, the low level inflammatory response that's achievable finally with therapies. It's very unusual to see complete normalization, and it is, I think, symptomatic of a clearance and replacement that is a therapeutic effect from the stem cell therapy at the target cell population. Okay. Regarding the primary efficacy endpoint for the GD phase II/III trial, can you elaborate on the multi-domain endpoint you intend to use? Are there any analogs for this endpoint? Sure. I'll pass this one right to our Chief Medical Officer, Essra. Thank you. The primary efficacy endpoint, it is a multi-domain endpoint, essentially it is incorporating several important domains of disease into the primary. This is an important clinical trial tool. It's used in rare diseases, in particular in lysosomal storage disorders like MPS IIIA. It has been used in MPS VII because it really allows us to accommodate the systemic and heterogeneous nature of the disease, where patients will invariably present with different clinical manifestations. It is highly variable in that regard. Additionally, it really allows our clinical trial population to be more reflective of the overall Gaucher disease type 3 population, which is very important to us as well. As you've heard, we have included in our multi-domain endpoint, ratings of ataxia, a progressive neurological feature of the disease, as well as measures of interstitial lung disease or the diffusing capacity of the lung, as well as the liver and spleen volume, which you all know. Really to meet that primary efficacy endpoint, improvements across all of those domains is not required. Really, this is due to the variable nature of the clinical manifestations of these patients. They won't all have disease in all four domains. Thank you very much. Great. Maybe as a follow-up, Essra, how well does ERT perform on these four measures of the primary endpoints? As we all know, standard of care therapy does not penetrate the blood-brain barrier, we don't really expect any treatment effect on neurological features of the disease. It also has a limited effect when it comes to tissues like the lungs, on infiltrating lung disease or interstitial lung disease in particular here. Obviously, the standard of care does have an impact on liver and spleen volume, but you have seen also what the stem cell gene therapy can do when switching a patient from standard of care to HSC GT as well. With that, I'd probably pass across to Helen Cross to elaborate further on some of the unmet need there, in particular for GD3. Well, certainly. Thank you. I mean, it is true to say that the substrate reduction therapy in the ENCORE trial was a multi-domain, a multi-domain endpoint for a substrate reduction therapy for stabilized patients on enzyme therapy with Gaucher disease type 1. There is a precedent for this, and it was they were all met by that therapy at that time. Of course, that's not GD3. There is a precedent. It's certainly true the penetration, the abnormal lymphocytes, the Gaucher, the lymph nodes, the Gaucher masses, the Gaucheroma, so-called, are just not acceptable to enzyme therapy at all. And as I showed you, of course, in that child, with the extensive infiltration of the lungs, the bone marrow transplantation, the macrophages are able to get there. Not everybody, of course, can have, their own selves as a donor, so that is a rescuing procedure in that child. The answer is those macrophages get to places that the other therapies don't get, and every expectation is that they'll do something, into the central nervous system, given their richness of activity. Thank you. We received two questions on a similar topic. The first one is the phase II/III powered for superiority, non-inferiority? Will crossover be limited? The second is, could there be a scenario where the drug is approved in GD3 based on it being non-inferior to ERT? Okay. All regulatory questions to you, Essra. Thank you. The trial is powered for superiority of AVR-RD-02 against the standard of care. As mentioned with the clinical trial, the patients will be randomized 1-to-1 to receive either the gene therapy itself or remain on the standard of care that they came into the trial on. We'll be looking for essentially superiority versus that standard of care. At the end of that observation period, we will allow for patients who would like to cross over from control into active. You know, as mentioned really, in the question earlier around, the standard of care and its effects on some of these domains of disease, we feel there is a high probability of success in terms of, the, AVR-RD-02 being able to show a treatment effect both in, the brain but also in the lungs as well as liver and spleen. Can you provide a little more information on the two SAEs from the Guard1 trial, including what they were and how long did it take for them to resolve if they have resolved? Sure. To you, Essra. Thank you very much. Two serious adverse events were reported within the Guard1 trial. The first of the serious adverse events was pancreatitis of grade two severity, and considered possibly related to GCSF and busulfan. It was transient in nature and resolved within approximately 19 days. The second of the serious adverse events was a febrile neutropenia of grade three severity, considered related to busulfan. Again, this one resolved within 10 days, so transient in nature. No adverse events were related to the gene therapy itself, AVR-RD-02. Based on the data to date from Guard1, how do you see AVR-RD-02 fit into the treatment paradigm? What kind of patients would you consider administering AVR-RD-02 to? Sure. If we limit the discussion to Gaucher disease type 1, because I think there's a very clear answer for Gaucher disease type 3. I call your attention to the nomenclature that Essra used earlier were ERT-controlled patients that were included in the Guard1 trial. Yet, what we've just shared with you is important improvements across multiple measures relative to baseline ERT, such as enzyme substrate, chitotriosidase or organomegaly. Clinically meaningful improvements in this subset of quote-unquote, ERT controlled population. Of course, that ERT controlled population benefits from being untethered from ERT, a lifetime of ERT, and the healthcare system benefits from millions of dollars of savings in that patient population. The eventual vision is broad utility. However, we recognize that the easy pragmatic first step is to target a patient population where ERT is underperforming. It is not performing as well. To discuss these patient segments, perhaps, I could call on you, Professor Jones, to talk a little bit about the different patient segments in type one Gaucher disease. Yeah. Thank you for that, yes. I mean, I think as has been stated already today in some of the presentations, Gaucher disease is a true spectrum. you know, we can see that within type 3 Gaucher disease, but we also see that within type 1 Gaucher disease, where there are some patients whose needs are entirely met by enzyme replacement therapies, whose patients who, the kids that I see who have no symptoms at all and normalized biomarkers. Whereas there are other populations within that broad type 1 group who aren't fully treated by enzyme therapy. A number who have significantly elevated biomarkers despite standard of care therapies. Really also, from the point of view of patient perspective, you have families no longer thinking about the next 2, 3, 4 years, but thinking about 30, 40, 50 years of life, and wanting as much control of the disease as is possible. I think as we get more and more data, through, especially from a safety point of view, but also efficacy, if we can demonstrate superiority over enzyme therapy, then I think we will gradually see a change in the perception of the community towards this type of therapy. You talked quite a bit about your CMC being ready for late-stage trials. Have you vetted your CMC strategy with the FDA? Sure. Azadeh. Yes. Our CMC package has been reviewed by multiple regulatory agencies: FDA, Health Canada, Ministry of Health in UK, and even Japan's PMDA, just to name a few. We have discussed really key topics. I talked about them today in our presentation. Our approach to potency, comparability, release and characterization, the strategy for both vector and drug product, and many more. Most importantly, the regulators' feedback is now incorporated. This makes for a CMC package that is not only supportive of our GD3 registrational trial, but also for the entire portfolio, given our platform approach to CMC. Is Gaucher disease still diagnosed based on clinical symptoms? There seems to be variability in symptom severity, such as the two patients on an earlier slide that had type three. Maybe I'll go back to Professor Jones. Do you wanna comment on that? Yeah. Thank you. I mean, most patients are diagnosed based on clinical symptoms and some through family screening, et cetera. But most still through clinical symptoms. Yeah, there is significant heterogeneity in the phenotype, even if we look and restrict ourselves just to the GD3 population. In fact, even if we look at the most common genotype here, L444P, and we look at those GD3 patients who are homozygous for that mutation, you will still see some who present at the age of, say, 18 months, like the young man that we described who had the gene therapy. You will see others who present in adolescence with less rapidly progressive disease. When you look at this population, you see some who have significantly persisting hepatosplenomegaly, some who have predominant neurological disease, some with interstitial lung disease, even within the same mutation. That's really the driver for the Multi-Domain Responder Index. All of these patients have an unmet need. What that need is, however, isn't exactly the same from patient to patient. So to make a realistic and reasonable clinical trial approach. The Multi-Domain Responder Index, I think allows us to encompass all of those patients who may benefit from this therapy. Were all of the patients reported today treated with Plato? Yes. I mean. Thank you for the question. It's an important point, and I think most on the line understand the steady drumbeat of CMC related delays that have plagued the field of gene therapy. They all really come down to not having your material process changes, your final process in place early. That is something we're very, very proud of, to say that the full plato platform optimized vector, closed automated roboticized manufacturing, large scale bioreactors, serum-free suspension, high titer, all. Let alone the analytics, as Azadeh talked about. Because really what has tripped up the community at large are comparability exercises done late, potency assays done late. We're very happy to say that all of that is in place prior to patient number one being treated in the entire Gaucher program, type one and three. Can you elaborate on the GD3 pediatric patient's treatment experience, including conditioning? Certainly. Professor Wynn, could I hand that to you? Hi. Thank you for the question. Actually, this was a remarkably smooth transplant, probably one of the most easy procedures that I've ever seen. This kid's busulfan is actually very well tolerated. We use it as a single agent busulfan, so there is no immune suppression in this transplant, in contrast to allograft. That's one of the reasons that it's safer. We don't give anything to suppress T cells or B cells. We only give myeloablative busulfan. It's a very well tolerated drug. We measure the levels, and so we target into a therapeutic range to ensure efficacy for stem cell engraftment without toxicity. Actually, for this customer, we saw no transfusion dependence. Busulfan depletes host stem cells, but by the time those host stem cells were depleted so that one might expect transfusion dependence, the gene-modified autologous infused stem cells were engrafted and making blood. He did not require a blood transfusion. He did not require platelet transfusion. And that's very different, actually, not just from allo transplant but from our other stem cell gene therapy experience in MPS IIIA and MLD, where those kids have required transfusion. It went very well. And he was in actually for a relatively short period of time. And we would anticipate using similar procedures and protocols for future kids on these on this trial. Thank you. Congrats on the regulatory progress from FDA and MHRA. What's your GD3 enrollment strategy? How quickly can you enroll? Where are the patients, and are they well-identified? Sure. Maybe I'll start with you, Essra, and then we could hand it off to one of the opinion leaders. Thank you, Geoff. As mentioned, there remains significant unmet medical needs for Gaucher disease type 3, and that's both visceral and CNS manifestations, which are not completely addressed with the current therapeutic options. That's one of the key factors in our ability to enroll effectively into this trial at a rapid pace. Additionally, the clinical trial will be a global trial where we really expect to receive referrals from experts in the field as well as global patient advocacy groups into what are major treatment hubs, which will be within the UK, EU, and the US. With that, I might hand over to Professor Cox, please, to elaborate further on the GD3 patients that he's seen globally. Sorry. Thank you. I have traveled to see patients in Europe, and in the East and in Scandinavia, and of course, know about them in the US and have an interesting international project on the variability of the disease in 14 countries. Yes, it varies, and there's much more of it than we ever recognized. It's just depending if you're looking for it, and there wasn't a great deal of incentive to look for it because there was no therapeutic trial that was going to deal with this at that time. In the UK, there are 250 known patients in our long-standing, stratified medicine cohort. Of those now, we know that at least 20% have type 3 disease, they have much more severe somatic manifestations, which would not have been apparent if we'd not segregated them out by looking very carefully, that was done by a mutual colleague of Dr. Jones and myself. It was interesting work. It is elsewhere in Europe and in the United States, I believe. There's no reason why it shouldn't be. There are many patients in Japan, probably more than there are relatively in the Occident. there they have a very big experience of type 3 disease and a great interest in doing this sort of work, and where the L444P mutation is recurrent repeatedly worldwide. It is just something that's the nature of the structural gene itself and its pseudogene that this keeps arising and is to be found, unfortunately, and needs to be dealt with. Most patients are homozygous in those countries, and I'm sure they'll be referred to their centers. We have centers of excellence, certainly in Europe. For referral and of course, in the U.K. and also I'm sure in the United States, there are some key centers there where this sort of work would be welcomed. Great. Since one of those centers of excellence will be in Manchester, perhaps I could ask invite our Manchester colleagues to comment on the general concept of the treatment hub and how you anticipate the interest from the patient community? Simon, do you wanna go first? Yeah. Thanks. Thanks, Rob. I mean, I think this has been relatively well telegraphed to the patient community, who is a very well-connected community, the Gaucher community worldwide, as well as within many developed countries. The Type 3 patients in particular, are a vibrant dynamic community who've been actively questioning academics, clinicians like ourselves and pharma for better treatments. Really for some time, there's been a real demand, and we must do better. It's great to be close to being in a position where we can actually answer that. I think there will be demand from all the places mentioned, Europe, UK, the US, but I think many other countries also. I think that's all manageable actually. There's a real model now for many of these ex vivo HSCGT studies, whereby you minimize the number of centers doing the transplant apheresis and transplants and move patients. I think that's a pretty well tried and tested model. We've done it for years. I know many other centers have as well. I don't really foresee that as a particular problem. I mean, we were... Rob, you can maybe talk to this. We were even able to recruit patients to studies like this through the pandemic. Yeah. I think, just in the practical terms, for this center, we would be very used to taking children for allogeneic transplant and stem cell gene therapy for a number of conditions. We are set up to bring kids, bring families. The family stays for a while during the apheresis or during the eligibility assessment, during the pre-transplant phase, then the transplant itself and go, and then, come back for follow-up, and we would share some care locally in between. That is a well-trodden model in metabolic disease, generally. This is rare disease and rare transplant, and we have well-developed links with referral centers. We do all the transplants for the UK, but also for the Republic of Ireland and take many Middle Eastern centers. I think you can be reassured that we will be able to recruit, and we will be able to do the transplant procedures in these central hubs. Patients will be well looked after. There'll be expert care, and there'll be very clear communication, both for the patient themselves and for the research trial and the data quality between that center and the referring hubs. It's not, we're not reinventing the wheel here, so to speak. We do this in many other conditions for patient benefit. Thank you. How do you plan on evaluating AVR-RD-02's impact on bone pain crisis, given its overwhelming quality of life impact on GD patients? Great. Thank you for the question. I'll hand it to you, Essra. Thank you. You're absolutely right that it's an important aspect of the disease. Within the clinical trial, we do plan to evaluate bone pain and crisis, and generally the symptomatology really with these patients using patient-reported outcomes, as well as quality of life assessments over the course of the trial. You know, for a measure like this, we really do need a period of time with which to assess, so we follow these patients for some time to really get a thorough evaluation of the effect of the gene therapy on these aspects of the disease, as well as imaging as appropriate. Yes, we have every intention of looking into that. What are the gating factors towards phase II, phase III GD3 study initiation, and why the second half of 2023? Yeah. I'll hand it to Essra, but I would just highlight that this is the number one priority in the company. I mean, we're really excited, as I opened up, that we're progressing to late-stage trials for both Gaucher disease and cystinosis, but we're really at the point of execution right now. Perhaps you could be a little bit more granular, Essra, on the next steps between us and actual trial execution. Thank you very much. Importantly, as we've mentioned, we've had our initial interactions with the FDA and the MHRA around our proposed clinical trial. Moving forward, our plan would be to submit the relevant paperwork, both IND amendments and CTAs, depending on the jurisdiction, moving forward with that, obtain those approvals. In parallel, we would conduct feasibility and really work with our clinical trial centers. Obviously, we've identified some, but we'll continue to identify more and work with them really in terms of study startup and set up activities, to get us to the second half of 2023, where we believe we can activate those trial sites and be ready to recruit. With GD3 trial, will the focus be a pediatric patient population, given the GD3 patient data shown? When would you gauge the ideal time for GD3 intervention with the gene therapy? Essra? The focus of the clinical trial for GD3 is the pediatric population. We are currently looking at an age range between 2 and 18 years of age. For a lot of the aspects of the disease, we'd like to, in an ideal world, treat as early as possible to prevent some of the sequelae of the that are associated and the complications that are associated with Gaucher disease type 3. That is the reason to go and treat patients as early as possible with this particular phenotype of Gaucher disease. One last question that we'll get to today. Can you walk me through how you view the commercial opportunity for Gaucher disease? Is your focus on GD1 or GD3? Sure. I'll take that. We define Gaucher as one disease. What we tried to share with you is, we're incredibly excited to be initiating the Gaucher disease type 3, phase II/III trial. Very proud that it's the first randomized controlled trial in hematopoietic stem cell gene therapy, and it's the number 1 priority of the company. We really highlight Gaucher is one disease. What Essra presented is our thoughts on how we will progress the Gaucher disease program overall. Is that, just to remind you, FDA's guidance documents tend to ask for one randomized controlled trial per indication. We're meeting and exceeding those requirements by right now executing not only one randomized controlled trial and the first randomized controlled trial for HSC gene therapy. We're meeting FDA's requirements, which resulted in a very positive reception, I would add. Also complementing that with 1 very well-designed within-patient controlled trial in Gaucher disease type 1. As Essra said, that exceeds 50 patients from a safety perspective. We think we have a comprehensive 2-study work package for a Gaucher disease clinical development program. In terms of the commercial opportunity, you know, keep in mind, as I mentioned earlier, Gaucher disease is the largest, most common lysosomal disorder, so it's very large. We believe that for Gaucher disease type 3, if we hit our target product profile, we would have very significant penetration, meaning we would be able to address the needs broadly of the Gaucher type 3 patient population. For Gaucher type 1, it's a more nuanced approach. At least initially, we would envision targeting patients that are not well controlled on enzyme replacement therapy. We shared some data around what that percentage is. You know, that's an ongoing debate, but certainly patients that have been splenectomized, patients that are not tolerating ERT, patients that have been late-onset ERT, and patients that just don't care for or don't have access to enzyme replacement therapy adds up to a sizable percentage. You know, commercial opportunity, first of all, is how many patients are we talking about? What we put forward is several thousand patients across both types of Gaucher disease. Of course, we believe that we will be first. We are first into the clinic by quite a margin for Gaucher disease with a genetic medicine, and we hope to accelerate or maintain our lead. The third element is pricing. We're targeting a disease that costs the healthcare system an absolute fortune. Most in the audience would note that hemophilia just got reimbursed at $3.5 million, the justification was that there's a $20 million lifetime cost in hemophilia, those numbers equate 1 to 1 with Gaucher disease. We believe with success, if we develop a safe, effective, durable medicine, we would be able to command a price commensurate with the value that we provide. We're pretty excited about the commercial opportunity. We're very excited at our lead, at our current position in developing a genetic medicine in Gaucher disease, it is the number 1 priority in the company. Great. Thank you all for your questions. If we did not get to your question, we will follow up with you directly. This concludes our call today. Thank you all for joining.