Ladies and gentlemen, thank you for standing by and welcome to the AVROBIO Virtual Investor event at the 17th Annual WORLDSymposium 2021. I would now like to hand the conference over to your speaker today, Mr. Geoff MacKay, President and CEO of AVROBIO. Please go ahead, sir. Thank you for tuning in to our AVROBIO Investor Update. This is the first of many events we have planned this week during the 17th Annual WORLDSymposium. I look forward to updating on our recent progress. Before we begin, the presentation today will contain forward-looking statements based on our current expectations and beliefs. Such statements are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those presented. We refer you to our SEC filings for further information. We recently celebrated our fifth anniversary as a company. Our founding purpose is unchanged: deliver freedom from a lifetime of genetic disease. Today's new clinical data give us further confidence in our belief that we're on track to do just that, to deliver functional cures for devastating genetic diseases and to untether patients from weekly or biweekly infusions. I'll share the podium with Dr. Chris Mason, our chief science officer, and I'm very happy to introduce Dr. Diana Escolar, our new chief medical officer. Diana brings tremendous experience in developing therapies for rare disease with a particular focus on neurogenetic disorders. For the first 10 minutes, I'll highlight our unique approach to developing first-line gene therapies across our portfolio. We'll share exciting new data across each of our 3 clinical stage programs. A point of differentiation of AVRO is that our programs are driven by the power of ex vivo lenti gene therapy. There are multiple approaches in genetic medicine. However, on the parameters outlined here, durability, safety, and broad applicability, lenti stands alone. Regarding durability, the integrating nature of lentiviral gene therapy has translated out 12+ years without waning of effect. In terms of safety, lentiviral gene therapy has a strong safety record in hundreds of patients across a growing list of genetic diseases. It does not suffer from the liver toxicity and immunogenicity issues now well documented with liver-directed AAV gene therapy. Lenti also has broad applicability across patient segments. No patients are excluded due to preexisting neutralizing antibodies, because the transgene integrates, the therapy grows with children as their cells divide, meaning it's appropriate not only for adults, but also kids. Lenti is also unique in its ability to access both CNS and peripheral tissues, making it ideally suited for diseases which require both an above-the-neck and below-the-neck impact. With multiple regulatory approvals, clinical studies in a dozen indications, and over a thousand patient years of data, it's no longer aspirational to state that lenti has a proven record and broad utility. Here's our pipeline. We've built the leading gene therapy portfolio treating lysosomal disorders, starting with the first gene therapy trials in the world in Fabry, Gaucher type 1, and cystinosis. Today, we'll share transformative data across these three programs. Beyond today's update, I highlight that 2021 is the year our second wave, Hunter, Gaucher type 3, and Pompe, reach the clinic. We expect to dose patients in at least two of these three indications this year. A key theme to highlight is strategic fit. These six lysosomal diseases are sister indications with somewhat similar biology, and the important implication is that our strong proof of concept data in Fabry de-risks the closely related programs. Programs which represent a significant commercial opportunity. The average annual direct cost for today's standard of care range from $350,000-$800,000 per patient per year for life. Fabry alone has a lifetime direct cost of $12 million-$14 million per patient. In terms of target patient population, we estimate that there are more than 50,000 patients across our first 6 indications in a subset of the markets where ERT is both available and well reimbursed. The Sanofi and Takeda generate almost $5 billion in annual revenue for today's standard of care. We believe we can replace these ERTs as a first-line therapy, our goal is to offer tens of thousands of patients a better solution, while at the same time saving the healthcare system a fortune. Why do we have the hubris to go up against these entrenched companies? If I had to answer in a soundbite, it would be today's therapies offer right enzyme, wrong pharmacokinetics. On the left, the blue graph represents a patient visiting an infusion center, getting a one-to-two-hour infusion every two weeks for life. Yet, if you measure the patient's blood, 12 hours post-infusion, the enzyme is gone. A small amount is taken up intracellularly, the majority is broken down by the liver, wasted. Across all six lysosomal disorders, today's approaches offer partial solutions, slowing but not halting disease progression. The central hypothesis of gene therapy, and in fact of AVROBIO specifically, is what if you can deliver long-term, continuous, functional protein expression, bathing cells, tissues, organs, and protein 24/7? Our goal is that this will translate into preventing, halting, or reversing disease progression. In other words, a functional cure with a single dose. One core element of a functional cure is, of course, durability. As an integrating vector, lenti has a clear advantage in this realm because the therapeutic gene doesn't wash out over time as cells divide. This is well documented in our field, it's what we see in our own data. To date, 13 patients have been dosed across four trials. 10 are out at least a year, several are out 2-plus years, and the furthest time point is 3.5 years. Across all patients with reported data, we're seeing what we would hope to see: durable benefit with no waning of effect over time. One key ingredient necessary to deliver long-term durability is the use of conditioning to enable the genetically modified cells to engraft in the bone marrow and CNS. We've pioneered an innovative approach, which we call Bu90-TCI, or Target Concentration Intervention. This single agent, single cycle approach is designed to optimize engraftment while avoiding out-of-range toxicity. On the left is an analysis of over 400 busulfan patients, which highlights what our target should be. The narrow band at the trough of the curve is our target, Bu90. Hitting this optimal exposure avoids out-of-range toxicity. However, doing so requires careful monitoring and titration, which we accomplish with our Bu90-TCI approach. On the right, we outlined a long list of possible grade 3 and 4 conditioning-related adverse events in a time course plotting 30 days. Why do we share this sparsely populated chart? Because were this to be a conventional bone marrow transplant in an oncology setting, this would likely be a densely populated chart. In sharp contrast, in magenta, we show the grade 3/4 adverse events for the first two patients dosed with Bu90-TCI. We believe we've optimized conditioning, which translates into a side effect profile, which is both limited in scope and short-term, transient. As you know well, many in the gene therapy space have struggled with manufacturing, resulting in several high-profile regulatory delays. AVROBIO has had a total commitment to CMC and analytics, and the result is plato, our end-to-end platform applied across our pipeline. I'll highlight four key elements. First, all large and medium process changes are FDA-approved and in place very early in development. Second, we are one of just a few teams operating in a 200-liter serum-free suspension bioreactor, resulting in a 10 to the ninth vector titer. Third, we are the only company to implement an automated closed manufacturing system, as well as be operational on three continents. Fourth, our analytics are well advanced and designed to avoid the most common regulatory delays. We're already in very active dialogue with regulators regarding our potency assay matrix, meaning it's being sorted early. We deploy one VCN assay across the entire portfolio, negating the need to recreate or revalidate across programs. We have a first-in-class rapid transduction assay, and we utilize single-cell VCN level data to provide deeper product characterization to regulators. All of these innovations translate into advanced control over manufacturing consistency. Why am I belaboring such technical details? Because you need to know that our intense five-year focus on developing plato has paid off with leadership in automated, scalable global manufacturing. Now for the data. I'll start with our take-home messages. The first Fabry plato patient showed complete clearance of substrate, a 100% reduction as measured via kidney biopsy at one year, the primary endpoint of the study. Long-term durability continues across all patients in both Fabry studies. We show strong cystinosis results across multiple functional measures and are now working on registration trial design in order to advance towards a much-needed therapy for patients. The first Gaucher type 1 patient to receive gene therapy is experiencing material reductions in multiple clinical biomarkers to levels well below baseline ERT. These are tremendously exciting and consistent results across the board in the first gene therapy trials in the world for all three indications. I'll now go through the first of our three clinical updates, our lead program in Fabry disease. We see an opportunity to improve upon today's standard of care. One goal is to clear the toxic substrate that accumulates in the kidney and heart, causing serious complications, including organ failure. Another crucial goal is to extend lives that are typically cut short by this insidious disease. Beyond that, it's essential to address debilitating symptoms which impact every single day of life, including peripheral pain, GI distress, cognitive dysfunction, deep fatigue, and significantly elevated risk of stroke. We aim to treat all patient segments, regardless of mutation or preexisting antibodies, and it's also ideal to treat patients while young, before organ damage sets in. Vision, a first-line functional cure, which depending on stage of disease, could prevent, halt, or reverse life-limiting symptoms of Fabry disease. As you know, we have two Fabry trials, a five-patient phase I study, which is fully enrolled. This study is assessing patients who have already been on ERT. In a global phase II ERT-naïve trial called FAB-GT, which has so far dosed four patients with several more now actively moving through the screening and consent process. Let's start with the FAB-GT trial. To help you interpret the new kidney biopsy data you're about to see, I call your attention to patient four, a 26-year-old man who has been experiencing symptoms of Fabry disease since the age of nine. There's a lot of attention on this patient because he was the first patient across our clinical programs to be dosed with our plato platform, meaning FDA-approved upgrades to vector and automated manufacturing, as well as Bu90-TCI conditioning. Here, we see that optimization at work. This patient has four times higher plasma enzyme activity and six times higher leukocyte enzyme activity than the average for the first three patients at the 12-month time point. The essential question, of course, is whether this enzyme activity translates into reduction of the toxic substrate that causes so much damage to people living with Fabry disease. In this patient, at one year, we are reporting a 100% reduction in substrate versus baseline, the primary endpoint of the study. This result was assessed by two blinded pathologists who independently scored 99 digital images of section kidney of the 12-month biopsy. Every one of these slices scored zero inclusions. In this study, we follow the method laid out in FDA guidelines for this endpoint. Pathologists use validated and standardized SOPs. Biopsies are scored with the BLIS methodology, which is a highly sensitive quantitative approach to scoring digital biopsy slides. I could not be more pleased with this extraordinary biopsy result. As a reminder, in the first patient we treated in this trial, we saw an 87% reduction of toxic substrate at the 12-month biopsy. We've shared the data from patient 1 with several nephrologists, and they all said that a reduction of 87% would be considered full effective clearance of the toxic substrate. A 100% reduction, of course, is complete clearance without question. Both results were statistically significant with a P value of less than 0.0001. The primary endpoint is also very significant from a regulatory perspective. GB3 substrate reduction, as measured by kidney biopsy, is cited in FDA Fabry disease guidelines as a surrogate endpoint for accelerated approval in Fabry. As noted, we are following FDA clinical trial guidance for evaluating these biopsies via the BLIS methodology. We feel we are well-positioned in terms of our primary endpoint selection for this trial. In fact, there is a recent regulatory precedent. GB3 substrate reduction, as measured via kidney biopsy, also using the BLIS methodology, was the basis for the accelerated approval of migalastat, a chaperone therapy for Fabry that has been approved for a subset of amenable Fabry mutations. As you can see here, migalastat substrate reduction from baseline varied from about 12% to about 64% in the subset of patients with amenable mutations submitted for FDA approval. Let's look at additional data across our Fabry trials. Here, you see that plasma and leukocyte alpha-galactosidase A activity, shown in the two graphs up top, is sustained across all patients in our phase II, with the longest patient out two and a half years. The patient with the highest activity, shown in black, is the one treated with our Plato platform. On the bottom, you see vector copy number performing as expected, hitting a therapeutic plateau across patients. Given the sustained enzyme activity, you would expect a reduction of plasma substrate and toxic metabolite levels. That's what we see across all classic male Fabry patients. In fact, an average 70% reduction. We see plasma lyso-Gb3, the toxic substrate, dropping and staying at a low plateau across all patients durable out as far as 2.5 years in patient number 1. Note that patient number 2 in blue is a cardiac variant, and therefore, we evaluate on other more relevant parameters over time. To sum up results from our global phase II to date, we are seeing very strong efficacy across all measures in all patients, with a particularly profound effect on the primary endpoint of the study. Switching to the Fabry phase I, assessing patients deemed ERT stable upon entering the study, we see a very similar pattern. Across all five patients, durability of enzyme activity attributable to gene therapy as measured in plasma and leukocytes out as far as 3.5 years, and stable VCN across all patients. If we ask the question, is this elevated enzyme activity controlling the toxic metabolite, lyso-Gb3, we see clearly the answer is yes. Each patient in the phase I study has a baseline measure while on ERT, we can compare this to their levels after gene therapy. The phase I safety trial protocol reinitiated ERT four weeks post gene therapy. A protocol amendment was then filed to permit patients to discontinue ERT over time if they meet specified criteria, and three of five have already done so. One of the patients, patient number 2, entered the study with multiple health issues, including moderate kidney disease, and so it's unclear if and when he will be able to meet the criteria for ERT discontinuation as per protocol. We can conclude the following points. We see durable control of disease as measured by lyso-Gb3 reduction across all patients for up to 3.5 years. Overall, gene therapy has led to a further average 25% reduction of lyso-Gb3 versus baseline ERT, and all patients who have discontinued ERT remain well controlled off ERT. We couldn't be more pleased with the results generated by our great collaborators up in Canada. Let's turn to an important clinical measure, kidney function. eGFR is a well-known surrogate estimation of kidney function. It's well documented to decline steadily in classic male Fabry patients year on year at a meaningful rate that is greater than a decline in normal healthy adults. We see this in published natural history on the left, and we see this in published ERT studies on the right. Now let's contrast this to our gene therapy data set. What is emerging across both of our Fabry trials is a very different slope. In fact, we see a largely stable eGFR across these patients. Eight of nine patients are progressing with slopes that compare favorably to what we see in natural history data. I've already referenced the patient at the bottom of the slide who entered the study with moderate kidney disease. Published ERT and natural history studies indicate that when disease progresses to the level this patient had at enrollment, an eGFR of 48 at screening, patients continue to decline. This is one of the key reasons he remains on ERT despite a very robust response to gene therapy. In addition to this promising renal function data, I will share new cardiac-related data, which we've measured in our phase II ERT-naive patients. Here we show measures of cardiac function and structure. Cardiac health is an important issue for Fabry patients, who often experience progressive left ventricular hypertrophy and fibrosis, leading to heart failure. The dark blue bars represent the mean baseline for this group across several parameters, including ejection fraction, end-diastolic volume, cardiac output, and left ventricular mass index. In the colorful bars, you see the mean status of the group at one year post-treatment. The overriding message of these new data is stability. These patients came into the study within the normal range for these measures and are not experiencing progression on these important cardiac measures. We recognize that these data are early, just 12 months post-infusion, but they are trending well. Stability is just what we want to see, and with each subsequent time point, these measures will increase in importance. Turning to safety, there have been no unexpected safety events or trends and no adverse events or serious adverse events related to our drug product. The AEs across both trials were generally consistent with myeloablative conditioning, underlying disease, or pre-existing conditions. Let's take a closer look at the conditioning-related Grade 3 and 4 adverse events in our phase II Fabry patients. On the chart on the right, we compare the first 3 patients who received melphalan relative to the 4th patient who received personalized Bu90-TCI conditioning. The melphalan adverse events are shown in blue. The busulfan adverse events are in magenta. We upgraded from melphalan to busulfan for several reasons, including busulfan's enhanced safety profile. These emerging data reinforce that point. As you can clearly see, there have been fewer Grade 3 and 4 adverse events with busulfan, and they are clustered in a more narrow window of time. Just as important as transients with Bu90-TCI, the side effects are also predictable. We know when, within a short defined window, patients may experience mild to moderate fatigue, nausea, vomiting, and mucositis, and we believe we can mitigate or even prevent these side effects with proactive supportive care. With strong data across all nine patients in both trials, a key focus for 2021 is clinical execution. I'd like to share with you one newly operational element of our overall clinical activities to accelerate enrollment, our international patient referral efforts. We undertook these efforts over the past year because we believe they would help us navigate the uncertainties of clinical trial execution in the COVID era and accelerate patient recruitment, and it's already proven effective. Three Fabry patients from Brazil now have feet on the ground for the screening and consent process at our first global center of excellence in Australia, and a fourth is expected to join them shortly. Their willingness to travel so far underscores the enthusiasm for gene therapy among Fabry patients worldwide. We're setting up a trial site and protocols in Brazil to enable easier follow-up in their native country. Although we fully expect to include a meaningful amount of patients in our standard within-country trial sites, this has proven to be an effective way to guard against unexpected COVID shutdowns. International referrals are giving us a boost out of the gate as we drive towards our corporate goal of dosing a total of 30 patients cumulatively across our pipeline by the end of this year. In 2020, we invested tremendous energy on the critically important question: what is needed to get approval? What data will we need to secure accelerated approval, and importantly, to achieve a broad first-line label with no meaningful restrictions on patient populations? After extensive dialogue with our advisory board of top Fabry KOLs, we submitted a briefing book to FDA, which outlined a proposal for accelerated approval laid out on this slide. Our phase I safety trial as a supportive trial, our ERT naive trial as designed with an expanded patient population to include females, and a confirmatory ERT switch trial run concurrently to ensure breadth of label as well as measure crucial elements such as cardiac function and CNS impact that are not well-served by today's standard of care. We hope to gain feedback and, in fact, regulatory clarity this year. We repeat the process with EMA. I will now turn it over to Chris to walk you through a growing data set across multiple functional measures in the first gene therapy study in cystinosis. Thank you, Geoff. Cystinosis, as many of you know, is an unrelenting lysosomal disorder. Patients face multiple serious life-limiting complications. They suffer severe visual impairment, a dramatically shortened lifespan, and 90% require a kidney transplant even on today's standard of care, cysteamine. This small molecule therapy is highly burdensome, both in regime and side effects, including eye drops every waking hour and dozens of pills per day. This is highly challenging for adults, but imagine how much more so for toddlers and children. On top of that, cysteamine side effects include frequent nausea and vomiting and breath that smells like rotten eggs. Our investigational gene therapy for cystinosis has a target product profile as a first-line functional cure that, depending on stage of disease, could prevent, halt, or reverse renal failure, eye symptoms, endocrine disorders, including diabetes, and CNS manifestations, all with a single dose. Let's take a look at the trial. The investigator-sponsored phase I/phase II is being run by our collaborator, Dr. Stephanie Cherqui, at the University of California, San Diego. This is the first and only gene therapy trial for cystinosis. Three patients have been dosed out of the planned six patients. Because of the vast unmet need, patients are eagerly lining up for screening. Thus, we expect to be fully enrolled this year. All three patients dosed to date are now independent of cysteamine. Remarkably, the first patient is 16 months post gene therapy and has been off cysteamine, both pills and eye drops, for that whole period. The cysteamine dosing regime is far more burdensome than you may realize. Here we see the daily cysteamine dosing regime for patient one before and after gene therapy. The blue section was before AVR-RD-04, when he was on 30 cysteamine pills a day and frequent eye drops. 16 months post gene therapy, he remains off all cysteamine. In addition, this patient reports a significantly improved quality of life. Likely as a result of discontinuing his cysteamine, he reports no vomiting at all, which is a major improvement to his quality of life. He also reports a reduction in thirst and fatigue. He is also able to work at a physically demanding job in construction. The direct and indirect benefits of discontinuing 30 poorly tolerated pills of cysteamine and near constant eye drops are quite profound. Let's turn to renal function. For years prior to gene therapy, patient 1 experienced a high rate in decline of renal function. Because of this, he was, like many other cystinosis patients, unfortunately heading towards a kidney transplant. Shortly after gene therapy, there was the usual brief period of metabolic fluctuation, and then his eGFR settled in the range for normal age-related decline of approximately 1 ml per minute per year. This is a significant improvement on his rate of decline at 8 mls per minute per year while on cysteamine. Since this patient has established progressive kidney disease, we're cautiously excited with what we've seen, since we recognize that his eGFR decline may accelerate due to the irreversible nature of end-stage renal disease. Our ultimate goal is to identify patients early and before any symptoms develop, thus preventing the onset of renal disease entirely. To treat the cystinosis patient population of today, we need to be aware of how kidney transplants, which are common in cystinosis patients in their teens and twenties, will respond to gene therapy. Here we see data for the first two patients. Patient one, who, as you know, has not yet had a kidney transplant, and in blue, patient two, who has had a kidney transplant. It is important to call out the large difference between the eGFR of patient one with established renal disease, despite years of cysteamine therapy, and the eGFR of patient two with a normal functioning transplanted kidney. This patient with a kidney transplant had a normal eGFR before the gene therapy, and then after the brief period of metabolic fluctuation, there was the expected fast return of eGFR to pre-gene therapy levels. By including both transplanted and non-transplanted patients in the trial, we are able to potentially demonstrate the broad applicability of AVR-RD-04 across the entire cystinosis patient population. Let's move to some exciting exploratory biomarkers. With the first patient in this trial now out more than one year, we have a significant amount of data to share. Skin and rectal biopsies show a large drop from baseline in both the number of toxic cystine crystals in each cell and the amount of cytoplasm occupied by these crystals. These reductions suggest that the patient is now producing and distributing throughout his body his own functional cystinosin protein, which he was unable to do before the gene therapy, and that the protein is doing one of its many jobs, preventing the pathological buildup of cystine crystals. Let's take an actual look at those crystals. A leading key opinion leader recently told us that the eye is the window to the world of cystinosis. A pathognomonic sign of cystinosis is cystine crystals in the cornea, a cause of severe photophobia. This baseline photograph clearly shows the crystals in cornea of patient 1. At the time, he, like many cystinosis patients, was on a prescription for cysteamine eye drops every waking hour. What's happened in the year since gene therapy? Here are some striking microscope images which capture the prevalence of the crystals shown in white, going from front to back of the cornea. Prior to baseline, the patient discontinued his frequent eye drops. Since gene therapy, the density of crystals has dropped dramatically. We've shown these images to several KOLs who were really impressed. This was summed up by Dr. Aude Servais, a leading expert based in Paris, who said, "No other treatment has done this. Really impressive." This biomarker appears to coincide with improvement in an important symptom, namely photophobia. Photophobia or light intolerance is one of the more debilitating effects of cystinosis. It can be extremely painful for patients to be exposed to any level of light. Some must wear dark glasses all the time, even at night. Photophobia is caused by the crystal buildup that you saw in the previous slide, as well as by inflammation and damage to the nerves in the cornea. You've seen how the cornea of patient one cleared in the year since gene therapy, with a marked reduction in crystal density. The key question is: Does this translate into functional improvement? We now have that answer. At baseline, patient one's photophobia grade was 3 out of 5. 12 months later, it had improved to grade 1. This improvement has made a meaningful difference in the patient's life. As just one example, before gene therapy, it was too painful for him to look at a bright screen in the dark. Now, he can read comfortably from his phone day and night, just like the rest of us. Our gene therapy is designed to enable endogenous production of the protein cystinosin. As we've seen, this protein can have a profound effect on crystal buildup, it also plays many other roles in the body, including in pigmentation. Just take a look at these photographs. This patient's eyebrows, hair color, and skin tone were all very pale at baseline, as is typical of many people with cystinosis. Since gene therapy, all appear to be getting progressively darker. The darkening of his hair, and particularly his eyebrows, is remarkable. Even more so for this patient, since darker hair and complexion is consistent with the rest of his family. These observations from patient one underscore our belief that gene therapy for lysosomal disorders has potentially broad effects across a diverse array of functions, not just substrate reduction. Let's look at VCN. As expected, the vector copy number for patient one remained stable at the therapeutic plateau that we've seen as a signal of durability across our clinical trials. Patient two is doing well, and overall trending consistently with what we saw with patient one, including his VCN data shown in blue. Patient three data at one-month post-infusion is also right in line with expectations. As with our other clinical programs, there have been no unexpected safety signals observed in the phase I/phase II. Importantly, there were no SAEs or AEs related to AVR-RD-04 drug product. The reported AEs were consistent with Bu90-TCI conditioning and preexisting disease. They were classified as transient, mild to moderate, and all have resolved. As we noted, we expect to have this trial fully enrolled by the end of the year. In the coming months, we plan to engage with the FDA on the design of our registration trial and identify trial locations worldwide. We're excited to advance this program in an indication with such a profound unmet need. I will now hand over to my colleague, Diana, to share exciting updates on Gaucher disease type 1. Thank you, Chris. I am thrilled to be on board at AVROBIO and glad for the opportunity to talk with you all. We are the first gene therapy company to tackle Gaucher disease type 1. As you can see, our target product profile is aimed broadly, with no exclusions for genetic variants, age, or gender. Symptoms such as bone crisis and fatigue, which tremendously impact the patient's quality of life, are not effectively addressed by ERT or SRT. We, on the other hand, expect the broad reach of lentiviral gene therapy will address these and other symptoms, including long-term health risks like Parkinson disease. We ambition a first-line functional cure that, depending on the state disease, could prevent, halt, or reverse symptoms from head to toe with a single dose. Our phase I/phase II trial, which will evaluate the safety and efficacy of AVR-RD-02, is underway, with sites open in Australia and Canada, and additional sites opening in the U.S. and Israel in the coming months. All patients in this trial will be dosed with plato. Importantly, this trial includes all the critical endpoints that have been used to support prior approvals in Gaucher, both by FDA and EMA, including liver size, spleen size, and multiple hematological measures and bone metrics. Let's now look at our first patient in this trial. This patient had an early onset of severe disease and began ERT at just 20 months of age. While she spent years on chronic ERT, not surprisingly, the biweekly infusions proved a significant burden. More than a decade ago, like many ERT patients with a large treatment burden, she began to skip her biweekly infusions, with the consequences that are seen in this graph, which chart her levels of plasma chitotriosidase, an important clinical marker of Gaucher, which is inappropriately released in massive quantities by macrophages. As you can see, her levels began to rise steeply when her ERT infusions became irregular. She then went off ERT entirely during the period shaded in blue, and her chito levels skyrocketed. Subsequently, she reinstated ERT. However, the damage was done, and soon after, she had to undergo a bilateral hip replacement at the age of just 28 for hip necrosis. While our primary goal is to prevent, halt, or reverse disease, we have also been driven by the potential to untether patients from a lifetime of chronic therapy. This patient's experience shows why that is so important. Let's look at this patient's updated data. We show that the patient's plasma chitotriosidase levels have dropped sharply since her gene therapy infusion, falling far below her baseline level on ERT. The decrease from baseline was 17% at just three months and has continued to decrease to an impressive 49% at six months, all off ERT. This is even more significant when you consider the last chart, which showed how the patient's chito levels have soared in the past when she skipped and then went off ERT. Importantly, we believe the decline since infusion suggests that the pathological Gaucher cells are being replaced with genetically modified macrophages carrying the therapeutic gene, and therefore producing the functional enzyme needed for healthy cellular function. In other words, we believe that this preliminary data represents an early signal of efficacy. Indeed, plasma chitotriosidase levels are a recognized clinical biomarker of treatment response. Here, we look at this patient's level of lyso-Gb1, a toxic metabolite and a highly sensitive and a specific biomarker for Gaucher disease. Elevated lyso-Gb1 levels contribute to the severe organ damage commonly seen in Gaucher disease. The normal value for a healthy person is 0.5 to 1.2 nanograms per mL. This patient had an abnormally high level of 32 nanograms per mL on a screening, again, after years of biweekly ERT infusions, in this case, VPRIV. At three months post-gene therapy infusion, her lyso-Gb1 levels decreased 22% from this baseline. This downward trend has continued, now down a very impressive 44%. We are extremely excited to see lyso-Gb1 levels decrease to levels substantially below what she achieved on ERT. These results are consistent with what we see in Fabry disease with lyso-Gb3. Lentiviral gene therapy drives down toxic metabolites below levels typically achieved with ERT. These results could be transformative for patients with these debilitating diseases. Next, we'll look at two hematological biomarkers. A core feature of a successful Gaucher disease treatment is to maintain platelet count and hemoglobin concentration in normal ranges. Continuing the trend we saw at three months, six months after the patient went off ERT, her platelet count and hemoglobin concentration remained well within the normal range. This is exactly what we want to see. The VCN we see at six months is trending as expected at what we consider therapeutic plateau. At six months, this patient's response across multiple biomarkers is consistent with what we have seen in the Fabry patients. Furthermore, the first patient reports feeling well and has not had an ERT infusion in seven months. Let's look now at the safety data. As in other programs, there have been no unexpected safety signals of sort to date in the phase I, phase II. Importantly, there were no SAEs or AEs related to the AVR-RD-02 drug product. This patient, just like Patient four in our phase II Fabry trial, received personalized busulfan TCI conditioning, and the data on the right showing the transient nature of the expected grade 3 and 4 adverse events reinforce our confidence in our precision approach to conditioning. In addition to being short-lived, these AEs are also predictable and manageable. Further, these transient adverse events resolve without clinical sequela. We close with our regulatory strategy. We are well-positioned with two biomarkers, two functional markers, and VCN all trending positively at six months. From a regulatory perspective, key advantages of our GuardOne trial are a trial design that includes both ERT switch and ERT naive patients, the inclusion of accepted primary and secondary registration endpoints highlighted under FDA guidelines. Of course, Plato was integrated from day one. Our first step prior to regulatory discussions is to focus on execution of this trial. Just like at the outset of our Fabry trial, enrollment in our Gaucher trial is debated at the start. We're identifying patients with the goal of a steadily advancing enrollment towards the second half of the year. I'll now hand it back to Geoff to close out the presentation. Thanks, Diana. We enter 2021 with strong wind at our backs. Our clinical data is extraordinary in large, first-in-class indications. We expect our second-wave programs to begin entering the clinic this year. In Fabry, we showed 100% substrate clearance in the kidney biopsy of the first Plato patient, as well as durability out up to three and a half years. In cystinosis, Patient 1 shows significantly reduced photophobia and a substantial reduction in cystine crystals across multiple tissues. In Gaucher, the first patient's clinical biomarkers dropped more than 40% lower than the patient's ERT baseline. Looking forward, with cash runway into the first quarter of 2023, I believe we are very well-positioned to deliver on our corporate goals. In 2021, that means having dosed 30 patients cumulatively and achieving registration clarity for multiple programs, beginning with Fabry disease at the front end of the year. Our purpose at AVRO is to free patients from a lifetime of relentless genetic disease. We're steadily advancing towards this goal for patients and families who've been waiting for years, in some cases, decades. Thank you again for joining us this morning. We're happy to answer your questions. Thank you. As a reminder, to ask a question, you need to press the star, then the one key on your touchtone telephone. Again, to ask a question, press the star, then the one key on your touchtone telephone. Our first question comes from Ritu Baral with Cowen. Your line is open. Hi, guys. Thanks for taking the question and congrats on the data updates this morning across the programs. I wanted to follow up just on your comments about the manufacturing consistency assay series that you spoke of, the potency assay matrix, VCN assay, and transduction assay. Your FDA meeting that's coming up, is that a CMC meeting or a clinical meeting? What specifically do you have CMC sign-off on, and what's left to sort out over the course of 2021? Thank you, Ritu. The meeting for which we've already submitted a briefing book is really focused on clarifying our registration pathway for accelerated approval for Fabry disease. Inclusive in that is a little bit of hypothesis clarification on the potency assay matrix, it's not the key point of that meeting. That's a registration protocol meeting where, as you know, we're proposing our three separate studies, our fully recruited Phase I, expanding Phase II to include females, and the confirmatory trial. On the CMC analytics side, this is such a critical issue, as I mentioned, it's really tripped up many. What we really like about our position right now is that we're entering year six as a company, we're entering year six of focusing on CMC analytics. Our characterization of our product, we think, is very robust and complete. All of the process changes that are material are behind us. We have FDA approval for pivoting to LV2 vector, for pivoting from a manual to a fully automated manufacturing system. As you're aware, even recently, others have been tripped up trying to move to the vector manufacturing of suspension culture. Right now, we are already approved for a 200-liter serum-free suspension bioreactor, and as I mentioned, delivering a really highly efficient 10 to the 9th vector titer. Those are the key things that we have in place now. As I mentioned, one of the benefits of how we built the company is these six sister indications can leverage the good work that's been done in Fabry. A lot of this innovation has been built over five years for Fabry, but it just fits like a glove. It just cascades through the portfolio. As I mentioned, great examples of that are the transduction assay, which historically in the field has taken weeks, now takes days, and one VCN approach that we just apply across all six lysosomal disorders. The potency assay matrix is also one of those things that, if you haven't sorted well ahead of BLA, has translated into delay. That's a key focus for us right now. Is it fair to say you'll have a consultative CMC meeting on the potency assay matrix sign-off before you start phase II expansion? I think it's fair to say that we expect to have it sorted well in advance of it being required for BLA submission. I think that it's hard for us to timeline FDA, but we know what we have to do. Our work is well advanced of what it needs to be to stay on schedule. This has been and will continue to be an ongoing dialogue with FDA, but we feel like we're in very good position for all things CMC analytics. Got it. One quick follow-up. Did your biopsy read in patient number four in Fabry include reading of podocytes? Were any of those captured, and what did you see there if you did? No. We didn't. Of course, we recognize that in academic circles and in the Fabry field, there certainly is interest to look at podocytes. Because we view this as a registration trial, we focused on FDA-recognized surrogate endpoints. Of course, the GB3 clearance and PTCs are absolutely that. With podocytes not currently being an endpoint that's recognized within the FDA Fabry guidelines and really not a validated way to measure it, we think that that day may one day come, but it's not here now for a registration caliber trial. We didn't look at it. Fair enough. Thanks for taking the questions. I'll hop back in the queue. Thanks, Ritu. Thank you. Our next question comes from Jim Birchenough with Wells Fargo. Your line is open. Yeah. Hi, guys. Let me add my congratulations on the great results. A few questions. I guess just first on the Bu90 conditioning regimen. Are you seeing interest from others in employing that regimen? Is there any way you could get more experience with the Bu90 conditioning regimen outside of your trials just to get a bit of a running start commercially? Thanks, Jim. I'll make a few points. A top KOL, Jaap Jan Boelens from MSK, really did this seminal work and publication which highlighted this Bu90 Goldilocks dose. He looked at over 400 non-oncology patients receiving multiple exposures of busulfan to really identify this sweet spot of Bu90. That's published, that's out there, and other companies are now targeting Bu90. That's step one. The challenge is not targeting Bu90. The challenge is hitting Bu90 as the optimal exposure. The reason for that is the tremendous inter- and intra-patient variability, meaning if you dose 10 patients, you're going to get 10 different outcomes. The innovation at AVRO, and this is really the focus of Bu90-TCI, Target Concentration Intervention, is to make sure that we hit Bu90 every time. We accomplish that by multiple blood draws over four days and titrating the dose carefully to hit an area under the curve. Even that, I think, is known in the field, but the challenge is how to do it. The innovation at AVRO is pioneering with a company called Saladax to develop and make available an automated immunoassay kit that can be just placed in any hospital in the world. It's a cheap, effective, fast kit. We've elected to make that open source. To your point, we would love the community to adopt it. I can tell you that beyond gene therapy, the transplant community are raving about it. They're lobbying to get it as early as possible because this same challenge applies to bone marrow transplant in general, not just to gene therapy. It is open source, and we're happy that others will have the opportunity to use it. Then maybe just a follow-up, Geoff, just in terms of the cystinosis program, do you have a sense of what the regulatory endpoint would most likely be? Then both for Fabry and cystinosis, and I guess it applies to the rest of the programs, the duration of follow-up that you expect to be required. I think we all have in our head two years with bluebird bio's sickle cell program. What do you think the length of follow-up will be required? Do you have any sense of what the cystinosis primary endpoint might be? Yeah, I think we're blessed with cystinosis that we do not have to rely on biomarkers, that there are multiple relevant functional measures that also show effect in the short term. That's, of course, the key learning from the first patient in the phase I/phase II. Our overall strategy was we wanted to learn, we wanted to dose a few patients, two, three, four patients in the phase I/phase II, learn from that, and then have that guide our registration strategy. Where we are now is that we believe, and the key opinion leaders that we shared the data with concur, that there appear to be multiple renal functions and corneal crystal scores as clinically meaningful measures. Of course, we're continuing to learn. We're still looking at patient two and three. In parallel, we're having a dialogue with our key opinion leaders to lock down these important measures. The goal is to translate this into regulatory interactions, meaning parallel scientific advice in 2021 to support the initiation of a pivotal trial in 2022. I'd say in early 2022. We're not being more specific than renal function and corneal crystal scores, until we just see a little bit more data from patient 2 and 3 and maybe 4. The work is happening now to finalize the protocol. Just on duration of follow-up, do you think you might need? Oh, excuse me. Sorry. Yeah. I think what we showed in patient 1 was a profound effect within months, and certainly a 12-month efficacy measure is what we would expect. We're not locking that in until we see data from a few more time points in patient 2 and patient 3, just to make sure that the effect that was so profound in the first patient is holding. Terrific. Thanks for taking the questions, Jeff. Thanks, Jim. Thank you. Our next question comes from David Lebowitz with Morgan Stanley. Your line is open. Thank you very much for taking my question. When you look towards the Fabry disease program that you have planned going forward, how should we look at it, I guess, from a timing standpoint? I guess, at what point should we see these trials getting off and underway? How long would you expect enrollment to take? Ultimately, when might we see data? We've taken the position that as soon as we reach agreement with FDA on our registration pathway, we'll give that level of granular guidance. Of course, the reason that we're a little bit hesitant right now is we don't want our guidance to bounce around. We know what we have proposed in our briefing book, we of course, require FDA to agree. We do see, hopefully, short-term clarity on the registration pathway with FDA, then in a staggered manner, we'll repeat the process with EMA. As soon as we get that clarity, we can really give much more specific last patient, last visit timelines and of course, timing to BLA. We're hesitant to do so now, just to speak more generally, our focus in 2020 has been to open sites around the world and to backlog patients. We got a little bit delayed due to COVID, and now we're in a very good advantageous position because we have the sites open and we have a backlog of patients, which now we can run through. We think we can execute the trials very efficiently, but just that last step of getting FDA clarity before we give more granular timelines. At this point, about what's the magnitude of patient backlog? We have a number of patients identified in the markets which we're already operating. We have open sites in Canada, Australia, and the U.S. We're currently opening sites in other geographies. As I mentioned, Brazil being one of them earlier. I, of course, was specific about 4 patients in Australia, coming from Brazil, that are being run through the trial right now. We haven't been more specific than that, other than to say that our challenge is not at all patient identification right now. I think we've made good use of 2020 as some of the sites got distracted from COVID, just to continue to identify patients. Now hopefully we can have a big bolus of dosing. I'd also highlight that towards the latter part of 2020, we were able to negotiate away the gating for the Fabry trial earlier than was initially anticipated from regulators. Now we are in a position of full competitive enrollment across all sites. Thank you for that. When you look forward to the other trials for cystinosis and Gaucher, what learnings, I guess, can you take from your experience with Fabry, I guess, to optimize the future clinical programs for these other two diseases so that you could potentially bring those to market even quicker? Well, what's beautiful about the six LSDs is they're almost like SKUs of one another. All of the infrastructure that we built for Fabry applies, meaning all of the Plato platform, of course, applies across the portfolio. Even our manufacturing sites, we are now manufacturing on three continents, four separate sites. Of course, we leverage that from day one. We're way ahead of the curve on manufacturing, but also just the understanding of everything from the duration and design of a preclinical tox study to the clinical regulatory requirements. In a large overlap, our key opinion leaders, meaning some of our key opinion leaders for Fabry are our Gaucher type 1 key opinion leaders. Right away, before you even start, you have the majority of the effort already complete. Diana did allude to this. The one thing that we want to guide for Gaucher type 1 is the same gating that applied in Fabry early in the trial does apply now. We do expect to treat a nice bolus of patients in 2021. The first half of the year will be measured as we work our way through that early gating. Thanks for taking my questions. Okay. Thank you. Our next question comes from David Nierengarten with Wedbush Securities. Your line is open. Hey, thanks for taking the question and congrats on the data. Most of it might have been answered, but on cystinosis program, are there additional steps or when can we look for you to essentially bring that under your umbrella as it's currently conducted now at UCSD? Do you plan to expand sites and such when that happens? Just are there any additional regulatory or other steps that you're working on right now or when can we expect that transfer over of the study into your corporate umbrella? Thanks. Yeah. Thanks, David. We weren't sure when we first partnered with Stephanie Cherqui at UCSD and the team, whether there would be benefit to transfer the phase I/phase II IND either early or mid-study. They're doing a really effective job running the trial. We're helping where we can. What we've really arrived at as a regulatory strategy is that our partners will continue to run this trial and complete this trial and hold the IND, and that we, in parallel, meaning now, are finalizing a protocol for the registration trial, and then we will seek regulatory interactions for that registration trial in 2021 that would position us to execute on that trial in 2022. There's no longer a requirement to transfer that IND to us. We collaborate with them. We'll be able to reference that data. I think, just to be clear, the phase I/phase II is leveraging a very solid vector, but not our LV2 vector, not automated manufacturing, but a pretty solid approach to be safe and conditioning. It's close, but not exactly our plato platform. In our registration trial, it will start from day one with all of our plato upgrades in place. Is there any anticipation, I assume not, of having to do a bridging study or one or two patients with your procedure before embarking on the phase III? I think what we've already shown with Fabry disease is where we were bridging from what we call an academic vector to our LV2 and from manual to fully automated mid-trial. The process was to meet with FDA to have a pre-IND meeting to reach agreement on in vitro comparability to produce that data in the same manufacturing setting, meet the same release criteria, and that was satisfactory for FDA and in fact, all of the other regulators around the world that we've sought approval from this process change. We do believe that there's a well-traveled path right now, and we would follow maybe to the previous question, that is a perfect example of one of the learnings that we've had from Fabry that we'll follow the exact regulatory path that has proven to be successful with Fabry disease. Got it. Thanks. Thank you. Our next question comes from Difei Yang with Mizuho. Your line is open. Hi, good morning, and thanks for taking my questions. Just a couple. With regards, a high-level question on Fabry disease as well as Gaucher disease, would you consider this as a threshold disease? Which meaning if we bring the enzyme level up to a certain level, then clinical outcome will be about the same, or do you think these diseases are really not a threshold, there's incentive to get to the normal range? Chris, why don't you take that one? Yeah. Difei, really nice question. Basically, yes, we see this as just needing a small amount of enzyme. As you know, enzymes are catalytic. We know from the community that something like 5%-10% enzyme activity restores normal function. Yes, we see it as a disease where we just have to produce a small amount of enzyme to get effectively a functional cure. Oh, thank you. Along those lines, on Gaucher disease specifically, when should we be expecting data on liver and spleen volume, or do you think that's a relevant measurement? Diana, do you want to take that? Sure. We know from ERT that the effects on splenomegaly and hepatomegaly, it could take two to four years. We are checking safety endpoints, your spleen and liver volume, DXA to look at bone mineral density, MRI measures of bone marrow burden. Quality of life, we have many functional outcomes. In this first patient that we presented, this patient does not have a spleen, but we are measuring the liver size. However, we would like to wait enough time to get meaningful data that could be interpreted before delivering that data. Thank you for taking my questions. Thank you. Thank you. As a reminder, if you'd like to ask a question, press star, then the 1 key on your touchtone telephone. Our next question comes from Mani Foroohar with SVB Leerink. Your line is open. Hey, good morning, everyone. This is Rick on the call for Mani. I'd also like to add my congrats here on the data updates. First, just looking at the guidance for the 30 patients dosed across all programs at the end of 2021. I was hoping for just a little more color here on which programs you expect to really see patient enrollment accelerate for this year based on where the sites are opening and which geographies the sites are in. Yeah, sure. Thanks, Rick. Just to level set, we usually don't give this level of guidance. The reason that we're being a little bit more prospectively granular is because the question is more pertinent in a COVID environment. As we said, top line, 30 patients cumulative across all trials. What we can say is that Fabry is undergoing a strong bolus of enrollment right now with enrollment consent screening, and we do expect quite a number to be dosed in the front end of the year, meaning Q1 and Q2. We're off to a great start with Fabry. Similarly with cystinosis, given the severity of the disease and the excitement in the community, this is, of course, a very well-organized, engaged community. Because of the excitement, there's a number of patients that are very interested in participating in the trial. Our partners at UCSD should have no problems completing the trial in 2021. It's a six-patient trial. We've dosed three patients to date, and we are guiding that that will be completed this year as we, in parallel, work on our registration trial. The only trial that we're saying is going to be a little bit slow in the first half of the year is Gaucher type 1 for reasons stated. A 2020 delay due to COVID got us off the blocks a little bit slower than some of the others. The gating that is just part of the protocol. In addition, what will begin to contribute to that number of 30 patients cumulative is that our second wave reaches the clinic this year as well, Gaucher type 3, Hunter, and Pompe. What we've guided is that we expect to be dosing in at least two of those three in 2021, in all likelihood in the second half of 2021. Got it. Thanks. One more question from me. In the phase I data you showed for the Fabry study, three out of the five patients were able to discontinue from ERT and remain stable. Could you remind us what the criteria were for allowing patients to discontinue from ERT, and if similar criteria are planned to be used in the ERT switch study going forward? Just to remind everybody, I know that you know this, Rick, but the initial trial was the first gene therapy study in the world for Fabry disease from our great partners up in Canada, Jeff Medin in the FACT trial. It was a phase I safety trial. It was silent on discontinuing ERT, meaning it was not part of the protocol. Only due to the very strong gene therapy results in the early patients prompted an amendment with Health Canada to be filed, giving them discretion if the patient was, quote-unquote, "controlled," and both patient and clinician determined that it was time to be discontinued. There were not specific quantitative criteria. It was really at their discretion to look holistically at the patient. In all likelihood, that will not be the approach in the confirmatory trial. We're not going to get into the methodology until we reach agreement with FDA on what that criteria will be. All right. Got it. Thanks for taking our questions. Thank you. Thank you. Our next question comes from Ritu Baral with Cowen. Your line is open. Hey, guys. Thanks for taking the follow-up. I just wanted to ask about the Fabry expansion to drive accelerated approval and some of the endpoints that you have listed on slide 29, I think, for the confirmatory. How much data do you think that you will need from cardiac and eGFR to drive accelerated approval, and will you be looking at GI symptomatology as well, given other companies that have spoken about the ability for that scale to drive approval? In your confirmatory trial, on the fourth bullet you've got, I think it's the fourth bullet, cognition scoring and CNS imaging. Can you elaborate a bit on that? Yeah, sure. Chris, do you want to take the question? Yeah, Ritu. The cognitive scoring and CNS imaging is critical part of Fabry disease. A large proportion of Fabry patients suffer from white matter lesions, which translate as loss of higher executive function. There's been publications over the last few years highlighting this, but none more so than the last couple of months than a paper from London, in fact, from University College London, which showed a very strong correlation between white matter lesions in the brain of Fabry patients and their loss of higher executive function. So we believe this is actually critical part of our study and really separates us out from ERT and AAVs because, as you know, we have the ability to impact on CNS as well as the body because of the microglial cells emanating from the transduced CD34 cells. What we're going to be doing going forward is basically doing an MRI imaging at baseline and then at follow-up, and at the same time, looking at their cognitive scores and other CNS measures as well as PNS measures to actually then correlate the two for our clinical trial. Ritu, for the front end of your question, we're not getting into the specifics of the cardiac measures until we reach agreement with FDA and other regulators. We can say that we don't think we're proposing anything controversial or maybe to say it more clearly, anything that is not already well-referenced in the Fabry guidelines as per FDA. The question about GI, we agree, we don't view this as a primary measure, but as a secondary measure, we are including a patient-reported outcome scale looking at GI specifically. Got it. A quick follow-up on one of your second-gen programs. Your Hunter program, how should we be thinking about clinical data once you start dosing patients? Like, what are the biomarkers of note, what are the clinical endpoints of note, and what follow-up is meaningful for that disease? Chris, do you want to take that? Yeah, Ritu. Hunter is a good one. The basic study we would do, the primary efficacy endpoint would really look at the actual cognitive measures again. These patients basically deteriorate very rapidly. The ones we would look at would have CNS impact, and they'd be aged something like three months to 24 months. We would look at things like cognitive change. We'd use things like established scores like the Bayley Scale and the Kaufman Assessment Battery. We can also look at, obviously, change in baseline on the things like the actual amount of enzyme activity they produce. We would look at adaptive behavior measures, things like Vineland. We really feel that we've got a really rich set of cognitive factors we can actually look at for these Hunter patients. We should bear in mind that the team we're working with at Manchester are extremely experienced in this area of assessing young children, both doing the gene therapy as well as cognitive assessment on these children. We feel very confident in this program. For the Bayley and Vineland, at what time point would that be sort of a meaningful measure of stability given the decline in these patients and the variability of those scales? Yeah. That's a good question. They do decline very rapidly, as you know. At this moment in time, we're still finalizing the actual process. Typically you would look at 12, 24, 36 months. Got it. Great. Thanks for taking the follow-up. Thanks, Ritu. Thank you. That's all the questions we have for today. I would like to thank everybody for their participation, and the call is now concluded. You may now disconnect.