Good afternoon, everyone. My name is Gena Wang. I'm Senior Biotech Analyst at Barclays. Welcome to our fifth Gene Editing and Gene Therapy Summit. It is my great pleasure to introduce our next speaker, Geoff MacKay, Chief Executive Officer of AVROBIO. Jeff, I will hand over to you. Thank you very much, Gena. Just share my slides, be right with you. Okay, thank you. It's a real honor to get to present the deck, and I'll try to be concise to make sure that we have some time for questions. Before I begin, the presentation will contain forward-looking statements based on current expectations and beliefs, and I refer you to our SEC filings for further information. The purpose of AVROBIO is to free patients from a lifetime of genetic disease. I'll share with you today data across four trials, 19 patients, that suggests that the ongoing data generated to date at least is giving us confidence that we're on track to do just that. What that means in our diseases is to deliver ideally functional cures, but also to untether patients from today's standard of care, which tends to be weekly or bi-weekly infusions of enzyme. Here's how we're doing so far. On the left are three important brag points, and on the right are metrics. To begin with, everything we do applies ex vivo lentiviral gene therapy to lysosomal disorders. We are first in class in rolling out what really is a leading franchise. We can say that we're the first gene therapy in Fabry disease to reach the clinic, the first gene therapy in Gaucher disease to reach the clinic, the first gene therapy in cystinosis to reach the clinic. Our second wave of Hunter, Pompe and Gaucher type 3 should be in the clinic in 2022, just around the corner. You're likely very well aware of these diseases because these were the very diseases that resulted in the formation and growth and foundation of companies like Genzyme and Shire. These are the large rare diseases. Even today, the old Genzyme, Shire franchises now, of course, Sanofi Takeda, still generate roughly $5 billion of annual revenue. We at AVROBIO, since we formed the company in 2015, have been heavily focused on what we call Plato, which is our industrial approach to commercialization to manufacturing. That is our commercial stage platform, which I'll talk about very quickly at the end. Now where are we so far? As I mentioned, 19 patients, four studies in three indications, and we can say, so far so good. Every patient, every blood draw, every trial is showing the kind of efficacy and durability that we would expect with a lentiviral gene therapy, but certainly what we are seeing going as far out as 3.5 years. We're at an important pivot point in the company because we have multiple very material, very important regulatory meetings in our near future. Multiple registration caliber trials are anticipated to be initiated in 2022 and our entire second wave into the clinic. A lot of regulatory touch points in Q1, Q2. Here is the portfolio, and I won't go through all of them with the upcoming milestones, but I'll just make a few points about the franchise in general. As I mentioned, the leading lysosomal disorder franchise, but we also believe because we're seeing strong data in our early indications in wave one, we think that de-risks, at least to some extent, increases the probability of success across the platform because it is one technology approach, same cells, same vector. We simply switch out a disease-specific transgene. We have multiple regulatory updates in Q1, Q2, but also multiple clinical updates, with the most important event of the year always for us is the WORLD Symposium in early February. You can anticipate a lot of new data coming. I would say that for the first time, we've waited an entire year prior to an efficacy update. The WORLD Symposium is quite important, quite meaningful to us. Now, not only are these large indications from a revenue perspective, but they also cost the healthcare system a fortune. I call your attention to the column in pink or magenta. What this is the five-year direct cost, meaning not indirect, not time away from work and so forth, but the direct cost offset of what today's standard of care costs over a five-year period. The reason we look at a five-year period is because many market access groups like ICER and NICE begin with what is the five-year cost offset. Then if you can demonstrate any incremental benefit, you may be able to argue from that point. We do think that if we hit our target product profile of a safe, effective one and done therapy, we have the potential to not only improve upon patient outcomes, but also save the healthcare system $ many millions for each and every patient dose. The premise is simple. Today's standard of care, which tends to be ERT, really is the right enzyme, but bad pharmacokinetics. On the left in blue, you see each of those spikes symbolizes a patient getting a 1- to 2-hour infusion at a hospital every two weeks. The major challenge is if you test the patient's blood 12 hours post-infusion, the enzyme's gone. The hypothesis around gene therapy and around AVROBIO specifically is what if you could deliver 24/7 expression of protein to bathe cells, tissues, organs and enzyme? Ideally, you would, as mentioned, untether patients from this onerous set of lifelong procedures, but also halt as opposed to slowing down disease progression. That is what we've set out to do across the franchise. As mentioned, so far so good in terms of durability, and of course, the whole rationale around an integrating vector is lifelong durability. That's what the field has seen in a dozen indications going out 10-plus years. Now importantly, that's what we're seeing in our own data set going out 3.5 years, where every patient to date is showing the kind of durability that we would hope to see. Now, efficacy and durability is important, but it is only half the story. The other half is safety. I can say that across our portfolio, we have not seen any AEs or SAEs related to the gene therapy. Our attention is focused on how do we continue to improve the patient experience related not to the gene therapy, but to the concomitant conditioning regimen. An important step in that direction is our improvement and pivot towards what we call Bu90 target concentration intervention. Step one in that journey is to identify what is the right exposure. What you see on the screen here is a seminal paper from Jaap Jan Boelens from MSK, which elucidated this mid-range, what we call our Goldilocks dose, where if you hit this Bu90 target every time, you can eliminate out of range toxicity. Step one is identifying the target, but of course step two is hitting the target because, as many of you would know, an alkylating agent has tremendous variability, inter- and intra-patient variability. AVROBIO has implemented very meticulous AUC monitoring over four days to make sure that we not only target Bu90, but we hit Bu90. What that has translated to is a set of what we would call predictable and transient conditioning-related adverse events that, in general, or typically, arrive at the beginning of week two following conditioning and depart at the end of week two following conditioning. I would never trivialize an adverse event, but we do believe that if we can continue to demonstrate the overall value proposition of a single infusion of gene therapy providing long-term benefit with a set of predictable and transient adverse events such that you see on this screen, we think that we do have the potential to redefine medicine. To jump into Fabry disease, of course, many are very familiar. It tends to be thought of as a kidney cardiac disease, but these patients manifest serious symptoms in the brain, central nervous system, GI, peripheral pain. It is a head to toe disease, and even on ERT, life is cut short several decades, meaning it's a serious disease with a high unmet need. Probably the most striking data that AVROBIO has generated to date are the first two evaluable patients in the global phase II trial. Here we're looking at classic male Fabry patients, naive to ERT. They've never received ERT or chaperone therapy. A kidney biopsy is done at baseline and then again at 1 year, where what you're looking at is the average number of GL-3 inclusions per peritubular capillary. You may recall the Bliss methodology used by the Amicus company. We followed that Bliss methodology with two improvements, electron microscopy, and we've extended the follow-up from 6 months to 12 months because we think that's more rigorous. Of course, what we're looking at are dramatic results, a 93% reduction from baseline in the substrate in the kidney to what a nephrologist would equate to full effective clearance. Very pleased with what is the primary endpoint of the phase II and also what we believe will be the primary endpoint in the global phase III. Now behind this, we've looked at all of the biomarkers that you would expect in a monogenic disease, which is an enzyme deficiency. First of all, enzyme, plasma alpha-galactosidase A, leukocyte alpha-galactosidase A. What you see after that single infusion is a stable plateauing of enzyme over time. Then below, vector copy number, also stable and plateauing. Of course, enzyme up is only half the story. The second half of the story is substrate down. Here we're looking at the toxic metabolite in the naive population, and we see a 70% reduction of plasma lyso-Gb1, which of course, compares favorably and is exactly what we would hope to see. You'll also note no waning of effect over time. These are in the ERT naive population, but of course, we've also studied ERT stable patients. This is from our Fabry phase I trial conducted by the FACTs team in Canada. Three sites across Canada, really pioneering work from our FACT colleagues. The beauty of this trial is you get to see a within patient control. How well was ERT controlling the patient? Then how good a job is gene therapy doing? We can make a few points. First of all, not only is gene therapy able to control the toxic metabolite, but it's actually able to control it 25% better, deeper, further reductions than baseline ERT. All patients who had discontinued ERT remain off ERT. As you can see clearly from the lines, no waning of effect over time going out three and a half years. We're very pleased of the data generated in the ERT naive population and very pleased with the data generated in the ERT switch population. As mentioned in the opening, the side effect profile is excellent related to the gene therapy and consistent, predictable, transient related to the concomitant conditioning regimen. Now, if I jump to cystinosis, our second lysosomal disorder, it tends to be a little bit less well known. There are 2,000 patients as opposed to 10 or 15 thousand in some of our larger indications, but a very debilitating, devastating disease. The standard of care is cysteamine pills, 30 pills a day with all of the challenges associated with that, and bi-hourly eye drops of cysteamine. Even with today's standard of care, 90% of these kids will end up having a kidney transplant, severe visual impairment, CNS complications. Certainly, the unmet need is very profound. I don't have time to share all of our data, but I would like to share some of it. What we see is in patient number one, what we have done is a skin biopsy and a rectal biopsy, really to demonstrate that the gene therapy is not only present but well-distributed. Here you see via the biopsy, a significant reduction in the crystals per cell and the volume of crystals per cell in the rectal biopsy and the skin biopsy. I should remind you that these patients had stopped all cysteamine from day 1 of the gene therapy, and here we're looking 12 months out. Not only is it looking like we can control crystal formation volume on par with baseline cysteamine, but in these two biopsies, further reductions. More striking, however, is the eye. Again, looking at the same crystal formation, this time in the cornea in blue on top is the baseline. Without a single cysteamine eye drop all year, 12 months later, what you see is not complete eradication, elimination of the crystals, but a very, very significant reduction such that the patient can now leave the house without the dark glasses, can check his phone at night without the pain of light sensitivity related to photophobia. A very important observation and something that translates into what eventually will be a primary endpoint in an eventual study. Before we leave cystinosis, I wanted to show one pretty striking result that illustrates not just the power of gene therapy in cystinosis, but invites us to think about trial design in gene therapy in general. On the left is how a typical cystinosis patient presents, drawn out, void of pigment, a little bit washed out. After a single infusion, you can see his entire appearance changes. This is because proteins moonlight. Proteins are multifunctional, and it turns out that the cystinosin protein not only addresses the crystals, but also is involved in the regulation of melanin. This young individual said for the first time in his life, he looks like his brother because he comes from a pigmented family. The reason I say this is it just so happens that melanin is a cutaneous marker that we can see, but it invites us to think differently about all of our diseases. For example, should we be narrowly measuring enzyme up, substrate down in Fabry, or thinking of the more holistic multifunctional benefits of gene augmentation? The adverse event profile, again, consistent. No AEs related to the gene therapy, predictable transient AEs related to the concomitant busulfan conditioning regimen. Jumping to the third indication, Gaucher type 1, I'd like to share data from the first patient, but of course, you're probably well aware of Gaucher, very much analogous to Fabry. Rather than kidney, cardiac, it tends to be liver, spleen, bone. But again, head-to-toe manifestations really impacting quality of life of these patients. This first patient received the gene therapy at the age of 32, but was on VPRIV, the Shire Takeda ERT since the age of 3. So biweekly infusions of enzyme for almost 30 years. What you're seeing on this chart is many years before gene therapy, she went through a period of non-compliance of her ERT. What you see is one of the known biomarkers, chitotriosidase, which is a marker of activated macrophage, jumped up from 150 to 3,000 when she became non-compliant on ERT. Let's look at that same patient again, stopping VPRIV, stopping ERT altogether at the beginning of the trial, but this time having a single infusion of gene therapy. On the left, what you see is not only did the chitotriosidase measure not jump from 150 to 3,000, it was actually cut in half by six months. Of course, the other known biomarker, lyso-Gb3, was also very significantly reduced. We're seeing a consistent picture with Fabry. Not only is the single infusion of gene therapy able to control these biomarkers, but so far control them at a level superior to baseline ERT. Both ERT and the gene therapy did a good job of keeping platelets and hemoglobin within the normal range. After stopping ERT, what we're seeing out six months is both of these important measures remain absolutely normal. The adverse event profile within expectation, no AEs related to gene therapy, predictable transient AEs related to the concomitant conditioning regimen. I'd like to finish with what is a very important aspect of AVROBIO, and that's our plato platform. plato is designed to be our commercial stage platform. What you see on the photo here is a picture of our fully closed, automated manufacturing. We do manufacture on three continents today, four different CMOs. Importantly, the definition of plato is that we've tried to optimize or implement best practice in every relevant manner. We've optimized our vector, we've optimized our conditioning, we've pivoted to serum-free suspension large-scale bioreactors, and with the optimized vector, a 10^9 titer. We've solved scale, we've solved manufacturing, globalization, and importantly, we have had a type C meeting recently with the FDA. I think we've clarified the path of where we are today to not only initiate phase III, but the path to BLA submission on the CMC assay side of the ledger for Fabry disease, but as a result for the entire platform. With that, I'll hand it back to you, Gena, if we wanted to have time for questions. Okay. Can you hear me? Yep. Loud and clear. Good. Okay, good. Chris, also nice to see you. Maybe I will start with Fabry disease. You know, we will see some update early next year, so important as FDA regulatory feedback. You did meet with the FDA regarding the CMC part. You know, any additional data you need to collect for the CMC package based on the FDA feedback? Yeah. I can certainly give you some color. We've elected not to go into the specifics until we close the loop with FDA, but also there's some competitive data that we'd elect not to share. What we can say is that we feel it's a very positive outcome and a very clarifying outcome, and that there was no what we internally call show stoppers that result in a change to our timelines to initiate our phase III. The way these meetings are structured is we say, you know, does the agency agree on A, B, C, D? Our view is either we align with the agency or what the agency requires is something that we have prepared, in contingency, and can pivot to an easy acquiescence to what the agency is looking for. We felt that the outlying issues were manageable and minor enough that rather than have another meeting with FDA, we're just gonna tack on to our clinical Type C meeting that we're now planning in Q1 of 2022 to close the loop. We don't think that anything that came out of the CMC meeting is material enough to dislodge our timelines. Importantly, and really on the positive side of the ledger, that this was a Fabry-specific meeting, but it's a clarifying event for AVROBIO across the board because of course, you know, as I mentioned, the automation applies across the board, the vector applies across the board, the VCN assay, the transduction assay, the large-scale bioreactors. I think that we have clarity on phase III readiness for Fabry, but as by definition, we now have clarity even for the programs that, you know, were it not for this platform approach would be in much earlier stage development. Okay. Thank you. Also we've seen quite a few data, the new data point on Fabry disease. Any thoughts, you know, based on those data sets, how you can maintain your leading position and differentiate your product from others? That includes maybe thoughts into the phase III trial design. Yeah, sure. To your point, 4D, Sangamo, and Freeline have issued early, you know, first-in-human clinical data. Some of it, you know, on the AAV side of the ledger, some of it's dose finding and stuff, so it's not. You know, I think it's premature to really make a conclusion with any confidence. But certainly there's interesting data. I think that the long-term durability of an AAV and non-integrating vectors is one of the important questions. Really what this early data has only shown is plasma enzyme levels that are quite high, in some cases, in sharp decline. The TBD is where will they level off. Interestingly, I think, still too early to draw conclusions, but what is beginning to emerge as a pattern is that high levels of AGA generated from a liver-directed AAV haven't translated into better plasma lyso-Gb3 reductions to date. You know? Why that is is unclear, but I think beyond that, there's not much that we can say. Now to your point about differentiation, I think that we do believe that there are very substantial potential differentiators with the lentiviral gene therapy approach. An integrating vector, of course, doesn't have to worry about washout, so just durability in general, but durability in adolescence is a particular advantage. We don't have the challenge of neutralizing antibodies excluding a quarter or half of the patient population, which is of course an advantage. Perhaps the most significant, which we have yet to demonstrate but aspire to demonstrate, is an impact on the central nervous system. As you're well aware, lentiviral gene therapy has really shined in the ability to impact CNS in diseases like MLD and ALD and even in transplant in 500 Hurler's patients. We hope that we will be able to demonstrate effect on the CNS. The reason that's so important is that just like ERT doesn't cross the blood-brain barrier, we don't have confidence that a liver-directed AAV would have a very different effect. If in fact we are successful in differentiating based on CNS, we think that that's very important. Now, 50% of Fabry patients have tremendous white matter lesions that lead to executive function deficit, so it is one of the primary concerns of the patient population. Great. Thank you very much. I think we are running out of time. Thank you for sharing all the highlights. Thank you. Thank you. Thank you, Gena. Take care. Thanks, Gena. Thank you. Okay. Bye-bye. Bye-bye.