Thank you. Good afternoon, everyone. My name is Gena Wang. I'm SMID-Cap Biotech Analyst. It is my great pleasure to introduce our next presenting company, AVROBIO. With us today, we have Geoff MacKay, President and CEO. Thank you, Gena. My name is Geoff MacKay, and I'll sum up my company, AVROBIO. Before I begin, of course, we'll be making forward-looking statements which are based on current expectations and beliefs, so I point you to our SEC filings. The goal of AVROBIO is to free patients from a lifetime of disease, and for us, that means a one-time single infusion of gene therapy targeting multiple serious genetic monogenic diseases. Our goal is to develop global therapies. Some real top-line points before I jump into the data is that our particular brand of gene therapy is hematopoietic stem cells that are gene-augmented to deliver supraphysiological levels of protein, and in our case, enzyme. That we're targeting indications where we're first in class, first type of gene therapy into the clinic in multiple indications. The main focus are lysosomal storage disorders, where we can demonstrate that really what is required is a 24/7 infusion of enzyme to modify disease, and that these diseases are well understood, well studied, clear biology. They have high unmet need, and the common thread is that in each of them, you need a head-to-toe delivery of an active protein. Our engine that powers our gene therapies is a lentiviral gene therapy platform that we call Plato that has been optimized, and I'll get into some of those optimizations, to be stage appropriate and as we advance into phase III, to be phase III-ready. Here is the pipeline. A few points is that it really is congruent in that in each case, these are lysosomal disorders. They tend to be on the large side of the lysosomal disorders, and many of them you would know from today's standard of care, enzyme replacement therapy from companies like the old Genzyme and Shire. We're in the clinic now with cystinosis, and I'll share some data on cystinosis. I don't have time to get into the Gaucher data, but we have generated Gaucher data, and we look forward probably in Q2 or no later than this summer, to give a comprehensive update on our overall Gaucher disease clinical program. Hunter disease is poised to enter the clinic, and we hope to dose first patient either Q4 or no later than Q1 of next year. Pompe also will navigate all of the CTA IND regulatory steps in order to initiate a trial next year. Now, we've, I would say, selected our indications very carefully to not only address indications with high unmet need, but with commercial attractiveness. A few things just to call out is that, one, today's standard of care, even today in 2022, generates $3.5 billion of revenue in these four indications. Importantly, they cost the healthcare system a fortune. The average annual cost in these indications of today's standard of care is anywhere from $300,000-$400,000 to $700,000-$800,000. The pink column represents what the five-year direct cost offsets are in each of these diseases. Of course, we look at five-year cost offset because in a single infusion gene therapy, groups like ICER and NICE and multiple healthcare technology agencies around the world have that as a starting point. What are the direct short-term, meaning five-year cost offsets? Over and above that, can you demonstrate clinical benefit? We believe that we've identified indications where if we're successful developing a safe, effective therapy, we think we would be very much entitled to command a premium price with a pretty obvious health economic saving potential. Just to give you a little bit of quick rationale as to why we think gene therapy makes sense in lysosomal disorders. Of course, the pioneering work over the last two decades of enzyme replacement therapy demonstrated pretty unequivocally that delivering an enzyme in these diseases does some good. Of course, the challenge is the pharmacokinetics of enzyme replacement therapy. In blue, you see each of these little spikes denotes a patient visiting a hospital, getting a one to two to three-hour infusion every two weeks forever for life. Yet, if you test the patient's blood 12 hours after one of those infusions, the enzyme's gone. Of course, the reason ERT works at all is because a small amount does get taken up intracellularly. The vision of gene therapy is what if you could deliver that 24/7 expression of enzyme head to toe, including into what we call the hard-to-reach compartments, notably the brain. We hope we would not only untether patients from ERT, stop those biweekly infusions, but hopefully do a better job at halting disease progression rather than just slowing it down, which is what today's standard of care accomplishes. Now, this is that engine that I referenced, Plato. One thing that we focus very heavily on since the day we founded the company is how do you take manual Petri dish academic science and turn it into a medicine? In hematopoietic stem cell gene therapy, really, we believe that the focus is automation, to really invest early and heavily in all things CMC analytics. At each step, we've tried to optimize to not only provide as safe a product as possible, but also to improve convenience at the clinic, have global reach, and importantly, drive down costs. Now to jump into one of our two lead programs, cystinosis, of all of the lysosomal disorders that we focus on, it may be one of the least known or understood. There's about 2,000 patients. It really is a devastating disease. These patients tend to make it into their thirties, so a pretty significantly shortened lifespan. Along the way, they suffer from just multiple manifestations of very aggressive disease progression. For example, 90% of them will have a kidney transplant into their teens. They have severe visual impairment. That's why this youngster is wearing those dark glasses, photophobia. They typically aren't even able to leave the house without dark glasses. Some of them say they can't check their phone in the middle of the night because of the light sensitivity, CNS manifestation, endocrine manifestation. Very, very serious. Today's standard of care is a drug called cysteamine, 30 pills a day, an hour, and eye drops every two hours of cysteamine. Just to give you a flavor of the challenges, patient 1 in our study was vomiting 13 times a day on today's standard of care, and then zero times in the first three months following gene therapy, unrelated to the gene therapy just by getting off the cysteamine pills. We do think that there certainly is a high unmet need and a opportunity to do better for these patients. Vector copy number is just one of the many things that we measure. It's sort of a surrogate for engraftment. Have these CD34 hematopoietic stem cells engrafted? Are they there? Are they present? Are they doing their job? What you really want to see is a plateau. The y-axis is a lot not that meaningful as long as you're seeing a plateau. The reason I say that is even a vector copy number of 0.1 translates into 5% or 10% of all nucleated cells having one to two copies of the transgene. In an adult, that's about 3 billion leukocytes manufacturing and distributing protein head to toe. You can see the levels are higher than that, but really what's important is that they reach a plateau. Now just some of the things that we've tried to measure in this first-in-human phase I/II investigator-sponsored trial is not only is the gene therapy present as measured by vector copy number, but is it distributed? We looked at skin via a skin biopsy. In the first three reported patients, what you see is a significant reduction in the crystals that form as a result of this disease. I should highlight, just to remind you that the blue, the baseline, is that 30 pills of cysteamine a day, and then they stopped completely upon receiving gene therapy. Not only are we able to control in a level comparable to the baseline cysteamine, but certainly as measured in the skin and improved a pretty dramatic further reduction of crystals. Similar data in the rectal biopsy, again in patients one, two, three, what you're seeing is versus the 30 pills of cysteamine, the single infusion of gene therapy after a year, 18 months in the case of patient number one, a significant reduction versus baseline standard of care. Now, the skin and rectal biopsies are important because what we really wanna ask ourselves and answer is the gene therapy not only present but distributed? More important to the patient are measures such as the eye. Of course, you can even see crystals form in person. You know, this is in fact patient number one. What you see on the top row is the baseline of this patient's cornea, different images of the cornea, and in white are the crystals that form, and they're so prevalent that they overlap. It's like looking up at a cloudy sky where all you see are the clouds overlapping one another. After a year without. Excuse me, 18 months without a single eye drop, you're seeing not a complete resolution, but certainly a material reduction of the crystals that did form. This patient, as an example, is now able to leave the house absent sunglasses, can check his phone at night without the pain that he did initially report prior to gene therapy. Where are we in these first three patients? You can see a pretty significant amount of months have accumulated where what we're able to show is control of disease absent the standard of care, absent cysteamine, where all three patients remain off cysteamine pills. Two of the three have not had a single eye drop. One of the patients preferred to go back on both eye drops and gene therapy. What we see is a pretty satisfactory outcome so far in this first-in-human, and really the only gene therapy clinical program in the field of cystinosis. Now, of course, everything is risk-benefit, just talk about the safety profile for a little bit. This is true across every patient that we've treated in our four different clinical programs where we can say that we've had zero adverse events and zero serious adverse events related to the gene therapy. The conversation and our focus is related to the concomitant conditioning regime which precedes the infusion of gene therapy. Of course, what we want to do is to create space in the bone marrow and in fact the microglia compartment, but in the bone marrow to give a home for these gene-modified cells once they're infused to reside and to engraft. That requires this conditioning treatment where there are known side effects. What we see is listed on this slide. Typically, a week after the conditioning, the patients continue to feel fine, but by week 2, predictably, as the platelets and neutrophils drop to a low nadir, there's a week of discomfort, flu-like symptoms, nausea, vomiting, temporary hair loss. Then as the platelets and neutrophils rebound, by the end of that second week, the adverse events tend to resolve. Importantly, you know, really not wanting to minimize the effects, but what is noteworthy is that they're predictable, you know when they arrive and when they leave, and that allows a clinician to manage them a little more carefully through things like nausea medication, magic mouthwash for mucositis, and just keeping the patient hydrated. You know when they arrive, and also typically, you know when they resolve. There's that week of sensitivity, and that really just is part of the value proposition to provide that long-term engraftment that that is actually a requirement. It's an exciting year for us. Many of you may know that we reset our priorities in January. We moved away from our Fabry program. On the slide here is what we are focused on this year, and we have a number of accretive events coming up. We released at WORLD a few weeks ago an update on cystinosis. Beyond that, we had a Type C FDA meeting in December, and we have two Type C FDA meetings pending in 2022 with FDA to be able to initiate our own AVRO-sponsored next stage of trial, our what we hope will be a phase II/III trial in 2023. Gaucher disease, we will complete enrollment of the GUARD1 phase I/II trial. It's an eight to 16 patient trial, and there's a lot of learnings. We do anticipate a pretty material Gaucher disease clinical update either in Q2 or Q3. We haven't locked in the date, but certainly around the corner. Importantly, we're very excited about Gaucher type 3. Because of the severity of the disease and because it springboards on the back of the Gaucher program, we believe that we can initiate a phase II/III trial. The CMC pre-clinical and safety data from Gaucher all can be leveraged to initiate an actual registration trial. As I mentioned, advancing what we call our second-wave assets, Hunter and Pompe. We just had one very positive clinical update. We're getting ready for our Gaucher clinical update and a number of regulatory milestones through the year. As we look towards 2023, what we hope and expect is that we'll be running multiple registration trials in multiple indications. Maybe just to close in terms of cash, we have cash into the first quarter of 2024. We have built our company in a way that we can get through these milestones in 2022 quite comfortably. Thank you. Thank you, Geoff. Maybe I will start with cystinosis, and it seems like very interesting and encouraging data. You mentioned that Type C meeting you will have with FDA in 2022. Can you narrow down a little bit more like timeline, at what point you think more likely we'll be meeting with the FDA? Then what will be leading to the pivotal Sure. Study initiation? Just to give a little bit of background, the phase I/II trial is an investigator-sponsored trial run not by AVROBIO, but by our collaborators at UCSD, Professor Stephanie Cherqui. We've had to take the IND over so that we could actually have direct dialogue with the FDA. We accomplished that last year in 2021. The first Type C meeting seems not to be such a big thing because it was focused on preclinical, but it actually was our first direct dialogue with the FDA. Although we had already treated patients in the IST, and they had already approved the preclinical from an academic perspective, it's a different question when industry is putting it forward. That was not exclusively focused on preclinical, but largely focused on preclinical. The next step is CMC readiness for phase III. We have a standalone meeting scheduled, you know, roughly, in Q2, Q3, but we haven't locked in a date with FDA. Then the final dialogue will be on the clinical protocol. If we can accomplish all of that in 2022, then we can start right on with our, you know, our ultimate trial in 2023. Is it fair to say like the CMC readiness, you know, the FDA meeting that will be Q2, Q3, then after that will be the clinical trial- Yeah. Okay. That's right. I would say that, you know, sometimes if you think of risk, we assign much less risk to our CMC encounters with FDA having already gone through them with our first indication. The reason that I say that is because that's really the power of plato, is that if you look across each of our diseases, it's the same cells, same vector. We just switch out a disease-specific transgene. The fact that we've already had dialogue with FDA on things like our vector copy number assay, our transduction assay, our large-scale bioreactors, our automated manufacturing, our potency assay approach means that. You know, you still have to go through those steps for the second, third and fourth indication, but at least it's largely de-risked. We understand FDA's position, and so we'd certainly hope and expect that we can meet that bar. On the clinical meeting with cystinosis, also, the first section of the trial will be in the pre-kidney transplant population for cystinosis. We also assign minimal risk on the endpoints because, you know, sometimes if you're coming in with a biomarker, you have to sell the agency on why it should be validated. That's not our situation here, as we agree with the endpoints that FDA has already put forward in the field of cystinosis. You know, the kidney measures, it will be more than eGFR, but of course eGFR will be a measure in the pre-transplant population. Multiple eye measures. The FDA has already approved drugs based on crystal reduction in the cornea, but we'll also look at photophobia. The third element is muscle weakness. You know, I think that we're not going in with a hard sell. We're going in and you know, proposing measures that they certainly know and are comfortable with. Okay. I have several questions here, maybe, starting with your CMC potency assay questions. You have quite a lot to learn from the Fabry program, right? Yeah. Here, now it's a new transgene, and potency assay and prediction is very different. Yeah. Like, what would be the most important steps that you need to for your CMC meeting with the FDA? What are the most important steps you need to pay attention to? Well, if we're speaking specifically of potency assay, I think that one of the things that we're very committed to is this concept of a potency assay matrix. What that means is that you measure as many things as you can think of measuring in early stage clinical development, because ultimately what you wanna do is to correlate it with eventual clinical efficacy. Having that matrix approach, you then have a collaborative discussion with FDA because you're sharing your data, and from there you agree on the potency assay. We've done that with previous programs, and that's the same approach that we're taking with cystinosis. Like in terms of a [measurement] cell line, would that be pretty consistent or would be different? We haven't disclosed all of them, so I have to be- Sure. A little bit careful, but some of them are unique to cystinosis. Okay. Yeah. Okay. For the clinical meeting, you mentioned like the renal, ocular, muscular, so I assume the primary endpoint would not be all three or maybe one or the other, like one or two that would be most important. What would be your proposal to the FDA that what could be the actual primary end-point? We are for the pre-transplant section, which is the first cohort. Mm-hmm. We are proposing multiple co-primary end-points. We don't have FDA alignment on that, but that. Mm-hmm. That is what we're proposing. Really it's in these diseases where there is some heterogeneity, we think that really does make sense, and it does make sense in many rare disease settings and certainly for cystinosis, that's what we're hopeful to get. A kidney measure, an eye measure, and a muscle weakness measure. When I say muscle weakness, something involuntary so that you know, because of course regulators prefer that, it's less subjective. Will you come up with some kind of a scoring system to? Yeah. Incorporate all three? Yeah, no, we haven't disclosed what our approach is, and we really don't want to until we align with FDA because of course. Mm. They may have other views, and so we don't want our guidance to bounce around. We will definitely be proposing something. We don't think that we're proposing anything that isn't already well-published and well understood in the cystinosis community, so we're hoping to gain agreement. You know, frankly, I think our goal is really just to align with the agency. Okay. If I kind of thinking out loud, I would assume with the only one primary endpoint incorporate all three, that will minimize the clinical risk. You have a three co-primary end-point, usually it's harder to hit all three. Is that the right way to think about it? Yeah. Well, I can't really answer without getting into the methodology, which we wanna, you know. There's all kinds of statistical approaches in rare disease, and we, you know, we don't wanna get into ours until we really understand that regulators on both sides of the Atlantic buy into our approach. Okay. That's fair. Yeah. Okay. We look forward to that. Yeah. Update. Oh, by the way, will you provide update, you know, after each meeting where you have with FDA? We will certainly provide an update after the clinical Type C meeting. We haven't decided whether we would on CMC. As I said, we don't assign a lot of risk to it, but I think the complexity of Type C meetings with FDA is what you're seeing CMC related is, you know, there's a series of questions with does the agency agree? There's always issues where you're trying to negotiate and really what you're trying to get to is a pragmatic solution. In our past we found it hard to synthesize that in a way that is easy to understand. We may hold until we've had both Type C meetings and then have a really in-depth, comprehensive update. Okay. Very helpful. We have one or two minutes left. Wanted to touch on Gaucher type 1. Mm-hmm. What are your initial thoughts on the path to registration? We expect to complete enrollment of the GUARD1 trial. Mm-hmm. In 2022. There'll still be some follow-up, but initially what we wanted to do is to really learn how the gene therapy is performing in order to design the ultimate registration trial. I can tell you that what has always been in our thoughts and what remains in our thoughts is should we design a registration trial that is first line across the board or target a recalcitrant subgroup of Gaucher disease type 1? We believe that all patients deserve a better solution. There's 14,000 Gaucher type 1 patients, but we do recognize that this is the lone indication that we target where there's a subset of patients where ERT does a fairly decent job. We would be perfectly satisfied if the eventual design targeted that subgroup of recalcitrant patients that have a less optimal outcome. Importantly, I think there's quite a lot of quantitative evidence, prospective registry data that highlights that recalcitrant population is anywhere from, you know, 30%-60% of patients, but at least 40% of patients, I would say. Even still, that represents a very sizable commercial opportunity. We wanna run our GUARD1 trial and then based on the results, design the trial, and have our regulatory encounters next year in order to initiate the registration trial. Importantly, while that's going on, as I mentioned, the other segment of Gaucher disease, Gaucher disease type 3, we hope to jump right to a phase II/III trial. We have multiple regulatory meetings in the books for this year in order to initiate that registration trial next year. Okay, very helpful. I know we're running out of time, I do want to quickly ask you about plato. Yeah. Can you remind us your current capacity of manufacturing and do you still see further improvements this year? Yeah. I think this is really a point of pride and focus on AVRO because we do believe that absent a lot of heavy lifting on CMC analytics early, you will not be able to get your cost structure under control, you will not be able to globalize, and you will not be able to scale. A few things have to be done early. One, your vector production has to be done in large bioreactors early. Each run right now is sufficient to treat 40 patients- 50 patients. To do the math that you ask, all it takes is three suites with one run a month to be able to get to enough vector to treat thousands of patients per year. One single run is enough to run an entire clinical development program. Of course, the vector is cryopreserved. What it really is now is a long lead time critical raw material, nothing more. It's been really taken off the critical path. The second half of manufacturing is the cell bioprocessing, and as I mentioned, to our knowledge, we're the only ones that are fully operational on multiple continents manufacturing in a closed automated system. The benefit that that accrues is, absent closed system automation, you can only produce enough drug product for one patient per clean room. With automation closed systems, you can have rows of them. Just to do simple math, if you have 10 of these automated pods in a clean room and you have three suites, you can certainly treat thousands of patients a year. All of what I've referenced is cleared through FDA right now in the clinic. That gets our cost of goods down to, I think, a pretty acceptable point. It's hard to understand what price is, but I think at any expected price, we would have a gross margin north of 90%. Then the work doesn't stop. You know, we can continue to ask ourselves, how do we continue to drive down costs, you know, in our field, which is analogous to CAR-T's. About 70% of the cost comes from labor. Automation certainly helps, but there's a lot of efficiencies that we can continue to incorporate to drive it further and further down. Well, thank you very much. We're running out of time, but this is very productive discussion. Thank you. Well, thank you, Gena. Thank you, everyone.