Good afternoon, and welcome once again to the 19th Annual Morgan Stanley Healthcare Conference. I'm one of the biotechnology analysts here. My name is David Lebowitz. Before we jump in, let me go through the requisite disclosures. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, I'm happy to have here for the next session, from AVROBIO, the management team. If you could give us quick introductions on yourselves and really give us a top-level introduction on AVROBIO itself, what the company does and what its overall mission is. Sure. Thank you, David. My name is Geoff MacKay, President, CEO. Joining me on the fireside chat is Chris Mason, our Chief Science Officer, and Erik Ostrowski, our Chief Financial Officer. To sum up AVROBIO just quickly and efficiently, we are an ex vivo lentiviral gene therapy company that applies this gene therapy approach to rare disease and specifically to lysosomal storage disorders. We founded ourselves in 2015, so we're entering our sixth year. I think a few points of distinction is that we do have the leading portfolio of lysosomal disorders for gene therapy and first in class across the board. First in class, first in the clinic for Fabry disease, first in the clinic for Gaucher, first in the clinic for cystinosis. By this time next year, we expect to be the first lentiviral approach in the clinic for Pompe disease and Hunter syndrome. We've targeted the big rare diseases. We've estimated that collectively, they comprise about 50,000 patients and the old Shire and Genzyme ERT franchises, even today, sell roughly about $5 billion of revenue annually. Perhaps our biggest brag point is our engine. We've invested five or six years in trying to really optimize, develop a state-of-the-art pharmaceutical-grade platform that we call plato. We're happy to go into more detail about that. We really think that we've optimized this lentiviral approach to maximize safety, manufacturability, potency. Where we are in this journey is we've dosed 18 or 19 patients across four trials. We can say so far that across every patient, every trial, we're seeing an effect of gene therapy. In fact, we're seeing no waning of effect in any patient. So far so good in terms of efficacy, durability, and safety. The key point that we're at right now is pivoting from getting into the clinic early-stage company to, with either Q4 or Q1 of next year, submitting multiple registration files to FDA and other regulators with the goal of initiating three registration caliber trials next year. Thank you for that nice introduction. Now, you work in lentiviruses with your gene therapy, and the diseases you are pursuing predominantly are lysosomal storage disorders. I guess, could you run us through the strategy for it? Certainly, some people think that lysosomal storage disorders, a lot of them are addressed somewhat by medicines that are already out there, including the ERTs. What you think of these respective medicines in the various markets and why lentivirus might lend itself to targeting these diseases as opposed to AAV. Yeah, sure. Happy to. First of all, the question about what remaining unmet need exists in these lysosomal disorders, for the last two decades, enzyme replacement therapy has been the standard of care. I'll make a few general points, and then I'll talk about some specific indications. First of all, enzyme replacement therapy, the simple way to describe it is, it's the right enzyme, bad pharmacokinetics. The proof source of that is these patients are required to go to a hospital every two weeks for half a day, several hours, and to have an infusion of enzyme, which in itself is, of course, onerous. There's compliance issues. The real issue is that if you test the patient's blood 12 hours post-infusion, post-hospital visit, the enzyme's gone from the blood. The reason ERT works at all is because a small amount does get taken up intracellularly during that narrow window of time. The whole premise of gene therapy and the raison d'être of AVROBIO is what if you could deliver 24/7 expression activity of enzyme to bathe cells, tissues, organs in enzyme. The goal would be not only to untether them from ERT, but ideally to halt disease progression instead of just slowing it down. That applies across the platform. When you look at each indication and ask, how well does ERT do? What we can say is, I've never met a classic male Fabry patient on ERT that's not in decline on kidney measures, eGFR, cardiac measures, peripheral pain. ERT has done a good job changing the slope of decline. It slows down disease progression. It doesn't halt it. On ERT, life is cut short two decades, but a Fabry patient wouldn't even really be raising that as the primary concern. The primary concern is how do I get through today and how do I get through every day. GI issues, peripheral pain, their fingers feel like they're on fire, cognitive dysfunction, what they call the Fabry fog, because of course, ERT doesn't cross the blood-brain barrier, so it doesn't address any of the CNS manifestations. I think that ERT was a godsend 20 years ago. There was nothing, and now these patients have a solution that helps but doesn't solve the problem. That's where we hope gene therapy could be the next major step forward for these patients. Now, beyond the Fabrys and Gauchers, we can get to diseases like cystinosis, Hunter, infantile Pompe, Gaucher disease type 3, where ERT is just wholly inadequate. For those patients, their lives are devastated, and I would say that although, for example, a Gaucher type 3 patient who has a primary manifestation in the brain receives ERT, the fact that it doesn't cross the blood-brain barrier just highlights what a significant unmet need they remain. For anybody that's seen the impact of infantile Pompe disease or Hunter syndrome, I think would certainly not argue in favor of today's options. What about lenti versus AAV? Do you think lenti is better suited for it? Yeah. Well, certainly that's our strong bias. Of course, when we founded the company, the very first thing that we had to answer was which vector approach would we opt for. Of course, we have all the respect in the world for these different approaches. The finesse is matching them to the right disease. It's our understanding and our view that where AAV has shined is in targeted disease, ophthalmology of course, local CNS, liver-targeted disease. The sweet spot for lentiviral gene therapy is when what you need is lifelong delivery of an active protein head to toe. In other words, including into hard-to-reach compartments like the muscle, like the brain. Of course, a liver-directed AAV gene therapy would suffer from the same limitations as ERT in terms of crossing the blood-brain barrier. When we've looked at these lysosomal disorders, the common denominator across all of them is what you need is that lifelong delivery of an active protein, both below the neck and above the neck, and that is something that we think lentiviral gene therapy is uniquely suited to be able to deliver, number one. Number two, we want to treat all patients. Currently, at least in AAV 1.0, today's versions of AAV, there are very significant patient segments where it has limitations. Just to name three quickly, one, X% of patients have preexisting neutralizing antibodies to AAV itself. Some companies suggest it's 20%, some 50%, but it's a sizable chunk of patients where either they're excluded or at least it's a substantial limitation. The second segment are young people, pediatrics, adolescents, because of course, a non-integrating vector suffers from washout as the liver grows. Lenti doesn't have that limitation. In fact, it really shines in the young population. Why that's so important is because the whole premise of gene therapy is to get ahead of disease progression. There's not a lot of optimism that we're going to be able to reverse fibrosis in a damaged kidney, so there's a lot of motivation to treat young, and that's an area where lenti has a differential advantage. The third big chunk we've already talked about, which is the CNS. Just for perspective, if 50% of Fabry disease patients, just as one indication, have tremendous white matter lesions, what leads to executive function deficit, and again, a liver-directed gene therapy just will have substantial limitations reaching that. Matching the right vector to the disease is the name of the game, and we think for these, for the lysosomal disorders, lenti is really the optimal approach. Let's look through what news has happened in the lenti space over the last year. There have been some challenges with one of your competitors, not a direct competitor, but a player in the lenti space that has had some tolerability issues pop up, and with one of their vectors. Investors naturally becoming concerned have become concerned with all lenti programs. Can you address what occurred and why you think that AVRO should not be concerned, AVRO investors? Yeah, that's right. Despite our own gene therapy-related safety profile remaining excellent, questions certainly have risen based on bluebird bio's reported safety issue. I don't mind mentioning the company because I think they've comported themselves very professionally. For some perspective, bluebird last spring reported safety issues in two patients in their sickle cell program. After extensive investigation, both their gene therapy and the concomitant conditioning regimen were about as clearly and quantitatively exonerated as could be hoped. Now, the first patient of suspected MDS was determined to be a misdiagnosis, so that patient can be removed from the analysis. The confirmed case of classical AML luckily had vector present in the AML cells because what that allowed bluebird to do is an insertion site analysis, which strongly suggested that vector integration was not the culprit. Of course, the reason we can also dismiss busulfan conditioning as causative is because it's a very short half-life drug administered 72 hours before the gene therapy is taken from the freezer, thawed, and infused. 12 half-lives later, the gene therapy is infused, meaning busulfan and the gene therapy-modified cells were never in the patient at the same time. Although it is and remains a serious issue for the sickle cell patient population, I think it's absolutely credible to say that there's no fair or reasonable read-through to the broader populations of the many patients that are benefiting from gene therapy. In terms of the broader field, this was a false alarm. Now, more recently, there's been focus on a bluebird bio cerebral adrenoleukodystrophy patient who is believed to have experienced a case of insertional oncogenesis. Two points to make here is, firstly, when assessing the event, we start by putting the overall record of lentiviral gene therapy into perspective, because there are several thousand patients now that have received lentiviral gene therapy across rare disease and oncology, meaning many dozens of trials over 10,000 patient years of experience. This ALD patient represents the only known possible case of insertional oncogenesis. Point 1 is that in terms of the safety record for the field, we strongly believe the risk-benefit equation remains compelling. The second point is, what is the implication to AVRO and what is different about AVROBIO and our approach? I would say that our multiple potential safety differences all manifest because of one major facet of our approach. What that is that we've targeted enzyme deficiencies. The reason that's so important is because we’ve already demonstrated that even delivering 5% or 10% of normal levels has been shown to be sufficient to control the disease. We know that enzymes are catalytic. They’re little worker horses. This critical point has allowed Chris and our R&D team to opt for safety as our driving criteria at each and every stage of development, at each fork in the road. I won’t get too deep into vectorology, but we don’t have to max out our vector copy number. We don’t have to opt for the most aggressive promoter. We can build safety into each feature. I think that Blue has stated that it suspects that the potential root cause in its ALD program could be vector promoter related, their MND promoter. In the absence of data, we don't know that that's the case, but it could be one of several root causes. In any event, AVROBIO uses a different promoter. Our EFS promoter is designed to be the safest, in fact, the weakest, the most benign. We have different vector composition, different manufacturing process, which is recognized to be potentially a variable to impact the site of integration. I mentioned our low VCN. We target about one to two. It's a different disease, a different transgene, a different approach to conditioning even. Where we net out is that the broader field has an excellent record. AVROBIO have many safety features inherent in our approach. Finally, we do look very carefully at each and every one of our patients, and we can say that across our four clinical stage programs, there's been zero, no evidence of persistent dominant clonal expansion in any patient across any of our programs. We feel very good about the safety profile. The topic of manufacturing is very important in the space, and obviously you have your plato platform, which really facilitates in being prepared ultimately for the FDA when they scrutinize your processes. Could you speak to this preparation to plato and how ultimately you will be able to manage the FDA process when they start evaluating your manufacturing and quality? First of all, I agree it's a really big, important issue and that the FDA has made it very clear that they will not cede, will not cut corners on quality CMC submissions. What this has done is it's led to very material delays across the field of gene therapy, which I think everybody in this virtual room is aware of, is that the bar for CMC analytics is clearly very high, and that won't change. At AVRO, the whole founding hypothesis in 2015 was to apply intense energy and, in fact, with the goal of leading the field of lentiviral gene therapy manufacturing. This has culminated into our plato platform, which is our engine. I think that the premise is that regulators expect you to know your drug product and process, and so you have to demonstrate that your production is controlled. You can't show control unless you can deeply characterize the product, and you can't characterize the product unless you have the right analytics in place. That's really what we've set out to do. We've done an in-depth analysis looking at the field to try to understand what has led to delays across the field, and there's really only a few buckets, is that companies have hit delays because of insufficient product characterization early in development, making late-stage process changes just either difficult or not acceptable. Comparability studies were performed late and or not meeting FDA requirements. Things like switching from adherent to suspension bioreactors, small to large bioreactors, and potency assays not being done in time. These are the things that we see impacting, and these are the things that we've prioritized. We certainly don't have the hubris to say we'll be the only company not to encounter these kinds of delays, but I can tell you that we have an entire workforce focused on getting ahead of these issues. We've invested huge energy in analytical tools, and our goal, and what we have done, is completed all major process changes, even before initiating early-stage clinical development. We've had several pre-IND meetings with FDA to gain agreement and alignment on exactly what is the in vitro comparability data required to do process optimization work. We've completed work to validate multiple assays early, such as vector copy number, transduction. The goal is that we will apply these assays across all programs. A few brag points is that we are unique in the field, having automated manufacturing in place very early, and that, of course, really gives control and consistency to the manufacturing process. We're one of only a few groups to have approved and in place large 200 L serum-free suspension bioreactors, and with a 10 to the 9th titer to really be able to manufacture at scale. We feel very, very good about our approach. Maybe to look in the near future, our view is that if we can really achieve what we hope to in 2021, which is to exit the year with agreement from regulators that we are phase III-ready with plato for Fabry disease, the implication is that we're phase III-ready or almost phase III-ready across the portfolio because it's the same vector, it's the same automated manufacturing, the same large bioreactors, the same VCN assay, the same transduction assay across the six indications. There's just a disease-specific potency assay. Certainly, that's really where the leverage of developing a platform can kick in. Thank you for that. Let's move on to the products. For Fabry disease, you have AVR-RD-01. Clearly, the data has been promising to this point in a handful of patients across two trials. Most notably, the kidney biopsy data certainly looked intriguing. Of course, the regulatory process did have to shift due to the out-of-left-field approval for Fabrazyme, I think 18 years after its conditional approval was granted. What should we expect going forward, and how do we look at the timing of the next trials? When could we actually see data and potentially be ready for a submission? Yeah. You're right, David. We had submitted a briefing book and had a meeting on March 30th with FDA. Days prior, and as you said, 18 years after conditional approval, Fabrazyme was approved, full traditional approval. What that did is it didn't officially, but pragmatically, it closed the door for the accelerated approval approach that many in the field were looking at. Upon first glance, that seemed only negative, but the positive outcome that also manifested from that Fabrazyme approval is the very next day, March 31st, FDA updated their list of surrogate endpoints for full traditional approval, and for the first time, they listed kidney substrate biopsy as an endpoint that can be used. Now for ERT, but we, of course, believe that it also applies to gene therapy. Why that's so important is because the kidney biopsy, first of all, we're showing excellent data, a net 93% reduction of substrate in the kidney in our primary endpoint of our phase II in the first two evaluable patients from baseline versus one year later after the single infusion of gene therapy. It's an endpoint that we know, that we're comfortable with, and that we assign high probability of success. Importantly, it's short-term because, but for this kidney biopsy, we would probably have to default to something like eGFR or long-term cardiovascular decline. Both of which are possible, but they're much longer studies, they're larger studies, they're more expensive studies. We recognized that we were delayed a few quarters while we had to go back, redesign a briefing book with an alternate methodology for a phase III trial, and only now resubmit to FDA with the hope of getting in front of them by the end of the year. The upside is at least it's with a primary endpoint that we're very pleased with. That's the status. In the meantime, we filed some amendments this summer to expand our phase II program to include females, to include patients that would otherwise be excluded due to neutralizing antibodies to the enzyme, to the ERT itself, which is a segment that we're quite keen on. The phase II progresses. The briefing book's going in literally momentarily. We'll be in front of FDA by the end of the year, and the goal is to initiate the phase III trial by mid-next year. Excellent. I guess it should be some data coming as well soon for RD01, an update. Yeah. We made the decision this year to hoard our data a little bit and to give more material updates less frequently. We gave a very material update at WORLDSymposium in February. We'll give another update a year later at WORLDSymposium. We should have a meaningful amount of clinical data to share across a dozen plus patients in Fabry disease in phase II and phase III. In the interim, at ASGCT next month, we're going to, for the first time, give a comprehensive look at the safety impact of our gene therapy, looking at both conditioning related and vector related safety, just because, A, we think it's a strength of the company and the results are compelling. We also think that there's some misperceptions about the tolerability profile of what we call our buTCI target concentration intervention. That will be only safety at ASGCT, but a deeper look than we've shared to date, and then the real efficacy data in Q1. Thank you for that. Looking at RD-02 and RD-04, both certainly cystinosis has had some very promising data. Gaucher RD-02 is a little earlier in stage, but obviously has a lot of similarities with Fabry. Could you tell us where both those programs stand right now and when we might be able to see additional data for those? Yeah. If I start with Gaucher disease. Gaucher disease, there's type 1, 2, and 3. The largest segment is type 1, and that's the study that we're running, our phase I/II trial. We shared some data in February that I think was really compelling. It was the first patient in the world to receive gene therapy for Gaucher disease type 1. What we were able to compare is that patient's effect on gene therapy alone versus how well VPRIV, the Shire Takeda product, was controlling the patient. This was a 32-year-old lady who was on ERT, the VPRIV product, every two weeks since the age of three. You can imagine how onerous that was. She stopped VPRIV, then we looked six months later after the single infusion, not only was her disease controlled, but by the known biomarkers of chitotriosidase and lyso-Gb1, it was controlled better than baseline VPRIV. Chito was in fact cut in half. Early data, but very compelling. The point that I think is one of the most exciting within AVROBIO is extending the Gaucher program to Gaucher type 3. Although there's only 1,500 or 2,000 patients with Gaucher type 3 versus the larger type 1 market, it's a set of patients where they just lack a reasonable solution. For the reasons I said earlier, is that because ERT doesn't cross the blood-brain barrier, these patients have the brain, CNS, as the primary manifestation. We very much look forward to advancing in Gaucher type 3. In fact, what we're proposing is a registration trial, meaning one well-designed trial, and we hope to get in front of regulators early in Q1 to clarify the path in order to dose the first patient next year. For cystinosis, as you said, it's a little bit more advanced. We treated a handful of patients in an investigator-sponsored trial at UCSD, so not an AVRO trial, but, of course, we own the rights to it, and we've used that trial to understand what are the endpoints that can be studied in our own AVRO-sponsored trial. From that, what's really emerged are kidney measures and eye measures. Right now we have a draft protocol. We're holding ad boards this week to sort of finalize it, get it in front of regulators with the same timeline of initiating our AVRO-sponsored trial in 2022. Beyond those initial programs, you're also looking to move forward in some other disorders. Obviously, Pompe is one of them. Could you talk about some of these other therapies? Yeah. I think Pompe is an interesting one, and Hunter, and they have some similarities. Pompe is one of the diseases where there are a number of AAV gene therapies that have targeted the late onset market. Although we haven't really seen data, we recognize that there are some AAV gene therapy options. The reason we haven't been dissuaded in moving forward is because when we look at a target product profile for Pompe disease, what we see is a disease that needs up to 20 times more enzyme than Fabry or Gaucher, and it needs to, in a clinically meaningful way, penetrate into muscle and have a broad CNS effect. If you can't check those three boxes, you're really not addressing the needs of Pompe disease. We think that standard AAV solutions may work, but certainly we assign higher probability of failure than to some other indications. What we really like about our approach is we've been able to start with our standard lentiviral gene therapy approach, but we've engineered into it a GILT tag that we've licensed exclusively from BioMarin. A lysosomal uptake tag, which has been shown in their hands and in our hands to increase uptake 25-fold. In our preclinical data, what we've shown is this one-two punch of lenti gene therapy with the GILT tag engineered in is the only approach that we've seen that can not only drive down glycogen levels systemically in the periphery to almost rock bottom, but can also do that in multiple areas of the central nervous system. We do think that we have a really novel, effective approach, and we look forward to advancing that. The final thing I'd say about Pompe is that lentiviral gene therapy approaches also should be amenable to the infantile Pompe population. That's a segment that AAV gene therapies have shied away from for obvious reasons because of the non-integrating nature and the concern for washout. We do hope to provide a first-line therapy across all patient segments in Pompe disease. The story is very similar in Hunter disease, where it is that same lenti gene therapy plus a lysosomal uptake tag has been shown to not only be effective, but to drive heparan sulfate down to normal levels in the appropriate disease models, animal models. That also will be in the clinic in 2022. Thank you for that. We're kind of running up on the end here. Just one last question. What is the current cash position and the runway going forward? Sure. We ended the second quarter with $226 million on the balance sheet, and we've guided that provides runway into the first quarter of 2023. Excellent. With that, thank you so much for attending virtually once again and look forward to chatting soon. Yeah. Thank you, David. Thanks. Take care. Thanks, David. Thank you. Bye-bye. Cheers.