Welcome to the AVROBIO WORLDSymposium 2022 Cystinosis Update Call. My name is John. I'll be your operator for today's call. At this time, all participants are in listen only mode. Later, we will conduct a question-and-answer session. During the question-and-answer session, if you do have a question, please press star then one on your touch-tone phone. Please note the conference is being recorded. Now I'll turn the call over to Geoff MacKay, Chief Executive Officer of AVROBIO. You may begin. Thank you for tuning in to our AVROBIO investor update on our investigational gene therapy program in cystinosis. We'll review new data being presented later today by our collaborator, Professor Stephanie Cherqui and her team at UCSD at this week's WORLDSymposium in San Diego. The press release announcing these updates can be found on the investor relations section of our website. Before we begin, I'll review our safe harbor statement. Today's discussion contains statements that are forward-looking under the Private Securities Litigation Reform Act of 1995, including statements based on our current plans, expectations, and beliefs. Such statements are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those presented. A description of these risks is contained in our SEC filings, which are available on the investor relations section of our website, which I refer you to for further information. As you can read on slide 3, AVROBIO's founding purpose is to deliver freedom from a lifetime of genetic disease. The clinical data we're sharing today strengthens our belief that we're on track to do just that. Our goal is to develop one-time gene therapies for devastating genetic diseases like cystinosis and to untether patients from burdensome standard of care. I'll be presenting with Essra Ridha, our Chief Medical Officer. Essra brings tremendous heritage in developing gene therapies for rare disease, having joined us after spending time at Sangamo and importantly, working on the pioneering lentiviral gene therapy studies while at GSK. I'll begin by highlighting our pipeline and Plato platform, provide some background on cystinosis, including a video from parents of 2 children with cystinosis, and then I'll pass it to Essra Ridha to share data and regulatory updates on the program. We'll close with a Q&A, at which point we'll be joined by Erik Ostrowski, our CFO, and Chris Mason, our Chief Science Officer. Shifting to slide 4. First, while we adjusted our pipeline priorities earlier this year, our central strategy at Avro is unchanged. We remain focused on building a pipeline of first-in-class gene therapies targeting major lysosomal disorder indications, each of which currently cost the healthcare system a fortune, even though many of today's standard of care medicines may not fully meet the range of patient needs. In some cases, we're developing the first and only gene therapy targeting a particular disease. This is the case for cystinosis, which we cover today. In each of these indications, we are or anticipate being the first hematopoietic stem cell gene therapy in the clinic. A common theme is that each of these lysosomal disorders could benefit from an approach that has both a full systemic and a CNS impact, which is really where our gene-augmented HSC approach is well suited. Finally, we are powered by Plato and differentiated by our leading CMC and analytics capabilities, which we intend to apply across the pipeline. That pipeline on slide 5 spans 5 different lysosomal disorders with 2 programs in the clinic currently. We believe we have the leading lysosomal disorder pipeline in the industry, and these disorders are strategically aligned in 4 key ways. These are all enzyme protein deficiencies with well-understood biology. Each of these disorders may benefit from both an above-the-neck and a below-the-neck therapeutic impact. Commercial call points significantly overlap, meaning the same doctors tend to treat all of these disorders or may be one door down from a colleague who may also treat. Of course, immense operational synergies on CMC and analytical assays apply across the programs. We're building a congruent portfolio of first-in-class gene therapies, which we believe have the potential to transform the treatment paradigm across these severe disorders. These large, well-established indications translate into a multi-billion dollar market opportunity. We see on slide 6 the math is easy. The average annual direct cost for today's standard of care range from $450,000 to $800,000 per patient per year for life. Cystinosis is at the top of this list with PROCYSBI, which we understand carries a five-year revenue price tag of more than $4 million per patient in the U.S. In terms of initial target patient population, we estimate there are more than 35,000 patients across these indications, and that number only includes geographies where ERT is well reimbursed. The Sanofi and Takeda collectively generate over $3 billion in annual revenue for today's standard of care. Our goal is to replace these treatments by developing first-line gene therapies to offer tens of thousands of patients a better solution, while at the same time saving the healthcare system a fortune. To accomplish this, we begin with our engine, our proprietary gene therapy platform, which we call Plato, our end-to-end platform captured on slide 7. AVROBIO has a total commitment to CMC and analytics, and the result is Plato. I'll highlight 4 key elements. First, our process is in place. All large and medium process changes are complete, and this required very early consultation meetings with FDA and other regulators around the world. Second, we manufacture vector at scale. We are just one of a few teams operating in a 200-liter serum-free suspension bioreactor, resulting in a 10^9 vector titer. Third, we are unique in our abilities to manufacture within a closed automated system shown on this slide. This not only drives down cost, but also enables future global production. Fourth, our analytics are well advanced and designed with regulatory considerations in mind. We prioritize our potency assay matrix approach. We deploy one optimized VCN assay across AVRO-sponsored trials. In fact, we also utilize single-cell VCN level data to provide deeper product characterization, and we have a first-in-class rapid transduction assay. We believe all of these innovations translate into advanced control over manufacturing consistency, and I think it's fair to say that we've established a leadership position in automated scalable manufacturing. Now let's dive into our cystinosis program, which enters 2022 with momentum. On slide 9, we list the key takeaways for today. The high degree of unmet need is undeniable. Cystinosis patients deserve a better solution. Today's standard of care does not stop the progressive nature of this debilitating disease. Today, you'll hear firsthand from the parents of children with cystinosis who will discuss the high pill burden as well as side effects such as odor on the body and GI disturbances, which ultimately can lead to poor compliance. As mentioned earlier, I again highlight the very high cost of today's standard of care. The phase I/II trial data from the first three patients in this study are showing consistent positive results across multiple measurements, with all patients out at least 1 year and patient 1 now out over 2 years. Importantly, data to date also suggests the safety profile remains strong. UCSD is completing this collaborator-sponsored trial, which allows us to move towards initiating our AVRO-sponsored trial. We plan to further discuss our approach with FDA this year. Before jumping into the data, we thought it would be helpful to remind you of the biology of cystinosis and how it impacts patients and families living with this devastating disorder. Cystinosis is characterized by the accumulation of cystine within the lysosomes of cells throughout all the tissues and organs of the body. This happens because cystinosis patients lack a functioning exporter protein called cystinosin, which is needed to transport cystine out of the lysosomes. The buildup of cystine in lysosomes results in organ and tissue damage, leading to the severe impairment of the kidneys, eyes, and skeletal muscle. Genetically modified cells produce mRNA encoding for active cystinosin, which reaches the cells that are deficient of active cystinosin by two mechanisms. The first is exosomes and microvesicles, which are packing systems for intercellular communication. The second involves tunneling nanotubes, whereby cells are physically coupled together to exchange lysosomes. This allows for the creation of functional lysosomes in the cells of the tissues and organs of the body, and this is the goal, to generate corrected lysosomes in cells throughout the body, which gets us to our target product profile, how we hope gene therapy can impact this disease and ultimately the lives of patients. Now on slide 12. Cystinosis's impact on the human body is unrelenting. 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, including very frequent eye drops and dozens of pills per day, which can cause frequent nausea and vomiting and body odor that one parent characterized as smelling like rotten eggs. Such a regimen is highly challenging for adults, and I invite you to imagine how much more so with toddlers and adolescents. Our target product profile for a cystinosis gene therapy is a first-line therapy with target attributes that, depending on the stage of disease, has potential to prevent, halt, and/or reverse eye complications, endocrine disorders, including diabetes, renal failure, and CNS manifestations, all with a single dose. As is the case with many degenerative diseases, early treatment is ideal to get ahead of the very serious and progressive clinical manifestations. As you can see on slide 13, vast majority of cystinosis is infantile, which begins in infancy, and our goal is to treat early. If these children are left untreated, they will likely face end-stage renal disease by the age of 10. In fact, even on cysteamine, most will likely have a kidney transplant by the age of 20. Over time, cystine accumulation may also translate into muscle deterioration, inability to swallow, diabetes, thyroid and nervous system problems, and infertility. Early diagnosis and treatment are critical, as you can hear for yourself when you listen to Brian and Chelsea, who have two sons with cystinosis. Jackson is now four and a half years old, and Miles is four months old. Brian and Chelsea are grateful about being able to start treatment for Miles right away, much earlier than was the case for Jackson. Let's listen to their story, which was taped before Miles was born. The emotional piece is huge. When you listen to truly amazing parents, it brings meaning to the headline we list on our website. What if one gene can change your entire world? Let me now hand it over to Essra, who will provide a clinical update and discuss our next steps. Thank you, Geoff. Jackson and Miles' story underscores the need for early diagnosis and early intervention, as well as the need for additional treatment options for cystinosis. Looking at slide 15, this collaborator-sponsored phase I/II clinical trial is being run by Professor Stephanie Cherqui at the University of California, San Diego. The trial has been funded in part by grants to UCSD from the California Institute for Regenerative Medicine, the Cystinosis Research Foundation, and National Institutes of Health. This is the first and only gene therapy trial for cystinosis. 4 adult patients have been dosed in this trial, which is focused on safety and tolerability, pharmacodynamic efficacy, and clinical outcomes, looking at a variety of measures which will inform the next phase of development. Let's start by looking at the demographics for the first 4 patients infused in the trial on the next slide. On slide 16, you can see the baseline characteristics of the four adult male patients with advanced disease in the trial. Two of the patients are categorized as infantile nephropathic cystinosis with the onset of symptoms in infancy, and the remaining two with the nephropathic juvenile form of the disease with a slightly later onset in adulthood. All patients have advanced disease as evidenced by severe organ impairment, particularly affecting the kidney, as well as a myriad of extra-renal manifestations of the disease. Focusing on the renal system, the first patient had progressive renal disease and had a moderate degree of renal impairment at CKD stage three at the time of gene therapy infusion. The second, third, and fourth patients have received renal transplants prior to gene therapy, demonstrating the progressive and severe nature of the disease. This again points to the need for early intervention in this patient population. Now let's review clinical data on slide 17. As you know, AVROBIO uses busulfan conditioning, which is transiently myeloid depleting. Following conditioning, neutrophil levels and platelet counts are reduced to a low nadir for a few days, followed by a recovery at around 10 days. As expected, the lymphocytes are mostly preserved by busulfan, minimally impacting the adaptive immune system. Busulfan conditioning is, of course, a key element of preparing the bone marrow for the potential long-term engraftment of our genetically modified stem cells. Let's look at these patients' engraftment patterns on slide 18, and we'll be focusing on the first three patients as the fourth patient has only very recently been infused. The first three patients infused, we see sustained engraftment of our genetically modified stem cells as evidenced by stable extra copy numbers, which have plateaued at between 1 and 2.6 at 1 to 2 years post gene therapy. Now we will move on to look at our biomarker measures, which are indicators of pharmacodynamic efficacy on slide 19. Here we measure the pathological accumulation of cystine crystals in the skin, and the biopsies show significant reduction from baseline in the number of toxic cystine crystals in each cell across all three patients at the 1-year time point. These reductions suggest that the patients are now producing endogenous functional cystinosin protein, which they were unable to do before gene therapy, and that the protein is doing one of its many jobs, preventing the pathological accumulation of cystine crystals. We see a similar impact on other tissues. Again, a substantial drop in crystal levels in the intestinal mucosa across all three patients can be seen on slide 20. Patient 1 at the 18-month time point and patients 2 and 3 at 12 months, demonstrating the sustained treatment effect. Now let's take a look at crystals in the eye. An expert in the field once told us that the eye is the window into the world of cystinosis. This is because a pathognomonic sign of cystinosis is cystine crystals in the cornea, a cause of severe photophobia. This baseline photograph clearly shows the crystals in patient 1's cornea. At the time, he, like many cystinosis patients, was administering eye drops as frequently as every hour of the day. What have we seen in this patient since treatment? Here on slide 22 are some striking microscope images for the first patient, which capture the prevalence of crystals shown in white, going from the front to the back of the cornea from left to right on the slide. Prior to baseline, the patient discontinued his frequent eye drop administration. Since gene therapy, the density of crystals has dropped dramatically. Additional data points analysis by a central reader is planned for this patient as well as patients 2 and 3. Now let's look at some durability data on slide 23. Overall, the first three patients have a significantly improved quality of life owing to the discontinuation of oral cysteamine post gene therapy. The direct and indirect benefits of discontinuing poorly tolerated pills of cysteamine for over 2 years now, as well as the near constant eye drop use, is profound for patient one. Patient two has been off oral cysteamine for a year and a half. However, he has restarted his cysteamine eye drops due to symptoms of photophobia. Patient three has now been off oral cysteamine and eye drops for a year. Turning to renal function on slide 24. As expected, patient one, who already had suffered a moderate degree of renal impairment at the time of treatment, continues to decline, heading towards a renal transplant. Our ultimate goal for this program is to identify patients early before any renal impairment has developed, thus potentially preventing the onset of renal disease entirely. Let's move over to updated safety data for the four patients infused on slide 25. As with our other clinical programs, we're pleased to report there have been no unexpected safety events or trends observed to date in the phase I/II clinical trial. Importantly, we have observed no serious adverse events or adverse events related to the gene therapy drug product to date and no serious adverse events in the trial overall. The reported adverse events were consistent with busulfan conditioning and/or the patient's pre-existing disease. They were classified as transient. The majority of adverse events are mild to moderate, and all have resolved. Finally, let's talk on slide 26 about the planned global, clinical, and regulatory strategy for this indication. Following several regulatory milestones in 2021, we're keen to build on our regulatory momentum in 2022. As you know, we have previously received orphan drug designation in the U.S. and EU, as well as Fast Track Designation for the indication from the FDA. In July 2021, the FDA approved our IND, under which we will conduct the long-term follow-up study of patients treated in the ongoing phase I/II study, as well as our planned company-sponsored clinical trial. This past autumn, we held a pre-clinically focused Type C meeting with FDA, which provided us with actionable feedback that is being incorporated into the program. We are now preparing for additional clinical and CMC interactions with regulators and have started to design our planned company-sponsored trial, which we expect will follow a two-part strategy. Initially, a pre-renal transplant population trial for initiation expected in 2023. A post-renal transplant population to follow as a second stage trial. Several endpoints across renal, muscular, and ocular systems are under evaluation, and we plan to conduct the trial in the U.S., E.U., and U.K. There is a lot more to come on this front, but we are excited about where this is heading and looking forward to sharing more details with you at the right time after we have received additional feedback. Let me hand it back to to close our update. Thank you, Ezra. Our cystinosis program enters 2022 with momentum. A better solution to this disease is urgently needed. The high unmet need is undeniable, and the cost to the healthcare system is enormous. The first three patients in our study are showing consistent positive results across multiple measures, with all three patients out at least one year and patient one now out over two years. Importantly, data to date suggests the safety profile remains strong. We now move towards initiating an AVROBIO-sponsored trial and look forward to discussing our approach with FDA this year. Our purpose at AVROBIO is to free patients from a lifetime of relentless genetic disease. Certainly, Jackson and his brand-new baby brother, Miles, bring into sharp focus why we do what we do. Thank you again for joining us, and we're happy to answer your questions. Thank you. We'll now begin the question and answer session. If you do have a question, press star then one on your touch tone phone. If you wish to be removed from the queue, please press the pound sign or the hash key. If you're using a speaker phone, you may need to pick up the handset first before pressing the numbers. Once again, if you do have a question, press star then one on your touch tone phone. Our first question is from Ritu Baral from Cowen. Good morning, guys. Thanks for taking the question. I had a question on what our expectations should be for renal function for patients two, three, and four. You talked about on slide 24 how early treatment is important and this patient with the native kidney continues to decline. You know, how does potential later treatment with the 46-, 22- and 33-year-old how is that sort of offset by the fact that I believe all these patients have transplant and therefore renal tissue that doesn't at least endogenously have elevated cystine levels? Understanding of course, that they're just sort of bathed in it from other tissues. Can you help us sort of think about how those offset each other? Yeah. Thanks for the question, Ritu. I mean, the short answer is I think it makes the kidney measures moot. As you referenced, patient number 2 and 3 in the trial each have had at least one kidney transplant, which is par for the course. It's not at all uncommon in cystinosis. Importantly, transplanted kidneys are not affected by cystinosis as the donor doesn't have the defect in the membrane transport protein, and so for us, I think that it does get to the implications as we look at our clinical trial design because we really bifurcate between the pre-transplant population and the post-transplant, and the kidney measures are absolutely relevant and in fact primary in the pre-transplant population, but will not be very relevant in the post-transplant. Will graft survival be important, or is that too long-term to think about in terms of pivotal? Essra has a great background in kidney transplant. Why don't you take that, Essra? Thanks, Jeff. The question really was around whether graft survival was going to be a measure. Importantly, we have to consider these populations slightly differently. Where you have a patient who has their native kidney, it is affected by cystinosis, the disease, and we would be looking at renal measures in that population. When it comes to the post-kidney transplant patients, these transplants that the donor kidney is not affected by cystinosis, they have a functional cystinosin protein. No, we wouldn't be looking at graft survival as that's really just a measure of how well the transplant does, not a measure of cystinosis and treatment for cystinosis. Understood. As you think about the pivotal study, how should we be thinking about any potential comparator arms, given that I believe CYSTARAN has full approval, is that something that's just gonna be par for the course as you talk to FDA or is there potential for it to be, I guess baseline or individual patient controlled? We've had multiple touch points now in 2021 with FDA. I think the regulatory dialogue is progressing, but not to the point of being able to adequately answer that question, you know, based on direct feedback from FDA. I think indirectly, I think that we do believe that there may be an opportunity to compare versus natural history. But either way, I think that what we really like about cystinosis as a clinical design approach is that we don't believe we have to rely on biomarkers. We can look at multiple functional measures in kidney, ocular, and different ways of measuring muscle weakness. Whether that translates into a superiority design versus a control or whether we can default to natural history, I think we'll punt that until we have direct feedback and alignment from FDA. Understood. Thanks for taking the questions, guys. Our next question is from Gena Wang from Barclays. Thank you for taking my questions. I have two questions. The first one is regarding the cysteamine drops. I think patient number 4 at the baseline, it seems they do not need cysteamine drops in 2021. What does that mean in terms of a patient baseline characteristics? The related question is slide 23, patient number 2 restarted in July 2021, that roughly 1 year after infusion started the oral cysteamine and the eye drops, you know. Can you give a little bit more color on that patient, what does that mean? The second question is for patient number 1, you did show a few 18 months data points. How's the 18 months data point compare to the 12 months regarding rectal biopsy data and also the cornea crystal data, regarding the photophobia grade? Sure. I'll pass those to you, Essra. Thank you. If I start with patient 2, the question, as I understood it, was about the oral cysteamine and the cysteamine eye drops. As you know, patient 2 has been off oral cysteamine for a year and a half. However, he has restarted his cysteamine eye drops due to symptoms of photophobia. The important thing to mention with regards to patient 2 is this patient is a renal transplant patient, and they have been transplanted prior to entry into the trial and prior to the gene therapy infusion. And obviously, this is secondary to cystinosis causing end-stage renal disease in this patient. The important thing to note here is that the patient who has a renal transplant is obviously on a immunosuppressant regimen, which is really there to protect the renal transplant from rejection. We hypothesized that it is this regimen that may have suppressed the levels of white cells, particularly macrophages, which are derived from our genetically corrected stem cells from reaching basically the cornea, retina, and other ocular structures to treat the disease cells of the eye. That's something that we're aware of with regard to patient two. With regard to patient four, I would need to look at the reasons for why the patient is not requiring cysteamine eye drops in 2021 and come back to you on that one. With regard to your other questions around intestinal mucosa, rectal biopsies and corneal crystals. If I speak to corneal crystals first, obviously we've presented patient one data for the time being. Our collaborator has further images of the corneas of patient 1 beyond this time point of 18 months and for patients 2 and 3. However, they haven't been read yet or interpreted by our central reader, so we will be coming back on those data. With regard to the rectal biopsies, we do see the substantial reduction in the number of cystine crystals across patients, suggesting that we are seeing the effect of the cystinosin protein preventing the accumulation of pathological crystals over time in these patients. Certainly additional data to follow to see that sustained effect over time in these patients. Sorry, just wanted to be clear. The 18 months data, when we compare 18 months to 12 months, did patients show further improvement or they largely maintained the clinical benefit, achieved at month 12? Patient one? Yeah. Is that- Yeah. Gena or Essra, I can jump in 'cause unless you have the data, Essra. I just pulled it up. Okay. The patient number one at baseline was 11.3. At 12 months, 2.7. At 18 months, 5.3. Basically cut in half at 18 months. Of course, you know, just to make an obvious point, this is versus 30 pills of cysteamine a day as the baseline measure. You know, we don't ascribe very much significance to the difference between 2.7 to 5.3. I think what we see is a sustained reduction versus the patient's baseline. Thank you. Our next question is from Michael Ulz from Morgan Stanley. Hey, guys. Thanks for taking the question. Maybe just to follow up on one of the earlier questions in terms of the trial design and just how you're thinking there, maybe in terms of patient numbers at this point, and then also on endpoints, you mentioned maybe using some functional measures there, but maybe if you can elaborate and maybe talk about is there a particular endpoint you think would be sort of a primary here, or do you get the sense that the FDA is going to be interested in multiple endpoints? Thanks. Well, one key point is that the current plan involves a two-part strategy. We begin with the pre-renal transplant population and then follow with the post-renal transplant population. As I mentioned, there are several endpoints across renal, ocular, and muscular systems that are all under evaluation. We don't wanna get too far ahead of our dialogue with FDA. Certainly, when we reach alignment with FDA, we'll disclose. I think that, you know, what we believe is that there are multiple functional measures, and whether they serve as co-primary or whether we default to one or the other. I mean, as was already mentioned, kidney would be exclusively for the pre-transplant population. We do think that we will be able to measure multiple. Of course, you know, it goes without saying that getting these patients off the cysteamine pills is life-changing. Just to remind some on the call, patient number one, the mother reported that he was vomiting 13 times a day on cysteamine and then 0 times in the 3 months following gene therapy. Probably nothing to do with gene therapy, but just getting off cysteamine. You know, one of the key measures, it will be secondary, but one of the key measures in terms of quality of life is just being able to completely titrate off oral cysteamine. Ezra, is there anything you wanted to add more about the functional measures? I would just add that, you know, cystinosis, essentially the systemic nature of disease for cystinosis, and it is very much our aim to show the benefits of a gene therapy treatment across multiple organ systems and tissues. That's probably all I'd say in addition to what you mentioned, Jeff. Got it. That's helpful. Maybe just one follow-up on the pre- and post- parts of the study. What do you hope to learn in the pre-transplant that you might sort of apply to the post-transplant? Just trying to understand why not start both those at the same time. Is there a particular reason there? Thanks. I'll pass that to you, Essra. Thanks, Jeff. Okay. Yeah, absolutely. We do have to consider these two populations differently, obviously, because of the nature of the disease in each of these patients. In the pre-renal transplant population, obviously, a focus is the renal system, as it were, but there are certainly gonna be multiple measures across extra renal manifestations of the disease. Some of that will certainly inform the post-renal transplant population, but we also have to consider that the breadth of the population for a post-renal transplant population would be wider as well, from pediatric all the way through to adults as well. Certainly more information to come on that. Yes, a multitude of extra renal measures across both populations for sure. Got it. Thank you. Our next question is from David Nierengarten from Wedbush Securities. All right, thanks for taking the question. Most of my regulatory questions have been answered, but I'm curious about the clinical results. It seemed in both the rectal and the skin biopsies that, you know, patients have gone down to, you know, roughly similar levels of cystine crystals despite very different baseline levels. Is there, a physiological reason for that? Are they, you know, just the background level? You know, how much higher is that than normal person? And yeah, you know, just to kind of if you could explain that, you know, after effective treatment. Thanks. Yeah, sure. I don't know if we can explain, but we can speculate, Essra. Sure. Yeah, of course. Obviously there's the effect of the gene therapy treatment. As soon as you obviously have the cystinosin protein, which is functional, you can prevent the accumulation and sort of further build up of crystals. What we see here is that you have these sort of significant reductions. Partly that's also related to the turnover of cells in these patient populations. You renew basically skin cells and intestinal mucosa cells over time. What we're seeing partially in these data is you're getting new cells as well and you're not getting accumulation or anywhere near as much accumulation in those cells. Those are the two factors impacting the kind of degree of reduction. It's hard to compare to normal or healthy controls as we don't typically look at this kind of accumulation of crystals, so I can't comment on that. Got it. Thank you. Our next question is from Yanan Zhu from Wells Fargo. Hi. Thanks for taking my question and congrats on the data. So I was wondering how early do you think the gene therapy would need to be conducted in order to slow the slope of renal function? Would you be able to start the pre-transplant trial at an age that is in that age range? Yeah. Of course, our goal is to treat as early as possible to prevent prior to progression of disease. I think most on the call know, there's a good body of data in other monogenic rare diseases and in fact in LSDs themselves that have shown benefit by treating early. Ezra was part of some of that early work, so I'll pass it to Ezra. Thank you, Jeff. Yeah. Importantly, the mechanism of action of the gene therapy is really to correct the metabolic defect. What we understand of the way in which gene therapy will work is if we give this early enough, we can correct the metabolic defect and therefore prevent worsening damage in a tissue as sensitive as the kidney in this patient population. In an ideal scenario, we'd be looking to recruit patients early in childhood prior to there being some significant damage to the kidney where the glomerular filtration rate of the kidney is impacted. In that way, essentially prevent the progression or halt the progression of any further disease in the kidney. That is feasible, is the other thing I would say. That is feasible, is the other thing I would say because these children start with a renal Fanconi syndrome, which is a disease of the proximal tubules within the kidney. Subsequently, they start to develop worsening glomerular disease. There is a point in time where one can capture these patients before glomerular filtration rate is impacted too severely. That's very, very helpful. Thank you. In terms of product attributes, as you're starting planning to start your own trial, do you look at VCN and consider adjusting the VCN further higher? In terms of additional biomarkers, would a biomarker for macrophage expression of cystinosis be a useful metric to look at? Do you think kidney biopsy for the crystal deposition is a good and new endpoint to look at? Thank you. Yeah. If I start with the VCN question, just for clarity, and it's very typical of these first-in-human trials, the target was quite broad, anywhere from 0.5-5 as a VCN target. You'll note that the first 3 patients actually were quite high in terms of drug product VCN, with patient 4 a little bit lower, but still very much within the release criteria. From Avro's point of view, a broad range of drug product VCNs at this early stage in this first-in-human study is fine and in fact may help inform the design and specifications for our own Avro-sponsored trial. We take your point. I think that, while we haven't locked into a target, we will be looking at the clinical results in all of these patients and, you know, in all likelihood, tighten that target a little bit in our own AVROBIO-sponsored trial. I think the second question was around other biomarkers. We elected not to share some of the biomarker data that you may see when Professor Stephanie Cherqui presents later today, despite the fact that it's very positive, just because we're still learning, and we're questioning how correlated it is to true functional outcome. The measures that we did share, we just have greater confidence of the correlation between the measures that we shared, such as, crystal count and so forth, as being correlated with functional measures. The biomarker data that Dr. Cherqui will be presenting is quite favorable. If we do include it in our trials, it would really be secondary. We don't see a scenario where it can serve, nor would we want it to serve as a primary measure. Macrophage. What was the macrophage question? I was wondering whether you have evaluated the expression levels of cystinosin in the patient's macrophage after the treatment. Yeah. Well, I'll hand it over to Chris or Ezra on some of our internal R&D work, so leave it to you. Sure. Absolutely. If I start with talking about sort of biomarkers in general, and obviously we are evaluating the potential of sort of an expansive biomarker plan for future studies. Most certainly, as you've rightly pointed out, will focus on things like cystinosin protein, mRNA encoding cystinosin and accumulation of crystals, renal and extrarenal and so on. I'll hand it over to Chris to speak to the granulocyte data in particular. Yeah. We absolutely have looked at the individual cell fractions in the laboratory and can actually look at the different, as Ezra said, the level of mRNA and also at the protein level. It is still very exploratory type data. Got it. Thank you for the color. Yeah. Our next question is from Yanan Zhu. Hi, guys. Thanks so much for taking my questions. I guess I have a couple of questions. The first is, just looking at the totality of the data and going before the FDA, like, what would you sort of expect would be challenges that you might you know confront with the FDA in terms of getting them to align? Like, what would keep you up at night? Like, is it what in the you know just essentially what about the data that you think might not convince the FDA to move this in the direction that you would like to move the project? Yeah. I mean, I can speculate. I would be. I guess the point that I would make is that the gene therapy has performed really optimally relative to expectation, you know. In terms of that totality of data, you know, we really believe that we're seeing sustained engraftment as measured by VCN. The patients are off oral cysteamine now 1-2 years and counting. Reduction in crystals across multiple measures, skin, mucosa, cornea, and the safety profile with an expectation. That is what we hope to be able to deliver on, and that so far is what we're seeing. It doesn't mean that there aren't, you know, gaps. I think that really comes down to the inclusion/exclusion criteria of what's included and what is more than just what this phase I/II trial is. This is a first in human and the first gene therapy ever studied in this indication, and we recognize that it's. I think what we can say is that we've established proof of concept in adult cystinosis patients. Of course, that's the beginning for us. We will have to negotiate with FDA and reach alignment on what is the path to expand well beyond that, into the, most importantly, the pediatric population and the pre-transplant population. One thing to call out is because of the patient selection in the phase I and II, there were only minimal learnings on the kidney measure, you know, because patient number one, I believe, initiated the trial with an eGFR south of 40 and in sharp decline. Of course, there's no expectation that gene therapy can reverse that, reverse fibrosis in a damaged kidney, and the other patients are post-kidney transplant. There will be further learnings and what we will propose are endpoints that are relevant for each of these segments. I think, you know, we couldn't be more satisfied with the performance of the gene therapy. I just think there's more to learn as we expand to broader patient populations. Okay. Thanks. Second question briefly. I noticed that, you know, in the patient characteristics where none of the four patients have homozygous 57-kb deletions. I'm just wondering whether you would consider enroll these patients, you know, or not and why, and why you wouldn't consider enrolling these patients. Yeah. It's a great question. Essra or Chris, do you wanna take that? Yeah. For the 57-kb, we don't really see a difference in the way the patients actually behave in terms of their disease characteristics. As far as we're concerned, we're agnostic to whether it's a single mutation or whether it's a whole 57-kb deletion. Okay, thanks. Just briefly, you presented the rectal biopsy data for patients number one at month 18, but I didn't see that for the skin biopsy. I'm just wondering whether there was further reduction or not, or just curious. Yeah, no. Thanks for pointing that out. We've included all the data that we have. That sample is just not taken, so we don't have it. Okay. Thanks so much. Yep. Thank you. If there were other questions we did not get to, we will follow up separately later. Now I'll turn the call back over to Geoff for closing comments. Well, thank you. I'd like to close just by acknowledging the great work by our wonderful partners at UCSD, Dr. Cherqui and her team. Thank you for your attendance. On behalf of the AVROBIO team, I wish you a good day.