Good afternoon, welcome to the Adverum Biotechnologies conference call. At this time, all participants are in a listen-only mode. Later, we will conduct a question- and- answer session after the prepared remarks. As a reminder, this conference call is being recorded. I would now like to hand the call over to Amy Figueroa, Vice President of Investor Relations and Corporate Communications of Adverum. Please go ahead. Thank you, Paul. Good afternoon. Thank you for joining today's call to discuss an update on the ADVM-022 gene therapy program. A copy of the press release is available in the investor relations section of our corporate website at www.adverum.com. Please note that a replay of today's call will be available on the events and presentations section of our website. Joining me today is Dr. Laurent Fischer, President and Chief Executive Officer, and Dr. Julie Clark, Chief Medical Officer. In addition, we are joined by Dr. Szilárd Kiss, Associate Professor in Ophthalmology and member of Adverum Scientific Advisory Board. For the Q&A session, we have Chris DeRespino, Chief Business Officer and Acting Chief Financial Officer, and Peter Soparkar, Chief Operating Officer with us today. As a reminder, we will be making forward-looking statements, which include our product development plans, anticipated milestones, and resources. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those forecasted. A description of these risks can be found under the caption Risk Factors described more fully in Adverum's quarterly report on 10-Q for the first quarter ended March 31st, filed on May 6, 2021, and any subsequent filings with the SEC under the heading Risk Factors. I will now turn the call over to our President and CEO, Dr. Laurent Fischer. Thank you, Amy. Good afternoon, everyone, and thank you for joining us today. Before we begin, I would like to thank Dr. Szilárd Kiss for being with us on the call. Dr. Kiss is a prominent retina specialist who serves as a member of our Scientific Advisory Board and has deep understanding of the preclinical and clinical data on ADVM-022, as he has served as an advisor for our company for six years. He has extensive experience across the field of gene therapy and is working with different investigational agents, bringing valuable insights for this new field of research as we work toward the collective goal to deliver durable and safe treatments to patients. We appreciate everyone joining this discussion on short notice today so that we can share our findings to date from the ongoing review of data available from the INFINITY clinical trial. These data have informed our decisions to plan for a future phase II clinical trial in wet age-related macular degeneration that will be evaluating lower doses of ADVM-022 and additional prophylactic regimens. We will no longer plan to develop our gene therapy product in diabetic macular edema and will not pursue the high dose. The development of our gene therapy product, ADVM-022, has been a multi-year journey from extensive preclinical work into the clinic, first in wet AMD with the first patient enrolled in December 2018 in OPTIC, a dose-finding study which has now demonstrated promising long-term efficacy and safety data. Following a well-established path paved by other ocular anti-VEGF therapies, Adverum initiated the INFINITY double-masked phase II study in DME in May 2020, following clearance of the IND by the FDA, with a goal to expand more broadly into additional anti-VEGF indications. I joined Adverum in June of last year based on the promise of ADVM-022, as we have learned since, when it comes to anti-VEGF treatments, there's no such thing as one size fits all. Treatments have different safety profiles in different patient populations, different indications, and at different doses, many times, dose-limiting toxicities are discovered during and as part of the drug development process. During this journey, patient safety has been and remains our absolute top priority and guides every decision we make as a company. This is the reason why we immediately unmasked INFINITY when we saw an unexpected SUSAR in one patient with DME treated at the high dose. AAV gene therapy has demonstrated a promising safety profile to date, this adverse event was completely unexpected and has not been seen before, either in ocular gene therapy or with other anti-VEGF treatments. Patient safety is the reason we asked all patients treated with ADVM-022 over the last two and a half years to return to their physician's office for a full clinical assessment and additional monitoring as we reviewed the entire data from OPTIC and INFINITY in a total of 55 patients, as well as data from clinical studies that were conducted in over 70 non-human primates to date, one of the most extensive preclinical programs ever conducted in the field. Patients are the reason that the Data Monitoring Committee, our Scientific Advisory Board, leading experts, and investigators from our trials have generously and tirelessly offered their insights and valuable time to work closely with us to assess, monitor, and develop the best treatment and risk mitigation plans. Patients are the reason that we have made the decision to no longer develop our gene therapy in DME and at this high dose, where we have unfortunately observed a dose-limiting toxicity that has not been seen previously in several high-dose patients in INFINITY. Gene therapy drug development is a relatively new field. We're pushing boundaries, and as we all know, dose finding has been a challenge across many programs. AAV has been used safely as a delivery system by Adverum and others, and unexpected adverse events can occur in the development of new biologics as we seek to push the boundaries to provide more durable treatments for patients. Our aim is to design studies that prioritize patient safety. We're committing to sharing our findings real-time with the field so that we can collectively advance new gene therapies for patients. While we continue to investigate the root cause, and we do not have the answer yet today, we felt it was important to share these very recent INFINITY events and our findings in a very transparent way as a company and in sync with how we are sharing it with the clinical sites and the FDA in real time so that patients and investigators can have the best possible treatment and care. In a minute, Julie Clark will share her insights, but what our review of data has shown is that disease matters and dose matters. It is important to understand that not all VEGF-driven diseases are the same, and that wet AMD and DME have different pathophysiological causes and different risk factors. While the root cause of the DLT is not yet known, we do know that diabetic patients with DME typically have multiple underlying comorbidities, such as severe vascular disease, which can contribute to both end organ failure and inflammatory factors that may induce an increase in vascular permeability and disrupts the blood ocular barrier in diabetic patients. What is next for our lead therapy? Once our ongoing analysis is completed, which we expect will be before the end of this year, we will plan for our next clinical trial in patients with wet AMD, where we will explore lower doses of ADVM-022 with alternative prophylactic regimens to support the best possible path to deliver ADVM-022 safely to patients. We saw remarkable durability and promising long-term safety from the OPTIC trial in wet AMD, in particular from patients in Cohort 3 treated with a low dose. Cohort 3 data, as well as learnings from this ongoing analysis, will provide the foundation for our next trial for ADVM-022 in wet AMD. Before I turn the call over to Julie, I want to say how grateful we are for the patients, investigators, the clinical sites, experts, and employees who are all essential in drug development. I'm inspired by the full dedication of our internal team and external advisors who are putting in long hours to support the best possible care for patients and investigate the data as part of this ongoing analysis. The team we have assembled at Adverum has extensive experience in gene therapy and ophthalmology and is committed to working cross-functionally to analyze the data and learn more every day so that learnings can be applied to patient care. Collectively, they are doing critical work to advance this field of gene therapy with novel treatments for patients with ocular diseases. I will now turn the call over to Julie. Julie? Thanks, Laurent. As you mentioned, we start with patients as the center of everything we do. We would like to provide an update on the initial patient and changes we have implemented into the clinical program to enhance patient monitoring and safety. In April, a patient who received high-dose 6E11 ADVM-022 in the INFINITY study presented with severely low IOP that was clinically relevant as it was associated with vision loss and worsening inflammation. This event occurred at approximately week 30 on study. This event of clinically relevant low IOP was unexpected, as it had not previously been observed in either of our clinical programs in wet AMD or DME or seen before in ocular gene therapy or anti-VEGF treatment. The patient was evaluated in person by three leading retina specialists across the U.S., and we consulted with additional expert advisors, including Dr. Kiss, who is on today's call, to determine the best treatment plan for the patient. The patient underwent surgery to repressurize the eye and steroid implant to manage inflammation. While it is too early in the patient's recovery to speculate on the outcome, at present, some ocular pressure and some vision have been restored to the treated eye. After this unexpected event, we immediately made the decision to prioritize patient safety by unmasking the INFINITY study. We immediately began a thorough review of all of the clinical data from the ADVM-022 program, as well as the preclinical data set. The INFINITY study is ongoing, and we continue to follow patients closely and review incoming data with advisors as patients progress through the study. While these learnings are in process, what we have seen to date shows us that disease and dose matter, and unfortunately, despite close monitoring and aggressive treatment, additional high-dose patients in INFINITY have experienced rapid, clinically relevant decreases in IOP refractory to steroids and have required subsequent additional treatment. Fortunately, no similar clinically relevant events have been observed to date in patients with wet AMD in OPTIC at either the high or the low dose, or in patients with DME in INFINITY to date treated with the low dose, and we continue to monitor these patients. While we have seen some transient decreases in IOP in patients treated with ADVM-022, as well as in patients in the aflibercept-only arm in the INFINITY study, to date, no similar clinically relevant events of rapid loss of IOP refractory to treatment with intravitreal steroids have been observed with either the high or low dose in OPTIC. It's important to note that patients in OPTIC have reached a follow-up of between 52 weeks and 2.5 years post-treatment. At this time, all patients in INFINITY have reached a minimum follow-up of 24 weeks. For the 12 patients with DME treated at the high dose in INFINITY, all patients are being monitored closely. Unfortunately, five of the 12 high-dose patients to date have experienced low IOP between 16 and 36 weeks post-treatment. To date, two additional patients have required surgical intervention. The remaining patients are being assessed and monitored closely by their PIs. We continue to consult with leading experts to review the latest clinical data and to guide the best treatment strategies. We have now recommended to initiate treatment with systemic immunomodulatory regimens to continue to further mitigate this risk. All INFINITY patients are expected to pass the 36-week visit in late September. Our plan is to present the INFINITY data at ASRS this fall. We intend to share our findings broadly with the medical community to help inform future gene therapy drug development programs for this emerging field. As a physician who's treated patients and has dedicated my career to developing new therapies for patients with ocular diseases, this period has been challenging for me and our team at Adverum. Patients are at the core of what we do, and we have shown that by prioritizing patient safety and unmasking the study immediately, supporting enhanced monitoring, and moving quickly to implement treatment strategies as data become available. We are grateful to these patients for their contributions to the immense learnings from this study that will be carried forward across all future gene therapy programs. We have received tremendous support from an extended team of expert advisors across the U.S. who have offered advice around the clock so we can collectively treat these patients who have experienced this dose-limiting toxicity, and we are grateful for their expertise and partnership. As Laurent shared, our review of the data shows disease matters. There are marked differences in the safety profile of ADVM-022 that we are observing in the wet AMD population versus the DME patient population. It is common for patients with DME to have underlying comorbidities such as severe cardiovascular disease, peripheral vascular disease, and impaired renal function. To date, our data review suggests that the IOP risk is much greater in DME patients receiving the high dose. We are still investigating the factors that may help explain why. The studies are ongoing. We are learning more each day as data and follow-up progress. The analyses we are running internally and with outside service providers are rigorous, involve outside expertise, deploy state-of-the-art technologies, and will take some time. We are also implementing enhanced imaging capabilities and interpretation to provide additional information. Before I turn the call back to Laurent Fischer, I want to take a minute to review the ADVM-022 data from OPTIC patients in wet AMD, which is a key reason why I was compelled to join Adverum. ADVM-022 in wet AMD has delivered durable efficacy not observed with current standard of care anti-VEGF injections. As presented at ARVO, after a single in-office intravitreal injection of ADVM-022, 60% of the patients treated with low dose were injection-free beyond one year. Wet AMD patients in OPTIC are between 52 weeks to 2.5 years out post-treatment, and the safety profile continues to be promising, particularly at the low [2E11] dose that we plan to move forward with. The team and I are motivated to advance this therapy because of its potential to help patients by reducing the burden of frequent anti-VEGF injections on them and their caregivers. We are working to complete our data analysis before the end of this year so that we can engage in discussion of next clinical steps with our advisors and the FDA. We are planning to develop a protocol for our next trial for ADVM-022, a planned phase II trial in wet AMD. While this analysis and the data from Cohort 3 of OPTIC will inform the protocol design, we know that we want to explore low doses, including 2E11 and a lower dose, and alternative prophylactic regimens to further mitigate potential risk in the future. We will continue to work closely with investigators and interact with the FDA during this process, we'll provide an update on our plans once closer to final. This fall, we plan to present additional long-term data from OPTIC in wet AMD, including 52-week data from Cohort 4, which evaluated the high dose with steroid eye drop prophylaxis, targeted for Retina Society in late September. I'll now turn the call back to Laurent. Thank you, Julie. I will now be joined by Dr. Szilárd Kiss to discuss a number of topics. Dr. Kiss, first of all, thank you for joining us on such short notice. It's great to have you today with us. You've been one of the retina specialists involved in ADVM-022 from the very beginning, from preclinical days of development, and you've also been involved in a number of gene therapy programs and other investigational treatments with the goal to extend the durability of efficacy for patients. What we would like to talk about today is to get your perspective on ADVM-022 first, on the AAV.7m8 platforms and methods of delivering gene therapy, whether intraretinal or subretinal, and maybe more broadly on gene therapy and ophthalmology, so that we can hear your thoughts on these topics and where we can go from here. First of all, when the patient experienced hypotony back in April, you were one of the first experts we called because of your involvement with 022 for the last six years. The patient was seen by you at your clinic. Would you mind describing what you observed and then recommended? Yes. Thank you, Laurent. Thank you for having me. Excuse the New York City sirens outside. It was really a group effort. I was among several retina specialists who actually examined the patient, then there were inside advisors at Adverum, as well as outside experts, members of the DMC and the SAB. Subject matter experts were also called in, experts on inflammation, intraocular diagnostics, and even experts on intraocular pressure. It was really a group effort between the Adverum group and the outside experts. When I saw the patient in my clinic, the intraocular pressure was low. Some minimal inflammation was noted in the eye, and I saw some steroid that remained in the posterior vitreous that was injected previously. Looking at the ultrasound, looking at the patient picture, and then discussing with the other experts that I mentioned, we determined that it was best interest for the patient to go to the operating room, really with the aim of re-pressurizing the eye and in the hope of restoring some vision. Some samples, of course, were also collected and sent for diagnostic testing to try to figure out what may be the underlying cause of the low intraocular pressure. Thank you, Dr. Kiss. These events are novel and completely unexpected findings in ocular gene therapy. Can you describe them a little bit and discuss how this is different than what you've seen before, either with gene therapy or the other anti-VEGF agents? I mean, Laurent, by definition, it's a SUSAR because it was unexpected. As you had mentioned previously, I've been involved in multiple gene therapy trials, intraocular trials, and even extraocular trials. To the best of my knowledge, this particular adverse event of low intraocular pressure has not been seen before. I think it's important to put it into context. It's a SUSAR in a subgroup of subgroup of patients. As I think Julie had mentioned that we're really talking about diabetic macular edema patients in the high dose. At this high dose in these diabetic macular edema patients, 26, 30+ weeks onward, for reasons that are beyond my understanding, the intraocular pressure is decreased. These are important learnings, I think, for the field as a whole, and they're important learnings as we conduct clinical trials with ADVM-022. I think it's also important to realize that this is a dose-limiting toxicity in a patient population, but in other patient populations, mainly the macular degeneration patients, and at other doses, the low dose, we don't seem to be seeing the same adverse events. Thank you for that. It doesn't appear that any of these events are linked with neutralizing antibody. I know we're still waiting for all the data to come back, but that's kind of an interesting fact. I think it'd be interesting to understand what you've seen with other drugs, and obviously side effect profiles can vary across different patient population. We've seen that with anti-VEGF more recently. What could contribute to these differences? Well, although primarily driven by VEGF upregulation, my diabetic patients don't look anything like my macular degeneration patients. Other than being nearly twice the age of my diabetic patients, my macular degeneration patients tend to be relatively healthy, 80, 85-year-old. I had a couple of over 95-year-olds today. Systemically, they're doing pretty well. It's just the eye that's affected. That's in great contrast to what we see with diabetic patients. These patients are very, very sick. They tend to be young, 40s and 50s. By the time somebody develops diabetic macular edema, diabetic retinopathy, they have severe comorbidities, including peripheral vascular disease, some heart disease. Kidney disease goes hand in hand with eye disease. Although they may be driven in the eye by a similar pathway, that is the VEGF pathway, they're very different patient populations. I suspect that this vasculopathy that is seen in diabetic patients, especially those that have eye conditions, may be contributing in some way to a different response to a gene therapy with anti-VEGF agents. Thank you, Dr. Kiss. That's very helpful. I'd like to get your perspective in light of this recent DLT in direct patients, how you view the efficacy and safety of ADVM-022 in wet AMD, and what would you like to see and understand in order to participate in the next phase II study we're planning in wet AMD, where, as Julie mentioned, we plan to evaluate lower doses, 2E11 and lower, and incorporate alternative prophylactic regimens. That's a great question, Laurent. We live and breathe these patients as retina specialists. First and foremost, in any clinical trial, in any investigative agent, patient safety is number one. After the patient's safety is checked, efficacy. You want to have something that's safe and that has some level of potential efficacy. Of course, the route of delivery. What are we going to do for the patient to get this treatment? When we understand these three factors, we are more confident in enrolling a patient in a trial and giving an investigational agent. I think the data that we have from OPTIC checks those three boxes, especially that Cohort 3 data set. There's favorable safety, efficacy, and a familiar route of delivery. Steroids, prophylactic steroids seem to be working much better than the DME populations. The doses for the safe response don't come close to the DLTs that we're seeing in the INFINITY trial. When you think about going forward, I agree with the company's decision to take a step back in a diabetic macular edema patients. There's something there that we have to understand as a field. There's something there that the company has to understand. I think it's very different when you look at the data and the long-term data in the AMD patient population. When you look at that population, you're decreasing a treatment burden that is severe for many patients, and you can see that threading of the safety and efficacy needle is beginning to be clear in AMD. Thank you. That's really helpful. I think generally people think, speaking, people would say that AAV gene therapy is overall safe, but of course, many novel therapies have dose-limiting toxicities as part of their drug development. I think subretinal gene therapy also has side effects. Maybe you can comment on those, but how do you view the intravitreal gene therapy and our AAV.7m8 platform, which is being used, beyond ADVM-022, as well as in GenSight Biologics' RP product, GS030, compared to subretinal delivery gene therapy? Laurent, that's always a question, right? 7m8 platform that Adverum is using is a novel platform. Intravitreal delivery is a route of delivery that we've been trying to crack for many, many years. You always wonder, is it the underlying technology or is it the patient population, or is it the dose? From the clinical data that we have thus far, it appears that it's the patient population and it's the dose. When you look at the AMD population with the platform of 7m8 and 022 specifically, you don't see the same dose-limiting toxicity. I think you bring up a very good point in terms of GenSight, a different transgene, but also using the 7m8 platform. There too, the low intraocular pressure that is noted in some patients in the high dose in the DME is not seen. I always tell my patients there is no free lunch, and that's true with long-term delivery. When you think about a benefit to risk ratio, you think about something that's given in the office via a platform that we use every day, that I used today, intravitreal injection, versus taking somebody to the operating room. There are inherent risks to the surgery itself, and there may be some side effects of the subretinal delivery. I think that when patients are given the benefit to risk ratios, it's something that they evaluate in addition to the investigator evaluating it. In the patient populations with AMD at the right dose, I think that needle is being threaded. Thank you very much, Dr. Kiss. I think given what you're saying and so the risk benefit of different therapies and what you've seen now being one of the experts who's seen the comprehensive data on ADVM-022, I think the question will be, would you put a patient on a future trial in wet AMD at doses of 3E11 and lower with an optimized prophylactic regimen? Yes. Knowing what I know, yes. I always say when working with companies, we're working with clinical trialists, I always say that we live and breathe these patients and their families. It's not a one-year trial, or it's a two-year trial. It's patients that we've known for years and will continue to know. For the macular degeneration patient population, with the data that we have from OPTIC, a low dose with a prophylactic regimen that's optimized, yes, I think that I would for sure put patients in the clinical trial and recommend it to them, and I know patients would be eager to sort of get over that treatment burden that we currently have with monthly injections. Great. Thank you very much, Dr. Kiss. I think with that, I'll now take some questions from the audience. Operator, we can queue up the questions. Thank you. We will now be conducting a question- and- answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions. Thank you, Paul. Thank you. Our first question comes from Alethia Young with Cantor Fitzgerald. Please proceed with your question. Hi, Alethia. Thanks for being on the call. Hi, this is Emily on for Alethia. Just a few questions from us. Hi, Emily. I was wondering if the adverse events that you saw were only at the high dose, why did you decide to discontinue the whole program? Is it because there were other concerns with the low dose, or was it just like a lack of efficacy or something else? How confident are you that these adverse events will not occur at the low dose or in your other studies with AMD? Thank you. Yeah. Thank you, Emily, for this question. Obviously, as we described, we've seen a very unexpected, for the first time described adverse events in the INFINITY study at the high dose in DME patients. Given what we've seen and the fact that it impacted now multiple patients, we decided that at this time it was prudent to discontinue the development of ADVM-022 for DME. We have not seen in our OPTIC study at either the 2E11 or 6E11 doses any such events of hypotony that required aggressive treatment and further evaluations. We feel much more confidence that given the differences in these patient populations and given the opportunity, wet AMD seems to be a much more straightforward way to get back in the clinic and at this time will be the focus of our evaluation. The difference between the two studies, one study is essentially we have all patients past week 28, some patients further out, that's in the INFINITY and DME patients. The OPTIC study, all patients are out beyond one year, some at two and a half years. We re-examine all these patients and ask them to come back for additional follow-up and monitoring. We haven't seen similar events. Obviously, there's a time course that is very different, and this is not like this happened just in one patient. In INFINITY, two eyes seem to have been a pattern. Very obvious, very different presentation at different time points. Julie, I don't know if you want to add to this. No, thanks, Laurent. I think you really sort of hit the key decision drivers here, right? We've seen this dose-limiting toxicity that is only appearing in the high-dose DME 1 patient population. We really do see a very distinct difference in the clinical profiles between the DME study and the neovascular AMD study. That's on top of the fact that the AMD patient follow-up, they've accumulated a lot more time on study, a lot more time for us to see how those patients are doing. We've not seen it there. Just to add that this is really meant to be a safety update. Emily will be presenting the totality of data later in the fall with both efficacy and safety at doses of INFINITY. Okay. Got it. Thank you. Thank you. Our next question comes from Luca Issi with RBC Capital. Please proceed with your question. Hi, Luca. Oh, terrific. Thanks for taking the call. Hey, how's it going? Absolutely. Thank you. Yeah. Yeah, just a couple questions here. The first is, I think all five AEs that were reported in the high dose of DME actually occur pretty late in the game. I think in some cases out of nine months post gene therapy. Wondering if you have any hypothesis for why inflammation can occur so late and maybe how should we think about implications for wet AMD. Maybe the second, wondering if you can provide any color on what is the alternative prophylactic regimen that you're exploring here or you're thinking to explore here. We've seen some companies exploring T-cell and B-cell depleter, at least for systemic gene therapy. Wondering if this is something that you're contemplating or maybe you have something else in mind. Thanks so much. Thanks, Luca. First of all, as you mentioned, there's a presentation of hypotony in the SUSAR occurred between roughly week 18 to 36, and was not necessarily associated with a high level of inflammation. A very different presentation than what you would necessarily expect. The root cause of the SUSARs are not known yet. That is the focus of our evaluation. The presentation and the timing of it is obviously very different from what we've seen in the OPTIC and wet AMD patients. We're collecting a lot of data, including going back to preclinical slides from our 7 NHP studies to try to understand what could drive potentially that immune response, which was not necessarily associated with visible inflammation. That will tell us how best to prophylax patients. Obviously, in the OPTIC study, as we've seen with steroid eye drops and other steroids, we've seen pretty effective prophylactic. We think there's quite a bit of room to improve from that. We'll be devising the phase II study design based on the totality of data in consultation with experts, AAV immunologists, as well as retina specialists with the input from the regulatory agencies to make sure that we can get back in the clinic in a phase II study at doses of 2E11 and lower with a safe prophylactic regimen. Got you. Any thoughts on what are some of the other regimen that you're contemplating here? We've seen people using tacrolimus, B-cell depleter, maybe rituximab. Is that something you guys are considering or too early to comment on that? I can have Julie comment a little bit on what we've done with the patients that are in the high dose in the DME study and what we recommend that we following up. I think it's premature to say whether these treatments are effective or not, but we are thinking along these lines as far as rescue therapy for patients who have obviously potentially severe dose-limiting toxicities. Whether those would apply for prophylactic or not is something we'll better understand as we see how these patients respond and react, as well as the data we get from all the exams, the specialized exam we're currently running in the INFINITY study. Julie, do you want to talk about the treatments we're proposing? Yeah, sure. Thanks, Laurent. Yeah, I think as we've been conveying on this call today, right, these events are unexpected. We don't have a good guidebook on exactly what the time course is going to look like for every patient, and what the different responses to therapies and sort of recovery journey will be for each of these patients. We continue to monitor all of the patients very closely. As these data become available, again, we're very lucky that we have the support of an extended team of experts that evaluates the data with us in conjunction with the PIs. We make the decisions based on what we're seeing. As we've talked about today, we have decided to add a broad immunosuppressive therapy to those patients that have received high dose in the DME study. Again, based on the review of available data and based on discussions with our expert advisors. Julie, thanks so much. Thank you. Thank you. Our next question comes from Graig Suvannavejh with Goldman Sachs. Please proceed with your question. Hey, thanks. Good afternoon. Hi, Graig. Thank you very much for the updates and taking my questions. I've got a few. One is really on the clinical development and regulatory path going forward. I just want to make sure I understood. Is the next step to conduct a phase II study in wet AMD and, I guess, in terms of what you had previously articulated as the plan going forward, I guess that's now been kind of put on hold. I just want to make sure I understood what the path was here, at least on the wet AMD side. I guess secondly, has the FDA been brought up to speed on your latest findings, or is it a situation where you plan on updating the FDA after you've concluded your full data analysis, which I think you indicated was expected by the end of the year? Great. Thank you, Graig. A couple of things. First of all, given the dose-limiting toxicities, we felt it was prudent no longer to pursue immediately phase III studies in wet AMD and take a step back and look at doses given the efficacy and safety we've seen at 2E11, no higher than 2E11 and even lower potentially, as well as more aggressive prophylactic regimen. This is a step back in a way because of something we've seen that was unexpected and our goal is to focus on patient safety first. The second point is, we've been obviously updating the FDA regularly on all these events. We have regular information we send to the agency. We intend to seek their feedback once we plan to get back into a phase II trial after we've analyzed all the data, and at this point, hope to get their input into the program. Okay. This might be, if I could ask just one more question, this might be a little premature. As we think about the potential revenue opportunity with this current program, is it still realistic to think that there is an opportunity beyond wet AMD, or should we be looking at this 022 program as strictly a wet AMD-only type of product? Thanks. Obviously, great questions. I think as you mentioned during the call, we now know that not all anti-VEGF therapies are suitable for all VEGF driven indications. That's true for other programs. We have decided at this time to discontinue DME. Obviously, should no longer be considered as a potential market, but obviously wet AMD is the largest market for anti-VEGF, and that will be our focus for the near term. Okay. Thank you very much and good luck. Thank you. Thank you. Our next question comes from Phil Nadeau with Cowen and Company. Please proceed with your question. Good afternoon. Thanks for taking my question. First of all, up to Graig's, in terms of the path forward, appreciating you haven't yet actually shared this with the FDA, it sounds like, I guess the fact is that there is now an association between 022 and these precipitous declines in IOP. I'm guessing the FDA is going to want you to eliminate or define the risk of that similar adverse event in a wet AMD patient population. Do you have any sense as to what the acceptable level of risk of a similar event in a wet AMD patient population would be, and therefore, how many patients are you going to need to have at a commercialized dose in order to file? Any preliminary thoughts on how big of a database you're now going to need to get the FDA comfortable with the level of risk in a wet AMD population? Yeah. Phil, first of all, thanks a lot for getting on the call. Really appreciate it. To clarify, first of all, we have been reporting all of these to the FDA, so the FDA is fully aware of all these events. Want to make sure that was clear. What we have not received yet is their thoughts and feedback on the development plan, which we have not submitted yet. That will be coming later this year, hopefully. I think the development of novel anti-VEGF agents is clearly based on the fact that the current treatments, while effective, require very frequent dosing, often not practical, available, or reimbursed. There's clearly an unmet medical need to develop longer-term agents. I can have Dr. Kiss comment further on that based on more recent reimbursement restrictions. There is definitely a need for safe and effective therapies. We will have to continue to demonstrate that, I think we will speak with the agency as far as the number of patients required. The development approval anti-VEGF therapies are based on non-inferiority studies, relatively large studies for all agents. We expect that we'll be held to the same standard. One of the main advantages is what we've seen is that the dose limiting toxicity we've seen in the patients with diabetes and DME was only at one dose and very clearly in a window of week 18-36. Obviously, we'll continue to follow these patients, we'll continue to follow them for five years at least. In OPTIC, we followed patients at both two and 6E11 from 52 weeks to two and a half years, we have not seen these events. This gives us great confidence that this is something unique to both the high dose and the DME patient population, and something that is seen unfortunately across many programs and particularly in gene therapy. Szilárd Kiss, if you want to comment further, I'd be happy to have you talk to fill in. Yeah, absolutely, Laurent. Actually, just latest developments. UnitedHealthcare, as some of you may have known, limited the number of injections to nine. A lot of pressure from the ASRS and other retina societies basically saying, "What do you mean nine injections only regardless of agent?" They just reversed it about an hour and a half ago. I think there's a huge unmet need for transformative therapy. I'm talking about something that really decreases the treatment burden, not extending it another month or two. My patients are asking for it. The healthcare system is asking for it, and this has the niche to fill. This can fill that niche, in the AMD patient population. We just have to find the right therapeutic window, which I think we have based on what we have in OPTIC. Dr. Kiss, I'd be curious to hear your thoughts on what risk of the IOP decreases would be acceptable in the AMD population. Is that something 1% of people? We haven't seen it. The data that I know from OPTIC and I know what you know is that this has not been seen in the AMD population. I think that going at a lower dose in different patient population, with the right prophylaxis to ensure that patients don't get any inflammation or any other side effects is going to be well-tolerated. Every day my patients ask me, "Is there anything else I can do?" when I'm giving them their 100th injection. I don't think it's going to happen. It hasn't happened in the clinical trials. We'll see as we go into a broader patient population. We'll see as we go into a larger patient population. One thing you have to remember also is that when you look at the efficacy in the OPTIC trial, these are heavily pretreated patients, right? These are patients that are anti-VEGF addicts. ADVM-022 seems to be performing very well in that patient population. I'm looking forward to expanding that where we don't have these VEGF addicts or anti-VEGF addicts in AMD and seeing what can be done to really transform the field. For diabetes, I think more to come. We only had an anti-VEGF injection and now, as we broaden with novel anti-VEGFs with gene therapy, we're beginning to realize that it's a different disease. I think taking a step back in diabetes is the right thing to do. Fair enough. Just two more questions from us. Quickly, I think I know the answer to this one. Was there any correlation between this effect and specific comorbidities other than diabetes? Any other comorbidity that consistently showed up in the patients who had the problem? Thanks for that question. Go ahead, Laurent. I'll let you take it. No, go ahead, Szilárd. We've had the world's experts. I didn't even know there were experts in intraocular pressure, but there are. There are experts in diagnosing of anything and everything inside the eye. The company and outside experts are working on it. There's nothing obvious that's come about so far. A lot of these things sort of take time to really analyze. The almost obvious question is: Is there any correlation with NAbs or inflammation? That does not seem to be the case, right? Everything that I could think of, that Adverum can think of, and that outside experts could think of are being looked at, and nothing that I know of has really popped out. All the obvious things have been looked at, and a lot of unobvious things are being looked at now. Perfect. I think the only thing I would add to that is what Dr. Kiss said earlier, is that DME patients who are much younger are much sicker and have often multi-organ disease and chronic kidney disease, peripheral foot ulcers, all these things. There's definitely a different profile with a much sicker patient population. That's all we can say at this point. Great. Last question, because I'm curious if you'd be willing to share the low dose in the OPTIC trial in AMD. How many patients are still on steroids or still have inflammation? Could you give us any updated data there, or do we have to wait for the medical meeting? No, we can share the data. Clearly, we've been very transparent. We'll share the totality of the data, obviously, at the meeting, but I'd be happy to have Julie answer that question. Obviously these things change, right? These patients have lots of things going on, cataract surgery, et cetera. Julie, do you want to answer the question? Yeah. At this point, amongst the two cohorts that have received the 2E11 dose, we still do have one patient receiving topical steroids. Perfect. Thanks for taking my questions. Absolutely. Thank you, Phil. Thank you. Our next question comes from Mani Foroohar with SVB Leerink. Please proceed with your question. Hi, Mani. Thanks for taking the call. Thanks for having me. I have what are two relatively boring, straightforward ones. How should we think about the impact on the tempo of R&D SG&A spend? Obviously, you guys are extremely well capitalized. How should we think about the impact of pivoting towards the phase II and then followed by presumptively future phase III on near term and then sort of longer term R&D spend? Secondarily, obviously moving into a phase II and wet AMD, different patient population, different dose level. What are possible preclinical models or other in vitro models that could be used to assess some of those non-obvious potential causes to provide a little more confidence around the potential safety as you go into early patients and other one in the Phase II study? We'll stop there. I do have one more follow-up. Great. I'll start and then we can have Chris DeRespino, our CBO and acting CFO, answer. Obviously, not going into phase III frees up quite a bit of resources to extend the runway, and we'll provide a full update on August 5 on the second quarter. Obviously, we brought on a CSO who has a remarkable track record in gene therapy, and we have an incredible team that has actually brought this 7m8 platform to the clinic with other programs that are preclinical that we look forward to share. We're being very careful about how we spend our cash because of the importance of extending cash runway in light of going back into phase II. Chris can add to that. As far as preclinical models, obviously, part of trying to understand the root cause of what we've seen is to review all the preclinical data from these 7m8 NHPs where we have tissue. We're going to start looking, we're doing tissue staining to try to understand what the cause is and see if there are models that can be developed to better understand that. It could be that this is what we describe as a dose-limiting toxicity, and you can't really tease it out or have a model that can predict it. That's a little too early to tell. Obviously, we are thinking about along these lines and we're making sure that our expertise in both capsid development and gene therapy product is put to good use in understanding the SUSAR, the root cause of the event, and moving back in the clinic with confidence. Chris? Yeah. Thanks, Laurent and Mani. Thanks for the question. I think not much to add there. Obviously, the focus of today's call is on the data update. What I would say is that, as you pointed out, we remain well-capitalized in order to achieve our objectives and are in a good position from that perspective. We look forward to sharing more at our earnings update later in August. With respect to R&D spend, clearly the next clinical experiment that we're planning is still in the early stages but will likely be a smaller clinical experiment than what we had previously planned for. Great. That's helpful. I guess another follow-up more on strategy. You mentioned that you're well-capitalized at the end of the last quarter of March 31st. You guys had a little over $400 million. Your stock's trading about $100 million discount to that and negative EV. Despite today's update, the stock's trading down further. As you think about the implicit view of your investors that your existing programs are destroying value versus a cash value of zero incrementally, how does the board consider the fiduciary responsibilities given the tremendous number of innovative biotech companies that are coming, the logjam in getting IPOs, the SPAC market, et cetera, which would imply there's a substantial and more value for investors and more safety for patients in not being exposed to ADVM-022 by pursuing the reverse merger route, bringing in potentially useful assets? If you could give us some how the board and how you yourself think about that opportunity versus continuing to those patients in ADVM-022, that would be really helpful. Thank you. Obviously, as you pointed out, we're trading below our cash value, which is unfortunate and somewhat understandable given the announcements of the SUSAR. There was unexpected the unblinding of a study in DME and the question around the value of the program. Based on what we've seen and hopefully made it clear on this call, we believe that actually ADVM-022 in wet AMD is actually a very promising future and meets a clear unmet medical need. Our focus has been really, A, on patient safety, B, on evaluating the path forward for ADVM-022 in wet AMD, and C, looking at all potential aspects of what creates value for all stakeholders, obviously, clearly including investors. Both the board and I are constantly thinking about these options. I would say as of date, our focus has been really on ADVM-022 in the pipeline because we believe that this has a great opportunity for patients as well as investors, and we'll need to get back in the clinic to demonstrate a path to clinical development. DLTs are not unique to this field, I've lived them through other programs, ended up being multi-billion dollar programs. Right now it's clear that we have a number of challenges we're dealing with, and we appreciate everybody's patience, including our investors, as we consider all options on the table. Great. Well, I'm going to echo everyone else and wish you good luck. Thanks. Thank you. Thanks. Thank you. Our next question comes from Joon Lee with Truist Securities. Please proceed with your question. Hi. Hi, Joon. Hi. Thanks for taking our questions. Do DME patients who get aflibercept or other anti-VEGFs also get ocular hypopyon as a known risk? The second part of the question is, you previously sort of pointed to viral capsid as the driver of inflammation. Given that this is happening 16-36 weeks into the trial, by which time viral capsid should be gone, can this be driven by something other than inflammation, maybe transgene product itself? I'm only asking because the steroid didn't seem to work. The last part of the question is, I understand that DME patients have a lot of comorbidities, including vascular disease, which you may be alluding to as a cause of the SUSARs. Isn't wet AMD patients, don't they also have vascular disease in the eye? Isn't that why they have a leakage in the eye? Thank you. Maybe I'll ask Dr. Kiss if he wants to try to give some of the answers to Joon's questions. Absolutely, Laurent. AMD and DR diabetic patients are very different. When we think about a vasculopathy, systemic vascular path, that's a diabetic patient. You think about high blood sugar, high blood pressure affecting blood vessels around the eye and then leading to leakage of fluid in the eye, causing diabetic macular edema, leading to blockage of blood vessels, causing the neovascularization. That process is very different than what we see in macular degeneration patients, where you have choroidal neovascularization. Typically, my macular degeneration patients are very healthy, otherwise they wouldn't make it to 97, 98. The underlying process that's driving it may be VEGF mediated, and that's proof in the anti-VEGF treatment's working. The patients look very different, and the vasculopathy that we think of in diabetic patients is different than the choroidal neovascularization that is the hallmark of wet macular degeneration. The other question I think that I could answer is in terms of low intraocular pressure, not that I know of. We've injected a lot of diabetic patients with anti-VEGF therapy, and sustained decreases in intraocular pressure is not something that I know has been seen, at least not with the currently available treatments. Thank you. In terms of what could be the cause that late into the trial. Capsid is gone by then, so is this a transgene? Is it the VEGF itself that you think is driving this hypotony? The answer is I don't know. I don't think anyone knows at this point. I think there's a lot of theories and hypotheses that are being looked at. If it were the anti-VEGF transgene, then one would suspect that you may be seeing it in other patient populations at the same dose. I don't think it is, but I don't know. It's something unique in the high dose in the diabetic patient population, that we're seeing this type of sustained decrease in intraocular pressure. I think you're correct in saying that it's not wicked inflammation that one may think of. I think more to come in terms of the neutralizing antibodies, but that's something that always comes up in terms of neutralizing antibodies in some of these patients. I think that what's been looked at so far doesn't seem to indicate that it's neutralizing antibodies. Okay. One last question. Typically, what causes ocular hypotony? What diseases lead to ocular hypotony? Any sort of learnings from that to what could be driving it here? Thank you. I think there are books written on what causes ocular hypotony. I think that each one is unique. After my surgeries, for example, not relevant to this discussion, a wound leak can cause hypotony. I think that the interesting features of what's going on in these diabetic patients in the high dose is that it occurs at some time after the injection. It's not a one or two or one month or two. It's really at later point where you wouldn't think that some of the factors that we can postulate cause low pressure are present. I don't think anyone knows. Thank you. Thank you, Joon. Thank you. Our next question comes from Patrick Dolezal with LifeSci Capital. Please proceed with your question. Hi, this is Valentina on for Patrick. Thanks for taking our question. A couple from us. First, we're wondering what specifically we can expect from the INFINITY data that you're planning to present later this year. Perhaps any data from the samples you mentioned collecting from patients on study or just any color you may be willing to give there. For Dr. Kiss, you've spoken on your perspective on the events that were presented today, which was very helpful. We're curious to hear specifically whether there may be any additional scrutiny by the KOL community around O22 and wet AMD, and how that might perhaps reflect on the willingness to enroll patients in future studies in the retina community more broadly. Thank you. Thanks, Valentina. Maybe Julie can talk first about INFINITY and what we're planning to present, and then we'll have Dr. Kiss answer the question on the impact of the DLT on the wet AMD program potentially. Thanks, Laurent. In terms of the data set, I think we're sitting on actually one of the most comprehensive data sets, I feel pretty comfortable saying, in a phase II study in DME, in gene therapy. Our intention is to share our learnings broadly with the community. We think there are really important key learnings here that can help everyone who's developing gene therapies in ocular diseases, in DME and neovascular AMD, that we all really need to understand. It's important for the field to learn from this experience and this data. Our intention is to share the data broadly. We will have the efficacy and safety data at that time. Obviously- on over to. Yeah. To Szilárd, or sorry, to Laurent for the next one. Yeah. Just quickly, obviously, the intent of INFINITY was to be a fully masked study comparing ADVM-022 to the standard of care, aflibercept. Once we unmasked the study, that had an impact on the conduct of the study as we evaluated efficacy and safety, but that was the original intent. Now the intent is to present comprehensive data from INFINITY, which is probably the largest phase II study in DME, and the first, actually, with a gene therapy product in DME patients. I'll let Szilárd take the second part of the question. Thank you, Laurent and Julie. I think it's an important question in terms of safety of our patients. That's the paramount in any clinical trial. Safety followed by any potential efficacy, especially in early trials. I think the data will drive the KOL's ultimate reaction. I think as Adverum releases data on the OPTIC trial and the data that's already out there, I think the differentiation between the disease states becomes evident. You're always cautious when you see a dose-limiting toxicity, and you try to get as much information as you can as an investigator so you can let your patients know. I think that when you have data, you've got to really rely on that data. The data that was presented at ARVO from OPTIC looks like it is a favorable benefit-to-risk ratio in AMD patient population. I think as more data is released, a longer-term follow-up, especially follow-up past where the SUSAR is being seen in the diabetic high-dose patients, I think the more confidence the KOL community will gain. There's such an unmet need that I think finding patients who want fewer injections is going to be something that will always be out there. It's just driving that decision based on the data that's out there on O22. Great. Thank you. Thank you, Valentina. Thank you. I am showing no further questions in the queue at this time. I'd like to turn the call back over to Dr. Fischer for any closing comments. Thank you, Paul. Thank you for joining us. As a reminder, we plan to report our financial results for the second quarter 2021 on August fifth after market. We can provide guidance on plans to extend our cash runway as we now plan for a phase II trial with ADVM-022 in wet AMD instead of two global phase III trials. We no longer pursue the development in DME, and we take a more measured spend for our commercial manufacturing facility. We'd like to thank Dr. Kiss for taking the time to share his thoughts and insights with us today. Also want to share our tremendous gratitude for the Data Monitoring Committee, the Scientific Advisory Board members, the investigators, the leading experts, the clinical sites, and most importantly, for all the patients who contribute to drug development in this new and emerging field of gene therapy. Of course, I want to recognize the dedication to patients shown by our team of employees at Adverum as we continue to work tirelessly to generate data to inform decisions on the best patient care and the path forward for ADVM-022 for patients with wet AMD. Thank you very much. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation. Have a wonderful evening.