Adverum Biotechnologies, Inc.

and welcome to the Adverum Biotechnologies conference call. At this time, all participants are in the 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 Maisha Lacey, Vice President of Investor Relations and Corporate Communications of Adverum. Please go ahead.

Thank you, Anastasia, and welcome, everyone. Today, we issued a press release to share our development planning for ADBM 022 for our wet age-related macular degeneration, or wet AMD program, recent business progress, and our fourth quarter 2020 financial results. A copy of this announcement is available on the press releases page of the investor relations section of our corporate website, www.advirum.com. Please note that a replay of today's call will also be available on the events and presentation section of our website. Joining me today is Dr. Laurent Fisher, Chief Executive Officer, Leonie Patterson, President and Chief Financial Officer, Dr. Aaron Osborne, Chief Medical Officer, In addition, we are honored to have Dr. Arshad Kanani of the Sierra Eye Institute and an enroller in our Optic and Infinity clinical trials join us today. As a reminder, we will be making forward-looking statements, which include our product development plans, research activities, and anticipated upcoming milestones and operations. 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 our quarterly report on Form 10-Q for the quarter ended September 30, 2020, and any subsequent filings with the FDC under the heading Risk Factors. And now I will turn the call over to our CEO, Dr. Laurent Fischer.

Thank you, Maisha. Good afternoon, everyone, and thank you for joining us today. I hope that everyone, including your family and friends, is staying safe and healthy. Before we begin, I'd like to personally thank Dr. Arshad Kanani for joining us today. We're very appreciative for his time, his deep expertise in the retina field, and his enthusiasm about the potential of our gene therapy product, ADDMO22, as a new and differentiated treatment option for patients with wet AMD and DME. Dr. Kanani is incredibly dedicated to his patients and to advancing new treatment options that have the potential to improve real-world outcomes. He's well known as an experienced investigator participating in many clinical trials. I also would like to thank all the patients, their families, and our investigators for continuing to enroll studies during this pandemic, which, as we know, is impacting this at-risk population of wet AMD patients we'll be talking about today. At Adverum, we're on a global mission to establish gene therapy as a one-time treatment that preserves patient sites for life. We are gene therapy pioneers, and we believe that we're at the forefront of disrupting the anti-VEGF market with our novel vector platform technology, AAD7 and 8. Our technology has the potential to dramatically alter the treatment paradigm for patients living with wet AMD and VME following a single in-office intravertebral injection, and we're keen to make it available to patients as efficiently and as soon as possible. Here's our agenda for today's virtual event. First, I will share some opening comments about our recent progress across the business. Next, Erin Osborne, our Chief Medical Officer, will provide details of our global Phase III program for ADDMO2-2. Then, Dr. Arshad Kanani will share a video of one of his patients living with wet ND who took part in our optic study. She will highlight her personal journey and the impact of ADDMO2-2 on her life. Then, I will have a fireside chat with Dr. Arshad Kanani. And finally, we'll take your questions. So I'm really excited to share today that we recently had a very collaborative meeting with the FDA and that based on the feedback from the agency on both the clinical development pathway and the CMC requirements for our pivotal program, we now have a clear path to targeted BLA submission for ADD-MO22 in wet AMD in 2024. As a reminder, we enrolled the first patient in OPTIC in late 2018 and have since made great progress advancing the development of our investigational gene therapy product. In uptake to date, we have observed that a single IVT injection of O2-2 demonstrates robust treatment responses with long-term durability and a favorable safety profile in well-ended patients who required frequent anti-AVGF injections to maintain their vision. Based on these positive results and the unmet need for a long-lasting treatment option, we proposed an accelerated timeline to the FDA to deliver ADDM022 to patients as quickly as we can. And now let me share with you the outcome of our FDA interaction. Previously, you may recall that we were planning to conduct first a Phase IIb study with a 2e and 6e11 doses, followed by a single Phase III study with one dose. With regards to dose selection, Given the impressive response and durability with 2E11 in this high treatment needs population and the predictable and minimal steroid eye drop prophylaxis, we have selected two doses that straddle the 2E11 to take into Phase III in newly diagnosed wet AMD patients. We're now moving directly to two global Phase III pivotal trials conducted in parallel that we plan to initiate in the fourth quarter of this year to support a BLA submission in 2024. We also plan to have interactions with international regulatory agencies in the coming months. These two phase three trials will be randomized mass studies, and we enroll a total of approximately 900 patients, comparing ADDM022 to Aflibrasan. We will evaluate two doses of ADDM022, one E11 and three 11, Importantly, we'll treat newly diagnosed patients in order to support a broad label in wet AMD. Finally, we plan to evaluate the potential for bilateral treatment with ADD-MO22 given the unmet medical need with up to one-third of patients developing bilateral disease. In a moment, Aaron will share additional details about our critical programs. Now let's revisit why we're focusing on developing a novel approach for the treatment of patients with wet AMD. We have conducted extensive market research, and we've had frequent discussion with retina specialists and patients, and our research has revealed that the largest unmet need for patients with wet AMD is for durable treatment that reduces the frequency of anti-VEGF injections for better efficacy, improved ease of administration, and better control of macular fluid. This is where ADD-MO2-2 fits in to addressing those patients' needs. If you look at the current treatment landscape, as well as treatments in development, we see that some approaches are extending the duration between treatment intervals by a magnitude of weeks. But ADD-MO2-2 is the only investigational non-surgical treatment option that has demonstrated long-term durability out to two years and is delivered as a single in-office IVT injection. and we plan to continue to follow patients in OPTIC out to five years. We believe that ADD-MO2-2 is uniquely positioned, unlike any other treatments on the market or in development, as an advanced gene therapy product with the potential to be a one-and-done approach for millions of people living with wet AMD globally. If we look at the clinical profile of ADD-MO2-2, including the recently presented data in GeoGenesis 2021, by Dr. Kanani, we strongly believe that ADD-MO22 has the potential to transform the treatment paradigm for patients living with wet AMD. Focusing on the 2E11 dose, you can see that two-thirds of the patients are injection-free for a follow-up of 68 weeks, and there's an 85% reduction in annualized anti-VEGF frequency. Importantly, This dose is a favorable safety profile and a predictable prophylactic steroid eyedrop regimen with no patients having any inflammation at the latest evaluation. With respect to the 611 dose, we continue to see remarkable durability and anatomical responses and a favorable safety profile. This dose is at the top of the response curve and is one that we continue to evaluate in DNE and plan to explore in additional indications of high unmet needs. We will share more about this in the future. Before I turn the call over to Aaron, I want to acknowledge that we continue to take precautions as a company to navigate the impact of COVID-19. We are optimistic to now have three approved vaccines, and we hope to return to normal soon. Despite the challenges during this pandemic, we were able to complete enrollment in our Infinity study in less than six months. and to invest in a new GMP commercial manufacturing facility in Durham, North Carolina. I would now like to turn the call over to Aaron. Aaron?

Thank you, Laurent. As an ophthalmologist, I've always believed that vision is our most important key sense. In our daily lives, unless it is being threatened, it's easy to forget just how essential good vision is to perform our day-to-day activities. Throughout my career, I've been fortunate to be involved with many of the anti-VEGF development programs, And I believe the progress that we have achieved with ADVM 022 has been a significant advance in the field of treating West A&D. We're excited to be initiating phase three trials and planning towards a 2024 BLA submission. Before going into further details on the planned phase three trials, I want to share some key data points from the OPTIC study that have informed the phase three study designs. Recall, The optic patient population represents a difficult-to-treat segment of the wet AMD patient population. These patients in optic required frequent and regular anti-VEGF injections prior to receiving ADVM022 in order to maintain their vision. As you can see on this slide from the swim lane plot, before ADVM022, these patients had frequent injections, whilst afterwards, following intravitreal ADVM022, the majority of patients at both of the doses have remained entirely free of anti-VEGF injections with a median of 48 weeks follow-up. There has also been a substantial reduction in injection frequency following ADDM-022 with both doses. At the 6E11 dose, we observed a 99% reduction in annualized anti-VEGF injection frequency, whilst at the 2E11 dose, we saw an 85% reduction. As for safety, ADVM022 has been well tolerated with a favorable safety profile for both doses evaluated. Overall, ADVM022-related AEs were mild to moderate with no severe and no non-ocular ADVM022-related AEs. Ocular inflammation has been managed with steroid eyedrops at both doses with no evidence of posterior retinal inflammation. Whilst average cellular inflammation has been low-grade with both doses, there has been minimal cellular activity and minimal steroid eyedrop use after a six-week prophylaxis regimen with the 2E11 dose. The most recent data that we shared with the FDA during our recent interaction showed that no patients receiving 2E11 in optic at the latest time point have any cellular inflammation. With the 2E11 dose in this optic population that previously required frequent anti-VEGF injections, across cohorts 2 and 3, we have seen sustained and stable anatomic improvements with stable vision. The phase 3 studies will enroll newly diagnosed patients with wet AMD at study sites around the world. The study designs and population will be similar to other treatment-naive intravitreal phase 3 studies in wet AMD, and they're expected to support a broad treatment label. Specifically, we will include both phakic and pseudophakic patients, and we will not exclude patients based on baseline serum neutralizing antibodies to AAD. In these trials, approximately 900 patients will be randomized to receive a single IVT injection of 3E11 or 1E11 of ADVMO2-2 or a Flivicept every eight weeks. Similar to Optic, patients receiving ADVMO2-2 will receive a two-month prophylactic steroid eye drop regimen. The primary endpoint will be non-inferiority to a Flivicept, based on change from baseline in best-corrected visual acuity at one year. Secondary endpoints will include safety and tolerability, any need for supplemental anti-VEGF injections post-ADVMO22, and change from baseline in central retinal thickness and other anatomical parameters as assessed by optical coherence tomography. Supplemental injection criteria will be similar to optic and based on vision and anatomic changes. We are now working with our investigators and regulators in the U.S. and around the world to finalize the study protocols and preparing for study initiation in Q4. We have had tremendous investigator interest in Optic and Infinity, and given the transformative potential of our in-office investigational gene therapy, we look forward to working with trial sites to rapidly enroll these studies. Before I turn the call over to Dr. Kanani, I want to share our future plans focusing on ABVM 022. In OPTIC, patients who complete this two-year study are now being enrolled into a three-year extension study, so these patients will be followed for a total of five years. We plan to present further data from OPTIC in the second quarter of this year, and these data will include longer-term outcomes, importantly one-year data from cohort three. The INFINITY study in diabetic macular edema is also progressing well. After completing patient enrollment earlier this year, we plan to present primary endpoint data from this randomized controlled study at a medical conference in the second half of the year. We are very pleased by the progress we have made in advancing our single IVT injection gene therapy for patients who are living with wet AMD and diabetic retinopathy. We have additional platform programs that are advancing as well, providing future opportunities for clinical development. I will now turn over the call to Dr. Kanani for a fireside chat with Laurent after we see a video of one of his patients sharing their experience living with wet AMD before and after ADVM022 as they participated in the OPTIC trial. This is an inspiring video that provides a patient perspective But before we share the video, I need to remind you that our esteemed legal counsel insists that we include a disclaimer about this video, which is a single patient's testimonial. Whilst this patient and the majority of patients in OPTIC have remained supplemental anti-VEGF injection-free, others have not. And obviously, we don't want to extrapolate these results to our therapy's potential as a treatment option for the millions of patients living with wet AMD. In sharing this video, we hope to bring the patient journey clearly into the picture. Patients are at the center of everything we do at Adverum, and this is why we are developing what we believe is a potentially transformative therapy. Let's play the video.

Okay, so first of all, Dr. Kanani, welcome, and thank you for sharing your patient's experience with us. It's very clear to me that you're incredibly connected with your patients as they rely on your expertise to manage their disease. I think you have a few slides that you'd like to share with us showing us how your patient responded to ADDMO2. Would you share a few comments around these slides, please?

Thanks, Laurent, and thanks for having me here. Really, this video is so powerful and so motivating. I have to take a deep breath every time I listen to it and look at it because this is why we are doing what we are doing. We are here to transform the lives of patients that we see on a daily basis who are struggling with this disease, the treatment burden, the uncontrolled nature of disease, even with frequent injections, and then having them an opportunity to live their lives and continue with their activities on a daily basis. So I am excited to be a part of this trial and obviously the prospect of this therapy going forward. I do have the slides here, if I can move to it. So this is the slide for this patient. So as you know, we discussed during the video, this patient who had persistent disease activity. So on the left, you can see prior to ADVM 022, that's an OCT where you can see those black cystic changes in the retina, and she does have some scarring underneath, and that's why her vision is not perfect. But even with frequent injections on a monthly basis, her disease was not controlled. And as you know, as physicians, we treat patients based on OCT. And Because of my early positive experience, I offered her the optic trial. You can see her baseline visual acuity was 63 letters. And after a single in-office injection of the low-dose 2E11, you can see how she looks like now. I just saw her a few weeks ago, and you can see 68 weeks after a single injection, you can see there's no disease activity. There is no fluid. and she has not required supplemental Flibercept injections for this time period. So that's why patients are excited. That's why physicians are excited. And that's why my colleagues that see this data and see the power of this drug are excited about it. Let's go to the next slide. Most of us have seen this case before. We have presented it at many meetings, including the latest angiogenesis meeting. But this is another patient of mine. And I think this case highlights two things. Number one, this patient was not controlled with four to five weeks of Flibercept injections. So you can see the CST fluctuations at the bottom where the disease is not controlled and the retina is getting dry and wet and dry and wet. And you can see there is fluctuations. And we know now, based on data from CAT and IVAN trial, as well as the Hawk and Harrier studies, the patients who have fluctuations in their CST actually do poorly long-term in terms of visual acuity. So when I look at this treatment, I not only look at having a single in-office injection that can essentially modify and control the disease for long-term in majority of patients, but I also look at this treatment as being transformative because we can have patients who will lose vision with regular, frequent anti-VEGF injections, and we can control their disease because we are getting such steady levels of FliberSap from a single in-office injection. So you can see on the left, patient had persistent fluid in the OCTs, and then after a single in-office injection, patient has done really, really well. You can see The BCVA has increased significantly to 83 letters, and the OCT continues to be dry at 48 weeks after the treatment. So really, Laurent, my goal here is to share my excitement and the patient's excitement with you today, and I am thrilled to hear that the programs are moving forward at a very rapid pace. Happy to take any questions you have.

Great. Thank you so much, Dr. Kanani. Really appreciate that color on this patient. You mentioned the potential to be treated in her other eye. What percent of patients develop bilateral wet AMD over time, and would you consider injecting the second eye with O2-2?

Absolutely. Laurent, the efficacy we have seen with ADVM O2-2, a single injection, has been so potent that patients in the trial are asking. So obviously this patient does not have bilateral disease at this point, but we know the risk of that is 10% per year. So most of my patients eventually will have bilateral disease, but the current patients who are in the trial actually are asking for it. You know, I talk about coincidence. I just saw a patient who finished a one year in the trial. And I asked her how her experience has been, and she's like, it's been fantastic, but my problem is you're not giving this treatment in my fellow eye, and I still have to get those injections. And when can I get the treatment in my fellow eye? And I said, you know, in clinical trials, we put the treatment in one eye, but obviously the potential for having treatment in the fellow eye is there. So absolutely, I think all of my patients in the trial who have fellow eye disease will be more than happy to receive it in their second eye.

Thank you, Dr. Konani. And obviously, as you recall, we did an NHB study showing that you could do that safely at the peak of immune response and see still, you know, a very good protein expression level. So we're planning to look into the potential to look at bilateral studies in the future. and that's very exciting to hear that. You presented the latest optic data at the angiogenesis meeting. Can you tell me how that data was received by your colleagues?

Absolutely. So, you know, we had a live presentation. It was not a prerecorded, and you saw Dr. Phil Rosenfeld, you know, raising the question that intravitreal approach obviously is more favorable than other approaches that we have seen. And, you know, my colleagues, I think the number one thing is the fact that you can deliver this in an office setting, like a routine intravitreal injection. And that procedure is all of us around the world can deliver it without having any special skills that are needed. So my partner, who is actually retiring soon, said, why would anybody look at any other mode of delivery? And my answer was the same. I gave it to Dr. Rosenfeld that I think we're still learning about gene therapy. Obviously, intravitreal is the preferred approach because we can treat patients around the world for this chronic disease. And really, the efficacy, when they look at that case, I think the efficacy is phenomenal. I get so many texts every time I present that case. They're like, how is the patient doing now? How is the patient doing now? And I think what we are all impressed with, not only the control of disease you know, initially, but continued control of disease throughout the patient course. And the patient is still in the trial and doing really, really well. So I think the power of a single in-office injection, the easy delivery, and then the continuous efficacy that we see with this, you know, approach has been very impressive. And, you know, my colleagues who do research, they're like, we want to be involved in the next trial. We want to be part of this because we feel like there is value to it. It's not an incremental benefit. It's really game-changing in terms of transforming how we manage patients with this lifelong disease. So I think the excitement is clearly there when I talk to my colleagues.

This is good to hear. So in terms of patient involvement, if you compare, you know, this, 900-patient trial to other trials that may require surgery. Can you talk about, you know, enrolling patients in this study? Do you anticipate any hurdles? Let's talk about previous trials like fericimab and other antiretroviral trials that enroll actually over 1,000 patients in a short time. How do you see that going?

Yeah, that's always a good question, right? How is the trial going to recruit? So because of the exciting data we have, I think investigators with research arms and top sites in the world are going to be, of course, excited about this trial. And then that next question is competitive landscape for trials. And, you know, we were the top site for the TANIA study of paracetamol. We are the top site for the DAZZLE trial for KSI301. And I can tell you that we enrolled those large trials as a community, as the retina space, within less than 12 months. And those, especially the Tenaya study, as you mentioned, is very, very large. So not having another competitive trial for naive patients, having this solid data from optic trial, I think there is going to be excitement. And I think all of us will want to participate in this study And I can confidently say, based on my experience being a top site in many of the naive AMD trials, that we should be able to recruit this trial within one year or less. And I think it's all going to be very good for our patients. The sooner we have this treatment for our patients, the sooner we can help patients around the world who are suffering from this chronic disease.

Obviously, we're very excited to partner with you to end all these studies as soon as we can start and look forward to also doing that globally. We talked about different delivery methods for gene therapy and either, you know, improvement and development. Can you walk us through what it's like to do a surgical procedure for a subretinal injection compared to an IVT injection?

Yes, so as I mentioned, Laurent, it's our job as researcher and clinicians to look at different delivery options and different treatment options for our patients and then look at, you know, efficacy of those approaches. So as you know, I'm also an investigator and a PI for Regenexx Bio subretinal delivery as well as GT005 for dry AMD, that gyroscope, as well as I'm a PI for supracordial approach. Your question about subretinal delivery obviously is something that after you have experience, you can perform that procedure. But obviously, going to OR is a bigger hurdle than delivering something in an office. So let's say I see a patient today and I do the screening for them. And then if everything looks good, I can bring them to clinic and randomize in a trial. Versus if I have a patient that needs to go to the OR, we have to have our staff coordinate that patients need to, you know, be ready. They have to go for a pre-op. They have to, you know, stay off their anticoagulant. And that's just not, you know, subretinal gene therapy. I'm also, we were one of the top sites for the poor delivery system, which is a surgical trial too. So obviously arranging and having patients go to surgery is a much bigger task on my coordinators and staff and then you know when you are in surgery obviously the companies want to you know make sure everything is done right so they have to coordinate their schedules to be available for surgery so yes it's doable it's not a problem but obviously anything in clinic whether it's intravitreal or supracoital is easier but obviously as you know the supracoital studies are going on and we don't have any data yet and that's a specialized procedure meaning that People around the world are not used to doing it, and they will need to be trained on it.

This is great. I'm always so impressed to see how many studies you're involved with. On top of all the patients you see, it's really great to have you as an investigator in our trials. Talking a little bit about kind of current standard of care versus the future, we know that real-world data is not as good as clinical trials. How do you see the treatment paradigm shifting from these current, you know, regular injections and follow-up to potentially something that O2-2 could bring as an option?

Yeah, Lohan, that's what I am after. I want to make sure that my patients do well long-term. We see these patients, they get treatment, they do fine in the first year, things start to slip in the second year, and then you look at four, five, six, or seven years. You know, we have CAT seven-year data, we have seven-up studies, these patients end up with really poor vision long-term. And of course, treatment burden is the biggest issue. And your comment about, I'm involved with everything because I'm involved with everything because I want to make lives better for my patients. And now I'm serving as a PI for almost 60 clinical trials. And this is an exciting time for our space. But when you look at our space, you have to divide treatment options into two buckets. You have to divide Treatment where you can do an intravitreal injection and be incrementally better in terms of durability, so you can add a month or two months or three months on top of what we have, and that's great for patients. And, you know, things like Fericimab and KSI-301, GB-102, those programs are moving forward, and that's really exciting. But then the other part is sustained delivery, the continuous delivery of which can lead to the disease control, which is very difficult to achieve with intravaginal injection, and that you saw in my case that I presented. So when you look at that, that is the paradigm shift that's happening. Obviously, poor delivery system has started that, but it's a surgical procedure in the OR, so it has its own, you know, risk and benefits, and it's not really a primary treatment. But what I see is I see O2-2 as a primary treatment for these patients after the we have controlled their disease. Of course, the trial with naive patient will give us more idea, but if I see a patient in my clinic that have naive disease, I'll do an intramural injection, obviously, and then get them primed up to go into, you know, receiving gene therapy for O2-2. So I think it's a chronic disease with poor long-term outcomes and treatment burden can easily be reversed with this approach. You saw the case I presented, both of those cases, and these are real patients that have really benefited from this approach.

Thank you, Rishabh. That was really a great and clear explanation about the potential future treatment of wet AMD. Any thought on the global impact this could have when you think about availability of anti-VEGF at a global level, particularly in DME?

I think it's going to be huge, Laurent. Both, in my opinion, New Vestlar AMD and DME. I mean, you see around the world, you look at, you know, India, you look at Mexico, you look at Africa. I mean, they don't have resources and they don't have the manpower to deliver, you know, continued monthly or every other month injection. Here we can modify these lifelong chronic diseases with a single injection. And obviously you have to initially monitor these patients. And as Erin said, I mean, you know, this is not a continuous process. I think once they've finished their topical drops and they're controlled, then you know, telemedicine would be huge. Telemedicine has really exploded because of COVID-19, and anybody can monitor these patients afterwards. So I think after the initial dosing, we monitor, but then after that, I mean, I'm not looking forward to seeing these patients every month or every other month, maybe every six months if they want to come in. So think about patients waiting for treatment around the world because they don't have access. You have one and done therapy, that's going to really help the patients and physicians be able to treat more patients because they don't have to treat them continuously. So I think this is going to be huge if efficacy continues to be, you know, as good as we have seen in uptake and then the manageable safety.

That is great. Thank you so much, Dr. Kanade. I want to take advantage of you being here to actually have some of our audience ask questions. So maybe we'll... open the call for questions, and then I'll direct them. So, operator, if you can open the call for questions.

Certainly. We will now begin the question and answer session. To join the question queue, you may press star, then 1 on your telephone keypad. You will hear a tone acknowledging your request. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star, then 2. We will pause for a moment as callers join the queue. The first question comes from Greg Souvenay with Goldman Sachs. Please go ahead.

Yeah, thanks. Thanks very much. And Dr. Kanani and the team, thanks for doing the call. This question is for Dr. Kanani. It's great to hear from you again. Just wanted to get your thoughts on the company's strategy of moving to a different dose than what was evaluated in the OPTICS study. And more specifically, you know, with the lower dose and the higher dose of one and three, what do you expect to see from those two doses? And perhaps more importantly, what, you know, what do you need from to see from those two doses to feel comfortable with the profile that you've seen thus far. And perhaps if I could then ask a question of Laurent. I just wanted to revisit, you know, the program. And I think, you know, we've been waiting for some protein expression data. Just wondering if there was an update on that. And then the last follow-up there would be, or a different question would be around DME and what are the current thoughts that we could perhaps take away from this with DME timelines. Thanks.

Hey, thanks, Greg. Before I pass it on to Dr. Kanani, I think it's important to know that what's unusual about this program is that we started our first study in the hardest-to-treat population with a dose we thought would be the last dose where we had actually 100% of the patients who had no need for additional anti-VEGF injection. So, we started at the top of the dose-response curve, and as we know in gene therapy, those are fairly flat. So, that 2E11 was, we thought, a great dose to straddle around. Now, going into first-line therapy, less demanding as far as anti-VEGF needs patients to really provide enough dose-response between what we've seen and what we believe will provide a good target product profile, but I'll let Dr. Karani answer in more detail.

Thanks, Laurent, and Greg, nice to hear from you, obviously. So I think your first question is the strategy about going 3E11 and 1E11. I think, in my opinion, that's an excellent approach because we have seen great efficacy with 2E11. So you can see both of the cases I presented today are actually from 2E11, and these are patients who were not controlled with injections that were very frequent every four to five weeks. So I think I'm expecting very potent efficacy from 3E11. And then, you know, as Laurent said, I think we need to remind ourselves the fact that these were heavily pretreated patients with longstanding history of their disease, and really tough to treat population. So since the pivotal, as Erin mentioned and gave a really nice overview, are looking at naive patient population, and those are fresher patients, and we know based on our experience, the sooner you treat the patient, the better control you're going to get. So in a naive population, I can easily see that even 1E11 can be beneficial. So I think In terms of having both doses, I think it's the right decision, in my opinion, and obviously people who are involved with designing this trial. So I will pass it to Aaron. Aaron, do you have any comments on top of what I mentioned?

No, I think that's exactly right. I mean, we've seen a favorable safety profile with both of the doses. What we've seen is that there's been a really strong anatomical response and great durability with both of those doses. As we've tracked the data longer and longer, you know, I think the lower dose, 2E11, has sort of pleasantly almost surprised us by this continuing great signal. It's kind of epitomized by those two patients that Dr. Kanani presented. And on the flip side, you know, if you look back at the higher dose, we're going to continue to evaluate that. We're evaluating it in DME. It's possible that in the future, you know, there are other indications that may benefit from, you know, the VEGF blocking ability with that high dose. We've already presented protein expression data from two patients who received that high dose, which really corresponded with about three weeks after an aflivicept bolus injection. You know, as we go forward, we'll certainly present more protein expression data, but I think those data give an idea of just you know, how robust that protein expression is. And as we look at the lower dose, we've got that continued stable visual acuity and anatomical response, again, in these tougher-to-treat patients. So going to 3E11 and 1E11, two doses that straddle that 2E11, provide some additional dose ranging. That seems to be an optimal approach for Phase 3, and it's something that we discussed, you know, with the agency, and they were in full alignment that this seemed a good approach.

and maybe just on DME timeline.

But we'll continue to present, yeah, we'll continue to present, obviously, data on protein expression as they mature, and we'll present data, one-year data on cohort three, and then one-year data on all the cohorts, including cohort four. And then DME, we're studying both doses, two and 6E11, and studies being fully enrolled. It's blinded, and we'll report, you know, in second half, as soon as we have the top-line data, obviously, Given this is a potentially large indication where we're going to look at DME as well as DRSF, so potential to go into DME or DR, the study is positive. We'll obviously report once we have this information.

But fair to assume it could be instead of a combined filing and SNDA or SBLA strategy?

Currently, we have two different INDs for each indication, and that's the case with most entire NGFs. So they're treated by the of separate indications. And to be discussed, obviously, once we have data and plan to move forward. Any other questions? Otherwise, we can move to the next caller.

The next question comes from Tyler Van Duren with Piper Sandler. Please go ahead.

Hey, guys. Good afternoon. Thanks for taking the questions. First, I wanted to follow up on the design. Are you assuming lower bound of the non-inferiority margin to be minus four or somewhere around there? It would be helpful if you could confirm that as well as the standard deviation of vision that we should be assuming for this newly diagnosed patient population at these doses. And then the second question or topic is related to The supplemental injection criteria I picked up on the slide that said it was similar to optic, so maybe not the exact same. So can you just maybe discuss exactly what it will be and how it will be handled if, you know, the incentive to treat change in BCBA will be, I guess, analyzed independent of supplemental injections?

Yeah, I'll let Aaron answer this question. Thank you, Tyler.

Perfect. Thank you, Lauren. Thank you, Tyler. Yeah, this will be a non-inferiority study against the Flibercept standard of care. And similar to sort of other treatment-naive studies, that non-inferiority margin, it would be four letters. So that means that the lower bound of the confidence interval for ADVMO22-related visual acuity needs to be within four letters of the point estimate for the control arm. So that's That's kind of established and has been used in several trials before. Where we're a little bit different, and we spent time with FDA on this, is how do we get to a number per arm that is actually much less than previous trials of approximately half the number? And that goes kind of to the second part of your question, which is standard deviation, which is driven a lot by the gains in visual acuity that are often experienced following the first injection. So what we plan to do with this study is actually take patients who are treatment naive, they have one injection, and provided they show a response to that and an anticipated need for further treatment, then their baseline starts at that point. They would then receive another ilea injection and receive ADDMO2. So they're still on the up phase of gaining visual acuity on average, but a lot of that initial gain has already taken place, which then means that the variability is reduced. So we expect the standard deviation to be significantly lower than it would be for a typical treatment-naive study, such as the ferrisimab or brolicizumab studies that Dr. Kanani mentioned. So the standard deviation is lower than it would be for those studies. So that's the non-inferiority and the standard deviation. I think the final question was on the re-treatment or supplemental anti-VEGF criteria. And, yeah, I mean, we plan to keep those similar to optic. Obviously, we want to minimize any changes going to these pivotal trials. We've seen great visual acuity maintenance in optic, great anatomical maintenance. And it's really always, you know, striking that balance between making sure that patients are optimally treated and they get the best possible visual acuity outcomes, whilst, you know, also avoiding administering injections that are not needed because maybe there's a constant gestal depression ongoing in the background. So we would plan to keep these very similar to Optic. We've got a little bit of time before reaching our very final protocol, so we'll continue to monitor the data in Optic. And as we speak, you know, to physicians and regulators, particularly XUS as well, you know, we'll keep the final precise details under wraps until we get a little bit closer to the time. But don't expect anything particularly different from Optic.

Very interesting. Thank you.

Thank you, Tyler.

The next question comes from Manny Furhar with SVB Lyrics. Please go ahead.

Thanks for taking the question. Obviously, you've gone through a lot of detail here. I want to have a little bit more nuanced question around what you've seen in terms of change in patient behavior during the pandemic period. how that's influenced patient enrollment across trials, given that you're an investigator across many different AMG trials, and how as we see the pandemic ease, resolve, whichever phrase you want to use, could we see a shift towards less severe patients as fear of coming to the office goes down? Just how do you think of that impact in terms of the population that gets enrolled into these two Phase 3s, versus perhaps populations that might be being currently enrolled in other clinical trials that were actively enrolling that you were a part of during the height of the pandemic?

Hey, Manny, thanks for this question. Great question. Obviously, I just, you know, as a reminder, we fully enrolled in the Infinity Study during COVID-19, all remotely in six months, which we thought was pretty remarkable. But obviously, Dr. Kanani is in the best position to answer your question about how this has changed and how this will change in the future.

Thanks, Manny, and thanks, Laurent. So I think the main thing to point out is that VET-AMD is a disease that can lead to irreversible blindness in patients. And if you don't get them treated, they're going to go blind. So even at the height of pandemic, you know, Throughout the pandemic, we have been really being good in terms of taking care of all the patients in the trials as well as our wet AMD patients. So we cut down patients who were routine follow-ups, but we continued injections, and we managed our study patients in a very unique way where we were able to, you know, provide them with isolated visits, weekend visits, after-hour visits, also putting in COVID protocol that have worked really, really well. So our wet AMD patient population enrollment in other trials didn't stop because of it. Some of the geographic atrophy trials were put on hold because those patients don't see an improvement and it's not an emergency for them to get into a trial. So wet AMD trials have done well, but I tell you what COVID has made us realize, and I think your question is very pertinent, As physicians, we cannot have patients coming in every month or every six weeks during this pandemic. These patients are high risk, also the diabetics. So really has put in our heads that we actually have to have therapies that are sustained over a long time so that patients don't have to come to our clinic. And that's why ADVMO 2.2 is a perfect fit for getting us ready for having, God forbid, another pandemic or having us in a situation where we are putting our patients at risk by bringing them to a clinic. But in terms of treatment, you know, enrollment in all the trials, we really cater to the clinical trials, and I don't see a difference in terms of enrolling patients in these pivotal trials. Most of my patients actually have been vaccinated now. I ask every single one or receive their first dose. And it is really promising to see that the numbers have also gone down significantly in our area because of COVID. So it really appears that things are hopefully going to be getting towards normal in the future.

Great. Thank you. I know we have a few more analysts in the queue, so we'll try to take them. Thanks, Mai.

The next question comes from Phil Nadu with Cohen & Company. Please go ahead.

Good afternoon. Hi. Congrats on the progress. A couple questions from us. First, on the O2-2 dose and inflammation, I think you mentioned that there's no cellular inflammation at the most recent time point. Is that correct? Did I hear that? And could you tell us whether patients are therefore in that dose all off steroids, and if so, for how long?

Anne, do you want to take this?

I can take that. Yeah, of course. Yeah. So, I mean, we did a data, the most recent data that we presented from a data cut in October of last year. And these are the data we presented at angiogenesis. We did review our data as we went into the FDA meeting. And really everything that we've seen is consistent. And we looked specifically at the numbers of patients who had any cellular inflammation or were taking steroid eyedrops. And on the low dose, I recall, no patients have any signs of cellular inflammation. There are three patients that were taking steroid drops at that point. So, I mean, this kind of plays into the decision to go with two doses around the 2E11. Whilst both have shown a really good safety profile and great efficacy, we're seeing, you know, really minimal episodes of inflammation after the prophylactic period and minimal steroid eye drop use after that prophylactic period as well with that low dose, whereas You know, there's been a few cases where patients have needed to go back onto steroid eye drops a little later with the high dose.

Great. And then the second question is on Aflib Recept in the comparator arm. How will it be dosed? And more generally, how did you come upon your assumptions for the visual acuity benefit you're going to get? It does seem like there's some risk that you now have to match the full-dose, or what I'm assuming is full-dose, F-librecept in the control arm in patients whose visual acuity is actually improving in their first year of treatment. So what gives you confidence that you'll be able to achieve that?

Yeah, that's a great question. So we'll be comparing to standard of care F-librecept, as in the label, which is three initial injections for a treatment-naive patient, followed by dosing every eight weeks. That's the standard comparator regimen that has been the case for the recently completed furosemab trials and paracizumab trials. In terms of what gives us confidence that we would be able to achieve that, I think it really comes back to the data points that, you know, presented today. When you look at cohorts two and three together at that low dose, in these difficult-to-treat patients that required many injections, the vast majority are rescue injection-free. And what we've seen is anatomical improvements. that had remained constant throughout all of the follow-up. That steady line that you see on the CST is, you know, frankly, it's extraordinary. And I think it's something that we have not seen before with a single injection or single treatment therapy. So that continual VEGF suppression, and we're seeing in some of the patient cases as well, that is actually leading to vision acuity gains. Really, we need to do as well as anti-VEGF therapy. I think what we're seeing in optic is that some patients are doing better than regular anti-VEGF therapy. So, You know, that's really predominantly what gives us the confidence. If we can stabilize the retina and restore the anatomy, then what should follow is that the visual acuity will improve, and we have a trial that is set up to show that.

Great. And then last question from us, just to Dr. Kanani. Let's say the profile in Phase III looks exactly like what we've seen, meaning patients are 67% injection-free, or 67% of patients approximately this dose are injection-free. How will you monitor patients in your practice? How often will you bring them back? Are there any signs that you can look for remotely to see if patients are having the disease process return?

Yeah, so that's an excellent question. You know, based on learnings from the OPTIC trial is that we have to see these patients, you know, more frequently initially. So I would say within the first six months of treatment. we'll have to, you know, see them maybe once a month. But afterwards, I think they can be monitored. Remember, all the inflammation here is anterior. There is no cases of posterior vasculitis, retinitis, or anybody with irreversible vision loss. So I think that's something to keep in mind. So patients can be monitored, you know, by optometrists or somebody else if they need it to be, and then they can be treated if they need to with topical drops. But my confidence comes from being an investigator in OPTIC and enrolling the highest number of patients. I feel like after the initial monitoring phase, patients can go much longer. I mean, I have patients who have been in this trial for one and a half years, and they keep asking me, why am I coming every month? And of course, in trials, we do that. But in practice, I think we can easily extend these patients once they are stable to six months.

That's very helpful. Thanks for taking our questions.

Great.

We'll take maybe one more question.

Yeah, we'll take one more question.

We have time for one more questioner. The next question comes from Alicia Young with Cantor Fitzgerald. Please go ahead.

Hey, guys. Thanks for taking my question. Hi, Alicia. Thanks for taking my question and congrats on the progress. I guess I just wanted to talk a little bit about, yeah, that's awesome. I want to talk a little bit about, like, you know, some secondary endpoints and the importance of, like, you know, kind of the rescue regimen as an endpoint that the FDA is thinking about maybe as a secondary. And I guess that's the same kind of correlated question to the doctor. I mean, in a way it feels like visual acuity, I mean, is obviously what the FDA needs, but, you know, this rescue notion is what probably doctors may want. is my first question. And my second question is a little bit more straightforward. Are there any kind of interims or any other analysis baked in before 52 weeks? Thanks.

Dan, do you want to take that? Yeah, I can take that. The second one's straightforward, actually, first, which is because these are registrational clinical trials, there would be no interim analyses. We would analyze the primary endpoint at one year and intend to use those data to support a BLA submission. You know, with regards to secondary endpoints, you raise a great point. There's a lot of different ways that we can look to differentiate this therapy. And one of the key things that we're learning more and more about is the fluctuations in anatomy that a patient's experience with currently available anti-VEGF agents And the fact that those fluctuations really lead to fibrosis, they lead to atrophy, and they lead to poorer long-term outcomes. And this is coming through, you know, these data are coming through more and more. So a product that can maintain stability could potentially reduce fibrosis, reduce atrophy, and lead to better long-term vision outcomes. That's why kind of primarily we want to follow patients long-term. But we'll also be looking at a number of OCT analyses that could potentially, you know, build that story up more and let us understand more about what that stability with O2-2 can lead to in terms of anatomical and functional outcomes. That's probably all I need to say on that one at the moment.

Great, thank you.

This concludes the question and answer session. I would like to turn the call back to Dr. Fisher for any closing remarks.

Thank you, operator, and thank you all for joining us. This has been really a great discussion. I'd like to thank Dr. Kanani and his patients for sharing their journey with us, as well as all the investigators and patients who participated in our clinical trials. I also want to acknowledge the important and incredible work that FDA has done during COVID-19 and great outcome. We certainly appreciate the guidance the agency gives to companies as they work to develop new therapies for patients with unmet needs. And last but not least, I want to acknowledge the commitment and hard work of our team of invariants, who bring their talent and expertise to work every day to advance our global mission to establish gene therapy as a one-time treatment that preserves patients' lives for life. I'm really enthusiastic about where we're heading as an organization, building on our 2024 vision to become a fully integrated gene therapy company. We're clearly focused on execution with our lead investigational gene therapy candidates, ADDM022, for two leading causes of blindness, with the goal of delivering this potentially transformative gene therapy to patients around the world. We're also continuing to develop our pipeline in ocular and rare diseases, leveraging our proprietary 7M8 and LSD1 platforms with the goal of filing an IMD in 2022. I hope everyone is staying healthy and well. We look forward to updating you on our continued progress in the future and wish you a good day. Thank you.

This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a pleasant day.