ADVM - NASDAQ

Thank you for standing by. This is the conference operator. Welcome to the Adverum Biotechnologies Conference Call. As a reminder, all participants are in a listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. [Operator Instructions]. I would now like to turn the conference over to Myesha Lacy of Investor Relations and Corporate Communications. Please go ahead.

Thank you, operator, and welcome, everyone. Today, we issued a press release to share new data from our OPTIC Phase 1 clinical trial of ADVM-022, report our financial results for the second quarter of 2020 and provide a business update. A copy of this release is available on the Press Releases page of the Investor Relations section of our corporate website at www.adverum.com. Please note that the reply of today's call and a copy of today's slide presentation will be available on the Events and Presentation section of the IR portion of our website. Joining me today is Dr. Laurent Fischer, Chief Executive Officer; Leone Patterson, President; Dr. Aaron Osborne, Chief Medical Officer; and Thomas Leung, Chief Financial Officer. In addition, we are honored to have Dr. Arshad Khanani, Managing Director and Director of Clinical Research of Sierra Eye Associates, Clinical Associate Professor of Ophthalmology at the University of Nevada, and our top enrolling principal investigator in OPTIC. And Dr. Khanani is also a principal investigator in the INFINITY trial. He will present the new OPTIC data. After his presentation, we will open up for questions. As a reminder, we will be making forward-looking statements, which include our product development plan, research activities, anticipated upcoming milestones and operations, as well as our financial outlook. These statements are subject to risks and uncertainties that may cause actual results to differ materially from the forecasted. A description of these risks can be found under the caption Risk Factors on our latest Form 10-Q which was filed this afternoon. I will now turn the call over to our CEO, Dr. Laurent Fischer.

Thanks, Myesha. Good afternoon, everyone. And thank you for joining us today. I hope that everyone is staying healthy and well this summer. First, I would like to personally thank Dr. Arshad Khanani for joining us today and for being the highest enroller in our OPTIC study, which to me speaks both to his credibility and enthusiasm to present our new data from OPTIC. In this trial, we have now treated 30 patients with a single intravitreal injection of our gene therapy ADVM-022. As a reminder, the patients in OPTIC previously required frequent anti-VEGF injections to manage their wet AMD and maintain their vision. I also want to take this opportunity to share a few thoughts on my joining the team in June. It has been an extremely exciting and fascinating first few months. Since coming on board, I've been engaged with the team and fully immersed in the operation of the business. One of my goals for onboarding was to meet and listen to as many stakeholders as possible. I've been on countless

Thank you, Dr. Fischer. It is really a pleasure for me to present this data update as of July 23rd data sets. And on behalf of OPTIC investigators and patients, I think I want the audience to really look at this data and see what it means to patients and physicians with chronic retinal diseases. And that's why we're going to have a video at the end showing that. So really as a top investigator in OPTIC as well as multiple other trials as a PI, I'm able to see what does new molecules and delivery systems can do for our patients. And I'm so excited on a daily basis when I see patients doing really well. Since I'm talking over, I see OPTIC patients on a daily or every other day basis. I actually saw a neighbor of mine who was in OPTIC study. She has failed all other treatments, with persistent fluid on monthly aflibercept. And when I'm offering these treatments to my neighbor, I better make sure that it's safe and it works because I don't want my house on fire. So that's why I'm so thrilled to be here to present this data because to me and to my patients this is a big deal. These are the key takeaways from my talk today: ADVM-022 continues to show robust treatment response; Long-term durability beyond 15 months from a single in-clinic intravitreal injection with zero rescue injections in Cohort 1; Further evidence of a dose response between the high and low doses; Substantial reduction in annualized anti-VEGF injection frequency; ADVM-022 continues to be well tolerated with a very favorable safety profile in all 4 cohorts, including encouraging early safety data from Cohort 4 using prophylactic steroid eye drops. This early warrants further investigation in larger studies. Why do we care about having treatment that has continuous delivery? Why do we care about having treatment that could be one and done? This is the reason. Based on our recent publication of the Sierra AMD study, with almost 100,000 eyes, we saw that even patients receiving seven to six injection per year were losing vision in the real world. So the bolus injection frequently and still not doing very well. That's why we need approaches that can show continuous delivery of anti-VEGF. And this is where ADVM-022 fits in. It is an in-office intravitreal injection of gene therapy for this huge unmet need of neovascular AMD. If you look at ADVM-022, as I said, it is a gene therapy vector that is designed for continuous delivery of aflibercept following an in-clinic single intravitreal injection. The 7m8 capsid allows for the efficient retinal transduction following intravitreal injection. If you look at data from non-human primate, you can see that intravitreal injection of 7m8 results in robust cellular transduction and protein expression in the eye. 7m8 vector was developed using directed evolution which enable intravitreal delivery, broad transduction in retinal cells and increased protein expression. This is really a very novel treatment approach with intravitreal in-office gene therapy to really have continuous delivery of aflibercept. If you look at preclinical data, it has shown that long-term durable protein expression out to 21 months and 30 months from a single intravitreal injection. Also the continuous delivery of aflibercept after a single 022 injection results in levels in 3 to 5 weeks after a bolus intravitreal injection aflibercept. This is why I put my neighbor in there, who was getting aflibercept on a monthly basis with worsening disease control. As a reminder, OPTIC is a Phase 1 study with four cohorts where the dose and steroid prophylaxis of steroid regimen were varied. As you know, in Cohorts 1 and 2, we enrolled six patients each, in Cohorts 3 and 4 year we enrolled nine patients each. Cohort 1 and 4 are at the high 6E11 dose while Cohorts 2 and 3 are at a threefold lower dose of 2E11. Again, a reminder usually we see dose escalation study. Here the efficacy was so good that the decision was made to use a lower dose and you will see the long-term data from high dose Cohort 1 later in this presentation. Another difference is the approach to steroid prophylaxis, Cohorts 1 and 2 were administered a 13 day course of oral steroids and a switch was made to a six week prophylactic steroid eye drop regimen for Cohorts 3 and 4. Obviously the Phase 1 study, so the primary objective is safety but efficacy in terms of vision, anatomy and the need for rescue therapy was also measured. And here at the bottom you can see their rescue criteria and patient received supplemental aflibercept if they met any of the criteria listed. Despite the pandemic, as Dr. Fischer said, we enrolled OPTIC quickly and successfully. And as an investigator, this truly shows the value of a treatment. Initially, studies have slow recruitment but once you see the data maturing and see this long-term efficacy, I think investigators are super excited. After my presentation at ARVO, I actually had friends who run clinical trials, and they called me and said, I want to be part of this trial because we think that this could be a game changer. But we were able to close OPTIC quickly, even during the pandemic. There have been some missed visits which were very limited and manageable. And in fact, in this COVID-19 situation, this really highlights the agility of a continuous delivery of a treatment where a patient knows that they are covered and where the physician knows that patients are covered, and patients really do not necessarily need to go to the site to receive their treatment. None of my patients missed their visit but if they called me and said, hey, I can’t come in, I'm worried about COVID, I'm high risk. I would have said, you have continuous delivery from a single injection and I think you will be okay. But obviously for clinical trial purposes, we brought them in, and we had no issues with COVID-19. I'm excited to now bring you updates to Cohorts 1 to 3 and provide a first interim look at Cohort 4. As I said earlier, the data cut is July 23rd for all four cohorts. For Cohort 4, due to the short follow-up, BCVA and CST outcomes and need for rescue injection will not be presented today. Two patients had some missed visit due to COVID-19 concerns. In Cohort 1, the patient number one had missed a few visits due to COVID-19. The patient has been seen by investigator during the home visit on August 1st, and I'm happy to report the patient is doing well, their wet AMD is stable, and there's no inflammation. If you look at the baseline characteristics for the study, you can see Cohort 4 is consistent with Cohorts 1 to 3. In Cohort 4, you can see that some patients were diagnosed more recently, less than 12 months prior to 022 administration. This shows confidence from the investigators in the study after seeing the efficacy and safety, they were really excited to enroll patients. And I forgot and I did the same, we were able to enroll Cohort 4 very quickly even during the pandemic. And as I said earlier, I was able to enroll one of my neighbors who had been not doing well with current standard-of-care. Everything else is consistent with other cohorts. Overall patients with neovascular AMD in this study were more difficult to treat and needed frequent anti-VEGF injections to maintain vision. I will also share a case later in this presentation to show you that. This is a swimlane plot, you can see that prior to entering OPTIC and receiving 022, this patient population needed very frequent injection. If you look at the data from Cohort 1 patient continue to do really well with now zero injections out to 15 months. Again, before 022 they’re receiving an average 9 to 10 injections to control their disease. And after a single in-office intravitreal injection of gene therapy with ADVM-022 patients have now gone out to 15 months or longer without requiring zero rescue injections. If you look at data from Cohort 2, you can see that patients have passed the one year milestone. There’s been now a third patient requiring supplemental anti-VEGF treatment. For this patient, a single injection at week 48 and patient is now being followed up for 56 after 022. If you look at Cohort 3, now all patients have past 20 weeks, with only two patients receiving supplemental anti-VEGF injections. One of these patients has received a single anti-VEGF injection only during 36 weeks of follow up. This was actually one of my patients that I treated. Overall, there's been a substantial reduction in need for anti-VEGF injections at both low and high dose with continuous evidence of a dose response. If you look at safety ADVM-022 has been well-tolerated with no systemic adverse events related to 022. There have been no death of discontinuation in this study. Inflammation has been responsive to and manageable with steroid eye drops. One thing I want to emphasize, there have been no clinical or fluorescein evidence of posterior inflammation. There have been no cases of retinal vasculitis, retinitis, choroiditis, vascular occlusions or endophthalmitis. All ADVM-022 related ocular events, 78% were mild and 22% were moderate. There was one adverse event of special interest of moderate recurrent uveitis deemed to be related to 022 and was response to steroid eye drops. There have been no new cases of IOP elevations since I gave the last update. If you can see the duration of follow up here as well as adverse events, and what we see that there are different duration of follow ups in number of subjects per cohort, but it appears that there are lower number of adverse events in Cohorts 3 and 4. Again, that’s the group that has utilized longer prophylaxis with steroid eye drops instead of oral steroids in Cohort 1 and 2. Now, let's look at cellular inflammation by cohort. From Cohort 1, we can see an overall resolving inflammation picture with now 2 out of 6 patients still taking steroids eye drops and no other patients having any cellular inflammation. Patient number two is the one with adverse events, of special interests, of moderate uveitis that recurred following the cessation of steroid eye drops at week 72. This has improved after starting steroid eye drops. Looking at Cohort 2, we can also see an overall resolving inflammation information picture as well that all patients now past the 52 week milestone. Four out of six patients are inflammation free and actually patient one and six are both my patients and they are super happy that they have not received rescue for over a year. They are although on steroid eye drops which they have no issues taking. In Cohort 3, all patients are beyond 20 week as of July 23rd. As you can see five out of nine patients have discontinued steroid eye drops. Steroid eye drops alone have successfully controlled inflammation in Cohort 3. Let's look at Cohort 4. Of course this is early in follow-up. We are back at the high dose of 6E11. We are closing looking at the first couple of weeks as oral steroids have been replaced with steroid eye drops. The good news is, there have been minimal to zero early inflammation with steroid eye drops prophylaxis consistent with Cohort 3. Only low grade inflammation was observed in some patients while tapering or stopping steroid eye drops. This is consistent with finding from Cohort 1 and 2 that inflammation when observed has been responsive to and manageable with steroid eye drops. Now let's look at vision, again, reminder this was a tough to treat patient population and the goal of single injection was to maintain BCVA over time and control disease activity. In terms of all the efficacy measures, long-term vision from Cohort 1 is stable out to 72 weeks, highlighting the potential of continuous delivery after a single in-office intravitreal injection of ADVM-022. As you can see, there's one outlier at week 48, skewing the average and the error bar, this was the patient as I mentioned in the last update that has unrelated pseudophakic retinal detachment that is repaired with vitrectomy and gas and when you have gas in the eye you can’t really see and that's why you see a little get there, but overall vision has been maintained with absolutely zero rescue injection in any of these patients. Looking at CST over time, in Cohort 1, you can see that CST measurement also show that anatomy is maintained out to the 72 week median for all six patients in Cohort 1. I think this is crucial, I think you need to make sure that when you have continuous delivery, you're also controlling the anatomy, and you're not undertreating the patients. And as I said, by getting levels that are as good as bolus aflibercept three weeks or five weeks after the intravitreal injection, I think this really resonates that this continuous delivery is really controlling the disease in these frequently tough to treat patient population. If you look at BCVA over time in Cohort 2, you can see the same pattern that was very consistent, maintenance of vision with all six patients now beyond 52 weeks. Looking at CST over time and the same is true for CST, once again showing a very consistent maintenance of anatomy over the 52 weeks with a slight improvement of 25 microns in the overall cohort. I had two patients who are still on steroid eye drops as I said in this cohort, their fellow eyes actually continued to receive injection, both had bilateral disease, both eyes were getting injections every four to six weeks, not only one eye is getting injection. The common question they ask me is why can’t I have this treatment in my fellow eye? And number two is why do I need to come and keep seeing you if I'm doing so well in one eye that's in the study? And I tell them, even though it's working very well, we still need to learn about long-term efficacy and safety. And that's why you keep coming back every month. So they are excited that one eye has been well-controlled and they're looking forward to having the treatment in the fellow eye, once there's an approval. In terms of BCVA over time in Cohort 3 with a median follow-up of 36 weeks, we see average BCVA slightly improve at four letters. But really, largely consistent with Cohorts 1 and 2, where we see maintenance of visual acuity. One thing to keep in mind 7 out of the 9 patients remain completely rescue free. If you look at CST, the main CST continuous to improve in all nine of these patients with average improvements of about 120 microns. Even higher in the six patients with no rescue at about 150 microns. As a reminder, looking at the baseline characteristic, patients in Cohort 3 had more fluid at baseline than patients in Cohort 1 and 2. Now let's look at this case that I presented before. This is one of my patients in Cohort 3 that required frequent injection of aflibercept without having disease control. So this brings me back to the point I said earlier about, we're getting levels as high as bolus aflibercept at three to five weeks, we expect the continuous delivery of aflibercept with 002 may improve visual acuity and anatomy in patients who are suboptimal responders to current treatment. And this is the reason I enrolled my neighbor, who has been sub-responder, because I saw this efficacy personally in this patient and many other patients where I'm seeing that the disease is being modified. As you can see on the left, patient was screened for the study received aflibercept to show a response. You can see that patient did respond after two weeks, but there's still sub-retinal fluid, patient received ADVM-022. And now you can see that we have 36 weeks data on this patient. This is a patient, who was not controlled with every four to five weeks aflibercept and as the data is maturing, what are we seeing? We are seeing the efficacy of continuous delivery of aflibercept using ADVM-022. As I mentioned earlier, he also have a twin that wants to get into the trial. And now that the trial is close, he's not very happy that he can get in where his brother is doing so well without any treatment. Let's come back to the swimlane plot to emphasize the point I made earlier. These are hard to treat patients that previously required frequent injections to maintain their vision, just like the patient I showed you in the case or just like my neighbor, who is not controlled with monthly aflibercept. Here we see the power of this treatment. We see that Cohort 1 has a zero rescue injection with 15 months or longer follow up, as I stated earlier patient one had some missed COVID visits, but as of recently, he's doing really well. Even in the lower two doses, we can lower dose cohorts, we can see that in Cohort 2 and 3, there's a dramatic reduction in injection burden after treatment with in-office intravitreal gene therapy with ADVM-022. If you don't remember anything from this talk, I think this is what you need to pay attention to. This is another way to look at the potential benefit of continuous delivery with ADVM-022. We looked at annualized injection frequency before and after 022. And as you can see, for the high dose Cohort 1, the average annualized injection frequency drops from 9.6 before 022 to zero. These are patients in Cohort 1 where we have gone 15 months or longer without requiring any rescue injection. I think this is a big deal. Combining the low dose Cohorts 2 and 3, the treatment burden decreased significantly from an average annualized injection frequency of 10 to an average 1.3 for 87% reduction, again, showing the benefit of continuous delivery of a single in-office injection. I wish I had this chart in my office today, where I can show patients what we have achieved since approval of ranibizumab in 2006. Personally, I feel this is very disruptive in terms of really benefiting the patients, their caregivers, and physicians to really control these diseases that are common cause of blindness in this country and globally. In summary, these data provide a meaningful update to the OPTIC study that evaluated a single intravitreal injection that provides continuous delivery of aflibercept through gene therapy for the treatment of wet AMD which showed the potential to dramatically reduce the treatment burden in hard to treat patient population. ADVM-022 shows robust treatment response, long-term durability beyond 15 month from a single injection with zero rescue injections in this hard to treat patient population. The two doses how a dose response as assessed by the need for rescue, a substantial reduction in the annualized injection frequency of 100% in the high dose and 87% in the low dose. A favorable safety profile across all four cohorts, low grade inflammation and observe has been responsive to topical eye drops. Still early, but evidence suggests a longer prophylactic regimen can be more effective at minimizing inflammation. As a result, ADVM-022 clearly warrants further investigation in larger study. We need this for our patients with neovascular AMD. I want to thank all the investigator, patients, our reading centers as well as the team at Adverum to really participating in this trial, to really change the disease course for our patients with neovascular AMD. Before we finish, I want to present to you INFINITY. INFINITY is a Phase 2 trial of ADVM-022 in diabetic macular edema. As you know, diabetic macular edema and diabetic retinopathy is the number one cause of blindness in working adults in this country. On a daily basis, we see patients who have had diabetes for a long time, who walk in our clinic blind looking for hope to reverse their vision. Some of these patients had been our patients in the past that failed to follow up, whether they got sick, whether they got busy, because they're working, or they lost their injection coverage. This is just the U.S., what about people globally, what about people in third world countries who don't have access to care and can’t afford to get the monthly or bimonthly injection? This is why I'm so excited about INFINITY and we were lucky to be the first site to enroll a patient in this trial. Other thing I want to mention is the smart trial design and that speaks to the team that Aaron Osborne is leading, where you can see this is designed to demonstrate superior disease control compared to a single aflibercept injection. And this has been -- this will be measured by time to worsening of DME disease activity. Very clever design, I think to really show the benefit of ADVM-022 in diabetic macular edema and diabetic retinopathy, which is the number one cause of blindness in working adults in this country. And I'm going to get emotional now, because I'm going to bring to you one of my patients next. She has been my patient for last eight years. She is like family to me. I look forward to seeing her every other week, because she has had diabetic macular edema and she was blind in both eyes before she got here. After seeing here clinic, I told her we need to really treat you aggressively and she has been a very compliant patient. But until recently, I really didn't realize what toll it takes on her and her family by coming to my clinic. They're always smiling and they're with me. But now I know what they go through on a weekly or every other week basis, because she has two eyes with the disease and she gets aflibercept one eye at a time. And she's been in my clinic, never missed appointment. So when I talk to her during an event, we asked her and her daughter about what really does it mean to have therapy like ADVM-022 and here is the video. [Audio/Video Presentation] This is the reason why I remember the child and this is the reason we’re all working together to bring this for our patients with diabetic macular edema and neovascular AMD because this is what I see on a daily basis and this is just one patient but we have millions of patients around the world who need us to provide them with better options, better disease control, better visual acuity. So their friend, sisters, brothers, kid, don't go blind with retinal vascular diseases. And I'm excited to see that the future looks really bright for these patients. I'm going to pass now to Dr. Fischer.

Thank you, Dr. Khanani. And before we begin the discussion portion of this call, I would like to express my gratitude for Dr. Khanani introducing Adverum to the patient, caregiver highlighted in this video. I think hearing firsthand the emotional testimony directly from them on the treatment burden in order for the patient to making the vision is a stark reminder as to why potential one time treatment such as ADVM-022 could offer a more patient centric approach to preserve vision in patients with wet AMD and DME. I'd like to open the call now for questions from those on the phone and turn it over to the operator for the first question.

Thank you. Our first question comes from Tyler Van Buren with Piper Sandler. Please go ahead.

Good afternoon and it's great to see the continued durability at 15 months. You guys are certainly keeping earnings interesting. I have a couple of questions, one on efficacy and one on safety. The first one on efficacy. I imagine it's too early to say whether Cohort 4 looks more like Cohort 1 versus 2 and 3. But as you look at Cohorts 1 and 2 as they go out to a longer period of time, current -- clearly the goal is to maintain visual acuity and anatomy. But it does appear that you're seeing improvement in the anatomy and CRT and you pointed that out in the release. So I wanted to get your thoughts on that. And then on -- the second question on safety, you mentioned encouraging early safety from 4 versus Cohorts 1 and 2, fewer AEs and less inflammation. But I want to ask you specifically about posterior inflammation. You said you haven't seen any. What gives you confidence that none of the inflammation events are similar to what has been observed with abicipar or Beovu?

Thank you so much. Thank you, Tyler. I'll take that one. Aaron Osborne here, CMO at Adverum. And you pointed out that some of the -- we have actually seen improved anatomy whereas the treatment goal for these patients -- the patients who have been having many injections for chronic wet AMD, so they're difficult to manage. And essentially the goal for these patients is to reduce their injection burden, whilst maintaining the vision and maintaining the anatomy. That's essentially what’s happened across the cohorts, but we see in Cohort 3 that there's been some improvements. And that is really largely to do that -- some of these patients had fluid at baseline. You see there is a central retinal thickness with baseline for Cohort 3, and that has been able to be improved and that it's best to pick an eye them by the case. Dr. Khanani presented, the patient who was getting frequent earlier injections still have a lot of fluid. But then with the continuous delivery of fluid effects with ADVM-022, you saw that the anatomy resolved, and actually that patient experienced visual improvements as well, because the anatomy had improved. It's a small study in nine patients, we focus more on anatomy than on vision. But when you can get anatomical improvements, it's often not surprising to see that there is some vision improvements as well. So really putting that down to the potential efficacy of continuous delivery. With regard to the second question, which was on safety. I mean, it is early, obviously -- it is obviously early data. We particularly wanted to share these data for Cohort 4, because we're looking at those first weeks after receiving 022, when we were previously giving stronger steroids in the form of oral steroids. And now we're giving just topical steroids. And what we're seeing is the topical steroids have controlled that early information within minimal to zero during the time period that has been covered. And overall, across Cohorts 3 or 4, I think it's really important none of these patients have needed more than topical steroids in order to control and manage their inflammation. And with regards to the question, how can you do sure that this is not back of the eye? We look carefully in terms of clinical examination, and the fact that all information is managed, with steroid eye drops also points in that direction as well. But I think, I'd like to bring back Dr. Khanani here as well, because he has been an investigator in many of these trials, including abicipar and bevacizumab trials where there has been some posterior inflammation, and perhaps to share the full string from a clinical perspective. Dr. Khanani?

Yes, thanks, Aaron. I think that's an excellent question, because, we are comfortable with the safety profile of current agent. And anything that's coming to the market, especially an intravitreal injection that's frequent, like abicipar or bevacizumab, we need to make sure that you don't get cases of irreversible blindness. We were the top sites for CEDAR study, which was the Phase 3 for abicipar and I had 21 patients in that study, and I saw two patients with panniculitis and vasculitis. And let me tell you, you don't need to look for that, it presents itself, you have eye full with inflammation in the back, you have vessels that are white. And patients will call you and tell you there's something wrong. So, I know there has been some discussion about subclinical vasculitis or retinal artery occlusions that were seen in HAWK and HARRIER. I think the confidence for me in 022 is the fact that the vector is including aflibercept. It is not a new molecule, we have data since 2011 on aflibercept in terms of safety. Obviously, we have some inflammation, which is mild and it's in the front of the eye, I have not seen anybody with posterior inflammation. And I think if you look at vitreous cells, they're looked by slit lamp and those are spillover cells really from the front of the eyes. So I really want people to understand that this is not what we have seen with abicipar, now having 11 patients in OPTIC that's a large number, I would have seen anything concerning and I'll tell you most of this information exists in the front, resolves really quickly with topical steroids. And again last thing Tyler we need to pay attention to is the fact is, the value for the patients. Why are people not or physician using Beovu first line or why did FDA didn't approve abicipar because they had incremental benefits compared to intravitreal injection of let’s say bevacizumab, ranibizumab or aflibercept. Here you're changing the disease course. You're changing the vision in terms of -- long term you're getting stable vision and anatomy, and you're controlling the disease, you're essentially changing the course of the disease. So here there's a huge value for the patients compared to what abicipar and Beovu brought, but the good news is that we don't have any posterior information, we don't expect it because it's including aflibercept which is out since 2011. Back to you Aaron.

Thank you. Let's get to the next question.

[Operator Instructions] Our next question comes from Alethia Young with Cantor Fitzgerald.

Though I have many, I will try to ask one. I guess, one of the cases that I've gotten a lot of questions around is kind of what happens when patients go off of their topical steroids. So I was wondering maybe if the doctor could give us a little bit of like details on like what happens when patients go off? Is it easy for everyone or is it difficult for some and just maybe frame that for us?

Thanks, Alethia. I mean, I'll hand over to Dr. Khanani in a moment but maybe just to share kind of the update again from Cohort 1 and this study says, there can be questions about coming from -- coming off steroids and we actually had two patients in Cohort 1 who were on once a day steroid eye drops with zero inflammation, had been that way for some period of time, and both attempted discontinue steroids in the recent past. And one of those patients discontinued the steroids, there were signs of inflammation and they've had a couple of follow up assessments since. And all is looking very good for that patient and inflammation free. The other patient did have a recurrence of inflammation. And one of the learnings here is that when you take a patient from one drop per day to zero drops per day, there may be a steroid rebound effect or there may be a low amount of [indiscernible], which people need to be potentially triggering inflammation that may be remaining. So regardless, this patient, when we stopped this steroid eye drop, from one drop a day to zero, they did experience a moderate recurrence of their inflammation. And what’s important here is the patient was then restarted on the steroid eye drops, and the situation has improved, and that patient is now tapering down on their steroid eye drops. So I think, when we look at this patient, again, in the future, we go from maybe one drop a day to zero, or potentially in other patients who have experienced recurrence, we're looking at maybe adding in an interim step or going down to one drop every other day, which is something that has been used in the clinic quite frequently in patients, who have had sometimes a challenge with tapering off steroid eye drops in other settings. So I think, that's what we see in OPTIC. And I'll hand over to Dr. Khanani who can perhaps have some additional source from his clinical perspective.

So I think Aaron the key question here is that, how can we know, which patients can come off and which patients will not require steroids after coming off. And I think people need to understand this is a Phase 1 study. It is really focused on safety and we're seeing amazing efficacy and durability. But we also want to learn how these patients do long-term. The good news from a clinician perspective is that majority of the patients are off the drop. So it's not like every patient will need four times a day forever. So majority of the patients, if you look at every cohort have been off the drops. Patients who actually need drops, majority of them are on one or two times a day. There are a few on four. But really, that number is small. So I saw a patient today who has fixed a retinal detachment about two years ago and has chronic macular edema and needs to take steroid drops. And I was taking the -- given this presentation today, so I actually asked him, even though it's a different indication, I said, your retina is working great on two times a day steroid, you have been on it for a couple of years. We know, we go down to one, and your vision drops. Do you want to try to get off the drop and how much of a burden it is? You know what he told me, he was like not a big deal. I like to see and I'm happy with my vision. So I think for a patient, who just post drop but imagine a patient who actually receive injection every month or every six weeks or eight weeks what would their response be? So I think the bottom-line is you're still learning and I agree with you that I think somebody is on one today, the learning go every other day. But again, the burden for the patient is minimal and -- but the benefit is huge here. So that's a learning, majority of them don't need drugs and the ones who do, we just need to make sure to take it and slowly taper over time.

Thank you so much, Dr. Khanani. I think we can go to the next question.

Our next question comes from Phil Nadeau with Cowen and Co. Please go ahead.

Dr. Khanani I wanted to follow up on the comments you just made, as my question. So the biggest controversy on Wall Street today with ADVM-022 is about the inflammation and how much is too much? I think we all appreciate that the reduction in treatment burden is pretty impressive. But people worry about how the inflammation is going to be perceived by the physician community. So can you give us your sense, maybe expand on what you just said, as to how much interior inflammation is too much. So what level of inflammation and what proportion of patients over what period of time would give you concern? And then kind of similarly, how many steroids are too much? So what doses, steroids, over what period of time again would give you pause and maybe just as important give your colleagues pause in deciding whether to use 022?

I think those are excellent questions. And I think when I talk to my colleagues after my talk at ARVO, they want to participate in this trial because they see the value for the patients. I think at the end of the day, it's all about me looking at the patient you saw on the video and saying, you know, I may have a treatment that's one and done. Majority of patients were required drops for six weeks but they’ve just said that may need longer. And I don't know at this point which group you're going be in, but are you willing to do it? And I think 100% of patients will agree that that because we see on a daily basis the burden as you talk about. Now talking about safety, and how much inflammation and what kind of inflammation? So I think when we look at inflammation, if there’s anything that is reversible response to treatment, and does not have long-term concerns in terms of irreversible vision loss, I think we are all okay with that. So with 022 as you have seen that patients get some inflammation when they're tapering their four times a day and if you continue on four times a day or so they do really well with zero inflammation. This is an inflammation that responds quickly to steroids. It does not have any long-term damage to the eye. It’s in the front of the eye, it's not posterior inflammation as I said, and there's no retinal vasculitis, no retinitis, no arterial occlusions. So I think those are the key. And as physicians, we want to look at this benefit of any treatment. And you know, I've said it before, I would only participate in a trial where I would enroll my mother, not mother-in-law, mother, as I said before. So this is a trial that has really shown that I'm not concerned about this, if they have some inflammation, I put them on drops and they come back and resolve. So I think, for the investor community, I think when we look at inflammation, it looks all the same sometimes, but it's not and as clinicians, talking to my colleagues, and what the uptake of this will be and they say listen, they’re on drops, big deal, they inject steroids in the eye in patients with DME, because they don't respond to anti-VEGF, and there is a current rate of IOP spread but we still take care of it here, because the amount of drops is one or two or even four, the rate of that is very low, find the data that no new patients have any IOP issue. So I think the bottom line is looking at information, separating it out, looking at value of the product to the patient, value to the physician, and the long-term treatment and the risk and benefits of those. So I think, really, I have the most patient, I had studies where I am talking roller in a lot of different trials, I think, all trials, there are many trials showing promise, but I think this is a game changer in terms of how we manage patients with vascular AMD.

Thank you so much, Dr. Khanani. And we go to the next question.

Our next question comes from Graig Suvannavejh with Goldman Sachs. Please go ahead.

[Technical Difficulty] patient in Cohort 2 prior to retreatment and maybe if what that patient's progression look like up until then, maybe how that inform dosing in your eventual pivotal trial in AMD?

I don't know, if you could ask -- I don't know if the operator you heard that clearly. I did not hear that, particularly that question, the audio was challenging maybe.

It was hard to hear. I think the question was between the response we've seen with the two doses, the informed doses you want to take forward in pivotal trial?

Yes. And specifically the one new patient who required treatments?

Thank you for the question, Greg. Because there's a new finding with this update that the additional patients that received rescue injection, they both had a single injection and really, this is why we're using the language more supplemental and see they just rather than rescue injection. When we look at both of these patients they were really stable, they appear to had a benefit clearly from ADVM-022 both in terms of only having a single injection representing a big decrease in terms of the injection burden prior. But also, when these patients did meet the retreatment criteria. They only just click the edge those retreatment criteria and I think these patients are definitely most of them in the category of as we design our pivotal trial moving forward. When we look at the retreatment criteria, we need to think of patients like these, because they both actually have very stable vision. And they were both rescued because of sort of changes in the appearance of the disease where the fluid or small amount of blood was visible. And these may potentially represent changes in the evolution of the disease in response to continuous delivery of anti-VEGF. We’ve seen another program the port delivery system from Roche Genentech demonstrate positive Phase 3 data using much more relaxed retreatment criteria than we see in OPTIC. So, despite in that study, there was more fluid allowed to be present before retreatment was performed. We saw that there was maintenance of vision at the same level as monthly injections of ranibizumab. And I think that really shows the potential benefits of continuous delivery, but also shows we need look at these patients who may have a small amount of fluids and whether they really need to be retreated or not. So I mean, I think across the both cohorts, we've seen benefits in terms of injection frequency reduction. We've seen a major reduction with the low dose as well. And as we move forward again, looking back at the Roche port delivery system program there’s an analogue there. We can move to slightly earlier in disease patients, who may potentially respond to even better to these very hard to treat later into disease patients that we've had in OPTIC. I think it's very -- we intend to go and discuss with FDA and other health authority, as well as clinicians and potential investigators for these studies. The very best ways to conduct them and one of those topics is certainly going to be the retreatment criteria as we move forward.

Our next question comes from Joon Lee with Truist Securities. Please go ahead.

Correct me if I'm wrong, but the typical trial for ADVM-022 in wet AMD will likely be just the best standard of care. Do you feel that the efficacy and safety on par would be two-monthly or two-every monthly IVR, and the non-ADVM-022 injected also get steroids prophylaxis and conversely with the non-IVR get a mark injection? Tell us about the potential design of the clinical trial?

Thank you for the question. And so as we turn towards pivotal trials, I mean, the program that we discuss as a potential analog is Roche port delivery system, pivotal trial program. So with that program, they did sequential kind of Phase 2b trial followed by pivotal trial. And the reason that we use as an analog is that we have two doses that look to be showing at this early stage a very positive benefit risk ratio. So what we've seen is we've seen a substantial reduction in both numbers of patients who need anti-VEGF injections, but also in annualized injection frequency both at high and low dose, but with a dose response in a tough to treat patient population. And we've seen -- we haven't seen really any differences on the safety side, we've seen that inflammation is generally low grade and manageable with steroid eye drops. So as we move forward, we would -- what we need to do is really get to a single dose, we tend to have a single dose that we would market for wet AMD and we really intend to take a single dose through to a Phase 3 trial. At the moment we have two doses. So performing a larger study to look at both of those doses seems a very logical next step. So that is really our intention to compare the standard-of-care which would be aflibercept. And aflibercept in registrational trials is typically given every other month, following three initial monthly doses. So if we go through the study population that is treatment experienced, but relatively early in disease, then we would be comparing to aflibercept every other month. And here we would take forward both of these doses that we've looked at in OPTIC. We think both of them are looking sort have a positive preliminary profile. And essentially, the trial would have a primary endpoint in the region of around nine months, you can take from that data point, you need to show that you have similar visual acuity maintenance with aflibercept injections. From that point, we've got to select our final dose. There are a few other open questions as well. At the moment, we're testing for neutralizing antibodies. We're currently open to around 95% of patients. But that doesn't mean we will screen some patients out, patients with very high neutralizing antibody counts. And one of the questions as we head towards Phase 3 and commercialization is whether we need to screen patients at all. So really that question is best to test in a relatively small trial where you can screen the patients early on, we can potentially include all comers and adapt the trial as we go forward. So with questions around dose, neutralizing antibodies, we feel to do a Phase 2b trial with our two doses. Looking at these questions makes a lot of sense as part of the pivotal trial program. And what we're doing now is we're looking forward to planning those meetings discussing with FDA and international regulatory authorities, with the intention of starting that program in the mid of next year.

Our next question comes from Mani Foroohar with SVB Leerink. Please go ahead.

So part one, when you think about kind of where you are in communication with regulators. It sounds from disclosures that you are apart of having more complete cohorts for data at the end of this year, will be meeting with U.S., EU and other regulators to work out a plan for a pivotal Phase 3, which will begin in mid next year. Is that correct? Or is the right answer, you guys have begun those conversations around study design already in into the patient of Cohort 4 data, which of -- where are we along in terms of the timing of those conversations? And then as a second question, of the recurrent uveitis patient, is there any interpretation of that in the press release of that patient, the previously experienced uveitis prior to the trial, or recurrent within the time horizon of the trial?

Thanks, Mani, it’s Aaron here. I'll take the second question, first, because that's the easiest one. No, it’s recurrent from within the trial. And that patient did not have a history of uveitis but the same patient that had an occurrence of uveitis adverse event at week 16, so it's the second patient in Cohort 1. So that recurrence was first to them being in the trial. And as I said that event has improved with topical steroids alone, and they are tapering the drops now at the anterior chamber cells down to zero. So that's patient number two in Cohort 1. With regards to the regulatory path, we are obviously in ongoing discussions with FDA. We have recently started the INFINITY trial. We had a number of interactions with them around that, including discussing the masking requirements, and the best way to conduct that trial. But we have not formally discussed a pivotal trial program. And we have really encouraging early data here. And shortly we'll have enough clinical data to put together a package which will really support those end of phase discussions. And as we said, I think we've got a pretty clear idea on the type of clinical program that we want to run. And we really look both of those discussions with FDA to be able to having to go ahead and start those trials in the mid of next year.

Our next question comes from Luca Issi with RBC Capital. Please go ahead.

Two quick one. Once again, regulatory, is there any update on the partial clinical hold here? And just to clarify, is the partial clinical hold just related to the high dose that you're no longer pursuing, the 6E12, was it manufacturing issue or potentially both? That's the first question. And the second on data. When I look at the baseline characteristics, the number of anti-VEGF injections in the prior 12 months was actually substantially lower in patients in Cohort 4 versus any of the other cohorts. One, why is that? And two, what are the possible implications of that difference? Thank you.

It's Aaron here. I'm happy to take the second one and maybe hand over to Leone regarding the second part, if that makes sense. So, regarding -- it's a really good point. Thank you for the question Luca on Cohort number 4, so Dr. Khanani presented. There are some patients who are earlier in their disease in Cohort 4. And that seems to be really driving why there's a lower number of anti-VEGFs in the previous 12 months. We have some patients that have been diagnosed as recently as two to three months before coming into the trial. So I should remind you that our protocol requirement is that they had two injections in the four months prior to coming in. So on an annualized basis, we'd expect that 6.8 to increase upwards, but we did have some patients who are a little bit earlier in disease. And, I think that represents again what Dr. Khanani was saying there’s increased confidence from investigators what the product is delivering in terms of continuous VEGF delivery that can control and improve anatomy in these tough to treat patients. So I think we saw a couple more early patients in late Cohort 2 and in Cohort 3, but now in Cohort 4, we've got a few more earlier patients, there's been no protocol changes whatsoever, we enrolled this cohort very quickly. And I think it's really helpful to have some earlier disease patients. As we said, as we plan for our population, in the pivotal trials, we'd likely intend to go to a slightly earlier in disease population similar to that Roche port delivery system program. So it's great to have some of those patients in the trial.

Yes, so I think, that's an interesting question, right? Why are we putting patients early because now we have efficacy data that is one year or longer and now, of course, it's close now, as of last update, we have one year longer and I use that for patients. And I said, we have an ongoing trial that has shown great efficacy in terms of BCVA maintenance and anatomy, and especially the patients that I presented today in terms of improving anatomy. And you know, people just said, sign me up, and especially my neighbor, she had worsening fluid with monthly aflibercept. And I enrolled her in OPTIC. So I think the data so far -- and I think this brings us back to the question that was asked earlier is like, what is the vision’s confidence with looking at risk benefit profile of this product? And again, some patients being on topical drops for long-term, it's a very small compromise for patients losing their visual acuity in the real world as you know, you saw in my Sierra AMD study where patients having just worsening disease. So I think I'm really excited to look at long-term data to see, can we get stable vision for five years because you see that CATT trial, you see SEVEN-UP study, you see all these studies where patients drop off in terms of agents starting at two to three years in either two and then third, fourth, fifth year they lose a lot of vision. So I think that is excitement I have for continuous delivery. And that's why we were able to bring a lot of patients. I wish there was that, that still open because on a daily basis, I'm seeing patients who can really benefit from this continuous delivery. So back to you.

All right. Hi. So you had a question that was around the partial clinical hold. And yes, you're correct there’s a partial clinical hold related to the dose of 6E12, which was part of the original dose escalation study. And we have -- at that time when that happened, and to this day, we don't change the dose at 6E12. We currently have three level of 6E11 and as Aaron was saying, these are the doses that we will probably take forward into our pivotal trial. As it relates to why the clinical hold is important. So the partial clinical hold is because the issues that were raised with the FDA related to CMC, and we do believe that we need to address these CMC issues in order to start our larger studies. And we've been working on those and I think I've mentioned this on previous calls, that it's been certainly a priority and a focus of the company to have these removed and we are on track. So we're confident they'll be resolved and would be ahead of those removed before we would start our pivotal program in 2021.

Our next question comes from Dane Leone with Raymond James. Please go ahead.

So maybe, I guess, Dr. Khanani, one thing that, I guess a lot of us are thinking about and when we speak to some of your peers. Indisputable Cohort 1 has had really good anatomical outcomes in patients need rescue injections. Some patients is needed supplemental injections in Cohorts 2 and 3 and it's still TBD on Cohort 4. But just to play a devil’s advocate here, I guess there’s speculation. Patient 3 in Cohort 3, for example, is on regular shots still after getting the treatment and is also on four drops daily of steroids into the follow up. When you think about that, like how would you explain that to a patient that there is a certain degree of risk with a non-absolute therapy, that they could end up in a situation where they're taking drops for this therapy, but also still on standard of care? How do you have that conversation? And how do you think that would need to be framed out for your peers as you go into larger studies with a potential risk, and then how you think about having a conversation with the patients?

I think, excellent question. Remember, we always have to put patients in a trial where there's a favorable benefit to them. And so to your question if somebody is getting supplemental treatment after having continuous delivery in their eye, that tells me that this patient is a super high need patient. I think we can put patients in one box. AMD is a very heterogeneous disease and each patient is different. We have patients on monthly aflibercept that have fluid. While we also have patients on every three months bevacizumab that did just fine. So I think the conversation for me is I have seen the value here where patients have benefited from this treatment even having monthly aflibercept before, like you saw in my case. So really having high levels of aflibercept, after a single injection with continuous delivery was favorable to my patients. So that's why I enrolled them. I think the question to ask is, what would this patient have required if they didn't have continuous delivery and are getting supplemental treatment? Could this patient would have required monthly injections? So, if you look at the swimlane plot, you can see that they were actually on more frequent treatment before they got into the OPTIC study. So I think it's still beneficial for the patient to get less injections. Nobody is saying that 100% of patients in a disease is heterogeneous as AMD will be injection free. I think, if we can get majority of the patients to be injection free and there are some patients with very active disease that need supplemental treatment, I think that's very acceptable for me and my peers. At the end of the day, our goal is to maintain visual acuity, control disease and reduce the treatment burden. But I think that's a very good question. And my answer is, I think the patient would have not been controlled, even with more frequent injection if they didn't have continuous delivery.

Our next question comes from Patrick Dolezal with LifeSci Capital. Please go ahead.

In regards to patient follow up first administration of 022, what sort of monitoring do you envision being required given the product profile to-date? And is there any standardization of that process worked into the protocol of OPTIC kind of, particularly earlier in the starting to reinitiate steroids? And Dr. Khanani, you've spoken a lot about patient satisfaction following treatment. Do you think some number of regular visits negates the benefit of avoiding injections at those visits or is there a greater emphasis on avoiding the injection in and itself?

Okay, great. I'll try and take the first part, then. Actually, just a reminder for the question there one second. So I think the question was on the follow-up schedule, and would we change anything in OPTIC on moving forwards and how do you see it in the real world the patients that are getting continuous delivery of 022 and specifically if they need to change their steroid treatment. And I can say from a sponsor perspective, and I think I'll hand over to Dr. Khanani, because there's some really important differences. In the study, obviously, we're following up patients extremely closely, we need to see them for assessments. And as we move to comparative studies, we'll need to continue to do that. We have some opportunities to extend visits of the patients, particularly in for example, extension studies, with plan to follow up with OPTIC with a study that would follow these patients potentially for many years. We've already seen that we have a couple of patients who have skipped visits due to concerns around COVID-19. And we feel that these scenarios are actually situations in which the benefits of 022 can potentially come to the full. So we're looking at that question really carefully, Patrick, and with technologies such as HOMO CP monitoring, for example, we could potentially show that patients with ADVM-022 are experiencing continued stability of disease. I mean I think they need to change a steroid regimen than they need to come in and be checked around that time points. However, they've been on steroid eye drops for a period of time. Really they just need a front of the eyes check. And then intraocular pressure check, which is often a lot easier than going to the retina specialist. So in terms of when we put together our CPP and monitoring schedules going towards commercialization, I think following ADVM-022, you're going to need a relatively intensive period of monitoring with at least monthly follow up visits, to see whether a patient needs rescue diseases, whether you need to adjust their steroid regimen. I think as you goes forward very quickly, that’s the position where you can extend out those intervals, and really realize the benefits of continuous delivery. And I think that's where you can maintain vision without frequent visits, and dramatically improve real world outcomes. That's why we're working on this. And that's why we're so laser-focused on that. I really thank you for the question because it's kind of summing up the essence of what we're trying to achieve. But, Dr. Khanani, you've got the most patients in OPTIC and in the CPP now. I mean, how do you see that monitoring schedule timeout in the real world?

I think Aaron I've been lucky that this is -- I have been involved in four sustained delivery trials. So, we are one of the top enrollers in the port delivery system Phase 2, Phase 3 and the extension Portal study, also the DME study. We are part of the REGENX RGX-314 and then obviously we are top enroller for ADVM-022. So there are two questions that were asked. Number one was, is clinic visits just by itself better than clinic visit plus an injection? Patients in OPTIC come to me and they have a smile on their face. And that's what happened with other sustained delivery like RGX-314 and PDS, because they know that majority of the time they're not getting an injection. They are happy, they come in with a smile, they can drive themselves, they cannot bug their daughter or their family member. They can keep moving and go on with their life after having a quick test. And I agree with you, I think initially, whether it's any delivery system and you need to monitor patients, make sure they have a good response in the first few months. And then for 022, just to make sure that they can taper off the drops without any issues. So let's say we have a patient that does two months or six weeks of drops and at two months had no inflammation, their disease is fully controlled. I would probably see that patient in two or three months after. And if they're doing well, maybe every three to six months, I think we'd like to see our patients, sometime they don't like it if we don't see them. So I think in real world I see a patient on 022 coming in maybe twice a year after they're stable. That's a huge improvement compared to monthly or every other month visit, plus injection visit, the family and caretaker burden. If somebody wasn't dropped, so I have a lot of patients on steroid drops that they came for macular edema from post cataract surgery or uveitis or anything like that. Once I know that they're not going to have IOP spike, which is usually in the first two months or so, then they can even go longer too. So even if a patient that has mild inflammation that needs to take drops twice a day, they can easily go to two to three months before coming for a follow up. So clearly the answer is, if you can cut down the injection burden by 90% or 80% or 100%, it's a huge win. And then that will translate into less clinic visits, which will also be events. So I think, as clinicians and patients I think this is very promising that continuous delivery in the eye of anti-VEGF to really control blinding diseases like neovascular AMD and diabetic macular edema.

This concludes the question-and-answer session. I would like to turn the conference back over to Dr. Laurent Fischer for any closing remarks.

Thank you, everyone, for joining us today. This has been a very productive discussion with great questions. I'd like to thank again Dr. Khanani for joining us today and sharing his perspectives on the data and insights we've learned from OPTIC. I just want to thank the patients for their participation in our clinical trials and acknowledge the frontline healthcare professionals for their critical care they continue to provide during this pandemic. And last but not least, I'd like to thank our employees, even during the pandemic this team continues to excel to deliver on our mission to make ADVM-022 available to patients as quickly as possible. I truly believe that we have the right team, the right assets and the right strategy to deliver ADVM-022 to the millions of patients suffering from wet AMD and DME globally. Before we end, I'd quickly reiterate our plan upcoming milestones. First we'll be presenting additional data from all four cohorts of OPTIC by the end of this year. Next will be advancing the ADVM-022 into a planned pivotal trial mid-2021. And finally, we'll continue to randomize patients in our ongoing INFINITY Phase 2 trial for DME, and we plan to report data from INFINITY in the second half of 2021. Please stay healthy and well and I look forward to updating everyone on our continued progress in the future. Thank you very much. Take care.