Q2 2020 Adverum Biotechnologies Inc Earnings Call

Thank you for standing by this is the conference operator, welcome to the Advair Biotechnologies Conference call.

Operator: Thank you for standing by. This is the conference operator. Welcome to the Adverum Biotechnologies conference call. As a reminder, all participants are in listen-only mode, and the conference is being recorded. After the presentation, there will be an opportunity to ask questions. To join the question queue, you may press star then 1 on your telephone keypad.

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Unnamed Speaker: Should you need assistance during the conference call, you may signal an operator by pressing star and 0. I would now like to turn the conference over to Maisha Lacey of Investor Relations and Corporate Communications. Please go ahead.

I would now like to turn the conference over to my Chalet see of Investor Relations a corporate communications. Please go ahead.

Thank you operator and welcome everyone.

Today, we issued a press release, just shared new data from our uptick phase one clinical trial, that's 80 B M O. Two to report our financial result for the second quarter of 2020.

Maisha Lacey: Thank you, operator, and welcome, everyone. Today, we issued a press release to share new data from our OPTIC Phase I 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 a replay of today's call and a copy of today's live presentation will be available in the Events and Presentations section of the Investor Relations 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 Leong, Chief Financial Officer. In addition, we are honored to have Dr. Arshad Kanani, 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. Dr. Kanani is also a Principal Investigator in the INFINITY trial.

And provide a business update a copy of this release is available on the press release. This page of the Investor Relations section of our corporate website at Www Dot dot.

Dot com.

Please note that a replay of today's call and our copy of today's slide presentation will be available on the events and presentations section of the IR portion of our website.

Joining me today as Dr. at lot Fischer Chief Executive Officer.

Patterson President.

Dr. Aaron Osborne, Chief Medical Officer, and Thomas <unk>, Chief Financial Officer.

In addition, we're honored to have Dr., our shot canady, managing director and director of clinical research Sierra <unk> Associates clinical associate professor of Ophthalmology at the University of Nevada, and our top enrollees principal investigator and.

Uptake and Dr. Kabbani, it's also a principal investigator and the affinity trial.

We will present, the new optic data after his presentation, we will open up for questions.

Maisha Lacey: He will present the new OPTIC data, and after his presentation, we will open up for questions. As a reminder, we will be making forward-looking statements, which include our product development plans, 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 those forecasted. A description of these risks can be found under the caption risk factors on our latest form, TIN-Q, which was filed this afternoon. I will now turn the call over to our CEO, Dr. Laurent Fischer.

As a reminder, we will be making forward looking statements, which include our product development plan research activities anticipated upcoming milestones and operation as well or sorry financial outlook.

These statements are subject to risks and uncertainties that may cause actual results to differ materially so don't forecast, but I.

A description of these risks can be found under the caption risk factors.

Our latest form 10-Q, which was filed this afternoon.

I will now turn the call over to our CEO Dr., Colorado Fisher.

Thanks, Michelle and good afternoon, everyone and thank you for joining us today I hope that everyone is staying healthy and while this summer.

Laurent Fischer: Thanks, Maisha. 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 Kanani for joining us today and for being the highest enroller in our OPTIC study, which 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 ADDM022. 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 fast-moving 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 would like to personally thank dr., Chuck and I need for joining us today, that's one being the highest enrollment uptick study, which to me speaks Betsy its credibility and enthusiastic to present, our new data from objects.

And this trial, we're not treated 30 patients with a single Intravitreal injection of our gene therapy it'd be ammo two to <unk>.

As a reminder, the patients an uptick previously required frequent that's out there is nothing Jackson to manage the where do you see and maintained their vision.

I also want to take this update you said few thoughts on my joining the team in June.

In an extremely exciting and fast moving first few months since coming on board I've been engaged the team and fully immersed in the operations it doesn't know what.

One of my goals for Onboarding was to meet and listen to as many stakeholders as possible.

Hi beat on Kalamazoo meetings getting to know employees, our investigators and even had the all that you need a piece and then her daughter.

Laurent Fischer: I've been to countless Zoom meetings, getting to know our employees, our investigators, and even had the honor of meeting a patient and her daughter. And I want to share this story today as they inspire all of us to be part of the momentum behind ADDM022's clinical development. And it has been a pleasure getting reacquainted with the SEL and Biosaf communities. I appreciate the continued interest in the potential value of ADVM-022 and our company. Let me start with why you should join Adverum.

And I wasn't sure. This story today as they expire all of us to be part of the momentum behind it to be able to choose clinical development.

It has been a pleasure getting reacquainted with the cell and Buyside community.

Appreciate the continued interest in the potential value.

To true I never company.

Let me say would why he joined the exam.

During the due diligence process I was impressed by the chain be thoughtful development program for what M.D. I'd be happy and the potential to truly revolutionize the treatment paradigm for a large number of patients living worldwide with Dr. diseases, we don't need therapy CDMO too too.

Laurent Fischer: During the diligence process, I was very impressed by the team, the thoughtful development program for WET-AMD, and the engineers, and the potential to truly revolutionize the treatment paradigm for a large number of patients living worldwide with ocular diseases with our elite therapy, EDDM022. Adverum has very innovative and industry-leading technology in vector development, gene therapy, and ophthalmology clinical development under our chief medical officer, Aaron Osborne' Importantly, under the leadership of Angela Fadinga, our chief technology officer, we're building our manufacturing capabilities, and she's already begun to hire a talented team to support our future commercial launch plans for ADVM-022. We have here a unique opportunity with ADDM022, a therapy that has the potential to not only disrupt but potentially expand the anti-VEGF market globally with a non-surgical one and done approach to greatly reduce the treatment For patients living with YMD and DME who currently receive frequent antibiotic injections in their eyes, as often as every 28 days, this one-and-done approach through continuous delivery of Flibercept following just one injection could truly be a game-changer.

Hi, Dan has varied and all that in an industry, leading technology in back to development gene therapy, and often Margie clinical development, I know chief Medical officer, and Osborne's expert guides.

Importantly, under the leadership of ads like the didn't go out seat technology officer.

Building or manufacturing capabilities and she has already begun to hiring talented team to support a future commercial launch plans for it to be able to too.

We have to hear a unique opportunity with maybe able to to therapy that has the potential to dolly disrupt but potentially expand the entire because that market globally, where they nonsurgical, one and done approach to greatly reduce the treatment burden for patients.

For patients living with what N D N D N who currently we see frequent anti there's different effects in Jackson.

As often as every 28 days this one and done approach through continuous delivery out of LIBOR sapped falling just one injection good truly be a game changer.

This weekend to me even more relevant in light of the current challenges with equipment that you've done that and if I've missed population that has to make the difficult choices between frequently Jackson's to treat nobody M.D. and staying at home to avoid exposure to covert 19.

Laurent Fischer: This became, to me, even more relevant in light of the current challenges with the COVID-19 pandemic and this at-risk population that has to make the difficult choice between frequent injections to treat their RADMD and staying at home to avoid exposure to COVID-19. This is why we're excited to present the most recent interim data from OPTIC that Dr. Kanani will share next, showing continued robust treatment responses from both high and low doses of ADVMO3. This treatment has now demonstrated long-term durability beyond 15 months from a single IVT injection with zero antivaginal stress-cure injections in patients from cohort 1.

This is why we're excited to present the most recent interim data from uptick that dr. cannot any worse than that.

I think continued robust treatment response from books high and low doses of maybe about your true.

This treatment has not demonstrate a long term durability beyond 15 months from a single Ivy teams action with zero I talked about that stress two injections in patients from called one.

Also.

Did you get more to two has been well tolerated across all cohorts with encouraging safety data from corked, forcing dot when they first occurs it can be manage what Stuart eye drops.

Laurent Fischer: Also, ADDM022 has been well-tolerated across all cohorts, with encouraging safety data from Court 4 showing that when inflammation occurs, it can be managed with steroid eye drops. With the OPTIC enrollment now complete, we look forward to presenting additional data from courses one through four by the end of this year. In parallel, given the positive data from OPTIC, we plan to seek input from US and international regulatory authorities as we progress towards initiating a pivotal clinical trial in mid-2021 in wet AMD. Advancing ADDM022 for two of the largest ocular diseases indications, WET-AMD and DME, is a very significant opportunity.

Well the optic enrollment now complete we look forward to presenting additional data from courts, one through four by the end of this year.

In parallel given the positive data from uptick we plan to see input from U.S. and international regulatory authorities as we progress towards initiating a pivotal clinical trial in that 2021 in wet AMD D.

Advancing it'd be able to two foot through the largest akio disease indications, where the M. D N D any he's a very significant opportunity.

We're beginning to accelerate our development and future commercial launch.

Given the size of these indications and the global potential my goal is to leaders Barents Nextera growth and readiness for plant a little trial, that's what the potential future commercial launch will they be able to too.

Laurent Fischer: And we're preparing to accelerate our development and future commercial launch. Given the size of these indications and the global potential, my goal is to lead Adverum's next stage of growth and readiness for a planned pivotal trial and for the potential future commercial launch of ADVM-022. Critical to running people's trials and launching a product is manufacturing, and we're already planning ahead by initiating in-house process scale-up from 200 liters to 1,000 liters to support the future commercial product launch of ADVM-022. In addition, we have initiated a site selection process to eventually build our own GMT capability.

Critical to running field trials are launching a product is manufacturing.

We already planning ahead by initiating in house process scale up from 200 leaders to 1000 meters to support the future commercial product launch or the gamut you too.

In addition, we have initiated a site selection process to eventually del dogs, you have to get their dogs.

I didn't ask about what keeps me awake at night to waste My biggest challenge as if there is and you see out.

Laurent Fischer: I've been asked about what keeps me up at night, and what my biggest challenge as Adverum's new CEO will be. My answer to that is being the best steward of the tremendous and truly unique commercial opportunities we have with ADDM022's gene therapy for a large and growing global population and to continue to advance our pipeline of novel gene therapy. To be prepared, we have continued to add industry-leading talent to our team and are beginning to expand our business operations and capabilities, including clinical, regulatory, manufacturing, and pre-commercial funding. But I must say that the bright future that Adverum has ahead is due to the vision and leadership that occurred during Leoni's tenure as CEO. Leone established an impactful corporate culture and hired an experienced leadership team to carry the company where it is today. I am pleased that in his continued role as Adverum's president, focus on key operational functions and manufacturing will allow our skill sets to complement one another and continue growing Adverum into, hopefully, becoming a global commercial organization. Truly, this is an exciting time for Adverum.

My answer to this is that being the best steward of the tremendous and truly unique commercial opportunities, we have with it'd be able to Jim therapy for large and growing global population and to continue to administer a pipeline of noble Jim parakeets.

To be prepared we have continued to out industry, leading talent George team.

Beginning to extend our business operations and capabilities and clean clinical regulatory body factoring and pre commercial functions.

But I must say that the bright future with them as hasn't had is due to the vision and leadership that happened that are the only his tenure as CEO.

The only established an impactful corporate culture and hired an experienced leadership teams care. The company awareness to that I'm pleased I know at least continued role as it Burns president focus on T. operational functions and manufacturing will allow skill sets to complement one another and continue growing advantage you hopefully becoming a global commercial opening.

Nation.

Julie This is an exciting time for that.

Before we get to the data presentation I want to acknowledge that we continued to take precautions and works hard as a copy it should not to get the two coated gene.

Laurent Fischer: Before we get to the data presentation, I want to acknowledge that we continue to take precautions and work hard as a company to navigate the impact of COVID-19. To date, we have experienced a limited impact from COVID-19 on our operations and ongoing OPTIC and INSANITY clinical trials. Of course, we will continue to monitor and attempt to limit the potential impacts of COVID-19 on our employees and operations and patients involved in our trials. I'm proud of how well our employees have adapted and how diligently everyone is working to deliver on our mission of delivering novel gene therapies to patients. Despite these challenges that the virus has presented to all of us in recent weeks, we were able to complete enrollment course four of uptake in three months and begin randomizing patients in infinity, our DME control trial, to continue the momentum in our ADDM 022 program.

Today, we had experiences and they did impact from giving that she's on our operations at an ongoing optic and infinity clinical trials.

Of course, we will continue to monitor and attempt to limit the potential impact so could actually then our employees operations and pay sensible trials.

I'm proud of how well our employees have adopted and how diligently everyone is working to deliver on our mission of delivering novel Gen gene therapies to patients.

Despite these challenges the diverse viruses presented to all of US in recent weeks were able to complete enrollment courts for about taken three months and they can be game randomizing patients and Infinity, Oh Dnbi controlled trial to continue the momentum in already beyond what you do programs.

Here's the agenda for today's event.

As mentioned, we're honored to have Dr. canady join us today with significant extent treating patients with why do you have de <unk>, Yeah me and as you recognize key opinion leader.

Laurent Fischer: Here's the agenda for today's event. As mentioned, we are honored to have Dr. Kanani join us today, who has significant experience treating patients with wet AMD and DME and is a recognized Q-opinion leader. Dr. Kanani will present the new interim data from OPTIC. After his presentation, we will open the call for Q&A, where I will moderate the discussion, and I will now turn the call over to Dr. Kanani. Dr. Kanani

Dr cannot any would present, the new interim data from uptick.

After his presentation, we'll open the call folks Una where I was moderated the discussion and I will not turn the call over to Dr. company took about it.

Thank you Dr. Fisher it is really a pleasure for me to present this data update as of July 23rd data like that and on behalf of.

Unknown Executive: Thank you, Dr. Fischer. It is really a pleasure for me to present this data update as of July 23rd's data cut. 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.

Big investigators invasions I think.

I want the audience to really look at this data and see what it means a two patients and physicians with chronic retinal diseases and that's why.

We're going to have.

A video IDN showing that.

So really you know as the top investigator in optic as not like multiple other trials as a P.I. I am able to see what these new molecules and delivery systems could do for our patients and I'm. So excited on a daily they did when they see patients doing really.

Unknown Executive: So really, you know, as a top investigator in optic neuropathy, as well as multiple other trials, as a PI, I'm able to see what these 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 a top enroller, I see optic patients on a daily or every other day basis. I actually saw a neighbor of mine who is an optometrist.

Wow.

Since I'm not dropping roller I see optic patients on a daily or every other day basis I actually saw neighbor Oh, My who is an uptick study.

She has failed all other treatments that persist in fluid on monthly Aflibercept and then I'm off thing these treatments do my neighbor.

Unknown Executive: She has failed all other treatments with persistent fluid on monthly affilier sets. 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.

Better make sure that it's safe and it works because I don't want my house and fire. So that's why I'm. So thrilled to be actually presented data because to me Andrew My patients. This is a big deal.

Unknown Executive: 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 and 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 four cohorts, including encouraging early safety data from Cohort 4 using prophylactic steroid iDrops. This clearly warrants further investigation in larger studies.

These are the key takeaways from my job today.

I'd be or do you do continues to show a bust treatment response.

Long term durability beyond 15 months from a single in clinic Intravitreal injection.

Zero rescue injections equaled one.

Further evidence of a dose response between the high and low doses.

Substantial reduction in annualized and tie that Jeff injection frequency.

80, M. old due to continues to be bell tolerate it made a very favorable safety profile in all four cohorts, including encouraging early safety data from cohorts for using prophylactic steroids eyedrops desk slowly warrants for their investigation in large your study.

Yeah.

Why do we care about having treatments that have 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 C. N. D study with almost 100000 lives we saw that even patients receiving so I've been to say.

Unknown Executive: Why do we care about having treatments that have continuous delivery? Why do we care about having treatments that could be one and done? This is the reason.

Unknown Executive: Based on our recent publication of the CIARA-AMD study, with almost 100,000 eyes, we saw that even patients receiving seven to six injections per year were losing vision in the real world. So the bolus injections are frequent and still not doing very well. That's why we need approaches that can show continuous delivery of anti-digest. And this is where ADVM-022 fits in.

Injection for a year, we're losing vision in the railroad.

So the bolus injection frequently.

And still not doing very well, that's why we need approaches that in show continuous delivery of anti that yeah, and this is where 80 BMO to do that sand it isn't in office Intravitreal injection, Oh gene therapy for this huge unmet need.

Unknown Executive: It is an in-office intramuscular injection of gene therapy for this huge unmet need in Neovascular AMD. If you look at ADVM-022, as I said, it is a gene therapy vector that is designed for continuous delivery of Flibersep following an in-clinic single intravitreal injection. The 7m8 capsid allows for efficient retinal transduction following intravitreal injection.

Oh, Neovascular and D.

If you look at 80 memo to do as I said it is a gene therapy factor that is designed for continuous delivery aflibercept following an inclination.

Single enjoy Mitchell injection.

When I made capsid allows for the education left no transduction following intravitreal injection.

If you look at data from non human Primate you can see that intramuscular injection of seven m- results and robust cielo transduction and protein expression in the high.

Unknown Executive: If you look at data from non-human primates, you can see that intravitreal injection of 7M8 results in robust cellular transduction and protein expression in the eye. The 7M8 vector was developed using directed evolution, which enabled intravitreal delivery. Broad Transduction in Retinal Cells and Increased Protein Expression

Well I mean, I mean, like Joe was dial up using direct.

The evolution, which enable intravitreal delivery.

Abroad that Shannon retinal cells and increased protein expression.

This is really a very novel treatment approach that intravitreal enough is gene therapy to really have continuous delivery of aflibercept.

Unknown Executive: This is really a very novel treatment approach with intramuscular in-office gene therapy to really have continuous delivery of liver cells. If you look at preclinical data, it has shown 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 O2-2 injection results in levels seen three to five weeks after a bolus intravital injection of Aflibercept. This is why I put my neighbor in there who was getting a flipper sep on a monthly basis with worsening disease control. As a reminder, OPTIC is a Phase I study with four cohorts, where the dose and steroid prophylaxis of the Steroid Regimen were varied. As you know, in Cohorts 1 and 2, we enrolled six patients each.

If you look at preclinical data it has shown that long from durable protein expression out to 21 months and 30 months from a single Intravitreal injection.

Also the continued delivery of Aflibercept after a single or to do injection results in levels seen lead to find me after a bolus in drumbeat deal injection mouth Aflibercept.

This is.

Why I put my neighbor in their who.

Was getting at live by step on a monthly basis with worsening disease control.

As a reminder, optic is a phase one study or cohorts.

What are the dose and do it broke black hills.

Oh, Dear White regimen, we're married as you know in cohorts one in Q, we enrolled six patients each in cohort three and four we enrolled nine patients each cohort one and for our at the high 60, 11 goes well cohorts two and three are at a meaningful.

Unknown Executive: In Cohorts 3 and 4, we enrolled nine patients each. Cohort 1 and 4 are at the high 6E11 dose, while Cohorts 2 and 3 are at the three-fold lower dose of 2E11. Again, a reminder, usually we see dose escalation studies. Here, the efficacy was. So it is good that the decision was made to use a lower dose, and you will see the long-term data from high-dose cohort one later in this presentation. Another difference is the approach to steroid prophylaxis.

Lower dose of to 11.

Yes, I remind you usually 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. One later in this presentation. Another defines as opposed to still like Buffalo axles cohorts, one and two were administered 13 they of course on oral steroids and a switching.

Unknown Executive: Cohorts one and two were administered a 13-day course of oral steroids, and a switch was made to a six-week prophylaxis steroid eyedrop regimen for cohorts three and four. Obviously, this is a phase one 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 the rescue criteria, and patients received supplemental effivercept if they met any of the criteria listed. Despite the pandemic, as Dr. Fischer said, we enrolled OPTIC quickly and successfully.

Made to a six week prophylactic steroids eyedrop regimen for cohorts three and four obviously the phase one study. So the primary objective is 60.

But I think I see in terms of Nugen anatomy and the need for rescue therapy was also a measure and here at the bottom you can see they were rescued like area and patient receives supplemental aflibercept. It didn't that any of the criteria listed.

Despite the fact that make as Dr. Fisher said, we enrolled optic quickly and successfully and as an investigator. This truly shows the value of a treatment. Initially you know studies have slow recruitment, but once you see the data maturing and see this long term efficacy.

Unknown Executive: And as an investigator, this truly shows the value of a treatment. Initially, you know, 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 up pretty quickly, even during the pandemic. There had been some missed visits, which were very limited and manageable.

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 would be a game changer, but we were able to close optic quickly even doing that then dynamic there had been something.

Visits which were very limited and manageable and in class you know in this current Nike situation, that's really highlights the utility off the continuous delivery of her treatment there a patient knows well they are covered under the physician knows that patients I covered and patients really do not necessarily.

Unknown Executive: And in fact, you know, in this COVID-19 situation, this really highlights the utility of 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, you know, I can't come in, I'm worried about COVID, I'm at high risk. I would have said, you know, 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 on 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.

Need to go to the site to see their treatment none of my patient <unk>. There's anybody there called me and said Hey, you know I can't comment I'm worried about Kobe Dime high risk I would have said you know you have continuous delivery from a single injection and I think you will be okay, but obviously for a clinical trial purposes, we brought.

Then in EMEA had no issues that coated 19.

I'm excited to now bring you updates to cohorts 123, and provide a first interim look at gold for as I said earlier than they did I thought it July 23rd for all four cohorts for coal for due to shop short follow up D. C. D N C S. The outcome and need for.

Unknown Executive: For Cohort 4, due to short follow-up, BCDA and CST outcomes and the need for rescue injection will not be presented today. However, two patients had some missed visits due to COVID-19 concerns. In cohort one, patient number one has missed a few visits due to COVID-19. The patient was seen by the investigator during a home visit on August 1st. And I'm happy to report the patient is doing well. They're RET-ANB stable, and there's no inflammation.

A rescue injection will not be presented today.

Two patients that some as visits you do go with 19 concerns in cohort one the patient number one has missed a few with if you do call. It 19. The basin has been seen by the investigator during the home visits on August 1st and I'm Happy to report the patient is doing well there like M.D. stable and there.

No inflammation.

If you look at the baseline characteristics from.

For the study you can see gold sport, it's consistent with cohorts 123.

Unknown Executive: If you look at the baseline characteristics for the study, you can see that 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 O2-2 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 put that, and I did the same.

In cold or you can see that some patients were diagnosed more recently.

Less than 12 months five two or two to 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 put that.

I did the same we were able to enroll cohort four very quickly even during the endemic and like I said earlier I was able to enroll one of my neighbors, who has been not doing well the current standard of care everything else, it's consistent with other cohorts or all patients live Neovascular N D. In this study.

Unknown Executive: 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 the 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 swim lane plot.

We're more difficult to treat and needed week, when I'm talking like Jeff injections to maintain vision I will also share a case later in this presentation to show you that.

This is a shamblin blog, you can see that Brian and King optic and receiving OTI to this station population need it very frequent injections.

Unknown Executive: You can see that prior to entering OPTIC and receiving O2-2, this station population needed very frequent injections. If you look at the data from Cohort 1, patients continue to do really well with zero injections out to 15 months. Again, before O2-2, they were receiving on average 9 to 10 injections to control their disease.

If you look at the gave out from cohort one station continue can do really well they now zero injection out to 15 months again.

Before due to the receiving on average nine to 10 injection to control their disease.

And after a single in office into other chill injection of gene therapy with AG and go to two patients have now gone out to 15 months or longer without requiring zero rescue injections.

Unknown Executive: And after a single in-office intradental injection of gene therapy with ADVM-O2-2, patients have now gone out for 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 now been a third patient requiring supplemental anti-adverse treatment. For this patient, a single injection at week 48, and the patient has now been followed up for 56 after. O2Q.

If you look at data from cohort two you can see that patients that path the money a milestone there's been now up those patients requiring supplemental and thought about Jeff treatment.

For this patient a single injection it meet 48.

In addition has now been followed up 56 after.

Oh two too.

If you look at cohort. The me now all patients that past 20 meet with only two patients receiving supplemental anti VEGF injections. One of these stations as me, Steve a single and anti VEGF injection only doing 36 weeks of follow up this was actually one of my patient.

Unknown Executive: If you look at Cohort 3, now all patients have passed 20 weeks, with only two patients receiving supplemental anti-VEGF injections. One of these patients received a single anti-VEGF injection only during 36 weeks of follow-up. This was actually one of my patients that I treated.

That I see that overall, there's been a substantial reduction in need grant dug up injection at both low and high dose with continuous evidence of a dose response.

Unknown Executive: Overall, there's been a substantial reduction in the need for antiviral injections at both low and high doses, 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 deaths or discontinuations in this study.

If you look at safety 80, B.M. OTI to has been well tolerated <unk> no systemic.

Worse events related to or to do there'd be no debt or discontinuation in this study.

Inclination has being responsive to and manageable with scantily eyedrops, one thing I want to emphasize there'd be no clinical or floor seen evidence for posterior inflammation.

Unknown Executive: Inflammation has been responsive to and manageable with steroid eye drops. One thing I want to emphasize, there will be no clinical or fluorescein evidence of posterior inflammation. There have been no cases of retinal vasculitis, retinitis, choroiditis, vascular occlusions, or endophthalmitis. Of all ADVM 022 related popular events, 78% were mild, and 22% were moderate.

There'd be no cases of retinal vasculitis retinitis Cora died as vascular occlusions or end up to Midas.

Oh 18 year old due to the Lady ocular event, 78% or mild and 22% were modeling there wasn't one adverse event of special interest of modern regarding uveitis deemed to be related to old do too and it wasn't responsive to steroids eye drops there.

Unknown Executive: There was one adverse event of special interest of moderate recurrent uveitis deemed to be related to O2-2, and it was responsive to steroid eye drops. There have been no new cases of IOP elevation since I gave the last update. You can see the duration of follow-up here, as well as the adverse events and what we see. There are different durations of follow-up and numbers of subjects per cohort, but it appears that there are fewer adverse events in cohorts three and four. Again, that's the group that utilized longer prophylaxis with steroid eye drops instead of oral steroids in cohort one and two. Now, let's look at cellular inflammation by cohort. From cohort one, we can see an overall resolving inflammation picture, with now two out of six patients still taking steroid eye drops and no other patients having any cellular inflammation.

To be known you cases of IP elevations and I gave the last update.

If you can see the duration of follow up here as well as adverse event and what we see that.

There are different direction, a follow up a number of subjects per cohort, but it appears that.

Our lower number of adverse event in cohorts three and four again that the group that has utilized longer prophylactic steroids eyedrops instead of oral steroids in cohort one and two.

Now, let's look at selling or inclination like cohort from cohort, one we can see and or all resolving inflammation picture. It now two out of six patients still taking steroids eye drops and no other patients having any cellular inflammation.

Patient number two is the one the adverse event of special interest a moderate you'd be ideas that record following the situation outstanding eye drops at week 72.

Unknown Executive: Patient number two is the one with an adverse event of special interest of moderate uveitis that recurred following the cessation of steroid eyedrops at week 72. This has improved after starting another steroid eyedrop. Looking at Cohort 2, we can also see an overall resolving inflammation picture as well, with all patients now past the 52-week milestone. Four out of six patients are inflammation-free, and actually, patients one and six are both my patients, and they're super happy that they have not received rescue for over a year. They are, however, on steroid eye drops, which they have no issues taking.

Just have improved after starting.

Steroids eye drops.

Looking at cohort do we can also see an overall resolving in all major inflammation picture as well that all patients now past the 52 week milestones.

Four out of six stations are inflammation free and actually based on what im sick or both my patients and their super happy.

That did not received rescue for over a year. They are all though on their like eyedrops, which they have no issues taking.

In gold three all patients are beyond 20 me as of July Twentyth, Eric as you can see five out of nine patients have guessed continued steroids eye drops.

Unknown Executive: In Cohort 3, all patients are beyond 20 weeks as of July 23rd. As you can see, five out of nine patients have discontinued steroid eye drops. Gerard Eyedrops 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.

Scott I dropped a loan or successfully control inflammation in cohort three.

Let's look at cohort poor of course. This is early in follow up we are back at the high dose of 60 11. We are closely looking at the first couple of weeks as oral steroids had been replaced with steroids eye drops.

Unknown Executive: We are closely looking at the first couple of weeks as oral steroids have been replaced by steroid eye drops. The good news is that there has 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 findings 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.

The good news is they'll be minimal to zero early inflammation that steroid eyedrops prophylactic consistent with cohort three only low grade inflammation was observed in some patients while tapering or stopping steroids eye drops.

This is consistent with binding on cohort, one and two that information man observed.

Being responsive to and manageable that's delayed I jobs, not let's look at vision. Again reminder, this was a tough to treat patient population and the goal of single injection wants to maintain BCB overtime and control disease activity in terms of all the efficacy measures long term.

Unknown Executive: Again, reminder, this was a tough-to-treat patient population, and the goal of the single injection was to maintain BCV 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 intravital injection of ADVM 022. As you can see, there is one outlier at week 48, skewing the average and the error bar. This was the patient, as I mentioned in the last update, that had an unrelated pseudophagic retinal detachment that was repaired with vitrectomy and gas. And when you have gas in your eye, you can't really see, and that's why you see a little gap there. But overall, vision has been maintained with absolutely zero rescue injections in any of these patients. Looking at CST over time in Cohort 1, you can see that CST measurements also show that anatomy is maintained out to the 72-week median for all six patients in Cohort 1. I think this is crucial.

Asian from cohort one is stable out to 72 weeks.

Hi, lighting the potential of continuous delivery after a single in office Intravitreal injection of 80, B M or to do.

As you can see there's one outlier at need 48 skewing to averaged in the air Bar. This was the patient as I mentioned in the last update that had unrelated pseudophakic retinal detachment that was repaired the crack to me and gas and then you have gas in the high you can't really see and that's why you see a little get.

There, but overall vision has been maintained that absolutely zero rescue injections in any of these patients.

Looking at CST over time in cohort one you can see that CST measure and then also showed that anatomy is maintained I'll do the 72 week median for all six patients in cohort what I think this is crucial I think you need to make sure that when you have continues delivery Youre also.

So controlling the anatomy and you're not under treating the patients and as I said by getting levels that are as good as Bulls aflibercept three weeks or five weeks. After they enjoy digital injection I think this really resonate that this continuous delivery is really controlling the disease in the frequent.

Unknown Executive: I think you need to make sure that when you have continuous delivery, you are also controlling the anatomy, and you're not under-treating the patients. And as I said, by getting levels that are as good as both a Flipper SEP three weeks or five weeks after the intramuscular injection, I think this really shows that this continuous delivery is really controlling the disease in these frequently tough-to-treat patient populations. If you look at BCV 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. Looking at CST over time, 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.

The tough to pre patient population.

You look at least give me over time in cohort two you can see the same pattern that was very consistent maintenance of vision that all six patients now beyond 52 weeks.

Looking at CST overtime, and the same is true for CST once again, showing a very consistent maintenance of anatomy or the 52 weeks, but a slight improvement of 25 microns into or all cohort I have two patients who are still on steroid drops as I said in this.

Cohort their fellow eyes actually continue to receive injection both at bilateral disease. Both eyes were getting injections every four to six weeks not only one eye is getting injection. The common question. They asked me is why can't I have the street. Many in my fellow lie and number two is why do I need to come and Keith.

Unknown Executive: I have two patients who are still on steroid drugs, as I said, in this cohort. Their fellow eyes actually continue to receive injections, both at bilateral disease. Both eyes were getting injections every four to six weeks, but now only one eye is getting injections. The common question they ask me is, why can't I have this treatment in my other 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?

See you if I'm doing so well everyone I'd that's in the study and I tell them you know, even though it's working really 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 I has been well controlled and they're looking forward to having the treatment.

Unknown Executive: And I tell them, you know, even though it's working really 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 other eye once there is approval. In terms of BCVA over time, in cohort three, with a median follow-up of 36 weeks, we see average BCVA slightly improved by four letters, but really largely consistent with cohorts one and two, where we see maintenance of visual acuity. One thing to keep in mind, seven out of these nine patients remain completely rescued.

Fellow lie once there is an approval.

Sounds a b C media or time in gold to me that the median follow up oney six weeks, we see I really see being slightly improved that's four levers, but really largely consistent with cohorts one into where do we see maintenance of visual acuity one thing to keep in mind seven out of these nine patients remain completely rescue.

Right.

If you look at Heskey. The me CST continues to improve in all nine of these stations that average improvements of about 120 micron even higher in the six stations with no rescue at about 150 my comp.

Unknown Executive: If you look at CST, the mean CST continues 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 characteristics, patients in Cohort 3 had more fluid at baseline than patients in Cohorts 1 and 2. Now, let's look at this case that I presented before.

As a reminder, looking at the baseline characteristics patients in cohort three had more fluid at baseline than patients in cohort one and two.

Now, let's look at best case that I presented before this is one of my patients in cohort three that required frequent injection nothing labor SAP without having to east control. So this brings me back to the point I said earlier about getting levels as high as bullets Aflibercept.

Unknown Executive: This is one of my patients in Cohort 3 that requires frequent injections of Aflibirsep without having disease control. So, this brings me back to the point I said earlier about getting levels as high as bolus Aflibirsep at three to five weeks. We expect a continuous delivery of Aflibirsep with O22 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 a 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, and received a Flipper Step to show our response. You can see that patient did respond after two weeks, but there's still subretinal fluid.

The two five weeks, we expect the continuous delivery of Aflibercept mean, Oh, two to may improve visual acuity and anatomy patients who are sub optimal responders to to current treatment and this is the reason I enroll my neighbor, who has been sub responder because I saw this.

They efficacy personally in this station and many other patients where I'm seeing that the diseases being modified and you can see on the left patient or suite for the study of his seat Aflibercept to show. Our response you can see that patient did respond after two weeks, but there's still sub retinal do it.

They should've received 80 B M or two two and now you can see that baby Half's 36 week data on this patient. This is the patient who was not controlled with at least four to five weeks aflibercept and as the data is maturing whatever be seeing we are seeing the efficacy.

Unknown Executive: The patient received ADVM 022. And now you can see that we have 36 weeks of data on this patient. This is a patient who was not controlled with every four to five weeks of Flipper Step. And as the data is maturing, what are we seeing? We are seeing the efficacy of continuous delivery of a Flipper Step using ADVM 022. As I mentioned earlier, he also has a twin that wants to get into the trial. And now that the trial is closed, he's not very happy that he can't get in where his brother is doing so well without any treatment. Let's come back to the swimlane plot to emphasize the points I made earlier.

Our continuous delivery aflibercept, using 80 million Boe to too as I mentioned earlier. He also has a twin that wants to get into the trial and now that the trial is close he is not very happy that he can get him where his brother is doing so well without any treatment.

Let's come back.

To the swim lane plot to emphasize the points I made earlier.

These are harder to patients with Feverously that previously required frequently injections to maintain that vision just like vacation I saw showed you in the case or just like my neighbor, who is not control that monthly aflibercept.

Unknown Executive: These are hard-to-treat patients that previously required frequent injections to maintain that vision, just like the patient I showed you in the case, or just like my neighbor who is not controlled with monthly Aflipracept. Here we see the power of this treatment. We see that cohort one has had zero rescue injections with 15 month or longer follow-up. As I stated earlier, patient one had some missed COVID visits but is doing really well recently. Even in the lower two doses, we can lower those cohorts, we can see that in cohort two and three, 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.

Yeah, we see the power of boosted this treatment, we see that cohort one has had zero rescue injection with 15 month or longer follow up as I stated earlier patient one had some misquoted visit but as it was recently is doing really well.

Even in the lower two doses weekends lower dose cohorts and you can see that in cohort two and to me. There's a dramatic reduction in injection burden after treatment with in office Intravitreal gene therapy with 80, the or two too.

If you don't remember anything from this dog 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 80 vehicle due to we looked at annualized injection frequency before and after or two two and as you can see for the high dose cohort one.

Unknown Executive: This is another way to look at the potential benefit of continuous delivery with ADVM-022. We analyzed the analyzed injection frequency before and after ADVM-022. And as you can see, for the high-dose cohort one, the average analyzed injection frequency drops from 9.6 before 022 to zero. These are patients in cohort one 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 an 87% reduction. Again, showing the benefit of continuous delivery of a single in-office in-job. I wish I had this chart in my office today so I can show patients what we have achieved since approval of Renovizumab in 2006.

Average annualized injection frequency drops from 9.6 before or two to two zero.

These are patients in cohort, one where we have gone 15 months or longer the dogs, requiring any rescue injection.

I think this is a big deal.

Combining the low dose cohorts, two and three the treatment burden decreased significantly from an average annualized injection frequency of 10.

To an average one point can read.

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 rather busy mob in 2006.

Personally I feel this is very disruptive in terms of really benefiting the patients their caregivers and position to really control. These diseases that are common cause a blindness in this country and globally.

Unknown Executive: 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 causes 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 the flippersep protein through gene therapy for the treatment of RET and D. It shows the potential to dramatically reduce the treatment burden in a hard-to-treat patient population. ADVM-022 shows robust treatment response and long-term durability beyond 15 months from a single injection with zero rescue injections in this hard-to-treat patient population. The two doses showed 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, and low-grade inflammation, when observed, has been responsive to topical eye drops. Still early, but evidence suggests a longer prophylactic regimen can be more effective at minimizing risk and inflammation. As a result, ADVM-022 clearly warrants further investigation in larger studies.

In summary, these data provide a meaningful update to the optics study that evaluated a single intravitreal injection that provides continuous delivery of aflibercept through gene therapy for the treatment of Red and de <unk>.

So the potential to dramatically reduce the treatment burden hard to tweet patient population.

Yeah, you'd be able to two shows a bus treatment response long term durability beyond 15 months from a single injection with zero rescue injections and that's hard to treat patient population.

The two doses show a dose response as assessed by the need for rescue.

Substantial reduction in the annualized injection speak wouldn't see.

<unk> hundred percent when the high go and 87% in the low dose.

Yeah rubble safety profile across all four cohorts low grade inflammation, then observed has been responsive to topical eye drops still early but other than suggest a longer prophylactic regimen can be more effective and minimizing inflammation.

As a result 80 of them well into two clearly warrant further investigation in larger study, we need as well or patients with Neovascular AMD D.

Unknown Executive: We need this for our patients with neovascular AMD. I want to thank all the investigators, patients, our reading centers, as well as the team at Adverum for really participating in this trial to really change the disease course for our patients with neovascular AMD. Before we finish, I want to present Infinity to you.

I want to thank all the investigator patients.

Our leading center as well as the team at Advair to really.

Participating in this trial to really changed the disease course portal or patients.

Vascular Andy.

Before Mr., Dennis I want to present to you.

Infinity Infinity the phase two trial of 80 me or two to in diabetic macular edema.

Unknown Executive: Infinity is a phase 2 trial of ADVM-022 in diabetic macular edema. As you know, diabetic macular edema and diabetic retinopathy are 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 into our clinic blind, looking for hope to reverse their vision. Some of these patients have been our patients in the past but failed to follow up, whether they got sick, whether they got busy because they were working, or they lost their injection. This is just the US.

As you know diabetic macular edema, and diabetic neuropathy is the number one cause a blindness in working adult symbols country.

On a daily basis, we see patients who had diabetes for a long time gowalk getting our could make blind looking for a whole to reverse their vision.

Some of these patients had been or patients in the past, but failed to follow up whether they've got sick, whether they got busy because they're working or they lost their injection tough wage.

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 buying monthly injection. This is why I'm. So excited about infinity and we were lucky to be the first sight to enroll patients in this trial.

Unknown Executive: 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 injections? 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. Another thing I wanna mention is the smart trial design, and that speaks to the team that Aaron Osborne is leading, where you can see that this is designed to demonstrate superior disease control compared to a single Aflibirazep injection. And this will be measured by time to the worsening of DNA.

Other thing I went out mention is the smart trial design and that speaks to the team that Guy and 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 too.

Unknown Executive: 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 Discipline. And I'm going to get emotional now because I'm going to bring to you one of my patients now. She has been my patient for the last eight years. She is like family to me. I look forward to seeing her every other week because she has diabetic macular degeneration, and she was blind in both eyes before she got it. After seeing her in clinic, I told her we need to really treat her aggressively, and she has been a very compliant patient. But until recently, I really didn't realize what a toll it took on her and her family for her to come to my clinic.

Worsening of Dnbi disease activity.

Very clever design I came to really show the benefit.

80, mammo to two 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 emotion allow because I'm going to bring to you one of my patients Mac.

Unknown Executive: They're always smiling when 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 a flipper sap in one eye at a time. She's been in my clinic, never missed a... So when I talked to her, during an event, we asked her and her daughter about what really means to have therapy like ADVM 022. And here is

She has been my patients or lost 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 times before she got here.

Unknown Executive: Presenters, your lines are live. I think they're having a rerun of that video here.

After seeing are in clinic, I told or we need to really treat you aggressively.

Unknown Executive: This is the reason why I do clinical trials, and this is the reason we're all working together to bring this to 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, and better visual acuity. Parents, sisters, brothers, kids, don't go blind with retinobascular diseases, and I'm excited to see that the future looks really bright for these patients. I'm going to pass this now to Dr. Fischer.

And she has been very compliant patient.

But until recently I really didn't realize what all it takes on her and her family like coming to my clinic that always smiling when they are with me, but now I know what they'd go through or not.

We are every other week basis, because she has to lies with the disease and she gets aflibercept one eye at a time.

Laurent Fischer: Thank you, Dr. Kanani. And before we begin the discussion portion of this call, I would like to express my gratitude for Dr. Kanani introducing Adverum to the patient and 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 maintain her vision is a stark reminder as to why a 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, Anastasia

And she's been in Mike Glenn They never missed appointment so when I talk to her.

During an event, we asked her and her daughter about what really doesn't mean to have.

Therapy, like 80, Vmoso too too.

And here is the video.

Presenter is your lines are alive.

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

Tyler Van Buren: Hey guys, 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 for a longer period of time, clearly, the goal is to maintain visual acuity and anatomy, but it does appear that you're seeing an improvement in the anatomy and CRT, and you've pointed that out in the release. I And then, on the second question on safety, you mentioned encouraging early safety from 4.

You are having a re around here on the video.

This is the reason why.

Nickel trials.

And this is.

The reason, they're all working together to bring this.

For our patients with diabetic macular edema, and Neovascular AMD be because this is what I see on a daily basis and this is just one patient when we have millions of patients around the world, who need us to provide them better options.

Better disease control better visual acuity so there.

Laurent Fischer: Thank you, Tyler. That's a great question.

Laurent Fischer: Go ahead. Thank you so much, Laurent. Thank you. And thank you, Tyler. I'll take that one.

Parents Sisters Brothers Kids don't go blinded, let no vascular diseases and I'm excited to see that that future looks really bright for these patients I'm going to pass now to Dr. Fisher.

Dr. Aaron Osborne: It's Aaron Osborne here, CMO of Adverum. And you pointed out that some of the patients we have actually seen improved anatomy, whereas, you know, the treatment goal for these patients, they're patients who've been having many, many injections for chronic West AMD, so they're difficult to manage. And essentially, the goal for these patients is to reduce their injection burden whilst maintaining vision and maintaining the anatomy. And that's essentially what happened across the cohorts.

Thank you Dr. down in before we begin to discuss some portion of this call I would like to express my gratitude for Dr. combined introducing them to the patient care giver highlighted this video I think fearing first hand, the emotional testimony directly from them on the treatment burden in order for the patient to maintain revision is it.

Stark reminder, as to why a potential one time treatments such as it did you know two to could offer more patient centric approach supervision in patients with wet AMD, India me.

Dr. Aaron Osborne: But we see in cohort three that there's been some improvement, and that is really largely due to the fact that some of these patients had fluid at baseline. You see that the central retinal thickness was thicker at baseline for Cohort 3, and that has been able to be improved. And that is best epitomized by the case that Dr. Kanani presented of the patient that was getting frequent ILEA injections, still had a lot of fluid, but then with the continuous delivery of Aflilisept with ADVM 022, you saw that the anatomy resolved, and actually, that patient experienced visual improvements as well It's a small study, you know, in nine patients; we focused more on anatomy than on vision, but when you can get anatomical improvements, it's often not surprising to see that there are some visual 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, and it is obviously early data.

I'd like to open the call now for questions from goes on the phone and turn it over to the operator for the first question on Stager.

Thank you. Our first question comes from Tyler Van Beurden with Piper Sand layer. Please go ahead.

Oh, Hey, guys. Good afternoon, and it's great to see those continue durability of 13 months you guys are certainly keeping earnings interesting a couple of questions. One on efficacy in one on safety or the first one on efficacy I imagine it's too early to say whether cohort for looks more like cohort one versus.

Two and three but.

As you look at cohorts one into as they go out to a longer period of time current.

Clearly the goal is to maintain visual acuity in anatomy, but.

Does appear that you're seeing an improvement in the anatomy and CRT and you pointed that out in the release I wanted to get your your thoughts on that and then on second question on safety you mentioned.

Dr. Aaron Osborne: We particularly wanted to share these data for Cohort 4, because we're looking at those first weeks after receiving O22 when we were previously giving stronger steroids in the form of oral steroids, and now we're giving just topical steroids. And what we've seen is that topical steroids have controlled that early inflammation, which is minimal to zero during the time period that that has been covered. And overall, across Cohorts 3 and 4, I think it's really important that none of these patients needed more than topical steroids in order to control and manage their inflammation. And, you know, with regard to the question, how can you be sure that this is not the back of the eye? We look carefully in terms of clinical examination.

Encouraging early safety from four.

Versus cohorts, one and two and if you're a ease unless inflammation, but I wanted to ask you specifically about posterior inflammation. You said you haven't seen any what gives you confidence that none of the.

Inflammation events or similar to what has been observed with this apart or pay a view.

Thank you talked about a great question.

Oh, sorry go ahead.

Thank you very much lower okay. Thank you Todd I'll take that one is there another one here I'm CMO fanfare and you pointed out that some of the we have actually seen improved in asks me where as you know the treatment goal for these patients that patients who've been having many into many injections to chronic why same days that difficult to manage.

And essentially the goal for these patients is to reduce their injection burden, whilst maintaining the vision and maintaining the anatomy and that's essentially what happened across the cohorts, but we see in cohort three that there's been some improvements and that is really largely to GE that summer tusa found at some of these patients had fluid.

Dr. Aaron Osborne: And the fact that all information is manageable with steroid eye drops also points in that direction as well. But I think, you know, I'd like to bring back Dr. Kanani here as well, because he's been an investigator in many of these trials, including, you know, Bicoparbolazizumab trials, where there has been some posterior inflammation, and perhaps to share, you know, the source from a clinical perspective. Dr. Pinane

Baseline you see the essential retinal thickness with pick a baseline for cohort three and that has been able to be improved I'm not if that's the victimized by the case that thoughts economic presented on the patient that was getting free Quinn I Lear injections are still had a lot of fluid, but then with the continuous delivery of liver.

Unknown Executive: Thanks, Aaron. Yes, thanks, Aaron.

Unknown Executive: I think that's an excellent question because, you know, we are comfortable with the safety profile of current agents. And anything that's coming to the market, especially an intravitreal injection that's frequent, like Abicapar or bolusizumab, we need to make sure that we don't get cases of irreversible blindness. We were the top site for the CDER study, which was phase three for Abicapar, and I had 21 patients in that study. And I saw two patients with panuviitis and vasculitis. And let me tell you, you don't need to look for those.

That's with 80 Vmoso OTI to you so that the anatomy resolved and actually that patient experience visually improvements as well because the an estimate improved its a small study you know when nine patients we focus more on a knock me then on vision, but when you can get anatomically prepayments itself not surprising to see that there was some vishal improvements as well so where do you.

Putting not down to the potential efficacy of continuous delivery.

We've got the second question, which was on safety.

Unknown Executive: It presents itself. You have eyes full of 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 Hawken Harrier. I think the confidence for me in O22 is the fact that the vector is secreting a flipper set.

It is early obviously.

It is obviously early data, we particularly the ones to share these data for cohort four because we're looking at those first weeks after receiving though to see when we were previously giving strongest steroids in the form the oral steroids and now we're giving just a topical steroids and what we've seen if the topical steroids of control that early information that the new.

Animal to zero during the time period that has been covered and overall across cohorts three to four I think it's really important none of these patients as needed more then topical steroids in order to control and manage their inflammation I'm you know with regards to question. How can you be sure that this is not back because they are we look Kathleen says a clinically examined.

Unknown Executive: It is not a new molecule. We have data since 2011 on Flibersep in terms of safety. Obviously, we have some inflammation, which is mild, and it's in the front of the eye. I've not seen anybody with posterior inflammation. And I think if you look at vitreous cells, they're looked at by sputum, and those are spillover cells, really, from the front of the eye.

Action and the fact that all information is manageable with Starwood eyedrops also points in that direction as well, but I think you know I'd like to bring back in Tulsa cannot be here as well because he's been an investigator and many of these trials, including you know because policy Seamap trials, where there has been some posterior inflammation and perhaps to share the source from from from a clinical.

Unknown Executive: So I really want people to understand that this is not what we have seen with Abicapar. Now, having 11 patients in OPTIC is a large number.

Unknown Executive: I would have seen anything concerning, and I'll tell you most of this information is just in the front results really quickly with topical steroids. And again, Tyler, what we need to pay attention to is the fact that it is good value for the patients. Why are people not physicians using BOVU first line? Or why did the FDA not approve Avicipar? Because they had incremental benefits compared to intravitreal injection of, let's say, Bevacizumab, Renuvizumab, or Eflibris. Here, you're changing the disease course, you are changing the vision for the long term, you are getting stable vision and anatomy, and you're controlling the disease. You're essentially changing the course of the disease. So here, there's huge value for the patient compared to what Ibogapar and BOV have brought. But the good news is that we don't have any posterior inflammation. We don't expect it because it's secreting a flipper set, which has been out since 2011. Back to you, Aaron.

Active.

Docs economic thanks, Aaron Yes, Thanks, Aaron I think that's an excellent question because you know we're comfortable with the safety profile of current agents and.

Anything that.

You know coming to the market, especially in Intravitreal injection that sequence like a big a bar or bolus isn't that we need to make sure that you don't get cases or irreversible blindness, we want the top site for Cedar study, which was the phase three for they can power and I had 21 patients in that study and I saw two.

Patients with Penn unique items, and vasculitis and let me tell you.

You don't need to look for that it presents itself you have I phone mid inflammation in the back you have vessels than a light.

And patients won't call you and tell you there's something wrong. So so I know there's been some discussion about subclinical.

Unknown Executive: Thank you. Thank you, Dr. Kanani. Let's go to the next question.

Vasculitis or retinal artery occlusion, there were seen in Oregon area, I think the confidence or mean OTI to is the fact that the vector is decreasing aflibercept.

Operator: Once again, to join the question queue, you may press star and 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.

It is not a new molecules, we have data since 2011 on aflibercept in terms of safety.

Operator: To withdraw your question, please press star then 2. Adverum Biotechnologies requests that callers limit themselves to one question. We will pause for a moment as more callers join the queue. Our next question comes from Alethea Young with Cantor Fitzgerald. Please go ahead. Hey guys, thanks for taking my question and congrats on the progress. Though I have many, I will try to ask one. I guess, you know, one of the cases that I've gotten a lot of questions about 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, detail on, like, what happens when patients go off. Is it easy for everyone, or is it difficult for some?

Obviously, we have some inflammation, which is milestones in the front of the I've not seen anybody that portion inflammation and I think if you look at mid year sells their loved by slit lamp and those are spillover ourselves really on the front on the eyes I really want people to understand that this is not what we have seen that.

Makeup are now having 11 patients in uptick.

That's a large number I would have seen anything concerning and I'll tell you. Most of these inflammation a just in the from resolves really quickly the topical steroids.

And again lasting Tyler we need to pay attention to is the fact is.

The value for the patients why are people not a physician using deal being first line or why didn't they didn't approve ADITC impart because that incremental benefits compared to intravitreal injection of let's say bevacizumab branded visit Mabry aflibercept.

Alethea Young: And just maybe frame that for us. Thanks.

Dr. Aaron Osborne: Thanks, Luthier. I mean, I'll hand over to Dr. Kanani in a moment, but maybe just to share the kind of update again from Cohort 1 in this study. As you said, there can be questions about 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 in that way for some period of time, and both attempted to discontinue steroids in the recent past. And one of those patients, they discontinued the steroids, there were zero signs of inflammation, and they've had a couple of follow-up assessments since, and all is looking very good for that patient; they have inflammation free. The other patient did have a recurrence of inflammation.

Here you are changing the disease course.

You are changing.

The vision on something in a long term you are getting stable vision and an AD I mean, you're controlling the disease essentially changing the course of the disease. So here there is huge value for the patient compared to what they make a bar and deal the abroad, but the good news is that we don't have an equal share information we don't expect.

It because it's like meeting Aflibercept niches.

Out since 2011 back to you Aaron.

Thank you. Thank you to what's going on it looks good for the next because in the next question.

[laughter].

Once again to join the question can you give me a press Star then one on your telephone keypad, you will hear telling acknowledging your request. If you are using a speakerphone. Please pick up your handset before pressing entities to withdraw your question. Please press Star then too.

Dr. Aaron Osborne: And you know, one of the learnings here is that when you take a patient from one drop a day to zero drops a day, there may be a steroid rebound effect, or there may be a low amount of steroid viral capsid material, which we believe is potentially triggering inflammation that may be remaining. So regardless, this patient, when we stopped the steroid eye drop from one drop a day to zero, they did experience a moderate recurrence of that inflammation. I think 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, you know, when we look at this patient again in the future and we go from maybe one drop a day to zero, or potentially, in other patients who have experienced a recurrence, we're looking at maybe adding in an interim step of going down to one drop every other day, which is, you know, something that has been used certainly in the clinic quite frequently in patients who have had, you know, sometimes a challenge with tape So I think, you know, that's what we see in OPTIC, and I'll hand over to Dr. Kanani, who can perhaps add some additional thoughts from his clinical perspective.

Adverum biotechnologies request that callers limit themselves to one question.

Well, we'll pause for a moment as more colors join the queue.

Our next question comes from Lithia Young with Cantor Fitzgerald. Please go ahead.

Hey, guys. Thanks for taking my question congrats on the progress.

No I had many I will I will try to ask one I guess you know one of the cases theyve gotten all my questions around as I'm kind of what happens in patients go off of their topical steroids I'm sorry, I was wondering maybe if the doctor who give us a little the like detailed unlike what happens when patients go out of it easy forever line or is a difficult for some and just maybe.

Maybe frame that for us. Thanks.

Thanks, Felicia I mean, I'll hand over to two starts currently in a moment, but maybe just to show the kind of the update again from cohort one and this studies. He said that can be it can be questions about coming from coming off steroids and we actually had two patients in cohort one on who were on once a day sterilized drops.

With yeah zero inflammation had been in that way for some period of time and both attempted to discontinue steroids in the recent past and one of those patients. They just continue to steroids. There was I was there were some signs of inflammation and they've had a couple of follow up assessment since I'm an old is looking very good for that patient ever inclination free.

The other patient did have a recurrence of inflammation.

And you know one of the learnings here is that when you take a patient for one drop but that it to zero drops today that may be a steroids rebound effect or the maybe a low amount of I'm still borrow caps material, which we believe to be potentially triggering information that may be remaining regardless. This patient one we stopped us teradata drop from one drop it down.

Unknown Executive: So I think, Aaron, the key question here is 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 one study. It is really focused on safety, and we are seeing amazing efficacy and durability. But we also want to learn how these patients do long-term.

Because there are they experience a moderate recurrence of inflammation I think what's important here is the patient was then restarted on this teradata drops and the situation has improved and that patient is now tapering down on that started hydrops. So I think you know when we look at this patient again in the future me go from maybe one drop it down to zero or potentially in other.

Unknown Executive: The good news from a clinician perspective is that most patients are off the drops. So it's not like every patient will need four times a day forever. So most of the patients, if you look at every cohort, have been off the drops. Patients who actually need drops, most of them are on one or two times a day. There are a few on four, but really, that number is small.

Patients who have experienced a recurrence you know we're looking at maybe adding in an interim step of going down to one drop every other day, which is something that has been you certainly in the clinic quite frequently in patients who have had you know sometimes a challenge with tapering will start eyedrops. Another setting. So I think that's what we see an uptick.

Unknown Executive: So I saw a patient today who had fixed the retinal detachment about two years ago and has chronic macular edema and needs to take steroid drops. And I was giving this presentation today, so I actually asked him, even though it's a different indication. I said, "Your retina is looking great on two times a day steroid. You've been on it for a couple of years." We know we go down to one when your vision drops. Do you want to try to get off the drop and see how much of a burden it is? You know what he told me? He said, "It's not a big deal."

Hand over to Dr. can army, who can perhaps had some additional thoughts from its clinical perspective.

So I think Aaron.

The key question here is that how can mean, though which stations can come off and make decisions will not require steroids after coming off and I think.

People need to understand this is a phase one study it is really focused around safety and.

We're seeing amazing efficacy and durability.

Unknown Executive: I like to see, and I'm happy with my vision. So I think for a patient who is just post-op, but imagine a patient who actually received injections every month or every six weeks or eight weeks. What would their response be? So I think the bottom line is we're still learning, and I agree with you that for somebody who's on once a day, the learning is to go every other day. But again, the burden for the patient is minimal, but the benefit is huge here. So that's the learning. The majority of them don't need drops. And the ones who do, we just need to make sure they take it and slowly taper off over time.

But we also on the line I'll be stations do long term the good news.

From a clinician perspective or is that majority of the patients are often drops. So it's not like every basin will need more times a day core ever so majority of the patients. If you look at any cohort had been off the drops patients who actually need drops majority of them are on one.

On the two times today, there are few on four but really that number's smile.

So I saw basin today, who I think.

Retinal detachment about two years ago, and has chronic macular edema and needs to take stairway drops and I was taking the giving this presentation today, so I actually ask them, even though it's a different indication I said.

Unknown Executive: Thank you so much, Dr. Kanani. I think we can go to the next question.

Phil Nadeau: Our next question comes from Phil Nadeau with Cohen & Co. Please go ahead.

And I was looking great onto times, a day stairway you've been on it for a couple of years. We know we go down to one on your vision drops you wanted to try to get off the drop and how much of a burden. It as you know what he told me like not a big deal I like to see an unhappy with my vision, So I think where a patient who just postop, but the amount.

Unknown Executive: Afternoon, thanks for taking my question. Dr. Kanani, 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 information 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 information 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 dose of steroids and for what period of time would give you pause, and maybe just as important, give your colleagues pause in deciding whether to use O2-2? Thanks.

You know patient, who actually received injection every month or every six weeks or eight week 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 who's on once a day the learning. It go every other day, but again the burden for the patient is minimal and but the benefit is huge here. So.

That's the learning majority of them don't need drops and the ones you do we just need to make sure the take it on slowly tip over time.

Thank you so much talk to kinda Arnie.

I think we can go to the Payslips has the next question that's easier pricing.

Our next question comes from found that there with Cowen <unk> co. Please go ahead.

Unknown Executive: I think those are excellent questions and I think, you know, when I talk to my colleagues after my talk at Arvo, they all want to participate in this trial because they see the value for the patient. So I think, at the end of the day, it's all about me looking at the patient you saw in the video and saying, you know, I may have a treatment that's one and done. The majority of patients will require drops for six weeks, but there's a subset that may need longer. And I don't know at this point which group you're going to be in, but are you willing to do it?

Definitely and thanks for taking my question are Dr. County, I wanted to follow up on the comments you just made US as my question. So the biggest controversial in Wall Street today, we say DVM or two as opposed to about the information and how much is too much I think we all appreciate that the reduction in treatment burden is.

Pretty impressive but people worry Bobby information is going to be perceived by the.

Physician community. So can you give is your sense, we've expanded and where you just said as to how much interior information is to March so what level information what proportion of patients over what period of time.

Unknown Executive: And I think 100% of patients will agree with that because we see on a daily basis the burden that 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, responds to treatment, and does not have long-term concerns in terms of irreversible vision loss, I think we are all okay with that.

Would give you concern and then kind of similarly.

How many steroids are too much so what dose steroids.

Over what period of time again were.

Well give you pause and maybe just as important give your colleagues pause in deciding whether to use or too. Thanks.

I think those upsell them questions and I think.

I think you know when I talk to my colleagues. After my talk at ARVO No not participated 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 that pace and you saw the video and thing.

Unknown Executive: So, with O2-2, as you have seen, patients get some inflammation when they're tapering their doses four times a day. And if you continue on four times a day or so, they do really well with zero inflammation. This is inflammation that responds quickly to steroids. It does not cause 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, and no arterial occlusions. So I think those are the key.

No I may have a treatment that's one and done majority of patients will require drops for six weeks, but there's a subset of may need longer.

And I don't know at this point, which group you're gonna 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 Burnett you talk about now talking about safety and how much inflammation and what kind of inflammation. So I think when we look at inflammation.

Unknown Executive: And as physicians, we want to look at risk-benefit of any treatment. And you know, I have said it before, I would only participate in a trial where I would enroll my mother, my mother-in-law mother, as I said before. So this is a trial that has really shown, you know, that I am not concerned about this. If they have some inflammation, I put them on drops and they come back and it resolves. 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 said, listen, you know, if they're on drops, big deal, we inject steroid in the eye in patients with DME because they don't respond to anti-VEGF and there is the herd rate of IOP spike, 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, as you saw in the data that no new patients have any IOP issues.

It does anything that is reversible.

The response to treatment and does not have long term concerns in terms of irreversible vision loss I think you're all okay with that so with all due to as you've seen that patients get some inclination when they're tapering their four times today and if you can.

Teeny on four times, a day or so they do really well with zero inflammation. This isn't inflammation that responds quickly to steroid. It does not have any long term damage to the eyes in the front of the I, it's not push your inflammation as I said and there's no retinal vasculitis no retinitis new order.

Aerial occlusions. So I think those are the key even as physicians. We won I look at most benefit of any treatment and you have said it before I would only participate in that trial, what I would enroll my mother My mother in law mother as I said before so there is there a trial.

Unknown Executive: So I think the bottom line is looking at inflammation, 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 that. So I think really, you know, I have the most patients. I have had studies where I'm dropping roller in a lot of different trials. I think all trials, you know, there are many trials showing promise, but I think this is a game changer in terms of how we manage patients with neovascular MD.

That has really shown.

You know that I'm not concerned about this if they had some information I put them on drops and they come back and it was also I think core that for the investment community I think when we look at inflammation. It looks all the same sometimes but it's not as clinicians talking to my colleague and what the uptake of this will be unless they listen you.

Unknown Executive: Thank you so much, Dr. Kanari. I think we should go to the next question.

I've done drops big deal injection steroids in the API indications would be a need because they don't respond blends and that job and there is the third rate I repeat spike, but we still get killed I've been here because the amount of drops as one or two or even for the rate of that is very low as you. So outside the data that no no mutations have any itll be.

Operator: Our next question comes from Graig Suvannavejh with Goldman Sachs. Please go ahead. Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum

Operator: I don't know if we could have...

Operator: It was hard to hear them.

Dr. Aaron Osborne: I think the question was, between the response we've seen with the two doses, how does that inform the doses you want to take forward in the criminal trial?

So I think the bottom line is looking at it inflammation separating it out looking at value of the product to the patient value to the position under long term treatment and the risk and benefits of that's I think really you know I have the most nation I had studies, where I'm talking all in a lot of difference.

Dr. Aaron Osborne: and also specifically the one new patient who required treatment.

Dr. Aaron Osborne: Got it. Thanks very much. Thank you, Greg. Thank you, Laurent.

Dr. Aaron Osborne: Yes, so thank you for the question, Graig, because there's a new finding with this update that the additional patients that received rescue injections, they both had a single injection. And really, this is why we're using the language more of supplemental anti-VEGF rather than rescue injection. When we look at both of these patients, they were really stable.

Ah trials I think all trial, you know there many trials showing promise, but I can this is a game changer in terms of how we manage patients with neovascular Indeed.

I guess I'm not starts can or I mean, we go to the next next question.

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

Dr. Aaron Osborne: They appear to have had a benefit, clearly, from ADVM and O2-2, both in terms of only having a single injection, representing a big decrease in terms of the injection burden prior. But also, you know, when these patients did meet the retreatment criteria, they only just clipped the edge of those retreatment criteria. And I think these patients are definitely, both of them in the category of, as we design our pivotal trial moving forward, you know, when we look at the retreatment criteria, we need to think of patients like these, because they both actually had very stable vision, and they were both rescued because of sort of changes in the appearance of the disease, whether fluid or a small amount of blood that was visible. And these may potentially represent changes in the evolution of the disease in response to continuous delivery of anti-VEGF.

[laughter].

Segment.

So.

Yeah.

Patients in cohort two part retreat eminently, maybe some color.

Color about what that patients congratulated look like up until that maybe.

How would inform dosing in your eventual pivotal trial, but Andy.

And then if we could ask.

If you ask the operator, if you heard that clearly I did not here that very clearly that question earlier, we've had challenging maybe they don't need it was harsher here.

I think the question was between the response, we seem to get two doses, how does that inform doses won't take forward and pivotal trial, yeah and elsewhere and so.

Specifically the wanting it.

And who require treatment.

Oh.

Got it thanks very much thank you, Greg and color on yes. So thanks for the question, Greg because through the new there's a new finding with this update that be additional patients that received rescue injections. They both had a single injection and really this is why we are using the language more supplement.

Rental and see that Jeff rather than rescue injection. When we look at both of these patients. They were really stable they appear to how to benefit clearly from Abbvie and Q2 boats in terms of only having a single injection that presenting a big decrease in terms of injection burden. Prior but also you know when these patients these meat.

Dr. Aaron Osborne: We've seen another program, the poor delivery system from Roche Genentech, demonstrate positive phase 3 data using much more relaxed retreatment criteria than we see in OPTIC. So 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 it also shows that we need to look at these patients who may have a small amount of fluid and whether they really need to be retreated or not. So I mean, I think across both cohorts, we've seen benefits in terms of injection frequency reduction. We've seen a major reduction with the low dose as well.

The retreatment criteria, they only just click the edge if those retreatment criteria and I think these patients that definitely most of them in the category of as we design our pivotal trial moving forward you know when we look at the Retreatment criteria.

We need to think of patients a lot like these because they actually had very stable vision and they were both rescued because it's sort of changes in the appearance of the days when a fluid or a small amount of not that was visible and these may potentially ret present changes in the evolution of the disease in response.

Dr. Aaron Osborne: And as we move forward, again, looking back at the Roche delivery system program, there's an analog there. We can move to slightly earlier-stage disease patients who may potentially respond even better to these very hard-to-treat later-stage disease patients that we've had in OPTIC. And I think it's very exciting. We intend to go and discuss with FDA and other health authorities, 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. So thank you for the question.

Just a continuous delivery of and seabed, Jeff I, we've seen another program other ports delivery system from Roche Genentech demonstrate positive phase three data using much more relaxed retreatment criteria than we see an uptick so despite in that study there was more.

Fluid allowed to be Crescent before Retreatment was performed.

We saw that news maintenance division at the same level as monthly injections around a busy and everything I really shows the potential benefits of continuous delivery, but also shows that we need to look at these patients who might have a small amount of fluid and whether they really need to be retreated or no I'm, sorry, I mean looking across the both cohorts we've seen benefits in terms of.

Dr. Aaron Osborne: Our next question comes from Joon Lee with Trust Securities. Please go ahead. Hi, thanks for taking my question. Correct me if I'm wrong, but the pivotal trial for ADVM-022 and what AMD will likely be against the best standard of care. Do you feel that the efficacy and safety are on par with two monthly or two every other month idea? And will the non-ADVM

Traction frequency reduction we've seen a major reduction with a low dose as well and as we move forward again looking back at the end watch sports delivery system program. There's an analog data we can move to study earlier in disease patients you may potentially respond to even better to these very hard to treat later into these patients that we've had.

Joon So Lee: AVMO2 to Injected Eye also gets steroid confluxes, and conversely,

Joon So Lee: I get a mock injection. Now, tell us about the potential design of the purple trompe l'oeil.

Dr. Aaron Osborne: Thank you. Thank you for the question. So as we move towards pivotal trials, I mean, the program that we discuss as a potential analog is the Roche Porte Delivery System Pivotal Trial Program. So with that program, they did a sequential kind of phase 2B trial followed by a pivotal trial. And the reason that we use that 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 a substantial reduction in both the number of patients who need anti-VEGF injections but also an injection, annualized injection frequency, both with high and low doses, 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.

In optic and I think it's very exciting we intend to go and discuss with Sci and other health authorities as well as clinicians and potential investigators to these studies you know the very best way to conduct them and I'm one of those topics, it's certainly going to either the retreatment criteria.

As for as we move forward. So so thank you for the question.

[laughter].

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

Hi, Thanks for taking my question.

Correct me, if I'm wrong, but.

Total trial for any BMO, two two and what M.D. will likely be against the best standard of care do you feel that the efficacy or safety on par with Q monthly or through every month, the idea and Ah, but little bit non kt, there Ed anymore to inject that I also get steroids collapses and Conversely, well the non idea.

Dr. Aaron Osborne: We've seen that inflammation is generally low grade and manageable with steroid eye drops. So as we move forward, we would really need to get to a single dose. We would plan 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.

I get a mock injection tell us about the potential design of the Triple trial. Thank you.

Well. Thank you. Thank you for the question.

Yes.

As we plan to was pivotal trials I mean, the program that we discuss potential analog is the Roche quote delivery system.

Pivotal trial program, so with that program. They did on sequential kind of phase to be trial, followed by a pivotal trial and the reason that we used as an analog is that we have two doses that looks to be showing at this early stage, a very positive benefit risk a ratio so what weve.

Dr. Aaron Osborne: 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 flivicept. And that flivicept in registrational trials is typically given every other month following three initial monthly doses. So if we go for a study population that is treatment experienced but relatively early in disease, then we would be comparing to flivicept every other month. And here we would look to take board, you know, both of these doses that we've looked at in OPTIC. We think both of them are looking as though they 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 that you need to show that you have similar visual acuity maintenance as with flivicept injections. From that point, we would look to select our final dose. There are a few other open questions as well.

Seen as we've seen a substantial reduction in both numbers of patients who need anti VEGF injections, but also an injection annualized injection frequency mix is 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 but inflammation is generally low grade and manageable.

With Starwood eye drops and so as 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 out west and pay me really intended to take a single dose through to a phase three trial at the minimum we have two doses so the forming a for a larger study.

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 tenacity sets in in a registrational trials. Its typically given every other month I'm. Following three initial monthly doses. So if we got for study population that is treatment experience.

Dr. Aaron Osborne: At the moment, we're testing for neutralizing antibodies. We're currently open to around 95% of patients, but that doesn't mean we're screening some patients out. Patients, you know, have very high neutralizing antibody counts. And one of the questions as we head towards phase three and commercialization is whether we need to screen patients at all. So really, that question is best assessed 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, you know, neutralizing antibodies, we feel like doing a phase two B trial with two doses. Looking at these questions makes a lot of sense as part of a typical 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.

But relatively early in disease than we would be comparing to after this that every other month.

And here, we would look support take board most of these doses that we've looked at an uptick we think both with them I looking ahead to have a positive preliminary profile.

And essentially the trial would have a primary endpoint in the region of around nine months you couldn't take from that disappoint you need to show that Ah you have similar visual acuity maintenance that's aflibercept injection.

From that point, we've got to select Cup final dose. There are few other open questions as well at the moment, we're testing neutralizing antibodies recurrently opening to around 95% of patients, but that doesn't mean, we're screen. Some patients out patients you know very high neutralizing antibody counts and one of the questions as we head towards our phase.

Dr. Aaron Osborne: Our next question comes from Mani Faroohar with SVB Lyrinc. Please go ahead. Thanks for taking my question, guys. So for part one, when you think about where you are in communications with regulators, it sounds from your disclosures that you, upon having more complete Cohort 4 data at the end of this year, will be meeting with US, EU, and other regulators to work out a plan for a pivotal phase three, which will begin in mid-next year. Is that correct, or is the right answer that you guys have begun those conversations around study design already in anticipation of Cohort 4 data? Where are we along in terms of the timing of those conversations? And then as a second question, apropos of the recurrent uveitis patient, is the right interpretation of that from the press release that that patient had previously experienced uveitis prior to the trial or recurrent within the time horizon of the trial?

Three and commercialization is whether we need to screen patients. The tool. So really that question is back to fast in a relatively small trial, where you can screen patients early on we can potentially include all comers and adapt the trial as we go forwards so.

So with questions around those you know neutralizing antibodies, we feel to do a phase twob trial with a 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 cutting those meetings discussing left yet and its national regulators.

Parties with the intention of starting that program in the mid next year.

Our next question comes from money through her with SVB Leerink. Please go ahead.

Okay. Thanks, taking my question guys.

So for part one when you think about where apparent on where you are communications and regulators. It sounds more disclosures that you a part of having more complete cohort for data at the end of this year will be meeting with you as you and other regulators to work out a plan for a pivotal phase three which will began in mid next.

Mani Faroohar: Great. Thanks, Manny. It's Aaron here. I'll take the second question first, because that's the easiest one.

Year is that correct or the right answer you had to be garden those conversations around study design already in anticipation of cohort for data, but which have where are we are in terms of the timing of those conversations.

Dr. Aaron Osborne: No, it was recurrent from within the trial, and that patient did not have a history of uveitis, but they're the same patient that had an occurrence of uveitis as an adverse event at Week 16. So it's the second patient in Cohort 1. So that recurrence refers 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 with the anterior chamber cells back down to zero. So that's patient number two in Cohort 1.

And then of the second second question Apropos of the recurrent uveitis patients their interpretation of that Oh, it's in the press release adapters and the previously experienced you'd be at his prior to the trial or a current within the time horizon Nova trial.

Great. Thanks. Thanks, My name is that if Aaron here I'll take the second question first because that's the easiest one knows recurrent from within the trial are not patient did not have a history of easy access but at the same patients that had had.

Dr. Aaron Osborne: With regard to the regulatory part, I mean, we're obviously in ongoing discussions with FDA. We 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 our 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 of the type of clinical program that we want to run, and we really look forward to those discussions with FDA with the aim of having to go ahead and start those trials in the middle of next year.

An occurrence of TV acts as an adverse event a week 16 says the second patient cohort one so that recurrence refer to them being in the trial and as I said that that Ben has improved with topical steroids alone and they are tapering the drops now with the anterior chamber cells that down to zero.

So that's patient number two in cohort one with regards to the regulatory.

The regulatory path I mean, obviously, an ongoing discussions with FDA. We recently started the affinity 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 our pivotal trial program and.

You know we have 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 and discussions and and as we said I think we've got a pretty clear idea on the type of clinical program that we want you run I really look both like discussions with Sta.

Leone Patterson: Our next question comes from Luca Issa with RBC Capital. Please go ahead.

Leone Patterson: Oh, terrific. Thanks for taking my question. Luke Hasey from RBC Capital.

Luca Issa: Two quick ones. One, 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 are no longer pursuing, the 6 times 10 to the 12, or to a manufacturing issue or to potentially both? That's the first question. And the second, on data, when I look at the baseline characteristics, the number of VEGF injections in the prior 12 months, it was that...

Yeah with the aim to to having a go ahead to start those trials in the mid of next year.

Okay.

Our next question comes from Luca Isa with RBC capital. Please go ahead.

Oh terrific. Thanks for taking my question Lucchese from RBC capital I have two quick ones. One again, a 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 those that youre no longer pursuing the six time tested as well.

We're manufacturing issue or to potentially both that's the first question and the second on data when I look at a baseline characteristics. The number of anti VEGF injection in the prior 12 month, well, that's a substantially lower in patients in cohort four versus any of you got a cohorts one why is that.

Luca Issa: are actually substantially lower in patients in cohort 4.

Luca Issa: Or, versus any of the other cohorts. One, why is that? And two, what are the possibilities?

Dr. Aaron Osborne: [inaudible] It's Aaron here. I'm happy to take the second one and maybe hand it over to Leone regarding the second part, if that makes sense. So, yeah, regarding, it's a really good point. Thank you for the question, Luca, on cohort number four. So, as Dr. Canale presented, you know, there are some patients who are earlier in their disease in cohort four, 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 were 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 have had two injections in the four months prior to coming in.

At into one of the possible nation of that different thank you.

So I'm I'm at fair and here I'm happy to pay the second one of them maybe hand over to to the only regarding the this is the second part but that makes sense. So yeah regarding its a really good good. Thank you for the question. The current on cohort on before so stocks can only presents it you know there are some patients.

Earlier in their disease in cohort for and that seems to be really driving why there's a low a number of and C. Bench asked in the previous 12 months. We have we have some patients that being diagnosed as recently as as two to three months before coming into the trial. So I should remind you the our protocol requirement is that they.

Two injections in the four months prior to coming in so on an annualized basis, we'd expect that 6.82 increase upwards, but we do have some patients who are little bit earlier in disease, and you know I've seen that represents a again, there's nothing going on even saying that there's increased confidence from investigators that the product is is delivering.

Dr. Aaron Osborne: So on an annualized basis, we'd expect that 6.8 to increase upwards. But we do have some patients who are a little bit earlier in the disease. And, you know, I think that represents, again, as Dr. Canale was saying, increased confidence from investigators that 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 two and in cohort three. But now, in cohort four, we've got a few more earlier patients. There have been no protocol changes whatsoever.

In terms of continuous that Jeff I'm delivery that can control and then proven asked me in these top to treat patients.

So I think we saw a couple more early patients in late Q2, I mean cohort three.

But now in cohort four we've got a few more earlier patients there's been no no protocol changes whatsoever. We enrolled this cohort very quickly and I think that's really helpful to have some earlier disease patients as as we said she knows we time for our population in the pivotal trials are we likely intend to go to a slightly earlier in disease.

Dr. Aaron Osborne: We enrolled this cohort very quickly, and I think it's really helpful to have some earlier-stage disease patients. As we've said, you know, as we plan for our population in the pivotal trials, we'd likely intend to go to a slightly earlier stage in the disease population, similar to that Rocheport delivery system program. So it's great to have some of those patients in the trial, and I'll hand over to Leonie for the question. Yeah, of course.

He's population similar to that Rossport delivery system program I'm, sorry, it's great to have some of those patients in the trial.

I don't know how does that make the yesterday for the question Yeah course.

Yes, so I think right. That's an interesting question right why are we putting patients or early because now we have efficacy data that is.

Leone Patterson: Yeah, so I think, that's an interesting question, right? Why are we putting patients early? Because now we have efficacy data that is, you know, one year or longer. And now, of course, it's closed now.

No one year or longer and now of course is close now as of last update me, a one year longer and I use that for patients and I said you know we have an ongoing trial that has shown great efficacy in terms of DTV and maintenance and anatomy and especially the patient when I presented today in terms of employee.

Unknown Executive: As of the last update, we have one year longer, and I use that for patients. And I said, you know, we have an ongoing trial that has shown great efficacy in terms of BCVA maintenance and anatomy, and especially in 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 afibicept, and I enrolled her in optics. The data so far, and I think this brings us back to the question that was asked earlier, is like, what is physicians' confidence in looking at the risk benefit profile of this product? And again, you know, some patients are on topical drops for the long term. It's, it's a very

During anatomy.

And and you know people just said signed me up and especially my neighbor. She had worsening fluid with monthly Aflibercept and I enrolled her in Uptakes I think.

The data so far and I think this brings us back to the question. There was asked earlier is like waters physicians call you know confidence when looking at.

Risk benefit profile of this product and again you know.

Some patients being on topical drops for long term, it's it's a very.

You know small compromise for patients losing their visual acuity in the real World. As you know you saw in mice here I am do study or patients, having just worsening disease I think I'm really excited you look at long term data do see can we get stable vision for five years, because usually glad.

Unknown Executive: Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Washington, D.C. So I think I'm really excited to look at long-term data to see if we can get stable vision for five years. Because you see the CAT trial, you see the 7-Up study, you see all these studies where patients drop off in terms of vision, starting at two to three years, and then in the third, fourth, fifth year, they lose a lot of vision. So I think that is the excitement I have for continuous delivery, and that's why we were able to recruit so many patients. I wish there was, the trial was still open, because on a daily basis, I'm seeing patients who can really benefit from this continuous delivery. Back to you.

Trial, you see seminars that you see all these studies where patients drop off in terms of Asian, starting at two to three years in end of two and then put a report that Theyll get moved a lot of visions I think that is the excitement I have spoken gene delivery and that's why we were able to but a lot of patients I wish I wish there was.

I will still open because on a daily basis, I'm seeing patients who can really benefited from this continuous delivery. So.

Back to you.

Right. Okay. So are there other question includes around the Patrick clinical hold and yes, you're correct that the Patrick Oklahoma related to the dose of 60, 12, which was probably the original dose escalation study and we have at that time when that happened and into the stay we don't plan to Dallas at 62.

Leone Patterson: Okay, so the other question was around the partial clinical hold, and yes, you're correct that the partial clinical hold related to the dose of 6012, which was part of the original dose escalation study. And at that time when that happened, and to this day, we don't plan to dose at 6012. We're currently at 311 and 6011, 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, the partial clinical hold is because of the issues that were raised with the FDA related to CMC.

Oh, we're currently at three live in a 60 11 and a as Aaron with say he's the doses that we will probably take forward into our pivotal trial.

As it relates to why the clinical hold is important still with Patrick clinical hold is because.

The issues that were rights with the FDIC related to CMC.

And we do believe that will need to address the CMC issues I noticed that allowed to study.

Leone Patterson: And we do believe that we're...

And we've been working allows me I think I've made this on previous calls that Spain, certainly a priority and a focus of the company to have teacher mood.

Leone Patterson: that will need to address these CMT issues in order to start our larger studies. And we've been working on those, and I think I mentioned this on previous calls that it's certainly been a priority and a focus of the company to have these removed. And we're on track, so we're confident they'll be resolved. And the plan would be to have those removed before we start our pivotal program in mid-2021. Our next question comes from Dane Leon, with Raymond James. Please go ahead.

And we're on track sorry, we're confident they will be resolved and to pay would be a hand does remain before we would start and pivotal program and 2021.

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

Hey, Thanks for taking your questions and Ah. Thank you for the update.

Dane Leon: Hey, thanks for taking the questions and thank you for the update. So maybe, I guess, Dr. Takani, one. I guess a lot of us are thinking about, and when we speak to some of your peers, you know, it's indisputable that cohort one has had really good anatomical outcomes, and no patients have needed rescue injections.

So maybe I guess.

Dr. Connie.

One.

Thing that I guess, a lot of a sort of thinking about it and when we speak to some of your peers.

You know its indisputable cohort one it's a really good anatomical outcomes no no patients in need rescue injections.

Some patients it's needed supplemental injections and cohorts two and three a in its still TBD encore for but just to play Devil's advocate here I guess, that's my position.

Dane Leon: Some patients have needed supplemental injections in cohorts two and three, and it's still TBD on cohort four. But just to play a devil's advocate here, I guess that's my position. Patient three in cohort three, for example, is still on regular shots after getting the treatment and is also on four drops daily of steroids in 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, you know, 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 that potential risk? And then how do you think about having a conversation with the patient? Thank you.

Patient three in cohort three for example is on regular shocks still after getting the treatment and is also on.

For drops daily of steroids entered 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 you know a non absolute therapy that it could end up in a situation where they're taking drops for this therapy, but also stone 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, a with a potential risk and then how you think about having a conversation with the patients. Thank you.

I think you know excellent question remember, we always have to put patients in that trial, where there is.

A favorable you know benefit to them you know and so do a question if somebody is getting a supplemental treatment after having continuous delivery in there I.

Unknown Executive: I think, you know, excellent question. Remember, we always have to put patients in trials where there's Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum. That tells me that this patient is a super-high-need patient. I think we can't 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 in them, while we also have patients on every three months Bevacuzumab who do just fine. So I think the conversation for me is, I have seen the value here where patients have benefited from this treatment even when they have had 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 were getting supplemental treatment? Could this patient have required more surgery?

That tells me that this station is cheaper hi need patients I think we can quotations in one box and these are very heterogeneous disease and each patient in different limitations on monthly aflibercept that have fluid while the I'll say a patients on every three months.

Bevacizumab they do just fine so I think the conversation for me is I have seen the value here, where patients had benefited from this treatment, even having monthly aflibercept before like you sign my case, so really having high levels of.

Aflibercept after a single injection with continuous delivery was favorable to my patients and that's why enroll 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.

This station whenever required monthly injections. So if you look at the same landslide you can see that they were actually on more frequent treatment before they got into the optics study. So I think it's still beneficial for the patients to get less injections nobody is saying that.

Unknown Executive: monthly injections. So if you look at the swim lane 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 fewer injections. Nobody is saying that, you know, 100% of patients in a disease as heterogeneous as AMD will be injection-free. I think if we can get the 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 decrease the treatment burden. But I think that's a very good question. And my answer is, I think this patient would not have been controlled even with more frequent injections if they didn't have continuous sterilization.

No 100% no patients a in a disease entered units as van de Wille. The injection three I thing is we can get majority of the patients to the injection three and there are some patients it very active disease that knee supplemental treatment I think thats very acceptable for me and my peers at the end of the.

Our goal is to maintain visual acuity control disease, and d. the treatment burden, but I think thats a very good question and my answer is I think the station would have not being controlled even with more frequent injection. If they didn't have been gene delivery.

Our next question comes from Patrick told Salt Life Science capital. Please go ahead.

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

Hi, Thanks for taking my question in regards to patient follow up post administration of or two to what sort of monitor monitoring do you envision being required given the product profile to date.

Dr. Aaron Osborne: Hi, thanks for taking the question. In regards to patient follow-up post administration of O2-2, what sort of monitoring do you anticipate 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 in deciding to reinitiate steroids? And Dr. Kanani, 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 itself? Thank you for having us.

And is there any standardization of that process works and some of the protocol optic kind of.

Particularly in deciding to re initiative steroids and Dr. Gozani, you've spoken a lot about patient satisfaction. Following treatment 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 itself. Thanks.

Thanks.

Hello, I'm trying to awesome.

Yeah.

Let me confirm my answer the second part.

Dr. Aaron Osborne: Yep. Yep.

Okay go ahead.

Dr. Aaron Osborne: Let me continue for a moment.

Okay, Great I'll take the I'll translate I'm trying to say the first our them.

Dr. Aaron Osborne: Okay.

Dr. Aaron Osborne: Okay, great. I'll try to...

Patrick just just this year just just remind just a reminder, so the question that one second.

Dr. Aaron Osborne: Okay, great. I'll take it.

Dr. Aaron Osborne: Patrick, just remind us of the question there for one second. So I think the question was about the follow-up schedule, and would we change anything in optic or moving forward, and how would you see it in the real world for patients that are getting continuous delivery with O2-2, and specifically if they need to change their steroid treatment? And I can say from a sponsor perspective, and then I think I'll hand over to Dr. Kanani because there are some really important differences. In the study, obviously, we're following up the 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. However, we have some opportunities to extend visits for patients, particularly in pre-trial extension studies.

So I think the question was on this follow up schedule and would be change anything and optical moving forwards and how would you say in the real world for patients that are getting continuous delivery without you too and specifically they need to change that Sarah treatment and I.

Can say from a sponsor perspective, and I think I'll hand over to Dr. can on it because it's a really important differences I'm in the study obviously, we're following other patients extremely closely we need to see them for assessments and as we move to comparative studies, we will need to continue to do that we have some opportunities to extend visits for patients.

Particularly in for example extension studies, we plan to follow up with uptake with a study that would follow these patients in a potentially for many years. We've already seen that we have a couple of patients who have skier visits due to concerns around kind of inline crane and when we feel that these scenarios are actually situations in which the benefits of oats you too.

Dr. Aaron Osborne: We plan to follow up with optic with a study that would follow up these patients 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 O2-2 can potentially come to the fore. So we're looking at that question really carefully, Patrick, and with technology such as HOMO-CT monitoring, for example, we could potentially show that patients with ADVM-O2-2 are experiencing continued stability of disease. I mean, I think if they need to change their steroid regimen, then they need to come in and be checked around that time point. However, if they've been on steroid eye drops for a period of time, really, they just need a front-of-the-eye check and an intraocular pressure check, which is often a lot easier than going to the retina specialist.

Can potentially come to the for so we're looking at that question really carefully Patrick and with technology, such as home, mostly T. monitoring for example, we could potentially showed that patients with 80 demo to too and we're experiencing continued stability of disease. I mean, I think they need to change of steroids regimen and they need to come.

And then be checks around that time point, however, if they've been on steroids eye drops for a period of time really they just need a front of the I check and 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 TPP and monitoring schedules going towards commercialization I think follow.

Dr. Aaron Osborne: So in terms of when we put together our TPP and monitoring schedules going towards commercialization, I think following ADVM-O2-2, 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 medications, whether you need to adjust their steroid regimen. But I think as you go forward, very quickly, you get to a position where you can extend those intervals and really realize the benefits of continuous delivery. And I think, therefore, 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, you know, we're so laser-focused on it. I really thank you for the question because it's kind of summing up the essence of what we're trying to achieve. But, you know, Dr. Kanani, you've got the most patients in OPTIC and in Affinity now. I mean, how do you see that monitoring schedule playing out in the real world?

Let me I'm actually two you're going to need a relatively intensive period of monitoring with at least must be follow up visits to see whether a patient needs rescue diseases, where they need to adjust that steroids regimen, but I think as you go forward very quickly you got the position where you can extend out those in schools and really realize the benefits of continuous delivery.

I think definitely you can maintain vision without frequent visits and dramatically improve real world outcomes. That's why we're working at less and that's what you know we're laser focused on I really thank you for the question because it's kind of summing up the essence of what we're trying to achieve but it's also going on in your you've got the most patients in optic and.

I didn't see now I mean, how do how do you see that monitoring scheduled Plano and ER and the real world.

[noise] I think and I'd been lucky that this is I'll get involved in for sustained delivery a trial. So we are.

Unknown Executive: So I think, Aaron, I've been lucky that this is, I've been involved in four sustained delivery trials. So we are one of the top enrollers in the port delivery system, phase two, phase three, and the extension portal study, also the DME study, we are part of the Region X RGX-314, and then obviously we are a top enroller for ADVM-022. So there are two questions that were asked.

One of the top Enrollers in the board delivery system Phase two phase three and the extension portals study also the Dnbi study there part of the region that are you three one for and then obviously they are top enroll or.

Or for ATM or two too. So there are two questions were asked number one was.

His clinic visit just buy sell better than clinic visit Bluffton injection, you know patients an uptick come to me and then less mylan their pace.

Unknown Executive: Number one was... Is a clinic visit just by itself better than a clinic visit plus an injection? You know, patients in OpTic come to me, and they have a smile on their faces, and that's what happened with other sustained delivery systems like RGS 314 and PDS because they know that the majority of the time they're not getting an injection. They are happy, they come in with a smile, they can drive themselves, they can't bother 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. Initially, whether it's any delivery system, you need to monitor patients, make sure they have a good response in the first few months. And then for O2-2, just to make sure that, you know, they can taper off the drops without any issues.

And that's what happened with other sustained delivery like Rgs me one more in pediatric because they know that majority of the time, they're not getting an injection. They are happy they coming at us mile. They can drag them. So they can not bug their daughter or their family member they can keep moving.

And along the airline after having a quick test and I agree with you I think initially whether it.

Any delivery system, and and you need to monitor patients make sure. They have a good response in the first few months and then for OTI to just to make sure that you know they can keep our off the drops it without any issues. So lets save you have a patient that does two months or six weeks of drops in at two months at no inflammation their disease.

Unknown Executive: So let's say we have a patient that does two months or six weeks of drops. After two months and no inflammation, their disease is fully controlled. I would probably see that patient again in two or three months after, and if they're doing well, maybe every three to six months. I think we like to see our patients; sometimes they don't like it if we don't see them. So, in the real world, I see a patient on O2-2 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, you know, caretaker burden. If somebody wasn't dropped, I have a lot of patients on steroid drops that they take for macular edema from, you know, post-cataract surgery or uveitis or anything like that.

Yes, it's fully control I would probably see that Asian, John and two or three months after.

And if they're doing well maybe every three to six months I think we'd like to see or patients sometimes they don't like it. If you don't Sam So I think in real World I see a patient on OTI to come in and maybe twice a year. After they're stable that's a huge improvement compared to a monthly or every other month visit plus injection is it the family.

And you know caretaker burden if somebody wasn't drops so I have a lot of patients on steroid drops that they take for macular edema from a in a post cataract surgery or usually items or anything like that once I know that they're not going to have IP spike which is usually in the first two months or so.

Unknown Executive: Once I know that they're not going to have an IOP spike, which is usually in the first two months or so, then they can even go longer. So even if a patient that has mild inflammation that needs to take drops twice a day, they can easily go for 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 fewer clinic visits, which will also be a win. So, as clinicians and patients, I think this is very promising, that continuous delivery in the eye of antibiotics to really control blinding diseases like neovascular AMD and diabetic macular edema.

Then they can even go longer choose even if a patient that has mile 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 burdened by 90% or 80% or 100% it.

So huge win and then that would translate into.

Less clinic visit which will also be again, so I think as clinicians and patients I think this is very promising that continues delivery in the islands and that Jack to really control blinding diseases like Neovascular, AMD, B and diabetic macular edema.

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

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

Okay. Thank you everyone for joining us today. This has been a very productive discussion with great questions I'd like to thing again, Dr. can only for joining us today answering his perspectives on the data and insights we've learned from uptick.

Laurent Fischer: Thank you, everyone, for joining us today. This has been a very productive discussion with great questions.

Laurent Fischer: I'd like to thank Dr. Kanani again for joining us today and sharing his perspectives on the data and insights we've learned from OPTIC. I also want to thank the patients for their participation in our clinical trials and acknowledge the frontline healthcare professionals for the critical care they continue to provide during this pandemic. And last but not least, I'd like to thank our employees.

So once thing to patients with their participation their clinical trials and acknowledge the frontline health care professionals with a critical care. They continue to provide during this endeavor and last but not least I'd like to thank our employees even during a pandemic. This team continues to excel to deliver on our mission to make it easy ammo due to available to patients as quickly as possible.

Operator: Even during a pandemic, the team continues to excel at making ADVM022 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 ADVM022 to the millions of patients suffering from white AMD and DME globally. Before I end, I'll quickly reiterate our planned upcoming milestones. First, we'll be presenting additional data from all four cohorts of OPTIC by the end of this year. Next, we'll be advancing ADM022 into a planned available trial in mid-2021. And finally, we'll continue to randomize patients in our ongoing INFINITY Phase 2 trial for VME, 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.

I truly believe that we have the writing the right assets and the right strategy to deliver ATM or two to two millions of patients suffering from where they have the and DMV globally before we end up quickly reiterate our planned upcoming milestones first we'll be presenting additional data from all four cohorts of optic by the end of this year now.

Next to be advancing it'd be able to through into a plan to a little trial mid 2021.

And finally, we'll continue to randomize patients in our ongoing Infinity phase two trial for DMV and we plan to report data from this infinity the second half of 2021.

Please to healthy in well and I look forward to bidding everyone on our continued progress in the future. Thank you very much take care.

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

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

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Mm.

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