Q1 2020 Earnings Call

Corporate update conference call will begin momentarily once again your conference call will be getting momentarily.

Operator: corporate update conference call will begin momentarily. Once again, your conference call will begin momentarily. Please remain on your lines.

Unknown Executive: Thank you. BF-WATCH TV 2021, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Good afternoon, and welcome to the Adverum Biotechnology's first quarter 2020 corporate update conference call. At this time, all participants are in a listen-only mode.

Thank you.

[music].

Operator: Later, we'll conduct a question and answer session after the prepared remarks. As a reminder, this conference call is being recorded. I would now like to hand the call over to Maisha Lacey, Vice President of Investor Relations and Corporate Communications of Adverum. Please go ahead.

Good afternoon, and welcome to the and thereby technologies first quarter 2020, corporate update conference call.

At this time, all participants are listen only mode.

Later, we'll conduct a question and answer session.

After the prepared remarks.

As a reminder, this conference call is being recorded I.

Maisha Lacey: Thank you and welcome everyone. Today, we issued a press release announcing our new INFINITY trial for ADVM-22 and diabetic macular edema, as well as reporting our financial results for the first quarter of 2020. A copy can be found on the Press Releases page of the Investor Relations section of our corporate website at www.adverum.com.

I wouldn't like to hand, the call somebody should lazy Vice president of Investor Relations.

Communication Oh Dear. Please go ahead.

[music].

Thank you and welcome everyone today, we issued a press release announcing our in our new Infinity trial for 80 them into in diabetic macular edema as long as reporting our financial results.

For the first quarter of 2020.

A copy can be found on a press releases page of the Investor Relations section of our corporate website at Www Dot Fearon Dot com.

Maisha Lacey: Also posted on our IR website is a slide presentation to accompany this call, which is available on the events and presentation page of the IR section of our website. Additionally, a replay of today's call will also be available. Joining me for the prepared remarks portion today is Leonie Patterson, President and Chief Executive Officer, and Dr. Aaron Osborne, Chief Medical Officer. Then, Leone, Aaron, and our Chief Financial Officer, Thomas Leong, will be available for the Q&A portion of the call. As a reminder, we will be making forward-looking statements regarding our product development plans, research activities, and operations, as well as our financial outlook. These statements are subject to risks and uncertainty that may cause actual results to differ materially from those forecasted.

Also posted on our IR website as a slide presentation to accompany this call which is available on the events and presentations page of the IR section of my website.

Also a replay of today's call will also be available.

Joining me for their prepared remarks portion today is Leoni Patterson, President and Chief Executive Officer.

Dr. Aaron Osborne, Chief Medical Officer, then Leoni, Erin and our Chief Financial Officer, Thomas Liam will be available for the Q and a portion of the call. As a reminder, we will be making forward looking statements regarding our product development plans Research Act.

Pivot east 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 forecasts.

A description of these risks can be found in our 10-Q, which was filed this afternoon.

Leonie Patterson: A description of these risks can be found in our 10-Q, which was filed this afternoon. I would now like to turn the call over to our President and CEO, Leonie Brown. Thank you, Maisha.

I would now like to turn the call over to our President and CEO Liani Patterson.

Thank you might show good afternoon, everyone. Thank you for joining us today.

Leonie Patterson: Good afternoon, everyone, and thank you for joining us today. Before we start talking about our recent business progress, I'd like to acknowledge the impact of COVID-19 on our community. As always, our primary focus is on the health and safety of our employees, patients, and healthcare providers. Since the mandated Shelter-in-Place Executive Order was put into place by the San Francisco Bay Area and the State of California, we immediately implemented the use of remote study monitoring and several precautionary measures at study sites to maintain the health of our patients. Like many companies, we are taking the necessary precautions to support our employees and conduct our business. Additionally, most of our employees have been working from home since March 13th.

Before we start talking about our recent business parkers I'd like to acknowledge the impact cobot 19 on now community.

As always upon me focus is on the health and safety, although I'm pleased patience and health care providers.

So some mandated so children place executive order was put into place by the San Francisco Bay area in the state of California.

Immediately implement that they use a promote study monitoring and have several precautionary measures. Its study sites to maintain the health about patient.

Like many companies, they're taking necessary precautions to support employees and conduct that business.

Definitely less about points have been working from time since last year tape.

Leonie Patterson: I am grateful for the achievements our employees have accomplished so far this year as we continue to advance our clinical pipeline and execute on our mission to develop and commercialize our novel gene therapies for patients with serious ocular diseases. We believe our lead gene therapy program, ADWM-022, has the potential to be a one-time interfacial injection gene therapy approach for two indications impacting patients with VEGF-driven ocular diseases. We're AMD and Diabetic Macular Dema, or DME. Aaron will review the significant clinical progress with OTTU for both wet AMD and now DME. We will then open the call for questions. Let's start with wet A&D.

I'm grateful Breakevens employees have accomplished so far this year as you continue to find a clinical pipeline and executing on our mission to develop and commercialize a novel gene therapies for patients with serious orphan diseases.

We believe amazing therapy program I used to be in our Q2 has potential to be a onetime interpersonal injection gene therapy approach, but two indications impact in patients with digits, driven or can it diseases, where I D and diabetic macular edema or do you mean.

I will review the significant clinical progress with our two to four boys with DMD and now DNA.

We will then open the call for questions.

Let's start with would I be and the ongoing Arctic phase one dose ranging trial, we have been exploring two dogs as opposed to too.

Leonie Patterson: In the ongoing OPTIC phase 1 dose-ranging trial, we have been exploring two doses of O2-2, a dose of 6011 and a three-fold lower dose of 2E11, and more recently, two propylactic steroid regimens, a short course of oral steroids and a longer course of steroid eye drops. Earlier this month, we presented new data from the first three cohorts. The day from OPTEC has continued to be very promising.

Just a 16, even in a threefold load doors to 11 and more recently to personalize Exterran regimens.

<unk> costs of oral steroids, and a lower cost and Stewart our jobs.

Early this month, we presented new data from the first three cohorts, but.

Good day from uptake has continued to be very promising.

Leonie Patterson: OG2 continues to demonstrate robust efficacy and evidence of a dose response. This therapy has shown long-term durability beyond one year with zero risk of injections in patients treated in Cohort 1. Also, encouragingly early... Dada from Cohort 3, including visual acuity and OCT improvement. OCU2 continues to be well tolerated with further evidence that steroid eye drops are effective in managing ocular inflammation.

Okay to continues to demonstrate robust if I can see and if it does have a dose response.

This therapy, a short and long term durability beyond one yet was zero risk or injections and patients treated in cohort one.

Also encouraging early.

I got from co, what three including visual acuity and always see improvements.

You too continues to be well tolerated with it but it's it's Stuart our drops are picked up and managing ocular inflammation.

We're now focused on completing enrollment in kobalt four with dosing underway.

Leonie Patterson: We are now focused on completing enrollment and cohort four, with dosing underway. We are on track to present data from all four cohorts in OPTIC by the end of this year. We also plan to develop O2-2 and DME.

We are on track to present data for all four cohorts and also by the end of this year.

We also plan to develop or two to India me.

Leonie Patterson: We are excited that the FDA has approved our IND for diabetic retinopathy. We have been preparing for this, and our INFINITY Phase 2 trial is open for patient enrollment, as Aaron will describe in more detail. Our team is executing effectively to position Adverum as a leader in gene therapy. Beyond these near-term opportunities for OT2, we are focused on developing a pipeline of novel gene therapy.

Excited that yeah has approved the I'd be in diabetic retinopathy, we've been preparing for the announcement of the phase two trial is open for patient enrollment is I will describe in more detail.

Oh payments executing effectively could position it varies as a leader in gene therapy.

On the Knick Remoxy any Sergey too we are focused on developing a parts like no one gene therapy.

We regulate present data on me.

Leonie Patterson: We regularly present data on these earlier stage therapies in our industry-leading AAP platform at scientific conferences, and we presented virtual posters at ARVO and ASBCT on these programs. Our expertise is in novel vector development, and we look forward to expanding our pipeline beyond O2-2 and sharing more about this progress later this year. And another exciting progress update. First, I'm pleased that Dr. Scott Whitcup has joined our board of directors. Scott is an experienced ophthalmologist and successful drug developer who is already providing valuable strategic contributions as we seek to bring our therapies to the market. And finally, in February, we completed successful financing and entered the first quarter with $297 million in cash, cash equivalents, and marketable securities.

Really I stay therapies in that industry meeting every platform, it's hard to the conferences, we presented vishal posters that although I think you keep on these programs.

Always fatigue is a novel Victor development, and we look forward to expand the ocotlan beyond are due to ensuring more about this progress later this year.

And then another exciting progress update this I'm pleased that Dr., Scott what cap joined our board of directors.

Got it is an experienced ophthalmologists and successful drug developer, who is already providing valuable strategic contributions as we seek to bring up therapies to the market and finally in February we completed a successful financing and ended the first quarter with 200 nice in Lilly and then cash cash equivalents and marketable securities.

Aaron Osborne: We expect this case to affect our operations into 2022. I'd now like to turn the call over to Aaron, who will provide further details on the progress for ADVM-OG2. Thanks, Leonie.

We expect this case the corner operations into 2022.

I'd now like to turn the call I've, the Aaron who will provide further details on that clinical progress for IDN Archie to Aaron.

Thanks Neely.

Aaron Osborne: First and foremost, we continue to work closely with our clinical trial sites to protect the health and well-being of our patients. Participants in our ongoing Optics Phase 1 trial have wet AMD and are in high-risk categories for COVID-19 complications based on age, comorbidities, or both. We have worked together with our sites to implement precautionary measures and alternative study conduct measures when required, including remote study monitoring and remote patient assessment. As the COVID-19 situation continues to evolve, we will continue to work closely with our trial sites, clinical study vendors, and industry partners to monitor best practices and guidance updates. We believe the need has never been greater than now for a one-time, intravitreal anti-VEGF agent that provides long-term control of disease activity.

First and foremost we continue to work closely with a clinical trial sites to protect the health and wellbeing about patients.

Because the comes in ongoing optics phase one trial have what TMT and are in high risk cost degrees to cope with 19 complications based on age co morbidities, but.

We have worked together without sites in implementing precautionary measures and alternative study conduct matches when required including remote still be monitoring on remote patient assessments.

That's the kind of did not seem situation continues to unfold. We will continue to work closely without trial sites clinical studies done does an industry partners to monitor the best practice and God himself sites.

We believe the need has never been great could the now for a onetime intravitreal anti VEGF agents that provides long term control of disease activity.

Aaron Osborne: Truly, this has been a very exciting time for our team working on advancing this novel gene therapy in the OPTIC trial for WET-AMD and now the INFINITY trial for diabetic macular edema. First, I'll... We continue to make strong progress advancing this trial. Our immediate focus is to quickly enroll cohort four.

Truly this has been a very exciting calling brought teams working on advancing this novel gene therapy in the LP trial for what they empty and now the infinity trial for diabetic macular edema.

That's the uptick.

We continue to make strong progress advancing this trial our immediate focus is to quickly enroll coke for there was strong support from the investigators and clinical sites to do this and we look forward to presenting data from eight full cohorts by the end of this year.

Aaron Osborne: There is strong support from the investigators and clinical sites to do this, and we look forward to presenting data from all four cohorts by the end of this year. 2020 has been a robust year of clinical data presentations for our OPTIC trial. Earlier this month, we presented an update from OPTIC, including interim data from patients in Cohort 3 who received the lower dose of O2-2, as well as the six-week prophylactic regimen of steroid eye drops instead of the 13-day oral steroid prophylaxis that was used in Cohorts 1 and 2. The key takeaways from this presentation of optic data through April 1, 2020, were as follows. Long-term durability beyond one year from a single interventional injection has been demonstrated with zero rescue injections in cohort one out to a median of 60 weeks follow-up. We saw further evidence of a dose response at 6E11 and 2E11 dose levels across all three cohorts. Evidence from Cohort 3 was presented, indicating that the prophylactic regimen of topical steroids is effective at minimizing early ocular inflammation.

Twentytwenty, it's been a robust year, a clinical data presentations for I'll pick trial.

Earlier. This month, we presented an update you promote think including interim data from patients in cohort three he received the lowest August two two as well that's six week prophylaxis regimen of Starwood eye drops instead of the 13 day oral steroids Lexus that was used in cohorts one of them too.

The key takeaways from this presentation voltac they come through April Twentytwenty wear out follows.

Long term and your ability beyond one year from a single Intravitreal injection has been demonstrates it wouldn't see every rescue injections in cohort one out to a median 60 weeks follow up.

We saw the evidence of that dose response fix the 11 until you 11 dose levels across all three cohorts.

As it comes from cohort three was presented indicating that the price a lot to regimen, a topical steroids is affected minimizing early.

So they should.

Early data in the first five patients with 20 weeks follow up in cohort three show improvements in visual acuity and reductions in Mccullough thickness as assessed by how does he see.

Aaron Osborne: Early data in the first five patients with 20 weeks of follow-up in Cohort 3 show improvements in visual acuity and reductions in macular thickness as assessed by OCT. As a reminder, OPTIC includes treatment-experienced wet AMD patients who previously required frequent anti-VEGF intravitreal injections to control their wet AMD. These data continue to show that a one-time intravitral injection therapy, like ADVM-022, could Given the promising data presented today for ADVM-022, we're excited to move forward with our plans to assess ADVM-022 in patients with diabetic retinopathy. DR affects approximately one in three adults with diabetes and puts patients at risk of vision loss. DR can be diagnosed at different severity levels, with the risk of sight-threatening complications being higher at higher severity levels. It is the most common cause of blindness in working-age adults in the US.

As a reminder, Oh concludes treatment experience, what 80 patients who previously required frequency by Jeff Intravitreal injections to control that what I can see.

These data continues to show that a one time intravitreal injection therapy like 80 be another two to could change the treatment paradigm for physicians and patients.

Given the promising data presented today Grady B.M. out you too we're excited to move forward without plans to assess ATP 022 in patients with diabetic retinopathy.

Approximately 30 million people all impacted by thought B piece in the United States and each of these individuals is at risk is developing diabetic neuropathy wont be oh.

He also affects approximately one in three adults with diabetes and puts patients at risk of vision loss.

Deal can be diagnosed at different severity levels with the risk of sight threatening complications being higher at higher severity levels I just the most common cause a blindness in working age adults in the U.S.

Aaron Osborne: And, as the prevalence of diabetes continues to grow, the prevalence of diabetic eye diseases is expected to increase. Diabetic Macular Edema, or DME, is a vision-threatening complication of DR that can occur at any severity level in people with diabetic retinopathy. DME is the leading cause of vision loss in patients with diabetic retinopathy and affects around 5% of adults with diabetes. The DME market therefore represents a significant opportunity. The current standard of care therapy for DME is anti-VEGF and intravitreal injections. These are effective, but typically require frequent and long-term injections for patients to maintain good vision. Compliance with these treatment regimens can be difficult for patients, leading to under-treatment and vision loss. Analyses of claims databases show that real-world outcomes in DME with anti-VEGF therapy are meaningfully worse than in clinical trials. Retinal specialists are very excited by the potential benefits that a long-lasting anti-vegetative therapy, such as ADVM-022, could offer for this growing population of patients. Now, let's discuss our own program in VME.

[laughter] precedence for diabetes continues to grow the prevalence of diabetic eye diseases is expected to increase.

Diabetic macular edema DMV, it's a vision threatening complication of de all that can occur at any severity levels in people with diabetes, that's not to say.

Do you have me, it's been leading cause of vision loss in patients with diabetic retinopathy on effects around 5% of adults with diabetes.

The DMC market, that's cool represents a significant opportunity. The current sounds just kind of therapy could be any on t. bed chats intravitreal injections.

These are affected but typically require frequent on long term injections to patients to maintain good patient.

Compliance with these treatment regimens can be difficult for patients leading to under treatment and vision loss.

Analyses of claims data bases shows real world outcomes in DMD with anti VEGF therapy, a meaningfully worse than in clinical trials.

Retina specialists I'm very excited by the potential benefit because our long lasting anti VEGF therapy, such as they give you a night you too could also for this growing population of patients.

Now, let's discuss our own program in DMD.

Infinity clinical trial, the baby demo two two and be any is a phase two multicenter randomized double masked active comparator controlled trial.

We just saw in this trial could demonstrate superior control if disease activity. Following a single injection the baby BMO to two compared to a single injection of the top as measured by time to worsening of DNA disease activity using protocol specified criteria.

Additional objectives include assessments of treatment burden visual acuity retinal anatomy, including my color. That's that's attached on IBCP unrest and all that disparity as assessed by photography.

Aaron Osborne: The INFINITY clinical trial of ADVM022 in DME is a phase two, multi-center, randomized, double-masked, active comparator-controlled trial. We designed this trial to demonstrate superior control of disease activity following a single injection of ADVM022 compared to a single injection of Aflibisept, as measured by time-to-worsening of DME disease activity using protocol-specified criteria. Additional objectives include assessments of treatment burden, visual acuity, retinal anatomy, including macular thickness as assessed on OCT, and retinopathy severity as assessed by photography, and Safety Out. Additionally, all patients will receive a course of prophylactic steroid eye drops. We expect to enroll approximately 33 patients with recently diagnosed diabetic macular edema. Infinity will evaluate the higher 6E11 dose and the lower 2E11 dose of ADVM-022. Patients in the control arm will receive flibicept only.

I'm safety outcomes.

All patients will receive the course of price elastic steroids eye drops.

We expect to enroll approximately 33 patients with recently diagnosed diabetic macular edema.

Infinity, we'll evaluate the Ohio fix the 11 boats and the lower to me 11, dice ATM or two too.

Hi ships in the control arm will receive aflibercept only.

All patients will be eligible for rescue Aflibercept injection from week eight onwards.

Infinity as a 48 week study with the primary objective being assessed firstly at week 24.

Fantasy has been designed to provide robust controlled data on 80, the IMO two to India me I will be conducted a trial sites across the United States.

Ill now turn the call back over to the army.

Thanks, Aaron before opening the call for questions I want to acknowledge my appreciation for the healthcare provider to remain committed to offtake and of appearing to get offended de clinical trial.

And we are equally grateful for the patients who continued to be treated and modern said, but then novel gene therapy to support this important development work I'm excited to me that Vera as we work to develop a potential transformative onetime treatment for patients with aim be India me.

Leonie Patterson: All patients will be eligible for rescue afliviceps injections from week 8 onwards. Infinity is a 48-week study with the primary objective being assessed firstly at week 24. Infinity has been designed to provide robust controlled data on ADVM-022 in DME and will be conducted at trial sites across the United States. I will now turn the call back over to Leonie.

We might we remain committed to ambition to advance these programs in our pipeline of novel gene therapy for patients with serious aka diseases.

Operator.

Thank you.

Ladies and gentlemen, if you have a question at this time. Please press star one on your telephone to.

To withdraw your question press the pound key please standby Bobby compiled that you when they roster.

Your first question comes from a lot of Tyler Van Buren with Piper Sandler.

Hey, guys good afternoon.

Ask about the D. I mean, you trial design, a very interesting design relative to the historical and so we've seen in terms of PCBA improvements or three line gainers.

Leonie Patterson: Thanks, Aaron. Before opening the call for questions, I want to acknowledge my appreciation for the healthcare providers who remain committed to OPTIC and are preparing for the INFINITY clinical trial. And we are equally grateful for the patients who continue to be treated and monitored with our novel gene therapy to support this important development work. I'm excited to lead Adverum as we work to develop a potential transformative one-time treatment for patients with wet AMD and DME. We remain committed to our mission to advance these programs in our pipeline of novel gene therapies for patients with serious ocular diseases. Operator, Thank you. Ladies and gentlemen, if you have a question at this time, please press star 1 on your telephone. To withdraw your question, press the pound key.

So I guess, just a quick point of clarification.

With respect to the study time to worsening of hear me disease activity is that's the fine that's a rescue injection further criteria and if that is indeed the case it appears as if.

It's very unlikely that this trial just not succeed I mean, what percentage of flipper separation.

It can go 24 weeks DMEA Aflibercept patients can go 24 weeks without an injection.

Thanks, Todd how to think through and then.

Yeah go ahead, I was going to say Aaron just quickly I'd say that that's a really good coined and obviously the expectations I think that given what we have done when optic.

Todd I really for the emphasizes how long term durable effect than we've seen it off that could be could be play through and then you're assuming that obviously would be made that that could be the case given that we have but you know to achieve that with the would I be patient, but in terms of the patient a this patient population for do you may probably would be helpful. The errand to talk through.

We really have the differences here and the patience and how how long they typically go without injections and a little bit further details on that.

Tyler Van Buren: Please stand by while we compile the Q&A roster. And our first question comes from the line of Tyler Van Buren with Piper Sample. Hey guys, good afternoon.

Thank you reality and thank you kinda for that for that question I'm, specifically on the second part the question, which is kind of how long would you expect aflibercept patients to go without an injection well based on evidence from other studies to that looked at on T. betcha compound with similar.

Leonie Patterson: I wanted to ask about the DME trial design, a very interesting design relative to the historical endpoints that we've seen in terms of BCBA improvements or three-line gainers. So I guess just a quick point of clarification, With respect to the study, time to worsening of DME disease activity, is that defined as a rescue injection per the criteria, and if that is, It's very unlikely that this trial does not succeed. I mean, what percentage of Flibersep patients.., can go 24 weeks, a DME, a flue-recept patient can go 24 weeks without an injection, that's a really good point and obviously the expectations that have been set given what we have done with OPTIC, Tyler really sort of emphasizes how a long-term durable effect that we've seen in OPTIC could be could be played through and then you're assuming that obviously with DME that that could be the case given that we have been able to achieve that with the wet but in terms of the patient population for DME it probably would be helpful to Aaron to talk through really the differences here in the patients and how long they typically go without injections and a little bit further on details on that. Thank you, Leone, and thank you, Tyler, for that for that question.

Retreatment criteria and you're right you know those retreatment criteria either at those and Infinity, we would consider to be a progression of CMV disease activity and if a patient meet me I've heard those criteria from that we take it. All works then they can be rescued with aflibercept and because it's up.

The mouse study the investigates the will not really knows the patient is all know two to work the patient is receiving aflibercept. So there's a robust design here, which allows for a robust comparison.

We would expect more than half off all the aflibercept patients to it required rescued by around weeks 16.

So to your point. These these are patients who had been recently diagnosed with diabetic macular edema visits to the high treatment need early in disease, and we'd expect more than half of those up to this that patients to to meet one of those criteria by we 16 until about a a rescue injection I don't see so I'd encourage you to we have not.

Tested this yet in diabetic macular edema, but based on.

That Jeff level that we see in studies comparing diabetic patients in patients with let's say empty. It's what are the retinal vascular diseases. We just broadly a similar amount of that you have to be produced and we'd expect expect a broadly similar type of effect within that range, obviously units in the first time in diabetic.

Aaron Osborne: And specifically on the second part of the question, which is kind of how long would you expect a Flivicep patient to go without an injection? Well, based on evidence from other studies that have looked at anti-VEGF compounds with similar retreatment criteria, and you're right, those retreatment criteria, either of those in Infinity, we would consider to be a progression of BME disease activity. And if a patient meets either of those criteria from their week 8 visit onwards, then they can be rescued with Flivicep. And because it's a fully masked study, the investigator will not really know if the patient is on O2-2 or if the patient is receiving Flivicep. So there's a robust design here which allows for a robust comparison.

But based on the all pick that you can certainly with the Hyatt place, where we've seen older patients treated with the highlights in cohort one to be out to a median of 60 weeks with no required rescue injections and the majority of patients at the lower dose has not received any rescue injections, either and remain stable from bye.

Anatomical individual perspective, so we'd expect a much lower proportion on on the I'd be it makes you two sides to reach one of those criteria and that's why we're able to other relatively small sample size in order to address stop primary endpoint. I mean is an early phase study, but it is robustly designed you may.

<unk> registration endpoints as well typically that would be a vision endpoint and this trial is not powered to robustly assessed fusion acuity.

And that's why we've gone for an endpoint. So we believe we should be able to see a difference between current standard of care I idea intravitreal injection compared to 80, B. I know, two two which potentially could be a onetime treatments for a document or Dan.

Aaron Osborne: And we would expect, you know, more than half of the Flivicep patients to have required rescue by around week 16. So to your point, these are patients who have recently been diagnosed with diabetic macular edema. There's a high treatment need early in the disease, and we'd expect more than half of those Flivicep patients to meet one of those criteria by week 16 and to have had a rescue injection. And obviously, ADVM-O2-2, we have not tested this yet in diabetic macular edema, but based on VEGF levels that we see in studies comparing diabetic patients and patients with WET-AMD as well as Obviously, you know, it's the first time in diabetic eyes.

Okay, Okay and my follow up question, what's your related to your interactions with the FDIC that help inform us novel trial design because.

Clearly the probability of success is quite high and I was curious it.

It would be some novelties your Registrational trial design, you, just I guess alluded to using more traditional points, but.

Curious to get your thoughts around bad assuming this study are successful it seems highly likely.

Yeah, I think I'm talking about I would say.

Because it's so I think on from its yet to say the <unk>. We certainly have been in close contact with them as you can imagine getting the sign the accrued then I think you know where you're hitting towards is and Aaron can probably expand on that says that there was the possibility of but this could mean a assuming this positive outcome here in terms of I'm trying to be little bit more creative.

On the ways to lose the sort fast and so I think a that's probably would be an option that we would like to see if its possibility of once you get further along and see the outcomes of the study a Aaron what do you want to add to that maybe a little bit more.

Yeah, I mean, just a little bit more thing you know it's a pretty good question. We collaborated closely with the FDIC. Its was a scientific advisory board. Our investigates is another experts because really designed this trial I mean, it's early phase first trial in diabetic retinopathy, let's try and and diabetic macular edema, but it does help those features built into it in.

Aaron Osborne: But based on the optic data, certainly with the higher dose where we've seen all of the patients treated with the higher dose in cohort one to be out to a median of 60 weeks with no requirement for rescue injections, and the majority of patients at the lower dose have not received any rescue injections either and have remained stable from both an anatomical and visual perspective, we'd expect a much lower proportion on the ADVM-O2-2 side to reach one And that's why we're able to have a relatively small sample size in order to address that primary endpoint. I mean, it is an early phase study, but it is robustly designed. You know, you mentioned registration endpoints as well.

It's all being a randomized double mosque trial design, which should enable robust data to be produced I'm. So in that sense. You know the level that they could produce is to a level above what you would see with an open label study and that's certainly something we want to pains to ensure that we could.

Included within the study and.

And therefore should be something that could potentially support they could package as we as we progress for <unk>.

That's great. Thanks for the additional thoughts fascinating trial design.

[noise]. Thank you.

Your next question comes from the model failed to do with Cowen and company.

Good afternoon, Thanks for taking my questions and maybe a couple follow ons to travelers first on the rescue criteria itself in the affinity trial.

Aaron Osborne: Typically, that would be a vision endpoint, and this trial is not powered to robustly assess visual acuity. And that's why we've gone for an endpoint that we believe we should be able to see a difference between the current standard of care, i.e., ILIA intravitreal injections compared to ADVM-O2-2, which potentially could be a one-time treatment for diabetic macular de Okay, and my follow-up question was just related to your interactions with the FDA that helped inform this novel trial design because, clearly, the probability of success is quite high, and I was curious whether there would be some novelty to your registrational trial design. You just, I guess, alluded to using more traditional points, but curious to get your thoughts around that. Assuming this study is successful, it seems highly likely. Yeah, I think on what I would say. Let me get this.

Can you talk about how those criteria compare to other furniture used to be me trials and maybe more generally how it was crutcher compare to what physician would use in clinical practice when deciding whether to give.

<unk> mutation in another aflibercept injection.

Yes for sure I can come straight into compared them to other clinical trials and there was the most stringent and off retreatment criteria used in any clinical trials in DNA essentially a patient is retreated or because he's rescue treatment. If they have a loss of more than five lessons or if they have an increase of more than 50 microns.

In central something thickness on the I see so degraded either at the tightest, we can get to whilst trying to avoid having too much variability boasted specifically the vision has to be related to the any in the investigators opinion, but these are he's a very stringent and they're right at the most stringent.

Leonie Patterson: So I think from the FDA's perspective, look, we certainly have been in close contact with them, as you can imagine, getting this IND approved. And I think, you know, where you're heading towards, and Aaron can probably expand on this, is that there is the possibility of what this could mean, assuming this positive outcome here, in terms of trying to be a little bit more creative on the way to move this forward fast. And so I think that's probably an option that we would like to see if there's the possibility of once we get further along and see the outcomes of the study. Aaron, what do you want to add to that? Maybe a little bit more?

And criteria that have been used in DMD trial, and that's really because they've been support all hypothesis and our assumptions that we would expect to have more than 50% <unk> patients treated by that time point and that is using those specific criteria. You can go look at the high to on the DMC trials.

And you kind of day empty with regard central still feel sick, that's because the rational and that's to me is generally less distorts. It you can measure that central sub feel thickness.

Generally more consistently in the DMC trials and therefore, it can be slightly more reliable indicator <unk> in the in in the clinic.

You know I think very much similarly to A.M.D., if there's an increase in a DEMA and especially if the visions impact than likely physicians will be injecting. They got primarily on the I see in a clinical trial, obviously you want to get those those decisions made robustly and consistently across the trial arm. So that's why we.

Aaron Osborne: Yeah, I mean, just a little bit more. I think, you know, it's a really good question. We've collaborated closely with the FDA, as well as our scientific advisory board, our investigators, and other experts to design this trial. I mean, it is an early phase, first trial in diabetic retinopathy, and first trial in diabetic macular edema, but it does have those features built into it in terms of being a randomized double mask trial design, which should enable robust data to be produced. So in that sense, you know, the level of data produced is at a level above what you would see with an open-label study. And that's certainly something we look to painstakingly ensure that we could include within the study. And, and therefore, it should be something that can potentially, you know, support our data package as we progress forward. That's great!

The the protocol specified retreatment criteria.

That's helpful and May be a second question just on the optics study in your prepared remarks, you mentioned, you're working to enrol cohort for.

Excuse is maybe a bit more information on how many patients had been enrolled in and whether you think there's any risk that koby will the way the completion of enrollment in that and that study.

Yeah, let me like that so we I think we were we reiterated again that we believe that we'll have died or that would be able to paint on all four cohorts by the end of this year and we still holding to that and I think Q pointer uncarded.

There is still still to be played out here in terms of the Olympic talk a little longer haul, but right now we feel pretty good about the amount of dialogue and interactions with the side said they the.

Screening in the and ongoing enrollment continues at a pretty good pace I think that what we Oh, we Bonnie talked about dusting off this patient I don't think we can share anything more than that other decided that we still feel comfortable that we'll be able to shoot tighter on on I'm hopeful cohorts, but ended this year.

Tyler Van Buren: Thanks for the additional thoughts. Fascinating trial design. Thank you. And our next question comes from the line of Phil Nadeau with Cowan & Company. Good afternoon.

That's great. Thanks for taking my questions.

Yeah.

Phil Nadeau: Thanks for taking my questions and maybe a couple of follow-ons to Tyler's. First, on the rescue criteria itself in the INFINITY trial, can you talk about how those criteria compare to other criteria used in DME trials and maybe more generally how those criteria compare to what a physician would use in clinical practice when deciding whether to give a DME patient another alpha-libracept injection. Yes, for sure.

Thank you.

Our next question comes from the line I believe you young we can't shore.

Hey, guys. Thanks for taking my questions and congrats on the progress on India Me.

One thing I mean, one maybe optic feature question. So on deal me I guess, you know do you kind of perceived a spectrum of disease disease severity is to be as why they are an A.M.D. and I guess I asked that just kinda. When we think about you know what we should sort of expect in this trial and it seems like from topic, maybe perhaps patients who are little bit less severe.

Actually do better even to the severe people didn't really well too.

And then second question as I have you guys thought about kind of have course, you haven't well you'd be willing to share you know if you what kind of thoughts might be polls. These four cohorts and how you might be thinking about kind of moving forward with different protocols as we move out by the initial study here. Thanks.

Aaron Osborne: I can come straight in to compare them to other clinical trials, and they're at the most stringent end of retreatment criteria used in any clinical trial in DME. Essentially, a patient is retreated or receives rescue treatment if they have a loss of more than five letters or if they have an increase of more than 50 microns in central subfield thickness on the OCT. So really, these are at the tightest we can get to whilst trying to avoid having too much variability. Specifically, the vision has to be related to DME in the investigator's opinion. But these are very stringent, and they are right at the most stringent end of criteria that have been used in DME trials. And that's really because they then support our hypothesis and our assumptions that we would expect to have more than 50% of the effluvistat patients treated by that time point. And that is using those specific criteria.

All right so starting on the severity in the the patients I think I want you take that in terms of the patient. So we're targeting we gave some that are now and now prepaid remarks, it maybe a little bit more color there.

Yeah no exactly so these are patients with D. I mean that DNA is causing a they've got some reduction ambitions that they have fluid in the center of the Mac Killer T. M is probably about 5% of the deal population I'm talking about center involving P.M. me. So it does more than 30 million patients.

With diabetes in the U.S. then we're looking at around you know one in a hospital 2 million patients with Dnbi likely in the U.S.. So it's pretty significant number and maybe even more than the number of patients who've got recalled West Ham D. In this trial with basically taking patients with any severity level as long as that.

Fluid is involving the sense, so all that much cooler than they have some vision impacts and they've got relatively recently diagnosed diabetic macular edema, weve comfort pretty sort of homogeneous population. It's a randomized trial, we got small groups in each of them and the macular edema can kind of act to some.

Aaron Osborne: And you can go a little bit tighter on the DME trials than you can in AMD with regard to central subfield thickness because the retinal anatomy is generally less distorted. You can measure that central subfield thickness generally more consistently in the DME trials, and therefore it can be a slightly more reliable indicator. And in the clinic, you know, I think very much similarly to AMD, if there's an increase in edema and especially if the vision's impaired, then likely physicians will be injecting. They go primarily on the OCT.

More of that that Jeff Amato, and it's a very tight traceable end point and something that you get good granular detail on so that's why we've chosen PMT and to have Oh, well control patient population I think as we move forward one of the one of the hopes for a onetime intravitreal treatment would be the it could actually.

Moved appointed intervention earlier in diabetic retinopathy, so when we set the diabetic retinopathy can prevent any stage and it patients get the anything that already losing vision or risk, losing more efficient patients with high severity at risk of developing developing proliferative complications. So if you could have a therapy that lost for.

Aaron Osborne: In a clinical trial, obviously, you want to get those decisions made robustly and consistently across the trial. So that's why we have the protocol-specified retreatment criteria. That's helpful.

A long time and is delivered in a it up and I read it to be non interventional why that could have a big impact and that's something that we would certainly look out in the future, it's potentially moving to kind of even bought a diabetic retinopathy population, but you know the Tammy population is a large population. This is nick significant unmet needs and see that Jeff.

Leonie Patterson: And then maybe a second question just on the optics study. In your prepared remarks, you mentioned you're working to enroll cohort four. Could you give us maybe a bit more information on how many patients have been enrolled and whether you think there's any risk that COVID will delay the completion of enrollment in that study? Yeah, let me take that, Phil. I think we reiterated again that we believe that we'll have data that we'll be able to present on all four cohorts by the end of this year, and we're still holding to that. And I think to your point around COVID, you know, there is still much to play out here in terms of the overall impact over the long haul.

Therapies work well, but they require frequent and long term administration to get good results I'm said, the seems an ideal populations and start with.

And then I'm on your plans for optic maybe as you go outside of the next four cohorts and then to like bigger studies, maybe any color I'm going to end points and or how you might think about kind of running what doesn't group.

So I'll start and then I'm throwing away and on on designs, we sort of planning Saudis play that out so I think it altogether.

About having released the died on cohorts 312, and three at the latest data presentation is that we really do want to see cohort for data, we need to see that couldn't get some confirmation and tens of he does response to be a efficacy that we thing with co. One then all the same thing how the safety profile plays out given are we using the.

Leonie Patterson: But right now, we feel pretty good about the amount of dialogue and interactions with the sites, and I think that the screening and the ongoing enrollment will continue at a pretty good pace. I think that we've only talked about dosing our first patient. I don't think we can share anything more than that other than to say that we still feel comfortable that we'll be able to share data on all four cohorts by the end of this year. That's great.

Topical steroids similar to Q3, so for US it's important to have that data right into place one meeting and then build to talk about the trial design. So that's all the caveat to say we haven't spoken to this yet, but we certainly are thinking about different ways that we could go as fast as we can to get to the latest stage studies, but Aaron you want to go.

Sure a couple of things we've been thinking about and by the way. This is there's I mean since we have a spike in the <unk>, but we have some preliminary thoughts.

No exactly exactly it still is preliminary and cobalt foods really important because that's the dose ranging objective. We're using the same two doses and I in the affinity study clearly we're seeing evidence for milk take the patient these doses seem to show some benefits in terms of anatomical.

Phil Nadeau: Thanks for taking my question. Thank you. And our next question comes from the line of Alethea Young with Kantor.

Alethea Young: Hey guys, thanks for taking my questions and congrats on the progress in DME, one DME and one maybe OPTIC future question. So on DME, I guess, you know, do you kind of perceive this spectrum of disease, disease severities to be as wide as they are in AMD? And I guess I ask that just kind of when we think about, you know, what we should sort of expect in this trial. And it seems like from OPTIC that maybe perhaps patients who are a little bit less severe actually do better, even though the severe people did really well too. And then the second question is, have you guys thought about kind of, of course you have, but will you be willing to share, you know, if you what kind of thoughts might be after these four cohorts and how you might be thinking about kind of moving forward with different protocols as we move outside of the initial study here? Thanks.

Segments, and reducing on T. that Jeff injection.

So I think you know that will be one of the questions and future studies do because for the most of these doses will do we see enough of the dose difference that we could make a choice based on how the optic to play play out I you know typically in late stage studies, we've seen going from uptick a phase one to two off I too would moving to randomized controlled studies so look for those.

Elements to be in future studies randomized controlled double masks and typically I mean more sta required I know the health authorities is that you show visual acuity results the comparable to the standard of care, which is the frequent anti VEGF injections, given you know label.

And yeah, we look forward to goes to those interactions with a hefty I know the health authorities.

Great. Thanks.

Thank you.

Your next question comes from a lot of any through our SVB Larry.

Hi, guys. Thanks for taking my question a couple of quick ones first we'll start DMD.

Exactly can you give a sense of how to think about central washout period of any prior to randomization regarding Peter six goes the.

I understand there's no back then and how to think about.

Oh, how much anti VEGF tone. These patients may or may not have coming into that day, one aflibercept slashed sham injection.

Leonie Patterson: Alright, so starting on the severity and the patients, I think, Aaron, why don't you take that in terms of the patients who we're targeting. We gave some of that in our prepared remarks, so maybe it's a little bit more color there. Yeah, no, exactly.

And then as a second question.

When you think about the potential what implications of this might be for a pivotal study I guess for infinity or for a more for uptick.

The phase three out or indication.

Should should we think of a single injection of an act of an approved anti VEGF. There therapy, followed by a potential rescue was sort of the equivalent of a placebo control or should we or should we think of.

Aaron Osborne: So these are patients with DME that DME is causing, they've got some reduction in vision, so they have fluid in the center of the macula. Now, DME is probably about 5% of the DR population, but I'm talking about the center involving DME. So there are more than 30 million patients with diabetes in the US, and then we're looking at around, you know, one and a half or two million patients with DME likely in the US. So it's a pretty significant number, and maybe even more than the number of patients who've got who've got wet AMD. In this trial, we're basically taking patients with any severity level, as long as that fluid is affecting the center of their macula, and they have some vision impact, and they've got relatively recently diagnosed diabetic macular edema. We've gone for a pretty sort of homogeneous population.

Different <unk> or do you think that are doing anything compared to our like that we're seeing here infinity isn't necessarily something would see interface three forget how likely do this model to be carried forward.

Great Aaron.

Early on you.

I am on me so I'm just coming off me I was waiting for maybe [laughter], yes, but let me take the second part for US which was on the on the number of treatment and the criteria for patients coming into the study. These are these I read it could be recently diagnosed diabetic macular edema patients. So they have either been diagnosed.

Ladies and had no injections all that had a low number of injections. So it's a little bit different to our optic population, which are generally patients who had been requiring a number of injections over long period of time I'm not to get a more homogeneous population because we've got relatively small sample size. So the key criteria coming into this study is that they have.

Aaron Osborne: It's a randomized trial; we've got small groups in each arm, and the macular edema can kind of act as somewhat of a VEGF meter. And it's a very tight traceable endpoint and something that you get good granular detail on.

With which is above the limit of normal so they've got pathological fluid accumulation in the center at the phobia and also that they've got some reduction in vision I'm, sorry, we have visual acuity criteria and it's a little bit below it. So that's sort of 2032 level is off the cuts off so we're not bringing in patients who were 20 foresee.

Aaron Osborne: So that's why we chose DME and to have a well-controlled patient population. I think as we move forward, one of the hopes for a one-time intravitreal treatment would be that it could actually move the point of intervention earlier in diabetic retinopathy. We've said that diabetic retinopathy can occur at any stage. And if patients get DME, then they're already losing vision or at risk of losing more vision. Patients with higher severity are at risk of developing proliferative complications.

So those are the read the two criteria that they have fluid and they have visual acuity reduction due to that fluid, which is due to the DNA and that it's been recently diagnosed and I think versus future studies.

When you got larger populations some of the variability will sort of wash out in the randomization groups I'm.

Little bit like yes, that's something that we could potentially but wasn't as we go forward, but given we call. It low number of patients we want to make sure that we have relatively good balance amongst those amongst those groups and maybe you could repeat the second part the question again Manny.

Okay. Thanks, a thing for the question should we think about the wash out a washout period, followed by potentially followed by a single injection of an approved anti VEGF agents.

Aaron Osborne: So if you could have a therapy that lasts for a long time and is delivered in a relatively non-interventional way, that could have a big impact. And that's something that we would certainly look at in the future, potentially moving to kind of a broader diabetic retinopathy population. But, you know, the DME population is a large population.

As what because as water compared to arm with likely look look like in the future in a phase three study.

Yeah I mean.

Typically the compared to in a phase three study would be as a D approved regimen or the regimen that demonstrate to the results led to the approval so kind of the best conditions, because typically it's a non inferiority tried and you would need to do that so that would likely be whereas here we're comparing.

Two.

Aaron Osborne: There are significant unmet needs. Anti-VEGF therapies work well, but they require frequent and long-term administration to get good results. So this seems an ideal population to start with.

Single dose of Aflibercept and then if this disease activity that getting rescued I mean, that's not be approved regimen here, but we're aiming to show superiority to it but superiority on disease activity to find its visual acuity and I see see there's it's possible you know it's possible and that's something we would.

Leonie Patterson: And then on your plans for OPTIC, maybe as you go outside of the next four cohorts and then to bigger studies, maybe any color on kind of endpoints and, or how you might think about kind of running what dosing groups? So I'll start and then I'm sure Aaron will weigh in on designs as we're sort of planning, starting to plan that out. So I think an obstacle, as you talked about having released the data on Cohorts 3, 1, 2, and 3 at the latest data presentation is that we really do want to see Cohort 4 data. We need to see that and get some confirmation in terms of the dose response, the efficacy that we've seen with Cohort 1, and obviously see how the safety profile plays out given we're using topical steroids similar to Cohort 3.

To regulators about whether there were different types of control group of than showing a you know noninferiority to kind of the labeled control group, but I think base case would be and that's what other anti that Jeff.

It's a nice compared to sort of the best regimen. That's approved the the for the comparison nothing that she got base case.

Great. That's definitely helpful. As one last little follow up.

Sounds good these patients are earlier in their disease or what are your patience and I'll pick up beats me early cohorts.

But our argue patients all known anti VEGF responders or some of them are some patients study potentially naive to all antibiotic treatment.

That's correct some of the patients will be naive to all anti VEGF treatment. We at you know extensive discussions with what about sizes and I mean anti VEGF works universally across you know diabetic macular edema. So without you know this is one of the discussion points that we had should we look for that response.

Leonie Patterson: So for us, it's important to have that data, get to the end of the Phase 1 meeting, and then be able to talk about the trial design. So that's all a caveat to say we haven't spoken to the FDA, but we certainly are thinking about different ways that we could go as fast as we can to get to the later stage studies. But Aaron, you want to go through a couple of things we've been thinking about. And by the way, this is, as I mentioned, we haven't spoken to the FDA yet, but we have some preliminary thoughts. No, exactly, exactly.

First or is it a you know should we should be try including the the treatment naive patients and that was where we went to so we do include treatment naive patients that had previous injection them were asking the investigator to be sure that there has been a response, but that's the investigators decision and also that I haven't been you know reaction or safety reaction to the.

For the on seabed, Jeff I'm, sorry, so you're correct, we are including a patient population here that is quite apart from BNP any it's quite different from that from not what sandy population that we have an uptick.

Leonie Patterson: It still is preliminary, and cohort 4 is really important because that's the dose ranging objective. We're using the same two doses in the INFINITY study, and clearly, we're seeing evidence from OPTIC that both of these doses seem to show some benefits in terms of anatomical improvements and reducing anti-VEGF injections. So I think, you know, that will be one of the questions in future studies.

Great. That's really helpful. Thanks, taking my question guys.

Thank you and our next question comes from the line Greg's Savannah bench with Goldman Sachs.

Oh good afternoon. Thanks for taking my questions I Congrats on the progress I've got three questions. If you don't mind the first.

Just as around dosing. So obviously 60 11 to 11 make a lot of sense. Given you know success, you've seen in wet AMD D. and I'm. Just wondering is there something different about the DMD patient population or their eyes at least where you know perhaps there might be.

Aaron Osborne: Do we go forward with both of these doses, or do we see enough of a dose difference that we could make a choice based on how the OPTIC data play out? You know, typically in later stage studies, we've seen going from OPTIC of phase 1-2 to phase 2, we're moving to randomized controlled studies. So look for those types of elements to be in future studies, randomized control, double masks. And typically, I mean, what FDA requires and other health authorities is that you show visual acuity results that are comparable to the standard of care, which is the frequent anti-VEGF injections given, you know, per label. And, you know, we look forward to those interactions with FDA and other health authorities right here.

Be you know considerations in terms of the low and high dose and whether there's a need to go either lower or higher. So just a question about dosing is kind of the first question. My second question has to do just what the clinical development path just going forward and obviously, it's a very novel.

Trial design, but depending on the data or let's assume it's positive data any thoughts or maybe you answered as previously, but just remind me what's your current thoughts on on what the next [noise].

Trial or trials could look like in terms of you know how many more trials might you need to do before you're in a place to be in or a registrational situation.

Alethea Young: Thank you. And our next question comes from the line of Manny Beruhar with SVB Lyric. Thanks for taking the question. A couple quick ones.

And then my third question is just just around data for Infinity and given that you're just kicking ass off just wondering if there's any guide posts on on when you think this data come out whether it's this year next year. Thanks.

Manny Foruhar: First, we'll start with DME. Can you give us a sense of how to think about a potential washout period, if any, prior to randomization regarding previous exposure to Aylea Lucinda-Savastin and how to think about..., how much anti-VEGF tone these patients may or may not have coming into that day one of FlibriSep slash sham injection. And then, as a second question, when you think about the potential Should we think of a single injection of an approved anti-VEGF therapy followed by a potential rescue as sort of the equivalent of a placebo control? Or should we think of something else? Or do we think that, or do we think a comparator arm like that, like we're seeing here, INFINITY, isn't necessarily something we'd see in phase three? So I guess how likely is this model to be carried forward? Oh, hey, Darren.

Okay sure. Thanks, Greg a everyone should take the phase two and then I can take that they'd want.

Sure. So the first homeless on de Emmy dosing for whose A.M.D. and we using the same two doses the love what does it to you 11 high doses Fixie 11 and.

I mean, I guess would.

I guess, we don't know for sure I think it's probably the first and most cracked onto this is the first study in diabetic patients and India me to unload. There's no. One has really tried this typist approach of a intravitreal gene therapy, producing do you feel that protein interacts with DMD, we know that Aflibercept works.

Well you know that's with DMD and we know that set us up when its administered at the idea drug has a pretty similar regimen and let's say MTN P.M. and that does she is the same at two milligrams I'm, so with with Intravitreal anti VEGF agents, we don't see it drastically different dose or requirement for inject.

Since sticking in the first year with the Aneel I M. B I'm said, we were pretty comfortable with proceeding with those two doses. We do have an interim analysis at week 24, and we do out there not the opportunity to analyze the data as we go through so you know where are we to see for example, the was.

Aaron Osborne: Aaron, are you on mute? I am on mute, so I'm just coming off the mute. I was waiting for a moment. Yes, so let me take the second part first, which was on the number of treatments and the criteria for patients coming into the study. These are relatively recently diagnosed diabetic macular edema patients. So they've either been diagnosed and had no injections, or they've had a low number of injections. So it's a little bit different to our optic population, which would generally be patients who've been requiring a number of injections over a long period of time. And that's to get a more homogeneous population because we want a relatively small sample size.

There was it was few tall from an efficacy perspective for example at the lower does somebody wanted to try high dose as well that's something that we could potentially adoption do if the data what to play out in that way, but but yeah. We are assumption is that you know there should be a broadly similar response in Dod that connects or demerits, there is in a and b.

Really based on the Intravitreal injection authentic that Jeff trials I think the next question was on the trial design moving forwards I think this was sort of the number of trials before we would go to potentially pivotal trials. The uptick is now enrolling cobalt for we've announced that we'd enrolled the first patient.

And I think we only just added that as well, but or reduce the rights that we need tween enrolled its patient cohort we need to look at the differences between the doses you always see continuing to see this dose ranging effect assess how well the topical steroids have I've worked in terms that you know managing the in trucker information that we've seen.

Aaron Osborne: So the key criteria coming into this study is that they have fluid, which is above the limit of normal. So they've got pathological fluid accumulation in the center of the fovea, and also that they've got some reduction in vision. So we have a visual acuity criteria, and it's a little bit below it. It's at the sort of 2032 level, which is our upper cutoff.

One that is done I think what we communicating is provided these deitrich directionally similar to what we've seen with the previous data in uptick we feel we have a good packaged potentially move forward to later stage trials following interactions with health authorities. So I think then the number of trials would depend somewhat.

Aaron Osborne: So we're not bringing in patients who are at 2040. So those are really the two criteria that they have fluid in their eye, and they have visual acuity reduction due to that fluid, which is due to the DME, and that it's been recently diagnosed. And I think that in future studies, when you've got larger populations, some of the variability will sort of wash out in the randomization groups. So a little bit like, yeah, that's something that we could potentially broaden as we go forward. But given that we've got a low number of patients, we want to make sure that we have a relatively good balance amongst those groups. Maybe you could repeat the second part of the question again, Manny. Thanks.

On the number of indications we work to pursue and it will also depend on the outcomes that those discussions with with health authorities I mean, I guess, one consultants, who will be working to you know device aggressive plans in conjunction with with our advisors and the health authorities to get I'd be I'm actually too.

The patients as a as quickly as is possible.

And I think the third question was around a data for Infinity I think what we'd like to I mean, obviously the team has worked very hard to get to this point 50 uncovered 19 to be in a place where we are actually in the she hasn't. This study a randomized study. So I think what we would plan to do with once we have actually enrolled.

And treated a patient and we would obviously announced that that will be out to give more guidance on time frames of Oh theater and or a enrollment site.

So stay tuned on that and we would have to be able to buy that at that time.

Okay. Thanks.

Thank you you know next question comes from the line Luca ice side with RBC capital markets.

Hello.

Aaron Osborne: The second part of the question: should we think about the washout, a washout period followed by, potentially followed by, a single injection of an approved anti-VEGF agent? as what a comparator arm would likely look like in the future in a phase 3 study? Yeah, I mean...

Taking my question.

RBC got.

Two quick questions on my side, one probably for Aaron going back to optics finished just talk about inflammation fanatics year is their time window post injection inflammation, most likely to occur or is this like I do see cradic events that can happen any time.

Aaron Osborne: Typically, the comparator arm in a phase three study would be as per the approved regimen or the regimen that demonstrated the results that led to the approval. So, kind of the best conditions, because typically it's a non-inferiority trial, and you would need to do that. So, that would likely be, whereas here we're comparing to a single dose of flibicept and then if there's disease activity, they're getting rescued. I mean, that's not the approved regimen here, but we're aiming to show superiority to it, but it's superiority on disease activity defined as visual acuity and OCT. So, it's possible, you know, it's possible, and that's something we would talk to regulators about whether there are different types of control group other than showing, you know, non-inferiority to kind of the labeled control group. But I think the base case would be, and that's what other anti-VEGFs have done, is that they've compared to sort of the best regimen that's approved for And I think that should be our base case.

I think any color there will be helpful.

Good question I think we saw in some of your recent filings that the collaboration with Regeneron has been terminated you provide any color there you.

Sure and once you go with it but.

Sure that's.

What we've seen what we saw in the non human primate data with regards to inflammation and the non human primates would not treats it typically with any steroids. So we kind of so the natural course of inflammation and we got long term follow up in those non human primates of up to 30 month follow up have you seen that there was stable protein expression, but looking at the inflammation.

Specifically, we see a peak early on and it's in that range for around four to six weeks, which corresponds with kind of peak transduction, they're off to we see a decline. So we would see more because of active inflammation, including cellular inclination at those earlier talking points and then generally we saw those markets decline.

And we would see potentially or sometimes some off because of a chronic inflammation remain that but not really anymore, because indicating an active inflammation. So indicates that most of the information is happening early and they acted information is is it's not something that continues not in Mark contrast of the protein expression, which is.

Aaron Osborne: Great. That's really helpful. And as one last little follow-up. Most of these patients are earlier in their disease than the wet AMD patients in OPTIC, at least in the early cohorts. But are these patients all known anti-VEGF responders, or are some of them, or some patients in the study potentially naive to all anti-VEGF? That's correct.

Hi, guys all parity in states off and that's why we think that the information it's related to actually protein and the caps the material can take several months or for that to be sort of washed out at the right.

In the human that we're treating them a topical steroids early on now so with that was one of the big reasons, why we switched from Orals, which were 13 days to start right eye drops because we knew from the animals that that actually seems to be the time to peak immune response, and we weren't covering a long enough period with the would see oral steroids.

Aaron Osborne: Some of the patients will be naive to all anti-VEGF treatment. We had, you know, extensive discussions with all of our advisors. And I mean, anti-VEGF works universally across diabetic macular edema. So it was felt, you know, this was one of the discussion points that we had. Should we look for that response first? Or is it, you know, should we try including treatment-naive patients? And that was where we went.

So I think what we've seen cohorts one and two is we haven't seen any new clinically relevant inflammation episodes lights, the time points, which gang fits with the non human primate data. So I think to kind of summarize it is the peak immune response is relatively early in humans, we were treated with steroids with thing that most of the patients. If you look at cone.

Aaron Osborne: So we do include treatment-naive patients. If patients have had previous injections, then we're asking the investigator to be sure that there has been a response, but that's the investigator's decision. And also that there hasn't been a reaction or a safety reaction to the anti-VEGF. So you're correct.

Three.

Five at the six patients who would go up to 12 weeks will be on what went on any exterran eyedrops. The other three as well.

Zero or well next to zero Senator inflammation. So the third eye drops to controlling it well I think that you some patients may need those trucks for a longer period of time, the individual patient access the influence how long and how Cynthia that inflammation is we don't fully understand all of those.

Manny Foruhar: We are including a patient population here that is quite, apart from being BME, quite different from that wet A&E population that we have in Oxford. Great. That's really helpful.

But what we do know is based on the current they choose the starwood eye drops to sufficient to control that and if we follow the patients longer it's small because of inflammation are coming down with being conservative tapering off the starwood eye drops. It you know the risks it being on separate eye drops and low frequency for for a long period of time.

Graig C. Suvannavejh: Thanks for taking my question, guys. Thank you. And our next question comes from the line of Graig Suvannavejh with Goldman Sachs. Good afternoon.

Graig C. Suvannavejh: Thanks for taking my questions. Congratulations on the progress. I've got three questions, if you don't mind. The first is around dosing. Obviously, 6E11 and 2E11 make a lot of sense given, you know, the success you've seen in wet AMD.

Very low we prefer to do that rather than sometimes than to take patients off too early and have another episode of inflammation, which results in kind of restarting the drops and may be going up in the frequency to three or four times a day I'm sorry, I got yeah. So it seems to decline over time and it seems to be manageable with Starwood <unk>.

Graig C. Suvannavejh: And I'm just wondering, is there something different about the DME patient population or their eyes, at least, where, you know, perhaps there might be considerations in terms of the low and high dose and whether there's a need to go either lower or higher? So, just a question about dosing is kind of the first question. My second question has to do just with the clinical development path just going forward. And, obviously, it's a very novel trial design, but depending on the data, or let's assume it's positive data, any thoughts, and maybe you answered this previously, but just remind me what your current thoughts on what the next trial or trials could look like in terms of, you know, how many more trials might you need to do before you're in a position to And then my third question is just around data for infinity, and given that you're just kicking this off, I was wondering if there are any guideposts on when you think this data could come out, whether it's this year or next year.

Yes, I smoke so.

Right. So and then on the second question was around that or do you know in collaboration which Adverum had been in collaboration with Regeneron since 2014, and they had extended one time and that's a that's actually expires in may this year and what that means is that there were a number of indications attack.

That day.

Had access to the result of that collaboration.

And there was one whats mistakes excellent witnessed consists with one of the indication was publicly known and there were three other undisclosed targets and so as a result of that that opens up the opportunity for them to explore those.

We see is actually a positive thing to enable us to actually.

Think about what else we could be using this platform using the caps that of saving a night and potentially other.

Indications that we could be going after.

Got it thank you.

Thank you.

We're now at the bottom of the hour and that's how I for one more question.

And that question comes from a lot of Patrick told Us all livestock capital.

Hi every line. This is valentina on for Patrick Thanks for taking your question I'm just two from RBC bearings. Please check your mute button.

Hello can you hear me.

Yes, yeah okay.

Leonie Patterson: Okay, sure. Thanks Greg. Everyone should take the first two, and then I can take the third one.

So question on uptick because you've heard me please check your mute button.

Aaron Osborne: Sure. So the first one was on DME dosing versus AMD, and we're using the same two doses, the lower dose of 2E11 and the higher dose of 6E11. I mean, I guess we'll...

Hi, there that's the upper right as the year as another person who's who's actually substituted for Patrick Animas Valentino and Patrick is not on the line right now.

Paul is that as beer, <unk>, President and CEO Leone Patterson.

So thanks, everybody I think what we'll do a mountain as well be able to told you after the call, but let me finish up the cold here. So I wanted to thank you all for joining US again today, it's been a remarkable year in America so far.

Aaron Osborne: I guess we don't know for sure, but I think it's probably the first and most correct answer. This is the first study in diabetic patients and in DME. To our knowledge, no one has really tried this type of approach of an intravitreal gene therapy producing the aflivicept protein in eyes with DME. We know that aflivicept works well in eyes with DME, and we know that aflivicept, when it's administered as the ILIA drug, has a pretty similar regimen in wet AMD and DME, and the dose is the same at two milligrams.

And what account and we expect it continue to execute and deliver on key catalyst switching quaid screens. This pricing on new Infinity phase two trial. The me in the coming weeks. Because then you got the data for all four cohorts by the end of this year and then advancing our preclinical gene therapy subordinate pipeline opportunities so stay tuned.

In closing employees have demonstrated a strong commitment to drive ambition poetry, they focus and dedication as evidenced by having two clinical trials underway, including the phase two Infinity Dia me trial.

Aaron Osborne: So with intravitreal anti-VEGF agents, we don't see a drastically different dose or requirement for injections, particularly in the first year with DME or AMD. So we were pretty comfortable with proceeding with those two doses. We do have an interim analysis at week 24, and we do have the opportunity to analyze the data as we go through. So were we to see, for example, that it was futile from an efficacy perspective, for example, at the lower dose, and we wanted to try a higher dose as well, that's something that we could potentially adapt and do if the data were to play out in that way. But yeah, our assumption is that there should be a broadly similar response in diabetic macular edema as there is in AMD, really based on the intravitreal injection of anti-VEGF trials.

They truly makeup hardware as possible and I am humbly grateful for a change.

Thank you for your time stay safe and healthy Ah that's been quizzical [noise].

Ladies and gentlemen, thank you for participating in todays conference. This does conclude the program and you may now disconnect.

[music].

Aaron Osborne: I think the next question was about the trial design. Moving forward, I think this is sort of the number of trials before we go to potentially pivotal trials. So OPTIC is now enrolling Cohort 4. We've announced that we've enrolled the first patient there, and I think Leonie just added there as well or reiterated that we need to enroll this patient cohort. We need to look at the differences between the doses, see if we are continuing to see this dose-ranging effect, and assess how well the topical steroids have worked in terms of managing the intraocular inflammation that we've seen. Once that is done, I think what we're communicating is, provided that these data are directionally similar to what we've seen with the previous data in OPTIC, we feel we have a good package to potentially move forward to later stage trials following interactions with health authorities.

Aaron Osborne: So I think then the number of trials would depend somewhat on the number of indications we were to pursue, and it will also depend on the outcomes of those discussions with health authorities. I mean, I guess what I can say is that we'll be working to devise aggressive plans in conjunction with our advisors and the health authorities to get ADBM02 to patients as quickly as possible. And I think the third question was around data for infinity.

Leonie Patterson: I think what we'd like to, I mean, obviously, the team has worked very hard to get to this point, especially in COVID-19, to be in a place where we are actually initiating a study, a randomized study. So I think what we would plan to do is once we have actually enrolled and treated a patient, and we would obviously announce that, we'll be able to give more guidance on timeframes for data and or enrollment. So stay tuned for that, and we would hope to be able to provide that at that time.

Luca Isi: Thank you. And our next question comes from the line of Luca Eisassai with RBC Capital Markets. Hi, hello, thanks for taking my question. I'm Luca Isi from RBC Capital.

Luca Isi: Two quick questions on my side. One probably for Aaron, going back to optics. Can you just talk about the inflammation kinetics here? Is there a time window post-injection where inflammation is most likely to occur? Or is this like an idiosyncratic event that can happen at any time? I think any caller there will be helpful.

Aaron Osborne: And then a second question. I think we saw in some of your recent filings that the collaboration with Regeneron has been terminated. Can you provide any caller there?

Leonie Patterson: Thank you. Sure, Aaron, why don't you go with the postcards? Sure. So what we've seen, what we saw in the non-human primate data with regard to inflammation, and non-human primates were not typically treated with any steroids. So we kind of saw the natural course of inflammation, and we got long-term follow-up in those non-human primates of up to 30 months. So we've seen that there was stable protein expression, but looking at the inflammation specifically, we see a peak early on, and it's in that range for around four to six months, which corresponds with kind of peak transduction, and thereafter we see a decline. So we would see markers of active inflammation, including cellular inflammation, at those earlier time points, and then, generally, we saw those markers decline, and we would potentially or sometimes some markers of chronic inflammation remain there, but not really any markers indicating active inflammation.

[noise].

Leonie Patterson: So it indicates that most of the inflammation is happening early, and the active inflammation is not something that continues, and that's in marked contrast to the protein expression, which goes up early and stays up, and that's why we think that the inflammation is related to the capsid protein, and the capsid material can take several months for that to be sort of washed out of the eye. In humans, we're treating them with topical steroids early on now, so that was one of the big reasons why we switched from oral steroids, which were 13 days, to steroid eye drops. Because we knew from the animals that that actually seemed to be the time of peak immune response, and we weren't covering a long enough period with the oral steroids.

Aaron Osborne: So I think what we've seen in cohorts one and two is we haven't seen any new clinically relevant inflammation episodes at the later time points, which again fits with the non-human primate data. So I think to kind of summarize it is the peak immune response is relatively early. In humans, we were treated with steroids.

Aaron Osborne: We're seeing, you know, most of the patients, if you look at cohort three, five of the six patients who had got to 12 weeks or beyond were not on any steroid eye drops. The other three, as well, had zero or next to zero cellular inflammation, so the steroid eye drops are controlling it well. I think that some patients may need those drops for a longer period of time. There are individual patient factors that influence how long and how severe that inflammation is.

Aaron Osborne: We don't fully understand all of these, but what we do know, based on the current data, is that steroid eye drops are sufficient to control them. And as we follow up the patients for longer, those markers of inflammation are coming down. We're being conservative with tapering off the steroid eye drops. The risks of being on steroid eye drops at a low frequency for a long period of time are very low.

[music].

Aaron Osborne: We prefer to do that rather than sometimes take patients off too early and have another episode of inflammation, which results in kind of restarting the drops and maybe going up in frequency to three or four times a day. So, yeah, it seems to decline over time, and it seems to be manageable with steroid eye drops. Great. So, and then the second question was around the Regeneron collaboration, which Adverum had been in a collaboration with Regeneron since 2014, and they had extended it one time, and this actually expired in May this year. And what that means is that there were a number of indications or targets that they had access to as a result of that collaboration. And there was one which was excellent written excuses was one of the indications was probably known, and there were three other undisclosed targets.

Leonie Patterson: And so, as a result of that, that opens up the opportunity for Adverum to explore those, which we see is actually a positive thing to enable us to actually think about what else we could be using this platform with using a capsule of 7M8 and potentially other indications that we could be going after. Thank you. Thank you. We are now at the end of the hour and have time for one more question. And that question comes from the line of Patrick Dolezal with Lifestyle Capital.

HM.

[music].

Operator: Hi everyone, this is Valentina on behalf of Patrick. Thanks for taking our questions. Just two from us...

Operator: Pardon me, Patrick, please check your mute button. Hello, can you hear me? Yes, yes. Okay. So, question on OPTIC, could you please check your mute button? Hi there, this is Operator. There is another person who has actually substituted for Patrick. Her name is Valentina, and Patrick is not on the line right now, but he's already been called by you. Adverum's President and CEO,

Leonie Patterson: So thanks, everybody. I think what we'll do, Valentina, is we'll be able to talk to you after the call. But let me finish up this call here. So I want to thank you all for joining us again today. It's been a remarkable year at Adverum so far, and more to come. And we expect to continue to execute and deliver on key catalysts, which include treating the fifth patients in our new Infinity Phase II trial and DME in the coming weeks, presenting OPSIG data for all four cohorts by the end of this year, and then advancing our preclinical gene therapies to broaden our pipeline opportunities. So stay tuned. In closing, our employees have demonstrated a strong commitment to driving our mission forward through their focus and dedication, as evidenced by having two clinical trials underway, including the Phase II Infinity DME trial.

Leonie Patterson: They truly make our progress possible and I am humbly grateful for our team. Thank you for your time, stay safe and healthy, and this concludes our call. Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may now disconnect. Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, [inaudible] © BF-WATCH TV 2021, [inaudible] Daniil Gataulin, Joon Lee, Laurent Fischer, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum Aydin Huseynov, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, © BF-WATCH TV 2021