Q4 2020 Adverum Biotechnologies Inc Earnings Call

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Good day.

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Operator: Good afternoon, and welcome to the Adverum Biotechnologies conference call. At this time, all participants are in the listen only mode.

Good afternoon, and welcome to the Asbury Biotechnologies Conference call.

At this time all participants are in a listen only mode.

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

Later, we will conduct a question and answer session. After the prepared remarks as a reminder, this conference call is being recorded I would now like to hand, the call over to my Asia Lacy, Vice President of Investor Relations and corporate communications of Advair them. Please go ahead.

Maisha Lacey: Thank you, Anastasia, and welcome, everyone. Today, we issued a press release to share our development planning for ADCM 022 for our wet age-related macular degeneration or wet AMD program, recent business progress, and our fourth quarter 2020 financial results. A copy of this announcement is available on the Press Releases page of the Investor Relations section of our corporate website, www.adverum.com. Please note that a replay of today's call will also be available on the events and presentations section of our website.

Thank you Anastasia and welcome everyone. Today, we issued a press release to share our development planning for a D. C. M O two two for wet age related.

Late at macular degeneration, or wet AMD program recent business progress and our fourth quarter 'twenty 'twenty financial result, a.

A copy of this announcement is available on the press releases page of the Investor Relations section of our corporate website www dot it for your own dotcom.

Please note that a replay of today's call will also be available on the events and presentation section of our website.

Maisha Lacey: Joining me today is Dr. Laurent Fischer, Chief Executive Officer; Leone Patterson, President and Chief Financial Officer; and Dr. Aaron Osborne, Chief Medical Officer. In addition, we are honored to have Dr. Arshad Kanani, who is an enroller in our OPTIC and INFINITY clinical trials, join us today. As a reminder, we will be making forward-looking statements that include our product development plans, research activities, and anticipated upcoming milestones and operations. These statements are subject to risk and uncertainty, which may cause actual results to differ materially from those forecasted.

Joining me today is doctor in Little Rock Fischer, Chief Executive Officer, Leoni, Patterson, President and Chief Financial Officer, Dr. Aaron Osborne Chief Medical Officer. In addition, we are honored to have Doctor are shot kind of any of the Sierra Eye Institute and an N roller in or.

Optic and Infinity clinical trials join us today.

As a reminder, we will be making forward looking statements, which include our product development plans research activities and anticipated upcoming milestones and operations. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those forecasts.

That's it.

Maisha Lacey: A description of these risks can be found under the Caption Risk Factors, described more fully in our quarterly report on Form 10-Q for the quarter ended September 30, 2020, and any subsequent filings with the FDC under the heading RISK FACTOR. Now, I will turn the call over to our CEO, Dr. Laurent Fischer. Thank you, Maisha. Good afternoon, everyone, and thank you for joining us today. I hope that everyone, including your family and friends, is staying safe and healthy.

A description of these risks can be found under the caption risk factors described more fully in our quarterly report on form 10-Q for the quarter ended Sept timber 30th 'twenty 'twenty and any subsequent filings with the FCC under the heading risk factors.

And now I will turn the call over to our C. E O doctors are Ron Fisher.

Okay.

Thank you Mike Good afternoon, everyone and thank you for joining us today I hope that everyone King your family and friends are staying safe and healthy.

Maisha Lacey: Before we begin, I'd like to personally thank Dr. Arshad Kanani for joining us today. We are very appreciative of his time, his deep expertise in the retina field, and his enthusiasm about the potential of our gene therapy product, ADDM022, as a new and differentiated treatment option for patients with wet AMD and DME. Dr. Kanani is incredibly dedicated to his patients and to advancing new treatment options that have the potential to improve real-world outcomes.

Before we begin I'd like to personally thank Dr. Arthur Tonight, he for joining us today.

I appreciate it force dawn his deep expertise in the red for Newfield and his enthusiasm about the potential of our gene therapy product <unk>, two other new and differentiated treatment option for patients with wet AMD and D. I b.

Toxic Konami is incredibly dedicated to these patients.

For advancing new treatment options that have the potential to improve real world outcomes.

Maisha Lacey: He's well known as an experienced investigator participating in many clinical trials. I also would like to thank all the patients, their families, and our investigators for continuing journal studies during this pandemic, which, as we know, is impacting this at-risk population of wet AMD patients we'll be talking about today. Adverum.

He is well known as an experienced investigator participating in many clinical trials.

So we'd like to thank all the patients their families and our investigators for continuing to run those studies during this pandemic, which as we know it is impacting this at risk population of wet AMD patients who will be talking about today.

Other than we are in a global mission to establish gene therapy as a onetime treatment that preserve patient sites for life.

Laurent Fischer: Global Mission to Establish Gene Therapy as a One-Time Treatment that Preserves Patient Sites for Life. We are gene therapy pioneers, and we believe that we're at the forefront of disrupting the inter-budget market with our novel vector platform technology, AD7MA. Our technology has the potential to dramatically alter the treatment paradigm for patients living with wet AMD and VME following a single in-office intravertebral injection, and we're keen to make it available to patients as efficiently and as soon as possible. Here's our agenda for today's virtual event.

We are gene therapy pioneers and we believe that we're at the forefront of disrupting day anti VEGF market.

With our novel vector platform technology, <unk> seven day mate.

Our technology has the potential to dramatically alter the treatment paradigm for patients living with wet AMD nvme. Following a single in office integral true on injection and we're keen to make it available to patients as efficiently and as soon as possible.

Here's our agenda for two days ago, we're talking about.

Laurent Fischer: First, I will share some opening comments about our recent progress across the business. Next, Aaron Osborne, our Chief Medical Officer, will provide details of our Global Phase III program for ADDM022. Then, Dr. Asha Kanani will share a video of one of these patients living with wet MD who took part in our optic study. She will highlight her personal journey and the impact of ADDMOQ2 on her life. Then I will have a fireside chat with Dr. Arshad Kanani. And finally, we'll take your questions.

First I will share some opening comments about our recent progress across the business.

Next Aaron Osborne, our Chief Medical Officer, who will provide details of our global phase III program for <unk> true.

Then Dr. Arthur Konami was for video of one of his patients living with wet AMD with took part in our optic study several highlights for a personal journey and the impact of <unk> on her life.

I will have the price starts out with Dr. <unk> Shah commodity and finally, we'll take your questions.

Laurent Fischer: So, I'm really excited to share today that we recently had a very collaborative meeting with the FDA and that, based on the feedback from the agency on both the clinical development pathway and the CMC requirements for our pivotal program, we now have a clear path to targeted BLA submission for ADDM022 in wet AMD in 2024. As a reminder, we enrolled the first patient in OPTIC in late 2018 and have since made great progress in advancing the development of our investigational gene therapy product.

So I'm really excited to share today that we recently had a very collaborative meeting with FDA and that based on the feedback from the agency on both the clinical development pathway.

For the CMC requirements for our pivotal program, we now have a clear path to targeted BLA submission for <unk> in wet AMD in 2024.

As a reminder, we enrolled the first patient in offtake in late 2018 and have since made great progress advancing the development of our investigational gene therapy products.

Laurent Fischer: In uptake to date, we have observed that a single IVT injection of O2-2 demonstrates robust treatment responses with long-term durability and a favorable safety profile in wet MD patients who require frequent IVF injections to maintain their vision.

And I'll take two day, we have observed that a single <unk> demonstrates robust treatment responses with long term durability and a favorable safety profile in wet AMD patients who required frequent anti VEGF injections to maintain their vision.

Laurent Fischer: Based on these positive results and the unmet need for a long-lasting treatment option, we propose an accelerated timeline to the FDA to deliver ADVM-022 to patients as quickly as we can. Now, let me share with you the outcome of our FDA interaction. Previously, you may recall that we were planning to conduct first a Phase IIb study with a 2E and 6E-11 dose, followed by a single Phase III study with one dose.

Based on these positive results and the unmet need for long lasting treatment option. We proposed an accelerated timeline to the FDA to deliver a DBM Q2 to patients as quickly as we can.

And now let me share with you the outcome of our FDA interaction.

Previously you may recall that we are planning to conduct for the phase III study with <unk> at 611 doses followed by single Phase III study with one dose.

Laurent Fischer: With regard to dose selection, given the impressive response and durability with 2E11 in this high-treatment-to-need population and the predictable and minimal steroid hydroxyprophylaxis, we have selected two doses that straddle the 2E11 to take into phase 3 in newly diagnosed wet AMD patients. We're now moving directly to two global phase three pivotal trials conducted in parallel that we plan to initiate in the fourth quarter of this year to support a B-Level submission in 2024. We also plan to have interactions with international regulatory agencies in the coming months.

With regards to dose selection given the impressive response and durability with 211 in this high treatment needs population and the predictable and minimal steroid eye drop prophylaxis. We have selected two doses that struggled the two year 11 to take into phase III in newly diagnosed wet AMD patients.

When I'm moving directly to two global phase III pivotal trials conducted in parallel that we plan to initiate in the fourth quarter of this year to support a BLA submission in 2024.

We also plan to have interactions with an international regulatory agencies in the coming months.

Laurent Fischer: These two-phase, three-trials will be randomized, mass-studied, and we will enroll a total of approximately 900 patients, comparing ADDM02-2 to a Flipper set. We will evaluate two doses of ADVM-022, 1E11 and 3E11. Importantly, we'll treat newly diagnosed patients in order to support a broad label in wet hands. Finally, we plan to evaluate the potential for bilateral treatment with ADVM-022 given the unmet medical need with up to one-third of patients developing bilateral disease. In a moment, Aaron will share additional details about our virtual program.

These two phase three trials will be randomized mass studies.

Enrolling a total of approximately 900 patients comparing <unk> to a flavor Seth.

Yeah.

We will evaluate two doses of <unk> two to 111 and 311.

Importantly, we will treat newly diagnosed patients in order to support a broad label in wet AMD.

Finally, we plan to evaluate the potential for bilateral treatment with <unk>, given the unmet medical need with up to one third of patients developing bilateral disease.

In a moment, Eric we will share additional details about our pivotal program.

Laurent Fischer: Now let's revisit why we're focusing on developing a novel approach for the treatment of patients with wet AMD. We have conducted extensive market research, and we've had frequent discussions with veteran specialists and patients. And our research has revealed that the largest unmet need for patients with wet AMD is for durable treatment that reduces the frequency of antivirgin injections for better efficacy, improved ease of administration, and better control of macular fluency. This is where ADDM-022 fits in to meeting those patients' needs.

Now, let's revisit why we are focusing on developing a novel approach for the treatment of patients with wet AMD.

We have conducted extensive market research and we have had frequent discussion with retinal specialists and patients.

And our research has revealed that the largest unmet need for patients with wet AMD as for durable treatment that reduces the frequency of any kind of a <unk> injections for better efficacy.

Improved ease of administration.

And better control of macular fluid.

This is where <unk> fits in to addressing those patients needs if.

If you look at the current treatment landscape as well as treatments in development, we see that some approaches or extending the duration between treatments are balanced by a magnitude of weeks.

Laurent Fischer: If you look at the current treatment landscape, as well as treatments and developments, we see that some approaches are expanding the duration between treatment intervals by a magnitude of weeks. But ADVM-022 is the only investigational, non-surgical treatment option that has demonstrated long-term durability for up to two years and is delivered as a single in-office IVT injection, and we plan to continue to follow patients in uptake for up to five years. We believe that ADVM-022 is uniquely positioned, unlike any other treatment on the market or in development, as an advanced gene therapy product with the potential to be a one and done approach for millions of people living with wet AMD globally.

But <unk> is the on the investing and debt investigational.

Investigational non surgical treatment option that has demonstrated long term durability out to two years and is delivered as a single in office IV teams action and.

And we plan to continued flow of patients in optic are two five years.

We believe that <unk> is uniquely positioned unlike any other treatments on the market or in development as an advanced gene therapy product with the potential to be a one and done approach for millions of people living with wet AMD globally.

If we look at the clinical profile of <unk>, two too, including the recently presented data in <unk> 2021 by Dr. <unk>, we strongly believe that <unk> has the potential to transform the treatment paradigm for patients living with wet AMD.

Laurent Fischer: If we look at the clinical profile of ADVM-022, including the recently presented data in Geogenesis 2021 by Dr. Kanani, we strongly believe that ADVM-022 has the potential to transform the treatment paradigm for patients living with wet AMD. Focusing on the 2E11 dose, you can see that two-thirds of the patients are injection-free for a follow-up of 68 weeks, and there's an 85% reduction in annualized Importantly, this dose has a favorable safety profile and is a predictable prophylactic steroid eyedrop regimen with no patients having any inflammation at the latest evaluation.

Focusing on the 211 dose you can see that two thirds of the patients are injection free true follow up of 60 weeks and there is an 85% reduction in annualized <unk> frequency.

Importantly, these doses a favorable safety profile and a predictable prophylactic steroid eye drop regimen with no patients having any inflammation at the latest evaluation.

With respect to the sixth 11 dose, we continue to see remarkable durability and anatomical responses.

And a favorable safety profile.

This dose is at the top of the response curve and is one that we continue to evaluate and DNA and plan to explore an additional indications of high unmet needs.

We will share more about this in the future.

Before I turn the call over to Erin I want to acknowledge that we continue to take precautions as a company to navigate the impact of COVID-19.

Laurent Fischer: With respect to the 6011 dose, we continue to see remarkable durability and anatomical responses and a favorable safety profile. This dose is at the top of the response curve and is one that we continue to evaluate in DME and plan to explore in additional indications of a high unmet need. We will share more about this in the future.

Optimistic to now have three approved vaccines and we hope to return to normal soon.

Despite the challenges there.

During this pandemic.

We were able to complete enrollment in our <unk> study in less than six months and to invest in our new GMP commercial manufacturing facility in Durham North Carolina.

I would now like to turn the call over to Aaron Aaron.

Thank you Laurel.

I Dunno Symbologist I've always believed that vision is our most important key.

Laurent Fischer: Before I turn the call over to Aaron, I want to acknowledge that we continue to take precautions as a company to navigate the impact of COVID-19. We are optimistic to now have three approved vaccines, and we hope to return to normal soon. Despite the challenges during this pandemic, we were able to complete enrollment in our INFINITY study in less than six months and invest in a new GNP commercial manufacturing facility in Durham, North Carolina. I would now like to turn the call over to Aaron. Okay?

And our daily lives unless it is being threats from this easy to forget just how essential good vision is to perform our day to day activities.

Turning my career I've been fortunate to be involved with many of the antibody development programs and I believe the progress that we've achieved with <unk> has been a significant advance in the field of treating wet AMD, we're excited to be initiating phase III trials and planning towards a 2020 for BLA submission.

Before going into further details on the planned phase III trials I want to share some key data points from the optic study that have informed the phase III study designs.

Aaron Osborne: Thank you, Laurent. As an ophthalmologist, I've always believed that vision is our most important key sense. In our daily lives, unless it is being threatened, it's easy to imagine just how essential good vision is to perform our day-to-day activities. Throughout my career, I've been fortunate to be involved with many anti-VEGF development programs, and I believe the progress that we have achieved with ADVM-022 has been a significant advance in the field of treating WEF-A and B.

Recall, the optic patient population represents a difficult to treat segment of the wet AMD patient population.

These patients in optic required frequent and regular anti VEGF injections prior to receiving <unk> in order to maintain that vision.

As you can see on this slide from the swim Lane plot before.

For <unk>. These patients had frequent injections, whilst afterwards following interdigital ADP MLP to the majority of patients most of the doses have remained entirely free of anti VEGF injections with a median of 48 week follow up.

Aaron Osborne: We're excited to be initiating Phase III trials and planning towards a 2024 BLA submission. Before going into further details on the planned Phase 3 trials, I want to share some key data points from the OPTIC study that have informed the design of the Phase 3 study. Recall, the optic patient population represents a difficult-to-treat segment of the wet AMD patient population. These patients in the optic zone required frequent and regular anti-VEGF injections prior to receiving ADVM-022 in order to maintain their vision.

There has also been a substantial reduction in injection frequency following 80 P M to two with both doses.

60, 11th dose, we observed a 99% reduction in annualized anti VEGF injection frequency while stopped the TUI 11 dose we saw an 85% reduction.

As for safety.

<unk> two has been well tolerated with a favorable safety profile for both doses evaluated.

Overall, ATM OTT related aes were mild to moderate with no severe and no non ocular <unk> related aes.

Aaron Osborne: As you can see on this slide from the swim lane plot, before ADVM-022, these patients had frequent injections, whilst afterwards, following intravitreal ADVM-022, the majority of patients at both of the doses have remained entirely free of anti-VEGF injections with a median of 48 weeks of follow-up. There has also been a substantial reduction in injection frequency following ADDM-022 with both doses. At the 6E11 dose, we observed a 99% reduction in annualized anti-VEGF injection frequency, whilst at the 2E11 dose, we saw an 85% reduction.

Okay. Their inflammation has been managed with steroid eye drops at both doses with no evidence of posterior retinal inflammation.

Whilst average cellular inflammation has been low grade with both doses the husband minimal cellular activity and minimal steroid eyedrop piece after a six week prophylaxis regimen with the two year lesson dose.

The most recent data that we share with the FDA during our recent interaction shows that no patients receiving 211 in uptick at the latest time point have any cellular inflammation.

With the 211 dose in this Arctic population that previously required frequent anti VEGF injections.

Cross cohorts, two and three we have seen sustained and stable anatomic improvement with stable vision.

Aaron Osborne: [inaudible] ADVM-022 has been well tolerated with a favorable safety profile for both doses evaluated. Overall, ADVM-022 related AEs were mild to moderate with no severe and no non-ocular ADVM-022 related AEs. Ocular inflammation has been managed with steroid eye drops at both doses with no evidence of posterior retinal inflammation.

The phase III studies will enroll newly diagnosed patients with wet AMD study sites around the world.

The study designs and population will be similar to other treatment naive interpret true phase III studies in wet AMD and they are expected to support a broad treatment label.

Specifically, we will include both cyclic and cheetah facing patients and we will not exclude patients based on baseline serum neutralizing antibodies to AAV.

Aaron Osborne: Whilst average cellular inflammation has been low grade with both doses, there has been minimal cellular activity and minimal steroid eyedrop use after a six week prophylaxis regimen with the 2E11 dose. The most recent data that we shared with the FDA during our recent interaction showed that no patients receiving 2E11 in OPTIC at the latest time point had any cellular inflammation at the 2E11 dose in this optic population that previously required frequent anti-VEGF injections.

And these trials approximately 900 patients will be randomized to receive a single IV injection of 311 or 111 of <unk> or <unk> every eight weeks.

Similar to uptake patients receiving <unk> will receive a two month prophylactic steroid eye drop regimen.

The primary endpoint will be non inferiority with fitness apps based on change from baseline in best corrected visual acuity at one year.

Secondary endpoints will include safety and Tolerability any need for supplemental anti VEGF injections per se DBM OTT and change from baseline in central retinal thickness and other anatomical parameters as assessed by optical coherence tomography.

Aaron Osborne: Across Cohorts 2 and 3, we have seen sustained and stable anatomic improvements with stable vision. The phase three studies will enroll newly diagnosed patients with WET-AMD at study sites around the world. The study designs and population will be similar to other treatment-naive, intravitreal phase three studies in WET-AMD, and they are expected to support a broad treatment label. Specifically, we will include both phakic and pseudophakic patients, and we will not exclude patients based on baseline serum neutralizing antibodies to AAD.

Supplemental injection criteria will be similar to uptick and based on vision and anatomic changes.

We are now working with our investigators and regulators in the U S and around the world to finalize the study protocols and preparing for study initiation in Q4.

We have had tremendous investigator interest and uptick in infinity and given the transformative potential of our in office investigational gene therapy, we look forward to working with trial sites to rapidly enroll these studies.

Before I turn the call out if I could talk for Konami I want to share our future plans focusing on ABB M O G suite.

Aaron Osborne: In these trials, approximately 900 patients will be randomized to receive a single IVT injection of 3E11 or 1E11 of ADVM022, or Aflidacept, every eight weeks. Similar to OPTIC, patients receiving ADVM-022 will receive a two-month prophylactic steroid eyedrop regimen.

They don't take patients who complete the two year study are now being enrolled interest three year extension study. So these patients will be followed for a total of five years.

We plan to present further data from optic in the second quarter of this year.

These data will include longer term outcomes importantly, one year's icon from cohort three.

The infinity studying in diabetic macular edema is also progressing well after completing patient enrollment earlier. This year, we plan to present primary endpoint data from this randomized controlled study at a medical conference in the second half of the year.

Aaron Osborne: The primary endpoint will be non-inferiority to silicept based on change from baseline in best corrected visual acuity at one year. Secondary endpoints will include safety and tolerability, any need for supplemental anti-VEGF injections post-ADVM022, and change from baseline in central retinal thickness and other anatomical parameters as assessed by optical coherence tomography. Supplemental injection criteria will be similar to optics and based on vision and anatomic changes. We are now working with our investigators and regulators in the US and around the world to finalize the study protocols and prepare for study initiation in Q4. We have had tremendous investigator interest in OPTIC and INFINITY.

So we are very pleased by the progress we have made in advancing a single IV injection of gene therapy for patients who are living with wet AMD and diabetic retinopathy.

We have additional platform programs that are advancing as well providing future opportunities for clinical development.

I will now turn over the call to Dr. <unk> for Fireside chat with loan after we see a video of one of his patients sharing their experience living with wet AMD before and after <unk> as they.

Weighted in the optic trial.

This is an inspiring video that provides the patient perspective, but before we share the video I need to remind you that our steam legal counsel insist that we include a disclaimer about this video which is a single patient testimonial.

Aaron Osborne: And given the transformative potential of our in-office investigational gene therapy, we look forward to working with trial sites to rapidly enroll these studies. Before I turn the call over to Dr. Kanani, I want to share our future plans focusing on ADVM-022. In OPTIC, patients who complete this two-year study are now being enrolled in a three-year extension study, so these patients will be followed for a total of five years. We plan to present further data from OPTIC in the second quarter of this year.

Whilst this patient on the majority of patients in optic I've remained supplemental anti VEGF injection free other stuff now and obviously, we don't want to extrapolate these results to our therapies potential as a treatment option for the millions of patients living with wet AMD.

And sharing this video we hope to bring the patient journey clearly into the picture patients who are at the center of everything we do it out there and this is why we are developing what we believe is a potentially transformative therapy.

Aaron Osborne: And these data will include longer-term outcomes, importantly, one year data from cohort three. The INFINITY study in diabetic macular edema is also progressing well.

Let's play the video.

Yeah.

Thank you again for participating in the interest until gene therapy program.

Aaron Osborne: After completing patient enrollment earlier this year, we plan to present primary endpoint data from this randomized controlled study at a medical conference in the second half of the year. We are very pleased by the progress we have made in advancing our single IVT injection gene therapy for patients who are living with WET-AMD and diabetic retinopathy. We have additional platform programs that are advancing as well, providing future opportunities for clinical development. I will now turn over the call to Dr. Kanani for a fireside chat with Laurent after we see a video of one of his patients sharing their experience living with WET-AMD before and after ADVM-022 as they participated in the OPTIC trial.

So excited to have years of patients tell us about.

How it was like before you got into the <unk>.

Graham.

New treatment.

Oh, yes.

It was terrible because it happened so fast and all of a sudden I just couldn't see.

I start to come in here of course day Chutney every year.

And I had to start having shops.

For the six weeks.

That was.

And I, just I didn't see him.

<unk> continued to see it getting worse in my profession, that's not something that I can do I don't know holistic institution, so I need to zero in on.

So this went on for almost a year and saw that I was a good candidate for the gene therapy.

It's been a blessing from heaven.

Results I'm, so impressed day.

I can see so much better I don't think you know.

Kitchen kept keep an.

And I out for my other IL two in case something happened with that.

It's just been the best year ever.

I'm excited and every month.

From an industry, though.

That's not so nice of you and we're lucky to have you as a patient and I would tell you even with getting to a shot every month as you mentioned and Youre actually getting worse.

And with this gene therapy are actually improved significantly.

Your scans of normal now.

Aaron Osborne: This is an inspiring video that provides a patient perspective, but before we share the video, I need to remind you that our esteemed legal counsel insists that we include a disclaimer about this video, which is a single patient's testimonial. Whilst this patient and the majority of patients in OPTIG have remained supplemental anti-VEGF injection-free, others have not, and obviously, we don't want to extrapolate these results to our therapy's potential as a treatment option for the millions of patients living with wet AMD.

Of course, you have some scarring definitely revisit it not perfect, but it has improved quite a bit and as you know you need that vision for your profession, So and tell US you were on drops initially was that a big deal taking drops when you started this treatment and I know you had in little flare up I need to draw for a few more Lee is that I have.

So let all day not at all because even in your other programs.

Your eyes for dry that Youre doing net six 810 times a day. So it's just a different colored vinyl that's good I've never heard of that yeah, we'll dig dropped in this area because there is there a total dry.

There is the branded prescription meds or just theaters and Youre right. Most of my patients day for Essex.

A day so so it sounds like drops are not.

Not at all not at all in fact, I, just I didn't I thought it would be more complicated and I didn't realize you only have one shot at the beginning and that was the gene therapy for.

Operator: In sharing this video, we hope to bring the patient journey clearly into the picture. Patients are at the center of everything we do at Adverum, and this is why we are developing what we believe is a potentially transformative therapy.

And having those other ones and having to be non didn't happen to be.

Oh, the tea afterwards.

It was not fun.

I tell everybody on camera about it because my mother about this time he works he habit out of six kids I'm. The only one that has it.

Macular.

She went well and he was fine for 25 years from that when that hit me I just thought Oh, My God I can't be blind.

Patient: Thank you again for participating in the Intravitreal Gene Therapy Program. We are so excited to have you as a patient. Tell us about how it was before you got into the program with this new treatment. Oh, it was terrible because it happened so fast, and all of a sudden, I just couldn't see.

I'll, probably live to 100, and what have you again read macula. Another I've would you take this free mobile app.

Absolutely I think I have baseline now, but that's what I say you take such good care of any debt you're always watching that other IL two and as fast as my last I changed.

That's exciting because then we can do something last question I have is tell me. When you were getting injections is just irritation is it anxiety, what's about injections. It's a hassle that you really don't want them.

Patient: So I started coming here, and of course, they checked me every year, and I had to start having shots in the eye. That was a... And I just, I didn't see the... I just continue to see it getting worse, and in my profession, that's not something that I can do. I'm a holistic esthetician, so I need to do something about it. Zero in on people's faces.

I don't get anxiety.

But it was just knowing that I had.

<unk>.

I would have to be patched it was time consuming but the pain at night.

After that start wearing off.

This would have to go to bad debt.

Irritation for Memorial day.

I am moving and so forth I'm, just sort of bad So you know and hear you don't have.

Patient: So this went on for almost a year, and they found that I was a good candidate for the gene therapy. And honestly, it's been a blessing from heaven. The results are so impressive. I can see so much better. I don't, you know, and you can't catch it.

And you can go work right away.

Right that's exactly right you missed the <unk> zone.

Okay. So for.

First of all Dr. Kulkarni welcome and thank you for starting new patients experience with us it's very clear to me that youre incredibly connected with your patients as they rely on your expertise to manage their disease I think in a few slides that you'd like to share with us showing us how your patient responded to it at the end of Q2 would you.

Patient: He keeps an eye out for my other eye too, in case something happens with that. It has just been the best. Every month I see tremendous progress. Oh, that's so nice of you. And you know, they're lucky to have you as a patient. And I tell you, even with getting those shots every month, as you mentioned, you're actually getting worse. And with this gene therapy, you're actually improved significantly; your scans look normal now. Of course, you have some scarring, that's why your vision is not perfect, but it has improved quite a bit. And, as you know, you need that vision for your profession. So and tell us you were on drops initially.

Sure a few comments around it like that.

Thanks, Laura and thanks for having me here really this video is so powerful and sole motivating I have to take a deep breath every time I listen to it and look at it because this is why we are doing what we are doing we are here to transform the lives of patients that we see on a daily basis.

Who are struggling with this disease.

The treatment burden the uncontrolled nature of disease, even with frequent injections and then having them an opportunity to live their lives.

Patient: Was it a big deal taking drops when you started this treatment? And I know you had a little flare-up, and you took drops for a few more weeks. Is that a hassle at all?

And continue with their their activities on a daily basis, So I am excited.

To be a part of this trial and obviously the prospect of this therapy going forward I do have.

Patient: Oh, not at all. Because even in your other programs, you know, your eyes are so dry that you're doing this 6, 8, 10 times a day, so it's just a different colored bottle. Oh, that's good. I've never heard of that.

The slides here if I can move to it. So this is the slide for this patient. So as you know we discussed during the video this patient who had persistent disease activity. So on the left you can see prior to <unk> or due to that's in OCD. There you can see.

Patient: So yeah, people take drops in this area because their eyes are so dry, whether it's the branded prescription meds or just tears, and you're right; most of my patients take them four or six times a day. So it sounds like drops are not a big deal. Oh, not at all, not at all.

Those black cystic changes in the retina and she does have some scarring underneath and that's why our vision is not perfect, but even with frequent injections on a monthly basis.

For disease was not control and as you know as physicians, we treat patients based on OTT.

Patient: And I didn't realize you only get one shot at the beginning, and that's the gene therapy. I mean, versus having those other ones and having to be numbed and having to, Oh, the pain afterward. It was not fun.

And because of my early positive experience I offered her the optic trial you can see our baseline visual acuity was 63 letters.

Patient: I just, I tell everybody I can because my mother, about this time she went, she had it. Out of six kids, I'm the only one that has it. Macular, and you know she went blind. She was blind for 25 years, and when that hit me, I just thought, oh my god. I can't be blind. You know cuz I'll probably live to 100. And what if you get red macular in the other eye? Would you take this treatment?

And after a single in office injection of the low dose to <unk> 11.

Can see how she looks like now I just saw her.

A few weeks ago and you can see 68 weeks after a single injection.

You can see there is no disease activity. There is no fluid and she has not required supplemental a flipper set of injections for this time period. So that's why patients are excited that's why physicians are excited and that's why my colleagues that see this data and see the power of this drug are.

Patient: Oh, absolutely. I think I have a baseline now, but that's what I say. You take such good care of me that you're always watching that other eye too, and as fast as my left eye changed. That's exciting, because then we can do something. The last question I have is, tell me when you were getting injections, is it just irritation, is it anxiety, what's with injections, is it a hassle, that you really don't want them? I don't; I don't get anxiety.

Excited about it let's go to the next slide.

Most of US have seen this case before we have presented it.

Many meetings, including the latest angiogenesis meeting, but this is another patient from mine and I think this case highlight two things number one the station was not control with for.

For the five weeks of flip our self injection. So you can see the CST fluctuations at the bottom where the disease is not control in the retina is getting dry and wet and dry and what you can see there is fluctuations and we know now based on data from <unk> and island trial as well as the Hawk and Harrier.

Patient: But it was just knowing that I'd have, you know, I'd have to be patched. It was time-consuming. But the pain at night was, After that started wearing off, I just would have to go to bed.

<unk> the patients who have fluctuations in their CST actually do poorly long term as in terms of visual acuity. So when I look at this treatment not only look at having a single in office injection that can essentially.

Patient: Yeah, just irritation from all the drops we put on you. Irritation from the eye moving and so forth. I'd just go to bed.

Patient: So, you know. And here you don't have to worry about that. You can go to work right away.

Patient: That's exactly right. That's exactly right. You're missing my pretty eyes.

Modify and control the disease for long term in majority of patients, but I also look at this treatment as being transformative because we can have patients who will lose vision with regular frequent anti VEGF injections and you can control their disease, because we're getting such steady.

Laurent Fischer: Okay, so first of all, Dr. Kanani, welcome, and thank you for sharing your patients' experience with us. It's very clear to me that you're incredibly connected with your patients as they rely on your expertise to manage their disease. I think you have a few slides that you'd like to share with us showing us how your patient responded to ADDM02.2. Would you share a few comments with us around these slides, please? Thanks, Laurent, and thanks for having me here. Really, this video is so powerful and so motivating. I have to take a deep breath every time I listen to it or look at it because this is why we are doing what we are doing.

Levels of liver sought for.

From a single in office injections. So you can see on the left <unk> had persistent fluid in the OCD and then after a single in office injection patient has done really really well you can see.

The BC VA has increased significantly to 83 letters and the OCD continues to be dry.

At 48 weeks after the treatment. So it really lined my goal here is to share my excitement in the patient excitement with you today and I am thrilled to hear that the programs are moving forward at a very rapid pace happy to take any questions you have.

Arshad Kanani: We are here to transform the lives of patients that we see on a daily basis who are struggling with this disease, the treatment burden, the uncontrolled nature of the disease, even with frequent injections, and then giving them an opportunity to live their lives and continue with their activities on a daily basis. So I am excited to be a part of this trial and, obviously, the prospect of this therapy going forward. I do have the slides here, so if I can move to them,

Great. Thank you so much Dr to come out here really appreciate that color on this basin.

You mentioned the potential to be treated in her other eye what percentage of patients develop bilateral wet AMD over time and would you consider injecting the second tier without Youtube.

Absolutely Laura.

The efficacy we have seen.

Arshad Kanani: So this is the slide for this patient. As you know, we discussed during the video, this patient who had persistent disease activity. So on the left, you can see prior to ADVM 022, that's an OCT where you can see those black cystic changes in the retina, and she does have some scarring underneath, and that's why her vision is not perfect. But even with frequent injections on a monthly basis, her disease was not controlled.

With Adv of motive to a single injection has been so potent that patients in the trial are asking for obviously this patient does not have bilateral disease at this point, but we know the risk of that is 10% per year. So most of my patients eventually will have bilateral disease, but the current patients who are.

In the trial actually are asking for it you know.

Talk about coincidence I just saw a patient who finished one year in the trial and I asked her how our experience has been and she's like has been fantastic, but my problem is youre not giving this treatment and my fellow eye and I still have to get those injections and when can I get debt treatment and my fellow Iron I said.

Arshad Kanani: And as you know, as physicians, we treat patients based on OCT. And because of my early positive experience, I offered her the optic trial. You can see her baseline visual acuity was 63 letters, and after a single in-office injection of the low-dose 2E11. You can see how she looks now. I just saw her, you know, a few weeks ago.

In clinical trials, we've put it the treatment in one eye, but obviously the potential for having treatment in the fellow eye is is there. So absolutely I think all of my patients in the trial, who have fellow eye disease will be more than happy to receive it in their second I.

Arshad Kanani: And you can see 68 weeks after a single injection. You can see there's no disease activity, there is no fluid, and she has not required supplemental flipper subinjection for this time period. So that's why patients are excited. That's why physicians are excited. And that's why my colleagues that see this data and see the power of this drug are excited about it. Let's go to the next slide.

Thank you Dr Economic and obviously as you recall, we did a non HD studies showing that you could do that safely at the peak of immune response and see its still very.

Hey, good protein expression levels. So we're planning to look into that potential too.

Let's look at bi lateral studies in the future.

And that's very exciting to hear that you presented the latest optic data. The angiogenesis meeting can you tell me how that data was received by your colleagues.

Arshad Kanani: Most of us have seen this case before. We have presented it at many meetings, including the latest angiogenesis meeting. But this is another patient of mine, and I think this case highlights two things.

Absolutely. So you know we had a live presentation. It was not a prerecorded and and you saw doctor favorable themselves in a raising the question that interdigital approach, obviously is more favorable than other approaches that we have seen and my colleagues I think the number.

Arshad Kanani: Number one, this patient was not controlled with four to five weeks of liver sap injection. So you can see those CST fluctuations at the bottom where the disease is not controlled, and the retina is getting dry and wet and dry and wet. And you can see there are fluctuations.

One thing is the fact that you can deliver this.

In an office setting like a routine intra virtual injection and that procedure is all of us around the world can deliver it without having any special.

Arshad Kanani: And we know now, based on data from the CAC and Ivan trials, as well as the Hawk and Harrier study, that the patients who have fluctuations in their CST actually do poorly long term, as in terms of visual acuity. So, when I look at this treatment, I not only look at having a single in-office injection that can essentially modify and control the disease for the long term and the majority of patients, but I also look at this treatment as being transformative because we can have patients who will lose vision with regular, frequent anti-VEGF injections.

Skills that are needed. So my partner, who is actually regarding soon said why would anybody look at any other.

Motive delivery and my answer was the same I gave it to Dr. Rosenfeld debt I think we are still learning about gene therapy, obviously interim vitriol is the preferred approach because we can treat patients around the world for this chronic disease and really the efficacy when they look at that case I think the <unk>.

Efficacy is phenomenal I get so many tax every time I present that case like Howard how does the patient doing now how is the patient doing now and I think what we are all impressed with not only the control of disease.

Arshad Kanani: And we can control their disease because we are getting such steady levels of liver sap from a single in-office injection. So, you can see on the left patient that there was persistent fluid in the OCTs. And then after a single in-office injection, the patient has done really, really well. You can see the BCVA has increased significantly to 83 letters, and the OCT continues to be dry at 48 weeks after the treatment. So, really, my goal here is to share my excitement and the patient's excitement with you today. And I am thrilled to hear that the programs are moving forward at a very rapid pace. I'm happy to take any questions you have. Great.

Italy, but continued control of disease throughout the patient course, and that patient is still on the trial and doing really really well. So I think the power of a single in office injection the easy delivery and then the continuous efficacy that we see with this.

Our approach has been very impressive and you know my colleagues of deletions or like do you want to be involved in the next trial do you want to be part of this because we feel like there is value to it is not an incremental benefit is really game changing in terms of transforming how we do how we manage patients with this life long disease.

So I think the excitement is.

Laurent Fischer: Thank you so much, Dr. Kanani. I really appreciate that color on this patient. You mentioned the potential to be treated in her other eye. What percent of patients develop bilateral wet AMD over time? And would you consider injecting the second eye with O2? Absolutely, Laurent, the efficacy we have seen with ADVM02 after a single injection has been so potent that patients in the trial are asking. So, obviously, this patient does not have bilateral disease at this point, but we know the risk of that is 10% per year.

<unk> is clearly there when I talked to my colleagues.

The business is great to hear and so in terms of patient enrollment. If you compare you know just 900 patient trial to other trials that would be required surgery can you talk about enrolled.

Enrolling patients in this study do you anticipate any hurdles.

Let's talk about previous trials like for us above and other inhibitor trials enrolled.

Well actually over 1000 patients in a short time, how do you see that.

Growing.

Okay.

Yeah, that's always a good question right how is the trial going to recruit so because of the exciting data. We have I think investigators with research arms and top sites in the World are then it will be of course excited about this trial and then the next question is competitive landscape for trials and and.

Laurent Fischer: So, most of my patients eventually will have bilateral disease, but the current patients who are in the trial are actually asking for it. You know, talk about coincidence, I just saw a patient who had finished one year in the trial, and I asked her how her experience had been, and she said, "It's been fantastic, but my problem is you're not giving this treatment in my other eye, and I still have to get those injections." And when can I get the treatment in my other eye?

We were the top site for the Tonight.

<unk> of Bristol Myers, we were out of the top site for the Dazzle trial for Ksi 301, and I can tell you that we enroll those large trials as a community as the retina space within less than 12 months and those especially the Tonight study. As you mentioned is is very very large so not having it.

Arshad Kanani: And I said, you know, in clinical trials, we put the treatment in one eye, but obviously, the potential for having treatment in the fellow eye is there. So, absolutely, I think all of my patients in the trial who have fellow eye disease will be more than happy to receive it in their second eye. Thank you, Dr. Konami.

Other competitors competitive trial for naive patients having this solid data from optic trial, I think theres going to be excitement and I think all of us will want to take participate in this study and I can confidently say based on my experience as being a top site in <unk>.

Many of the naive AMD trial that we should be able to recruit the trial.

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

In a one year or less and I think it's all going to be very good for our patients. The sooner. We have this treatment for patients for sooner. We can help patients around the world who are suffering from this chronic disease.

Obviously, we're very excited to partner with you to enroll these studies as soon as we can start and I look forward to also doing that globally, we talked about different bellevue delivery methods for gene therapy and either.

Program development can you walk us through what it's like to do a surgical procedure for sub retinal injection compared to an IV injection.

Arshad Kanani: So, you know, we had a live presentation. It was not pre-recorded, and you saw Dr. Phil Rosenfeld, raising the question that the intravital approach obviously is more favorable than other approaches that we have seen. And, you know, my colleagues, I think the number one thing is the fact that you can deliver this in an office setting, like a routine intravital injection. And that procedure, all of us around the world can deliver it without having any special skills that are needed. So my partner, who is actually retiring soon, said, why would anybody look at any other, you know, mode of delivery? And my answer was the same.

Yes, so as I mentioned.

It's our job as researchers and clinicians to look at different delivery options and different treatment options for patients and then look at.

Efficacy.

Those approaches so as you know I'm also a an investigator in our Pi for.

Region expires sub retinal delivery as well as the G. P 005 for dry AMD that gyroscope as all of them RPI for supercritical approach. Your question about sub retinal delivery, obviously is something that after you have experience.

Can you can perform that procedure, but obviously going to or is a bigger hurdle than delivering something in an office. So let's say I see a patient today and I do the screening for them and then if everything looks good I can bring them to clinic and randomized in a trial, whereas if I have a patient that needs to go to the old.

Arshad Kanani: I told Dr. Rosenfeld that I think we're still learning about gene therapy. Obviously, intravital is the preferred approach because we can treat patients around the world for this chronic disease. And really, the efficacy, when they look at that case, I think the efficacy is phenomenal. I get so many texts.

Or we have to have our staff coordinate that patients need to you know be ready they have to go for a pre up they have to see.

Arshad Kanani: Every time I present that case, they're like, "How is the patient doing now?". How is the patient doing now? And I think what we are all impressed with, not only the control of disease, you know, initially, but continued control of disease throughout the patient's course, and the patient is still in the trial and doing really, really well. So, I think the power of a single in office injection, the easy delivery, and then the continuous efficacy that we see with this approach has been very impressive. And, and, and, you know, my colleagues who do research, they're like, we want to be involved in the next trial. We want to be part of this because we feel like there is value in it.

Pay off their anti coagulant and that's just not you know sub retinal gene therapy. I'm also we were one of the top sides for the port delivery system, which is a surgical trial too. So obviously arranging an end and having patients go to surgery is a much bigger task.

On my coordinators and staff and then you know when you're in surgery. Obviously the companies want to you know make sure everything is done right. So they have to coordinate their schedules to be available for <unk>. So yes, it's doable, it's not a problem, but obviously anything in clinic.

Whether it's intra vitriol or supercritical is.

Easier, but obviously as you know the Super Gorilla studies are going on and we don't have any data yet and that's a specialized procedure, meaning that basically people around the world are not used to doing it and they will need to be trained on it.

Arshad Kanani: It's not an incremental benefit. It's really game changing in terms of transforming how we manage patients with this lifelong disease. So, I think the excitement excitement is clearly there when I talk to my colleagues.

This is Greg I'm always surprised to see how many studies youre involved with on top of all the pace of new here, it's really great to have you as an investigator in our trial.

Laurent Fischer: This is great to hear. And so, in terms of patient enrollment, if you compare this 900 patient trial to other trials that may require surgery, can you talk about enrolling patients in this study? Do you anticipate any hurdles? Let's talk about previous trials, like for FERSIMAB and other antibiotic trials that involve actually over a thousand patients in a short time. How do you see that going? Yeah, that's always a good question, right?

Talking a little bit about kind of current standard of care versus the future, we know that real world kind of.

Real World data that agree with clinical trial, how do you see that their treatment paradigm shifting from described in our regular injections in follow up to potentially something that <unk> could bring as an option.

Yes, that's.

That's what I am after I wanted to make sure that my patients do well long term, we see these patients they get treatment. They do fine in the first year things start to slip in the second year and then you look at for a five six or seven years. You know we have cat seven year data via a <unk> study. These patients end up being really poor vision long term and of course treatment burden.

Arshad Kanani: How is the trial going to recruit? So because of the exciting data we have, I think investigators with research arms and top sites in the world are going to be, of course, excited about this trial. And then the next question is the competitive landscape for trials. And, you know, we were the top site for the Tenaya study of barista map. We are the top site for the DAZL trial for KSI 3.0.1.

Is the biggest issue and your comment about I'm involved with everything because I'm involved with everything because I cannot make life better for my patients and now.

Now we are I am serving as the pie for almost 60 clinical trials and this is an exciting time for our space, but when you look at our space you have to divide our treatment options into two buckets you have to divide treatment, where you can do an intramuscular injection and be incrementally better in terms of durability. So you can.

Arshad Kanani: And I can tell you that we enrolled those large trials as a community in the retina space within less than 12 months. And those, especially the Tenaya study, as you mentioned, are very, very large. So not having another competitive trial for naive patients, having this solid data from the optic trial, I think there's going to be excitement. And I think all of us will want to participate in this study. And I can confidently say, based on my experience being a top site in many naive AMD trials, that we should be able to recruit this trial within one year or less.

Add a month or two months from three months on top of what we have and that's great for patients and you know things like for S. A mab and Ksi 301, GB one or two of those programs are moving forward and that's the really exciting, but then the other parties sustained delivery the continuous delivery, which can lead to the disease control, which is very.

Difficult to achieve an <unk> injection and that you saw in my case that I presented so when you look at that that is the paradigm shift that is happening obviously for delivery system has started that but it's a surgical procedure in the ore. So it has.

Arshad Kanani: And I think it's all going to be very good for our patients. The sooner we have this treatment for our patients, the sooner we can help patients around the world who are suffering from this chronic disease. Obviously, we're very excited to partner with you to end all these studies as soon as we can start and look forward to also doing that globally. We talked about different delivery methods for gene therapy and, you know, improvement and development. Can you walk us through what it's like to do a surgical procedure for a subjectal injection compared to an IVT injection?

Its own you know risk and benefits and it's not really a primary treatment, but what I see is I see or two too as a primary treatment for these patients. After we have control of their disease of course, the trial with naive patients will give us more idea, but if I see a patient in my clinic that have naive disease I'll do an interim you Julien.

Jackson, obviously, and then get them primed up to go into.

We're receiving gene therapy for all true too. So I think it's a chronic disease with for a long term outcomes and treatment burden can easily be a reverse for this this approach you saw the case I presented both of those cases and these are real patients that have really benefited from this approach.

Laurent Fischer: Yes, so as I mentioned, Laurent, it's our job as researchers and clinicians to look at different delivery options and different treatment options for our patients and then look at, you know, the efficacy of those approaches. So, as you know, I'm also an investigator and a principal investigator for Regenexx Bio subretinal delivery, as well as GT005 for dry AMD gyroscope, as well as I'm Your question about subretinal delivery is obviously something that, after you have experience, you can perform that procedure. But obviously, going to the OR is a bigger hurdle than delivering something in an office.

Thank you ever so there was really a great clear explanation about the potential future treatments for wet AMD and any thought on the global impact that's going to have when you're thinking about availability of anti VEGF at a global level, particularly nvme.

I think it's going to be used both in my opinion, Neovascular, AMD and and D&B I mean, you see around the oral abuse you look at our you know.

India you look at Mexico, you look at Africa I mean.

They don't have resources and they don't have the manpower to deliver.

You know continued monthly or every other month injection here, we can modify these lifelong chronic diseases with a single injection and obviously you have to initially monitor these patients and as Aaron said I mean, you know this is not a continuous.

A process I think once a day they have finished their topical drops in their control then tele medicine would be huge tele medicine has really exploded because of COVID-19, and anybody can monitor these patients afterwards, so I think after the initial dosing day monitor, but then after that I mean, I'm not looking forward to seeing these pay.

Arshad Kanani: So, let's say I see a patient today, and I do the screening for them, and then if everything looks good, I can bring them to clinic and randomize them into a trial. On the other hand, if I have a patient that needs to go to the OR, we have to have our staff coordinate that patients need to be ready. They have to go for a pre-op.

Every month or every other month, maybe every six months.

They want to come in so think about patients waiting for treatment around the world because they don't have access you have won and done a therapy, that's going to really help the patients and physician be able to treat more patients.

Arshad Kanani: They have to stay off their anticoagulants, and that's just not subretinal gene therapy. We were one of the top sites for the port delivery system, which is a surgical trial too. But obviously, arranging and having patients go to surgery is a much bigger task for my coordinators and staff. And then, when you are in surgery, obviously, the companies wanna make sure everything is done right. So, they have to coordinate their schedules to be available for surgery. So, yes, it's doable. It's not a problem.

Because they don't have to treat them continuously. So I think this is gonna be huge if efficacy continues to be.

As good as we have seen an uptick and then the manageable safety.

Ben It's Greg. Thank you so much from the commodity I want to take advantage of you being here to actually have some of our audience to ask questions. So maybe we'll open the call for questions and then I'll I'll direct pattern. So operator, if you can open the call for questions.

Arshad Kanani: But obviously, anything in clinic, whether it's intravitreal or supracordial, is easier, but obviously, as you know, the supracordial studies are going on, and we don't have any data yet. And that's a specialized procedure, meaning that people around the world are not used to doing it, and they'll need to be trained on. This is great.

Certainly.

We will now begin the question and answer session to join the question queue. You May Press Star then one on your telephone keypad, you will hear a tone acknowledging your request. If you are using a speakerphone. Please pick up your handset before pressing any keys to withdraw your question. Please press Star then two.

We will pause for a moment as callers join the queue.

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

The first question comes from Graig <unk> with Goldman Sachs. Please go ahead.

Yeah. Thanks, Thanks, very much and the Dr. Connie and team. Thanks for for during the call. This question is for Dr. Connie that's great to hear from you again, just wanted to get your thoughts on the company's strategy of moving to a different dose than what was evaluated in the optic study.

And more specifically.

With the lower dose in the higher dose of one and three what do you expect to see from those two doses and perhaps more importantly, what.

Arshad Kanani: I want to make sure that my patients do well long term. We see these patients, they get treatment, they do fine in the first year, things start to slip in the second year. And then you look at four or five, six or seven years. We have cat seven-year data, we have seven-up study. These patients end up with really poor vision long term.

What do you need.

Need to see from those two doses to feel comfortable with them with the profile that you've seen thus far.

And perhaps if I could then ask the question of Lorac, just I just wanted to revisit.

Arshad Kanani: And of course, the treatment burden is the biggest issue. And your comment about being involved with everything because I'm involved with everything, because I want to make life better for my patients. And, you know, now we are, I'm serving as a PI for almost sixty clinical trials. And this is an exciting time for our space, but when you look at our space, you have to divide treatment options into two buckets. You have to divide treatment where you can do an interventional injection and be incrementally better in terms of durability.

The program.

And I think we've been waiting for some protein expression data just wondering if there was an update on that and then the last follow up there would be a different question would be around DMA in is what are the current thoughts.

That we could.

Perhaps take away from this with do you have any timeline. Thanks.

Okay. Thanks, Greg.

Before I pass to pass it on to Dr. Canady, I think it's important to know that what's unusual about this program is that we started our first study and the hardest to treat population with a dose we thought it would be the last two years, where we had actually a 100% of the patients who had no need for additional anti VEGF injection.

Arshad Kanani: So you can add a month or two months or three months on top of what we have, and that's great for patients. And, you know, things like charisma and KSI three zero one GB, one or two of those programs are moving forward. And that's really exciting.

So we started at the at the top of the dose response curve and as we know a gene therapy. Those are fairly flat. So that <unk> 11 was we thought a great dose to struggle around now going into first line therapy less demanding as far as any kind of adds up need patients choose.

Arshad Kanani: But then the other part is sustained delivery, the continuous delivery, which can lead to disease control, which is very difficult to achieve with introvertual injection and that you saw in my case that I presented. So, when you look at that, that is the paradigm shift that's happening. Obviously, a poor delivery system has started that, but it's a surgical procedure and the OR.

To really provide enough dose response.

Between what we've seen and what we believe will provide a good target product profile, but I'll, let the doctor can I answer in more detail.

Thanks, Laura and then Greg Nice to hear from you. Obviously, so I think your first question is the strategy about going 311, and 111 I think.

Arshad Kanani: So it has its own risk and benefits, and it's not really a primary treatment. But what I see is I see oh, two, two as a primary treatment for these patients after we have controlled their disease. Of course, the trial with my patient will give us more ideas. But if I see a patient in my clinic who has naive disease, I'll do an interventional injection, obviously, and then get them primed up to go into receiving gene therapy for oh, two, two. So, I think it's a chronic disease with poor long-term outcomes, and the treatment burden can easily be reversed with this approach. You saw the case.

In my opinion, that's an excellent approach because we have seen great efficacy with Tuohy 11. So you can see both of the cases I presented today are actually from 211 and these are patients who are not controlled with injections that were very frequent every four to five weeks. So I think I'm expecting.

<unk>.

Very potent efficacy.

From 311, and then you know as Lauren said I think we need to remind ourselves. The fact that these are heavily pretreated patients with long standing history of their disease and really tough to treat population. So since a pivotal that Aaron mentioned and gave a really nice or view is are looking at.

Laurent Fischer: I presented both of those cases, and these are real patients that have really benefited from this approach. Thank you, Rashad. That was really a great and clear explanation about the potential future of treatment for wet AMD. Any thoughts on the global impact this could have when you think about the availability of anti-VEGF at a global level, particularly in DME? I think it's going to be huge, Laurent. Both, in my opinion, New Vestal AMD and DMV. I mean, you look around the world; you look at, you know, India, you look at Mexico, you look at Africa.

At naive patient population and those are fresh our patients and we know based on our experience the sooner you treat the patient.

For the better.

Control, you're going to get to in a naive population and I can easily see that even 111 can.

Can be beneficial so I think in terms of having both doses I think it's the right decision in my opinion, and obviously people who are involved with.

<unk> this trial.

So I will pass it to Aaron Aaron do you have any comments on top of what I mentioned.

Arshad Kanani: I mean, they don't have resources, and they don't have the manpower to deliver, you know, continued monthly or every other month injections. Here, we can modify these lifelong chronic diseases with a single injection. And obviously, you have to initially monitor these patients. And as Aaron said, I mean, you know, this is not a continuous process.

No I think I think I think that's exactly right I mean, we've seen.

A favorable safety profile with both of the doses.

What we've seen is that there's been a really strong anatomical response for great durability with both of those doses as we've tracked the data longer longer you know I think the lower dose to 11 has sort of pleasantly almost surprised us by this continuing great signal of kind of pick from ours by those two patients that Dr. <unk> presented.

Arshad Kanani: I think once they've finished their topical drops and their control, then, you know, telemedicine would be huge. Telemedicine has really exploded because of COVID-19. And anybody can monitor these patients afterwards. So I think after the initial dose, we monitor, but then after that, I'm not looking forward to seeing these patients every month or every other month, maybe every six months, if they want to come in. So think about patients waiting for treatment around the world because they don't have access.

And on the flip side, you know as you look back at the higher dose we're going to continue to evaluate that we're evaluating and DMA.

It's possible that in the future you know there are other indications that may benefit from <unk>.

For the.

Beth just blocking ability without high debt as we've already presented protein expression data from two patients who received that high value switch really corresponded with about three weeks after bolus injection.

Arshad Kanani: You have one and done therapy that's gonna really help the patients and physicians be able to treat more patients because they don't have to treat them continuously. So I think this is gonna be huge if efficacy continues to be as good as we have seen in the uptake and then manageable safety. That was great.

Yeah.

As we go forward for semi present more protein expression data, but I think those day to give an idea of just how robust that that protein expression is unless we look at the lower dose. We'd go back continued stable visual acuity and anatomical response again in these tougher to treat patients.

Laurent Fischer: Thank you so much, Dr. Kanani. I want to take advantage of you being here to actually have some of our audience ask questions. So maybe we'll open the call for questions and then I'll direct them. Operator, could you open the call for questions?

So going to 311 am 111, two doses that straddle that 211 provides some additional dose ranging.

But that is that it seems to be an optimal approach for phase three and it's something that we discussed with the agency and they were in full alignment seems a good approach.

Okay.

And maybe just on day anytime, but we will continue to present.

Operator: Certainly. We will now begin the question and answer session. To join the question queue, you may press star and then one 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.

Well continue to present, obviously data and protein expression I have them.

Sure and will present day, one year data on cohort three and then one year data on older cohorts, including called for and then Dnb. We're studying book doses, two and 611 and that has been fully enrolled its blind. There. Then we'll report you know in second half as soon as we have the topline data obviously given this is a potential.

Operator: To withdraw your question, please press star then two. We will pause for a moment as callers join the queue. The first question comes from Graig Suvannavejh with Goldman Sachs. Please go ahead. Yeah, thanks. Thanks very much.

Honestly, a large indication where we're going to look at the EMEA as well as the aricept for a potential to go into D. M D or the study is positive.

Honestly report once we have this information.

Graig C. Suvannavejh: And Dr. Kanani and the team, thanks for taking the call. This question is for Dr. Kanani. It's great to hear from you again.

Fair enough fair to assume it could be instead of a combined filing an NDA for SPN like strategy.

Currently we have two different ideas for each indication and that's the case with most of the entire two anti VEGF. So they're they're treated by the ophthalmology division are separate indications.

Graig C. Suvannavejh: Just wanted to get your thoughts on the company's strategy of moving to a different dose than what was evaluated in the optic study. And more specifically, you know, with the lower dose and the higher dose of one in three, what do you expect to see from those two doses? And perhaps more importantly, what, you know, what do you need to see from those two doses to feel comfortable with the profile that you've seen thus far? And perhaps if I could then ask a question of Laurent, I just wanted to revisit the program.

And to be discussed obviously, once we have data and plan to move forward.

Any other question otherwise, we can move to the next caller.

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

Hey, guys.

Good afternoon, thanks for taking the questions.

First wanted to follow up on the design are you assuming a lower bound of the non inferiority margin to be.

Linus whore or somewhere around there it would be helpful. If you could confirm that as well as the standard deviation of the vision that we should be assuming for this newly diagnosed patient population at these doses and then the second question.

Graig C. Suvannavejh: And I think, you know, we've been waiting for some protein expression data. I'm just wondering if there was an update on that, and then the last follow-up there would be, or a different question would be around DME, and is what are the current thoughts that we could perhaps take away from this with DME timelines. Thanks.

Or topic is related to the supplemental injection criteria are picked up on the slide but instead it was similar to offset so maybe not the exact same so could you just maybe discuss exactly what it will be and how it will be handled if you know the the incentive.

Laurent Fischer: Hey, thanks, Greg. Before I pass it on to Dr. Kanati, I think it's important to know that what's unusual about this program is that we started our first study in the hardest-to-treat population with a dose we thought would be the last dose, where we actually had 100% of the patients who had no need for additional anti-VEGF injections. And so we started at the top of the dose-response curve, and as we know in gene therapy, those are fairly flat.

Free change in D. C. B that it will be I guess analyzed independent of supplemental injunctions.

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

Thank you Laura and thank you Carlos.

Yeah. They start day this will be a non inferiority study against standard of cash and similar to sort of other treatment naive study is that non inferiority margin. It would be would be for lessors. So that means a lower bound of the confidence interval for AVB M. O T T related visual acuity needs to be within for.

All actors of the point estimate for the control arm. So that's yeah, that's kind of establishing that's been used in several trials before we're a little bit different and we spent time with FDA. On this is is how do we get to it to a number per is actually much less than previous trials of approximately half the number on it.

Laurent Fischer: So that 2E11 was, we thought, a great dose to straddle around, now going into first-line therapy, less demanding as far as anti-VEGF needs patients are concerned, to really provide enough dose response between what we've seen and what we believe will provide a good target product profile. I'll let Dr. Kanati answer in more detail. Thanks, Laurent and Greg. Nice to hear from you, obviously.

That goes kind of for the second half of your question, which is standard deviation, which has driven a lot by the gains in visual acuity are often experienced following the first injection.

Arshad Kanani: So I think your first question is about going 3E11 and 1E11. I think, in my opinion, that's an excellent approach because we have seen great efficacy with 2E11. So you can see both of the cases I presented today are actually from 2E11. And these are patients who were not controlled with injections that were very frequent every four to five weeks. So I think I'm expecting very potent efficacy from 3E11.

What we plan to do with this study is actually take patients who.

For a treatment naive they have one injection and provided they show a response to that and then anticipated need for or need for further treatment than the baseline starts at that point. They would then receive another eylea injection of receive ABB Emirates you too. So that's still on the face of gaining visual acuity on average, but a lot of that initial gain has already taken place.

Which then means for the variability is reduced.

So we expect the standard deviation to be significantly lower than it would be for a typical treatment naive study such as the for risk and Apple Alcoholicity Mouse studies that other Konami mentioned so there.

Arshad Kanani: And then, you know, as Laurent said, I think we need to remind ourselves the fact that these were heavily pre-treated patients with a long-standing history of their disease and a really tough to treat population. So since the pivotal, as Erin mentioned, and gave a really nice overview, we are looking at a naive patient population. And those are younger patients. And based on our experience, the sooner you treat the patient, the better, you know, control you're going to get.

A standard deviation is lower than it would be for those studies. So that's been non inferiority and the standard deviation I think a final question was on the re treatment or supplement plant feed that Jeff criteria.

And yeah, I mean, we plan to keep those similar to uptick obviously, we want to minimize any changes going to these pivotal trials, we've seen great visual acuity maintenance.

And I'll take great anatomical maintenance.

Arshad Kanani: So in a naive population, I can easily see that even, you know, 1E11 can be beneficial. So I think, in terms of having both doses, I think it's the right decision, in my opinion, and obviously, people who are involved with designing this trial. So I will pass this to Erin. Erin, do you have any comments on top of what I mentioned? No, I think that's exactly right.

And it's really always striking that balance between making sure that patients ultimately treat couldn't make it the best possible visual acuity outcomes, whilst also avoiding administering injections that are not needed because maybe those are constant that Jeff suppression all going in the background. So we would kind of Takeda is very similar to uptake, we've got a little bit of time.

Before reaching a very final protocol. So we'll continue to monitor the data and uptick and as we speak to physicians and regulators, particularly ex U S. As well you know, we'll keep the the the final precise details.

Aaron Osborne: I mean, we've seen a favorable safety profile with both of the doses. What we've seen is that there's been a really strong anatomical response and great durability with both of those doses. As we've tracked the data longer and longer, you know, I think the lower dose, 2E11, has sort of pleasantly surprised us with this continuing great signal as kind of epitomized by those two patients that Dr. Kanani presented. And on the flip side, you know, if you look back at the higher dose, we're going to continue to evaluate that.

Under wraps until we got a little bit closer to the time, but don't expect anything particularly different from uptake.

Okay.

Very interesting thank you.

Thank you Tyler.

The next question comes from Manny for her with SBB Leerink. Please go ahead.

Hey, guys. Thanks for taking my question.

Obviously, you've gone through a lot of detail here I want to have a little bit more nuanced question around what you've seen in terms of change in patient behavior.

During the pandemic period.

Aaron Osborne: We're evaluating it in DME, but it's possible that in the future, there are other indications that may benefit from, you know, the VEGF blocking ability of that high dose. We've already presented protein expression data from two patients who received that high dose, which really corresponded with about three weeks after an Aflivicept bolus injection.

How that's influenced patient.

Across trials given that your <unk> investigator across major for wet AMD trials and.

And how as we see the pandemic.

Resolve which I'm afraid I'm gonna here could we see a shift towards less severe patient fear coming to the office goes down.

Just how do you think of that impact in terms of the population that gets enrolled into these two phase III versus perhaps population, but might be being currently enrolling other clinical trials, but we're actively enrolling but you were a part of during the height of the pandemic.

Aaron Osborne: You know, as we go forward, we'll certainly present more protein expression data, but I think those data give an idea of just, you know, how robust that protein expression is. And as we look at the lower dose, we've got that continued stable visual acuity and anatomical response, again, in these tougher-to-treat patients. So going to 3E11 and 1E11, two doses that straddle that 2E11 provide some additional dose ranges. That seems to be an optimal approach for phase three.

And many thanks for this question Great question, obviously I just get a reminder, we fully enrolled in today's day during COVID-19, all remotely fixing bugs, which accounts.

Pretty remarkable but obviously.

The value of the best positioned John for your question about how that could change that and other small savings in the future.

Laurent Fischer: And it's something that we discussed, you know, with the agency, and they were in full alignment that this seemed a good approach, and maybe just on the DME timeline, but we'll continue to present. Yeah, we'll continue to present, obviously, data and related expression as they mature, and we'll present data, one-year data on Court 3, and then one-year data on all the courts, including Court 4. And then DME, we're studying both doses, 2 and 6C11, and studies are being fully enrolled, it's blinded, and we'll report, you know, in the second half, as soon as we have the top-line data.

Thanks, Manny and thanks, Laura So I think the main thing to point out is that wet AMD is a disease that can lead to any universal blindness.

In patients and if you don't get them treated they're gonna go blind so even at the height of pandemic you know.

Throughout the pandemic have been.

Really.

Being good in terms of taking care of all the patients in the trials as well as our wet AMD patients. So we cut down patients or routine follow ups would be continued injections and we managed our study patients in a very unique way wherever you are able to.

Provide them that are isolated visits weekend visits after our visits also putting in Covid protocol that have worked really really well so or wet AMD.

Laurent Fischer: Obviously, given this is a potentially large indication where we're going to look at DME as well as DRSF, so potential to go into DME or DR, the study is positive. We'll obviously report once we have this information. It's fair to assume it could be, instead of a combined filing, an SNDA or SBLA strategy.

Patient population enrollment in other trials and stopped because of the some of the geographic atrophy trials were put on hold because those patients don't see an improvement in its on an emergency for them to get into a trial. So wet AMD trials have done well, but I tell you what COVID-19 has made us realize and I think your question is very pertinent.

Tyler Van Buren: Currently, we have two different INDs for each indication, and that's the case with most anti-virus drugs. So they're treated by the ophthalmology division as separate indications and to be discussed, obviously, once we have data and plan to move forward. Any other questions?

As physicians, we cannot have patients coming in every month or every six weeks. During this pandemic. These patients are high risk also the diabetics. So really has put in.

Our heads and we actually have to have therapies that are sustained over a long time, so that patients don't have to come to our clinic and that's why a D. A M O two true.

Tyler Van Buren: Otherwise, we can move to the next caller. The next question comes from Tyler Van Buren with Piper Sandler. Please go ahead. Hey guys, good afternoon.

Is a perfect fit for getting us ready for having Oh, God forbid another pandemic or or having us in a situation, where we are putting all of our patients as risk at risk by bringing them to a clinic, but in terms of treatment with <unk>.

Tyler Van Buren: Thanks for taking the questions. Just a first one to follow up on the design. Are you assuming the lower bound of the non-inferiority margin to be minus four or somewhere around there?

Enrollment in all the trials you really catered to the clinical trials and I don't see a difference in terms of enrolling patients in these pivotal trials most of my patients actually had been vaccinated now I ask every single one or receive their first dose and it is really promising to see that our the.

Aaron Osborne: It would be helpful if you could confirm that as well as the standard deviation and vision that we should be assuming for this newly diagnosed patient population at these doses. And then the second question or topic is related to the supplemental injection criteria picked up on the slide that you said it was similar to OPTIC, so maybe not the exact same. So can you just maybe discuss exactly what it will be and how it will be handled if, you know, the incentive to treat change in BCBA will be, I guess, analyzed independent of supplemental injection? Yeah, I'll let Aaron answer that question. Thank you, Tyler. Perfect. Thank you, Laurent. Thank you, Tyler.

<unk> have also gone down significantly in our area because of Covid. So really it appears that things are hopefully going to be getting towards normal in the future.

Great. Thank you I know, we have a few more airlift from mature so we'll try to take that thanks, Mike.

The next question comes from cell now deal with Cowen and company. Please go ahead.

I've got a couple of questions hi, Congrats on the progress a couple of questions from us firstly on the.

For two two dosing information and I think you mentioned that there's no cellular information at the most recent time point is that correct did I hear that.

And could you tell us whether patients are there for on that.

Aaron Osborne: The stat, This will be a non-inferiority study against the Flivicep standard of care. And similar to the other treatment-naive studies, that non-inferiority margin would be four letters. So that means that the lower bound of the confidence interval for ADVM 022-related visual acuity needs to be within four letters of the point estimate for the control arm.

There's all off steroids.

And if so for how long.

And do you want to take that.

I can tell you that yes sure of course, yeah. So I mean, we did have.

I think the most recent data that we presented to it from a data cut in October of last year and these other data we presented at the angiogenesis.

To review our dates for as we went into the FDA anything and really everything that we've seen is is consistent and we looked specifically at the.

Aaron Osborne: So that's kind of established and has been used in several trials before. Where we're a little bit different, and we spent time with FDA on this, is how do we get to a number per arm that is actually much less than in previous trials that are approximately half the number? And that goes kind of to the second part of your question, which is standard deviation, which is driven a lot by the gains in visual acuity that are often experienced following the first injection.

Numbers of patients who had any cellular inflammation you were taking steroid eye drops and on the low dose article this with no patients have any signs of cellular inflammation with three patients that were taking a state taking steroid drops so that at that point. So I mean this is this kind of plays into the decision to go with two doses around the 211 wells.

Aaron Osborne: So what we plan to do with this study is actually take patients who are treatment-naive, they have one injection, and provided they show a response to that and an anticipated need for further treatment, then their baseline starts at that point. They would then receive another ILIA injection and receive ADVM 022. So they're still in the up phase of gaining visual acuity on average, but a lot of that initial gain has already taken place, which then means that the variability is reduced.

Both have shown a really good safety profile and great efficacy were seeing you know.

Britain minimal episodes of inflammation off for the prophylactic period, and minimal steroid eye drop news after that prophylactic period, as well without low dose, whereas you know there's been a few cases, where patients have needed to go back on the steroid eye drops a little later with the high dose.

Great and then second.

Second question is on a flight receptor in the comparator arm, how long would it be dosed and.

More generally.

How did you come upon your your assumptions for the visual acuity benefits you're going to get.

Aaron Osborne: So we expect the standard deviation to be significantly lower than it would be for a typical treatment-naive study, such as the Forissimab or Brolicizumab studies that Dr. Kanani mentioned. So the standard deviation is lower than it would be for those studies. So that's the non-inferiority and the standard deviation.

It does seem like there is for some risk.

So you don't have to match for those who don't I'm assuming is for those 5%.

And the control arm in patients, who visual acuity is actually improving in their first year of treatment. So so what gives you confidence that you will be able to achieve that.

Yeah, that's a great. It's a great question. So we will be comparing to standard of care for a except as in the label, which is three initial injections for treatment naive patients followed by dosing every eight weeks.

Aaron Osborne: I think the final question was on the retreatment or supplemental antidepressant criteria. And, yeah, I mean, we plan to keep those similar to OPTIC. Obviously, we want to minimize any changes going to these pivotal trials. We've seen great visual acuity maintenance in OPTIC, and great anatomical maintenance. And it's really always striking that balance between making sure that patients are optimally treated and they get the best possible visual acuity outcomes, whilst also avoiding administering injections that are not needed because maybe there's a constant digestive pressure going on in the background. So we would plan to keep these very similar to OPTIC.

As the standard comparator regimen, that's been the case for debt.

First from recently completed for Mount Trolling productivity in that trial.

In terms of what gives us confidence that we would be able to achieve that I think it really comes back for the data points that presented today. When you look at cohorts, two and three to get below that low dose in these difficult to treat patients who required many injections. The vast majority a rescue injection free and what we see what we've seen as anatomic.

Improvements that.

Have remained constant throughout all of the follow up that steady line that you see on the CFC is frankly, it's extraordinary and I think it's something that we have not seen before with a single injection or single treatment therapy cause that continue on for Jeff suppression and we're seeing some of the patient cases, as well that is actually leading visual acuity gains.

Aaron Osborne: We've got a little bit of time before reaching our very final protocol, so we'll continue to monitor the data in OPTIC. And as we speak, you know, to physicians and regulators, particularly XUS, we'll keep the final precise details under wraps until we get a little bit closer to the time. But don't expect anything particularly different from OPTIC.

Really we need to do as well as anti VEGF therapy, I think what we're seeing an uptick is that some patients are doing better than regular anti VEGF therapy.

That's really predominantly what gives us the confidence if we can stabilize the retina and restore the anatomy.

What should follow is that the visual acuity will improve and we have a trial, but its got up to each other.

Tyler Van Buren: It was very interesting. Thank you. Thank you, Tyler. The next question comes from Manny Sorohar with SVB Lyrics. Please go ahead. Yeah, thanks for taking the time to ask the question. Obviously, you've gone through a lot of detail here. I want to have a little bit more nuanced question around what you've seen in terms of change in patient behavior during the pandemic period, how that's influenced patient enrollment across trials, given that you're an investigator across many different AMD trials, and how, as we see the pandemic ease, resolve, whichever phrase you want to use, could we see a shift towards less severe patients as fear of coming to the office goes down? Just how do you think of that impact?

Great and then last question from US just the Dutch economy.

Let's say that for the profile and fish there it looks exactly like where we've seen meaning patients or 67 per cent injection free or 67 per cent of patients approximately this dose for injection free.

How about your monitor patients from your practice, how often will you bring them back.

Are there any signs that you can look for remote we too I'm sure for patients who are having their disease process return.

Yes. So that's an excellent question you know based on learnings from the optic trial as that'd be up to see these stations are you know more frequently initially so I would say that in the first six months of treatment.

We'll have to see them, maybe once a month, but but afterwards I think they can be monitored remember all of the inflammation and Jr.

Manny Sorohar: Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, Hey, Manny, thanks for this question. A great question. Obviously, I just, you know, as a reminder, we fully enrolled in the study during COVID-19 all remotely in six months, which we thought was pretty remarkable. But obviously, Dr. Kanani is in the best position to answer your question about how this has changed and how this will change in the future. Thanks Manny and thanks Laurent.

No cases of post share vasculitis, retinitis or anybody that irreversible vision loss. So I think that's something to keep in mind. So so patients can be monitored.

By optometrists or somebody else if they needed to be and then they can be treated if they need to but with the topical drops but my confidence comes from being an investigator.

In uptake and enrolling the highest number of patients I feel like the after the initial monitoring phase patients can go much longer I mean, other patients who have been in this trial for one and half years and they keep asking me why am I coming every month and of course in trials. When you do that but in practice I think we can easily extend these patients one.

Laurent Fischer: So I think the main thing to point out is that VET-AMD is a disease that can lead to irreversible blindness in patients. And if you don't get them treated, they're gonna go blind. So even at the height of the pandemic, you know. Throughout the pandemic, we have been really good in terms of taking care of all the patients in the trials, as well as our wet AMD patients. So we cut down patients who were routine follow-ups, but we continued injections, and we managed our study patients in a very unique way, where we were able to, you know, provide them with isolated visits, weekend visits, after-hour visits, also putting in a COVID protocol that worked really, really well.

They are stable to six months.

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

Great.

One more question and.

Yes, we have time for one more question here.

The next question comes from Alicia Young with Cantor Fitzgerald. Please go ahead.

Hey, guys. Thanks for taking my questions Hi.

Thanks for taking my question and congrats on the progress I.

I guess I, just one time for it for about.

Yeah.

I want to talk a little bit about like the you know from secondary endpoint from the importance of like you know kind of the rescue regimen as as a as an endpoint that the FDA thinking about maybe other secondary I guess, that's the same kind of a corollary question for the Doctor I mean in a way it feels like visual acuity I mean, obviously, what they need but you know this rescue notion is one probably doctors may want isn't there.

Hi, My first question and my second question is one of the more strict parameters are there any kind of interims or any other analysis analogy.

Laurent Fischer: So our wet AMD patient population enrollment in other trials didn't stop because of it. But some of the geographic atrophy trials were put on hold because those patients don't see an improvement, and it's not an emergency for them to get into a trial. So the wet AMD trials have done well, but I'll tell you what COVID has made us realize, and I think your question is very pertinent. As physicians, we cannot have patients coming in every month or every six weeks during this pandemic.

Analysis is baked into the growth, particularly.

Yeah.

Dan you want to take that.

Yeah I can tell you that can take the second one is straightforward actually for us which is because its up a registered neither registrational clinical trials that would be no interim analyses, we would analyze the primary endpoint of one year and use those intend to use those data to support a BLA submission.

With regards to secondary end points you raise are you ready for a great point, there's a lot of different ways that we can look to differentiate this therapy and one of the key things that come the we're learning more and more about is the fluctuations in and that's to me that a patient's experience with currently available anti VEGF agents and the fact that those fluctuations.

Arshad Kanani: These patients are at high risk, also diabetics. So it has put in our heads that we actually have to have therapies that are sustained over a long time so that patients don't have to come to our clinic. And that's why ADVM 022 is a perfect fit for getting us ready for having, God forbid, another pandemic or putting our patients at risk by bringing them to the clinic.

<unk> lead to fibrosis, they lead to atrophy and they lead to core long term outcomes and this is coming through you know these these dates for coming through more and more so.

But can maintain stability could potentially reduce fibrosis with G such free and lead to better long term vision outcomes. That's why kind of primarily we want to follow patients long term, but we'll also be looking at a number of OTT analyses.

Arshad Kanani: But in terms of treatment for all, you know, enrollment in all the trials, we really cater to the clinical trials. And I don't see a difference in terms of enrolling patients in these pivotal trials. Most of my patients have actually been vaccinated, but now I ask every single one or receive their first dose. And it is really promising to see that the number of cases has also gone down significantly in our area because of COVID.

That could potentially.

Build that story up more and let us understand more about what that stability without you too can lead to in terms of anatomical and functional outcomes.

That's the that's probably only to say on that one at the moment.

Great. Thank you.

This concludes great flow to answer session.

I would like to turn the call back to Dr. Fischer for any closing remarks.

Thank you operator, and thank you all for joining US this has been really a great discussion.

Arshad Kanani: So it really appears that things are hopefully going to be getting towards normal in the future. Great, thank you. I know we have a few more analysts in the queue, so we'll try to take them. Thanks, Matt.

I'd like to spend back to Canadian it's based in sharing their journey with us as well as all the investigator and patient who participated in our clinical trials. I also heard that can always be important incredible work by FDA has done during COVID-19, and great outcome. We certainly appreciate the guidance there and see it gives the companies as they work to develop new therapies for patients with unmet needs.

Phil Nadu: The next question comes from Phil Nadu with Cohen & Company. Please go ahead. Good afternoon, I have a couple of questions. Hi, congrats on the progress. A couple of questions from us. First, on the O22 dose and inflammation, I think you mentioned that there was no cellular inflammation at the most recent time point. Is that correct? Did I hear that right? And could you tell us whether patients are therefore on that, at that dose, all off steroids? And if so, for how long?

And last but not least I want to acknowledge the commitment and hard work of our team are at variance who bring their talent and expertise to work every day to advance our global mission, just average gene therapy as a onetime treatment that pillar patient side for life.

I'm really enthusiastic about where we're heading as an organization building on our 2020 for vision to become a fully integrated gene therapy company.

<unk> focused on execution with our lead investigational gene therapy candidates. If you about your true for two leading causes of blindness with a goal of delivering this potentially transformative gene therapy to patients around the world. We're also continuing to develop our pipeline and ocular and rare diseases, leveraging our proprietary seven day made analysts day old platforms with it.

Aaron Osborne: And do you want to take them? I can take them, yeah, of course. Yeah, so we did a data cut in October of last year, and these are the data we presented at Angiogenesis. We did review our data as we went into the FDA meeting, and really, everything that we've seen is consistent. And we looked specifically at the numbers of patients who had any cellular inflammation and were taking steroid eye drops.

Oh of filing an IND in 2022, I hope everyone is staying healthy and well we look forward to building on our continued progress in the future and wish you a good day. Thank you.

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

Aaron Osborne: And on the low dose recall, no patients had any signs of cellular inflammation. There were three patients that were taking steroid drops at that point. So, I mean, this kind of plays into the decision to go with two doses around the 2E11. Whilst both have shown a really good safety profile and great efficacy, we're seeing, you know, really minimal episodes of inflammation after the prophylactic period, and minimal steroid eye drop use after that prophylactic period as well with that low dose.

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Aaron Osborne: Whereas, you know, there have been a few cases where patients have needed to go back onto steroid eye drops a little later with the high dose. Great, and then the second question is on F-Libracept in the comparator arm. How will it be dosed? And more generally, how did you come up with your assumption?

Aaron Osborne: For the visual acuity benefit you're going to get. It does seem like there's some risk that you now have to match full dose, or I'm assuming it's full dose, F-Libra set, in the control arm in patients whose visual acuity is actually improving in their first year of treatment. So what gives you confidence that you'll be able to achieve?

Aaron Osborne: Yeah, that's a great question. So we'll be comparing it to standard of care for Flibaxept as in the label, which is three initial injections for a treatment-naive patient followed by dosing every eight weeks. That's the standard comparator regimen that has been the case for the recently completed Faricimab trial and the Brolicizumab trial. In terms of what gives us confidence that we would be able to achieve that, I think it really comes back to the data points that, you know, were presented today.

Aaron Osborne: When you look at cohorts two and three together at that low dose, in these difficult-to-treat patients that require many injections, the vast majority are rescue injection free. And what we've seen is anatomical improvements that have remained constant throughout all of the follow-up. That steady line that you see on the CST is, you know, frankly, extraordinary.

Aaron Osborne: And I think it's something that we have not seen before with a single injection or single treatment therapy. So that continual VEGF suppression, and we're seeing in some of the patient cases as well, is actually leading to visual acuity gains. Really, we need to do as well as anti-VEGF therapy. I think what we're seeing in optic neuropathy is that some patients are doing better than regular anti-VEGF therapy. So, you know, that's really predominantly what gives us confidence.

Phil Nadu: If we can stabilize the retina and restore the anatomy, then what should follow is that the visual acuity will improve. And we have a trial that is set up to show that. Great.

Arshad Kanani: And then last question from us, just to Dr. Kanani, let's say the profile in phase three looks exactly like what we've seen, meaning patients are 67% injection free, or 67% of patients, approximately this dose, are injection free. How will you monitor patients in your practice? How often will you bring them back?

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Arshad Kanani: Are there any signs that you can look for remotely to see if patients are having the disease process returned? Yeah, so that's an excellent question. Based on learnings from the optic trial, we have to see these patients more frequently initially, so I would say within the first six months of treatment, we'll have to see them maybe once a month, but afterwards, I think they can be monitored. Remember, all the inflammation here is anterior. There are no cases of posterior vasculitis, retinitis, or anybody with irreversible vision loss.

Phil Nadu: So, I think that's something to keep in mind. Patients can be monitored, you know, by optometrists or somebody else if they need to be, and then they can be treated if they need to with topical drops, but my confidence comes from being an investigator in optics and enrolling the highest number of patients. I feel that after the initial monitoring, patients can go much longer. I mean, I have patients who have been in this trial for one and a half years, and they keep asking me why I come every month. And, of course, in trials, we do that. But in practice, I think we can easily extend these patients once they are stable for six months. That's very helpful. Thanks for taking our questions. Great. We'll take maybe one more question and then... We have time for one more questioner. The next question comes from Alicia Young with Cantor Fitzgerald. Please go ahead.

Alicia Young: Hey guys, thank you for taking my question. I guess I just wanted to talk a little bit about, yeah, that's awesome, and I want to talk a little bit about some secondary endpoints and the importance of like, you know, kind of the rescue regimen as an endpoint that the FDA is thinking about maybe as a secondary. And I guess that's the same kind of corollary question to ask the doctor. I mean, in a way, it feels like visual acuity.

Alicia Young: I mean, it's obviously what the FDA needs, but, you know, this rescue notion is probably what doctors may want. My first question. And my second question is a little bit more straightforward. Are there any kind of interims or any other analysis baked in before 52 weeks? Karen, do you want to take this? Yeah, I can take that. I can take the second one.

Aaron Osborne: It's straightforward, actually, first, which is because these are registration or clinical trials; there would be no interim analyses. Instead, we would analyze the primary endpoint at one year and intend to use those data to support a BLA submission. You know, with regard to secondary endpoints, you raise a great point. There are a lot of different ways that we can look to differentiate this therapy. And one of the key things that we're learning more and more about is the fluctuations in anatomy that patients experience with currently available anti-VEGF agents and the fact that those fluctuations lead to fibrosis, they lead to atrophy, and they lead to poorer long-term outcomes.

Aaron Osborne: And this is coming through, you know, these data are coming through more and more so. A product that can maintain stability could potentially reduce fibrosis, reduce atrophy, and lead to better long-term vision outcomes. That's why, kind of primarily, we want to follow patients long-term, but we'll also be looking at a number of OCT analyses that could potentially, you know, build that story up more and let us understand more about what that stability with O2-2 can lead to in terms of anatomical and functional outcomes. That's probably all I need to say on that one at the moment.

Laurent Fischer: This concludes the question and answer session. I would like to turn the call back to Dr. Fischer for any closing remarks. Thank you, Operator, and thank you all for joining us. This has been a really great discussion.

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Laurent Fischer: I'd like to thank Dr. Conanti and his patients for sharing their journey with us, as well as all the investigators and patients who participated in clinical trials. I also want to acknowledge the important, incredible work the FDA has done during COVID-19 and the great outcome. We certainly appreciate the guidance the agency gives to companies as they work to develop new therapies for patients with unmet needs.

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Laurent Fischer: And last but not least, I want to acknowledge the commitment and hard work of our team at Advariance, who bring their talent and expertise to work every day to advance our global mission to establish gene therapy as a one-time treatment that preserves patients' lives for life. I'm really enthusiastic about where we're heading as an organization, building on our 2024 vision to become a fully integrated gene therapy company. We're clearly focused on execution with our lead investigational gene therapy candidate, ADDM022, for two leading causes of blindness with the goal of delivering this potentially transformative gene therapy to patients around the world. We are also continuing to develop our pipeline in ocular and rare diseases, leveraging our proprietary 7M8 and LSD1 platforms with the goal of filing an IND in 2022.

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Operator: I hope everyone is staying healthy and well. We look forward to updating you on our continued progress in the future and wish you a good day. Thank you. This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a pleasant day. Andres Gomes, Aydin Huseynov, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, Joseph John, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum [inaudible] [inaudible] [inaudible] Daniil Gataulin, Joon Lee, Laurent Fischer, Adverum Fischer, Daniil Gataulin, Joon Lee, Laurent Fischer, Adverum, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum [inaudible] 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, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, Aydin Huseynov, Joon Lee, Laurent 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 Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum, Szilard Kiss, Daniil Gataulin, Graig Suvannavejh, Unknown Executive, Aydin Huseynov, Joon Lee, Laurent Fischer, Adverum

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