Adverum Biotechnologies Inc

NASDAQ:ADVM

Earnings Call Transcript 2020-Q4

[Operator]

Good afternoon and welcome to the Adverum Biotechnologies Conference Call. At this time all participants are in a listen-only mode later we will conduct 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 Myesha Lacy, Vice President of Investor Relations and Corporate Communications of Adverum. Please go ahead.

[Myesha Lacy]

Thank you, Anastasia, and welcome, everyone. Today, we issued a press release to share our development planning for ADVM-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 the reply of today's call will also be available on the Events and Presentation section of our website.

Joining me today is Dr. Laurent Fischer, Chief Executive Officer; Leone Patterson, President and Chief Financial Officer; Dr. Aaron Osborne, Chief Medical Officer. In addition, we are honored to have Dr. Arshad Khanani, of the Sierra Eye Institute, and an enroller in our OPTIC and INFINITY clinical trial joined us today.

As a reminder, we will be making forward-looking statements, which include our product development plans, research activities, anticipated upcoming milestones and operations. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those forecasted. A description of these risks can be found under the caption Risk Factors described more fully in our quarterly report on Form 10-Q for the quarter ended September 30, 2020 and any subsequent filings with the SEC under the heading risk factors.

And now I will now turn the call over to our CEO, Dr. Laurent Fischer.

[Laurent Fischer, Chief Executive Officer]

Thanks, Myesha. Good afternoon, everyone. And thank you for joining us today. I hope that everyone including your family and friends are staying safe and healthy. Before we begin, I would like to personally thank Dr. Arshad Khanani for joining us today. We're very appreciative for this time, his deep expertise in the retina field and [indiscernible] potential of our gene therapy product ADVM-022 as a new and differentiated treatment option for patient with wet AMD and DME.

Dr. Khanani is incredibly dedicated to his patients and to advancing new treatment options that have the potential to improve real world outcomes. He's well known as an experienced investigator participating in many clinical trials. I also would like to thank all the patients, their families and our investigators who are continuing to enroll studies during this pandemic which as we know is impacting this at risk population of wet AMD patients; we'll be talking about today.

At Adverum, we're in a global mission to establish team therapy as a one-time therapy that preserves patients sights for life. We're gene therapy pioneers and we believe that we're at the forefront of disrupting the anti-VEGF market with our novel vector technology, AAV.7m8. Our technology has the potential to dramatically alter the treatment paradigm for patient living with wet AMD and DME following a single in-office intravitreal injection and we're keen to make it available to patient as efficiently and as soon as possible.

Here's our agenda for today's virtual event. First, I will share some opening comments about our recent progress across the business. Next, Aaron Osborne our Chief Medical Officer will provide details of our global Phase 3 program for ADVM-022 then Dr. Arshad Khanani will share video of one of his patients living with wet AMD who took part in our OPTIC study to highlight her personal journey and the impact of the ADVM-022 on her life. Then I'll have a fireside chat with Dr. Arshad Khanani and finally, we'll take your questions.

So I'm really excited to share today that we recently had a very collaborative meeting with the FDA and 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 submissions for ADVM-022 in wet AMD in 2024. As a reminder, we enrolled the first patient in OPTIC in late 2018 and we've since made great progress advancing the development of our investigational gene therapy product.

In OPTIC to-date, we have observed that single IVT injection of 022 demonstrates robust treatment responses with long-term durability and a favorable safety profile in wet AMD patients who require frequent anti-VEGF injections to maintain their vision. Based on these positive results and the unmet need for a long-lasting treatment option, we proposed an accelerated timeline to the FDA to deliver ADVM-022 to patients as quickly as we can.

And now that we shared with you the outcome of our FDA interaction. Previously, you may recall that we're planning to conduct first the Phase 2b study with a 2E and 6E11 doses followed by single Phase 3 study where the one goes. With regards to those selection, given the impressive response and durability with 2E11 and this high treatments need population and the predictable and minimal eye drop prophylaxis. We have selected two doses that straddle 2E11 to take into Phase 3 in newly diagnosed wet AMD patients. We're now moving directly to two global Phase 3 pivotal trials conducted in parallel that we plan to initiate in the fourth quarter of this year to support of either submission in 2024.

We also planned to have interactions with international regulatory - during season to coming months. These two Phase 3 trials will be randomized mass studied and we'll enroll a total of approximately 900 patients comparing ADVM-022 to aflibercept. 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 AMD.

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 pivotal program. Now let's revisit why we're focusing on developing a model approach with a treatment of patients with wet AMD. We have conducted extensive market research and we've had frequent discussion with retina specialist and patients and our research has revealed that the largest unmet need for patients with wet AMD is for durable treatment that reduced the frequency of anti-VEGF injections for better efficacy, improved these of administration and better control of macular fluid.

This is where ADVM-022 fits in to addressing those patients needs. If you look at the current treatment landscape, as well as treatments and development, we see that some approaches are expanding the duration between treatments by a magnitude of weeks. But ADVM-022 is the omni-investigational non-surgical treatment option that has demonstrated long-term durability up to two years and is delivered as a single in-office IVT injection and we plan to continue to follow-up in OPTIC up to five years.

We believe that ADVM-022 is uniquely positioned unlike any other treatments on the market or in development as an advanced gene therapy product with a potential to be one and done approach for millions of people living with wet AMD globally. If you look at the clinical profile of ADVM-022 including the recently presented data Angiogenesis 2021 by Dr. Khanani, 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 60 weeks and there's an 85% reduction in annualized anti-VEGF frequency. Importantly, this dose is a favorable safety profile and a predictable prophylactic steroid eye drop regimen with no patients any inflammation at the latest evaluation. With respect to the 6E11 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 would continue to evaluate DME 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 Aaron. I want to acknowledge that we continue to take precautions as a company to navigate the impact of COVID-19. We're optimistic to now have three approved vaccines and we hope to return to normal soon. Despite the challenges during this pandemic, we were able to complete enrollment in our INFINITY study in less than six months and to invest in a new GMP commercial manufacturing facility in Durham, North Carolina.

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

[Aaron Osborne, Chief Medical Officer]

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 is easy to skip just how essential good vision is to perform our day-to-day activities. Throughout my career, I've been fortunate to be involved with many of the anti-VEGF development programs and I believe the progress that we've achieved with ADVM-022 has been a significant advance in the field of treating wet AMD. We're excited to be initiating Phase 3 trials and planning towards 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 Phase 3 study designs. Recall, the OPTIC patient population represents a difficult to treat segment of the wet AMD patient population. These patients in OPTIC required frequent and regular anti-VEGF injections prior to receiving ADVM-022 in order to maintain their vision.

As you can see on the slide from the swimlane plot, before ADVM-022 these patients have frequent injections whilst afterwards following into ritual ADVM-022. The majority of patients at both of those doses have remained entirely free of anti-VEGF injections with a median of 48 weeks follow-up. There has also been a substantial reduction in injection frequency following ADVM-022 with both doses.

At the 6E11 we observed 99% reduction in annualized anti-VEGF injection frequency; whilst at the 2E11 dose we saw an 85% reduction. As for safety, ADVM-022 has been well tolerated with a favorable safety profile both doses evaluated. Overall, ADVM-022 related IEs were mild to moderate with no severe and non-ocular ADVM-022 related IEs. Ocular inflammation has been managed steroid eye drops at both doses with no evidence of posterior retinal inflammation. Whilst average cellular inflammation has been low grade with both doses there has been minimal cellular activity and minimal steroid eye drop use after a six-week prophylactic regimen with the 2E11 dose.

The most recent data that we shared with the FDA during our recent interaction showed that no patients receiving 2E11 in OPTIC at the latest time point have any cellular inflammation. With the 2E11 dose, in this OPTIC population that previously required frequency anti-VEGF injections across cohorts two and three we have seen sustained and stable anatomic improvements with stable vision. The Phase 3 studies will enrol newly diagnosed patients with wet AMD at study sites around the world. The study designs and population will be similar to other treatment naïve intravitreal Phase 3 studies in wet AMD and they're expected to support a broad treatment label.

Specifically, we will include both phakic and pseudophakic patients and we will not exclude patients based on baseline serum neutralizing antibodies to AAV. In these trials, approximately 900 patients will be randomized to receive a single IVT injection of 3E11 or 1E11 or ADVM-022 or aflibercept every eight weeks. Similar to OPTIC, patients receiving ADVM-022 will receive a two months prophylactic steroid eye drops regimen. The primary endpoint will be non-inferiority to aflibercept based on change from baseline in best corrected visual acuity out in one year.

Secondary endpoints will include safety and tolerability any needs can supplement anti-VEGF injections post ADVM-022 and change from baseline in central retinal fitness and other anatomical parameters as assessed by optical coherence tomography. Supplemental injection criteria will be similar to OPTIC and based on vision and anatomic changes. We're now working with our investigators and regulators in the US and around the world to finalize the study protocols and preparing for study initiation in Q4.

We have had tremendous investigator interest in OPTIC 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 over to Dr. Khanani, I want to share our future plans focusing on ADVM-022. In OPTIC, patients who complete this two-year study are now being enrolled into a three-year extension study so these patients will be followed for a total of five years. We plan to present further data from OPTIC in the second quarter of this year and these data will include longer term outcomes importantly one-year data from Cohort 3.

The INFINITY study in diabetic macular edema is also progressing well. After completing patient enrollment earlier this year we plan to present primary endpoint data from this randomized control 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. Khanani 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. This is an inspiring video that provides the patients perspective. But before we share the video, I need to remind you that our esteemed legal counsel insist that we include the disclaimer about this video which is a single patients testimonial. Whilst this patient and the majority of patients in OPTIC have remained supplemental anti-VEGF injection free, others have not and obviously we don't want to extrapolate these results to our therapies potential as a treatment option for the millions of patients living with wet AMD. In sharing this video, we hope to bring the patient journey clearly into the picture. Patients are the center of everything we do at Adverum and this is why we're developing, what we believe is potentially transformative therapy.

Let's play the video.

[Audio/Video Presentation]

[Laurent Fischer, Chief Executive Officer]

First of all Dr. Khanani, welcome and thank you for sharing the 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 ADVM-022, would you share a few comments around these slides please?

[Arshad Khanani]

Thanks Laurent and thanks for having me here. Really this video is so powerful and so motivating. I have to take deep breath every time I listen to it and look at it because this is why we're doing, what we're doing. We are here to transform the lives of patients that we see on a daily basis who are struggling with this disease, the treatment burden, the uncontrolled nature of disease even with frequent injections and then having them an opportunity to live their lives and continue with their activities on a daily basis.

So I'm excited to be part of this trial and obviously the prospect of this therapy going forward. I do have the slides here. If I can move to it. So this is the slide for this patient. So as you know, we discussed during the video. This patient who had persistent disease activity saw on the left you can see prior to ADVM-022 that an OCT where you can see those black cystic changes in the retina and she does have some scaring underneath and that's why her vision is not perfect. But even with frequent injections on a monthly basis, her disease was not controlled and as you know, as physicians we treat patients based on OCT and because of my early positive experience, I offered her the OPTIC trial, you can see her baseline visual acuity was 63 letters and after a single in-office injection of the low dose 2E11, you can see how she looks like now.

I just saw her few weeks ago, you can see 68 weeks after a single injection you can see there is no disease activity. There's no fluid and she has not required supplemental aflibercept injection for this time period. So that's why patients are excited. That's why physicians are excited and that's why my colleagues, that see this data and see the power of this drug are excited about it.

Let's go to the next slide. Most of us have seen this case before, we have presented it at many meetings in including the latest Angiogenesis meeting. But this is another patient of mine. And I think this case highlights two things. Number one, this patient was not controlled with four to five weeks of aflibercept injections. 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 is fluctuations and we know now based on data from [indiscernible] trial as well as the HAWK and HARRIER studies, that patients who have fluctuations in their CST actually do poorly long-term in terms of visual acuity.

So when I look at this treatment, I not only look at having a single in-office injection that can essentially modify and control the disease for long-term and majority of patients but I also look at this treatment as being transformative because we can have patients who will lose vision with regular frequency anti-VEGF injections and we can control their disease because we're getting such steady levels of aflibercept from a single in-office injection. So you can see on the left patient has persistent fluid in the OCTs and after a single in-office injection patient has done really, really well. You can see the BCVA has increased significantly to 83 letters and the OCT continues to be dry at 40 or eight weeks after the treatment.

So really Laurent, my goal here is to share my excitement and the patients excitement with you today and I'm thrilled to hear that the programs are moving forward at a very rapid pace. Happy to take any questions you have.

[Laurent Fischer, Chief Executive Officer]

Great, thank you so much Dr. Khanani, really appreciate that and color on this patient. Your patient has shown the potential to be treated in her other eye, what percentage of patient develop bilateral wet AMD at the time and would you consider injecting the second eye with 022?

[Arshad Khanani]

Absolutely Laurent. The efficacy we've seen with ADVM-022 a single injection has been so potent. The patients in the trial are asking. So obviously this patient does not 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. Talk about coincidence, I just saw a patient who finished one-year in the trial. And I asked her, how her experience has been and she's like it's been fantastic. But my problem is, you're not giving this treatment in my fellow eye and I still have to get those injections and when can I get the treatment in my fellow eye.

And I said, 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.

[Laurent Fischer, Chief Executive Officer]

Thank you, Dr. Khanani. And obviously as we recalled we did an NHP study showing that, you could do that safely at the peak of in response and see still very good pertaining special level. So we're planning to look into the potential to look bilateral 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 Khanani]

Absolutely, we had a live presentation. It was not a pre-recorded and you saw Dr. Phil Rosenthal, raising the question that intravitreal approach obviously is more favourable than other approaches that we have seen. My colleagues I think the number one thing is, the fact that you can deliver this in an office setting like a routine intravitreal injection and that procedure is all of us around the world can deliver it without having any special skills that are needed. So my partner who is actually retiring soon said, why would anybody look at any other mode of delivery and my answer was the same I gave it Dr. Rosenthal. I think we're still learning about gene therapy obviously intravitreal is the preferred approach because we can treat patients around the world for this chronic disease.

And really the efficacy when they look at that case, I think the efficacy is phenomenal. I guess so many times every time I present the case, they're like how's the patient doing now? How's the patient doing now? And I think what we're all impressed with not only the control of disease initially but continued control of disease throughout the patient course and the 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 approach has been very impressive and 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's value to it. It's not an incremental benefit. It's really game changing in terms of transforming how we manage patients this lifelong disease. So I think the excitement is clearly there when I talk to my colleagues.

[Laurent Fischer, Chief Executive Officer]

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

[Arshad Khanani]

Yes, 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 on in top sites in the world are going to be of course excited about this trial and next question is, competitive landscape for trials? And we were at the top site for the TENAYA study of faricimab. We are the top site for the DAZZLE trial for KSI-301 and I can tell you, we enroll those large trials as a community, at the retina space within less than 12 months and those especially the TENAYA study as you mentioned is very, very, large.

So not having another competitive trial for naïve patients having this solid data from OPTIC trial. I think there's going to be excitement and I think all of us will want to take participate in this study and I can confidently said based on my experience being a top site in many of the naïve AMD trial that we should be able to recruit this trial within one-year or less and I think, it's all going to be very good for our patients. The sooner we have this treatment for our patients the sooner we can help it, patients around the world. Who are suffering from this chronic disease?

[Laurent Fischer, Chief Executive Officer]

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

[Arshad Khanani]

Yes, as I mentioned Laurent. It's our job as researcher and clinicians to look at different delivery options and different treatment options for our patients and then look at efficacy of those approaches. So as you know, I'm also an investigator and a PI for [indiscernible] subretinal delivery as well GT005 for dry AMD, Gyroscope as well as I'm PI for suprachoroidal approach. Your question about subretinal approach obviously it's something that after you have experienced you can perform that procedure. But obviously going to OR is a bigger hurdle than delivering something in an office.

So let's say I see a patient today and I do the screening for them and then if everything looks good, I can bring them to clinic and randomize in a trial versus if I have a patient that needs to go to the OR, we have to have our staff coordinate that patients need to be ready, they have to go for a pre-op, they have to stay off their anticoagulant and that's just not subretinal gene therapy and I'm also - we were one of the top sites for the Port Delivery System which is a surgical trial too.

So obviously arranging and having patient go to surgery is a much bigger task on my coordinators and staff and then when you're in surgery obviously the companies want to make sure everything is done right, so they have to coordinate their schedules to be available for surgery. So yes, it's doable it's not a problem. But obviously anything in clinic whether its intravitreal or suprachoroidal, it's easier. But obviously as you know the suprachoroidal 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 train on it.

[Laurent Fischer, Chief Executive Officer]

This is great. I'm only so impressed to see how many studies you're involved on top of all the patients you see, it's really great to have you as an investigator in our trials. Talking a bit about current standard of care versus the future. We know that real world data is not good with clinical trials. How do you see the treatment paradigm shifting from these current regular injections and follow-up to potentially something about 022 can bring as an option?

[Arshad Khanani]

Yes, Laurent that's what I'm after. I want to make sure that my patients do well long-term. We see these patients they get treatment, they do fine in the first year, things start to slip in the second year and then you look at four, five, six, seven years. You know we have cap seven years data, we have seven up study. These patients end up being really poor vision long-term and of course treatment burden is the biggest issue and your comment about I'm involved with everything because I'm involved with everything because I want to make lives better for my patients and now, I'm serving as a PI for almost 60 clinical trials. And this is exciting time for our space but when you look at our space. You have to divided treatment options into two buckets.

You have to divide treatments where you can do an intravitreal injection and be incrementally better in terms of durability. So you can add a month or two months or three months on top of what we have and that's great for patients and you know things like faricimab and KSI-301 GB102 [ph] those programs are moving forward and that's really exciting. But then the other part is sustained delivery. The continuous delivery which can lead to the disease control which is very difficult to achieve with intravitreal 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 Port Delivery System has started that, but it's a surgical procedure in the OR, so it has its own risk and benefits and it's not really a primary treatment. But what I see is, I see 022 as a primary treatment for these patients after we have controlled their disease. Of course the trial with naïve patient will give us more idea. But if I see a patient in my clinic that have naïve disease, I'll do an intravitreal injection obviously and then get them primed up to go into receiving gene therapy for 022.

So I think it's a chronic disease with poor long-term outcomes and treatment burden can easily be reversed with this approach. You saw the case I presented both of those cases and these are real patients that have really benefited from this approach.

[Laurent Fischer, Chief Executive Officer]

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

[Arshad Khanani]

I think it's going to be huge, Laurent. Both in my opinion in vascular AMD and DME. I mean you see around the world, you look at 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 continuous monthly or every other month injection. Here, we can modify these lifelong chronic diseases with a single injection and obviously you've to initially monitor these patients and as Aaron said, this is not a continuous process. I think once they've finished their topical drops and they're controlled. Telemedicine would be used. Telemedicine has really exploded because of COVID-19 and anybody can monitor these patients afterwards.

So I think after the initial dosing, we monitor. But then after that I mean I'm not looking forward to seeing these months every month or every other month, maybe every six months. If they want to come in. so think about patients waiting for treatment around the world because they don't have access. You have one and done therapy that's going to really help the patients and physicians be able to treat more patients because they don't have to treat them continuously. So I think this is going to be huge, if efficacy continues to be as good as we've seen in uptake and then the manageable safety.

[Laurent Fischer, Chief Executive Officer]

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

[Operator]

[Operator Instructions] the first question comes from Graig Suvannavejh with Goldman Sachs. Please go ahead.

[Graig Suvannavejh, Goldman Sachs]

This question is for Dr. Khanani. It's great to hear from you again. Just wanted to get your thoughts on the company's strategy of moving to different dose than what was evaluated in OPTIC study and more specifically, with the lower dose and the higher dose of one and three. What do you expect to see from those two doses? And perhaps more importantly, what do you need to see from those two doses to feel comfortable with the profile that you seem thus far and perhaps if I could then ask a question, Laurent. I just wanted to revisit 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 or different question would be around DME. What are the current thoughts that we could perhaps a takeaway from this with DME timeline? Thanks.

[Laurent Fischer, Chief Executive Officer]

Thanks Graig. Before I pass it on to Dr. Khanani. I think it's important to know that, what's unusual about this program is that, we started our first study in the hard-to-treat population with the dose we thought it will be last dose, so we've had actually 100% of the patients with no need for additional anti-VEGF injection. So we started a day at the top of the dose response curve and as we know, in gene therapy those are fairly flat. So that 2E11 was we thought a great dose to straddle around now going to first line therapy less demanding as far as anti-VEGF need patients to really provide enough dose response between what we've seen and what we believe will provide a good drug profile. But I'll let Dr. Khanani, answer in more detail.

[Arshad Khanani]

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

So I think I'm expecting very potential efficacy from 3E11 and then as Laurent said, I think we need to remind of ourselves the fact that these were heavily pre-treated patients with longstanding history of their disease and really tough to treat population. So since the pivotal as Aaron mention and you have a really nice overview is are looking at naïve patient population and those are fresher patients and we know based in our experience the sooner you treat the patient, the better control you're going to get.

So in a naïve population I can easily see that even 1E11 can be beneficial. So I think in terms of having both doses I think it's the right decision in my opinion and obviously people who are involved with designing this trial. So I'll pass it to Aaron. Aaron, do you have any comments on top of what I mentioned?

[Aaron Osborne, Chief Medical Officer]

No, I think that's exactly right. I mean we've seen a favorable safety profile with both of the doses. What we've seen is that there's been a really strong anatomical response and great durability with both of those doses as we've tracked the data longer and longer. I think the lower dose 2E11 has sort of pleasantly almost surprised us by this continuing great signal is kind of optimized by those two patients that Dr. Khanani presented. And on the flipside, if you look back at the higher dose, we're going to continue to evaluate that. We're evaluating in DME. It's possible within a few treatment there are other indications that may benefit from the VEGF blocking ability with that high dose. We've already presented protein expression data from two patients who receive that high dose which really correspondent with about three weeks after aflibercept bonus injection.

As we go forward, we'll certainly present more protein expression data. But I think those data given idea are just how rough and robust that protein expression is and as you we look at the lower dose, we've got that continued stable, visual acuity and anatomical response again in these top of - to treat patients. So going to 3E11 and 1E11 two doses that straddle at 2E11 provides some additional dose ranging that seems to be an optimal approach for Phase 3 and it's something that we discussed with the agency and they were in full alignment that seemed to have a good approach.

[Graig Suvannavejh, Goldman Sachs]

And maybe just on DME timeline?

[Laurent Fischer, Chief Executive Officer]

We'll continue to present obviously data in protein expression as they mature and we'll present one-year data in Cohorts 3 and then one-year data on all the Cohorts including Cohorts 4. And then DME, we're studying both doses 2 and 6E11 and study is being fully enrolled. It's blinded. And we'll report in second half as soon as we have the top line data. Obviously given this is a potentially large indication where we're going to look at DME as well as DRSS who have potential to go into DME or DI [ph] which study is positive. We'll obviously report once we have risk [ph] side information.

[Graig Suvannavejh, Goldman Sachs]

Fair to assume, it could be instead of a combined filing an sNDA for sBLA strategy?

[Laurent Fischer, Chief Executive Officer]

Currently we have two different INDs for each indication and then that's the case of most [indiscernible] they're treated by the ophthalmology division a separate indication 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?

[Operator]

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

[Tyler Van Buren, Piper Sandler]

First wanted to follow-up on the design. Are you assuming lower bound of the non-inferiority margin to be minus four or somewhere around there? Could be helpful if you could confirm that as well as the thinner deviation, the 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 supplemental injection criteria picked up on the slide that and 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 the incentive treat change and PCBA [ph] will be I guess analyzed independent of supplemental injections?

[Laurent Fischer, Chief Executive Officer]

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

[Aaron Osborne, Chief Medical Officer]

Thank you, Laurent. Thank you, Tyler. This will be in non-inferiority study against the aflibercept standard of care and similar to sort of other treatment naïve study that non-inferiority margin. It will be four letters. So that means the lower bound of the confidence into both ADVM-022 related visual acuity needs to be within four letters of the point estimate for the controlled arm. So that's kind of established and is being used in several trials before.

Where we're little bit different and we spend time with FDA on this, is how we get to a number per arm that is actually much less than previous trials approximately half the number. And that goes kind of to the second part of your question, which is standard deviation. Which has driven a lot by the gains in visual acuity there are often experience following the first injection. So what we plan to do with this study, is actually take patients who are treatment naïve. They have one injection and provided they share a response to that and an anticipated need for or need for future treatment then their baseline starts at that point. They'll then receive another injection and receive ADVM-022.

So that's still on the up phase of gaining visual acuity on average. But a lot of that initial gain has already taken place which then means is the variability has reduced. So expect the standard deviation to be significantly lower than it would be for a typical treatment naïve study such as the faricimab or [indiscernible] study that Dr. Khanani mentioned. So the standard deviation is lower than it would be for those study. So that's the non-inferiority and the standard deviation.

I think the final question was on the retreatment or supplemental anti-VEGF criteria. I mean plan to see 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 rate anatomical maintenance and it's really always striking a 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 that constant adjust suppressional [ph] going in the background. So we plan to keep these very similar to OPTIC.

We've got a little bit time before reaching our very final protocol. So we'll continue to monitor the data in OPTIC and as we speak to physicians and regulatory particularly ex-US as well. 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.

[Tyler Van Buren, Piper Sandler]

Very interesting, thank you.

[Operator]

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

[Mani Foroohar, SVB Leerink]

Obviously, you've got a lot of detail here. I want a little bit of more nuanced question around what you've seen in terms of changed and patient behaviour during the pandemic period. How that's influenced patient enrollment across trial given that your - Dr. Khanani investigator across mainly for wet AMD trials and how as we see the pandemic ease results which I'm afraid is only use, could see a shift towards less of your patients as fewer coming and the office goes down. Just how do you think of that impact in terms of the population that gets enrolled in view, two Phase 3s versus perhaps population that might be, being currently enrolled in other clinical trials that were actively enrolling that you were part of during the height of the pandemics?

[Laurent Fischer, Chief Executive Officer]

Mani, thanks for the question, great question. As a reminder, we fully enrolled into today's study during COVID-19 all remotely in six months which we thought was pretty remarkable. But obviously Dr. Khanani is in the best - question about how this has changed and how this will change in the future.

[Arshad Khanani]

Thanks Mani and thanks Laurent. And so I think the main thing to point out is that wet AMD is a disease that can lead to irreversible blindness in patients. And if you don't get them treated, they're going to go blind. So even at the height of pandemic throughout the pandemic, we've been really been 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 with me continued injection and we managed our study patients in a very unique way, where we were able to provide them with isolated visits, we can visit, after hour visit. Also putting in COVID protocol that have worked really, really well. So our wet AMD patient population enrollment in other trials didn't stop because of it some of the geography atrophy trials were put on hold because those patients don't see an improvement and it's on emergency for them to get into a trial.

So wet AMD trials have done well. But I tell you what COVID has made us realize and I think your question is very pertinent. As physicians, we cannot have patients coming in every month or every six weeks during this pandemic. These patients are high risk, also the diabetics. So really has put in our heads that we actually have to have therapies that are sustained over 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 having us in a situation where we're putting our patients at risk by bringing them to clinic. But in terms of treatment enrollment in all the trials, we really cater to the clinical trials and I don't see a difference in terms of enrolling patients in these pivotal trials.

Most of my patients actually have been vaccinated now. I ask every single one or received their first dose and it is really promising to see that the numbers have also gone down significantly in our area because of COVID. So really appears that things are hopefully going to be getting towards normal in the future.

[Laurent Fischer, Chief Executive Officer]

Great, thank you. I know we have a few more analyst in the queue. So we try to take them, thanks Mani.

[Operator]

Your next question comes from Phil Nadeau with Cowen & Co. please go ahead.

[Phil Nadeau, Cowen & Co]

Couple questions from us. First on the 022 dose and information. 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 therefore in that dose all of steroids? And if so, for how long?

[Laurent Fischer, Chief Executive Officer]

Aaron, do you want take this?

[Aaron Osborne, Chief Medical Officer]

I can take that, yes, sure of course. The most recent data that we presented from a data in October of last year and these were the data we presented at Angiogenesis. We did review our data that 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 that were taking steroid eye drops and on the low dose - no patients have any signs of cellular inflammation, that's 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 of them showing a really good safety profile and great efficacy. We're seeing really minimal - inflammation after the prophylactic period and minimal steroid eye drop use after that prophylactic period as well with that low dose wears. There's been few cases where patients who needed to go back onto steroid eye drops, a little later with the high dose.

[Phil Nadeau, Cowen & Co]

Great and then second question is on, aflibercept in the comparative arm. How would it be dosed? And more generally how did you come upon your assumptions for the visual acuity benefit you're going to get? It does seem like there's some risk that you now have to match full dose, what I'm assuming full dose at aflibercept in the controlled arm and patients whose visual acuity is actually improving in their first year of treatment. So what gives you confident that you'll be able to achieve that?

[Aaron Osborne, Chief Medical Officer]

Yes, it's a great question. So we'll be comparing to standard of care aflibercept as in the label, which is three initial injection for treatment naïve patients followed by dosing every eight weeks. That's what standard comparative regimen that has been the case for us recently complete the faricimab trial and [indiscernible] trial. In terms of what gives us confidence that we would be able to achieve that. I think it really comes back to data point presented today. When you look at Cohorts 2 and 3 together with low dose in these difficult to treat patients that require many inactions. The vast majority 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 frankly it's extraordinary and I think it's something that we've not seen before with a single injection or single treatment therapy. So that continual VEGF suppression and we're seeing in some of the patient cases as well that has actually means visual acuity gains. Really, we need to do is well as anti-VEGF therapy.

I think what we're seeing in OPTIC, is that some patients are doing better than regular anti-VEGF therapy. So that's really predominantly all gives us the confidence and we can stabilize the retina and restore the anatomy than what should follow, is the visual acuity will improve and we have a trial that is set up to show that.

[Phil Nadeau, Cowen & Co]

Great and then last question just to Dr. Khanani. Let's say the profile in Phase 3 looks exactly like what we've seen meaning patients are 67% injection free or 67% of patients approximately in this dose are injection free. How will monitor patients in your practice? How else and when you them bring back? Are there any signs that you can look for remotely to see if patients are having the disease process return?

[Arshad Khanani]

Yes, so that's an excellent question. Based on learning's from the OPTIC trial as then we have to see these patients more frequently, initially. So I will 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 interior there's no cases of posterior vasculitis, retinitis or anybody that in reversible vision loss. So I think that's something to keep in mind.

So patients can be monitored by optometrist or somebody else, if they needed to be and then they can be treated if they need to with topical drops. But my confidence comes from being an investigator in OPTIC and enrolling the highest number of patients. I feel like after the initial monitoring phase patients can go much longer. I mean I have patients who have been in this trial for one and half years and they keep asking me, why am I coming every month and of course in trials we do that. But in practice I think we can easily extend these patients once they're stable to six months.

[Phil Nadeau, Cowen & Co]

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

[Laurent Fischer, Chief Executive Officer]

Great, we'll take maybe one more question then.

[Operator]

We've got time for one more questioner. The next question comes from Alethia Young with Cantor Fitzgerald. Please go ahead.

[Alethia Young, Cantor Fitzgerald]

I wanted to talk a little bit about some secondary endpoints and the importance of like kind of the rescue regimen as an endpoint. The FDA thinking about maybe as a secondary and I guess that's the same kind of correlated question to doctor. I mean in a way it feels like visual acuity. I mean it's obviously what the FDA needs. This rescue notion is what probably doctors may want, is my first question. And my second question is a little bit more straightforward. Are there any kind of interims or any other analyses baked into 52 weeks [ph]? Thanks.

[Laurent Fischer, Chief Executive Officer]

Aaron, can you take that?

[Aaron Osborne, Chief Medical Officer]

Yes, I can take - the second one is straight forward. actually first, which is because it's a these are registrational [ph] pivotal trials there would be no interim analyses, we would analyze the primary endpoint at one year and intent to use those data to support the BLA submission. With regards to secondary endpoints, you raised a, there's a lot 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 and that's either to patients experience with currently available anti-VEGF patients and the fact that those fluctuations lead to fibrosis, they lead to atrophy and they lead to poor or long-term outcomes. These data are coming through more and more so product that can maintain stability. Could potentially reduce fibrosis, reduce atrophy and lead to better long-term vision outcomes.

And so primarily we want to follow patients long-term. But we'll also be looking at number of OCT analyses that could potentially build that story up more and let us understand more about what that stability with 022 can lead to in terms of anatomical and functional outcomes. That's probably we'll need to say now on at the moment.

[Alethia Young, Cantor Fitzgerald]

Great thank you.

[Operator]

This concludes today's question-and-answer session. I would like to turn the call back to Dr. Fischer for any closing remarks.

[Laurent Fischer, Chief Executive Officer]

Thank you, operator, and thank you all for joining us. This is been really good discussions. I'd like to thank Dr. Khanani and his patients to sharing their journey with us. All well as all the investigating patients who participated in our clinical trials. I also want to acknowledge the important and incredible work the FDA has done during COVID-19 and great outcome. We certainly appreciate the guidance the agency gives the company as they work to develop new therapies for patients with unmet needs. And last but not least, I want to acknowledge the commitment and hard work of our team of Adverum's. 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 preserve patient sight for life?

I'm very enthusiastic about where we're heading as an organization building on our 2024 vision to become fully integrated gene therapy company. We're clearly focused on execution with our lead investigational lead therapy candidate ADVM-022 for two leading causes of blindness with the goal of delivering this potentially transformative gene therapy to patients around the world. We're also continuing to develop our pipeline in ocular and rare disease leveraging our proprietary [indiscernible] platforms with a goal of filing an IND in 2022 and I hope everyone staying healthy and well. We look forward to updating on our continued progress in the future and wish you a good day. Thank you.

[Operator]

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