Adverum Biotechnologies Inc

NASDAQ:ADVM

Earnings Call Transcript 2020-Q1

[Operator]

Good afternoon, and welcome to the Adverum Biotechnologies First Quarter 2020 Corporate Update Conference Call. At this time, all participants are in a listen only mode. 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 Myesha Lacy, Vice President of Investor Relations and Corporate Communications of Adverum. Please go ahead.

[Myesha Lacy]

Thank you, and welcome, everyone. Today we issued a press release announcing our new INFINITY trial for ADVM-022 and diabetic macular edema, as well as reporting our financial results for the first quarter of 2020. A copy can be found on the press releases page of the Investor Relations section of our corporate website at www.adverum.com.

Also posted on our IR website is a slide presentation to accompany this call, which is available on the Events and Presentation page of the IR section of our website. Also a replay of today's call will also be available.

Joining me for the prepared remarks portion today is Leone Patterson, President and Chief Executive Officer and Dr. Aaron Osborne, Chief Medical Officer. Then Leone, Aaron and our Chief Financial Officer, Thomas Leung, will be available for the Q&A portion of the call.

As a reminder, we will be making forward-looking statements regarding our product development plans, research activities and operations, as well as our financial outlook. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those forecasted. A description of these risks can be found in our 10-Q, which was filed this afternoon.

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

[Leone Patterson, President & Chief Executive Officer]

Thank you, Myesha. Good afternoon, everyone, and thank you for joining us today. Before we start talking about our recent business progress, I'd like to acknowledge the impact of COVID-19 on our community. As always our primary focus is on the health and safety of employees, patients and health care providers. Since the mandated shelter-in-place executive order was put into place by the San Francisco Bay Area in the state of California, we immediately implemented the use of remote study monitoring and of several precautionary measures at study sites to maintain the health of our patients. Like many companies, we are taking necessary precautions to support our employees and conduct our business.

Additionally most of our employees have been working from home since March 13. I am grateful for the achievements our employees have encompassed so far this year as we continue to advance our clinical pipeline and executing on our mission to develop and commercialize our novel gene therapies for patients with various ocular diseases.

We believe our leading therapy program ADVM-022 has the potential to be a one-time intravitreal injection gene therapy approach for two indications, impacting patients with VEGF-driven ocular diseases: wet AMD; and diabetic macular edema or DME. Aaron will review the significant clinical progress with those two for both wet AMD and now DME. We will then open the call for questions.

Let's start with wet AMD and the ongoing optic Phase I dose raising trial we have been exploring two doses of 022, a dose of 6E11 and a three times lower dose of 2E11 and more recently two prophylactic steroid regimens, a short course of oral steroids and a lower course of steroid eyedrops.

Earlier this month, we presented new data from the first three cohorts. The data from OPTIC has continued to be very promising. 022 continues to demonstrate robust efficacy and an evidence of a dose response. This therapy has shown long-term durability beyond one year with zero rescue injections and patients treated in Cohort 1 also encouragingly early data from Cohort 3 including visual acuity and OCT improvements.

022 continues to be well tolerated with further evidence that steroid eye drops are effective in managing ocular inflammation and we are now focused on completing enrollment in Cohort 4 with dosing underway.

We are on track to present data from all four cohorts in OPTIC by the end of this year. We also plan to develop 022 in DME. We're excited that the FDA has approved their IND in diabetic retinopathy. We have been preparing for this and our INFINITY Phase 2 trial is open for patient enrollment as Aaron will describe in more detail.

Our team is executing effectively to position Adverum as a leader in gene therapy. Beyond these near-term opportunities for 022, we are focused on developing a pipeline of novel gene therapy.

We regularly present data on these earlier stage therapies in our industry-leading AAV platform at scientific conferences, and we presented virtual posters at ARVO and ASGCT on these programs. Our expertise is a novel vector development and we look forward to expanding our pipeline beyond 022 and sharing more about this progress later this year.

In another exciting progress update, first, I'm pleased that Dr. Scott Whitcup, joined our Board of Directors. Scott is an experienced ophthalmologist and successful drug developer, who is already providing valuable strategic contributions as we seek to bring our therapies to the market.

And finally, in February, we completed a successful financing and ended the first quarter with $297 million in cash, cash equivalents and marketable securities. We expect this cash to the finance operations until 2022.

I'd now like to turn the call over to Aaron, who will provide further details on our clinical progress for ADVM-022. Aaron?

[Aaron Osborne, Chief Medical Officer]

Thanks Leone. First and foremost, we continue to work closely with our clinical trial sites to protect the health and well-being of our patients. Participants in our ongoing OPTIC Phase 1 trial, have wet AMD and are in high-risk categories for COVID-19 complications based on age, comorbidities or both.

We have worked together with our sites in implementing precautionary measures and alternative study conduct measures when required, including remote study monitoring and remote patient assessments.

As the COVID-19 situation continues to evolve, we will continue to work closely with our trial sites, clinical study vendors and industry partners to monitor best practice and guidance updates. We believe the need has never been greater than now for a one-time intravitreal anti-VEGF agent that provides long-term control of disease activity.

Truly, this has been a very exciting time for our teams working on advancing this novel gene therapy in the OPTIC trial for wet AMD and now the INFINITY trial for diabetic macular edema.

Firstly OPTIC, we continue to make strong progress advancing this trial. Our immediate focus is to quickly enroll Cohort 4. There is strong support from the investigators and clinical sites to do this, and we look forward to presenting data from all four cohorts by the end of this year.

2020 has been a robust year of clinical data presentations for our OPTIC trial. Earlier this month, we presented an update from OPTIC including interim data from patients in Cohort 3 who received the lower dose of 022 as well as a 6-week prophylactic regimen of steroid eye drops instead of the 13-day oral steroid prophylaxis that was used in Cohorts 1 and 2.

The key takeaways from this presentation of OPTIC data through April 1, 2020 were as follows: long-term durability beyond one year from a single intravitreal injection has been demonstrated with zero rescue injections in Cohort 1 out to a median of 60 weeks follow-up; we saw further evidence of a dose response at 6E11 and 2E11 dose levels across all three cohorts; evidence from Cohort 3 was presented indicating that the prophylactic regimen of topical steroids is effective at minimizing early ocular inflammation; early data in the first five patients with 20 weeks follow-up in Cohort 3 show improvements in visual acuity and reductions in macular thickness as assessed by OCT.

As a reminder, OPTIC includes treatment-experienced wet AMD patients, who previously required frequent anti-VEGF intravitreal injections to control their wet AMD. These data continue to show that a one-time intravitreal injection therapy like ADVM-022 could change the treatment paradigm for physicians and patients.

Given the promising data presented to date for ADVM-022, we are excited to move forward with our plans to assess ADVM-022 in patients with diabetic retinopathy. Approximately 30 million people are impacted by diabetes in the United States, and each of these individuals is at risk of developing diabetic retinopathy or DR.

DR affects approximately one in three adults with diabetes and puts patients at risk of vision loss. DR can be diagnosed at different severity levels with the risk of sight threatening complications being higher at higher severity levels and is the most common cause of blindness in working-age adults in the U.S. And as the prevalence of diabetes continues to grow, the prevalence of diabetic eye diseases is expected to increase.

Diabetic macular edema or DME is a vision-threatening complication of DR that can occur at any severity level in people with diabetic retinopathy. DME is the leading cause of vision loss in patients with diabetic retinopathy and affects around 5% of adults with diabetes.

The DME market therefore represents a significant opportunity. The current standard-of-care therapy for DME is anti-VEGF intravitreal injections. These are effective, but typically require frequent and long-term injections for patients to maintain good vision.

Compliance with these treatment regimens can be difficult for patients leading to under-treatment and vision loss. Analyses of claims databases show that real-world outcomes in DME with anti-VEGF therapy are meaningfully worse than in clinical trials.

Retinal specialists are very excited by the potential benefit that a long-lasting anti-VEGF therapy such as ADVM-022 could offer for this growing population of patients.

Now, let's discuss our own program in DME. The INFINITY clinical trial of ADVM-022 in DME is a Phase 2 multicenter randomized double-masked active comparator controlled trial. We designed this trial to demonstrate superior control of disease activity following a single injection of ADVM-022 compared to a single injection of aflibercept as measured by time to worsening of DME disease activity using protocol-specified criteria.

Additional objectives include assessments of treatment burden; visual acuity; retinal anatomy, including macular thickness as assessed on OCT, and retinopathy severity as assessed by photography; and safety outcomes. All patients will receive a course of prophylactic steroid eye drops.

We expect to enroll approximately 33 patients with recently-diagnosed diabetic macular edema. INFINITY will evaluate the higher 6E11 dose and the lower 2E11 dose of ADVM-022. Patients in the control arm will receive aflibercept only. All patients will be eligible for rescue aflibercept injections from week eight onwards.

INFINITY is a 48-week study with the primary objective being assessed firstly at week 24. INFINITY has been designed to provide robust controlled data on ADVM-022 in DME and will be conducted at trial sites across the United States.

I will now turn the call back over to Leone.

[Leone Patterson, President & Chief Executive Officer]

Thanks Aaron. Before opening the call for questions I want to acknowledge my appreciation for the healthcare providers who remain committed to OPTIC and are preparing for the INFINITY clinical trial. And we are equally grateful for the patients who continue to be treated and monitored with our novel gene therapy to support this important development work.

I'm excited to lead Adverum as we work to develop a potential transformative one-time treatment for patients with wet AMD and DME. We remain committed to our mission to advance these programs in our pipeline of novel gene therapies for patients with serious ocular diseases. Operator?

[Operator]

Thank you. [Operator Instructions] Your first question comes from the line of Tyler Van Buren with Piper Sandler.

[Tyler Van Buren, Piper Sandler]

Hey guys. Good afternoon. I wanted to ask about the DME trial design. A very interesting design relative to the historical endpoints that we've seen in terms of BCVA improvements or three-line gainers. So, I guess, just a quick point of clarification.

With respect to the study time to worsening of DME disease activity is that defined as a rescue injection for the criteria? And if that is indeed the case it appears as if it's very unlikely that this trial does not succeed. I mean what percentage of aflibercept patients can go 24 weeks DME, aflibercept patients can go 24 weeks without an injection?

[Leone Patterson, President & Chief Executive Officer]

Thanks Tyler.

[Aaron Osborne, Chief Medical Officer]

I was just…

[Leone Patterson, President & Chief Executive Officer]

Yes. Go ahead. I was going to say Aaron just quickly I would say that's a really good point. And obviously the expectations that have been set given what we have done in OPTIC, Tyler really sort of emphasizes how a long-term durable effect that we've seen in OPTIC could be played through. And then you're assuming that obviously with DME that that could be the case given that we have been able to achieve that with wet AMD patients. But in terms of the patient population for DME it probably would be helpful if Aaron to talk through really the differences here in the patients and how long they typically go without injections and a little bit further details on that.

[Aaron Osborne, Chief Medical Officer]

Thank you, Leone and thank you, Tyler for that question. And specifically on the second part of the question, which is kind of how long would you expect aflibercept patients to go without an injection. Well based on evidence from other studies that have looked at anti-VEGF compounds with similar retreatment criteria and you're right those retreatment criteria either of those in INFINITY, we would consider to be a progression of DME disease activity. And if a patient meets either of those criteria from their week eight visit onwards then they can be rescued with aflibercept.

And because it's a fully-masked study the investigator will not really know if the patient is on 022 or if the patient is receiving aflibercept. So there's a robust design here which allows for a robust comparison. And we would expect more than half of the aflibercept patients to have required rescue by around week 16. So to your point these are patients who have been recently diagnosed with diabetic macular edema. There's a high treatment need early in disease and we'd expect more than half of those aflibercept patients to meet one of those criteria by week 16 and to have had a rescue injection.

And obviously so ADVM-022 we have not tested this yet in diabetic macular edema, but based on VEGF levels that we see in studies comparing diabetic patients and patients with wet AMD as well as other retinal vascular diseases, we'd expect broadly a similar amount of VEGF to be produced and we'd expect a broadly similar type of effect within that range. Obviously, it's the first time in diabetic eyes, but based on the OPTIC data certainly with the higher dose where we've seen all of the patients treated with the higher dose in Cohort 1 to be out to a median of 60 weeks with no requirement for rescue injections.

And the majority of patients at the lower dose have not received any rescue injections either and have remained stable from both an anatomical and visual perspective so we'd expect a much lower proportion on the ADVM-022 side to reach one of those criteria. And that's why we're able to have a relatively small sample size in order to address that primary endpoint.

I mean, it is an early phase study but it is robustly designed. You mentioned registration endpoints as well. Typically that would be a vision endpoint and this trial is not powered to robustly assess visual acuity. And that's why we've gone for an endpoint that we believe, we should be able to see a difference between current standard of care i.e., Eylea intravitreal injections compared to ADVM-022, which potentially could be a onetime treatment for diabetic macular edema.

[Tyler Van Buren, Piper Sandler]

Okay. And my follow-up question was just related to your interactions with the FDA that help inform this novel trial design because clearly the probability of success is quite high. And I was curious if there would be some novelty to your registrational trial design. You just, I guess, alluded to using more traditional endpoints, but curious to get your thoughts around that assuming this study is successful which seems highly likely.

[Leone Patterson, President & Chief Executive Officer]

Yes. I think…

[Aaron Osborne, Chief Medical Officer]

I think I can take that one.

[Leone Patterson, President & Chief Executive Officer]

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

Aaron, what do you want to add to that? Maybe a little bit more?

[Aaron Osborne, Chief Medical Officer]

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

[Tyler Van Buren, Piper Sandler]

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

[Operator]

Thank you. And our next question comes from the line Phil Nadeau with Cowen & Company.

[Phil Nadeau, Cowen & Company]

Good afternoon. Thanks for taking my questions in Maybe a couple of follow-ons to Tyler's. First on the rescue criteria itself in the INFINITY trial, can you talk about how those criteria compare to other criteria used in DME trials? And maybe more generally how those criteria compare to what a physician would use in clinical practice when deciding whether to give a DME patient another aflibercept injection?

[Aaron Osborne, Chief Medical Officer]

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

You can go a little bit tighter on the DME trials than you can in AMD with regard the central subfield thickness, because the retinal anatomy is generally less distorted. You can measure that central subfield thickness, generally more consistently in the DME trials and therefore it can be slightly more reliable indicator.

In the clinic, I think very much similarly to AMD if there's an increase in edema and especially if the vision's impaired then likely physicians will be injecting. They go primarily on the OCT. In a clinical trial, obviously you want to get those decisions made robustly and consistently across the trial so that's why we have the protocol-specified retreatment criteria.

[Phil Nadeau, Cowen & Company]

That's helpful. And then maybe a second question just on the OPTIC study. In your prepared remarks you mentioned, you're working to enroll Cohort 4. Could you give us just maybe a bit more information on how many patients have been enrolled and whether you think there's any risk that COVID will delay the completion of enrollment in that study?

[Leone Patterson, President & Chief Executive Officer]

Yeah. Let me take that. So I think we were – we reiterated again that we believe that we'll have data that we'll be able to present on all four cohorts by the end of this year, and we're still holding to that. And I think to your point around COVID, there is still to be played out here in terms of the overall impact over the longer haul. But right now, we feel pretty good about the amount of dialogue interactions with the sites that the screening and the ongoing enrollment will continue at a pretty good pace. I think that what we – we've only talked about dosing of this patient I don't think we can share anything more than that other to say that we still feel comfortable that we'll be able to share data on all four cohorts by the end of this year.

[Phil Nadeau, Cowen & Company]

Thanks for taking my questions.

[Operator]

Thank you. And our next question comes from the line of Alethia Young with Cantor.

[Alethia Young, Cantor]

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

[Leone Patterson, President & Chief Executive Officer]

All right. So starting on the severity and the patients I think Aaron why don't you take that in terms of the patients who we're targeting? We gave some that in our prepared remarks but maybe just a little bit more color there.

[Aaron Osborne, Chief Medical Officer]

Yes. No exactly. So these are patients with DME that DME is causing -- they've got some reduction in vision, so they have fluid in the center of the macula. DME is probably about 5% of the DR population. I'm talking about center-involving DME. So there's more than 30 million patients with diabetes in the U.S. then we're looking at around 1.5 million or two million patients with DME likely in the U.S. So it's a pretty significant number and maybe even more than the number of patients who've got wet AMD.

In this trial, we're basically taking patients with any severity level as long as that fluid is involving the center of their macula and they have some vision impact and they've got relatively recently-diagnosed diabetic macular edema. We've gone for a pretty sort of homogeneous population. It's a randomized trial. We've got small groups in each arm and the macular edema can kind of act as somewhat of a VEGF-ometer and it's a very titratable endpoint and something that you get good granular detail on.

So that's why we've chosen DME and to have a well-controlled patient population. I think as we move forward, one of the hopes for a onetime intravitreal treatment would be that it could actually move the point of intervention earlier in diabetic retinopathy. So we've said that diabetic retinopathy can present at any stage and if patients get DME then they're already losing vision or at risk of losing more vision patients with a higher severity are at risk of developing proliferative complications. So if you could have a therapy that lasts for a long time and is delivered in a relatively non-interventional way that could have a big impact.

And that's something that we would certainly look at in the future is potentially moving to kind of a even broader diabetic retinopathy population. But the DME population is a large population. There's significant unmet needs. Anti-VEGF therapies work well, but they require frequent and long-term administration to get good results, so this seems an ideal population to start with.

[Alethia Young, Cantor]

And then on your plans for OPTIC maybe as you go outside of the next four cohorts and then to like bigger studies, maybe any color on kind of endpoints or how you might think about kind of running what dosing group?

[Leone. Patterson]

So I'll start and then I'm sure Aaron will weigh in on designs as we're sort of trying to plan out. So I think an answer, I guess we've talked about having released the data on Cohorts 3 -- one, two and three at the latest data presentation is that we really do want to see Cohort 4 data. We need to see that and get some confirmation in terms of the dose response, the efficacy that we've seen with Cohort 1 and obviously seeing how the safety profile plays out given we're using the topical steroids similar to Cohort 3. So for us, it's important to have that data get to an end of Phase 1 meeting and then be able to talk about trial design. So that's all the caveat I have to say. We haven't spoken to the FDA, but we certainly are thinking about different ways that we could go as fast as we can to get to the later stage studies. But Aaron, you want to go through a couple of things we've been thinking about? And by the way this is -- as I mentioned, we haven't spoken to the FDA, but we have some preliminary thoughts.

[Aaron Osborne, Chief Medical Officer]

No exactly. It still is preliminary and Cohort 4 is really important, because that's the dose-ranging objective. We're using the same two doses in the INFINITY study and clearly, we're seeing evidence from OPTIC that both of these doses seem to show some benefits in terms of anatomical improvements and reducing anti-VEGF injections. So I think that will be one of the questions in future studies. Do we go forward with both these doses or do we see enough of a dose difference that we could make a choice based on how the OPTIC data play out? Typically in later stage studies, we've seen go from OPTIC a Phase 1/2 to a Phase 2, we're moving to randomized controlled studies.

So look for those types of elements to be in future studies: randomized controlled double-masked. And typically, I mean what FDA requires and other health authorities is that you show visual acuity results that are comparable to the standard of care, which is the frequent anti-VEGF injections given per label and we look forward to those interactions with FDA and other health authorities.

[Operator]

Thank you. Our next question comes from the line of Mani Foroohar with SVB Leerink.

[Mani Foroohar, SVB Leerink]

Thanks for taking the question. A couple of quick ones. First, I'll start with DME. Can you give us a sense of how to think about a potential washout period; if any, prior to randomization regarding previous exposure to Eylea, Lucentis, Avastin, how to think about -- how much anti-VEGF tone these patients may or may not have coming into that day one aflibercept/sham injection?

And then as a second question when you think about the -- what implications of this might be for a pivotal study, I guess for INFINITY or for OPTIC it's a Phase III indication, should we think of a single injection of an approved anti-VEGF therapy followed by a potential rescue as sort of the equivalent of a placebo control, or should we think of a different -- or do we think that -- do we think compared to an arm like that like we're seeing here INFINITY isn't necessarily something we'd see in a Phase III? So I guess how likely is this model to be carried forward?

[Leone Patterson, President & Chief Executive Officer]

Aaron, are you on mute?

[Aaron Osborne, Chief Medical Officer]

I am on mute. I'm just going off mute. I was waiting for a moment. Yes. So let me take the second part first which was on the number of treatment and the criteria for patients coming into the study. These are relatively recently-diagnosed diabetic macular edema patients. So they have either been diagnosed and had no injections or they've had a low number of injections, just a little bit different to our OPTIC population which were generally patients who've been requiring a number of injections over a long period of time and that's to get a more homogeneous population because we are a relatively small sample size.

So the key criteria coming into this study is that, they have fluid which is above the limit of normal so they've got pathological fluid accumulation in the center of the fovea and also that they've got some reduction in vision. So we have visual acuity criteria and it's a little bit below it's at the sort of 20/32 level is our upper cutoff so we're not bringing in patients who are at 20/40.

So those are really the two criteria: that they have fluid; and they had visual acuity reduction due to that fluid which is due to the DME and that it's been recently diagnosed.

And I think versus future studies, when you've got larger populations some of the variability will sort of wash out in the randomization groups. So a little bit like -- yes that's something that we could potentially broaden as we go forward. But given we've got a low number of patients, we want to make sure that we have relatively good balance amongst those groups. So maybe you could repeat the second part of the question again Mani?

[Mani Foroohar, SVB Leerink]

Same for the question, should we think about the washout period -- potentially followed by a single injection of an approved anti-VEGF agent as what a comparator arm would likely look like in the future in a Phase III study?

[Aaron Osborne, Chief Medical Officer]

Yes. I mean typically the comparator arm in a Phase III study would be as per the approved regimen or the regimen that's demonstrated the results that led to the approval. So kind of the best conditions because typically it's a non-inferiority trial and you would need to do that. So that would likely be -- whereas here we're comparing to a single dose of aflibercept. And then if there's disease activity they're getting rescued.

I mean that's not the approved regimen here, but we're aiming to show superiority to it but it's superiority on disease activity defined as visual acuity and OCT. So it's possible it's possible and that's something we would talk to regulators about whether there are different types of control group other than showing non-inferiority to kind of the labeled control group, but I think base case would be and that's what other anti-VEGFs have done is that they've compared to sort of the best regimen that's approved for the comparator. And I think that should be our base case.

[Mani Foroohar, SVB Leerink]

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

[Aaron Osborne, Chief Medical Officer]

That's correct. Some of the patients will be naive to all anti-VEGF treatment. We had extensive discussions with all of our advisers. And I mean anti-VEGF works universally across diabetic macular edema, so it was felt -- this is one of the discussion points that we had. Should we look for that response first, or is it -- should we try including the treatment-naive patients?

And that was where we went to so, we do include treatment naive. If patients have had previous injections, then we're asking the investigator to be sure that there has been a response, but that's the investigator's decision and also that there hasn't been a reaction or a safety reaction for the anti-VEGF. So you're correct, we are including a patient population here that is -- apart from being DME it's quite different from that wet AMD population that we have in OPTIC.

[Mani Foroohar, SVB Leerink]

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

[Operator]

Thank you. And our next question comes from the line of Graig Suvannavejh with Goldman Sachs.

[Graig Suvannavejh, Goldman Sachs]

Good afternoon. Thanks for taking my questions. Congrats on the progress. I've got three questions, if you don't mind. The first, just is around dosing. So, obviously, 6E11 and 2E11 make a lot of sense, given the success you've seen in wet AMD. And I'm just wondering is there something different about the DME patient population or their eyes at least, where perhaps there might be considerations in terms of the low and high dose and whether there's a need to go either lower or higher? So just a question about dosing is, kind of, the first question.

My second question has to do just with the clinical development path, just going forward and, obviously, it's a very novel trial design, but depending on the data or let's assume it's positive data any thoughts? Maybe you answered this previously, but can you just remind me what's your current thoughts on what the next trial or trials could look like, in terms of how many more trials might you need to do before you're in a place to be in a registrational situation?

And then my third question is just around data for INFINITY. And given that you're just kicking this off, just wondering if there's any guideposts on when you think this data could come out, whether it's this year or next year. Thanks.

[Leone Patterson, President & Chief Executive Officer]

Okay. Sure. Thanks, Graig. Aaron, why don't you take the first two and then I can take the third one.

[Aaron Osborne, Chief Medical Officer]

Sure. So the first one was on DME dosing versus AMD and we're using the same two doses, the lower dose of 2E11, the higher dose of 6E11. And I mean, I guess, we don't know for sure. I think it's probably the first and most correct answer. This is the first study in diabetic patients and in DME.

To our knowledge, no one has really tried this type of approach of intravitreal gene therapy producing the aflibercept protein in eyes with DME. We know that aflibercept works well in eyes with DME and we know that aflibercept, when it's administered as the EYLEA drug has a pretty similar regimen in wet AMD and DME and the dose is the same at two milligrams.

So with intravitreal anti-VEGF agents, we don't see a drastically different dose or requirement for injections, particularly in the first year with DME or AMD. So we were pretty comfortable with proceeding with those two doses. We do have an interim analysis at week 24 and we do have the opportunity to analyze the data as we go through.

So were we to see, for example, that there was -- that it was futile from an efficacy perspective, for example, at the lower dose and we wanted to try a higher dose as well, that's something that we could potentially adapt and do if the data were to play out in that way. But, yes, our assumption is that, there should be a broadly similar response in diabetic macular edema as there is in AMD really based on the intravitreal injection of anti-VEGF trials.

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

So I think then the number of trials would depend somewhat on the number of indications we were to pursue and it would also depend on the outcomes of those discussions with health authorities. I mean, I guess, what I can say is we would be working to devise aggressive plans in conjunction with our advisers and the health authorities to get ADVM-022 to patients as quickly as is possible.

[Leone Patterson, President & Chief Executive Officer]

And I think the third question was around data for INFINITY. I think what we'd like to – I mean obviously the team has worked very hard to get to this point, especially in COVID-19 to be in a place where we are actually in the sharing the study, a randomized study.

So I think what we would plan to do is once we have actually enrolled and treated a patient and we would obviously announce that that we'll be able to give more guidance on time frames of data and/or enrollment. So stay tuned on that and we would hope to be able to provide that at that time.

[Graig Suvannavejh, Goldman Sachs]

Okay. Thanks.

[Operator]

Thank you. And our next question comes from the line of Luca Issi with RBC Capital Markets.

[Luca Issi, RBC Capital Markets]

Hi, hello. Thanks for taking my question. Luca Issi from RBC Capital. two quick questions on my side. One probably for Aaron. Going back to OPTIC, can you just talk about the inflammation kinetics here? Is there a time window post-injections where inflammation is most likely to occur, or is this like an idiosyncratic events that can happen at any time? I think any color there will be helpful.

And then my second question. I think we saw in some of your recent filings that the collaboration with Regeneron has been terminated. Can you provide any color there? Thank you.

[Leone Patterson, President & Chief Executive Officer]

Sure. Aaron, why don't you go ahead with the first one?

[Aaron Osborne, Chief Medical Officer]

Sure. So what we see – what we saw in the nonhuman primate data with regards to inflammation and the nonhuman primates were not treated typically with any steroids so we kind of saw the natural course of inflammation and we've got long-term follow up in those nonhuman primates of up to 30 months follow up.

We've seen that there was stable protein expression but looking at the inflammation, specifically, we see a peak early on and it's in that range for around four to six weeks, which corresponds with kind of peak transduction and thereafter we see a decline. So we would see markers of active inflammation including cellular inflammation at those earlier time points.

And then generally, we saw those markets decline and we would see potentially or sometimes some markers of chronic inflammation remain there but not really any markers indicating an active inflammation. So it indicates that most of the inflammation is happening early and the active inflammation is not something that continues. And that's in marked contrast to the protein expression which is – goes up early and stays up. And that's why we think that the inflammation is related to the capsid protein and the capsid material can take several months for that to be sort of washed out of the eye.

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

So I think what we've seen in Cohorts 1 and 2 is we haven't seen any clinically-relevant inflammation episode at the later time points, which again fits with the nonhuman primate data. So I think to kind of summarize it is the peak immune response is relatively early.

In humans who were treated with steroids, we're seeing most of the patients, if you look at Cohort 3, five of the six patients who had got to 12 weeks or beyond were not on any steroid eye drops. The other three as well at zero or next to zero cellular inflammation. So the steroid eye drops are controlling it well.

I think that some patients may need those drops for a longer period of time with individual patient factors that influence how long and how severe that inflammation is. We don't fully understand all of those. But what we do know is based on the current data is that, steroid eye drops are sufficient to control that. And as we follow-up the patients for longer, is that those markers of inflammation are coming down. We're being conservative with tapering off the steroid eye drops.

It's -- the risks of being on steroid eye drops at low frequency, for a long period of time are very low. We prefer to do that rather than sometimes, than to take patients off too early. And have another episode of inflammation which results in, kind of restarting the drops and maybe going up in the frequency to three or four times a day. So yeah, so it seems to decline overtime. And it seems to be manageable with steroid eye drops. That's my answer.

[Leone Patterson, President & Chief Executive Officer]

Great, so, and then on the second question was around the Regeneron collaboration, which Adverum been in collaboration with Regeneron for 2014. And they had extended one-time and this actually expired in May this year. And what that means is that, there are a number of indications or targets that they had access to as a result of that collaboration.

And there was one which was excellent in [Indiscernible] was one of the indications was public in one. And there were three other undisclosed targets. And so as a result of that, that opens up the opportunity for Adverum to explore those which we see is actually a positive thing to enable us to actually think about what else we could be using this platform, using the capture of simulate and potentially other indications that we could be going after.

[Luca Issi, RBC Capital Markets]

Got it. Thank you.

[Operator]

Thank you. We are now at the bottom of the hour, and have time for one more question. And that question comes from the line of Patrick Dolezal with LifeSci Capital.

[Valentyna Chebanova, LifeSci Capital]

Hi, everyone. This is Valentyna on for Patrick. Thanks for taking my question. Just two from us...

[Aaron Osborne, Chief Medical Officer]

Sorry Patrick, please check mute button.

[Valentyna Chebanova, LifeSci Capital]

Hello, can you hear me?

[Leone Patterson, President & Chief Executive Officer]

Yes. Yes.

[Valentyna Chebanova, LifeSci Capital]

Okay. So, question on OpEx. Could you provide insight …

[Aaron Osborne, Chief Medical Officer]

Sorry Patrick, please check mute button.

[Operator]

Hi. This is operator; there is another speaker which helps that to substitute for Patrick. Her name is Valentyna and Patrick is not online right now.

[Aaron Osborne, Chief Medical Officer]

No. I think he called back again.

[Operator]

And I'll turn the call back to Adverum's President and CEO, Leone Patterson.

[Leone Patterson, President & Chief Executive Officer]

So thanks everybody. I think what we'll do Valentyna is we'll be able to talk to you after the call. But let me finish up the call here.

So I want to thank you all for joining us again today. It's been a remarkable year, at Adverum so far. And more to come and we expect to continue to execute and deliver on key catalysts which include, treating the first patients in our new INFINITY Phase II trial, in DME in the coming weeks, presenting OPTIC data for all four cohorts by the end of this year and then, advancing our preclinical gene therapies to broaden our pipeline opportunities, so stay tuned.

In closing, our employees have demonstrated a strong commitment to drive our mission forward through their focus and dedication, as evidenced by having two clinical trials underway, including the Phase II and 30 DME Trial. They truly make our progress possible. And I am humbly grateful for our team. Thank you for your time. Stay safe and healthy. And this concludes the call.

[Operator]

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