ADVM - NASDAQ

Good afternoon and welcome to the Adverum Biotechnologies Second quarter 2019 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.

Thank you, and welcome, everyone, to our second quarter 2019 conference call. The press release reporting our financial results is available on the press release page of the Investor Relations section of our corporate website at www.Adverum.com.Please note that a replay of today's call also will be available on the Event and Presentation section of our website.Joining me for the prepared remarks portion of the call today is Leone Patterson, Chief Executive Officer; and Dr. Aaron Osborne, Chief Medical Officer. Then Leone, Aaron and 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 most recent Form 10-K on file with the SEC.I would now like to turn the call over to our CEO, Leone Patterson.

Thank you, Myesha. Good afternoon, everyone, and thank you for joining us today. At Adverum, everything we do is focused on our goal to discover, develop and deliver novel gene therapies to make an impact in the lives of patients living with serious ocular and rare diseases. We believe that gene therapy can be transformative for patients and this is why we are laser focused on developing ADVM-022 as a single intravitreal injection approach to treating VEGF-driven retinal diseases.In addition to developing ADVM-022 for wet AMD, we have announced today that we plan to expand the development of ADVM-022 for the treatment of diabetic retinopathy. During this call, we will highlight the work we are doing to advance our development pipeline including outlining upcoming milestones. Then Aaron will provide an update on the clinical progress with ADVM-022 before we take questions.This year we have achieved significant clinical and regulatory milestones with our lead product candidate. As background, the first indication we are targeting wet AMD is a leading cause of vision loss in patients 60 years and older. Approximately 1.2 million individuals in the US are impacted by wet AMD and this number is expected to grow as the country's population ages. As gene therapy, ADVM-022 uses the standard-of-care intravitreal injection and is potentially less frequent more durable treatment options that we believe could be game changing for patients with the serious ocular disease.I would now highlight the great progress we have made with the Phase I OPTIC cohort trial for wet AMD. Standing with cohort 1, we have completed dosing and look forward to presenting 24 week data on all six patients at The Retina Society Annual Meeting in London on September 12. Additionally, we announced in June that we commenced dosing patients in the second cohort of the Phase 1 OPTIC trial. And I'm pleased to share that we have already completed dosing all six patients in this cohort.We expect to present 24 week data from the second cohort as well as longer term 52 week data from the fifth cohort at a scientific meeting in the first half of 2020. Further, we will provide an update on our development plans for the OPTIC trial in the fourth quarter of this year. These are important upcoming milestones for this program.In addition to wet AMD, we believe there are opportunities for ADVM-022 to treat patients with other OPTIC diseases that currently are treated with anti-VEGF therapies. As the next indication for ADVM-022, we are targeting Diabetic Retinopathy. Diabetic Retinopathy is a leading cause of vision impairment and blindness among working age adults and the prevalence of diabetes and diabetic retinopathy are growing rapidly. These younger working age adults could benefit greatly from a one time Intravitreal Injection gene therapy approach and we plan to submit an idea for this indication in the first half of 2020.Now turning to our rare disease programs, we have discontinued development of our gene therapy program targeting A1AT deficiency. Additionally, we have made that gene therapy program targeting Hereditary Angioedema back into early development. Our immediate priority continues to be focused on developing a lead product candidate ADVM-022 to for AMD and diabetic retinopathy.As we progress our clinical programs, we are scaling up our manufacturing process to support the product requirements for later stage development and commercial use. A new corporate headquarters in Redwood City will allow for the expansion of in-house process development capabilities to 1000 litre to scale. And we expect to be able to occupy a new facility by the end of this year.Before turning the call over to Aaron, I would like to talk about our corporate update that we announced last week. First, board member and co-founder, Mitch Finer has retired from the Board of Directors to focus on a new industry role. We also announced that our President and Chief Scientific Officer, Mehdi Gasmi, will retire from his management position on September 16th and will transition to the Adverum Board of Directors. We look forward to Mehdi’s continued engagement as a board member and we will initiate our broad effort to identify our new CSO.Looking forward, this is a pivotal time for the company. We continue to expand our depth of talent with recent senior management additions and a number of key functional areas. I'm excited to work with this team as we pursue a mission of delivering novel gene therapy to patients with ocular and rare diseases.I'd now like to introduce our CMO; Aaron Osborne to provide an update on ADVM-022 clinical development. Aaron joined our team in April and as an ophthalmologist and biotechnology industry veteran, he brings extensive experience in clinical practice drug development and global medical seeds. He's been at the forefront of many exciting therapeutic developments for patients in the field of ophthalmology and has executed Phase II and Phase III studies and with AMD and diabetic eye disease. Aaron's breadth of experience has been a fantastic addition to the team. I'm thrilled to be working with him.

Thank you, Leone and good afternoon everyone. As an ophthalmologist, who has spent much of my career developing treatments for retinal diseases in particular Anti-VEGF therapies, I am excited to lead the clinical development of ADVM-022. There is a robust body of long term preclinical data which supports advancing ADVM-022 Intravitreal Injection gene therapy that has significant potential to improve Real World Vision outcomes for patients wet AMD into the clinic.The current standard of care treatment is Intravitreal Injection with anti-VEGF therapy oftentimes requiring frequent injections for several years to maintain vision. Around 50% of patients need injections every 4 to 8 weeks to control their wet AMD disease activity and this is a major burden for patients, for caregivers and healthcare systems. This need for frequent injections results in under treatment and vision loss for many patients.ADVM-022 has the potential to deliver sustained efficacy and maintain vision with a single standard of care intravitreal injection and could be transformative for patients living with wet AMT or other VEGF-driven retinal disorders.Turning to the Phase 1 OPTIC trial of ADVM-022 in wet AMD as Leone mentioned the first clinical data will be presented during a podium presentation at the Retina Society Annual Meeting on September the 12th In London. Dr. Szilard Kiss, the Director of Clinical Research and Associate Professor of Ophthalmology at Weill Cornell Medical College will present 24 week primary and secondary outcomes data from the first cohort of 6 patients.These patients who had previously required frequent injections for their wet AND, all had received at least 2 anti-VEGF injections in the four months prior to enrolling in OPTIC and were given a single intravitreal injection at ADVM-022 at a dose of 6 x 10^11 vg/eye at baseline.Recall that the OPTIC trial as a Phase 1 first in human study safety is the primary endpoint. As we have previously shared no FAs and no DLTs have been observed in this first cohort of patients. As the primary objective of OPTIC, we will be presenting 24 week safety and tolerability outcomes for this cohort of patients. We have also previously shared that in the first cohort of OPTIC we saw a robust preliminary anatomical response which led to our decision to use the lower dose of 2x10^11 vg/eye for the second cohort.The following secondary endpoints are important to help us assess both anatomically and functionally, the potential benefits from a single intravitreal injection of ADVM-022. We are assessing patients vision, a change in best corrected visual acuity in trials of patients with wet AMD who have not previously been treated, we would expect to see improvements from baseline and vision.However in this trial which is for patients who have been receiving ongoing treatment with frequent anti-VEGF injections to preserve their vision, a successful outcome is to maintain visual acuity with fewer injections.Another secondary endpoint is change in central retinal thickness in 24 weeks as measured by optical coherence tomography or OCT. Anatomical assessment on OCT is an important and objective measure of wet AMD disease activity similar to BCVA because patients have already been treated previously with ant-VEGF therapy, a successful quantitative outcome on OCT would be to see maintained central retinal thickness through 24 weeks.OCT also gives us the ability to qualitatively view and assess the presence of pathological fluid in different compartments of the retina to assess the effectiveness of the therapy. Overall, we are looking for stability on the OCT and if we see OCT improvements, this would represent decreased wet AMD disease activity.The most important secondary data point in OPTIC many retina specialists and patients will be the percentage of patients requiring anti-VEGF injections and the main number of anti-VEGF rescue injections with 24 week follow up on all 6 patients, we will be able to assess the potential of AVDM-022 to reduce treatment burden.As is the standard approach in this type of clinical trial, there are protocols defined rescue injection criteria based on OCT and vision. Overall, we are looking for stability on vision and OCT with a minimal number of rescue treatments being required in these patients who had previously required frequent intravitreal injections.Beyond the first cohort, we continue to make strong progress in the OPTIC trial, as we only mentioned we recently completed dosing the six patients in the second cohort at a lower dose of 2x10^11 vg/eye. We plan to present a 24-week data from the second cohort of the OPTIC trial at a scientific meeting in the first half of 2020.The OPTIC trial aims to establish ADVM-022 potential wet AMD, the next ocular VEGF-driven disease we are pursuing with this therapy is in diabetic retinopathy. Diabetic retinopathy is the result of micro vascular damage to the blood vessels in the retina caused by raised blood sugar and occurs frequently in both Type 1 and Type 2 diabetics.Of the estimated 8 million people with diabetic retinopathy in the U.S. only 2 million are diagnosed and only 1 million are being treated. Diabetic retinopathy is the leading cause of vision loss among working age adults in the U.S. Anti-VEGF therapy can effectively treat diabetic macular edema and can reduce the risk of other side threatening events overall in diabetic retinopathy.However, the short duration of effect of currently available anti-VEGF therapy limits their use, because when their effects wears off diabetic retinopathy can quickly progress and may cause irreversible side loss. Therefore, we believe there is a significant unmet need in diabetic retinopathy for a long lasting intravitreal vitriol anti-VEGF therapy. We are working on clinical development plans for ADVM-022 in diabetic retinopathy and plan to submit an IND to the FDA in the first half of 2020.I will now turn the call back over to our CEO, Leone Patterson. Leone?

Thank you, Aaron. I want to add some further details around the plans for presenting 24-week OPTIC data for the first cohort of six patients at the Retina Society annual meeting in London. Although, this is a close meeting, we plan to share the OPTIC data transparently and broadly. We will issue a press release at the beginning of the podium presentation, followed by a conference call and webcast. A copy of the slide presentation will be available on our corporate website after the call.With that, we will now open the call to questions. Operator?

[Operator Instructions] Our first question comes from the line of Tyler Van Buren of Piper Jaffray. Your line is open.

Hey, guys. Good afternoon, and thanks for taking the questions. Tom, you did a pretty good job of explaining the OPTIC trial design and the expectations on visual acuity and central retinal thickness and to maintain it. I was hoping that you could provide a little bit more clarity on the types of patients that are being enrolled. You mentioned that they have at least two injections in the four months prior to the OPTIC. So they're treated -- being treated with Eylea, what's the possibility that some of these patients would be dry or stable through those six months. Just do the simple fact that they've had Eylea prior to the study.

Thank you for the question. It’s Aaron Osborne here. So yes in the protocol we stipulate that patients must have had two injections, at least two injections in the previous four months. So these patients that are requiring frequent anti-VEGF injections have gone through pain to ensure that that is within the protocol. I mean if you kind of extend that that would equate to, obviously, injections every other month. So as we said around 50% of patients or more would require anti-VEGF injections at eight or four weekly intervals.So really we were looking to recruit that type of population in optic and what we can also do is look at the previous treatment history, look at the intervals between those injections. And as I said, we've really tried hard to include the population that requires frequent ongoing anti-VEGF injections.They have the Eylea injection in the protocol to show that they can respond to Eylea, because Eylea is aflibercept and ADVM-022 is producing the protein aflibercept on a sustained basis. So given that we're presenting 24-week data and given that the patients previously had required injections at least really every two months based on the protocol inclusion criteria, we believe that over the 24 weeks that that is significantly longer than one could possibly expect from the screening Eylea injection.So I think that that should summarize your answer that we're defining by protocol patients that require frequent anti-VEGF injections and with 24 week follow-up on all patients we should have a very good idea as to the potential for ADVM-022 to reduce those number of injections.

Yeah, that's helpful. And in terms of rescue injections, you mentioned that it was based on OCT envision, which makes sense. So can you speak a little bit more about how stringent that criteria is such that someone doesn't accidentally provide a rescue injection when maybe the patient is still relatively stable? And also what magnitude or what percent reduction in rescue injections implied over those first six months would you view as a win?

Yes. So I mean clearly the fewer rescue injections that we see will be the better. I mean, that's the feedback that we've had from retina specialist, our investigators and in our research. So the lower number of rescue injections, really the better. We look at the criteria for rescue injections these are really similar to other clinical trials and they're based primarily on OCT and vision and essentially without going to the specifics of the numbers and thresholds that patients experience an increase of fluid on the OCT or their vision drops as a result of what the investigator believes is what they view activity then essentially they're eligible for a rescue injection.I mean the challenge with Wet AMD is it's an aggressive disease, if fluid accumulates and vision drops and you don't treat that then there's the possibility that the patient may irreversibly lose vision. So our rescue criteria are actually very stringent and if a patient experiences increasing fluid or dropping vision due to Wet AMD disease activity then they would receive a rescue injection.

Okay. And just final question on the prophylactic oral steroid dosing and tapering. Can you just speak towards why you guys used that in the study is it due to anticipation of just general inflammation that you would see that you've seen historically with gene therapy that you would expect to resolve over 13 days. And do you think that could go down with a lower dosing or that you could potentially move to topical steroid dosing over time?

Yes, so absolutely. I mean an immune response following any form of gene therapy is something that is expected and that's the reason why -- you recall this is, obviously, a first in-human study as well. So we're giving the patient a tapering dose of prednisone. They have six days of 60 milligrams and then it tapers -- it tapers off. And that's, yes, specifically because there is an immune response expected.Regarding further plans for the OPTIC study, currently, as we've mentioned, we've enrolled the second cohort, and we'll be looking at whether we add additional cohorts and what the dose might be and whether we adjust the steroid regimen, because potentially that's certainly something that we would be considering whether we could move to topical therapy as well. So at the moment, really we're waiting for a little more data from the second cohort and we will plan to update later on this year.

Thanks very much for taking the questions.

Thank you. Our next question comes from Phil Nadeau of Cowen and Company. Your line is open.

Greeting and thanks for taking my questions. A follow up to Tyler’s last question there on the inflammation. For the intravitreal injections, physicians have little tolerance for any sort of inflammation in the eye. What's your sense for less frequently administered intravitreal gene therapy? How much information would be acceptable to the physicians in your opinion?

Yes, I mean I would come back to the point that some of these patients are having very frequent intravitreal injections and saving injections. It's got that potential to improve Real World Vision outcomes as well as the poising an unpleasant procedure, which carries risks such as endophthalmitis even which although rare when you're having many, many injections those risks can increase.So, I think everybody would expect that there will be some immune response following a gene therapy. But if you can get a long lasting reduction in the requirement for rescue injections then that's certainly a trade-off that people will be willing to look at. So I think it really -- we look forward to presenting the data. I think on September the 12th, we'll be able to provide a much fuller picture of the primary outcome measures, which is around safety and tolerability as well as the secondary outcome measures around -- anatomical outcomes around visual acuity and about the numbers of rescue injections that might be required.

Okay great. That’s helpful. And then second on your decision to lower the dose. You mentioned that there's no DOT at the initial dose cohort. Can you talk about what was the criteria for dose limiting toxicity -- probably why you -- why you dose reduced.

Yeah. Of course, so we have an independent data monitoring committee, and if you recall the plan was to dose escalate following the first cohort. The data would be IBM C they met. They considered any adverse events that had occurred in the early period following treatment. And they unanimously recommended to escalate to the second dose. So they were very comfortable with the safety profile that the decision to those down was not based on safety. It was based on the fact that we saw a robust preliminary anatomic efficacy signal. And based on this, we did not feel that there would be value in increasing the dose.Because as you recall, a key aim of the Phase 1 trial is to dose range, so we wanted to establish the effectiveness of different doses. We saw this robust response. We did not see that that could be incremental anatomic efficacy with a higher dose. So we decided to dose down to see if we could achieve similar types of results, except for the lower dose. And obviously we recruited that cohort now and we're in the period after that. We're waiting to see the data and we'll share our findings later in the year.

That's helpful. And then last question for me, its just one rescue injections, again an answer to the Tyler question you've noted that the fewer injections the better. But it does seem like just play devil's advocate, if you need rescue injections in decent proportionate of patients such that everyone who gets the gene therapy still has to be monitored on a regular schedule. The benefits of gene therapy are much diminished versus a cleaner profile, where very few patients need rescue injections. What do you think of that -- that argument? Is it accurate or do you think just reducing the treatment burdened by some percentage would create successfully – a successful product?

Yes. I think it's a great, it's a great question. And we've done research around this as well as also having many conversations with retina specialists. So whilst any reduction or a significant reduction is deemed to be helpful, certainly the greater that reduction, the more beneficial. And I think that comes exactly back to the point that you made, which is can you predict which patients are going to require those rescue injections, and how many they would be, and what would be the subsequent monitoring schedule. So all of those play into it, and if you can't accurately predict these things then obviously the lower the number and the fewer the number of patients to have these will make a very big difference to the uptake in usage. So I think that's why it does come back to lower is better. And really, the ideal outcome would be to have a minimal number of additional rescue injections.

That's perfect. Sorry. Just one last question on the awesome programs. What was the postmortem as to what went wrong with the A1AT program was it the vector or the trans gene. Could you give us some sense of what the prognosis was or the diagnosis?

Sure. This is Leone. So for the rare disease programs, as you know we were using the same data RH10 late last year we had results in the A1AT program which we shared around not achieving their therapeutic levels far below actually the expected level we would need to have to be therapeutic. And since, we're using the same vector for A1AT – and HAE that obviously there was a potential impact on the efficacy for HAE, as a result of using the same vector.We had spent some time over the last six months reviewing our possibilities of how we could continue to move forward in either of those programs. I think where we came out on that is A1AT. We believe given the therapeutic levels you need to get through that we don't believe that is a program that we will continue to with. HAE, however we have as you saw led back to early development for us to continue to see, if this way that we can explore to get to a better therapeutic level for HAE given the retinopathy potential from when we got to A1AT level.So we believe that's still worthwhile to proceed, to see what's possible, but we didn't want to raise expectations that we're going to be entering the clinic anytime soon. So we wanted to make sure that, people were clear that, we were continuing to explore how we could move forward with that program, but recognize that it's back in the early development stage.

Perfect. Thanks for my taking questions. Congrats on the progress.

Thanks.

Thank you. Our next question comes from Joon Lee of SunTrust Robinson. Your line is open.

Hi. Thanks for the question. Can you talk about what you view as the right therapeutic range for anti-VEGF or aflibercept and wet AMD? Is that something that you will determine based strictly on clinical outcomes, or will you at least, in part, determine that based on how much protein is produced from ADVM-022 and how that compares to steady state amount of IND, and I have a follow-up. Thank you.

Thank you. Thank you for the question. As you know we've got a robust and long-term preclinical data package where we did extensive aqueous, vitreous and retinal sampling for aflibercept levels. I guess what the key finding was here that across the range of doses that we saw levels that we deemed to be therapeutic in each of those compartments up to and an including 30-months follow-up. So I think we see very stable long-term therapeutic levels of expression of specific to that in the preclinical models.In the clinic, we have patients who already have the disease. They have wet AMD what really matters. As we have effective treatments out there is whether we can see a clinical response. And as we've spoken about that's going to be mainly on the OCT is the most accurate and small numbers of patients. And obviously the vision is very important as well. And then that will ladder up to the numbers of rescue injections.At the current stage in optic, we are not sampling for protein levels and we're relying fully on the clinical outcomes. And as we said we're really looking forward to and excited about presenting those 24-week data across those key secondary endpoints on September 12th in London.

Okay. So we're looking forward to that as well. And the follow-up question is, please correct me if I'm wrong, but my understanding is that some patients actually spontaneously recover from wet AMD. Can you discuss the natural history of wet AMD? And if this is steadily progressive disease or if there are some fluctuations in the wet age levels over the course of the disease process? Thank you.

Thank you. Yes, so of course really good question. So generally wet AMD requires ongoing treatment for several years and that's for the vast majority of patients. You may get around up to 10% of patients may improve and settle just with one or two injections but that is sort of 10% maximum. The remaining say, 90% -- at least 50% of those would generally require anti-VEGF injections every four to eight weeks.The remaining sort of 40% may be able to extend beyond that to 12 weeks and that's really the currently available therapies. But I think really when you look at the trials also therapies in development that seems to be pretty consistent and I think that's really a factor of these intravitreal injections they've got relatively short half life. So the reality of it is that many patients with wet AMD around 50% require 4 to 8 weekly injections on a long-term ongoing basis. And we've really taken a lot care in the optic trials to make sure that we recruit that patient population that requires frequent ongoing injections, but also that they're responsive to anti-VEGF therapy in order to kind of robustly assess the potential of 022.

So is this therapeutic does get approved by the FDA? What are some strategies that you're thinking about to make sure that you're only giving this one time therapy that is not reversible to patients who will need it for the rest of their life and not by accident give it to someone who might otherwise will cover it or might not need…

I mean, I would come back to sort of benefit risk of anti-VEGF treatment wet AMD. Really the – now the challenge with the current therapies is that they are under utilized because they require frequent treatments and patients loose vision. I think if you speak to retinal specialist they fully agree that the risks of under treatment are greater than the risks of over treatment. So a therapy delivered with a one-time injection that can provide long lasting anti-VEGF coverage is likely to be a very attractive therapeutic option across the entire patient spectrum for wet AMD. It's sometimes very hard to predict those patients that may only require a very small number of injections.And as I said earlier on that's a very small percentage as well. So, a much bigger risk if the patients are under treated and I think that's the biggest risk. Obviously, we're taking care in the trials to ensure that the patients we enroll are those that require frequent injections.

Thank you very much.

Thank you. Our final question is from Dane Leone of Raymond James.

…for updates and everything. And we're definitely looking forward to that OPTIC data. Just a few for me. So you made some interesting comments about how you think about the market for 022. And just wanted to help to find out maybe a little bit more, so when you guys gave -- the teaser that you've given about the study is that you've seen robust anatomical responses. And in the context of that that's obviously a 24-week study with six patients, the goal that you've said is reduce -- fewer injections, standard anti-VEGF therapy post dosing.I think classically we thought of the goal of maybe the gene therapy what gene therapy as making a patient absent of standard injections, maybe over the course of 24 to 36 months. Is that not the case I guess because like you dosed down in the second cohort based off of anatomical responses, but also said that coming into the study, these patients were relatively dry and the goal is stability on OCT. So, I'm trying to kind of bridge how you guys view the market versus maybe what some of us had is that longer term view that I guess might not be right.

Let me take that, there are some really good questions and obviously, we're going to share the full details of the patient's baseline and how they respond to treatment over 24 weeks of that interim data presentation, Retina Society so there will be many more details. But I think a couple of points in response and Leone may wish to add some things as well.Firstly, this is actually a 104-week study, so it's a two year study. This is just the first presentation is interim at 24 weeks, so obviously, the aim is to is to reduce the numbers of injections not just to 24 weeks, but for a much longer period of time.And I think if you go back to our preclinical data package, we've shown very stable long-term protein expression after 30 months. So, there's -- we've clearly shown that potential pre-clinically, but this happens to be our first read-out clinically.So, hopefully that addresses the question somewhat. I don't know if any.

I think the only thing is reminding you said about the -- at the start of the study what's the baseline for patients. I think what we would remind you as you -- I think you're referring to the fact that they're getting an Eylea injection at the time of starting the study. So, I think we believe that the time period we have up to 24 weeks is a meaningful time point to start with.And then to Aaron's point, clearly, we're going out to 104 weeks and that will be also meaningful and it's what we stated that we planned to give an update on these patients after 52 weeks recognizing that this is a preliminary endpoint and therefore, we'll be giving an update on that when we get to that time point as well.

Okay. And then, on something you actually just kind of alluded to. So, one discussion point that, I guess, might be outside of the realm of the optic data that you can elucidated a little bit. The dosing down in the next cohort, right, has generated a lot of interesting questions and as we've spoken about before this call. And the predication of that has been on the anatomical responses that you've seen in the optic study and there's been no safety issues.I guess, the question -- two questions. One is what's actually the goal of dosing down? And you're kind of alluding to maybe reducing steroids. Is that the primary goal of dosing down? Or is there another goal of dosing down? And two, how did you choose the three-fold reduction in the vector.So you've alluded to like the stable non-human primate protein data. The data that we've seen would have been actually equivalent to the second dose cohort, if you'd dosed up. Now on the second dose cohort where you've dosed down, you're actually an order-of-magnitude below the non-human primate data. So, I guess, what kind of made you comfortable about that change in magnitude away from the translational data? Thank you.

Yes. That's a really, really good question. So in terms of the dosing downwards, as you said, that was due to the robust preliminary anatomic response that we observed. And, I think, one thing to say here is that these are patients that require frequent injections in order to maintain their vision. And what we would want -- what we plan to do at the Retina Society presentation is, provide additional detail on that previous treatment and also what their anatomical response had been to previous treatments.So really when we talk about a robust preliminary anatomic response, we have that information available and we were able to look at the timing of the injections and also looked at the OCT outcomes. So it's really on that basis that we could see that it was such a robust response.Another purpose besides safety for Phase 1 is obviously dose ranging and trying to identify the best doses to take forward, as well as to demonstrate to FDA and other regulators that you've looked at a broad range. So when we look at the effect on OCT, we did not see that we could get additional effects that we're looking to titrate efficacy and also tolerability.So if we've reached, which is the point that we felt that we had reached, that we could not see additional efficacy, certainly not in an early time point that would help us make timely clinical development decisions, then really the question was, could we get that same type of efficacy but with a lower dose.Because if you can see that, obviously, that is preferable to providing a higher dose. And with regards to their number or to the reduction of dose magnitude, we went down three-fold. So initially our plan was to go up three-fold. And really a three-fold change in dose is a common practice in gene therapy studies.

Okay. And just final one for me I promise. Obviously, everyone's been very confused about this, but just for the public call, can you just state whether or not anatomical, robust anatomical response does or does not equal additional standard anti-VEGF injections. You said a number of times to reduce the amount of fewer injections reduce the injections just to make it clear for what you've kind of been implying of like how you look at the world on OCT. Does that mean a patient has not gotten a rescue injection or is that just looking specifically at OCT scans in isolation.

So the robust anatomical responses based on assessing the OCT of these patients and we look forward to presenting the full data on the on the 12th of September.

Excellent. Thank you so much.

I would now turn the call back to the interim CEO, Leone Patterson.

Thank you again for joining our call today. This is an exciting time for the company and I'd like to summarize the key upcoming milestones that were highlighted today. We plan to see a 24 week data in September from the first cohort of patients in the optic trial. We plan to provide an update on our development plans for the optic trial in the fourth quarter of this year. We also plan to submit a 9D in diabetic retinopathy in the first half of 2020.And lastly, we plan to present 52 week data from the fifth cohort and 24 week data from the second cohort of the optic trial in the first half of 2020. We are very excited by our accomplishments so far and I look forward to working with the advance team as we continue to execute on our mission of delivering novel gene therapy to patients with Ochsner and rare diseases.In closing, I'd like to thank the patients, caregivers and retinal specialists for their participation in the OPTIC trial. Additionally, I would also like to thank the Adverum employees for the commitment and for the continued dedication to our mission. Thank you for your time and this concludes our call.